Air pollution and mortality in patients with chronic obstructive pulmonary disease: a cohort study in South Korea.

Background: Evidence on whether long-term exposure to air pollution increases the mortality risk in patients with chronic obstructive pulmonary disease (COPD) is limited. Objectives: We aimed to investigate the associations of long-term exposure to particulate matter with diameter <10 µm (PM10) and nitrogen dioxide (NO2) with overall and disease-specific mortality in COPD patients. Design: We conducted a nationwide retrospective cohort study of 121,423 adults ⩾40 years diagnosed with COPD during 1 January to 31 December 2009. Methods: Exposure to PM10 and NO2 was estimated for residential location using the ordinary kriging method. We estimated the risk of overall mortality associated with 1-, 3-, and 5-years average concentrations of PM10 and NO2 using Cox proportional hazards models and disease-specific mortality using the Fine and Gray method adjusted for age, sex, income, body mass index, smoking, comorbidities, and exacerbation history. Results: The adjusted hazard ratios (HRs) for overall mortality associated with a 10 µg/m3 increase in 1-year PM10 and NO2 exposures were 1.004 [95% confidence interval (CI) = 0.985, 1.023] and 0.993 (95% CI = 0.984, 1.002), respectively. The results were similar for 3- and 5-year exposures. For a 10-µg/m3 increase in 1-year PM10 and NO2 exposures, the adjusted HRs for chronic lower airway disease mortality were 1.068 (95% CI = 1.024, 1.113) and 1.029 (95% CI = 1.009, 1.050), respectively. In stratified analyses, exposures to PM10 and NO2 were associated with overall mortality in patients who were underweight and had a history of severe exacerbation. Conclusion: In this large population-based study of patients with COPD, long-term PM10 and NO2 exposures were not associated with overall mortality but were associated with chronic lower airway disease mortality. PM10 and NO2 exposures were both associated with an increased risk of overall mortality, and with overall mortality in underweight individuals and those with a history of severe exacerbation.

Portulaca oleracea L. Extract Regulates Hepatic Cholesterol Metabolism via the AMPK/MicroRNA-33/34a Pathway in Rats Fed a High-Cholesterol Diet.

This study examined the effect of extruded Portulaca oleracea L. extract (PE) in rats fed a high-cholesterol diet through the AMP-activated protein kinase (AMPK) and microRNA (miR)-33/34a pathway. Sprague-Dawley rats were randomized into three groups and fed either a standard diet (SD), a high-cholesterol diet containing 1% cholesterol and 0.5% cholic acid (HC), or an HC diet containing 0.8% PE for 4 weeks. PE supplementation improved serum, liver, and fecal lipid profiles. PE upregulated the expression of genes involved in cholesterol efflux and bile acids' synthesis such as liver X receptor alpha (LXRα), ATP-binding cassette subfamily G5/G8 (ABCG5/8), and cholesterol 7 alpha-hydroxylase (CYP7A1), and downregulated farnesoid X receptor (FXR) in the liver. In addition, hepatic gene expression levels of apolipoprotein A-l (apoA-1), paraoxonase 1 (PON1), ATP-binding cassette subfamily A1/G1 (ABCA1/G1), lecithin-cholesterol acyltransferase (LCAT), and scavenger receptor class B type 1 (SR-B1), which are related to serum high-density lipoprotein cholesterol metabolism, were upregulated by PE. Furthermore, hepatic AMPK activity in the PE group was higher than in the HC group, and miR-33/34a expression levels were suppressed. These results suggest that PE improves the cholesterol metabolism by modulating AMPK activation and miR-33/34a expression in the liver.

Association of Estrogen-Related Polygenetic Risk Scores with Breast Cancer and Interactions with Alcohol Intake, Early Menarche, and Nulligravida.

BACKGROUNDS: Early menstruation, late menopause, no pregnancy, and genetic factors are known risk factors of the disease, but their effects may differ in Asian and Caucasian women. The purpose of this study was to identify genetic variants of genes related to estrogen signaling in a large city hospital-based cohort and to determine their interactions with lifestyles. METHODS: This is a case-control study. Three hundred ninety participants diagnosed with breast cancer were compared with 36,290 controls(no cancer)to explore the genetic variants to influence breast cancer risk. Based on GWAS results, the selected genetic variants were subjected to their interactions by generalized multifactor dimensionality reduction (GMDR) analysis. RESULTS: Early menstruation(OR=1.55), early menopause (OR=1.70), and no experience of pregnancy(OR=2.86) had a positive association with breast cancer risk(P<0.05). The selected polygenetic risk score(PRS) models included four SNPs and seven SNPs: The four-SNP PRS model included CDH13_rs12600325, SMYD3_rs3753686, FGF12_rs2134635, and ESRRB_rs10873289, and in the seven-SNP PRS model, ESR1_ rs2046210, estrogen-related receptor gamma(ESRRG)_rs17043393, and EGFR_ rs6958497 were added into the four-SNP PRS model. Early menstruation, early menopause, and no pregnancy experience interacted with four-SNP PRS. For the participants who had early menstruation and early menopause, high-PRS had an association with a much higher breast cancer risk than the low-PRS in the four-SNP model. However, metabolic parameters, nutrient intakes, and different dietary patterns did not interact with PRS for breast cancer risk. However, alcohol intake interacted with PRS for breast cancer risk (OR=2.33 and 8.07 for mild and moderate alcohol consumption, respectively; P=0.0004). CONCLUSION: Consideration of age at menarche and menopause, pregnancy experience, and alcohol intake may be required to reduce breast cancer risk in women with a high-PRS of genes related to the estrogen signaling pathway.

Association between Polygenetic Risk Scores of Low Immunity and Interactions between These Scores and Moderate Fat Intake in a Large Cohort.

White blood cell (WBC) counts represent overall immunity. However, a few studies have been conducted to explore the genetic impacts of immunity and their interaction with lifestyles. We aimed to identify genetic variants associated with a low-WBC risk and document interactions between polygenetic risk scores (PRS), lifestyle factors, and nutrient intakes that influence low-WBC risk in a large hospital-based cohort. Single nucleotide polymorphisms (SNPs) were selected by genome-wide association study of participants with a low-WBC count (<4 × 109/L, n = 4176; low-WBC group) or with a normal WBC count (≥4 × 109/L, n = 36,551; control group). The best model for gene-gene interactions was selected by generalized multifactor dimensionality reduction. PRS was generated by summing selected SNP risk alleles of the best genetic model. Adjusted odds ratio (ORs) of the low-WBC group were 1.467 (1.219-1.765) for cancer incidence risk and 0.458 (0.385-0.545) for metabolic syndrome risk. Vitamin D intake, plant-based diet, and regular exercise were positively related to the low-WBC group, but smoking and alcohol intake showed an inverse association. The 7 SNPs included in the best genetic model were PSMD3_rs9898547, LCT_rs80157389, HLA-DRB1_rs532162239 and rs3097649, HLA-C rs2308575, CDKN1A_rs3176337 and THRA_rs7502539. PRS with 7 SNP model were positively associated with the low-WBC risk by 2.123-fold (1.741 to 2.589). PRS interacted with fat intake and regular exercise but not with other nutrient intakes or lifestyles. The proportion with the low WBC in the participants with high-PRS was lower among those with moderate-fat intake and regular exercise than those with low-fat intake and no exercise. In conclusion, adults with high-PRS had a higher risk of a low WBC count, and they needed to be advised to have moderate fat intake (20-25 energy percent) and regular exercise.

Alcohol, Carbohydrate, and Calcium Intakes and Smoking Interactions with APOA5 rs662799 and rs2266788 were Associated with Elevated Plasma Triglyceride Concentrations in a Cross-Sectional Study of Korean Adults.

BACKGROUND: Plasma triglyceride (TG) concentrations are markedly higher among Asians, which may be associated with the interaction of genetics and lifestyle factors. OBJECTIVE: The purpose of this study was to investigate the genetic variants that have a strong association with plasma TG concentrations from genome-wide association study and to identify lifestyle interactions with the genetic variants that are associated with dyslipidemia in a cohort of Korean adults. DESIGN: Korean genome and epidemiology study utilized a cross-sectional design of Koreans to determine genetic variants and lifestyle factors, including nutrient intakes, in a retrospective hospital-based city cohort conducted by the Korean Center for Disease and Control during 2004-2013. PARTICIPANTS: Korean adults aged 40 to 77 years were participants (n=28,445). MAIN OUTCOME MEASURES: The genetic variants that influence plasma TG concentrations were selected by genome-wide association study using an allele genetic model after adjusting for age, sex, area of residence, and body mass index. Lipid profiles and nutrient intakes from food frequency questionnaires were measured. The interactions between the single nucleotide polymorphisms and lifestyle factors were determined to influence plasma TG levels. RESULTS: Carrying the minor alleles of APOA5 rs662799 and rs2266788 had an association with higher plasma TG concentrations by 1.86- and 1.51-fold, respectively, compared with those with the major allele (P=8.89E-150 and P=4.75E-68, respectively). Sex had an interaction with these single nucleotide polymorphisms, with males having higher plasma TG concentrations. The single nucleotide polymorphisms had significant interactions with carbohydrate, fat, and calcium intakes; alcohol consumption; and smoking status that were associated with plasma TG concentrations. Carriers with the minor allele of each single nucleotide polymorphisms had higher plasma TG concentrations when consuming-low fat (<15%) and high carbohydrate (≥72%) diets than those with major alleles. Carriers of the minor alleles with low calcium intakes (<500 mg/day) experienced elevated plasma TG concentrations compared with carriers of the major alleles. Smokers and alcohol drinkers with either of the minor alleles of APOA5, rs662799 or rs2266788, had higher plasma TG concentrations than those with its major allele. CONCLUSIONS: These results indicated that carrying the minor alleles of APOA5 rs662799 and rs2266788, especially for men, was associated with elevated TG concentrations and suggested that Korean carriers of the minor alleles could be at increased risk of hypertriglyceridemia. Further research is needed to investigate the efficacy of modulating lifestyle factors to prevent dyslipidemia in people carrying the minor alleles of APOA5 rs662799 and rs2266788.

Severe calcium deficiency increased visceral fat accumulation, down-regulating genes associated with fat oxidation, and increased insulin resistance while elevating serum parathyroid hormone in estrogen-deficient rats.

Menopause impairs calcium(Ca) metabolism and reduces bone mineral density (BMD), but the interaction of menopause with Ca deficiency in energy, glucose, lipid, and bone metabolism has not been studied. Herein we hypothesized that Ca deficiency at levels for post-menopausal women would impair energy, glucose, lipid, and bone metabolism in estrogen-deficient rats. This hypothesis was examined in ovariectomized (OVX) rats fed high-fat diets with different Ca levels for 12 weeks. OVX rats were allocated into either very low Ca (0.02%, VLCA), low Ca (0.7%, LCA), adequate Ca (1.18%, ACA, control), or excessive Ca (2.1%, EXCA). Sham-operated rats had the same diet as ACA (Normal-control). Ca intake was 37, 107, 190, and 311 mg/kg bw/d in the VLCA, LCA, ACA, and EXCA groups. The ACA group had higher serum parathyroid hormone concentrations than the Normal-control but were highest in VLCA. VLCA decreased BMD and lean body mass compared to ACA. Fasting serum glucose concentrations, even with higher serum insulin concentrations, were higher in the VLCA than ACA, indicating increased insulin resistance in VLCA. VLCA deteriorated glucose tolerance after oral glucose administration and impaired lipid profiles. LCA and EXCA had similar effects on metabolism as ACA, but LCA did not improve insulin sensitivity and lipid profiles as much as ACA. Expressions of hepatic genes related to fatty acid and cholesterol synthesis (FAS and SREBP-1c and HMGCR) were much higher in the VLCA than ACA and expressions of genes related fatty acid degradation(CPT1 and CYP7A1) were much lower in VLCA than ACA. In conclusion, we accepted the hypothesis. Very low Ca intake (350-400 mg/d as a human equivalent) exacerbated estrogen-deficiency-induced impairments of energy, glucose, and lipid metabolism by elevating serum parathyroid hormone levels and inducing visceral fat accumulation and insulin resistance in estrogen-deficient rats, but there was no added benefit of excessive Ca.

The combination of luteolin and l-theanine improved Alzheimer disease-like symptoms by potentiating hippocampal insulin signaling and decreasing neuroinflammation and norepinephrine degradation in amyloid-ß-infused rats.

Luteolin and l-theanine have anti-inflammatory, antioxidant, and possible antidiabetic activities, and they may synergistically protect against dementia. Here, we hypothesized that a combination of luteolin and l-theanine would synergistically act to improve memory function and glucose disturbances in rats infused with amyloid-ß, and the mechanisms underlying these actions were investigated. Rats that received an amyloid-ß(25-35) infusion into the CA1 region of the hippocampus were fed dextrin (AD-CON), 0.1% luteolin (AD-Lut), 0.2% l-theanine (AD-Thea), or both 0.05% luteolin and 0.1% l-theanine (AD-LuTh) in conjunction with a high-fat diet over 8 weeks. AD-LuTh improved memory function, as determined by water maze and passive avoidance tests, by potentiating the hippocampal insulin signaling and reducing inflammation: Luteolin mainly potentiated insulin signaling via the pAkt➔pGSK➔pTau pathway, and l-theanine primarily reduced tumor necrosis factor-α. In the metabolomics analysis of the hippocampus lysates, the concentration of proline, phenylpyruvic acid, and normetanephrine decreased in the AD-LuTh compared to AD-CON. Norepinephrine contents were lower in the AD-CON than non-AD rats with a high fat diet with 0.2% dextrin, whereas AD-Thea and AD-LuTh inhibited the decrease. Both the AD-Lut and AD-LuTh increased glucose infusion rates and decreased hepatic glucose output under basal and hyperinsulinemic conditions, indicating improved whole-body and hepatic insulin sensitivity. Disturbances in glucose-stimulated insulin secretion during hyperglycemic clamp were most effectively corrected by the AD-Lut and AD-LuTh treatments. In conclusion, the hypothesis of the study was accepted. The combination of luteolin and l-theanine prevented Alzheimer disease-like symptom, possibly by improving hippocampal insulin signaling, norepinephrine metabolisms, and decreasing neuroinflammation. The combination of luteolin and l-theanine may be a useful therapeutic option for preventing and/or delaying the progression of memory dysfunction.

Low-dose brain estrogen prevents menopausal syndrome while maintaining the diversity of the gut microbiomes in estrogen-deficient rats.

We evaluated the effects of intracerebroventricular administration (ICV) of brain estrogen and progesterone on menopausal symptoms and their effects on the secretion of follicle-stimulating hormone(FSH) and luteinizing hormone (LH) in estrogen-deficient rats. Three weeks after ovariectomy (OVX) or sham operation, OVX rats were given ICV infusions of either 17ß-estradiol (4 µg/day; ICV-E), progesterone(0.8 µg/day; ICV-P), or vehicle (control) for 4 wk. OVX rats in the positive-control group were orally provided 150 µg 17ß-estradiol·kg body wt-1·day-1. Sham rats had ICV vehicle infusion (normal-control). Serum 17ß-estradiol levels of ICV-E and ICV-P groups were higher than the control group but much lower than the normal- and positive-control groups. Tail skin temperature was higher in the control group than the other groups. Serum FSH and LH levels were much higher in the control group than positive- and normal-control groups, but ICV-E and ICV-P lowered the levels similar to the normal-control treatment. ICV-E and ICV-P prevented the decreased energy expenditure in OVX rats. Homeostasis model assessment estimate of insulin resistance was lowered in the descending order of the control, positive-control, ICV-P, ICV-E, and normal-control treatments. The decreased bone mineral density was prevented by the positive-control, ICV-E, and ICV-P treatments. The control group exhibited decreased short-term memory and spatial memory compared with the other groups. Surprisingly, the control group exhibited a decreased richness of the gut microbiome compared with normal-control group, and ICV-E protected against the decrease the most. In conclusion, small amounts of brain estrogen and, to some extent, progesterone improved menopausal symptoms by decreasing serum FSH levels and maintaining the diversity of the gut microbiome in estrogen-deficient rats.

Intermittent fasting protects against the deterioration of cognitive function, energy metabolism and dyslipidemia in Alzheimer's disease-induced estrogen deficient rats.

Intermittent fasting may be an effective intervention to protect against age-related metabolic disturbances, although it is still controversial. Here, we investigated the effect of intermittent fasting on the deterioration of the metabolism and cognitive functions in rats with estrogen deficiency and its mechanism was also explored. Ovariectomized rats were infused with ß-amyloid (25-35; Alzheimer's disease) or ß-amyloid (35-25, Non-Alzheimer's disease; normal cognitive function) into the hippocampus. Each group was randomly divided into two sub-groups: one with intermittent fasting and the other fed ad libitum: Alzheimer's disease-ad libitum, Alzheimer's disease-intermittent fasting, Non-Alzheimer's disease-ad libitum, and Non-Alzheimer's disease-intermittent fasting. Rats in the intermittent fasting groups had a restriction of food consumption to a 3-h period every day. Each group included 10 rats and all rats fed a high-fat diet for four weeks. Interestingly, Alzheimer's disease increased tail skin temperature more than Non-Alzheimer's disease and intermittent fasting prevented the increase. Alzheimer's disease reduced bone mineral density in the spine and femur compared to the Non-Alzheimer's disease, whereas bone mineral density in the hip and leg was reduced by intermittent fasting. Fat mass only in the abdomen was decreased by intermittent fasting. Intermittent fasting decreased food intake without changing energy expenditure. Alzheimer's disease increased glucose oxidation, whereas intermittent fasting elevated fat oxidation as a fuel source. Alzheimer's disease and intermittent fasting deteriorated insulin resistance in the fasting state but intermittent fasting decreased serum glucose levels after oral glucose challenge by increasing insulin secretion. Alzheimer's disease deteriorated short and spatial memory function compared to the Non-Alzheimer's disease, whereas intermittent fasting prevented memory loss in comparison to ad libitum. Unexpectedly, cortisol levels were increased by Alzheimer's disease but decreased by intermittent fasting. Intermittent fasting improved dyslipidemia and liver damage index compared to ad libitum. Alzheimer's disease lowered low-density lipoprotein cholesterol and serum triglyceride levels compared to Non-Alzheimer's disease. In conclusion, Alzheimer's disease impaired not only cognitive function but also disturbed energy, glucose, lipid, and bone metabolism in ovariectomized rats. Intermittent fasting protected against the deterioration of these metabolic parameters, but it exacerbated bone mineral density loss and insulin resistance at fasting in Alzheimer's disease-induced estrogen-deficient rats. Impact statement Intermittent fasting was evaluated for its effects on cognitive function and metabolic disturbances in a rat model of menopause and Alzheimer's disease. Intermittent fasting decreased skin temperature and fat mass, and improved glucose tolerance with decreasing food intake. Intermittent fasting also prevented memory loss: short-term and special memory loss. Therefore, intermittent fasting may prevent some of the metabolic pathologies associated with menopause and protect against age-related memory decline.

Codonopsis lanceolata Water Extract Increases Hepatic Insulin Sensitivity in Rats with Experimentally-Induced Type 2 Diabetes.

We examined the mechanisms and efficacy of Codonopsis lanceolata water extract (CLW) for treating type 2 diabetic (T2DM) symptoms. Partial pancreatectomized (Px) rats, a non-obese T2DM model, were provided high fat diets containing cellulose (control), 0.3% (CLW-L) or 1% CLW (CLW-H) for eight weeks. The positive control group was provided with rosiglitazone (20 mg/kg bw/day). The control group had lower epididymal fat masses than the CLW and the positive control groups, possibly due to urinary glucose loss, although CPT-1 and SIRT-1 expression was higher in the CLW group. CLW-H significantly reduced serum glucose levels and urinary glucose loss compared to the untreated control. The improvement of glucose utilization was associated with a higher fat mass in the CLW-H and positive control groups. Glucose-stimulated insulin secretion was higher in the untreated control than other groups and CLW tightly regulated insulin secretion as much as the positive control, and it was much tighter than the untreated control. Glucose infusion rates were higher during the hyperinsulinemic euglycemic clamp in the CLW and positive controls than the untreated control, and liver glucose outputs were lower during basal and hyperinsulinemic conditions in the CLW and positive control groups than the untreated control group. The increased hepatic insulin sensitivity was associated with enhanced insulin signaling in CLW (pAkt➔pGSK-1ß). In conclusion, CLW consumption effectively alleviated diabetic symptoms by improving insulin sensitivity, potentiating hepatic insulin signaling and tightly regulating the insulin secretion capacity in non-obese T2DM rats.

Gastroprotective actions of Taraxacum coreanum Nakai water extracts in ethanol-induced rat models of acute and chronic gastritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Taraxacum coreanum Nakai has been traditionally used for treating inflammatory diseases including gastrointestinal diseases. AIM OF THE STUDY: We studied whether water extracts of Taraxacum coreanum Nakai (TCN) had a protective effect on acute and chronic gastritis induced by ethanol/HCl in an animal model of gastritis and its mechanism was also explored. MATERIALS AND METHODS: In the acute study, rats were orally administered 0.15g/mL dextrin (normal-control), 0.15g/mL dextrin (control), 0.05g/mL TCN (TCN-L), 0.15g/mL TCN (TCN-H), or 0.01g/mL omeprazole (orally; positive-control), followed by oral administration of 1mL of 60% ethanol plus 150mM HCl (inducer). In the chronic study, rats were administered 10% diluted inducer in drinking water, and 0.6% dextrin, 0.2% or 0.6% TCN, and 0.05% omeprazole were administered in chow for 4 weeks. Acid content, gastric structure, oxidative stress, and markers of inflammation in the stomach tissue were measured at the end of experiment. RESULTS: Acute and chronic ethanol/HCl administration caused the inner layer of the stomach to redden, hemorrhage, and edema in the control group; TCN-H reduced these symptoms more effectively than did the omeprazole positive-control. Acid production and total acidity in the stomach increased in the control group, which was markedly suppressed by omeprazole. TCN also reduced the acid production and acidity, but not to the same degree as omeprazole. H-E and PAS staining revealed that in the inner layer of the stomach, cellular structure was disrupted, with an increased nuclear size and thickness, disarrangement, and decreased mucin in the control group. TCN prevented the cellular disruption in the inner layer, and TCN-H was more effective than the positive-control. This was associated with oxidative stress and inflammation. TCN dose-dependently reduced the infiltration of mast cells and TNF-α expression in the inner layer of the stomach, and decreased lipid peroxides by increasing superoxide dismutase and glutathione peroxidase expression. CONCLUSIONS: TCN-H acutely and chronically protected against gastritis and gastric ulcer by reducing oxidative stress and inflammation, not by completely suppressing gastric acid production.

Tetragonia tetragonioides (Pall.) Kuntze protects estrogen-deficient rats against disturbances of energy and glucose metabolism and decreases proinflammatory cytokines.

Tetragonia tetragonioides (Pall.) Kuntze (TTK) and JakYakGamCho-Tang (JGT) have been used for improving women's health and treating inflammatory diseases. We determined that the long-term consumption of these herbal extracts alleviates the progression of postmenopausal symptoms in high-fat-diet fed ovariectomized (OVX) rats, and further explored the mechanisms involved. Five groups of OVX rats were fed high fat diets that were supplemented with either 2% dextrin (control), 2% TTK (70% ethanol extract), 2% JGT (water extract), 1% JGT + 1% TTK (JGTT), or 30 µg/kg body weight/day of 17ß-estradiol (positive control). After eight weeks of dietary intervention, the herbal treatments did not change the serum concentrations of 17ß-estradiol or uterine weight in control rats, but they were higher in the positive-control group. TTK rats exhibited higher daily energy expenditure, particularly fat oxidation, without modifying the energy intake than the controls. TTK lowered the fat mass but lean body mass of the abdomen and leg were increased. JGT decreased periuterine fat mass and lean body mass more than the control but the decrease was not as much as TTK. TTK resulted in substantially lower serum concentrations of the proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1, than the control and JGT had lesser effect than TTK. Insulin resistance, determined by homeostasis model assessment estimate for assessing insulin resistance (HOMA-IR) and insulin tolerance test, was reduced in the decreasing order of control, JGT, JGTT, and TTK and the HOMA-IR of TTK was similar to the positive control. TTK, but not JGT, enhanced glucose tolerance compared with the control, although the serum insulin levels in TTK were lower compared to the control. Interestingly, the ß-cell masses were much greater in the TTK and JGTT groups than in the control, and they were comparable to the positive control. The increases in ß-cell masses in TTK and JGTT groups were associated with enhanced ß-cell proliferation and suppressed apoptosis, which was related to the decreased TNF-α and interleukin-1ß expressions. In conclusion, JGTT did not improve menopausal symptoms better than TTK itself. TTK itself prevented the OVX-induced impairments in energy, lipid, and glucose metabolism, similar to the positive control, without changing serum 17ß-estradiol levels and potentiating insulin signaling and decreasing proinflammatory cytokines. TTK may be a useful intervention to alleviate some menopausal symptoms similar to selective estrogen receptor modulators and should be investigated with further human study. Impact statement Menopause decreases the quality of life in middle-aged women and herbal remedies are sometimes used as alternatives for hormone replacement therapy, which may have detrimental side effects. Although several herbal extracts have been studied, no remedies improve all the menopausal symptoms. In this study, the 70% ethanol extract of Tetragonia tetragonioides (Pall.) Kuntze (TTK) reduced the symptoms of hot flushes and improved energy, glucose, and lipid metabolism in estrogen-deficient animals without increasing serum 17ß-estradiol levels. This extract acts like a selective estrogen receptor modulator and it may be a useful intervention for alleviating menopausal symptoms. This is the first study to show that the 70% ethanol extract of TTK has the potential to treat menopause-associated symptoms and metabolic disturbances. It may be a useful intervention for alleviating the symptoms of menopause in women if its efficacy can be confirmed in human studies.

Agrimonia pilosa Ledeb., Cinnamomum cassia Blume, and Lonicera japonica Thunb. protect against cognitive dysfunction and energy and glucose dysregulation by reducing neuroinflammation and hippocampal insulin resistance in ß-amyloid-infused rats.

OBJECTIVES: The water extracts of Cinnamomum cassia Blume bark (CCB; Lauraceae), Lonicera japonica Thunb. flower (LJT; Caprifoliaceae), and Agrimonia pilosa Ledeb. leaves (APL; Rosaceae) prevented amyloid-ß (25-35)-induced cell death in PC12 cells in our preliminary study. We evaluated whether long-term oral consumption of CCB, LJT, and APL improves cognitive dysfunction and glucose homeostasis in rats with experimentally induced AD-type dementia. METHODS: Male rats received hippocampal CA1 infusions of amyloid-ß (25-35, AD) or amyloid-ß (35-25, non-plaque forming, normal-controls, Non-AD-CON), at a rate of 3.6 nmol/day for 14 days. AD rats were divided into four groups receiving either 2% lyophilized water extracts of CCB, LJT, or APL or 2% dextrin (AD-CON) in high-fat diets (43% energy as fat). RESULTS: Hippocampal amyloid-ß deposition, tau phosphorylation, and expressions of tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) (neruoinflammation markers) were increased, and insulin signaling decreased in AD-CON. CCB, LJT, and APL all prevented hippocampal amyloid-ß accumulation and enhanced hippocampal insulin signaling. CCB, LJT, and APL decreased TNF-α and iNOS in the hippocampus and especially APL exhibited the greatest decrease. AD-CON exhibited cognitive dysfunction in passive avoidance and water maze tests, whereas CCB, LJT, and APL protected against cognitive dysfunction, and APL was most effective and was similar to Non-AD-CON. AD-CON had less fat oxidation as an energy fuel, but it was reversed by CCB, LJT, and especially APL. APL-treated rats had less visceral fat than AD-CON rats. AD-CON rats exhibited impaired insulin sensitivity and increased insulin secretion during oral glucose tolerance test compared with Non-AD-CON, but CCB and APL prevented the impairment. DISCUSSION: These results supported that APL, LJT, and CCB effectively prevent the cognitive dysfunction and the impairment of energy and glucose homeostasis induced by amyloid-ß deposition by reducing neuroinflammation and enhancing insulin signaling. APL exhibited the greatest effectiveness for improving cognitive function.

Curcumin and tetrahydrocurcumin both prevent osteoarthritis symptoms and decrease the expressions of pro-inflammatory cytokines in estrogen-deficient rats.

BACKGROUND: Menopausal symptoms are associated with inflammation. Curcumin is a well-known anti-inflammatory bioactive compound from turmeric whereas tetrahydrocurcumin (THC) is a major metabolite of curcumin that may have different efficacies. However, they have not been studied for anti-menopausal symptoms and anti-osteoarthritis effects. We compared the efficacies of curcumin and THC for preventing postmenopausal and osteoarthritis symptoms in ovariectomized (OVX) obese rats with monoiodoacetate (MIA) injections into the right knee to generate a similar pathology as osteoarthritis. METHODS: OVX rats were provided a 45 % fat diet containing either (1) 0.4 % curcumin (curcumin), (2) 0.4 % THC, (3) 30 µg/kg body weight 17ß-estradiol + 0.4 % dextrin (positive control), (4) 0.4 % dextrin (placebo; control), or (5) 0.4 % dextrin with no MIA injection (normal control) for 4 weeks. At the beginning of the fifth week, OVX rats were given articular injections of MIA or normal-control saline into the right knee and the assigned diets were provided for an additional 3 weeks. RESULTS: Curcumin and THC had similar efficacies for skin tail temperature in OVX rats whereas THC, but not curcumin, prevented glucose intolerance, which might be involved in exacerbating osteoarthritis. Both protected against osteoarthritis symptoms and pain-related behaviors better than 17ß-estradiol treatment in estrogen-deficient rats. Curcumin and THC prevented the deterioration of articular cartilage compared to control. They also maintained lean body mass and lowered fat mass as much as 17ß-estradiol treatment. The improvement in osteoarthritis symptoms was associated with decreased gene expressions of matrix metalloproteinase (MMP)3 and MMP13 and tumor necrosis factor-α, interleukin (IL)1ß, and IL6 in the articular cartilage. CONCLUSIONS: THC and curcumin are effective for treating postmenopausal and osteoarthritis symptoms in OVX rats with MIA-induced osteoarthritis-like symptoms and may have potential as interventions for menopausal and osteoarthritic symptoms in humans.

The combination of Artemisia princeps Pamp, Leonurus japonicas Houtt, and Gardenia jasminoides Ellis fruit attenuates the exacerbation of energy, lipid, and glucose by increasing hepatic PGC-1α expression in estrogen-deficient rats.

BACKGROUND: Artemisia princeps Pamp (APP), Leonurus japonicas Houtt (LJH), and Gardenia jasminoides Ellis fruit (GJE) have been traditionally used in East Asia to treat women's diseases related to reproductive system. They may attenuate the deterioration of energy, lipid, glucose and bone metabolism by estrogen deficiency. The present study explored the combination of APP, LJH, and GJE to overcome the symptoms of estrogen deficiency and the mechanism was explored. METHODS: Ovariectomized (OVX) rats were divided into five groups and fed high-fat diets supplemented with 2 % dextrin (control), 2 % APP, 2 % APP + LJH (15:5), APP + LJH + GJE (10:5:5) or 17ß-estradiol (30 µg/kg bw/day) for 8 weeks. After 8 weeks of their consumption, energy, lipid, glucose and bone metabolisms were investigated and hepatic insulin signaling and fatty acid metabolism were determined. RESULTS: APP + LJH + GJE, but not APP itself, improved energy metabolism and attenuated a decrease in energy expenditure by the same amount as estrogen. Moreover, APP + LJH + GJE reduced visceral fat and intramuscular fat and increased lean body mass measured by DEXA by as much as the positive-control. APP itself suppressed increased LDL cholesterol and triglyceride levels in OVX rats and APP + LJH + GJE alleviated dyslipidemia in OVX rats. Overnight-fasted serum insulin levels and HOMA-IR were reduced in the descending order of APP, APP + LJH, APP + LJH + GJE, positive-control in OVX rats. APP and APP + LJH elevated insulin secretion in the 1st part of OGTT to decrease serum glucose levels while APP + LJH + GJE reduced serum glucose levels without increasing serum insulin levels during OGTT. APP + LJH + GJE decreased insulin resistance during ITT in OVX rats more than the positive-control. The APP + LJH + GJE group exhibited increased hepatic peroxisomal proliferator-activated receptor-γ coactivator-1α expression, which increased the number of genes involved in fatty acid oxidation and decreased fatty acid synthesis. Hepatic insulin signaling (pAkt and pGSK-1ß) was also potentiated to reduce phosphoenolpyruvate carboxykinase proteins. CONCLUSION: The combination of APP + LJH + GJE attenuated various menopausal symptoms in OVX rats. Thus, it may have potential as a therapeutic agent for the treatment of postmenopausal symptoms.

Should healthy children who will undergo minor surgery be screened for coagulation disorder?

The objective of this study is to analyze the major causes of abnormal findings seen in the preoperative coagulation tests of asymptomatic pediatric patients and to discuss the usefulness of coagulation tests prior to minor surgery. Among patients who received minor surgery in Kyung Hee University Medical Center from March 2008 to April 2015, a total of 7114 pediatric patients (ages 1-18) were included in our study. Of these, 226 (3.1%) were referred to the pediatrics hematology-oncology department because of abnormal preoperative coagulation tests. A review of the coagulation tests indicate the majority (n = 216, 95.5%) have prolonged activated partial thromboplastin time (aPTT), whereas a smaller number (n = 10, 4.5%) have prolonged prothrombin time international normalized ratio (PT INR). When the coagulation tests were repeated, 136 displayed abnormal findings again. Of these 136 patients, 128 patients underwent mixing tests, and 127 showed results of correction and were composed as follows: normal (n = 83), subnormal (n = 26), factor deficiency (n = 15), and lupus anticoagulant positive (n = 3). Breakdown by factor deficiencies was as follows: (i) factor XII (n = 9), (ii) factor IX (n = 2), (iii) factors XII and IX (n = 1), (iv) factor VIII (n = 1), (v) factor XI (n = 1), (vi) von Willebrand factor (vWF; n = 1), and (vii) factor V (n = 1). Each factor activity range was mild (21%-39%), so no patients received preoperative medications or clotting factors/blood products. Even in the presence of factor deficiencies, bleeding symptoms were mild and postoperative complications did not occur. These results suggest that coagulation tests may not be needed in healthy children and should be reserved for patients with positive bleeding and/or family history.

Methyl jasmolate treated buckwheat sprout powder enhances glucose metabolism by potentiating hepatic insulin signaling in estrogen-deficient rats.

OBJECTIVES: Methyl jasmolate (MeJA)-treated vegetables produce higher concentrations of various bioactive compounds. We investigated whether long-term oral consumption of MeJA-treated and untreated buckwheat sprout powder improves energy, glucose, lipid, and bone metabolism induced by estrogen deficiency in ovariectomized (OVX) rats fed high-fat diets, and explored the mechanisms involved. METHODS: OVX rats were divided into four groups and fed high-fat diets supplemented with 3% dextrin (OVX-control), buckwheat sprout powder (BWS), or MeJA-treated buckwheat sprout powder (MJ-BWS) for 12 wk. Sham rats without estrogen deficiency had a control diet as a normal-control. RESULTS: MeJA-treatment increased total polyphenols and flavonoids by about 1.6 fold and isoorientin, orientin, rutin, and vitexin were elevated by about 18% in buckwheat. After 12 wk, OVX rats exhibited increased weight gain, fat mass, skin temperature, hyperglycemia, and decreased bone mineral density (BMD) compared to sham rats. BWS prevented the increase of skin temperature and decrease of femur BMD, but did not improve energy glucose homeostasis as much as MJ-BWS. MJ-BWS prevented increases in body weight and fat mass. Energy expenditure was lowest in OVX-control, followed by BWS, MJ-BWS, and normal-control. Furthermore, MJ-BWS exhibited greater improvements in glucose and insulin tolerance than OVX-control and BWS. Phosphorylation of hepatic Akt and AMPK was potentiated, in ascending order of OVX-control, BWS, MJ-BWS, and normal-control, whereas PEPCK expression was decreased. CONCLUSIONS: MJ-BWS prevented and ameliorated the disturbances in energy and glucose metabolism in estrogen-deficient animals better than BWS. Therefore, besides flavonoids in BWS, other components such as phytoalexins produced in MJ-BWS during MeJA-treatment might play a crucial role in the improvement.

Asian Elm tree inner bark prevents articular cartilage deterioration in ovariectomized obese rats with monoiodoacetate-induced osteoarthritis.

OBJECTIVE: We investigated whether long-term consumption of Korean mistletoe or Asian Ulmi cortex would prevent or delay menopausal symptoms and progression of osteoarthritis in estrogen-deficient obese rats. METHODS: Ovariectomized (OVX) rats were provided a 45% fat diet containing either (1) 0.6% lyophilized water extract of Korean mistletoe (KME) + 1.4% dextrose (KME; n = 10), (2) 2% lyophilized water extract of Ulmi cortex (UCE; n = 10), (3) 30 µg/kg bw 17ß-estradiol + 2% dextrose (positive control; n = 10), (4) 2% dextrose (placebo; OVX-control; n = 10), or (5) 2% dextrose (normal-control; n = 10) for 4 weeks. At the beginning of the 5th week, OVX rats, except in the normal-control group, were given articular injections of monoiodoacetate into the right knee and the assigned diets were provided for an additional 3 weeks. The rats in the normal-control had injections of saline into the right knee. RESULTS: KME, but not UCE, partially prevented the insulin resistance and the loss of bone mineral density and lean mass. The limping scores were lower in the descending order of the OVX-control > KME and 17ß-estradiol > UCE > normal-control at day 14 and 21 (P < 0.05). The scores for pain behaviors measured by weight distribution on the right leg, maximum running velocity on a treadmill and locomotive activity, were markedly decreased in the same order as limping scores. Monoiodoacetate increased the expression of matrix metalloprotinase-3 and metalloprotinase-13 in the articular cartilage and elevated the production of inflammatory markers such as tumor necrosis factor-α, interleukin-1ß, and interleukin-6, but they were lower in the UCE than in the other groups (P < 0.05). Histology of the right knee revealed cartilage damage near the tidemark of the knee and proteoglycan loss was markedly less in UCE. CONCLUSIONS: UCE was an effective therapeutic agent for preventing osteoarthritis and KME prevented decreases in lean body mass, bone mineral density, and insulin sensitivity in estrogen-deficient rats.

Synergistic topical application of salt-processed Phellodendron amurense and Sanguisorba officinalis Linne alleviates atopic dermatitis symptoms by reducing levels of immunoglobulin E and pro-inflammatory cytokines in NC/Nga mice.

Atopic dermatitis is a chronic inflammatory skin disease, and salt-processed Phellodendron amurense (CPE) and Sanguisorba officinalis Linne (SOE) are widely used as anti-inflammatory agents in Asia. Therefore, the present study investigated the efficacy of CPE, SOE, and CPE+SOE in the treatment of atopic dermatitis-like symptoms in mice. Following topical application of 1,3­butylen glycol (control), 30% CPE, 30% SOE, 15% CPE+15% SOE or 0.1% hydrocortisone (HC) on the atopic dermatitis­like skin lesions of 2,4-dinitrochlorobenzene­treated NC/Nga mice for 5 weeks, the severity of clinical atopic dermatitis, mast cell infiltration, serum expression levels of immunoglobulin (Ig)E, IgG1, interleukin (IL)-4 and interferon (IFN)-γ, and cytokine expression in the dorsal skin were measured. Compared with the control group, treatment with CPE alleviated the clinical severity of the AD symptoms, with decreased numbers of mast cells, decreased expression levels of serum tumor necrosis factor (TNF)­α, IL­4 and IFN­Î³, and decreased expression levels of inflammatory cytokines in the dorsal lesions. Treatment with SOE did not reduce these expression levels, however, the serum expression levels of IgE and IgG1 were suppressed to similar levels as those in the CPE group. Furthermore, synergistic treatment with CPE and SOE relieved the clinical severity of atopic dermatitis, reduced the serum expression levels of IgE, IgG1, TNF­α, IL­4 and IFN­Î³, and suppressed the mRNA expression levels of TNF­α, IL­4, IL­13, and IFN­Î³ in the dorsal skin lesions. Treatment with CPE+SOE was superior to treatment with HC alone for reducing dermal thickness and suppressing the production of several cytokines. Therefore, combined treatment with CPE and SOE may be an effective alternative intervention for the management of atopic dermatitis.

The supplementation of Korean mistletoe water extracts reduces hot flushes, dyslipidemia, hepatic steatosis, and muscle loss in ovariectomized rats.

Since Korean mistletoe (Viscum album) has been used for alleviating metabolic diseases, it may also prevent the impairment of energy, glucose, lipid, and bone metabolisms in an estrogen-deficient animal model. We determined that long-term consumption of Korean mistletoe water extract (KME) can alleviate menopausal symptoms such as hot flush, increased abdominal fat mass, dyslipidemia, hyperglycemia, and decreased bone mineral density in ovariectomized (OVX) rats fed a high-fat diet, and explored the mechanisms of the effects. OVX rats were divided into four groups and fed high-fat diets supplemented with either 0.6% dextrin (control), 0.2% lyophilized KME + 0.4% dextrin (KME-L), or 0.6% lyophilized KME (KME-H). Sham rats were fed with the high-fat diets with 0.6% dextrin as a normal-control without estrogen deficiency. After eight weeks, OVX rats exhibited impaired energy, glucose and lipid metabolism, and decreased uterine and bone masses. KME-L did not alleviate energy dysfunction. However, KME-H lowered serum levels of total-, LDL-cholesterol, and triglycerides and elevated serum HDL-cholesterol levels in OVX rats with dyslipidemia, to similar levels as normal-control rats. Furthermore, KME-H improved HOMA-IR, an indicator of insulin resistance, in OVX rats. Surprisingly, KME-H fed rats had greater lean mass in the abdomen and leg without differences in fat mass but neither dosage of KME altered bone mineral density in the lumbar spine and femur. The increased lean mass was related to greater phosphorylation of mTOR and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in the quadriceps muscles. Hepatic triglyceride contents were lowered with KME-H in OVX rats by increasing carnitine palmitoyltransferase-1 (CPT-1) expression and decreasing fatty acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c) expression. In conclusion, KME may be useful for preventing some menopausal symptoms such as hot flushes, dyslipidemia, hepatic steatosis, and loss of muscle mass in post-menopausal women.