Childhood adversity and suicidal ideation in older Korean adults: unraveling the mediating mechanisms of mental health, physical health, and social relationships.

BACKGROUND: Suicide rates in older adults are much higher than those in younger age groups. Given the rapid increase in the proportion of older adults in Korea and the high suicide rate of this age group, it is worth investigating the mechanism of suicidal ideation for older adults. Generally, adverse childhood experiences are positively associated with suicidal ideation; however, it is not fully understood what mediating relationships are linked to the association between these experiences and current suicidal ideation. METHODS: The data from 685 older Korean adults were analyzed utilizing logistic regression, path analyses, and structural equation modeling. Based on our theoretical background and the empirical findings of previous research, we examined three separate models with mental health, physical health, and social relationship mediators. After that, we tested a combined model including all mediators. We also tested another combined model with mediation via mental health moderated by physical health and social relationships. RESULTS: The univariate logistic regression results indicated that childhood adversity was positively associated with suicidal ideation in older adults. However, multivariate logistic regression results demonstrated that the direct effect of childhood adversity became nonsignificant after accounting all variables. Three path models presented significant mediation by depression and social support in the association between childhood adversity and suicidal ideation. However, combined structural equation models demonstrated that only mediation by a latent variable of mental health problems was statistically significant. Social relationships moderated the path from mental health problems to suicidal ideation. CONCLUSIONS: Despite several limitations, this study has clinical implications for the development of effective strategies to mitigate suicidal ideation. In particular, effectively screening the exposure to adverse childhood experiences, early identification and treatment of depressive symptoms can play a crucial role in weakening the association between childhood adversity and suicidal ideation in older adults.

Comparison of Positive/Inconclusive Xpert Xpress SARS-CoV-2 with the Standard M nCoV Real-Time Detection.

BACKGROUND: COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can be diagnosed using rapid real-time PCR, real-time reverse transcription PCR (rRT-PCR), or rapid antigen testing. Among these, rRT-PCR is considered the gold standard assay. The Xpert Xpress SARS-CoV-2 assay is a rapid real-time PCR test, approved by the Korean Disease Control and Prevention Agency in 2020. The overall concordance and positive concordance rates of the Xpert assay with the STANDARD M nCoV Real-Time Detection kit were determined. METHODS: All samples with positive or inconclusive Xpert test results from July 2021 to February 2023 that underwent confirmatory testing using the reference rRT-PCR assay were included in the analysis. RESULTS: Samples from 224 patients (93 men and 131 women) with a median age of 59 years (range 15 - 90 years) were included. Of 212 samples that tested positive using Xpert, 112 (52.8%) were true positves and 100 (47.2%) were false positives on rRT-PCR testing. The overall concordance and positive concordance rates were 52.8% (112/212) and 54.5% (112/224), respectively. In the Xpert positive group, the samples had a lower Ct value for the E gene than the N2 gene. The Ct values for the E and N2 genes were significantly lower in the positive group than in the inconclusive group. CONCLUSIONS: Positive or inconclusive Xpert results should be confirmed by the gold standard rRT-PCR for early control of this disease. Furthermore, Korea's policy should be reconsidered given the high false-positive rate of the rapid real-time PCR Xpert Xpress SARS-CoV-2 assay.

Parent-to-child aggression, intimate partner aggression, conflict resolution, and children's social-emotional competence in early childhood.

Early childhood is critical to the development of children's social-emotional competence, which predicts peer relations and school adjustment in later periods of childhood. The effects of experiencing or witnessing aggression on children's social-emotional development are well known, yet the role of conflict resolution within the family has not been sufficiently studied. Social information processing models suggests that children who experience positive forms of conflict resolution within the family are likely to generalize these experiences and related skills outside the family, and thus develop greater social-emotional competence. In this longitudinal study, 128 parents (representing 79 families) participated in four quarterly telephone interviews in which they described aggressive conflicts that occurred in their family for which their children were present, including the degree to which each conflict was resolved. They also reported on the frequency of intimate partner aggression (IPA) and parent-to-child aggression (PCA) that occurred while the child was in toddlerhood and preschool as well as children's social-emotional competence at the end of the study. Multi-level models reveal that parents' reports of positive conflict resolution mitigated the concurrent and longitudinal negative effects of children's exposure to both IPA and PCA on their social-emotional competence. These findings reinforce prevention scientists' emphasis on conflict resolution skills as an essential component of parent education programs.

La primera infancia es fundamental para el desarrollo de la competencia socioemocional de los niños, la cual predice las relaciones entre pares y la adaptación escolar en periodos posteriores de la niñez. Se conocen muy bien los efectos que producen el sufrir o ser testigos de agresión en el desarrollo socioemocional de los niños, sin embargo, aún no se ha estudiado de manera suficiente el papel que desempeña la resolución de conflictos dentro de la familia. Los modelos de procesamiento de la información social sugieren que los niños que viven formas positivas de resolución de conflictos dentro de la familia son propensos a generalizar estas experiencias y las habilidades afines fuera de la familia y, por lo tanto, a desarrollar una mayor competencia socioemocional. En este estudio longitudinal, 128 padres (que representaban 79 familias) participaron en cuatro entrevistas telefónicas cada tres meses en las cuales describieron conflictos agresivos que hubo en su familia en los cuales sus hijos estuvieron presentes, incluido el grado en el cual se resolvió cada conflicto. También informaron la frecuencia de agresión en la pareja y de agresión de padres a hijos que tuvo lugar durante sus primeros años de vida y en la etapa del preescolar, así como la competencia socioemocional de los niños al final del estudio. Los modelos multinivel indican que los informes de los padres sobre la resolución positiva de los conflictos mitigaron los efectos negativos longitudinales y simultáneos de la exposición de los niños a la agresión en la pareja y a la agresión de padres a hijos en su competencia socioemocional. Estos resultados refuerzan el énfasis en las habilidades de resolución de conflictos de los científicos de la prevención como componente esencial de los programas de educación para padres.

Impact of the COVID-19 Pandemic on Parent, Child, and Family Functioning.

To quantify the impact of the COVID-19 pandemic and public health interventions on parent and child mental health and family relationships, we examined change in individual and family functioning in a sample of parents enrolled in a prevention trial; we examined change before the pandemic (2017-2019) when children were an average of 7 years old to the first months after the imposition of widespread public health interventions in the United States (2020) with paired t tests and HLM models. We examined moderation by parent gender, education, family income, and coparenting conflict. We found large deteriorations from before the pandemic to the first months of the pandemic in child internalizing and externalizing problems and parent depression, and a moderate decline in coparenting quality. Smaller changes were found for parent anxiety and parenting quality. Mothers and families with lower levels of income were at particular risk for deterioration in well-being. Results indicate a need for widespread family support and intervention to prevent potential family "scarring," that is, prolonged, intertwined individual mental health and family relationship problems.

Para cuantificar el efecto de la pandemia de la COVID-19 y de las intervenciones de salud pública en la salud mental de los padres y los niños y en las relaciones familiares, analizamos los cambios en el funcionamiento individual y familiar en una muestra de padres inscriptos en un ensayo de prevención; estudiamos el cambio antes de la pandemia (2017-2019) cuando los niños tenían un promedio de 7 años hasta los primeros meses después de la imposición de las intervenciones generalizadas de salud pública en los Estados Unidos (2020) con pruebas t apareadas y modelos lineales jerárquicos. Analizamos la moderación por género, educación, ingresos familiares y conflicto de cocrianza de los padres. Hallamos grandes deterioros desde antes de la pandemia hasta los primeros meses de la pandemia en problemas de interiorización y exteriorización de los niños y depresión de los padres, y una disminución moderada de la calidad de la cocrianza. También encontramos cambios más pequeños en la ansiedad de los padres y la calidad de la crianza. Las madres y las familias con niveles más bajos de ingresos estuvieron en riesgo particular de deterioro del bienestar. Los resultados indican la necesidad de apoyo familiar generalizado y de intervenciones para prevenir posibles «secuelas¼ familiares, p. ej.: salud mental individual interconectada y prolongada y problemas en las relaciones familiares.

Building long-term family resilience through universal prevention: 10-year parent and child outcomes during the COVID-19 pandemic.

As the COVID-19 pandemic has been highly stressful for parents and children, it is clear that strategies that promote long-term family resilience are needed to protect families in future crises. One such strategy, the Family Foundations program, is focused on promoting supportive coparenting at the transition to parenthood. In a randomized trial, we tested the long-term intervention effects of Family Foundations on parent, child, and family well-being one to two months after the imposition of a national shelter-in-place public health intervention in 2020. We used regression models to test intervention impact on outcomes reported on by parents in a standard questionnaire format and a series of 8 days of daily reports. We also tested moderation of intervention impact by parent depression and coparenting relationship quality. Relative to control families, intervention families demonstrated significantly lower levels of individual and family problems (general parent hostility, harsh and aggressive parenting, coparenting conflict, sibling relationship conflict, and children's negative mood and behavior problems), and higher levels of positive family relationship quality (positive parenting, couple relationship quality, sibling relations, and family cohesion). For some outcomes, including coparenting conflict, harsh parenting, and child behavior problems, intervention effects were larger for more vulnerable families-that is, families with higher pre-pandemic levels of parent depression or lower levels of coparenting relationship quality. We conclude that targeted family prevention programming is able to promote healthy parent and child functioning during unforeseen future periods of acute stress. The long-term benefits of a universal approach to family support at the transition to parenthood indicate the need for greater investment in the dissemination of effective approaches.

Dado que la pandemia de COVID-19 ha sido muy estresante para padres e hijos, está claro que se necesitan estrategias que promuevan la resiliencia familiar a largo plazo para proteger a las familias en crisis futuras. Una de esas estrategias, el programa Family Foundations, se centra en promover la crianza compartida de apoyo en la transición a la paternidad. En un ensayo aleatorizado, probamos los efectos de la intervención a largo plazo de Family Foundations en el bienestar de los padres, el niño y la familia uno o dos meses después de la imposición de una intervención nacional de salud pública de refugio en el lugar en 2020. Usamos modelos de regresión para evaluar el impacto de la intervención en los resultados informados por los padres en un formato de cuestionario estándar y una serie de 8 días de informes diarios. También probamos la moderación del impacto de la intervención por la depresión de los padres y la calidad de la relación de coparentalidad. En relación con las familias de control, las familias de intervención demostraron niveles significativamente más bajos de problemas individuales y familiares (hostilidad general de los padres, crianza dura y agresiva, conflicto de crianza conjunta, conflicto de relaciones entre hermanos y problemas de comportamiento y estado de ánimo negativos de los niños) y niveles más altos de calidad de relación familiar positiva (crianza positiva, calidad de la relación de pareja, relaciones entre hermanos y cohesión familiar). Para algunos resultados, incluido el conflicto de crianza compartida, la crianza severa y los problemas de comportamiento infantil, los efectos de la intervención fueron mayores para las familias más vulnerables, es decir, familias con niveles más altos de depresión de los padres prepandémicos o niveles más bajos de calidad de la relación de crianza compartida. Concluimos que los programas de prevención familiar específicos pueden promover el funcionamiento saludable de padres e hijos durante períodos futuros imprevistos de estrés agudo. Los beneficios a largo plazo de un enfoque universal del apoyo familiar en la transición a la paternidad indican la necesidad de una mayor inversión en la difusión de enfoques eficaces.

Serotonergic sensitivity alleles moderate relations between attachment security at age three and socioemotional competence at age five.

Children with higher socioemotional competence are more likely to build constructive relationships with others and experience more positive adjustment outcomes in later periods. Securely attached children are likely to develop better socioemotional competence, but genetic moderation of associations between attachment and later socioemotional competence has received less attention. Using structural equation modeling, this study analyzed data collected from 1,337 children (51% male) born from 1998 to 2000 in the Fragile Families and Child Wellbeing study. The results demonstrated that relations between attachment security at age 3 years and their social competence at age 5 years differed by two serotonin transporter variants (5-HTTLPR, STin2). Effect sizes of these interactions were larger than effect sizes of main effects and the benefit of having sensitive alleles was consistently supported. This implies that having more secure attachment in the early developmental period is advantageous especially for children with minor alleles who have greater environmental sensitivity.

Coparenting Intervention for Expectant Parents Affects Relationship Quality: A Pilot Study.

Research has shown that the transition to parenthood is a particularly challenging period of life which is often associated with a decline in relationship quality and an increase in mental health problems. Emerging parents often experience difficulties in coping with new tasks and challenges in the relationship, resulting in inadequate mutual support, stress, conflicts and even depressive symptoms. To support expectant parents in establishing an effective and strong coparenting alliance, we have employed an educational coparenting intervention to teach important coparenting skills. The intervention was a non-randomized case-control study with 126 expectant parents. The intervention group participated in a five-session intervention, whereas the control group received an information booklet and had an optional meeting postpartum. The purpose of this study was to ease the transition to parenthood in order to prevent postpartum conflict and depression. Parents in the intervention group (n = 34 couples) showed significantly fewer conflicts postpartum than before (Z = -3.28, p = 0.00), and scored better in postnatal delegated dyadic coping (ß = 0.25, p = 0.00, R2 = 0.32), a form of mutual support. Neither the intervention group (Z = -0.83, p = 0.40) nor the control group (Z = -0.86, p = 0.38) showed a significant increase in depression scores after childbirth. Although conflicts during the transition to parenthood declined and postnatal delegated dyadic coping strengthened, the study design does not allow to draw conclusion on group effects. Nevertheless, the promising results of this pilot intervention are a base for future studies.

Osmunda japonica Extract Suppresses Pro-Inflammatory Cytokines by Downregulating NF-κB Activation in Periodontal Ligament Fibroblasts Infected with Oral Pathogenic Bacteria.

Periodontal diseases are caused by bacterial infection and may progress to chronic dental disease; severe inflammation may result in bone loss. Therefore, it is necessary to prevent bacterial infection or control inflammation. Periodontal ligament fibroblasts (PDLFs) are responsible for the maintenance of tissue integrity and immune and inflammatory events in periodontal diseases. The formation of bacterial complexes by Fusobacterium nucleatum and Porphyromonas gingivalis is crucial in the pathogenesis of periodontal disease. F. nucleatum is a facultative anaerobic species, considered to be a key mediator of dental plaque maturation and aggregation of other oral bacteria. P. gingivalis is an obligate anaerobic species that induces gingival inflammation by secreting virulence factors. In this study, we investigated whether Osmunda japonica extract exerted anti-inflammatory effects in primary PDLFs stimulated by oral pathogens. PDLFs were stimulated with F. nucleatum or P. gingivalis. We showed that pro-inflammatory cytokine (IL-6 and IL-8) expression was induced by LPS or bacterial infection but decreased by treatment with O. japonica extract following bacterial infection. We found that the activation of NF-κB, a transcription factor for pro-inflammatory cytokines, was modulated by O. japonica extract. Thus, O. japonica extract has immunomodulatory activity that can be harnessed to control inflammation.

N-[2-(4-Acetyl-1-Piperazinyl)Phenyl]-2-(3-Methylphenoxy)Acetamide (NAPMA) Inhibits Osteoclast Differentiation and Protects against Ovariectomy-Induced Osteoporosis.

Osteoclasts are large, multinucleated cells responsible for bone resorption and are induced in response to the regulatory activity of receptor activator of nuclear factor-kappa B ligand (RANKL). Excessive osteoclast activity causes pathological bone loss and destruction. Many studies have investigated molecules that specifically inhibit osteoclast activity by blocking RANKL signaling or bone resorption. In recent years, we screened compounds from commercial libraries to identify molecules capable of inhibiting RANKL-induced osteoclast differentiation. Consequently, we reported some compounds that are effective at attenuating osteoclast activity. In this study, we found that N-[2-(4-acetyl-1-piperazinyl)phenyl]-2-(3-methylphenoxy)acetamide (NAPMA) significantly inhibited the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells from bone marrow-derived macrophages in a dose-dependent manner, without cytotoxic effects. NAPMA downregulated the expression of osteoclast-specific markers, such as c-Fos, NFATc1, DC-STAMP, cathepsin K, and MMP-9, at the transcript and protein levels. Accordingly, bone resorption and actin ring formation were decreased in response to NAPMA treatment. Furthermore, we demonstrated the protective effect of NAPMA against ovariectomy-induced bone loss using micro-CT and histological analysis. Collectively, the results showed that NAPMA inhibited osteoclast differentiation and attenuated bone resorption. It is thus a potential drug candidate for the treatment of osteoporosis and other bone diseases associated with excessive bone resorption.

Bidirectional Associations between Youth Adjustment and Mothers' and Fathers' Coparenting Conflict.

Research demonstrates significant associations between coparenting conflict and child adjustment problems. However, the implications of youth adjustment for coparenting, especially during youth's adolescence, remain poorly understood. Addressing several gaps in the literature, this study examines the longitudinal trajectory of mothers' and fathers' reported coparenting conflict from youth ages 10-17 and tests bidirectional associations between youth social anxiety, hostility, risk-taking behaviors, and mothers' and fathers' coparenting conflict. Participants include 757 mothers, fathers, and youth in two-parent families (M youth age = 11.28, SD = 0.49; 53% female) who participated in 5 waves of data collection when youth were in the 6th to 9th grades. Multilevel growth curve models revealed significant non-linear change in mothers' and fathers' coparenting conflict, such that coparenting conflict declined through youth's transition to adolescence, leveled off in early adolescence, and declined in the mid-late adolescent years. Cross-lagged models showed significant positive associations between youth social anxiety and hostility and coparenting conflict at the following time point, but coparenting conflict did not predict later youth adjustment problems in these domains. There were significant bidirectional associations between mother-reported coparenting conflict and youth risk-taking behaviors; the associations between coparenting conflict and risk-taking were not significant for fathers. The findings demonstrate that investigating longitudinal associations between youth adjustment and coparenting conflict may provide new insights into the role of child effects for mothers' and fathers' coparenting experiences.

Advancing Research and Measurement on Fathering and Child Development.

Fathers are more than social accidents. Research has demonstrated that fathers matter to children's development. Despite noted progress, challenges remain on how best to conceptualize and assess fathering and father-child relationships. The current monograph is the result of an SRCD-sponsored meeting of fatherhood scholars brought together to discuss these challenges and make recommendations for best practices for incorporating fathers in studies on parenting and children's development. The first aim of this monograph was to provide a brief update on the current state of research on fathering and to lay out a developmental ecological systems perspective as a conceptual framework for understanding the different spaces fathers inhabit in their children's lives. Because there is wide variability in fathers' roles, the ecological systems perspective situates fathers, mothers, children, and other caregivers within an evolving network of interrelated social relationships in which children and their parents change over time and space (e.g., residence). The second aim was to present examples of empirical studies conducted by members of the international working group that highlighted different methods, data collection, and statistical analyses used to capture the variability in father-child relationships. The monograph ends with a commentary that elaborates on the ecological systems framework with a discussion of the broader macrosystem and social-contextual influences that impinge on fathers and their children. The collection of articles contributes to research on father-child relationships by advancing theory and presenting varied methods and analysis strategies that assist in understanding the father-child relationship and its impact on child development.

Inhibitory Effects of N-[2-(4-acetyl-1-piperazinyl) phenyl]-2-(2-chlorophenoxy) acetamide on Osteoclast Differentiation In Vitro via the Downregulation of TRAF6.

Osteoclasts are poly-nuclear cells that resorb mineral components from old or damaged bone tissue. Primary mononuclear cells are activated by receptor activator of nuclear factor kappa-Β ligand (RANKL) and differentiate into large multinucleated cells. Dysregulation of osteoclast differentiation can lead to pathological bone loss and destruction. Many studies have focused on the development of new molecules to regulate RANKL-mediated signaling. In this study, N-[2-(4-acetyl-1-piperazinyl)phenyl]-2-(2-chlorophenoxy) acetamide (PPOA-N-Ac-2-Cl) led to a significant decrease in the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells in a dose-dependent manner, without inducing significant cytotoxicity. PPOA-N-Ac-2-Cl affected the expression of osteoclast-specific marker genes, such as TRAF6, c-fos, DC-STAMP, NFATc1, MMP9, CtsK, and TRAP (Acp5), during RANKL-mediated osteoclastogenesis. Moreover, PPOA-N-Ac-2-Cl significantly attenuated the protein levels of CtsK, a critical protease involved in bone resorption. Accordingly, bone resorption activity and F-actin ring formation decreased in the presence of PPOA-N-Ac-2-Cl. In conclusion, this study shows that PPOA-N-Ac-2-Cl acts as an inhibitor of osteoclast differentiation and may serve as a potential candidate agent for the treatment of osteoclast-related bone diseases by virtue of attenuating bone resorption.

PSTP-3,5-Me Inhibits Osteoclast Differentiation and Bone Resorption.

Osteogenesis is an orchestrated process regulated by osteoclastogenesis and osteoblastogenesis. Excessive osteoclastogenesis causes bone diseases, such as osteoporosis. Although a few drugs are effective in osteoporosis treatment, these drugs lead to side effects, including cellulitis, flatulence, and hypocalcemia. In this study, we reported a 2-(N-Phenylmethylsulfonamido)-N-(2-(phenylthio)phenyl)propanamide (PSTP) compound, PSTP-3,5-Me, as a potential therapeutic agent for osteoporosis. Mouse bone marrow-derived macrophages (BMMs) were differentiated into osteoclasts by receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of PSTP-3,5-Me. PSTP-3,5-Me inhibited osteoclast differentiation by reduced tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and suppressed the expression of osteoclast marker genes, such as cathepsin K (Ctsk) and TRAP (Acp5). We investigated signaling pathways mediated by RANKL and its receptor, RANK, and found that PSTP-3,5-Me inhibits nucleus translocation of nuclear factor of activated T cell cytoplasmic-1 (NFATc1). Moreover, PSTP-3,5-Me inhibited F-actin ring formation and mineral resorption. Overall, our data suggests that PSTP-3,5-Me attenuates osteoclast differentiation by blocking the activation of NFATc1.

Preparation of Herbal Formulation for Inflammatory Bowel Disease Based on In Vitro Screening and In Vivo Evaluation in a Mouse Model of Experimental Colitis.

Many medicinal plants have been used traditionally in East Asia for the treatment of gastrointestinal disease and inflammation. The aim of this study was to evaluate the anti-inflammatory activity of 350 extracts (175 water extracts and 175 ethanol extracts) from 71 single plants, 97 mixtures of two plants, and seven formulations based on traditional medicine, to find herbal formulations to treat inflammatory bowel disease (IBD). In the in vitro screening, nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels were determined in LPS-treated RAW264.7 cells and the TNF-α induced monocyte-epithelial cell adhesion assay was used for the evaluation of the anti-inflammatory activity of the compounds. Dextran sulfate sodium (DSS)-induced colitis model and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model were used to evaluate the therapeutic effect against IBD of the samples selected from the in vitro screening. KM1608, composed of Zingiber officinale, Terminalia chebula and Aucklandia lappa, was prepared based on the screening experiments. The oral administration of KM1608 significantly attenuated the severity of colitis symptoms, such as weight loss, diarrhea, and rectal bleeding, in TNBS-induced colitis. In addition, inflammatory mediators, such as myeloperoxidase, TNF-α, and IL-6 levels decreased in the lysate of colon tissues treated with KM1608. Collectively, KM1608 ameliorated colitis through the regulation of inflammatory responses within the colon, which indicated that KM1608 had potential for the treatment of IBD.

BCPA {N,N'-1,4-Butanediylbis[3-(2-chlorophenyl)acrylamide]} Inhibits Osteoclast Differentiation through Increased Retention of Peptidyl-Prolyl cis-trans Isomerase Never in Mitosis A-Interacting 1.

Osteoporosis is caused by an imbalance of osteoclast and osteoblast activities and it is characterized by enhanced osteoclast formation and function. Peptidyl-prolyl cis-trans isomerase never in mitosis A (NIMA)-interacting 1 (Pin1) is a key mediator of osteoclast cell-cell fusion via suppression of the dendritic cell-specific transmembrane protein (DC-STAMP). We found that N,N'-1,4-butanediylbis[3-(2-chlorophenyl)acrylamide] (BCPA) inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in a dose-dependent manner without cytotoxicity. In addition, BCPA attenuated the reduction of Pin1 protein during osteoclast differentiation without changing Pin1 mRNA levels. BCPA repressed the expression of osteoclast-related genes, such as DC-STAMP and osteoclast-associated receptor (OSCAR), without altering the mRNA expression of nuclear factor of activated T cells (NFATc1) and cellular oncogene fos (c-Fos). Furthermore, Tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells were significantly decreased by BCPA treatment compared to treatment with the Pin1 inhibitor juglone. These data suggest that BCPA can inhibit osteoclastogenesis by regulating the expression of the DC-STAMP osteoclast fusion protein by attenuating Pin1 reduction. Therefore, BCPA may be used to treat osteoporosis.

DPIE [2-(1,2-diphenyl-1H-indol-3-yl)ethanamine] Augments Pro-Inflammatory Cytokine Production in IL-1ß-Stimulated Primary Human Oral Cells.

Interleukin-1β (IL-1β) is a prominent pro-inflammatory cytokine that is implicated in a variety of autoimmune diseases and plays an important role in host defense against infections. IL-1β activity increases with its increasing binding capacity to IL-1 receptors (IL-1Rs). Thus, numerous studies have targeted the discovery of molecules modulating the interactions between IL-1β and IL-1R1. We have conducted an IL-1R1 structure-based virtual screening to identify small molecules that could alter IL-1β activity, using in silico computational analysis. Sixty compounds from commercial libraries were predicted to bind to IL-1R1, and their influence on cytokine production in IL-1β-stimulated gingival fibroblasts (GFs) was determined. Of these, only (2-(1,2-diphenyl-1H-indol-3-yl)ethanamine (DPIE) showed a synergistic increase in inflammatory molecules and cytokine production (IL-6, IL-8, and COX-2) at both mRNA and protein levels in IL-1β-stimulated GFs. The enhancing activity of DPIE in IL-1β-induced cytokine production increased in a dose-dependent manner without cytotoxicity. This pattern was also observed in IL-1β-stimulated primary human periodontal ligament cells (PDLs). Furthermore, we measured the impact of DPIE on the IL-1β⁻IL-1R1 system using surface plasmon resonance and demonstrated that DPIE increased the binding affinity of IL-1β to IL-1R1. These data indicate that DPIE boosts IL-1β signaling by enhancing the binding of IL-1β to IL-1R1 in oral primary cells.

Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-N-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression.

Osteoclasts are large multinucleated cells which are induced by the regulation of the receptor activator of nuclear factor kappa-Β ligand (RANKL), which is important in bone resorption. Excessive osteoclast differentiation can cause pathologic bone loss and destruction. Numerous studies have targeted molecules inhibiting RANKL signaling or bone resorption activity. In this study, 11 compounds from commercial libraries were examined for their effect on RANKL-induced osteoclast differentiation. Of these compounds, only 2-(3-(2-fluoro-4-methoxyphenyl)-6-oxo-1(6H)-pyridazinyl)-N-1H-indol-5-ylacetamide (2N1HIA) caused a significant decrease in multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cell formation in a dose-dependent manner, without inducing cytotoxicity. The 2N1HIA compound neither affected the expression of osteoclast-specific gene markers such as TRAF6, NFATc1, RANK, OC-STAMP, and DC-STAMP, nor the RANKL signaling pathways, including p38, ERK, JNK, and NF-κB. However, 2N1HIA exhibited a significant impact on the expression levels of CD47 and cathepsin K, the early fusion marker and critical protease for bone resorption, respectively. The activity of matrix metalloprotease-9 (MMP-9) decreased due to 2N1HIA treatment. Accordingly, bone resorption activity and actin ring formation decreased in the presence of 2N1HIA. Taken together, 2N1HIA acts as an inhibitor of osteoclast differentiation by attenuating bone resorption activity and may serve as a potential candidate in preventing and/or treating osteoporosis, or other bone diseases associated with excessive bone resorption.

Cascade Polymerization via Controlled Tandem Olefin Metathesis/Metallotropic 1,3-Shift Reactions for the Synthesis of Fully Conjugated Polyenynes.

We demonstrate the first example of cascade polymerization by combining olefin metathesis and metallotropic 1,3-shift reactions to form unique conjugated polyenynes. Rational design of monomers enabled controlled polymerization, and kinetic investigation of the polymerization mechanism was conducted.

Diversity-Oriented Polymerization: One-Shot Synthesis of Library of Graft and Dendronized Polymers by Cu-Catalyzed Multicomponent Polymerization.

Graft and dendronized polymers have attracted much attention in the polymer community, and there have been significant efforts to develop better synthetic methods. Herein, we report the highly efficient synthesis of graft and dendronized polymers by using Cu-catalyzed multicomponent polymerization (MCP). Based on diversity-oriented synthesis, we prepared a library of various graft and dendronized polymers from combinations of three types of monomers (mono-functionalized alkynes, bis-sulfonyl azides, and diamines/diols) that are bench stable and readily accessible. After reaction optimization, 54 samples of high-molecular-weight graft and dendronized polymers were prepared, the MCP method allowing simultaneous manipulation of the structures of both the main chains and the side chains. Moreover, because of the severe steric hindrance of the side chains, these polymers adopted extended conformations, as shown by the large shape parameter in solution. Also, the extended morphology of the single polymer chains was directly visualized by atomic force microscopy and transmission electron microscopy in the solid state. Most importantly, this diversity-oriented polymerization became possible because of highly step-economical and efficient one-step MCP, paving the way toward the easily tunable synthesis of graft and dendronized polymers.

Bcl-2 is a highly significant prognostic marker of hormone-receptor-positive, human epidermal growth factor receptor-2-negative breast cancer.

B-cell lymphoma-2 (Bcl-2) is one of the most important anti-apoptotic genes. Although Bcl-2 promotes tumor cell survival in vitro, previous studies have shown conflicting results regarding the association between Bcl-2 and breast cancer survival. The aim of this study was to assess the prognostic significance of Bcl-2 according to the molecular tumor subtype in primary invasive breast cancer patients. The relationship between immunohistochemical Bcl-2 expression and overall survival was analyzed in 2399 primary invasive breast cancer patients treated by curative surgery. Patients were classified into four subtypes based on hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status: HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. A total of 1304 patients (54.4 %) had Bcl-2 positive (+) tumors by immunohistochemistry. Bcl-2 (+) tumors were significantly associated with a younger age (<50 years), early stage, lower grade, positive expression of HR, and negative expression of HER2. In the HR+/HER2- group, patients with Bcl-2 (+) tumors showed a significantly better prognosis (p < 0.001). In contrast, there was no significant prognostic effect of Bcl-2 expression in other subtypes. In multivariate analysis, Bcl-2 positivity remained an independent, favorable prognostic factor in the HR+/HER2- subtype (hazard ratio, 0.609; 95 % confidence interval, 0.424-0.874; p < 0.007). The prognostic significance of Bcl-2 expression differed according to the molecular subtype of breast cancer. The expression of Bcl-2 was an independent, favorable prognostic factor in breast cancer patients with the HR+/HER2- subtype.