PKCα-LSD1-NF-κB-Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response.

The inflammatory response mediated by nuclear factor κB (NF-κB) signaling is essential for host defense against pathogens. Although the regulatory mechanism of NF-κB signaling has been well studied, the molecular basis for epigenetic regulation of the inflammatory response is poorly understood. Here we identify a new signaling axis of PKCα-LSD1-NF-κB, which is critical for activation and amplification of the inflammatory response. In response to excessive inflammatory stimuli, PKCα translocates to the nucleus and phosphorylates LSD1. LSD1 phosphorylation is required for p65 binding and facilitates p65 demethylation, leading to enhanced stability. In vivo genetic analysis using Lsd1SA/SA mice with ablation of LSD1 phosphorylation and chemical approaches in wild-type mice with inhibition of PKCα or LSD1 activity show attenuated sepsis-induced inflammatory lung injury and mortality. Together, we demonstrate that the PKCα-LSD1-NF-κB signaling cascade is crucial for epigenetic control of the inflammatory response, and targeting this signaling could be a powerful therapeutic strategy for systemic inflammatory diseases, including sepsis.

A comparison of factors associated with unmet healthcare needs in people with disabilities before and after COVID-19: a nationally representative population-based study.

BACKGROUND: People with disabilities, who require numerous healthcare services, are vulnerable to unmet healthcare needs. This study aimed to investigate and identify the factors that influence unmet healthcare needs among people with disabilities and to compare these factors before and after the COVID-19 pandemic in South Korea. METHODS: A propensity score matching analysis was conducted using two datasets from the National Survey of Disabled Persons collected in 2017 and 2020. The participants were matched based on variables known to influence healthcare utilization. Based on the Andersen model, logistic regression was performed to analyze the key characteristics of the factors associated with unmet healthcare needs, including predisposing, enabling, and need factors. RESULTS: Propensity score matching resulted in the inclusion of 1,884 participants in each group: an experimental group and control group. Before COVID-19, factors associated with unmet healthcare needs included sex, age, marital status, and education level (predisposing factors), instrumental activities of daily living dependency, satisfaction with medical staff's understanding of disability, satisfaction with medical institutional facilities and equipment (enabling factors), subjective health status, and depressive symptoms (need factors). After COVID-19, factors included physical disability, instrumental activities of daily living dependency, and discrimination (enabling factors), and subjective health status, chronic diseases, depressive symptoms, and regular medical care (need factors). No significant predisposing factors affecting unmet healthcare needs were identified after COVID-19. CONCLUSIONS: This study compared the factors affecting unmet healthcare needs among people with disabilities before and after COVID-19. Recognizing the different factors associated with unmet healthcare needs before and after COVID-19, (e.g., sex, type of disability, satisfaction with medical staff's understanding of disabilities, medical institutional facilities and equipment considering the disabled, discrimination, chronic diseases, and regular medical care) may help governments and policymakers establish strategies to reduce and prevent unmet healthcare needs during and a future crisis.

A mixed-method systematic literature review of health literacy interventions for people with disabilities.

AIMS: To identify the components and characteristics of health literacy interventions for people with disabilities and to explore the outcomes in terms of health literacy competencies. DESIGN: A mixed-method systematic literature review. REVIEW METHODS: The search results were reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The quality appraisal was guided by the Mixed Methods Appraisal Tool. The contents of each intervention were mapped to the health literacy intervention model and the outcomes were annotated using the integrated model of health literacy. DATA SOURCES: The literature search was conducted using several electronic databases, including PubMed, EMBASE, CINAHL, Cochrane library and PsycINFO in December 2022. RESULTS: Ten studies were selected for this systematic literature review. Seven studies were quantitative, two were qualitative and one was a mixed-methods study. The four components of the health literacy interventions included empowering individuals with low-health literacy (n = 10), strengthening individuals' social support system (n = 3), improving communication with health professionals (n = 1) and reducing barriers to access health systems (n = 3). No intervention addressed improving health professionals' health literacy competencies. Health literacy competencies identified as outcomes in the studies included access (n = 1), understand (n = 7), appraise (n = 1) and apply (n = 9) the health information. CONCLUSIONS: The significant findings of this systematic literature review provide baseline data and evidence for developing health literacy interventions for people with disabilities. However, this review demonstrates that only a handful of intervention studies have addressed the low-health literacy of people with disabilities. Further and more rigorous interventions addressing health literacy for people with diverse disabilities are warranted. IMPACT: This review provides insights into how health literacy interventions can be tailored to the type of disability. Further, efforts should be expanded to comprehensively promote all the four core competencies of health literacy to reduce health disparities for individuals living with disabilities. NO PATIENT OR PUBLIC CONTRIBUTION: Systematic literature review.

Structure-activity relationship analysis of novel GSPT1 degraders based on benzotriazinone scaffold and its antitumor effect on xenograft mouse model.

Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC50 = 0.5 nM) and TMD-8 (EC50 = 5.2 nM) cell lines. Compound 34f effectively induced GSPT1 degradation with a DC50 of 0.269 nM and Dmax of >95 % at 10 nM concentration in KG-1 cells. An in vivo xenograft study showed that compound 34f effectively suppressed TMD8-driven tumor growth, suggesting a potential role in the development of novel GSPT1 degraders.

Phosphorylation of LSD1 by PKCα is crucial for circadian rhythmicity and phase resetting.

The circadian clock is a self-sustaining oscillator that controls daily rhythms. For the proper circadian gene expression, dynamic changes in chromatin structure are important. Although chromatin modifiers have been shown to play a role in circadian gene expression, the in vivo role of circadian signal-modulated chromatin modifiers at an organism level remains to be elucidated. Here, we provide evidence that the lysine-specific demethylase 1 (LSD1) is phosphorylated by protein kinase Cα (PKCα) in a circadian manner and the phosphorylated LSD1 forms a complex with CLOCK:BMAL1 to facilitate E-box-mediated transcriptional activation. Knockin mice bearing phosphorylation-defective Lsd1(SA/SA) alleles exhibited altered circadian rhythms in locomotor behavior with attenuation of rhythmic expression of core clock genes and impaired phase resetting of circadian clock. These data demonstrate that LSD1 is a key component of the molecular circadian oscillator, which plays a pivotal role in rhythmicity and phase resetting of the circadian clock.

Factors and at-risk group associated with hypertension self-management patterns among people with physical disabilities: a latent class analysis.

BACKGROUND: People with disabilities are vulnerable to chronic diseases such as hypertension. In South Korea, over half of the population living with a physical disability suffer from hypertension. Understanding the typology of hypertension self-management patterns will assist with behavioural interventions for people with physical disabilities. Thus, this study aims to identify the typology of hypertension self-management behavioural patterns, the factors associated with the latent classes, and to recognise potential at-risk populations by comparing potential health outcomes among hypertensive adults with physical disabilities. METHODS: Data of 1551 participants were extracted from the 2017 National Survey of Disabled Persons. Latent classes were analysed using five indicators of self-management: smoking, alcohol consumption, physical activity, diet, and weight control. Determinants of self-management patterns, such as general characteristics, health-related factors, and social relationships, were identified using multinomial logistic regression. Further, health measures, such as health profile, psychological health, and patient experience, were compared. RESULTS: The following three latent classes were identified: "high self-management" group (40.8%), "harmful habitual behaviour" group (20.6%), and "inactive behaviour" group (38.6%). Compared with the high self-management group, the predictors of belonging to the harmful habitual behaviour group were being male, young, and single. Being female, employed, severely disabled, dependent, and unsatisfied with friendships were predictors of the inactive behaviour group. Those in the inactive behaviour group had a poor health-related quality of life, poor subjective health, depression, and unmet medical needs. CONCLUSIONS: This study provides evidence that there are mutually exclusive subgroups of patients with hypertension regarding self-management patterns, identifies an array of predictive factors in each latent class membership, and distinguishes a high-risk group by comparing the health measures among patients with hypertension with physical disabilities. Analysing subgroups may assist in identifying and meeting the diverse needs of self-management support in hypertensive patients with physical disabilities.

The life experiences of living liver donors: A qualitative meta-synthesis.

As living liver transplantation has become a standard treatment method with a high success rate, many studies have investigated the experiences of living liver donors; however, their results have not been integrated. This qualitative meta-synthesis aimed to explore the life experiences of living liver donors to provide an in-depth understanding of meaningful common experiences. A comprehensive search on qualitative studies published in English or Korean was conducted in October 2021. The PRISMA statement was used for reporting each phase of the literature search, and MAXQDA2020 software was used for data analysis. Data synthesis was conducted using the three-step thematic synthesis method suggested by Thomas and Harden. Ten articles met the inclusion criteria. The analysis revealed five main themes: "Becoming an earnest donor," "Transitioning from a potential donor to an actual donor," "Difficulties in returning to normal life," "Re-examining the meaning of donation," and "Wishes for prospective donors." The study emphasizes that living liver donors need medical attention and intervention from multilateral perspectives as well as the need for systematic change in the society to enhance support for donors. This review provides comprehensive insights on how individuals became the living liver donor and the important aspects of living donation and other considerations in an integrated manner. Transplant teams, including nurses and coordinators, should have a comprehensive understanding of physical, psychological, and social experiences of donors ranging from decision-making to post donation health management.

PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them.

PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40-70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.

Epigenetic Regulation in Breast Cancer.

Aberrant epigenetic alteration has been associated with development of various cancers, including breast cancer. Since epigenetic modifications such as DNA methylation and histone modification are reversible, epigenetic enzymes, including histone modifying enzymes and DNA methyltransferases, emerge as attractive targets for cancer therapy. Although epi-drugs targeting histone deacetylation or DNA methylation have received FDA approval for cancer therapy, a very modest anti-tumor activity has been observed with monotherapy in clinical studies of breast cancer. To improve efficacy of epi-drugs in breast cancer, combination of epi-drugs with other therapies currently has been investigated. Additionally, basic researches to elucidate molecular causes of cancer should be extensively and intensively conducted in order to find novel epigenetic druggable targets. In this chapter, we summarize how epigenetic regulation affects the development of breast cancer and how to control cancer phenotype by modulating abnormal epigenetic modifications, and then suggest future research directions in epigenetics for breast cancer treatment.

The novel bZIP transcription factor Fpo1 negatively regulates perithecial development by modulating carbon metabolism in the ascomycete fungus Fusarium graminearum.

Fungal sexual reproduction requires complex cellular differentiation processes of hyphal cells. The plant pathogenic fungus Fusarium graminearum produces fruiting bodies called perithecia via sexual reproduction, and perithecia forcibly discharge ascospores into the air for disease initiation and propagation. Lipid metabolism and accumulation are closely related to perithecium formation, yet the molecular mechanisms that regulate these processes are largely unknown. Here, we report that a novel fungal specific bZIP transcription factor, F. graminearum perithecium overproducing 1 (Fpo1), plays a role as a global transcriptional repressor during perithecium production and maturation in F. graminearum. Deletion of FPO1 resulted in reduced vegetative growth, asexual sporulation and virulence and overproduced perithecium, which reached maturity earlier, compared with the wild type. Intriguingly, the hyphae of the fpo1 mutant accumulated excess lipids during perithecium production. Using a combination of molecular biological, transcriptomic and biochemical approaches, we demonstrate that repression of FPO1 after sexual induction leads to reprogramming of carbon metabolism, particularly fatty acid production, which affects sexual reproduction of this fungus. This is the first report of a perithecium-overproducing F. graminearum mutant, and the findings provide comprehensive insight into the role of modulation of carbon metabolism in the sexual reproduction of fungi.

Hypoxia-induced methylation of a pontin chromatin remodeling factor.

Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Although Pontin is frequently overexpressed in human cancers of various types and implicated in oncogenic functions, the upstream signaling network leading to the regulation of Pontin that in turn affects transcription of downstream target genes has not been extensively studied. Here, we identify Pontin is methylated by G9a/GLP methyltransferases in hypoxic condition and potentiates HIF-1α-mediated activation by increasing the recruitment of p300 coactivator to a subset of HIF-1α target promoters. Intriguingly, Pontin methylation results in the increased invasive and migratory properties by activating downstream target gene, Ets1. In contrast, inhibition of Pontin methylation results in the suppression of tumorigenic and metastatic properties. Together, our data provide new approaches by targeting Pontin methylation and its downstream targets for the development of therapeutic agents for human cancers.

Pathways linking health literacy to self-care in diabetic patients with physical disabilities: A moderated mediation model.

INTRODUCTION: Health literacy is widely considered to be a determinant of self-care behavior in people with diabetes. However, the mechanisms underlying how health literacy is linked to self-care behaviors have not been clearly elucidated. The aim of the present study was to explore the mediating roles of access to healthcare, provider-patient interaction, motivation, self-efficacy in the effect of health literacy on diabetes self-care behaviors among diabetic patients with physical disabilities and investigate the moderating effect of age in a moderated mediation model. METHODS: The online survey was participated by a total of 214 diabetic patients with physical disabilities from November to December 2021. The moderated mediation analysis was examined using the Hayes' PROCESS macro modeling tool based on the bias-corrected bootstrapping method. RESULTS: After controlling for education, the results yielded a significant indirect effect of health literacy on diabetes self-care through motivation and self-efficacy. A partially mediating relationship also was confirmed, as there is a positive direct effect of health literacy on diabetes self-care. Furthermore, age groups (i.e., age <40 and ≥ 40) functioned as a moderator of the mediating effects of motivation and self-efficacy between health literacy and diabetes self-care. CONCLUSION: This study emphasized the important role of motivation and self-efficacy which play in linking health literacy and self-care behavior, especially for younger diabetic patients with physical disabilities. In the light of these findings, a health-literacy tailored motivation and self-efficacy enhancing program may be key targets for interventions promoting diabetes self-care behaviors in people with physical disabilities.

[Support Needs for Health Promotion of Community-Dwelling People with Disabilities: Perspectives of Operators Managing Disability Supportive Housing].

PURPOSE: Recent studies have focused on policies aimed at supporting the independence of individuals with disabilities in communities. As part of this initiative, supportive housing, integrated care, and residential spaces offer tailored services based on individual needs and autonomy. The attitudes and knowledge of the administrators supporting supportive housing residents regarding health management can influence the well-being of individuals with disabilities. Therefore, this study aimed to explore the challenges faced by supporting housing workers in enhancing the self-management skills of individuals with disabilities. METHODS: In this qualitative study, focus group interviews were conducted in August 2023 with nine administrators working to support housing in Seoul. Qualitative content analysis was used to analyze the interview data. RESULTS: The needs and challenges in enhancing the self-management skills of individuals with disabilities were as follows: (1) the complexity of health management challenges, (2) bidirectional strategies for strengthening health management capabilities, and (3) support for systematic health management. Additionally, eight subthemes were derived. CONCLUSION: By investigating the difficulties experienced and identifying the necessary support requirements for supportive housing workers, this study seeks to uncover insights and identifies areas for improvement and strategies for health management. This study acknowledges the educational and institutional support necessary to improve the health and quality of life of individuals with disabilities residing in supportive housing.

Post-translational modifications of lysine-specific demethylase 1.

Lysine-specific demethylase 1 (LSD1) is crucial for regulating gene expression by catalyzing the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) and non-histone proteins through the amine oxidase activity with FAD+ as a cofactor. It interacts with several protein partners, which potentially contributes to its diverse substrate specificity. Given its pivotal role in numerous physiological and pathological conditions, the function of LSD1 is closely regulated by diverse post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation. In this review, we aim to provide a comprehensive understanding of the regulation and function of LSD1 following various PTMs. Specifically, we will focus on the impact of PTMs on LSD1 function in physiological and pathological contexts and discuss the potential therapeutic implications of targeting these modifications for the treatment of human diseases.

MeCP2 dysfunction prevents proper BMP signaling and neural progenitor expansion in brain organoid.

OBJECTIVES: Sporadic mutations in MeCP2 are a hallmark of Rett syndrome (RTT). Many RTT brain organoid models have exhibited pathogenic phenotypes such as decreased spine density and small size of soma with altered electrophysiological signals. However, previous models are mainly focused on the phenotypes observed in the late phase and rarely provide clues for the defect of neural progenitors which generate different types of neurons and glial cells. METHODS: We newly established the RTT brain organoid model derived from MeCP2-truncated iPS cells which were genetically engineered by CRISPR/Cas9 technology. By immunofluorescence imaging, we studied the development of NPC pool and its fate specification into glutamatergic neurons or astrocytes in RTT organoids. By total RNA sequencing, we investigated which signaling pathways were altered during the early brain development in RTT organoids. RESULTS: Dysfunction of MeCP2 caused the defect of neural rosette formation in the early phase of cortical development. In total transcriptome analysis, BMP pathway-related genes are highly associated with MeCP2 depletion. Moreover, levels of pSMAD1/5 and BMP target genes are excessively increased, and treatment of BMP inhibitors partially rescues the cell cycle progression of neural progenitors. Subsequently, MeCP2 dysfunction reduced the glutamatergic neurogenesis and induced overproduction of astrocytes. Nevertheless, early inhibition of BMP pathway rescued VGLUT1 expression and suppressed astrocyte maturation. INTERPRETATION: Our results demonstrate that MeCP2 is required for the expansion of neural progenitor cells by modulating BMP pathway at early stages of development, and this influence persists during neurogenesis and gliogenesis at later stages of brain organoid development.

A new mussel-inspired polydopamine sensitizer for dye-sensitized solar cells: controlled synthesis and charge transfer.

The efficient electron injection by direct dye-to-TiO(2) charge transfer and strong adhesion of mussel-inspired synthetic polydopamine (PDA) dyes with TiO(2) electrode is demonstrated. Spontaneous self-polymerization of dopamine using dip-coating (DC) and cyclic voltammetry (CV) in basic buffer solution were applied to TiO(2) layers under a nitrogen atmosphere, which offers a facile and reliable synthetic pathway to make the PDA dyes, PDA-DC and PDA-CV, with conformal surface and perform an efficient dye-to-TiO(2) charge transfer. Both synthetic methods led to excellent photovoltaic results and the PDA-DC dye exhibited larger current density and efficiency values than those in the PDA-CV dye. Under simulated AM 1.5 G solar light (100 mW cm(-2)), a PDA-DC dye exhibited a short circuit current density of 5.50 mW cm(-2), corresponding to an overall power conversion efficiency of 1.2 %, which is almost 10 times that of the dopamine dye-sensitized solar cell. The PDA dyes showed strong adhesion with the nanocrystalline TiO(2) electrodes and the interface engineering of a dye-adsorbed TiO(2) surface through the control of the coating methods, reaction times and solution concentration maximized the overall conversion efficiency, resulting in a remarkably high efficiency.

Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3-SPOP E3 ubiquitin ligase complex.

Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis without affecting primary tumorigenesis. The regulatory mechanism of BRMS1 at the protein level has not been revealed until recently. Here, we found that cullin 3 (Cul3), a component of E3 ubiquitin ligase, is a new binding partner of BRMS1 and the interaction between BRMS1 and Cul3 is mediated by the SPOP adaptor protein. Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells. These results suggest that the novel regulatory mechanism of BRMS1 by Cul3-SPOP complex is important for breast cancer progression.

Autophagy Modulators in Cancer: Focus on Cancer Treatment.

Uncontrolled autophagy has been associated with the development and progression of various cancers that are resistant to cancer therapy. Therefore, many efforts to modulate uncontrolled autophagy as a cancer treatment have been attempted, from basic science to clinical trials. However, it remains difficult to equally apply autophagy modulators to cancer therapy because autophagy is a double-edged sword in cancer: it can be tumor-suppressive or tumor-protective. Therefore, the precise mechanisms of autophagy modulators and their varied responsiveness to each cancer type should be addressed in detail. This study will describe the precise mechanisms of developing various autophagy modulators, their current therapeutic applications and future perspectives.

Linking Health Literacy to Self-Care in Hypertensive Patients with Physical Disabilities: A Path Analysis Using a Multi-Mediation Model.

Hypertension has been identified as the most prevalent chronic disease, accounting for the majority of premature deaths in people with physical disability in South Korea. Self-care is vital in controlling high blood pressure. Health literacy has been implicated in self-care behaviors; however, the mechanisms behind this relationship remain unclear. Therefore, the present study aimed to test a hypothetical path model estimating the association between health literacy and hypertension self-care behaviors and to verify the mediating effects of access to healthcare, provider-patient interactions, hypertension knowledge, and hypertension control self-efficacy in hypertensive people with physical disability. In total, 211 hypertensive adults with physical disability completed an online survey. A path analysis using a multi-mediation model was performed using AMOS 17.0 (IBM SPSS Inc., Chicago, IL, USA), and indirect effects were estimated using phantom variables. As a result, the model fit indices were deemed excellent. Significant indirect pathways were determined from health literacy to hypertension self-care behavior via provider-patient interactions, knowledge, and self-efficacy, although no direct association was found between health literacy and self-care behaviors. The study findings supported the importance of provider-patient interactions, knowledge, and self-efficacy, which play a role in linking health literacy and self-care behavior in hypertensive patients with physical disability.

Glioblastoma patient-derived cell-based phenotypic drug screening and identification of possible action mechanisms through proteomic analysis.

Because glioblastoma (GBM) exhibits high heterogeneity, it is desirable to use patient-derived cells from the first stage of screening for GBM drug discovery. Here, we describe a protocol to culture patient-derived GBM cells on the extracellular matrix-coated plates to allow high-throughput screening. Further, we detail approaches to identify the mechanism of action (MOA) of the selected effective drug through proteomics. This protocol will be useful for researchers interested in drug screening and the MOA of drugs. For complete details on the use and execution of this protocol, please refer to Nam et al. (2021).