Synthesis of 1-O-acyl- and 1-oxo-kamebanin analogues and their cytotoxic activity.

A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C3-C5 carbon chain increased the cytotoxic activity.

Atopic dermatitis is associated with the clinical course of inflammatory bowel disease.

OBJECTIVES: There are a few studies about the relationship between inflammatory bowel disease (IBD) and atopic dermatitis (AD). It is implied that both diseases have common pathophysiologic mechanisms and can affect each other. However, little information is available on the effect of AD on the clinical course of patients with IBD. METHODS: This is a multi-center, retrospective, observational study. We define AD as a chronic eczematoid dermatosis diagnosed by dermatologists. Patients with concurrent IBD and AD were defined as a case group. Age, gender, and IBD subtype-matched patients without AD were included as a reference group. RESULTS: The numbers of patients in the case and reference groups were 61 and 122 respectively. There was a significantly shorter biologics-free survival in the case group than that in the reference group according to the multivariable-adjusted Cox regression analysis with the onset age, disease duration, smoking status, use of steroid, use of immunomodulator, initial C-reactive protein, initial erythrocyte sedimentation rate, presence of other allergic diseases and initial disease severity [hazard ratio (HR) 1.828, 95% confidence interval (CI) 1.022-3.271, p = .042]. The trend was consistent in the subgroup analysis with ulcerative colitis (HR 3.498, 95% CI 1.066-11.481, p = .039), but not with Crohn's disease (HR 1.542, 95% CI 0.720-3.301, p = .265). CONCLUSIONS: AD showed a significant effect on the biologics-free survival of patients with IBD and especially the UC subtype. Further mechanistic research is required to elucidate the pathogenesis of AD on the clinical course of IBD.

Nuclear mRNA Export and Aging.

The relationship between transcription and aging is one that has been studied intensively and experimentally with diverse attempts. However, the impact of the nuclear mRNA export on the aging process following its transcription is still poorly understood, although the nuclear events after transcription are coupled closely with the transcription pathway because the essential factors required for mRNA transport, namely TREX, TREX-2, and nuclear pore complex (NPC), physically and functionally interact with various transcription factors, including the activator/repressor and pre-mRNA processing factors. Dysregulation of the mediating factors for mRNA export from the nucleus generally leads to the aberrant accumulation of nuclear mRNA and further impairment in the vegetative growth and normal lifespan and the pathogenesis of neurodegenerative diseases. The optimal stoichiometry and density of NPC are destroyed during the process of cellular aging, and their damage triggers a defect of function in the nuclear permeability barrier. This review describes recent findings regarding the role of the nuclear mRNA export in cellular aging and age-related neurodegenerative disorders.

SUMOylation and Major Depressive Disorder.

Since the discovery of the small ubiquitin-like modifier (SUMO) protein in 1995, SUMOylation has been considered a crucial post-translational modification in diverse cellular functions. In neurons, SUMOylation has various roles ranging from managing synaptic transmitter release to maintaining mitochondrial integrity and determining neuronal health. It has been discovered that neuronal dysfunction is a key factor in the development of major depressive disorder (MDD). PubMed and Google Scholar databases were searched with keywords such as 'SUMO', 'neuronal plasticity', and 'depression' to obtain relevant scientific literature. Here, we provide an overview of recent studies demonstrating the role of SUMOylation in maintaining neuronal function in participants suffering from MDD.

Incidence of Psoriasis in Patients with Inflammatory Bowel Disease: A Nationwide Population-Based Matched Cohort Study.

BACKGROUND: Emerging data suggest that inflammatory bowel disease (IBD) and psoriasis are associated, sharing common genetic predispositions and immunological mechanisms. However, concrete data on psoriasis risk in IBD patients compared to the general population are limited. OBJECTIVE: We investigated the risk of developing psoriasis in IBD patients compared to controls without IBD. METHODS: Using the Korean National Health Insurance Database, patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) between 2005 and 2008 were age- and sex-matched 1:4 to non-IBD subjects from 2003 to 2018. IBD patients were defined by combining the International Classification of Diseases 10th revision code and at least one prescription of IBD-specific medications. Disease phenotypes, including psoriasis severity and psoriatic arthritis, were also identified. We investigated newly diagnosed psoriasis from 2009 to 2018. Incidence rates and risk of psoriasis were assessed with multivariate Cox regression models. Subgroup analyses for age and sex, and sensitivity analysis involving tumor necrosis factor (TNF) inhibitor-naïve patients were performed. RESULTS: During nearly a decade of follow-up, 20,152 IBD patients were identified (14,619 [72.54%] UC and 5,533 [27.46%] CD). Among them, 439 patients were newly diagnosed with psoriasis (incidence rate of 217.68 per 100,000 person-years and 228.62 per 100,000 person-years for UC and CD, respectively). The psoriasis risk was higher in IBD patients than in the matched controls (adjusted hazard ratio, aHR, 2.95, 95% confidence interval, CI, 2.60-3.33). Moreover, IBD patients aged <30 years were at an increased risk (aHR 3.35, 95% CI 2.58-4.35), a trend that was unchanged across all psoriasis phenotypes. Sensitivity analysis of TNF inhibitor-naïve patients revealed consistent results. CONCLUSIONS: IBD patients were more likely to develop psoriasis compared to non-IBD subjects, including younger patients at an elevated risk regardless of TNF inhibitor use. This advocates the interplay between IBD and psoriasis; thus, inspection of cutaneous manifestation and dermatological consultation may be helpful in IBD patients at risk.

Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression.

Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors.

Bidirectional relationship between atopic dermatitis and inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND: Recently, atopic dermatitis has been suggested as a systemic inflammatory disorder that can accompany other inflammatory diseases, including inflammatory bowel disease. However, comprehensive reviews that specifically focus on the association between inflammatory bowel disease and atopic dermatitis are lacking. OBJECTIVE: To determine the association between inflammatory bowel disease and atopic dermatitis. METHODS: We searched for relevant studies from MEDLINE, EMBASE, and the Cochrane Library from inception to November 22, 2019. Considering a potential bidirectional relationship, studies reporting inflammatory bowel disease in patients with atopic dermatitis and atopic dermatitis in patients with inflammatory bowel disease were evaluated separately. RESULTS: We included 10 studies with 95,291,110 patients (4 studies on the prevalence of atopic dermatitis in inflammatory bowel disease, 2 on the prevalence and incidence of inflammatory bowel disease in atopic dermatitis, and 4 on either the prevalence or incidence of inflammatory bowel disease in atopic dermatitis). Meta-analyses revealed a statistically significant association between inflammatory bowel disease and atopic dermatitis in both directions (4 studies on atopic dermatitis prevalence in inflammatory bowel disease, odds ratio 1.39, 95% confidence interval 1.28-1.50; 5 on inflammatory bowel disease prevalence in atopic dermatitis, odds ratio 1.35, 95% confidence interval 1.05-1.73; and 3 studies on inflammatory bowel disease incidence in atopic dermatitis, relative risk 1.46, 95% confidence interval 0.98-2.17). LIMITATIONS: A small number of observational studies were reviewed. CONCLUSION: Published literature suggests a bidirectional relationship between inflammatory bowel disease and atopic dermatitis.

Adipose-derived stem cells attenuate atopic dermatitis-like skin lesions in NC/Nga mice.

There is an unmet need in novel therapeutics for atopic dermatitis (AD). We examined the effects of autologous adipose-derived stem cells (ADSCs) on AD-like skin lesions induced by the application of 2,4-dinitrochlorobenzene (DNCB) in NC/Nga mice. Autologous ADSCs and ADSC-conditioned medium (ADSC-CM) were injected intralesionally three times. Clinical severity and histopathologic findings were compared in sham naïve control, saline-treated, ADSC-treated, ADSC-CM-treated and 2.5% cortisone lotion-applied animals. The severity index, skin thickness, mast cell number, as well as expression levels of thymic stromal lymphopoietin, CD45, chemoattractant receptor-homologous molecule, chemokine ligand 9 and chemokine ligand 20 were significantly lower in mice treated with ADSC, ADSC-CM, or 2.5% cortisone lotion. Tissue levels of interferon-γ as well as serum levels of interleukin-33 and immunoglobulin E levels were also decreased in those groups. We conclude that autologous ADSCs improved DNCB-induced AD-like skin lesions in NC/Nga mice by reducing inflammation associated with Th2 immune response and interferon-γ.

Comparison of the Treatment Outcome of Oral Tofacitinib with Other Conventional Therapies in Refractory Alopecia Totalis and Universalis: A Retrospective Study.

Treatment of alopecia totalis and alopecia universalis is often challenging and unsatisfactory. Recently, Janus kinase inhibitor has shown promising results. The aim of this study is to compare the efficacy and tolerability of oral tofacitinib and conventional modalities for treating refractory alopecia totalis/universalis. A total of 74 patients (18 treated with tofacitinib, 26 treated with conventional oral treatment (steroid ± cyclosporine), and 30 treated with diphenylcyclopropenone) were included in the study. The patients' medical records were reviewed retrospectively. After 6 months, 44.4% of patients in the tofacitinib group, 37.5% in the conventional oral treatment group, and 11.1% in the diphenylcyclopropenone group achieved 50% improvements in the Severity of Alopecia Tool score. During treatment, 10% of patients in the tofacitinib group, 73.1% in the conventional oral treatment group, and 10% in the diphenylcyclopropenone group experienced adverse drug reactions. In conclusion, oral tofacitinib was more effective than diphenylcyclopropenone immunotherapy and more tolerable than conventional oral treatment after 6 months of treatment.

Imiquimod-applied Interleukin-10 deficient mice better reflects severe and persistent psoriasis with systemic inflammatory state.

Previous studies have shown that imiquimod-induced psoriasis-like skin inflammation in mice resembles phenotypic changes and cytokine profiles of human psoriasis. However, a psoriasis animal model reflecting the chronic inflammatory course and comorbidities has not yet been established. We aimed to evaluate the imiquimod-applied interleukin (IL)-10 deficient mouse model in comparison with previous models. IL-10 deficient and wild-type (WT) mice received either imiquimod or vehicle cream for 12 days and were sacrificed on day 15. For earlier time point data, either imiquimod or vehicle cream was applied for 2 days, and the mice were sacrificed on day 3. Imiquimod-applied IL-10 deficient mice showed more persistent psoriasis-like inflammation and higher severity index than did WT between day 8 and 15. Histopathologically, they demonstrated significantly thicker epidermis and larger number of CD45+, myeloperoxidase+ and IL-17+ cell counts on day 15. Quantitative reverse transcription-polymerase chain reaction with skin tissue revealed significantly higher imiquimod-induced IL-23p19 expression in imiquimod-applied IL-10 deficient mice on day 15. IL-10 deficient mice also showed significantly higher serum levels of imiquimod-induced IL-17A and tumor necrosis factor-α by enzyme-linked immunosorbent assay on day 15. Furthermore, IL-10 deficient mice showed more prominent increase of spleen weight and decrease of body weight in response to imiquimod application on day 3 and 15. In conclusion, IL-10 deficient mice model with imiquimod application may better reflect severe and persistent psoriasis with systemic inflammatory state.

Misclassification of study designs in the dermatology literature.

BACKGROUND: The appropriate classification of study designs is important for review and assessment of the relevant scientific literature as a basis for decision making; however, little is known about whether study designs have been appropriately reported in the dermatology literature. OBJECTIVE: We aimed to validate the study designs in the dermatology literature and investigate discrepancies between author-reported and actual study designs. METHODS: We reviewed all issues of 3 major dermatology journals from January to December 2016. A total of 295 original articles investigating associations between exposures and health outcomes were included for analysis. We used a validated algorithm to classify the study designs. RESULTS: Among the 295 articles, 174 (59.0%) clearly mentioned the study design in the text. All interventional studies were correctly classified on the basis of study design (n = 42); however, 35 of 132 observational studies (26.5%) showed discrepancies between the author-reported and actual study design. When the author-reported design was a prospective cohort, retrospective cohort, or case-control study (n = 61), approximately half of the studies were misclassified by the authors (n = 30). LIMITATIONS: We analyzed only 3 journals in the dermatology field. CONCLUSIONS: Our findings revealed substantial discrepancies between author-reported and actual study designs in the dermatologic literature, particularly among observational studies.

Role of the Growth Temperature in MoS2 Growth by Chemical Vapor Deposition.

In this paper, we discuss the effect of synthesis temperature on the lateral growth of MoS2 thin films in chemical vapor deposition. With increasing temperature, surface coverage with MoS2 triangular islands is significantly improved due to an increase in the density of nuclei and fully continuous MoS2 thin film is grown when the growth temperature reached 800 °C. The MoS2 triangular islands grown at the temperature from 650 to 750 °C are monolayer and highly crystalline, whereas the large-area continuous film grown at the temperature of 800 °C is composed of double-layer or overlapping MoS2 nanosheets. Our research provides that synthesis temperature is the key to growth large area and high quality single crystal MoS2 films.

Evidence for glucagon-like peptide-1 receptor signaling to activate ATP-sensitive potassium channels in pancreatic beta cells.

Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic beta cells. GLP-1 has been shown to confer glucose-insensitive beta cells with glucose sensitivity by modulation of the activity of the ATP-sensitive potassium (KATP) channel. The channel closing effect of GLP-1, interacting with corresponding G-protein-coupled receptors, has been well established; however, to our knowledge, no study has shown whether GLP-1 directly induces activation of beta-cell KATP channels. Here, we aimed to evaluate whether the activation of beta-cell KATP channels by GLP-1 exists and affects intracellular Ca(2+) levels ([Ca(2+)]i). KATP channel activity was measured in isolated rat pancreatic beta cells by whole-cell perforated patch-clamp recordings with a diazoxide-containing pipette solution. Changes in [Ca(2+)]i and the subcellular localization of KATP channels were observed using the calcium-sensitive dye fura-4/AM and anti-Kir6.2 antibodies in INS-1 beta cells, respectively. To eliminate the well-known inhibitory effects of GLP-1 on KATP channel activity, channels were fully inhibited by pretreatment with methyl pyruvate and epigallocatechin-3-gallate. In the pretreated beta cells, GLP-1 and exendin-4 promptly activated the channels, reducing [Ca(2+)]i. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 blocked the effects of GLP-1 on channel activity. Moreover, phosphatidylinositol-3,4,5-trisphosphate mimicked the effects of GLP-1. These results suggested that beta-cell GLP-1 receptor signaling involved activation of KATP channels via a PI3K-dependent pathway. This alternative mechanism of GLP-1 function may act as a negative feedback pathway, modulating the glucose-dependent GLP-1 inhibition on KATP channel activity.

Detection of huntingtin exon 1 phosphorylation by Phos-Tag SDS-PAGE: Predominant phosphorylation on threonine 3 and regulation by IKKß.

Expansion of a CAG triplet repeat within the first exon of the HUNTINGTIN gene encoding for a polyglutamine tract is the cause of a progressive neurodegenerative disorder known as Huntington's disease. N-terminal fragments of mutant huntingtin have a strong propensity to form oligomers and aggregates that have been linked to the Huntington's disease pathology by different mechanisms, including gain of toxic functions. The biological and biophysical properties of the polyglutamine expansion within these huntingtin fragments are influenced by neighboring domains, in particular by the first 17 amino acids of huntingtin (N17), which precede the polyglutamine expansion. It has been suggested that N17 phosphorylation modulate mutant huntingtin aggregation and toxicity, but the study of its functional and pathological relevance requires the capacity to detect this modification in biological samples in a simple, robust way, that ideally provides information on the abundance of a phosphorylated species relative to the total pool of the protein of interest. Using a modified SDS-PAGE protocol (Phos-Tag) followed by Western blotting with specific anti-HUNTINGTIN antibodies, we efficiently resolved huntingtin fragments expressed in cellular contexts based on the presence of phosphorylated residues, we defined threonine 3 as the major site of huntingtin N17 phosphorylation and, finally, we identified IKK-beta as a kinase capable of phosphorylating threonine 3 in N-terminal hungtingtin fragments.

Unnoticed problems and overlooked opportunities: How and when employees fail to speak up under ambiguous threats.

Organizations often need to deal with ambiguous threats, which are complex, unprecedented, and difficult-to-predict events that hold the potential to cause harm. Drawing on the attention-based view of work behavior, we propose that employees do not always remain vigilant to such threats. Consequently, we argue that, in the face of those threats, employees can fail to notice or recognize problems or vulnerabilities in their organizations' work processes or products that can hinder coping. We posit that this effect is, paradoxically, more pronounced when employees are working with trustworthy managers who are perceived as capable and focused enough on the well-being of their units to adequately deal with work challenges. Thereby, we highlight that employees may overlook problems and thus not speak up, precisely when their input is highly desired to address ambiguous threats and can be effectively used by competent and caring managers. Using a combination of field surveys and preregistered experiments, we demonstrate support for our arguments. In the process, we present an alternative attention-based perspective to the voice literature that has so far predominantly focused on cost-benefit-based explanations (i.e., how employees evaluate the perceived costs of speaking up vs. presumed benefits) when describing hurdles to employee voice. (PsycInfo Database Record (c) 2024 APA, all rights reserved).