Novel role of MHC class II transactivator in hepatitis B virus replication and viral counteraction.

Background/Aims: The major histocompatibility class II (MHC II) transactivator, known as CIITA, is induced by Interferon gamma (IFN-γ) and plays a well-established role in regulating the expression of class II MHC molecules in antigen-presenting cells. Methods: Primary human hepatocytes (PHH) were isolated via therapeutic hepatectomy from two donors who tested negative for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV). The hepatocellular carcinoma (HCC) cell lines HepG2 and Huh7 were used for the mechanistic study, and HBV infection was performed in HepG2-NTCP cells. HBV DNA replication intermediates and secreted antigen levels were measured using Southern blotting and ELISA, respectively. Results: We identified a non-canonical function of CIITA in the inhibition of hepatitis B virus (HBV) replication in both HCC cells and patient-derived PHH. Notably, in vivo experiments demonstrated that HBV DNA and secreted antigen levels were significantly decreased in mice injected with the CIITA construct. Mechanistically, CIITA inhibited HBV transcription and replication by suppressing the activity of HBV-specific enhancers/promoters. Indeed, CIITA exerts antiviral activity in hepatocytes through ERK1/2-mediated down-regulation of the expression of hepatocyte nuclear factor 1α (HNF1α) and HNF4α, which are essential factors for virus replication. In addition, silencing of CIITA significantly abolished the IFN-γ-mediated anti-HBV activity, suggesting that CIITA mediates the anti-HBV activity of IFN-γ to some extent. HBV X protein (HBx) counteracts the antiviral activity of CIITA via direct binding and impairing its function. Conclusions: Our findings reveal a novel antiviral mechanism of CIITA that involves the modulation of the ERK pathway to restrict HBV transcription. Additionally, our results suggest the possibility of a new immune avoidance mechanism involving HBx.

Cycloolivil Isolated from Nardostachys jatamansi Inhibits TNF-α/IFN-γ-Induced Chemokine Production by Blocking NF-κB and JAK/STAT Activation in HaCaT Keratinocytes.

Nardostachys jatamansi is widely used as a traditional medicine in Asian countries. Numerous recent studies have reported the biological activities of its secondary metabolites and extracts. In this study, a total of 14 components were isolated, including cycloolivil and 2-(3'-hydroxy-5'-ethoxyphenyl)-3-hydroxylmethyl-7-methoxy-2,3-dihydrobenzofuran-5-carboxylic acid, which were first discovered in N. jatamansi. The isolated compounds were investigated for their anti-inflammatory effects on HaCaT keratinocytes and their potential to alleviate skin inflammation. The results of the screening revealed that cycloolivil and 4ß-hydroxy-8ß-methoxy-10-methylene-2,9-dioxatricyclo[4.3.1.03,7]decane reduced the production of inflammatory cytokines induced by TNF-α/IFN-γ, such as IL-6, IL-8, and RANTES, in keratinocytes. This study focused on exploring the biological effects of cycloolivil, and the results suggested that cycloolivil inhibits the expression of COX-2 proteins. Further mechanistic evaluations confirmed that the anti-inflammatory effects of cycloolivil were mediated by blockage of the NF-κB and JAK/STAT signaling pathways. These results suggest that cycloolivil isolated from N. jatamansi could be used to treat skin inflammatory diseases.

Social support during re-entry period and long-term quality of life in breast cancer survivors: a 10-year longitudinal cohort study.

PURPOSE: This study evaluated the association between social support during the re-entry period and long-term health-related quality of life (HRQoL) in breast cancer survivors using a longitudinal cohort study. METHODS: This is a prospective cohort study with 275 breast cancer survivors who reported HRQoL at 5 and 10 years after diagnosis. Social support for the re-entry period was measured 3 years after diagnosis using the Medical Outcome Study Social Support Survey (MOS-SSS). HRQoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Breast Cancer-Specific Module (BR-23). Multivariable linear regression analysis was performed to evaluate HRQoL at 5 and 10 years after diagnosis by level of social support during the re-entry period. RESULTS: The mean (SD) of social support during re-entry period was 68.5. The low social support (LSS, score < 55) group during the re-entry period had a significantly lower HRQoL (mean difference = - 12.93) compared to moderate or high social support (MHSS, score ≥ 55) group. 5 and 10 years after diagnosis, the LSS group continued to demonstrate lower HRQoL (5 years: - 7.17; 10 years: - 7.85) compared to the MHSS group. The LSS group were more likely to have lower role and social function scores, and higher fatigue, pain, and financial problems compared to the MHSS group at 10 years after diagnosis. CONCLUSIONS: Breast cancer survivors who received lower social support during the re-entry period were more likely to experience poorer HRQoL in the long term than those who did not.

Sodium Butyrate Inhibits the Expression of Thymidylate Synthase and Induces Cell Death in Colorectal Cancer Cells.

The most commonly used chemotherapy for colorectal cancer (CRC) is the application of 5-fluorouracil (5-FU). Inhibition of thymidylate synthase (TYMS) expression appears to be a promising strategy to overcome the decreased sensitivity to 5-FU caused by high expression of TYMS, which can be induced by 5-FU treatment. Several compounds have been shown to potentially inhibit the expression of TYMS, but it is unclear whether short-chain fatty acids (SCFAs), which are naturally produced by bacteria in the human intestine, can regulate the expression of TYMS. Sodium butyrate (NaB) is the most widely known SCFA for its beneficial effects. Therefore, we investigated the enhancing effects on inhibition of cell viability and induction of apoptosis after co-treatment of NaB with 5-FU in two CRC cell lines, HCT116 and LoVo. This study suggests that the effect of NaB in improving therapeutic sensitivity to 5-FU in CRC cells may result from a mechanism that strongly inhibits the expression of TYMS. This study also shows that NaB inhibits the migration of CRC cells and can cause cell cycle arrest in the G2/M phase. These results suggest that NaB could be developed as a potential therapeutic adjuvant to improve the therapeutic effect of 5-FU in CRC.

Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas.

Frugivory evolved multiple times in mammals, including bats. However, the cellular and molecular components driving it remain largely unknown. Here, we use integrative single-cell sequencing (scRNA-seq and scATAC-seq) on insectivorous (Eptesicus fuscus; big brown bat) and frugivorous (Artibeus jamaicensis; Jamaican fruit bat) bat kidneys and pancreases and identify key cell population, gene expression and regulatory differences associated with the Jamaican fruit bat that also relate to human disease, particularly diabetes. We find a decrease in loop of Henle and an increase in collecting duct cells, and differentially active genes and regulatory elements involved in fluid and electrolyte balance in the Jamaican fruit bat kidney. The Jamaican fruit bat pancreas shows an increase in endocrine and a decrease in exocrine cells, and differences in genes and regulatory elements involved in insulin regulation. We also find that these frugivorous bats share several molecular characteristics with human diabetes. Combined, our work provides insights from a frugivorous mammal that could be leveraged for therapeutic purposes.

PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer.

Tumor necrosis factor superfamily (TNFSF) resistance contributes to the development and progression of tumors and resistance to various cancer therapies. Tumor-intrinsic alterations involved in the adaptation to the TNFSF response remain largely unknown. Here, we demonstrate that protein kinase C substrate 80K-H (PRKCSH) abundance in lung cancers boosts oncogenic IGF1R activation, leading to TNFSF resistance. PRKCSH abundance is correlated with IGF1R upregulation in lung cancer tissues. Specifically, PRKCSH interacts with IGF1R and extends its half-life. The PRKCSH-IGF1R axis in tumor cells impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, leading to an imbalance between cell death and survival. PRKCSH deficiency augmented the antitumor effects of natural killer (NK) cells, representative TNFSF effector cells, in a tumor xenograft IL-2Rg-deficient NOD/SCID (NIG) mouse model. Our data suggest that PRKCSH plays a critical role in TNFSF resistance and may be a potential target to improve the efficacy of NK cell-based cancer therapy.

(E)-2-Methoxy-4-(3-(4-Methoxyphenyl) Prop-1-en-1-yl) Phenol Suppresses Breast Cancer Progression by Dual-Regulating VEGFR2 and PPARγ.

In cancer treatment, multi-target approach has paid attention to a reasonable strategy for the potential agents. We investigated whether (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) could exert an anticancer effect by dual-regulating VEGFR2 and PPARγ. MMPP showed modulating effects in TNBC type (MDA-MB-231 and MDA-MB-468) and luminal A type (MCF7) breast cancer cell lines. MMPP enhanced PPARγ transcriptional activity and inhibited VEGFR2 phosphorylation. MMPP-induced signaling by VEGFR2 and PPARγ ultimately triggered the downregulation of AKT activity. MMPP exhibited anticancer effects, as evidenced by growth inhibition, inducement of apoptosis, and suppression of migration and invasion. At the molecular level, MMPP activated pro-apoptotic proteins (caspase3, caspase8, caspase9, and bax), while inhibiting the anti-apoptotic proteins (bcl2). Additionally, MMPP inhibited the mRNA expressions of EMT-promoting transcription factors. Therefore, our findings showed molecular mechanisms of MMPP by regulating VEGFR2 and PPARγ, and suggested that MMPP has potential to treat breast cancer.

Modulatory effects of point-mutated IL-32θ (A94V) on tumor progression in triple-negative breast cancer cells.

Breast cancer is a frequently diagnosed cancer and the leading cause of death among women worldwide. Tumor-associated macrophages stimulate cytokines and chemokines, which induce angiogenesis, metastasis, proliferation, and tumor-infiltrating immune cells. Although interleukin-32 (IL-32) has been implicated in the development and modulation of several cancers, its function in breast cancer remains elusive. Mutation of interleukin-32θ (IL-32θ) in the tissues of patients with breast cancer was detected by Sanger sequencing. RT-qPCR was used to detect the mRNA levels of inflammatory cytokines, chemokines, and mediators. The secreted proteins were detected using respective enzyme-linked immunosorbent assays. Evaluation of the inhibitory effect of mutant IL-32θ on proliferation, migration, epithelial-mesenchymal transition (EMT), and cell cycle arrest in breast cancer cells was conducted using MTS assays, migration assays, and Western blotting. A point mutation (281C>T, Ala94Val) was detected in IL-32θ in both breast tumors and adjacent normal tissues, which suppressed the expression of pro-inflammatory factors, EMT factors, and cell cycle related factors. Mutated IL-32θ inhibited the expression of inflammatory factors by regulating the NF-κB pathway. Furthermore, mutated IL-32θ suppressed EMT markers and cell cycle related factors through the FAK/PI3K/AKT pathway. It was inferred that mutated IL-32θ modulates breast cancer progression. Mutated IL-32θ (A94V) inhibited inflammation, EMT, and proliferation in breast cancer by regulating the NF-κB (p65/p50) and FAK-PI3K-GSK3 pathways.

Phorbal-12-mysristate-13-acetate-induced inflammation is restored by protectin DX through PPARγ in human promonocytic U937 cells.

AIMS: Protectin DX (PDX), a specialized pro-resolving mediator, is an important pharmaceutical compound with potential antioxidant and inflammation-resolving effects. However, the fundamental mechanism by which PDX's ameliorate chronic inflammatory diseases has not yet been elucidated. This study aims to evaluate the anti-inflammatory properties and PPARγ-mediated mechanisms of PDX in phorbal-12-mysristate-13-acetate (PMA)-stimulated human promonocytic U937 cells. MAIN METHODS: We confirmed the effects of PDX on expressions of pro-inflammatory cytokines, mediators, and CD14 using conventional PCR, RT-qPCR, ELISA, and flow cytometry. Using western blotting, immunofluorescence, and reactive oxygen species (ROS) determination, we observed that PDX regulated PMA-induced signaling cascades. Molecular docking analysis and a cellular thermal shift assay were conducted to verify the interaction between PDX and the proliferator-activated receptor-γ (PPARγ) ligand binding domain. Western blotting was then employed to explore the alterations in PPARγ expression levels and validate PDX as a PPARγ full agonist. KEY FINDINGS: PDX attenuated protein and mRNA expression levels of interleukin-6, tumor necrosis factor-α, and cyclooxygenase-2 in PMA-treated U937 cells. PDX acts as a PPARγ agonist, exerting a modulating effect on the ROS/JNK/c-Fos signaling pathways. Furthermore, PDX reduced human monocyte differentiation antigen CD14 expression levels. SIGNIFICANCE: PPARγ exhibits pro-resolving effects to regulate the excessive inflammation. These results suggest that PDX demonstrates the resolution of inflammation, indicating the potential for therapeutic targeting of chronic inflammatory diseases.

Disparities in Cancer Incidence across Income Levels in South Korea.

BACKGROUND: Recent nationwide studies of disparities in cancer incidence by income are scarce in Korea. This study investigated such disparities in cancer incidence and the stage at cancer diagnosis across income groups in Korea. METHODS: This study utilized data from a national cancer database, specifically focusing on cases recorded in the year 2018. Income levels were categorized into quintiles according to the insurance premium paid in addition to the Medicaid benefit. The slope index of inequality (SII) and relative index of inequality (RII) were used to measure absolute and relative differences in cancer incidence by income. A multivariable logistic regression was performed to estimate the risk of a distant stage at cancer diagnosis. RESULTS: The total number of cases of incident cancer was 223,371 (men: 116,320, women: 107,051) with shares of the total of 29.5% (5Q), 20.4% (4Q), 16.0% (3Q), 13.5% (2Q), 15.6% (1Q), and 5% (Medicaid). The most common cancer type was thyroid cancer, followed by gastric and colorectal cancers. The age-standardized incidence rate for all cancers was lowest in the highest income group, but the SII was not statistically significant (SII: -35.7), and the RII was -0.07. Colorectal and cervical cancers had lower incidence rates for higher income groups, while thyroid and prostate cancers had higher incidence rates for higher income groups. The odds ratio for a distant stage at diagnosis for all cancers increased for lower income groups relative to 5Q. CONCLUSIONS: Disparities in cancer incidence in a Korean population differed by cancer type, and lower income was a significant predictor of a distant stage at diagnosis for cancers overall. These results emphasize the need for further study of the underlying causes of disparities in cancer incidence and the stage at diagnosis, as well as the need for interventions to mitigate these disparities.

MMPP is a novel VEGFR2 inhibitor that suppresses angiogenesis via VEGFR2/AKT/ERK/NF-κB pathway.

Many types of cancer are associated with excessive angiogenesis. Anti-angiogenic treatment is an effective strategy for treating solid cancers. This study aimed to demonstrate the inhibitory effects of (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) in VEGFA-induced angiogenesis. The results indicated that MMPP effectively suppressed various angiogenic processes, such as cell migration, invasion, tube formation, and sprouting of new vessels in human umbilical vein endothelial cells (HUVECs) and mouse aortic ring. The inhibitory mechanism of MMPP on angiogenesis involves targeting VEGFR2. MMPP showed high binding affinity for the VEGFR2 ATP-binding domain. Additionally, MMPP improved VEGFR2 thermal stability and inhibited VEGFR2 kinase activity, suppressing the downstream VEGFR2/AKT/ERK pathway. MMPP attenuated the activation and nuclear translocation of NF-κB, and it downregulated NF-κB target genes such as VEGFA, VEGFR2, MMP2, and MMP9. Furthermore, conditioned medium from MMPP-treated breast cancer cells effectively inhibited angiogenesis in endothelial cells. These results suggested that MMPP had great promise as a novel VEGFR2 inhibitor with potent anti-angiogenic properties for cancer treatment via VEGFR2/AKT/ERK/NF-κB signaling pathway.

Anti-Inflammatory Activity of 1,6,7-Trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone Isolated from Cudrania tricuspidata via NF-κB, MAPK, and HO-1 Signaling Pathways in Lipopolysaccharide-Stimulated RAW 264.7 and BV2 Cells.

Neuroinflammation activated by microglia affects inflammatory pain development. This study aimed to explore the anti-inflammatory properties and mechanisms of 1,6,7-trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone (THMX) from Cudrania tricuspidata in microglia activation-mediated inflammatory pain. In RAW 264.7 and BV2 cells, THMX has been shown to reduce lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory mediators and cytokines, including nitric oxide (NO), prostaglandin (PG) E2, interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α). THMX also decreased LPS-induced phosphorylation of mitogen-activated protein kinase (MAPK) and the activation of p65 nuclear factor kappa B (NF-κB). Interestingly, THMX also activated heme oxygenase (HO)-1 expression. These findings suggest that THMX is a promising biologically active compound against inflammation through preventing MAPKs and NF-ĸB and activating HO-1 signaling pathways.

Socioeconomic differences in the perception of inequalities in healthcare utilization and health in South Korea.

This study investigated the lay perception of inequalities in society, healthcare utilization, and health in Korea. We also examined the association between socioeconomic status (SES) and perception of inequalities. Data from an online survey on the perception of health and healthcare inequalities related to cancer conducted between October 19, 2021, and November 12, 2021, were used. Data of 3,769 participants aged 20 to 74 years from 17 provinces were analyzed. We examined the perceived level of inequalities according to SES or residential area using frequency analysis, a t-test or analysis of variance (ANOVA), multiple linear regression analysis, and multiple logistic regression analysis. The mean score for perception of social inequality was 5.99 [Standard Deviation (SD) = 1.95] and that for perception of healthcare utilization inequality was 4.75 (SD = 1.96). The perception rate of health inequality according to SES and residential area was approximately 59 % and 61 %, respectively. Higher the income level, lower the level of perception of social inequalities ß = -0.22, p < 0.01). Higher the education level, higher the level of perception of healthcare utilization inequalities (ß = 0.21, p < 0.01). Higher the education level, higher the level of perception of health inequalities according to SES or residential area [adjusted odds ratio (aOR): 2.33 (95 % CI: 1.48, 3.66); aOR: 2.73 (95 % CI: 1.73, 4.31)]. Socioeconomic inequalities were observed in the perception of inequalities in healthcare utilization and health. Policymakers should establish policies to bridge the gap between perceived healthcare utilization inequalities and health inequalities. Future research should investigate the perception of healthcare utilization and health inequalities.

Supplementation with rumen-inert fat in the growing phase altered adipogenic gene expression and the size and number of adipocytes in Hanwoo steers.

We hypothesized that the provision of rumen-inert fat (RIF) to growing cattle (9 to 13 mo of age) would affect the expression of genes involved in lipid metabolism and thereby affect the size and number of adipocytes of steers slaughtered at 30 mo of age. Thirty steers with an average initial body weight (BW) of 239 ±â€…25 kg were allocated to six pens, balanced for BW and genetic merit for marbling, and assigned to one of two treatment groups: control (only basal diet) or test diet (basal diet with 200 g of RIF per day, on an as-fed basis) for 5 mo. Biopsy samples of longissimus lumborum (LM) muscle were then collected for analysis of fatty acid composition and gene expression. Both groups were then fed the same basal diets during the early and late fattening phases, without RIF, until slaughter (average shrunk BW = 759 kg). Supplementation with RIF increased the longissimus thoracis (LT) intramuscular fatty acid concentration at slaughter (P = 0.087) and numerically increased the quality grade score (P = 0.106). The LM intramuscular relative mRNA expression of genes such as PPARα, ZFP423 and SREBP1, FASN, SCD, FABP4, GPAT1, and DGAT2 were downregulated (P < 0.1) following RIF supplementation. Supplementation of RIF decreased (P < 0.1) diameter and concomitantly increased intramuscular adipocytes per viewing section at slaughter. This likely was caused by promotion of triacylglycerol hydrolysis during the growing phase. Another possible explanation is that the relative mRNA expression of gene ATGL was upregulated by RIF supplementation during the growing (P < 0.1) and the fattening phases (P < 0.05), while the genes associated with fatty acid uptake (FABP4) and esterification (DGAT2) were downregulated during the growing phase and upregulated (P < 0.1) during the fattening phase. This implies that the lipid turnover rate was higher for steers during the growing than fattening phase. This study demonstrated that RIF supplementation during the growing phase induced a carryover effect on the lipogenic transcriptional regulation involved in adipocyte lipid content of intramuscular adipose tissue; increased triacylglycerol hydrolysis during the growing phase subsequently was followed by increased lipid accumulation during the fattening phases.

Rumen inert fat (RIF) is a type of fat supplement that is used in the diets of beef cattle as early as 6 mo of age in calves and continues through the finishing period to improve the dietary energy density which can be used by the animal to deposit more lipid in the muscle tissue. However, for Hanwoo beef cattle, the precise time of RIF supplementation has not yet been determined. This study hypothesized that supplementing RIF at the growing phase (9 to 13 mo of age) would have a positive influence on the marbling characteristics of meat at slaughter. The growth rate and performance of steers were not improved by RIF supplementation, however, an increase in intramuscular fatty acid content was noted that was accompanied by the increased number of intramuscular adipocytes and decreased intramuscular adipocyte diameter. Supportively, upregulation of the genes associated with fatty acid uptake and esterification during the fattening phase of RIF-fed animals was noted. Overall, supplementing RIF at the growing stage could improve the lipid content of the meat which is supported by the increased lipid hydrolysis during the growing phase and followed by increased lipid accumulation during the fattening phases.

Development of peptide-based ratiometric fluorescent probe for sensing heparan sulfate and heparin in aqueous solutions at physiological pH and quantitative detection of heparan sulfate in live cells.

Heparan sulfate (HS) plays a critical role in various biological processes as a vital component of the extracellular matrix. In this study, we synthesized three fluorescent probes (1-3) comprising Arg-rich peptides as HS receptors and a fluorophore capable of exhibiting red-shifted emissions upon aggregation. All three probes demonstrated ratiometric responses to HS and heparin in aqueous solutions. Remarkably, probe 3 exhibited a unique ratiometric response to HS in both aqueous solutions at physiological pH and HS proteoglycans on live cells. Probe 3 displayed exceptional sensing properties, including high biocompatibility, water solubility, visible light excitation, a large Stokes shift for ratiometric detection and remarkable selectivity and sensitivity for HS (with a low limit of detection: 720 pM). Binding mode studies unveiled the crucial role of charge interactions between probe 3 and negatively charged HS sugar units. Upon binding, the fluorophore segments of the probes overlapped, inducing green and red emission changes through restricted intramolecular rotation of the fluorophore moiety. Importantly, probe 3 was effectively employed to quantify the reduction of HS proteoglycan levels in live cells by inhibiting HS sulfation using siRNA and an inhibitor. It successfully detected decreased HS levels in cells treated with doxorubicin and irradiation, consistent with results obtained from western blot and immunofluorescence assays. This study presents the first ratiometric fluorescent probe capable of quantitatively detecting HS levels in aqueous solutions and live cells. The unique properties of peptide-based probe 3 make it a valuable tool for studying HS biology and potentially for diagnostic applications in various biological systems.

Impact of health disparities on national breast cancer screening participation rates in South Korea.

Socioeconomic barriers to cancer screening exist at a regional level. The deprivation index is used to estimate socioeconomic gradients and health disparities across different geographical regions. We aimed to examine the impact of deprivation on breast cancer screening participation rates among South Korean women. Municipal breast cancer screening participation rates in women were extracted from the National Cancer Screening Information System and linked to the Korean version of the deprivation index constructed by the Korea Institute for Health and Social Affairs. A generalised linear mixed model was employed to investigate the association between the deprivation index and age-standardised breast cancer screening participation rates in 2005, 2012, and 2018. Participation rates increased gradually across all age groups from 2005 to 2018. Participants in their 60 s consistently had one of the highest participation rates (2005: 30.37%, 2012: 61.57%, 2018: 65.88%). In 2005, the most deprived quintile had a higher estimate of breast cancer screening participation than the least deprived quintile (2nd quintile; estimate: 1.044, p = 0.242, 3rd quintile; estimate: 1.153, p = 0.192, 4th quintile; estimate: 3.517, p = 0.001, 5th quintile; estimate: 6.913, p = < 0.0001). In 2012, the participation rate also increased as the level of deprivation increased. There were no statistically meaningful results in 2018. Regions with high deprivation have a higher participation rate in breast cancer screening. The role of health disparities in determining cancer outcomes among women in Korea requires further examination.

Psychotropic Medication Use and Changes During Hospitalization for Older Adults Living With Dementia.

To describe the use of psychotropic medications among older hospitalized patients. This was a descriptive study using baseline data from the first 308 older patients in a function focused care intervention study. Age, gender, race, comorbidities, admitting diagnosis, and medications (antidepressants, antianxiety medications, anticonvulsants, dementia drugs, antipsychotics, sedative-hypnotics, and opioids) were obtained at baseline and discharge. To compare change over time, generalized estimating equations were used. Participants were mostly female (63%) and White (69%) and were 83.1 years old on average. Antidepressant, antianxiety, anticonvulsant, dementia medication, sedative-hypnotic, and opioid use remained essentially unchanged between admission and discharge. Antipsychotic medication use increased significantly from 16% to 21% at discharge. There was persistent use of psychotropic medication among hospitalized older adults living with dementia and little evidence of deprescribing. There was some indication of changes made during hospitalization that may be appropriate, even without a focused deprescribing initiative.

Unsaturated oxidated fatty acid 12(S)-HETE attenuates TNF-α expression in TNF-α/IFN-γ-stimulated human keratinocytes.

Chronic skin inflammatory diseases are associated with abnormal immune responses characterized by skin barrier dysfunction. Keratinocytes participate in immune homeostasis regulated by immune cells. Immune homeostasis dysfunction contributes to the pathogenesis of skin diseases mediated by pro-inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, which are produced by activated keratinocytes. 12(S)-Hydroxy eicosatetraenoic acid [12(S)-HETE], an arachidonic acid metabolite, has anti-inflammatory properties. However, the role of 12(S)-HETE in chronic skin inflammatory diseases has not been elucidated yet. In this study, we investigated the effect of 12(S)-HETE on TNF-α/interferon (IFN)-γ-induced pro-inflammatory cytokine and chemokine expression. Our data showed that 12(S)-HETE modulates TNF-α mRNA and protein expression in TNF-α-/IFN-γ-treated human keratinocytes. Molecular docking analyses demonstrated that 12(S)-HETE bound to extracellular signal-regulated kinase (ERK)1/2, thus preventing ERK activation and downregulating phosphorylated ERK expression. We also demonstrated that 12(S)-HETE treatment inhibited IκB and ERK phosphorylation and nuclear factor (NF)-κB, p65/p50, and CCAAT/enhancerbindingproteinß (C/EBPß) translocation. Overall, our results showed that 12(S)-HETE attenuated TNF-α expression and secretion by inhibiting the mitogen-activated protein kinase ERK/NF-κB and C/EBPß signaling pathways. Overall, these results suggest that 12(S)-HETE effectively resolved TNF-α-induced inflammation.

MMPP Exerts Anti-Inflammatory Effects by Suppressing MD2-Dependent NF-κB and JNK/AP-1 Pathways in THP-1 Monocytes.

(E)-2-methoxy-4-[3-(4-methoxyphenyl) prop-1-en-1-yl] phenol (MMPP), a novel synthetic analog of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), exerts anti-inflammatory and anticancer effects by downregulating the STAT3 pathway. It has also been recently reported that MMPP can act as a PPAR agonist which enhances glucose uptake and increases insulin sensitivity. However, it has not yet been elucidated whether MMPP can act as an antagonist of MD2 and inhibit MD2-dependent pathways. In this study, we evaluated the underlying modulatory effect of MMPP on inflammatory responses in LPS-stimulated THP-1 monocytes. MMPP inhibited the LPS-induced expression of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, as well as the inflammatory mediator COX-2. MMPP also alleviated the IKKαß/IκBα and JNK pathways and the nuclear translocation of NF-κB p50 and c-Jun in LPS-stimulated THP-1 monocytes. In addition, the molecular docking analyses and in vitro binding assay revealed that MMPP can directly bind to CD14 and MD2, which are expressed in the plasma membrane, to recognize LPS first. Collectively, MMPP was directly bound to CD14 and MD2 and inhibited the activation of the NF-κB and JNK/AP-1 pathways, which then exerted anti-inflammatory activity. Accordingly, MMPP may be a candidate MD2 inhibitor targeting TLR4, which exerts anti-inflammatory effects.

Protein-based nanocages for vaccine development.

Protein nanocages have attracted considerable attention in various fields of nanomedicine due to their intrinsic properties, including biocompatibility, biodegradability, high structural stability, and ease of modification of their surfaces and inner cavities. In vaccine development, these protein nanocages are suited for efficient targeting to and retention in the lymph nodes and can enhance immunogenicity through various mechanisms, including excellent uptake by antigen-presenting cells and crosslinking with multiple B cell receptors. This review highlights the superiority of protein nanocages as antigen delivery carriers based on their physiological and immunological properties such as biodistribution, immunogenicity, stability, and multifunctionality. With a focus on design, we discuss the utilization and efficacy of protein nanocages such as virus-like particles, caged proteins, and artificial caged proteins against cancer and infectious diseases such as coronavirus disease 2019 (COVID-19). In addition, we summarize available knowledge on the protein nanocages that are currently used in clinical trials and provide a general outlook on conventional distribution techniques and hurdles faced, particularly for therapeutic cancer vaccines.