"Because I Am a Female": Stigma and Safety Perspectives from Racially/Ethnically Diverse Women with Serious Mental Illnesses.

Individuals with serious mental illnesses (SMIs) face safety risks related to their mental health conditions that are often compounded by experiences of trauma, victimization, residence in impoverished neighborhoods, and histories of homelessness. Stigma and safety challenges significantly impact community integration for individuals with SMIs, particularly women, who often bear a disproportionate burden of vulnerability, gender-based stigma, violence, and other inequalities. This study investigates how women with SMIs engage in the meaning-making of their safety and stigma experiences that, in turn, influence their community integration. From a large multi-site study exploring community experiences of racially/ethnically diverse participants with SMIs, a subsample of 28 cis and trans-gender women, who reported experiencing gendered stigma and a lack of safety, were chosen for the current study. The interviews were analyzed using modified principles of Interpretive Phenomenological Analysis (IPA) to understand how women with SMIs made meaning of their safety and stigma encounters in their families, communities, and neighborhoods. IPA analysis resulted in the emergence of themes within a broad category of safety that represented participants' meaning-making about their physical safety and stigma experiences. Specifically, we used the broad themes from an existing framework of safety called 'Navigating Safety' model as sensitizing concepts for our analysis. Physical and psychological aspects of safety for this study were experienced in tandem whereby the women made sense of how their experiences of a lack of physical safety in multiple contexts shaped their sense of self, internalized stigma, and their social relationships. Within the broad theme of physical safety, participants described unsafe neighborhoods, exposure to domestic and intimate partner violence, and vulnerability to sexual violence. Additionally, under psychological safety, we identified how gender-based norms, race and ethnicity, sources of stigma (internalized, familial, and societal), and social isolation contributed to their mental health and social relationships (particularly with family). These findings highlight how the compounding influence of the intersection of multiple stigmatized identities exerts safety challenges on the lives and community experiences of women with SMIs. Focusing on access and affordability of appropriate gender-responsive resources for women, including trauma-informed care, could reduce hospitalizations, mental health symptoms, and stigma so they can safely integrate into their communities.

Mental health care utilization in individuals with high levels of psychosis-like experiences: Associations with race and potentially traumatic events.

Objective: Racial inequities in mental health care utilization (MHCU) are well documented. Marginalized racial groups are more likely to report psychosis-like experiences (PLEs) and are at elevated risk for racial discrimination and trauma, impacting PLE severity. Little is known about how factors associated with race impact treatment seeking among individuals reporting PLEs. The present study examined associations between race, trauma, discrimination, PLEs, and MHCU among people endorsing high levels of PLEs. Method: Participants were Asian/Asian American, Black/African American, or White/European American college students ages 18-25 years meeting PLE self-report measure cutoff scores (N = 177). Binary logistic and multiple linear regressions were used to examine associations between past, current, and prospective MHCU and race, potentially traumatic events, discrimination, and PLEs. Results: Participants endorsing more PLEs were more likely to report past and current treatment and to be considering future services. Asian/Asian American and Black/African American participants were less likely to endorse past, current, and prospective future mental health care. Potentially traumatic events predicted increased utilization of past treatment. Conclusions: Results suggest service differences among participants, such that Black/African American and Asian/Asian American young adults reporting PLEs were less likely than White/European American counterparts to seek treatment even when accounting for traumatic events and discrimination. These findings highlight the need to further elucidate MHCU among marginalized racial groups experiencing psychosis-like symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Definitions of Community for Individuals with Serious Mental Illnesses: Implications for Community Integration and Recovery.

While recent work on community integration for individuals with serious mental illnesses (SMIs) has focused on the multi-dimensionality of community integration, it has not been fully rooted in how consumers define and experience communities for themselves. Guided by symbolic interactionism theory, the goal of the present study is to explore definitions of community as provided by individuals with SMIs, and to incorporate those definitions into a theoretical framework of community to inform community integration efforts in the context of mental health services and recovery. Semi-structured interviews were conducted between November 2017 and September 2018 with 90 racially/ethnically diverse participants who were 18 years and older with an SMI and receiving community mental health services. Interviews were audio-recorded, transcribed, and analyzed using ResearchTalk's "Sort and Sift, Think and Shift" methodology. Themes derived from participants' definitions of community included a structural aspect of people and places; a functional aspect of socializing, helping and receiving resources; and an experiential aspect of shared struggles and experiences, finding safety, and identifying with others. To this end, we propose a Structural, Functional and Experiential (SFE) model of community. The SFE model of community provides a conceptual framework and guidance for clinicians, researchers, policy makers and service stakeholders regarding the complexity and variability of community for their consumers, which is essential to their recovery. Application of the SFE framework for assessment and intervention is discussed.

Social Networks, Community Integration and Recovery for Individuals with Severe Mental Illnesses in India and the U.S: A Comparative Study.

Community integration is central to recovery for individuals with severe mental illnesses (SMIs). However, cross-national research on community experiences of persons with SMIs is limited. Utilizing quantitative and social network data from a sample of individuals with SMIs, the current study (1) examined the social networks and experiences of community integration in India (n = 56) and (2) compared India and U.S. (n = 30) participants on social network characteristics, community integration, and psychosocial functioning. Results showed significant differences in demographic and psychosocial functioning between the samples. Regarding community integration, U.S. participants were more integrated into the mental health community than Indian participants. Differences in social networks revealed that Indian participants had significantly more family members and colleagues while U.S. participants had significantly more friends. Results suggest that caution be taken in generalizing mental health research cross-nationally and highlight the importance of sociocultural contexts of recovery and community integration of individuals with SMIs.

Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle.

Ceramide is a sphingolipid that serves as an important second messenger in an increasing number of stress-induced pathways. Ceramide has long been known to affect the mitochondria, altering both morphology and physiology. We sought to assess the impact of ceramide on skeletal muscle mitochondrial structure and function. A primary observation was the rapid and dramatic division of mitochondria in ceramide-treated cells. This effect is likely to be a result of increased Drp1 (dynamin-related protein 1) action, as ceramide increased Drp1 expression and Drp1 inhibition prevented ceramide-induced mitochondrial fission. Further, we found that ceramide treatment reduced mitochondrial O2 consumption (i.e. respiration) in cultured myotubes and permeabilized red gastrocnemius muscle fibre bundles. Ceramide treatment also increased H2O2 levels and reduced Akt/PKB (protein kinase B) phosphorylation in myotubes. However, inhibition of mitochondrial fission via Drp1 knockdown completely protected the myotubes and fibre bundles from ceramide-induced metabolic disruption, including maintained mitochondrial respiration, reduced H2O2 levels and unaffected insulin signalling. These data suggest that the forced and sustained mitochondrial fission that results from ceramide accrual may alter metabolic function in skeletal muscle, which is a prominent site not only of energy demand (via the mitochondria), but also of ceramide accrual with weight gain.

Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1.

Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies with poor prognosis and with no standard or effective treatment strategies. RTs are characterized by biallelic inactivation of the INI1 tumor suppressor gene. INI1 directly represses CCND1 and activates cyclin-dependent kinase (cdk) inhibitors p16(Ink4a) and p21(CIP). RTs are exquisitely dependent on cyclin D1 for genesis and survival. To facilitate translation of unique therapeutic strategies, we have used genetically engineered, Ini1(+/-) mice for therapeutic testing. We found that PET can be used to noninvasively and accurately detect primary tumors in Ini1(+/-) mice. In a PET-guided longitudinal study, we found that treating Ini1(+/-) mice bearing primary tumors with the pan-cdk inhibitor flavopiridol resulted in complete and stable regression of some tumors. Other tumors showed resistance to flavopiridol, and one of the resistant tumors overexpressed cyclin D1, more than flavopiridol-sensitive cells. The concentration of flavopiridol used was not sufficient to down-modulate the high level of cyclin D1 and failed to induce cell death in the resistant cells. Furthermore, FISH and PCR analyses indicated that there is aneuploidy and increased CCND1 copy number in resistant cells. These studies indicate that resistance to flavopiridol may be correlated to elevated cyclin D1 levels. Our studies also indicate that Ini1(+/-) mice are valuable tools for testing unique therapeutic strategies and for understanding mechanisms of drug resistance in tumors that arise owing to loss of Ini1, which is essential for developing effective treatment strategies against these aggressive tumors.

Alcohol Use and Physical Intimate Partner Violence Perpetration Among Black Men: The Moderating Effect of Interpersonal Social Support.

Studies have consistently shown an association between alcohol use in adulthood and intimate partner violence (IPV) perpetration. Yet, no known studies have examined this relationship when considering social support as a potential moderator with a sample of Black men. To address this gap in knowledge, we examined the moderating role of interpersonal social support on alcohol use in adulthood and physical IPV perpetration among Black men. Data for 1,127 Black men were obtained from the National Epidemiologic Survey of Alcohol and Related Condition (NESARC, Wave 2). Descriptive and logistic regression models were run with weighted data using STATA 16.0. Results from logistic regression analyses revealed that alcohol use in adulthood significantly predicted IPV perpetration (odds ratio [OR] = 1.18, p < .001). Interpersonal social support significantly moderated (OR = 1.01, p = .002) the relationship between alcohol use and IPV perpetration among Black men. Additionally, age, income, and perceived stress were significantly associated with IPV perpetration among Black men. Our study findings highlight the role of alcohol use and social support in exacerbating IPV perpetration among Black men, and the need for culturally responsive interventions to address these public health concerns throughout the life course.

Effects of Neighborhood Disconnection on Psychological Distress and Suicide Risk Associated with Interpersonal Violence Within Racial Groups.

Negative mental health outcomes have been associated with adverse childhood experiences (ACEs) and intimate partner violence (IPV); however, few studies have identified risk and protective factors across levels of the social ecology that mitigate the onset of psychological distress and suicide risk associated with trauma. This study examines the relationship between ACEs, IPV, and mental health (i.e., psychological distress, suicidal ideation, and suicide attempts) within racial sub-populations of Black American, Latinx, and White adults. An online, cross-section survey was administered to a general population sample of adults in Baltimore and New York City. ACEs, IPV, and mental health outcomes were assessed within racial sub-populations of Black American (N = 390), Latinx (N = 178), and White (N = 339) adults, while accounting for within-group demographic differences. Moderating effects of social support and neighborhood disconnection on the relationship between ACEs, IPV, and mental health outcomes were also assessed. IPV was associated with psychological distress and suicidal ideation for Black and Latinx adults, but not for White adults. ACEs were associated with increased psychological distress for all three groups, and increased odds for suicidal ideation among Black and Latinx adults.. A significant negative interaction effect for neighborhood disconnection was found in the relationship between ACEs and psychological distress for Black adults. Findings highlight the significant mental health burdens of ACEs and IPV within racial and ethnic groups. Neighborhood disconnection may exacerbate psychological distress associated with ACEs among populations most impacted by interpersonal violence and mental health inequalities.

The Influence of Adverse Childhood Experiences on Perpetration of Intimate Partner Violence Among Black Men: The Moderating Role of Alcohol Use.

This study examined the moderating role of alcohol use on the association between adverse childhood experiences (ACEs) and intimate partner violence (IPV) perpetration among Black men in the United States. We conducted bivariate and logistic regression analyses using data from Wave 2 of the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC). Bivariate results revealed significant relationships between eight of the 10 ACE factors physical neglect; emotional, physical and sexual abuse; witnessing a mother being abused; and having a parent guardian with an alcohol and drug problem and who was incarcerated and IPV perpetration. Similarly, examination of the relationship between ACEs and alcohol use in adulthood also revealed significant associations, with the exception of exposure to emotional neglect, emotional and sexual abuse, and witnessing a mother being abused. Findings from the logistic regression models revealed that alcohol use significantly moderated the relationship between ACEs and IPV perpetration, but only for men exposed to 1, 2, and ≥4 adversities in childhood. However, alcohol use appeared to exacerbate the relationship between ACEs and IPV perpetration for men without childhood adversity. Implications for practice, policy, and areas for further research are discussed.

Social work training to reduce duration of untreated psychosis: Methodology and considerations of a web-based training for community providers.

AIM: Outcomes for individuals with psychotic disorders can be improved through early intervention services; however, identification continues to be a major problem in connecting individuals with these services. Social workers form a vast majority of the human service and mental health workforce in the United States and therefore have the potential to play a unique role in identifying and referring those who may benefit from specialty early intervention services. METHODS: The current article describes the methodological design, implementation, and participant recruitment procedures of a large-scale, web-based training program for social workers promoting identification and referral of individuals with emerging symptoms of a mental illness with psychosis in the context of a randomized clinical trial. RESULTS: The web-based study enrolled 1384 individuals. More than half of study participants enrolled within the first 3 months of the 14-month recruitment period. Completion of all study components was achieved by 959 individuals (69% of total enrolled), and completion status did not vary significantly by gender, ethnicity, or facility at which the individual was employed. Completion rates varied by race, such that participants identifying as White were more likely to complete the study, while those identifying as Black were less likely. DISCUSSION: The results suggest the feasibility of using a web-based training program to engage social workers in early psychosis identification practices. Challenges related to encouraging participants to complete the training and lessons learned during the study recruitment are discussed.

In vitro activities of novel 4-HPR derivatives on a panel of rhabdoid and other tumor cell lines.

BACKGROUND: Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis. N-(4-hydroxy phenyl) retinamide (4-HPR or fenretinide) is a potential chemotherapeutic for RTs with activity correlated to its ability to down-modulate Cyclin D1. Previously, we synthesized novel halogen-substituted and peptidomimetic-derivatives of 4-HPR that retained activity in MON RT cells. Here we analyzed the effect of 4-HPR in inhibiting the growth of several RT, glioma, and breast cancer cell lines and tested their effect on cell cycle, apoptosis and Cyclin D1 expression. METHODS: Effect of compounds on RT cell cycle profiles, and cell death were assessed by MTS cell survival assays and FACS analysis. The effects of treatment on Cyclin D1 expression were determined by immunoblotting. The efficacy of these compounds on glioma and breast cancer cell lines was also determined using MTS assays. RESULTS: Low micromolar concentrations of 4-HPR derivatives inhibited cell survival of all RT cells tested. The 4-HPR derivatives altered RT cell cycle profiles and induced high levels of cell death that was correlated with their potency. ATRA exhibited high IC50 values in all cell lines tested and did not cause cell death. In MON RT cells, the iodo-substituted compounds were more active than 4-HPR in inducing cell cycle arrest and apoptosis. Additionally, the activity of the compounds correlated with their ability to down-modulate Cyclin D1: while active compounds reduced Cyclin D1 levels, inactive ATRA did not. In glioma and breast cancer cell lines, 4-HPR and 4-HPR derivatives showed variable efficacy. CONCLUSIONS: Here we demonstrate, for the first time, that the inhibitory activities of novel halogen-substituted and peptidomimetic derivatives of 4-HPR are correlated to their ability to induce cell death and down-modulate Cyclin D1. These 4-HPR derivatives showed varied potencies in breast cancer and glioma cell lines. These data indicate that further studies are warranted on these derivatives of 4-HPR due to their low IC50s in RT cells. These derivatives are of general interest, as conjugation of halogen radioisotopes such as 18F, 124I, or 131I to 4-HPR will allow us to combine chemotherapy and radiotherapy with a single drug, and to perform PET/SPECT imaging studies in the future.

Potent inhibition of rhabdoid tumor cells by combination of flavopiridol and 4OH-tamoxifen.

BACKGROUND: Rhabdoid Tumors (RTs) are highly aggressive pediatric malignancies with poor prognosis. There are currently no standard or effective treatments for RTs in part because treatments are not designed to specifically target these tumors. Our previous studies indicated that targeting the cyclin/cdk pathway is a novel therapeutic strategy for RTs and that a pan-cdk inhibitor, flavopiridol, inhibits RT growth. Since the toxicities and narrow window of activity associated with flavopiridol may limit its clinical use, we tested the effect of combining flavopiridol with 4-hydroxy-Tamoxifen (4OH-Tam) in order to reduce the concentration of flavopiridol needed for inhibition of RTs. METHODS: The effects of flavopiridol, 4OH-Tam, and their combination on RT cell cycle regulation and apoptosis were assessed by: i) cell survival assays, ii) FACS analysis, iii) caspase activity assays, and iv) immunoblot analysis. Furthermore, the role of p53 in flavopiridol- and 4OH-Tam-mediated induction of cell cycle arrest and apoptosis was characterized using RNA interference (siRNA) analysis. The effect of p53 on flavopiridol-mediated induction of caspases 2, 3, 8 and 9 was also determined. RESULTS: We found that the combination of flavopiridol and 4OH-Tam potently inhibited the growth of RT cells. Low nanomolar concentrations of flavopiridol induced G2 arrest, which was correlated to down-modulation of cyclin B1 and up-regulation of p53. Addition of 4OH-Tam did not affect flavopiridol-mediated G2 arrest, but enhanced caspase 3,7-mediated apoptosis induced by the drug. Abrogation of p53 by siRNA abolished flavopiridol-induced G2 arrest, but enhanced flavopiridol- (but not 4OH-Tam-) mediated apoptosis, by enhancing caspase 2 and 3 activities. CONCLUSIONS: Combining flavopiridol with 4OH-Tam potently inhibited the growth of RT cells by increasing the ability of either drug alone to induce caspases 2 and 3 thereby causing apoptosis. The potency of flavopiridol was enhanced by abrogation of p53. Our results warrant further studies investigating the combinatorial effects of flavopiridol and 4OH-Tam as a novel therapeutic strategy for RTs and other tumors that have been shown to respond to flavopiridol.

The impact of exposure to gun violence fatality on mental health outcomes in four urban U.S. settings.

RATIONALE: Given the widespread availability of firearms, high prevalence of gun violence in the U.S., and the intersection of race, cumulative violence and adverse mental health outcomes, it is important to understand the mental health consequences of exposure to gun violence fatality on racially/ethnically diverse secondary victims. OBJECTIVE: The aims of this study were to examine 1) the prevalence and demographic differences in exposure to gun violence fatality; 2) the associations between exposure and depression, psychological distress, suicidal ideation and psychosis-like experiences; and 3) the interaction between race and exposure in relation to depression, psychological distress, suicidal ideation and psychotic experiences. METHODS: Participants (n=1615) were adult community residents from Baltimore, New York, Philadelphia, and Washington, D.C, who participated in the online Survey of Police-Public Encounters. Chi-square, linear, and logistic regression were used to test study aims. RESULTS: Twenty-four percent of respondents reported exposure to gun violence fatality. Black, Latinx, younger, and those of lower income and education were disproportionately exposed. Exposed respondents had significantly higher levels of psychological distress, depression, suicidal ideation and/or psychotic experiences compared to those not exposed. There was a significantly stronger association between exposure and depression among Latinxs and "other" races relative to Whites. CONCLUSIONS: Findings suggest that vicarious exposure to gun violence fatality is widespread, disproportionately experienced by racial/ethnic minorities, and related to a higher prevalence of mental health symptoms. Implications of these findings are that clinicians should attend to the mental health needs of people vicariously exposed to gun violence fatality, and that gun violence reduction interventions may positively impact community-level mental health. Given that Blacks and Latinxs are disproportionately exposed to gun violence, a more extensive examination of exposure to gun violence fatality as a social determinant of mental health is warranted using longitudinal and nationally representative data.

Rhabdoid tumor growth is inhibited by flavopiridol.

PURPOSE: Rhabdoid tumors are aggressive and incurable pediatric malignancies. INI1/hSNF5, a tumor suppressor biallelically deleted/inactivated in rhabdoid tumors, directly represses cyclin D1. Rhabdoid tumors and cells are exquisitely dependent on cyclin D1 for genesis and survival, suggesting that targeting the cyclin/cyclin-dependent kinase (cdk) axis may be an effective therapeutic strategy for these tumors. Because cdk inhibitors have not been used for preclinical or clinical testing on rhabdoid tumors, we investigated the effect of flavopiridol, a pan-cdk inhibitor with promising clinical activity, on rhabdoid tumors. EXPERIMENTAL DESIGN: The effect of flavopiridol on rhabdoid cells was tested in vitro using survival, cell cycle, and apoptosis assays. Its effect was assessed in vivo using xenografted rhabdoid tumor models. Immunoblot and immunohistochemical analysis was used to assess the effect of flavopiridol on cyclin D1 and p21 expression in vitro and in vivo, respectively. RESULTS: Nanomolar concentrations of flavopiridol inhibited rhabdoid cell growth (IC(50) approximately 200 nmol/L), induced G(1) and G(2) arrest, and apoptosis in vitro in a concentration-dependent manner. These effects were correlated with the down-modulation of cyclin D1, up-regulation of p21, and induction of caspase 3/7 activities. Flavopiridol (at 7.5 mg/kg) significantly inhibited the growth of xenografted rhabdoid tumors, and its effect was correlated with the induction of p21 and down-modulation of cyclin D1. CONCLUSIONS: Flavopiridol is effective in inducing cell cycle arrest and cytotoxicity in rhabdoid tumors. Its effects are correlated with the down-regulation of cyclin D1 and the up-regulation of p21. Flavopiridol is potentially a novel chemotherapeutic agent for rhabdoid tumors.

Evidence for Differential Predictive Performance of the Prime Screen Between Black and White Help-Seeking Youths.

OBJECTIVE: Self-report screening instruments for emerging psychosis have the potential to improve early detection efforts by increasing the number of true positives among persons deemed to be at "clinical high risk" of the disorder, but their practical utility depends on their validity across race. This study sought to examine whether a commonly used self-report screening tool for psychosis risk performed equally among black and white youths in its ability to predict clinical high-risk status. METHODS: Black (N=58) and white (N=50) help-seeking individuals ages 12-25 (61% female) were assessed with the Prime Screen and the Structured Interview for Psychosis-Risk Syndromes (SIPS). A logistic regression model estimated race differences in the strength of the relation between Prime Screen scores and SIPS-defined risk status. RESULTS: Higher Prime Screen scores significantly predicted clinical high-risk status among white (p<.01) but not black participants. Among black youths without clinical high risk, self-reported Prime Screen scores more closely resembled scores for youths (black or white) with clinical high risk than scores of white peers who were also without clinical high risk. CONCLUSIONS: Results suggest that consideration of race or ethnicity and associated cultural factors is important when screening for clinical high-risk status. Findings support the need to develop culturally valid early psychosis screening tools to promote appropriately tailored early intervention efforts.

Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors.

Rhabdoid tumors (RTs) are an extremely aggressive pediatric malignancy that results from loss of the INI1/hSNF5 tumor suppressor gene. Loss of INI1 results in aberrant expression of Cyclin D1, which supports rhabdoid tumorigenesis and survival. 4-HPR, a synthetic retinoid that down-modulates Cyclin D1, has shown promise in treating various tumors including RTs. In this study, we have generated a chemical library of peptidomimetic derivatives of 4-HPR in an attempt to create a more biologically active compound for use as a therapeutic agent against RTs and other tumors. We have synthesized novel peptidomimetic compound by substituting alkene backbone with a ring structure that retains the biological activity in cell culture models of rhabdoid tumors. We further identified derivative of peptidomimetic compound (11d, IC(50) approximately 3 microM) with approximately five times higher potency than 4-HPR (1, IC(50) approximately 15 microM) based on a survival assay against rhabdoid tumor cells. These studies indicate that peptidomimetic derivatives that retain the cytotoxic activity are promising novel chemotherapeutic agents against RTs and other tumors.

Design and synthesis of 4-HPR derivatives for rhabdoid tumors.

Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis that arise due to loss of the hSNF5/INI1 tumor suppressor. Molecular studies indicate that cyclin D1, a downstream effector of INI1 is up regulated in RT, and is essential for this tumor formation. Previously we demonstrated that 4-HPR, a synthetic retinoid that targets Cyclin D1, is a potential chemotherapeutic agent for RT. To facilitate further chemical development of this retinoid, and to determine its active moiety, we synthesized small chemical libraries of 4-HPR and tested their cytotoxic effect on RT cells. We synthesized 4-HPR (1) and the derivatives (5a-5n) starting from retinoic acid. First, retinoic acid was converted to acid chloride derivatives, then in the presence of DMF, base, and aniline derivatives, we synthesized the corresponding 4-hydroxy phenyl amine derivatives (5a-5n). This procedure gave 70-90% yield. Then, the 4-HPR derivatives were tested for their ability to inhibit RT cells using an in vitro cell survival assay. We found that the 4-hydroxy group at para-position is essential for cytotoxic activity against RT cells. Furthermore, we identified a few derivatives of 4-HPR with higher cytotoxic potencies than 4-HPR. In addition, we demonstrate that either chloro, fluoro or iodo derivatives at meta-position of phenyl ring retain the cytotoxic activity. Interestingly, substitution of iodo-moiety at meta-position (5j) substantially increased the efficacy (IC(50) approximately 3muM, Fig. 1D). These results indicate that chemical modification of 4-HPR may result in derivatives with increased therapeutic potential for RTs and that halogen substituted 4-HPR that retain the activity can be synthesized for further therapeutic and diagnostic use.

AICAR inhibits ceramide biosynthesis in skeletal muscle.

BACKGROUND: The worldwide prevalence of obesity has lead to increased efforts to find therapies to treat obesity-related pathologies. Ceramide is a well-established mediator of several health problems that arise from adipose tissue expansion. The purpose of this study was to determine whether AICAR, an AMPK-activating drug, selectively reduces skeletal muscle ceramide synthesis. METHODS: Murine myotubes and rats were challenged with palmitate and high-fat diet, respectively, to induce ceramide accrual, in the absence or presence of AICAR. Transcript levels of the rate-limiting enzyme in ceramide biosynthesis, serine palmitoyltransferase 2 (SPT2) were measured, in addition to lipid analysis. Student's t-test and ANOVA were used to assess the association between outcomes and groups. RESULTS: Palmitate alone induced an increase in serine palmitoyltransferase 2 (SPT2) expression and an elevation of ceramide levels in myotubes. Co-incubation with palmitate and AICAR prevented both effects. However, ceramide and SPT2 increased with the addition of compound C, an AMPK inhibitor. In rats fed a high-fat diet (HFD), soleus SPT2 expression increased compared with normal chow-fed littermates. Moreover, rats on HFD that received daily AICAR injections had lower SPT2 levels and reduced muscle ceramide content compared with those on HFD only. CONCLUSIONS: These results suggest that AICAR reduces ceramide synthesis by targeting SPT2 transcription, likely via AMPK activation as AMPK inhibition prevented the AICAR-induced improvements. Given the role of skeletal muscle ceramide in insulin resistance, it is tempting to speculate that interventions that activate AMPK may lead to long-term ceramide reduction and improved metabolic function.