Investigating the effects of suicide exposure among a clinical sample of active duty service members.

Suicide exposure warrants further investigation as a risk factor for suicide among military service members. This study aimed to examine associations among suicide exposure, suicidal ideation (SI), and psychological symptoms in a clinical sample of service members (N = 1,565, 64.4% suicide-exposed) and identify how one's relationship with the deceased impacts suicidality and psychological health in exposed individuals. A secondary analysis of cross-sectional survey data was conducted. Generalized linear regression analyses were used to identify associations between suicide exposure and both current SI and psychological symptoms among all participants; the associations between suicide exposure characteristics and psychological symptoms were only examined among exposed individuals. Exposure was not significantly associated with higher SI, ß = .007, SE = .16, p = .965, but was associated with PTSD, ß = 1.60, SE = 0.49, p = .001; anxiety, ß = .68, SE = .31, p = .031; and insomnia symptoms, ß = .98, SE = .25, p < .001. Among participants who had been exposed, high/long impact of exposure was positively associated with SI, ß = 0.94, SE = .26, p < .001, and psychological symptoms, PTSD: ß = 2.32, SE = .77, p = .002; anxiety: ß = 1.39, SE = .50, p = .005; insomnia: ß = .96, SE = .39, p = .015. Results illustrate the significant issue of suicide exposure within the military and show consideration of suicide exposure as a potential risk factor for adverse psychological outcomes is warranted.

Internalization of muscularity and thinness ideals: Associations with body dissatisfaction, eating disorder symptoms, and muscle dysmorphic symptoms in at risk sexual minority men.

OBJECTIVE: In the tripartite influence model, appearance-ideal internalization is identified as a prominent risk factor for the development of body dissatisfaction and subsequent eating disorder (ED) behaviors. For men, prior research has emphasized the importance of both thin-ideal internalization and muscular-ideal internalization in explaining later ED behaviors and muscle dysmorphia (MD) symptoms. Previous research in heterosexual men has shown that the associations between muscular-ideal internalization and ED or MD symptoms may depend on whether the individual has also internalized the thin ideal. However, this interaction has not been examined in research with sexual minority men (SMM). METHOD: The current study collected self-report data from 452 at risk SMM (i.e., endorsed body dissatisfaction), with ages ranging from 18 to 35 years. Linear regression models were conducted to test the interaction effects between thinness and muscularity internalization on ED symptoms, MD behaviors, and general body dissatisfaction. Simple slopes and the Johnson-Neyman technique were used to investigate significant interaction terms. RESULTS: Thin- and muscular-ideal internalization were positively associated with muscular appearance intolerance and dietary restriction with no significant interaction. Muscular drive for size was highest when both muscularity internalization and thinness internalization were high. Muscular-ideal internalization was positively associated with both cognitive restraint and general body dissatisfaction, but only at lower levels of thinness internalization. DISCUSSION: Given the interacting association between thinness and muscularity internalization and aspects of body dissatisfaction, attitudes, and behavior, prevention and intervention programs for EDs and MDs in SMM should seek to dismantle both thinness and muscularity internalization. PUBLIC SIGNIFICANCE STATEMENT: Internalizing-or adopting as one's own-the ideal of a body with low body fat and high muscularity has been shown to lead to muscle dysmorphia and eating disorder symptoms in men. The current study examines whether the combination of thin-ideal and muscular-ideal internalization is associated with worse symptoms than either facet alone in sexual minority men. Treatment efforts in sexual minority men should address both types of internalization.

Structural stigma and sexual orientation-related reproductive health disparities in a longitudinal cohort study of female adolescents.

INTRODUCTION: Sexual minority female adolescents have worse reproductive health than heterosexual peers; research into the origins of these disparities is limited. Our objective was to examine whether exposure to structural stigma (e.g., societal-level conditions, cultural norms, institutional policies/practices that constrain the lives of the stigmatized) is associated with sexually transmitted infections (STIs) and teen pregnancy in sexual minority female adolescents. METHODS: Longitudinal data were utilized from 6581 female adolescents aged 9-14 years at baseline (1996) in the U.S.-based Growing Up Today Study and followed through 2007. We used a previously-validated structural stigma scale composed of four state-level items (e.g., employment non-discrimination policies) with one item added relevant to reproductive health. Risk ratios were generated from multivariate models. RESULTS: Sexual minority female adolescents were significantly more likely than heterosexual peers to have an STI diagnosis and teen pregnancy. Sexual minority female adolescents living in states with lower, compared to higher, levels of structural stigma were significantly less likely to have an STI diagnosis, after adjustment for individual- and state-level covariates (relative risk [RR] = 0.70, 95% confidence interval [CI]: 0.51, 0.97). In contrast, among completely heterosexual adolescents, structural stigma was not associated with STI diagnosis. Teen pregnancy risk-a rare outcome-did not vary by level of structural stigma for sexual minority or heterosexual adolescents. CONCLUSIONS: Structural stigma is a potential risk factor for adverse reproductive health among sexual minority female adolescents. Changing laws and policies to be inclusive of all people, regardless of sexual orientation, can help alleviate entrenched reproductive health disparities.

Clinical Trial of Human Umbilical Cord Blood-Derived Stem Cells for the Treatment of Moderate-to-Severe Atopic Dermatitis: Phase I/IIa Studies.

Mesenchymal stem cells (MSCs) have been proven to be therapeutically effective against atopic dermatitis (AD) in preclinical studies. However, the safety and efficacy of MSCs against AD have not yet been investigated in a clinical study. To establish the safety and efficacy of human umbilical cord blood-derived MSCs (hUCB-MSCs) in AD, 34 adult patients with moderate-to-severe AD were enrolled in two phase trials with a follow-up for 1 month and 3 months, respectively. Patients were randomly allocated to receive low dose (2.5 × 107 ) or high dose (5.0 × 107 ) of hUCB-MSCs subcutaneously. An Eczema Area and Severity Index (EASI) score, Investigator's Global Assessment (IGA) score, Severity Scoring for Atopic Dermatitis (SCORAD) score, adverse effect assessments, and serum biomarker levels were evaluated as end points. A single treatment of hUCB-MSCs resulted in dose-dependent improvements in AD manifestation. Fifty-five percent of patients in high dose hUCB-MSC-treated group showed a 50% reduction in the EASI score. The IGA score and SCORAD score decreased by 33% and 50%, respectively, in high dose-treated group. Particularly, the administration of high dose hUCB-MSCs reduced the pruritus score by 58%. The serum IgE levels and number of blood eosinophils were downregulated by the treatment. No serious adverse events occurred, and none of the patients discontinued the trial due to adverse events. This is the first report to demonstrate a marked improvement of AD features with cell therapeutics. These data suggest that the infusion of hUCB-MSCs might be an effective therapy for patients with moderate-to-severe AD. Stem Cells 2017;35:248-255.

Esotropia following botulinum toxin type A injection for facial wrinkles.

We report a rare case of eye complication following botulinum toxin type A (BTA) injection. A 36-year-old healthy woman received BTA injections on the glabella, forehead, and periocular area to improve her wrinkles. Four days after BTA injection, diplopia and esotropia developed on her right eye.

Developmental Latent Patterns of Identification as Mostly Heterosexual Versus Lesbian, Gay, or Bisexual.

Scant research exists on the development of mostly heterosexual identity, the largest sexual orientation minority subgroup. We used longitudinal latent class analysis to characterize the patterns of identification with lesbian, gay, bisexual (LGB), or mostly heterosexual identities from ages 12 to 23 in 13,859 youth (57% female) in a U.S. national cohort. Three classes emerged: completely heterosexual (88.2%), mostly heterosexual (9.5%), and LGB (2.4%). LGB class youth generally identified with sexual minority identities by ages 12-17. In contrast, mostly heterosexual class youth identified with sexual minority identities gradually, with steady increases in endorsement starting at the age of 14. Developmental implications of these differential patterns are discussed.

Food ordering for children in restaurants: multiple sources of influence on decision making.

OBJECTIVE: Restaurants are playing an increasingly important role in children's dietary intake. Interventions to promote healthy ordering in restaurants have primarily targeted adults. Much remains unknown about how to influence ordering for and by children. Using an ecological lens, the present study sought to identify sources of influence on ordering behaviour for and by children in restaurants. DESIGN: A mixed-methods study was conducted using unobtrusive observations of dining parties with children and post-order interviews. Observational data included: child's gender, person ordering for the child and server interactions with the dining party. Interview data included: child's age, restaurant visit frequency, timing of child's decision making, and factors influencing decision making. SETTING: Ten independent, table-service restaurants in San Diego, CA, USA participated. SUBJECTS: Complete observational and interview data were obtained from 102 dining parties with 150 children (aged 3-14 years). RESULTS: Taste preferences, family influences and menus impacted ordering. However, most children knew what they intended to order before arriving at the restaurant, especially if they dined there at least monthly. Furthermore, about one-third of children shared their meals with others and all shared meals were ordered from adult (v. children's) menus. Parents placed most orders, although parental involvement in ordering was less frequent with older children. Servers interacted frequently with children but generally did not recommend menu items or prompt use of the children's menu. CONCLUSIONS: Interventions to promote healthy ordering should consider the multiple sources of influence that are operating when ordering for and by children in restaurants.

A restaurant-based intervention to promote sales of healthy children's menu items: the Kids' Choice Restaurant Program cluster randomized trial.

BACKGROUND: Away-from-home eating is an important dietary behavior with implications on diet quality. Thus, it is an important behavior to target to prevent and control childhood obesity and other chronic health conditions. Numerous studies have been conducted to improve children's dietary intake at home, in early care and education, and in schools; however, few studies have sought to modify the restaurant food environment for children. This study adds to this body of research by describing the development and launch of an innovative intervention to promote sales of healthy children's menu items in independent restaurants in Southern California, United States. METHODS: This is a cluster randomized trial with eight pair-matched restaurants in San Diego, California. Restaurants were randomized to a menu-only versus menu-plus intervention condition. The menu-only intervention condition involves manager/owner collaboration on the addition of pre-determined healthy children's menu items and kitchen manager/owner collaboration to prepare and plate these items and train kitchen staff. The menu-plus intervention condition involves more extensive manager/owner collaboration and kitchen staff training to select, prepare, and plate new healthy children's menu items, and a healthy children's menu campaign that includes marketing materials and server training to promote the items. The primary outcome is sales of healthy children's menu items over an 18-week period. In addition, dining parties consisting of adults with children under 18 years of age are being observed unobtrusively while ordering and then interviewed throughout the 18-week study period to determine the impact of the intervention on ordering behaviors. Manager/owner interviews and restaurant audits provide additional evidence of impact on customers, employees, and the restaurant environment. Our process evaluation assesses dose delivered, dose received, and intervention fidelity. DISCUSSION: Successful recruitment of the restaurants has been completed, providing evidence that the restaurant industry is open to working on the public health challenge of childhood obesity. Determining whether a restaurant intervention can promote sales of healthy children's menu items will provide evidence for how to create environments that support the healthy choices needed to prevent and control obesity. Despite these strengths, collection of sales data that will allow comprehensive analysis of intervention effects remains a challenge. TRIAL REGISTRATION: NCT02511938.

Linalool is a PPARα ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome.

We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs. Reporter gene and time-resolved fluorescence resonance energy transfer assays demonstrated that linalool is a direct ligand of PPARα. Linalool stimulation reduced cellular lipid accumulation regulating PPARα-responsive genes and significantly induced FA oxidation, and its effects were markedly attenuated by silencing PPARα expression. In mice, the oral administration of linalool for 3 weeks reduced plasma TG concentrations in Western-diet-fed C57BL/6J mice (31%, P < 0.05) and human apo E2 mice (50%, P < 0.05) and regulated hepatic PPARα target genes. However, no such effects were seen in PPARα-deficient mice. Transcriptome profiling revealed that linalool stimulation rewired global gene expression in lipid-loaded hepatocytes and that the effects of 1 mM linalool were comparable to those of 0.1 mM fenofibrate. Metabolomic analysis of the mouse plasma revealed that the global metabolite profiles were significantly distinguishable between linalool-fed mice and controls. Notably, the concentrations of saturated FAs were significantly reduced in linalool-fed mice. These findings suggest that the appropriate intake of a natural aromatic compound could exert beneficial metabolic effects by regulating a cellular nutrient sensor.

Cyanidin is an agonistic ligand for peroxisome proliferator-activated receptor-alpha reducing hepatic lipid.

To investigate the underlying mechanism of targets of cyanidin, a flavonoid, which exhibits potent anti-atherogenic activities in vitro and in vivo, a natural chemical library that identified potent agonistic activity between cyanidin and peroxisome proliferator-activated receptors (PPAR) was performed. Cyanidin induced transactivation activity in all three PPAR subtypes in a reporter gene assay and time-resolved fluorescence energy transfer analyses. Cyanidin also bound directly to all three subtypes, as assessed by surface plasmon resonance experiments, and showed the greatest affinity to PPARα. These effects were confirmed by measuring the expression of unique genes of each PPAR subtype. Cyanidin significantly reduced cellular lipid concentrations in lipid-loaded steatotic hepatocytes. In addition, transcriptome profiling in lipid-loaded primary hepatocytes revealed that the net effects of stimulation with cyanidin on lipid metabolic pathways were similar to those elicited by hypolipidemic drugs. Cyanidin likely acts as a physiological PPARα agonist and potentially for PPARß/δ and γ, and reduces hepatic lipid concentrations by rewiring the expression of genes involved in lipid metabolic pathways.

Structural stigma and cigarette smoking in a prospective cohort study of sexual minority and heterosexual youth.

BACKGROUND: Sexual minority youth are more likely to smoke cigarettes than heterosexuals, but research into the determinants of these disparities is lacking. PURPOSE: This study aimed to examine whether exposure to structural stigma predicts cigarette smoking in sexual minority youth. METHODS: Prospective data from adolescents participating in the Growing Up Today Study (2000-2005) were utilized. RESULTS: Among sexual minority youth, living in low structural stigma states (e.g., states with non-discrimination policies inclusive of sexual orientation) was associated with a lower risk of cigarette smoking after adjustment for individual-level risk factors (relative risk [RR] = 0.97; 95 % confidence interval [CI], 0.96, 0.99; p = 0.02). This association was marginally significant after additional controls for potential state-level confounders (RR = 0.97; 95 % CI, 0.93, 1.00; p = 0.06). In contrast, among heterosexual youth, structural stigma was not associated with past-year smoking rates, documenting specificity of these effects to sexual minority youth. CONCLUSIONS: Structural stigma represents a potential risk factor for cigarette smoking among sexual minority adolescents.

trans-Caryophyllene is a natural agonistic ligand for peroxisome proliferator-activated receptor-α.

Intake of dietary aroma compounds may regulate cellular lipid metabolism. We demonstrated that trans-caryophyllene, a flavor compound in plant foods and teas, activates peroxisome proliferator-activated receptor (PPAR)-α through direct interaction with the ligand-binding domain of PPAR-α. The agonistic activity of trans-caryophyllene was investigated by the luciferase reporter assay, surface plasmon resonance, and time-resolved fluorescence resonance energy transfer assay. Following the stimulation of cells with trans-caryophyllene, intracellular triglyceride concentrations were significantly reduced by 17%, and hepatic fatty acid uptake was significantly increased by 31%. The rate of fatty acid oxidation was also significantly increased. The expressions of PPAR-α and its target genes and proteins in fatty acid uptake and oxidation were significantly up-regulated as well. In HepG2 cells transfected with small interfering RNA of PPAR-α, the effects of trans-caryophyllene on PPAR-α responsive gene expressions, intracellular triglyceride, fatty acid uptake and oxidation were disappeared. These results indicate that the aroma compound, trans-caryophyllene, is PPAR-α agonist thus regulates cellular lipid metabolism in PPAR-α dependent manners.

A split-face, evaluator-blind randomized study on the early effects of Q-switched Nd:YAG laser versus Er:YAG micropeel in light solar lentigines in Asians.

BACKGROUND: Asians are prone to develop epidermal pigmentary lesions as a result of photoaging. Solar lentigines, especially those which are light in color, show somewhat limited response to pigment lasers and intense pulsed light sources. OBJECTIVES: We sought to compare the early effects as well as side effects of Q-switched Nd:YAG and Er:YAG micropeel in treating light solar lentigines in Asians. PATIENT AND METHODS: This was a split-face, evaluator-blind, randomized controlled study. A single session of treatment was performed on Asian patients with light facial lentigines. Q-switched Nd:YAG laser was allocated to one half of the face, and Er:YAG micropeel to the other half. The response to therapy was evaluated by two independent dermatologists with standardized photographs taken 2 weeks and 1 month after the laser treatment. Patients' satisfaction and preference in treatment were also assessed. RESULTS: Fifteen patients completed the study and were analyzed. A reduction in pigment was observed with both lasers during the study period. The degree of pigment reduction in the Q-switched Nd:YAG treated side of the face was significantly higher than that of the Er:YAG micropeel treated side at 2-week follow-up (p < 0.001). The degree of pigment reduction between the Q-switched Nd:YAG-treated side and the Er:YAG micropeel-treated side was similar at 1-month follow-up (p = 0.110). CONCLUSION: While there is no perfect therapy for light solar lentigines, a single session of Q-switched Nd:YAG laser and Er:YAG micropeel was shown to reduce pigmentation. The immediate effects (2-week follow-up) were better with the Q-switched Nd:YAG laser but there was no great difference between the two laser types at 1-month follow-up due to the greater degree of post-inflammatory hyperpigmentation following Q-switched Nd:YAG. Both laser types could be applied either singly in turns, or in combination for maximal efficacy in future.

Varicella-zoster virus as a possible cause of pityriasis lichenoides et varioliformis acuta.

The etiologic agents for pityriasis lichenoides et varioliformis acuta (PLEVA) are largely unknown, although it has been suggested that foreign antigens such as infectious agents are the pathogenic mechanism. We present a case suggesting a possible relationship between varicella-zoster virus and PLEVA.

A split-face, evaluator-blind randomized study on the early effects of Q-switched Nd:YAG laser plus Er:YAG micropeel (combined therapy) versus Q-switched Nd:YAG alone in light solar lentigines in Asians.

Solar lentigines are a common sign of aging in Asians, who often asked for treatment. Various lasers, including Q-switched Nd:YAG and Er:YAG, have been adopted, but the results are not always satisfactory, especially for those who are relatively light in color. Our objective was to compare the early effects as well as side effects of Q-switched Nd:YAG laser plus Er:YAG micropeel (combined therapy) with those of Q-switched Nd:YAG laser (QSNY) alone in light solar lentigines in Asians. This was a split-face, evaluator-blind, randomized controlled study. A single session of treatment was performed on Asian patients with light facial lentigines. A combined treatment with QSNY and Er:YAG micropeel was allocated to one half of the face, and QSNY alone to the other half. The response to therapy was evaluated by two independent dermatologists, with standardized photographs taken 2 weeks and 1 month after the laser treatment. Patients' satisfaction and preference in treatment were also assessed. Fifteen patients completed the study and were analyzed. Overall, a reduction in pigment was observed with both treatment arms during the study period. The degree of pigment reduction following combined therapy and QSNY alone was similar at 2 weeks' follow-up ( = 0.433). However, due to the higher incidence of postinflammatory hyperpigmentation (PIH) with combined therapy (73.3 vs 40%), the degree of pigment reduction in the combined side of the face was found significantly lower than that of the QSNY-alone side at 1-month follow-up (P = 0.014). Although our study results show that both combined therapy and QSNY alone are capable of reducing pigmentation, QSNY alone is considered to have more favorable qualities than combined treatment for light solar lentigines in Asians.

NT-PGC-1α protein is sufficient to link ß3-adrenergic receptor activation to transcriptional and physiological components of adaptive thermogenesis.

PGC-1α is an inducible transcriptional coactivator that regulates cellular energy metabolism and adaptation to environmental and nutritional stimuli. In tissues expressing PGC-1α, alternative splicing produces a truncated protein (NT-PGC-1α) corresponding to the first 267 amino acids of PGC-1α. Brown adipose tissue also expresses two novel exon 1b-derived isoforms of PGC-1α and NT-PGC-1α, which are 4 and 13 amino acids shorter in the N termini than canonical PGC-1α and NT-PGC-1α, respectively. To evaluate the ability of NT-PGC-1α to substitute for PGC-1α and assess the isoform-specific role of NT-PGC-1α, adaptive thermogenic responses of adipose tissue were evaluated in mice lacking full-length PGC-1α (FL-PGC-1(-/-)) but expressing slightly shorter but functionally equivalent forms of NT-PGC-1α (NT-PGC-1α(254)). At room temperature, NT-PGC-1α and NT-PGC-1α(254) were produced from conventional exon 1a-derived transcripts in brown adipose tissue of wild type and FL-PGC-1α(-/-) mice, respectively. However, cold exposure shifted transcription to exon 1b, increasing exon 1b-derived mRNA levels. The resulting transcriptional responses produced comparable increases in energy expenditure and maintenance of core body temperature in WT and FL-PGC-1α(-/-) mice. Moreover, treatment of the two genotypes with a selective ß(3)-adrenergic receptor agonist produced similar increases in energy expenditure, mitochondrial DNA, and reductions in adiposity. Collectively, these findings illustrate that the transcriptional and physiological responses to sympathetic input are unabridged in FL-PGC-1α(-/-) mice, and that NT-PGC-1α is sufficient to link ß(3)-androgenic receptor activation to adaptive thermogenesis in adipose tissue. Furthermore, the transcriptional shift from exon 1a to 1b supports isoform-specific roles for NT-PGC-1α in basal and adaptive thermogenesis.

Physical and sexual abuse in childhood as predictors of early-onset cardiovascular events in women.

BACKGROUND: Although child abuse is widespread and has been associated with cardiovascular disease (CVD) risk factors, its association with CVD events is not established. METHODS AND RESULTS: We examined associations of child abuse with CVD events among 66 798 women in the Nurses' Health Study 2. Proportional hazards models estimated hazard ratios and 95% confidence intervals (CIs) for myocardial infarction (n=262), stroke (n=251), and total CVD (n=513). Severe physical abuse was reported by 9% and forced sex by 11% of participants. After adjustment for age, race, childhood body type, parental education, and family CVD history, the hazard ratios for CVD events were 0.91 (95% CI, 0.70-1.17) for mild physical abuse, 1.02 (95% CI, 0.82-1.26) for moderate physical abuse, and 1.46 (95% CI, 1.11-1.92) for severe physical abuse compared with no abuse. Compared with women without childhood sexual abuse, the hazard ratio was 1.10 (95% CI, 0.88-1.35) for unwanted sexual touching and 1.56 (95% CI, 1.23-1.99) for forced sex. After adjustment for adult lifestyle and medical risk factors, the hazard ratio for severe physical abuse was 1.13 (95% CI, 0.85-1.51) and that for forced sex was 1.25 (95% CI, 0.98-1.60); these intermediates accounted for much of the association of severe child abuse with CVD. Associations were similar for retrospectively and prospectively reported events. Women with abuse were less likely to release medical records. The associations were stronger for unconfirmed self-reported events than end points that were corroborated with additional information or medical record review. CONCLUSION: Severe child abuse is a prevalent risk for early adult CVD that is partially mediated by preventable risk factors.

Ombuin-3-O-ß-D-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors α and δ/ß.

We demonstrated that ombuin-3-O-ß-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) α and δ/ß. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPARα and δ/ß but not to PPARγ or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPARα and δ/ß. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPARα stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPARα and δ/ß with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages.

Induction of ABCA1 and ABCG1 expression by the liver X receptor modulator cineole in macrophages.

We investigated the effect of cineole on the expression of genes related to reverse cholesterol transport and hepatic fatty acid metabolism. Cineole, a small aroma compound in teas and herbs, significantly stimulated the transactivation of liver X receptor modulator (LXR)-α and LXR-ß. The mRNA and protein expression of LXRs and their target genes, including ABCA1 and ABCG1, was significantly increased in macrophages stimulated with cineole. This led to the subsequent removal of cholesterol from the cells. Interestingly, cineole showed tissue-selective LXR induction: hepatocytes stimulated with cineole showed significantly reduced expression of LXR-α and LXR-α-responsive genes, including FAS and SCD-1 (P <0.05). Accordingly, hepatocytes treated with cineole displayed reduced cellular lipid accumulation compared with control cells, as assessed by Oil Red O lipid staining and cholesterol quantification. These results suggest that cineole is a selective LXR modulator that regulates the expression of key genes in reverse cholesterol transport in macrophages without inducing lipogenesis in hepatocytes. This selective LXR modulator may have practical implications for the development of hypocholesterolemic or anti-atherosclerotic agents and also suggests.

Cyanidin, a natural flavonoid, is an agonistic ligand for liver X receptor alpha and beta and reduces cellular lipid accumulation in macrophages and hepatocytes.

Cyanidin, a natural flavonoid abundant in fruits and vegetables, is known to regulate cellular lipid metabolism; however, its underlying mechanism of action and protein targets remain unknown. Here, the ligand binding activity of cyanidin on liver X receptors (LXRs) was investigated utilizing surface plasmon resonance and time-resolved fluorescence energy transfer (TR-FRET) analyses. LXRs are nuclear receptors which function as critical transcription factors in the regulation of cellular lipid and glucose metabolism. This includes the stimulation of high-density-lipoprotein synthesis and activation of reverse cholesterol transport. The present findings show that cyanidin induces the transactivation of LXRs and binds directly to the ligand-binding domain of both LXRα and LXRß with dissociation constants of 2.2 and 73.2µM, respectively. Cell-free FRET analysis demonstrated that cyanidin induces the recruitment of co-activator peptide for LXRα and LXRß with EC50 of 3.5µM and 125.2µM, respectively. In addition, intracellular cholesterol and triglyceride (TG) concentrations were reduced in macrophages following cyanidin stimulation. In cultured hepatocytes, cyanidin mildly induced SREBP1c gene expression but marginally affected cellular TG concentrations as well as reduced cellular cholesterol accumulations which activated the expression of genes for reverse cholesterol transport. Two cyanidin metabolites, procatechic acid and phloroglucinaldehyde, did not directly bind or activate LXRs. These results demonstrate that cyanidin is a direct ligand for both LXRα and LXRß, suggesting that cyanidin may operate, at least in part, through modulation of cellular LXR activity.