GHSR Deletion in ß-Cells of Male Mice: Ineffective in Obesity, but Effective in Protecting against Streptozotocin-Induced ß-Cell Injury in Aging.

Insulin secretion from pancreatic ß cells is a key pillar of glucose homeostasis, which is impaired under obesity and aging. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin. Previously, we showed that ß-cell GHSR regulated glucose-stimulated insulin secretion (GSIS) in young mice. In the current study, we further investigated the effects of GHSR on insulin secretion in male mice under diet-induced obesity (DIO) and streptozotocin (STZ)-induced ß-cell injury in aging. ß-cell-specific-Ghsr-deficient (Ghsr-ßKO) mice exhibited no glycemic phenotype under DIO but showed significantly improved ex vivo GSIS in aging. We also detected reduced insulin sensitivity and impaired insulin secretion during aging both in vivo and ex vivo. Accordingly, there were age-related alterations in expression of glucose transporter, insulin signaling pathway, and inflammatory genes. To further determine whether GHSR deficiency affected ß-cell susceptibility to acute injury, young, middle-aged, and old Ghsr-ßKO mice were subjected to STZ. We found that middle-aged and old Ghsr-ßKO mice were protected from STZ-induced hyperglycemia and impaired insulin secretion, correlated with increased expression of insulin signaling regulators but decreased pro-inflammatory cytokines in pancreatic islets. Collectively, our findings indicate that ß-cell GHSR has a major impact on insulin secretion in aging but not obesity, and GHSR deficiency protects against STZ-induced ß-cell injury in aging.

ZnPP-laden nanoparticles improve glucose homeostasis and chronic inflammation during obesity.

BACKGROUND AND PURPOSE: Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity. EXPERIMENTAL APPROACH: We delivered DMSO-dissolved ZnPP (DMSO-ZnPP) and ZnPP-laden nanoparticles (Nano-ZnPP) to diet-induced obese male mice for 6 weeks. Glucose and insulin tolerance tests were carried out, liver and adipose tissue gene expression profiles analysed, and systemic inflammation analysed using flow cytometry. KEY RESULTS: Nanoparticles significantly increased the delivery efficiency of ZnPP in both cells and mice. In mice with diet-induced obesity, inhibition of HO-1 by Nano-ZnPP significantly decreased adiposity, increased insulin sensitivity, and improved glucose tolerance. Moreover, Nano-ZnPP treatment attenuated both local and systemic inflammatory levels during obesity. Mechanistically, Nano-ZnPP significantly attenuated glucagon, TNF, and fatty acid synthesis signalling pathways in the liver. In white adipose tissue, the oxidative phosphorylation signalling pathway was enhanced and the inflammation signalling pathway diminished by Nano-ZnPP. Our results show that Nano-ZnPP has better effects on the improvement of glucose homeostasis and attenuation of chronic inflammation, than those of DMSO-dissolved ZnPP. CONCLUSIONS AND IMPLICATIONS: These findings indicate that ZnPP-laden nanoparticles are potential therapeutic agents for treating T2DM.

Development of service standards and manpower calculation criteria for hospital clinical pharmacies in South Korea: a survey-based study.

BACKGROUND: After the revision of the Korean Pharmaceutical Affairs Act, the certification of specialized pharmacists is scheduled to be legally recognized in 2023. Considering that the specialized pharmacist certification was developed based on the working model of hospital clinical pharmacists, it is necessary to establish standards for clinical pharmacists in hospitals and to calculate appropriate manpower. Through this study, we aim to establish practical standards for clinical pharmacists and propose a method for calculating staffing levels based on an investigation of actual workloads. METHODS: This survey-based study consisted of two phases. In the first phase, a literature review was conducted to establish standards for clinical pharmacy services, and tasks in relevant literature were classified to identify clinical pharmacy service tasks that are applicable to the practice of Korean hospitals. Additionally, a preliminary survey was conducted to investigate the essential tasks. In the second phase of the investigation, a multicenter survey was conducted targeting pharmacists in facilities with more than 1,000 beds to explore their perceptions and actual workloads related to tasks. RESULTS: According to the standards for clinical pharmacists in Korea, clinical pharmacy services consist of a total of 23 tasks, of which 16 have been identified as essential tasks. Essential tasks accounted for 93% of the total tasks in clinical pharmacy services. The average full-time equivalent (FTE) through workload calculation was 2.5 ± 1.9 for each field, while the FTE allocated to actual practice was 2.1 ± 1.6. The distribution of each type of clinical pharmacy service was as follows: 77% for medication therapy management, 13% for medication education, 8% for multidisciplinary team activities, and 3% for medication use evaluation. CONCLUSION: This study identified essential tasks common to clinical pharmacy services across different healthcare institutions. However, the FTE of clinical pharmacists in actual practice was insufficient compared to the required amount. In order to establish and expand clinical pharmacy services in a hospital, it is necessary to ensure an adequate workforce for essential tasks.

Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation.

OBJECTIVE: Obesity-associated chronic inflammation, aka meta-inflammation, is a key pathogenic driver for obesity-associated comorbidity. Growth hormone secretagogue receptor (GHSR) is known to mediate the effects of nutrient-sensing hormone ghrelin in food intake and fat deposition. We previously reported that global Ghsr ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f). METHODS: LysM-Cre;Ghsrf/f and control Ghsrf/f mice were subjected to 5 months of high-fat diet (HFD) feeding to induce obesity. In vivo, metabolic profiling of food intake, physical activity, and energy expenditure, as well as glucose and insulin tolerance tests (GTT and ITT) were performed. At termination, peritoneal macrophages (PMs), epididymal white adipose tissue (eWAT), and liver were analyzed by flow cytometry and histology. For ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied. RESULTS: We found that Ghsr expression in PMs was increased under HFD feeding. In vivo, HFD-fed LysM-Cre;Ghsrf/f mice exhibited significantly attenuated systemic inflammation and insulin resistance without affecting food intake or body weight. Tissue analysis showed that HFD-fed LysM-Cre;Ghsrf/f mice have significantly decreased monocyte/macrophage infiltration, pro-inflammatory activation, and lipid accumulation, showing elevated lipid-associated macrophages (LAMs) in eWAT and liver. Ex vivo, Ghsr-deficient macrophages protected against PA- or LPS-induced pro-inflammatory polarization, showing reduced glycolysis, increased fatty acid oxidation, and decreased NF-κB nuclear translocation. At molecular level, GHSR metabolically programs macrophage polarization through PKA-CREB-IRS2-AKT2 signaling pathway. CONCLUSIONS: These novel results demonstrate that macrophage GHSR plays a key role in the pathogenesis of meta-inflammation, and macrophage GHSR promotes macrophage infiltration and induces pro-inflammatory polarization. These exciting findings suggest that GHSR may serve as a novel immunotherapeutic target for the treatment of obesity and its associated comorbidity.

Nutrient-Sensing Ghrelin Receptor in Macrophages Modulates Bisphenol A-Induced Intestinal Inflammation in Mice.

Bisphenols are environmental toxins with endocrine disruptor activity, yet bisphenol A (BPA) and its analogs are still widely used in manufacturing plastic products. There is evidence showing that BPA elicits inflammation in humans and animals, but the target cell types of BPA are not well understood. In this study, we sought to determine BPA's direct effect on macrophages and BPA immunotoxicity in mouse intestine. Ghrelin is an important nutrient-sensing hormone, acting through its receptor growth hormone secretagogue receptor (GHSR) to regulate metabolism and inflammation. We found that BPA promotes intestinal inflammation, showing increased infiltrating immune cells in colons and enhanced expression of Ghsr and pro-inflammatory cytokines and chemokines, such as Il6 and Ccl2, in colonic mucosa. Moreover, we found that both long- and short-term BPA exposure elevated pro-inflammatory monocytes and macrophages in mouse peripheral blood mononuclear cells (PBMC) and peritoneal macrophages (PM), respectively. To determine the role of GHSR in BPA-mediated inflammation, we generated Ghsr deletion mutation in murine macrophage RAW264.7 using CRISPR gene editing. In wild-type RAW264.7 cells, the BPA exposure promotes macrophage pro-inflammatory polarization and increases Ghsr and cytokine/chemokine Il6 and Ccl2 expression. Interestingly, Ghsr deletion mutants showed a marked reduction in pro-inflammatory cytokine/chemokine expression in response to BPA, suggesting that GHSR is required for the BPA-induced pro-inflammatory response. Further understanding how nutrient-sensing GHSR signaling regulates BPA intestinal immunotoxicity will help design new strategies to mitigate BPA immunotoxicity and provide policy guidance for BPA biosafety.

Proton pump inhibitor use and hearing loss in patients with type 2 diabetes: Evidence from a hospital-based case-control study and a population-based cohort study.

OBJECTIVES: This study aimed to investigate the association between proton pump inhibitor (PPI) use and risk of sensorineural hearing loss (SNHL) or tinnitus in patients with type 2 diabetes using hospital- and population-based data. METHODS: For the case-control study using the Asan Biomedical Research Environment database, the characteristics between cases and sex-, age- and index-year-matched controls were compared by the chi-squared test. Conditional logistic regression was used to estimate the odds ratios (ORs). For the cohort study using the Korean National Health Insurance Service - National Sample Cohort, the hazard ratios (HRs) for SNHL or tinnitus associated with PPI use were analysed by the Cox proportional hazard regression model. RESULTS: The case-control study included 1379 cases and 5512 matched controls. After adjustment, PPI use was associated with an increased risk of SNHL or tinnitus (OR 1.61, 95% confidence interval [CI] 1.30-1.99). The ORs were higher for current or recent use of PPI and high average daily dose. In the cohort study including 17 233 pairs of PPI users and nonusers after propensity score matching, the risk of SNHL or tinnitus increased in PPI users compared with nonusers (HR 1.50, 95% CI 1.40-1.61). In the stratified analyses, risks remained significant and the magnitude of association was relatively high in those of younger age, patients without gastroesophageal reflux disease and patients not receiving histamine 2 receptor blockers. CONCLUSIONS: Our study suggests that PPI use is associated with an increased risk of SNHL or tinnitus. Given the widespread use of PPIs, the potential ototoxic effects of PPIs remain an important concern.

Association between Statin Use and Sensorineural Hearing Loss in Type 2 Diabetic Patients: A Hospital-Based Study.

Statins have emerged as protective agents against sensorineural hearing loss (SNHL) associated with dyslipidemia, but the effects of statins on SNHL are not consistent. The purpose of this study was to investigate the association between statin use and the risk of SNHL using a hospital cohort. This nested case-control study included type 2 diabetic patients over the age of 18 years without a history of hearing loss. Of these, 1379 patients newly diagnosed with SNHL or tinnitus were classified as cases, and 5512 patients matched to the cases based on age, sex, and index year were classified as controls. Chi-squared tests were used to compare categorical variables between the two groups. Odds ratios (ORs) and adjusted odds ratios (AOR) were calculated from univariate and multivariable unconditional logistic regression analyses, respectively. There was a significant difference in the prevalence of statin use between the cases and controls (53.7% vs. 61.2%, respectively; p < 0.001). The use of statins in type 2 diabetic patients significantly reduced the risk of SNHL or tinnitus by 24.8% (95% CI 14.2-34.1%, p < 0.001) after controlling for confounders. Similar results were found for the association between statin use and SNHL (AOR = 0.706; 95% CI 0.616-0.811, p < 0.001). The protective effects of statins against SNHL were consistent regardless of age and sex. The use of statins for type 2 diabetic patients was significantly associated with a reduced risk of SNHL, regardless of age and sex. Further studies are needed, especially large cohort studies, to evaluate the long-term protective effects of statins.

ß Cell GHS-R Regulates Insulin Secretion and Sensitivity.

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in ß and α cells. We then generated ß-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic ß and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, ß cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.

Factors Associated With Voriconazole Concentration in Pediatric Patients.

BACKGROUND: Serum concentrations of voriconazole are difficult to predict, especially in pediatric patients, because of its complex pharmacokinetic characteristics. This study aimed to identify the factors associated with the concentration of voriconazole in pediatric patients. METHODS: This cohort study was based on retrospective data collection and involved the administration of voriconazole to pediatric patients younger than 18 years, between January 2010 and August 2017. Electronic medical records of the patients were reviewed to collect demographic characteristics, voriconazole treatment regimen, and factors that could potentially influence voriconazole trough concentrations. A voriconazole trough serum concentration of less than 1.0 mcg/mL or greater than 5.5 mcg/mL was defined as outside the therapeutic range and was set as the outcome of this study. RESULTS: Among the 114 patients enrolled, 61 patients were included in the analysis. Oral administration of a maintenance dose of voriconazole and C-reactive protein (CRP) level were significantly and independently associated with a low initial trough concentration of voriconazole (<1.0 mcg/mL). Alanine aminotransferase levels were a significant factor associated with a high initial trough concentration of voriconazole (>5.5 mcg/mL) after adjusting for sex, age, weight, and serum creatinine (odds ratio 5.42; 95% confidence interval 1.34-21.97). CONCLUSIONS: Considering the variability of voriconazole concentrations in pediatric patients, monitoring certain parameters and considering the route of administration could help determine the therapeutic range of voriconazole and subsequently avoid unwanted effects.

Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study.

PURPOSE: Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I-II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III-IV) hepatotoxicity of TKIs. METHODS: This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. RESULTS: Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255-3.944) and 3.3-fold (95% CI 1.260-8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561-7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106-0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. CONCLUSION: The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

Potential Photoprotective Effect of Dietary Corn Silk Extract on Ultraviolet B-Induced Skin Damage.

Ultraviolet B (UVB) irradiation causes adverse effects on the skin. Corn silk contains flavonoids and other bioactive compounds and antioxidants, which may prevent skin photoaging through antioxidant and anti-inflammatory effects. We aimed to investigate the potential photoprotective effects of dietary corn silk on UVB-induced skin damage in mice and the mechanisms behind these effects on human skin cells. Oral administration of corn silk water extract (CS) (2 or 4 g/kg/day) for 19 weeks decreased epidermal thickness, wrinkle formation, and positive staining for PCNA, Ki67, and 8-OHdG, and increased collagen staining in UVB-irradiated SKH-1 hairless mice compared with controls. The pro-inflammatory NF-κB target genes (IL-1ß, iNOS, and COX-2) and MMP-9 expressions were lower in the CS groups, and TGF-ß/Smad signaling increased. Low skin lipid peroxidation and blood DNA oxidation levels and high blood glutathione were detected. Antioxidant transcription factor Nrf2-related catalase and SOD1 proteins and glutaredoxin mRNA levels increased. The results of CS extract treatment and UVB irradiation in HaCaT cells showed the same results in Nrf2 and NF-κB target genes. An LC-MS/MS analysis showed that the CS extract contained potential antioxidants, which might have contributed to its anti-photoaging effects in tissues and cells. CS extract may reduce UVB-induced skin damage through antioxidant and anti-inflammatory mechanisms.

Effects of proton pump inhibitor use on risk of Clostridium difficile infection: a hospital cohort study.

BACKGROUND: Although there are several studies on the association between use of proton pump inhibitors (PPIs) and increased Clostridium difficile infection (CDI) risk, detailed studies analyzing the effects of PPI use on CDI risk are lacking. The present study investigated the association of the dose, duration, and types of PPIs with CDI risk. METHODS: A single-center, cohort study was conducted on patients admitted to a hospital. The exposed cohort comprised patients who were prescribed PPIs at least once during the study period, and a control cohort was prepared by randomly assigning an index date to patients who did not use PPIs ensuring the same distribution of index dates as in the exposed cohort and matching sex, age, hospitalization period, and date of admission. RESULTS: PPI use increased the risk of CDI by 1.8-fold [95% confidence interval (CI) 1.5-2.2]. CDI risk increased by 1.8-fold with esomeprazole (95% CI 1.4-2.2) and 2.0-fold with pantoprazole (95% CI 1.5-2.8). Patients who used a high dose had a higher risk than those who used a medium dose [adjusted hazard ratio (HR) 2.0 vs 1.3]. The risk of CDI increased 4.2-fold when the PPI exposure period was 6 days or shorter than 6 days. CONCLUSIONS: Our study showed that PPI use was associated with an increased risk of developing CDI and the risk of CDI was dose dependent. Therefore, PPIs should only be used at proper doses and only for the necessary indications to avoid CDI risk.

Sodium Selenite Alleviates Breast Cancer-Related Lymphedema Independent of Antioxidant Defense System.

Long-term surveillance is necessary to identify patients at risk of developing secondary lymphedema after breast cancer surgery. We assessed how sodium selenite supplementation would affect breast cancer-related lymphedema (BCRL) symptoms and parameters in association with antioxidant effects. A randomized, double-blind, controlled trial was conducted on 26 participants with clinical stage II to III BCRL. The control group (CTRL, n = 12) and selenium group (SE, n = 14) underwent five sessions of 0.9% saline and 500 µg sodium selenite (Selenase®) IV injections, respectively, within 2 weeks. All patients were educated on recommended behavior and self-administered manual lymphatic drainage. Clinical diagnosis on lymphedema by physicians, bioimpedance data, blood levels of oxidative markers, including glutathione (GSH), glutathione disulfide (GSSG), malondialdehyde (MDA), glutathione peroxidase activity (GSH-Px), and serum oxygen radical absorbance capacity (ORAC) levels, were investigated at timelines defined as baseline, 2-week, and follow-up. Sodium selenite increased whole blood selenium concentration in the SE group. Compared to the baseline, at 2 weeks, 75.0% of participants in clinical stage showed improvement, while there was no change in the CTRL group. At follow-up, 83.3% and 10.0% of the SE and CTRL, respectively, showed stage changes from III to II (p = 0.002). Extracellular water (ECW) ratios were significantly reduced at 2 weeks and follow-up, only in the SE group. Blood GSH, GSSG, GSH/GSSG ratio, MDA, and ORAC levels did not change by selenium supplementation. Sodium selenite improved diagnostic stages of BCRL along with ECW ratios, although the beneficial effect might not be related to its antioxidant activity. Selenite's effect on lymphedema may be associated with non-antioxidant properties, such as anti-inflammation and immune function. Further mechanistic research using a larger population is needed.

Association of symptom control with changes in lung function, bronchial hyperresponsiveness, and exhaled nitric oxide after inhaled corticosteroid treatment in children with asthma.

BACKGROUND: A key therapeutic approach to asthma, which is characterized by chronic airway inflammation, is inhaled corticosteroid (ICS). This study evaluated the association of symptom control with changes in lung function, bronchial hyperresponsiveness (BHR), and exhaled nitric oxide (eNO) after ICS treatment in asthmatic children. METHODS: A total of 33 children aged between 5 and 12 years with mild to moderate persistent asthma were treated with 160 µg ciclesonide per day for 3 months. At days 0 and 90, the following parameters were assessed: asthma symptom scores; lung function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%); BHR to methacholine and adenosine 5-monophosphate (AMP); and eNO. RESULTS: Asthma symptom scores, lung function parameters, BHR to methacholine and AMP, and eNO levels at day 90 were significantly improved versus day 0 (all p < 0.001). Symptom scores at day 90 were not correlated with changes in lung function and BHR to methacholine during the follow-up period, whereas those at day 90 were more closely correlated with changes in BHR to AMP (r = 0.511, p = 0.003) than with eNO (r = -0.373, p = 0.035). Additionally, changes in PC20 AMP were correlated with changes in PC20 methacholine (r = 0.451, p = 0.011) and eNO (r = -0.474, p = 0.006). CONCLUSIONS: Changes in the BHR to AMP, and to a lesser extent eNO, correlate with asthma symptom control after ICS treatment. BHR to AMP may better reflect the relationship between improved airway inflammation due to ICS treatment and asthma symptoms.

Genistein upregulates LDLR levels via JNK-mediated activation of SREBP-2.

BACKGROUND: Genistein has been proved in vitro and in vivo to lower LDLR level. It is also widely consumed and implicated for its anti-atherogenic effects. However, the molecular mechanism by which genistein lowers the LDL level is still unknown. OBJECTIVE: To understand the anti-atherogenic molecular mechanism of action, genistein was investigated for its impact on the expression of LDLR, the receptor for LDL cholesterol, and related signaling pathways in a human hepatoma cell line. DESIGN: HepG2 cell was used for the experiments. Genistein with different concentrations was diluted in media and was incubated for 24 h or more as indicated. Protein levels were measured by western blotting, and mRNA expression was detected by RT-qPCR. Chromatin immunoprecipitation assay (CHIP) assay was used to determine protein binding levels, and luciferase assay was used to measure promoter activity. RESULT: Genistein increased the mRNA and protein levels of LDLR in a time-dependent manner. Genistein increased the transcriptional activity of the LDLR promoter containing the reporter gene (pLDLR-luc, -805 to +50). But the sterol regulatory element deletion mutant construct failed to be activated by genistein. Genistein increased the nuclear fraction of SREBP-2 and the DNA-binding activity of SREBP-2 to LDLR promoter, as assessed by CHIP. The genistein-phosphorylated JNK inhibitor (SP600126) abolished the genistein-stimulated levels of LDLR and the nuclear SREBP-2. The addition of cholesterol up to 5 µg/mL for 24 h did not affect the effect of genistein on LDLR protein expression. Even the addition of 40 µM genistein increased the cholesterol uptake by more than 10% in the human hepatoma cell line. CONCLUSION: Our data support the idea that genistein may have anti-atherogenic effects by activating JNK signals and SREBP-2 processing, which is followed by the upregulation of LDLR.

High degree of supervision improves adherence to inhaled corticosteroids in children with asthma.

PURPOSE: Adherence to treatment with inhaled corticosteroids (ICS) is a critical determinant of asthma control. The objective of this study was to assess factors that determine adherence to ICS therapy in children with asthma. METHODS: Fifty-eight children with asthma, aged 5 to 16 years, used ICS with or without a spacer for 3 months. Adherence rates as measured from questionnaires and canisters, asthma symptom scores, and inhalation technique scores were assessed every 30 days. The degree of supervision by caregivers was assessed at day 30. RESULTS: Adherence rates measured using canisters were lower at day 60 than at day 30 (P=0.044) and did not change thereafter (74.4%±17.4% at day 30, 66.5%±18.4% at day 60, and 67.4%±22.2% at day 90). Adherence rates at days 60 and 90 and during the total study period were significantly different when measured by using questionnaires versus canisters (P<0.001, P=0.022, and P=0.001, respectively). In the comparison of adherence rates repeatedly measured at days 30, 60, and 90 and adherence rates during the total study period among the 3 groups, adherence rates in the high-degree supervision group were significantly higher than those in the low-degree supervision group (82.0±16.0 vs. 66.1±14.5, 75.4±14.4 vs. 56.2±18.4, 75.0±18.3 vs. 55.0±19.7 [P=0.027]; 77.9±12.2 vs. 59.1±11.4 [P=0.021]) after adjustment for sex and age. CONCLUSION: The level of caregiver supervision is an important factor affecting adherence to ICS therapy in children with asthma. Therefore, a high degree of supervision may be required to increase adherence to ICS therapy in children with asthma.

Beneficial effects of soy milk and fiber on high cholesterol diet-induced alteration of gut microbiota and inflammatory gene expression in rats.

We sought to evaluate whether a soy milk and fiber mixture could improve high cholesterol diet-induced changes in gut microbiota and inflammation. Sprague-Dawley rats were administered four different diets: CTRL (AIN76A diet), CHOL (AIN76A with 1% (w/w) cholesterol), SOY (CHOL diet, 20% of which was substituted with freeze-dried soy milk), or S.FIBER (SOY diet with 1.2% (w/w) psyllium, 6.2% (w/w) resistant maltodextrin, and 6.2% (w/w) chicory powder). A lipid profile and gene expression analysis demonstrated that SOY and S.FIBER improved the serum HDL-cholesterol and colonic expression levels of genes in tight junction (ZO-1 and occludin) and inflammation-related (IL-1ß, IL-10, and Foxp3) proteins. S.FIBER lowered the serum MCP-1 concentration as well. A gut microbial analysis revealed that CHOL increased the ratio of Firmicutes to Bacteroidetes (F/B ratio). SOY increased the F/B ratio due to an increased proportion of Lactobacillus spp. S.FIBER greatly decreased the F/B ratio. Allobaculum spp. and Parabacteroides spp. exhibited a negative correlation with colonic expression of anti-inflammatory genes such as Foxp3, IL-10, occludin and ZO-1. CHOL increased the relative proportions of Allobaculum spp. and Parabacteroides spp. in the gut, while SOY and S.FIBER decreased these proportions. Diets containing soy milk and fiber mixtures could be beneficial by limiting CHOL-induced colonic inflammation and rescuing CHOL-disturbed gut microbiota.

Fermentation of soy milk via Lactobacillus plantarum improves dysregulated lipid metabolism in rats on a high cholesterol diet.

We aimed to investigate whether in vitro fermentation of soy with L. plantarum could promote its beneficial effects on lipids at the molecular and physiological levels. Rats were fed an AIN76A diet containing 50% sucrose (w/w) (CTRL), a modified AIN76A diet supplemented with 1% (w/w) cholesterol (CHOL), or a CHOL diet where 20% casein was replaced with soy milk (SOY) or fermented soy milk (FSOY). Dietary isoflavone profiles, serum lipids, hepatic and fecal cholesterol, and tissue gene expression were examined. The FSOY diet had more aglycones than did the SOY diet. Both the SOY and FSOY groups had lower hepatic cholesterol and serum triglyceride (TG) than did the CHOL group. Only FSOY reduced hepatic TG and serum free fatty acids and increased serum HDL-CHOL and fecal cholesterol. Compared to CHOL, FSOY lowered levels of the nuclear forms of SREBP-1c and SREBP-2 and expression of their target genes, including FAS, SCD1, LDLR, and HMGCR. On the other hand, FSOY elevated adipose expression levels of genes involved in TG-rich lipoprotein uptake (ApoE, VLDLR, and Lrp1), fatty acid oxidation (PPARα, CPT1α, LCAD, CYP4A1, UCP2, and UCP3), HDL-biogenesis (ABCA1, ApoA1, and LXRα), and adiponectin signaling (AdipoQ, AdipoR1, and AdipoR2), as well as levels of phosphorylated AMPK and ACC. SOY conferred a similar expression profile in both liver and adipose tissues but failed to reach statistical significance in many of the genes tested, unlike FSOY. Our data indicate that fermentation may be a way to enhance the beneficial effects of soy on lipid metabolism, in part via promoting a reduction of SREBP-dependent cholesterol and TG synthesis in the liver, and enhancing adiponectin signaling and PPARα-induced expression of genes involved in TG-rich lipoprotein clearance, fatty acid oxidation, and reverse cholesterol transport in adipose tissues.

Lessons learned from the development of health applications in a tertiary hospital.

BACKGROUND: Adoption of smart devices for hospital use has been increasing with the development of health applications (apps) for patient point-of-care and hospital management. To promote the use of health apps, we describe the lessons learned from developing 12 health apps in the largest tertiary hospital in Korea. MATERIALS AND METHODS: We reviewed and analyzed 12 routinely used apps in three categories-Smart Clinic, Smart Patient, and Smart Hospital-based on target users and functions. The log data for each app were collected from the date of release up until December 2012. RESULTS: Medical personnel accessed a mobile electronic medical record app classified as Smart Clinic an average of 452 times per day. Smart Hospital apps are actively used to communicate with each other. Patients logged on to a mobile personal health record app categorized as Smart Patient an average of 222 times per day. As the mobile trend, the choice of supporting operating system (OS) is more difficult. By developing these apps, a monitoring system is needed for evaluation. CONCLUSIONS: We described the lessons learned regarding OS support, device choice, and developmental strategy. The OS can be chosen according to market share or hospital strategic plan. Smartphones were favored compared with tablets. Alliance with an information technology company can be the best way to develop apps. Health apps designed for smart devices can be used to improve healthcare. However, to develop health apps, hospitals must define their future goals and carefully consider all the aspects.