Contemplative Practices Behavior Is Positively Associated with Well-Being in Three Global Multi-Regional Stanford WELL for Life Cohorts.

Positive associations between well-being and a single contemplative practice (e.g., mindfulness meditation) are well documented, yet prior work may have underestimated the strength of the association by omitting consideration of multiple and/or alternative contemplative practices. Moreover, little is known about how contemplative practice behavior (CPB) impacts different dimensions of well-being. This study investigates the relationship of CPB, consisting of four discrete practices (embodied somatic-observing, non-reactive mindfulness, self-compassion, and compassion for others), with multiple dimensions of well-being. As with other canonical lifestyle behaviors, multiple contemplative practices can be integrated into one's daily routine. Thus, it is critical to holistically consider these behaviors, extending them beyond a simple uni-dimensional measure (e.g., daily mindfulness meditation practice). We developed an integrative measure of four types of contemplative practice and found it to be significantly associated with a multi-dimensional measure of well-being. Importantly, our findings were from three large global multi-regional cohorts and compared against better-understood lifestyle behaviors (physical activity). Data were drawn from California/San Francisco Bay Area, (n = 6442), Hangzhou City (n = 10,268), and New Taipei City (n = 3033). In all three cohorts, we found statistically significant (p < 0.05) positive associations between CPB and well-being, both overall and with all of the constituent domains of well-being, comparable to or stronger than the relationship with physical activity across most well-being outcomes. These findings provide robust and cross-cultural evidence for a positive association between CPB and well-being, illuminate dimensions of well-being that could be most influenced by CPB, and suggest CPB may be useful to include as part of fundamental lifestyle recommendations for health and well-being.

Impact of mHealth interventions for reproductive, maternal, newborn and child health and nutrition at scale: BBC Media Action and the Ananya program in Bihar, India.

BACKGROUND: Mobile health (mHealth) tools have potential for improving the reach and quality of health information and services through community health workers in low- and middle-income countries. This study evaluates the impact of an mHealth tool implemented at scale as part of the statewide reproductive,maternal, newborn and child health and nutrition (RMNCHN) program in Bihar, India. METHODS: Three survey-based data sets were analysed to compare the health-related knowledge, attitudes and behaviours amongst childbearing women exposed to the Mobile Kunji and Dr. Anita mHealth tools during their visits with frontline workers compared with those who were unexposed. RESULTS: An evaluation by Mathematica (2014) revealed that exposure to Mobile Kunji and Dr. Anita recordings were associated with significantly higher odds of consuming iron-folic acid tablets (odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.8-3.1) as well as taking a set of three measures for delivery preparedness (OR = 2.8, 95% CI = 1.9-4.2) and appropriate infant complementary feeding (OR = 1.9, 95% CI = 1.0-3.5). CARE India's Community-based Household Surveys (2012-2017) demonstrated significant improvements in early breastfeeding (OR = 1.64, 95% CI = 1.5-1.78) and exclusive breastfeeding (OR = 1.46, 95% CI = 1.33-1.62) in addition to birth preparedness practices. BBC Media Action's Usage & Engagement Survey (2014) demonstrated a positive association between exposure to Mobile Kunji and Dr. Anita and exclusive breastfeeding (58% exposed vs 43% unexposed, P < 0.01) as well as maternal respondents' trust in their frontline worker. CONCLUSIONS: Significant improvements in RMNCHN-related knowledge and behaviours were observed for Bihari women who were exposed to Mobile Kunji and Dr. Anita. This analysis is unique in its rigorous evaluation across multiple data sets of mHealth interventions implemented at scale. These results can help inform global understanding of how best to use mHealth tools, for whom, and in what contexts. STUDY REGISTRATION: ClinicalTrials.gov number NCT02726230.

Use of mobile technology by frontline health workers to promote reproductive, maternal, newborn and child health and nutrition: a cluster randomized controlled Trial in Bihar, India.

BACKGROUND: mHealth technology holds promise for improving the effectiveness of frontline health workers (FLWs), who provide most health-related primary care services, especially reproductive, maternal, newborn, child health and nutrition services (RMNCHN), in low-resource - especially hard-to-reach - settings. Data are lacking, however, from rigorous evaluations of mHealth interventions on delivery of health services or on health-related behaviors and outcomes. METHODS: The Information Communication Technology-Continuum of Care Service (ICT-CCS) tool was designed for use by community-based FLWs to increase the coverage, quality and coordination of services they provide in Bihar, India. It consisted of numerous mobile phone-based job aids aimed to improve key RMNCHN-related behaviors and outcomes. ICT-CCS was implemented in Saharsa district, with cluster randomization at the health sub-center level. In total, evaluation surveys were conducted with approximately 1100 FLWs and 3000 beneficiaries who had delivered an infant in the previous year in the catchment areas of intervention and control health sub-centers, about half before implementation (mid-2012) and half two years afterward (mid-2014). Analyses included bivariate and difference-in-difference analyses across study groups. RESULTS: The ICT-CCS intervention was associated with more frequent coordination of AWWs with ASHAs on home visits and greater job confidence among ASHAs. The intervention resulted in an 11 percentage point increase in FLW antenatal home visits during the third trimester (P = 0.04). In the post-implementation period, postnatal home visits during the first week were increased in the intervention (72%) vs the control (60%) group (P < 0.01). The intervention also resulted in 13, 12, and 21 percentage point increases in skin-to-skin care (P < 0.01), breastfeeding immediately after delivery (P < 0.01), and age-appropriate complementary feeding (P < 0.01). FLW supervision and other RMNCHN behaviors were not significantly impacted. CONCLUSIONS: Important improvements in FLW home visits and RMNCHN behaviors were achieved. The ICT-CCS tool shows promise for facilitating FLW effectiveness in improving RMNCHN behaviors.

Effects of team-based goals and non-monetary incentives on front-line health worker performance and maternal health behaviours: a cluster randomised controlled trial in Bihar, India.

INTRODUCTION: We evaluated the impact of a 'Team-Based Goals and Incentives' (TBGI) intervention in Bihar, India, designed to improve front-line (community health) worker (FLW) performance and health-promoting behaviours related to reproductive, maternal, newborn and child health and nutrition. METHODS: This study used a cluster randomised controlled trial design and difference-in-difference analyses of improvements in maternal health-related behaviours related to the intervention's team-based goals (primary), and interactions of FLWs with each other and with maternal beneficiaries (secondary). Evaluation participants included approximately 1300 FLWs and 3600 mothers at baseline (May to June 2012) and after 2.5 years of implementation (November to December 2014) who had delivered an infant in the previous year. RESULTS: The TBGI intervention resulted in significant increases in the frequency of antenatal home visits (15 absolute percentage points (PP), p=0.03) and receipt of iron-folic acid (IFA) tablets (7 PP, p=0.02), but non-significant changes in other health behaviours related to the trial's goals. Improvements were seen in selected attitudes related to coordination and teamwork among FLWs, and in the provision of advice to beneficiaries (ranging from 8 to 14 PP) related to IFA, cord care, breast feeding, complementary feeding and family planning. CONCLUSION: Results suggest that combining an integrated set of team-based coverage goals and targets, small non-cash incentives for teams who meet targets and team building to motivate FLWs resulted in improvements in FLW coordination and teamwork, and in the quality and quantity of FLW-beneficiary interactions. These improvements represent programmatically meaningful steps towards improving health behaviours and outcomes. TRIAL REGISTRATION NUMBER: NCT03406221.

Thrombophilia testing in the inpatient setting: impact of an educational intervention.

BACKGROUND: Thrombophilia testing is frequently ordered in the inpatient setting despite its limited impact on clinical decision-making and unreliable results in the setting of acute thrombosis or ongoing anticoagulation. We sought to determine the effect of an educational intervention in reducing inappropriate thrombophilia testing for hospitalized patients. METHODS: During the 2014 academic year, we implemented an educational intervention with a phase implementation design for Internal Medicine interns at Stanford University Hospital. The educational session covering epidemiology, appropriate thrombophilia evaluation and clinical rationale behind these recommendations. Their ordering behavior was compared with a contemporaneous control (non-medicine and private services) and a historical control (interns from prior academic year). From the analyzed data, we determined the proportion of inappropriate thrombophilia testing of each group. Logistic generalized estimating equations were used to estimate odds ratios for inappropriate thrombophilia testing associated with the intervention. RESULTS: Of 2151 orders included, 934 were deemed inappropriate (43.4%). The two intervention groups placed 147 orders. A pooled analysis of ordering practices by intervention groups revealed a trend toward reduction of inappropriate ordering (p = 0.053). By the end of the study, the intervention groups had significantly lower rates of inappropriate testing compared to historical or contemporaneous controls. CONCLUSION: A brief educational intervention was associated with a trend toward reduction in inappropriate thrombophilia testing. These findings suggest that focused education on thrombophilia testing can positively impact inpatient ordering practices.

Association of Elevated Plasma Interleukin-18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome.

OBJECTIVE: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial. DESIGN: Retrospective analysis of randomized controlled clinical trial. SETTING: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis. PATIENTS: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population. INTERVENTIONS: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge. MEASUREMENTS AND MAIN RESULTS: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however. CONCLUSIONS: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial.

Reducing Telemetry Use Is Safe: A Retrospective Analysis of Rapid Response Team and Code Events After a Successful Intervention to Reduce Telemetry Use.

Interventions guiding appropriate telemetry utilization have successfully reduced use at many hospitals, but few studies have examined their possible adverse outcomes. The authors conducted a successful intervention to reduce telemetry use in 2013 on a hospitalist service using educational modules, routine review, and financial incentives. The association of reduced telemetry use with the incidence of rapid response team (RRT) and code activations was assessed in a retrospective cohort study of 210 patients who experienced a total of 233 RRT and code events on the inpatient internal medicine services from January 2012 through March 2015 at a tertiary care center. The incidence of adverse events for the hospitalist service was not significantly different during the intervention and postintervention period as compared to the preintervention period. Reducing inappropriate telemetry use was not associated with an increase in the incidence rates of RRT and code events.

Early Cerebral Vein After Endovascular Ischemic Stroke Treatment Predicts Symptomatic Reperfusion Hemorrhage.

BACKGROUND AND PURPOSE: Parenchymal hemorrhage (PH) after endovascular mechanical thrombectomy in acute ischemic stroke leads to worse outcomes. Better clinical and imaging biomarkers of symptomatic reperfusion PH are needed to identify patients at risk. We identified clinical and imaging predictors of reperfusion PH after endovascular mechanical thrombectomy with attention to early cerebral veins (ECVs) on postreperfusion digital subtraction angiography. METHODS: We performed a retrospective cohort study of consecutive acute ischemic stroke patients undergoing endovascular mechanical thrombectomy at our neurovascular referral center. Clinical and imaging characteristics were collected from patient health records, and random forest variable importance measures were used to identify predictors of symptomatic PH. Predictors of secondary outcomes, including 90-day mortality, functional dependence (modified Rankin Scale score, >2), and National Institutes of Health Stroke Scale shift, were also determined. Diagnostic test characteristics of ECV for symptomatic PH were determined using a receiver operating characteristic analysis. Differences between patients with and without symptomatic PH were assessed with Fisher exact test and the Wilcoxon rank sum (Mann-Whitney U test) test at the 0.05 significance level. RESULTS: Of 64 patients with anterior circulation large-vessel occlusion identified, 6 (9.4%) developed symptomatic PH. ECV was the strongest predictor of symptomatic PH with more than twice the importance of the next best predictor, male sex. Although ECV was also predictive of 90-day mortality and functional dependence, other characteristics were more important than ECV for these outcomes. The sensitivity and specificity of ECV alone for subsequent hemorrhage were both 0.83, with an area under the curve of 0.83 and 95% confidence interval of 0.66 to 1.00. CONCLUSIONS: ECV on postendovascular mechanical thrombectomy digital subtraction angiography is highly diagnostic of subsequent symptomatic reperfusion hemorrhage in this data set. This finding has important implications for post-treatment management of blood pressure and anticoagulation.

Reversals and limitations on high-intensity, life-sustaining treatments.

IMPORTANCE: Critically ill patients often receive high-intensity life sustaining treatments (LST) in the intensive care unit (ICU), although they can be ineffective and eventually undesired. Determining the risk factors associated with reversals in LST goals can improve patient and provider appreciation for the natural history and epidemiology of critical care and inform decision making around the (continued) use of LSTs. METHODS: This is a single institution retrospective cohort study of patients receiving life sustaining treatment in an academic tertiary hospital from 2009 to 2013. Deidentified patient electronic medical record data was collected via the clinical data warehouse to study the outcomes of treatment limiting Comfort Care and do-not-resuscitate (DNR) orders. Extended multivariable Cox regression models were used to estimate the association of patient and clinical factors with subsequent treatment limiting orders. RESULTS: 10,157 patients received life-sustaining treatment while initially Full Code (allowing all resuscitative measures). Of these, 770 (8.0%) transitioned to Comfort Care (with discontinuation of any life-sustaining treatments) while 1,669 (16%) patients received new DNR orders that reflect preferences to limit further life-sustaining treatment options. Patients who were older (Hazard Ratio(HR) 1.37 [95% CI 1.28-1.47] per decade), with cerebrovascular disease (HR 2.18 [95% CI 1.69-2.81]), treated by the Medical ICU (HR 1.92 [95% CI 1.49-2.49]) and Hematology-Oncology (HR 1.87 [95% CI 1.27-2.74]) services, receiving vasoactive infusions (HR 1.76 [95% CI 1.28, 2.43]) or continuous renal replacement (HR 1.83 [95% CI 1.34, 2.48]) were more likely to transition to Comfort Care. Any new DNR orders were more likely for patients who were older (HR 1.43 [95% CI 1.38-1.48] per decade), female (HR 1.30 [95% CI 1.17-1.44]), with cerebrovascular disease (HR 1.45 [95% CI 1.25-1.67]) or metastatic solid cancers (HR 1.92 [95% CI 1.48-2.49]), or treated by Medical ICU (HR 1.63 [95% CI 1.42-1.86]), Hematology-Oncology (HR 1.63 [95% CI 1.33-1.98]) and Cardiac Care Unit-Heart Failure (HR 1.41 [95% CI 1.15-1.72]). CONCLUSION: Decisions to reverse or limit treatment goals occurs after more than 1 in 13 trials of LST, and is associated with older female patients, receiving non-ventilator forms of LST, cerebrovascular disease, and treatment by certain medical specialty services.

Thyroid Function Variations Within the Reference Range Do Not Affect Quality of Life, Mood, or Cognitive Function in Community-Dwelling Older Men.

BACKGROUND: Variations in thyroid function within the laboratory reference range have been associated with a number of clinical outcomes. However, quality of life, mood, and cognitive function have not been extensively studied, and it is not clear whether mild variations in thyroid function have major effects on these neurocognitive outcomes. METHODS: Data were analyzed from the Osteoporotic Fractures in Men (MrOS) Study, a cohort of community-dwelling men aged 65 years and older in the United States. A total of 539 participants who were not taking thyroid medications and had age-adjusted TSH levels within the reference range underwent detailed testing of quality of life, mood, and cognitive function at baseline. The same quality of life, mood, and cognitive outcomes were measured again in 193 of the men after a mean follow-up of 6 years. Outcomes were analyzed using thyrotropin (TSH) and free thyroxine (FT4) levels as continuous independent variables, adjusting for relevant covariates. RESULTS: At baseline, there were no associations between TSH or FT4 levels and measures of quality of life, mood, or cognition in the 539 euthyroid men. Baseline thyroid function did not predict changes in these outcomes over a mean of 6 years in the 193 men in the longitudinal analysis. CONCLUSIONS: Variations in thyroid function within the age-adjusted laboratory reference range are not associated with variations in quality of life, mood, or cognitive function in community-dwelling older men.

Growth modeling of the maternal cytokine milieu throughout normal pregnancy: macrophage-derived chemokine decreases as inflammation/counterregulation increases.

Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant women (N = 16) at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1ß, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed.

Mechanistic insights into isoform-dependent and species-specific regulation of bile salt export pump by farnesoid X receptor.

Expression of bile salt export pump (BSEP) is regulated by the bile acid/farnesoid X receptor (FXR) signaling pathway. Two FXR isoforms, FXRα1 and FXRα2, are predominantly expressed in human liver. We previously showed that human BSEP was isoform-dependently regulated by FXR and diminished with altered expression of FXRα1 and FXRα2 in patients with hepatocellular carcinoma. In this study, we demonstrate that FXRα1 and FXRα2 regulate human BSEP through two distinct FXR responsive elements (FXRE): IR1a and IR1b. As the predominant regulator, FXRα2 potently transactivated human BSEP through IR1a, while FXRα1 weakly transactivated human BSEP through a newly identified IR1b. Relative expression of FXRα1 and FXRα2 affected human BSEP expression in vitro and in vivo. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed the binding and recruitment of FXRα1 and FXRα2 to IR1b and IR1a. Sequence analysis concluded that IR1b was completely conserved among species, whereas IR1a exhibited apparent differences across species. Sequence variations in IR1a were responsible for the observed species difference in BSEP transactivation by FXRα1 and FXRα2. In conclusion, FXR regulates BSEP in an isoform-dependent and species-specific manner through two distinct FXREs, and alteration of relative FXR isoform expression may be a potential mechanism for FXR to precisely regulate human BSEP in response to various physiological and pathological conditions.

Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer.

Most patients with ovarian cancer are diagnosed late in progression and often experience tumor recurrence and relapses due to drug resistance. Surface expression of matrix metalloprotease (MMP)-14 on ovarian cancer cells stimulates a tumor-stromal signaling pathway that promotes angiogenesis and tumor growth. In a cohort of 92 patients, we found that MMP-14 was increased in the serum of women with malignant ovarian tumors. Therefore, we investigated the preclinical efficacy of a MMP-14 monoclonal antibody that could inhibit the migratory and invasive properties of aggressive ovarian cancer cells in vitro. MMP-14 antibody disrupted ovarian tumor-stromal communication and was equivalent to Avastin in suppressing blood vessel growth in mice harboring Matrigel plugs. These effects on angiogenesis correlated with downregulation of several important angiogenic factors. Furthermore, mice with ovarian cancer tumors treated with anti-MMP-14 monotherapy showed a marked and sustained regression in tumor growth with decreased angiogenesis compared with immunoglobulin G (IgG)-treated controls. In a model of advanced peritoneal ovarian cancer, MMP-14-dependent invasion and metastasis was effectively inhibited by intraperitoneal administration of monoclonal MMP-14 antibody. Together, these studies provide a preclinical proof-of-concept for MMP-14 targeting as an adjuvant treatment strategy for advanced ovarian cancer.

Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: implications for antiangiogenic therapy.

Ovarian cancer is a lethal gynecologic malignancy that may benefit from new therapies that block key paracrine pathways involved in tumor-stromal interactions and tumor vascularity. It was recently shown that matrix metalloprotease-1 (MMP1) activation of the G protein-coupled receptor protease-activated receptor-1 (PAR1) is an important stimulator of angiogenesis and metastasis in peritoneal mouse models of ovarian cancer. In the present study, we tested the hypothesis that MMP1-PAR1 promotes angiogenesis through its paracrine control of angiogenic chemokine receptors. We found that MMP1-PAR1 activation induces the secretion of several angiogenic factors from ovarian carcinoma cells, most prominently interleukin (IL)-8, growth-regulated oncogene-alpha (GRO-alpha), and monocyte chemoattractant protein-1. The secreted IL-8 and GRO-alpha acts on endothelial CXCR1/2 receptors in a paracrine manner to cause robust endothelial cell proliferation, tube formation, and migration. A cell-penetrating pepducin, X1/2pal-i3, which targets the conserved third intracellular loop of both CXCR1 and CXCR2 receptors, significantly inhibited endothelial cell proliferation, tube formation, angiogenesis, and ovarian tumor growth in mice. Matrigel plugs mixed with MMP1-stimulated, OVCAR-4-conditioned media showed a dramatic 33-fold increase in blood vessel formation in mice. The X1/2pal-i3 pepducin completely inhibited MMP1-dependent angiogenesis compared with a negative control pepducin or vehicle. Conversely, a vascular endothelial growth factor-directed antibody, Avastin, suppressed angiogenesis in mice but, as expected, was unable to inhibit IL-8 and GRO-alpha-dependent endothelial tube formation in vitro. These studies identify a critical MMP1-PAR1-CXCR1/2 paracrine pathway that might be therapeutically targeted for ovarian cancer treatment.

Differential modulation of farnesoid X receptor signaling pathway by the thiazolidinediones.

Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are agonists of peroxisome proliferator-activated receptor (PPAR)-gamma and belong to a class of insulin-sensitizing drugs for type 2 diabetes mellitus. However, member-specific, PPARgamma-independent activities and toxicity have been reported, especially for troglitazone. Currently, the underlying mechanisms are not fully understood. In this study, we demonstrated that troglitazone but not rosiglitazone or pioglitazone modulated expression of farnesoid X receptor (FXR) target genes bile salt export pump (BSEP) and small heterodimer partner (SHP) in Huh-7 cells. More specifically, troglitazone acted as a partial agonist of FXR to weakly increase BSEP and SHP expression but functioned as a potent antagonist to significantly suppress bile acid-induced expression. Consistent with the finding, troglitazone partially induced but markedly antagonized bile acid-mediated BSEP promoter transactivation. However, such modulating effects were not detected with rosiglitazone or pioglitazone. Using the crystal structure of ligand-bound FXR ligand binding domain (LBD), molecular docking predicted that troglitazone, but not rosiglitazone or pioglitazone, could form a stable complex with FXR LBD. The specific alpha-tocopherol side chain of troglitazone significantly contributed to the formation of such a stable complex through extensive interactions with FXR LBD. The docking model was further validated by functional analyses of a series of docking-guided FXR mutants. In summary, the data demonstrated that troglitazone, but not rosiglitazone or pioglitazone, was an FXR modulator and potently antagonized bile acid-induced expression of FXR target genes. Such differential modulation of FXR signaling pathway by TZDs may represent one of the mechanisms for member-specific, PPARgamma-independent activities and toxicity.

Effect of guggulsterone and cembranoids of Commiphora mukul on pancreatic phospholipase A(2): role in hypocholesterolemia.

Guggulsterone (7) and cembranoids (8-12) from Commiphora mukul stem bark resin guggul were shown to be specific modulators of two independent sites that are also modulated by bile salts (1-6) to control cholesterol absorption and catabolism. Guggulsterone (7) antagonized the chenodeoxycholic acid (3)-activated nuclear farnesoid X receptor (FXR), which regulates cholesterol metabolism in the liver. The cembranoids did not show a noticeable effect on FXR, but lowered the cholate (1)-activated rate of human pancreatic IB phospholipase A2 (hPLA2), which controls gastrointestinal absorption of fat and cholesterol. Analysis of the data using a kinetic model has suggested an allosteric mechanism for the rate increase of hPLA2 by cholate and also for the rate-lowering effect by certain bile salts or cembranoids on the cholate-activated hPLA2 hydrolysis of phosphatidylcholine vesicles. The allosteric inhibition of PLA2 by certain bile salts and cembranoids showed some structural specificity. Biophysical studies also showed specific interaction of the bile salts with the interface-bound cholate-activated PLA2. Since cholesterol homeostasis in mammals is regulated by FXR in the liver for metabolism and by PLA2 in the intestine for absorption, modulation of PLA2 and FXR by bile acids and selected guggul components suggests novel possibilities for hypolipidemic and hypocholesterolemic therapies.

Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression.

The metabolic conversion of cholesterol into bile acids in liver is initiated by the rate-limiting cholesterol 7 alpha-hydroxylase (CYP7A1), whereas the bile salt export pump (BSEP) is responsible for the canalicular secretion of bile acids. Liver receptor homolog 1 (LRH-1) is a key transcriptional factor required for the hepatic expression of CYP7A1. We hypothesized that LRH-1 was also involved in the transcriptional regulation of BSEP. In support of our hypothesis, we found that overexpression of LRH-1 induced, whereas knockdown of LRH-1 decreased, BSEP expression. Consistent with its role in transcriptional regulation, LRH-1 dose-dependently transactivated the BSEP promoter. In addition, such transactivation by LRH-1 was required for maximal induction of BSEP expression through the bile acid/farnesoid X receptor (FXR) activation pathway. Bioinformatic and mutational analysis led to the identification of a functional liver receptor homolog 1-responsive element (LRHRE) in the BSEP promoter. Specific binding of LRH-1 to the LRHRE and recruitment of LRH-1 to the BSEP promoter were demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, respectively. In conclusion, LRH-1 transcriptionally activated the BSEP promoter and functioned as a modulator in bile acid/FXR-mediated BSEP regulation. These results suggest that LRH-1 plays a supporting role to FXR in maintaining hepatic bile acid levels by coordinately regulating CYP7A1 and BSEP for bile acid synthesis and elimination, respectively.