CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction.

Hepatic stellate cells (HSCs) are primary cells for development and progression of liver fibrosis. Mitophagy is an essential lysosomal process for mitochondrial homeostasis, which can be activated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a representative mitochondrial uncoupler. However, little information is available on the role of CCCP-mediated mitophagy in HSC activation and liver fibrogenesis. In this study, we showed that CCCP treatment in HSCs caused mitochondrial dysfunction proved by decreased mitochondrial membrane potential, mitochondrial DNA, and ATP contents and increased mitochondrial ROS. Moreover, CCCP induced mitophagy and impaired mitophagy flux at the later stage. This blockade of mitophagic flux effect was mediated by suppression of lysosomal activity; CCCP decreased expression of lysosomal markers and cathepsin B activity, and increased lysosomal pH. Intriguingly, CCCP treatment in LX-2 cells or primary HSCs elevated plasminogen activator inhibitor-1, a typical fibrogenic marker of HSCs which was attenuated by mitochondrial division inhibitor 1, a mitophagy inhibitor. The up-regulation of PAI-1 by CCCP was not due to altered transcriptional activity but lysosomal dysfunction. In vivo acute or sub-chronic treatment of CCCP to mice induced mitophagy and fibrogenesis of liver. Hepatic fibrogenic marker (plasminogen activator inhibitor-1) was incremented with mitophagy markers (parkin and PTEN-induced putative kinase 1) in the livers of CCCP injected mice. Furthermore, we found that 5-aminoimidazole-4-carboxyamide ribonucleoside reversed CCCP-mediated mitophagy and subsequent HSC activation. To conclude, CCCP facilitated HSC activation and hepatic fibrogenesis via mitochondrial dysfunction and lysosomal blockade, implying that attenuation of CCCP-related signaling molecules may contribute to treat liver fibrosis.

Changes in the tumor immune microenvironment during disease progression in clear cell ovarian cancer.

OBJECTIVE: The tumor immune microenvironment in ovarian clear cell carcinoma has not been clearly defined. We analyzed the immunological changes from treatment-naive to recurrence to correlate them with clinical outcomes. METHOD: We compared the changes in immune infiltration of advanced-stage ovarian clear cell carcinoma samples before treatment and at the time of recurrence via immunohistochemistry (Programmed Cell Death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8+), forkhead box P3 (Foxp3+)), tumor-infiltrating lymphocytes (TIL), and next-generation sequencing (54 patients). We analyzed the association between platinum sensitivity status and tumor immune microenvironment. RESULTS: Immunohistochemistry revealed significantly increased PD-L1 (p=0.048) and CD8+T cells (p=0.022) expression levels after recurrence. No significant differences were observed in TIL density or Foxp3+T cells. There was no significant correlation between TIL, PD-L1, CD8+T cell, and Foxp3+T cell levels in treatment-naive tumors and survival outcomes. The most common genomic alterations were PIK3CA (41.7%) and ARID1A (41.7%) mutations. There were no differences in the immunological changes or survival outcomes according to PIK3CA and ARID1A mutations. Patients with recurrent platinum-sensitive disease showed higher TIL expression levels. There were no significant differences in PD-L1, CD8+T cells, or Foxp3+T cells between platinum-sensitive and platinum-resistant diseases. CONCLUSION: We characterized the tumor immune microenvironment in patients with advanced-stage ovarian clear cell carcinoma. PD-L1 and CD8+T cell expression significantly increased after recurrence. Whether this could be used to select patients for immunotherapy in the recurrence setting should be investigated.

Validation of the efficacy of a personalized information-provision and exercise-coaching app on the quality of life of menopausal women.

OBJECTIVES: Menopausal symptoms severely impact women's quality of life (QoL). Digital health interventions provide an accessible, personalized alternative for managing menopausal symptoms. In this study, we validated the Menopause Assistant Manager (MAMA®; Hudit, Seoul, S. Korea) app developed to provide personalized information, exercise coaching, and management of appointments and medications to menopausal women, and evaluated its efficacy on their QoL. STUDY DESIGN: This nonrandomized interventional trial enrolled 48 peri- and postmenopausal women into experimental (MAMA) and control (Waitlist) groups (n = 24 each). Participants in the MAMA group used the app for 8 weeks, whereas the Waitlist group received no intervention. Both groups continued their usual treatments. MAIN OUTCOME MEASURES: Clinical assessments at baseline and study completion included the World Health Organization Quality of Life Brief Version (WHOQOL-BREF), Menopause Rating Scale, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-15 (PHQ-15), Menopause Emotional Symptom Questionnaire, and Subjective Memory Complaints Questionnaire. RESULTS: Compared with the Waitlist group, the MAMA group showed postintervention improvements in WHOQOL-BREF physical health (F = 4.84, P = .03) and environmental (F = 5.01, P = .03) domains and GAD-7 (F = 5.53, P = .02) and PHQ-15 (F = 4.14, P = .048) scores. Changes in WHOQOL-BREF physical health scores negatively correlated with PHQ-15 scores (ρ = -0.53, P = .004). CONCLUSION: By increasing treatment accessibility, the app improved physical and environmental QoL and reduced anxiety and somatic symptoms. App-based exercise coaching alleviated somatic symptoms, and the in-app psychological content reduced anxiety by normalizing menopausal symptoms, providing accurate information, decreasing uncertainty, and improving symptom perception. TRIAL REGISTRATION: Clinical Research Information Service KCT 0008603; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=25078&status=5&seq_group=25078&search_page=M.

Efficacy of cognitive behavioral therapy for menopausal symptoms and quality of life in Korean perimenopausal women: A pilot randomized controlled trial.

OBJECTIVES: Therapeutic interventions are crucial for perimenopausal women, given the challenging physical and psychological symptoms they face. This study focused on the development and verification of the efficacy of a cognitive behavioral therapy (CBT) protocol designed specifically for Korean perimenopausal women. STUDY DESIGN: A CBT protocol for perimenopausal women was newly developed based on theory and evidence. Forty menopausal women were randomly assigned to either the CBT group (n = 19) or treatment-as-usual (TAU) group (n = 21). Participants in the CBT group underwent 60-min weekly sessions for eight weeks. The TAU group received standard care from gynecologists. MAIN OUTCOME MEASURES: At baseline and follow-up, participants completed the Menopausal Rating Scale (MRS), World Health Organization Quality of Life Brief Version (WHOQOL-BREF), Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-15 (PHQ-15), Menopause Emotional Symptom Questionnaire (MESQ), and Subjective Memory Complaints Questionnaire. RESULTS: The CBT group showed significant changes in their MRS (F = 4.18, p = .048), WHOQOL-BREF (7.60, 0.009), GAD-7 (4.61, 0.038), PHQ-15 (5.49, 0.025), and MESQ scores (7.19, 0.011) compared to the TAU group. In the CBT group, changes in GAD-7 scores were correlated with PHQ-15 (ρ = 0.57, p < .05), MESQ (0.57, < 0.05), and WHOQOL-BREF scores (-0.53, < 0.05). CONCLUSION: CBT prevents the worsening of menopausal and emotional symptoms, anxiety, and quality of life. CBT may have had a therapeutic effect through the following mechanisms: managing anxiety by changing perceptions of menopause through education and training for coping with various menopausal symptoms and improving self-efficacy in symptom management. CLINICAL TRIAL REGISTRATION NUMBER: KCT0007517.

Recombinant Human IL-32θ Induces Polarization Into M1-like Macrophage in Human Monocytic Cells.

The tumor microenvironment (TME) is formed by several immune cells. Notably, tumor-associated macrophages (TAMs) are existed in the TME that induce angiogenesis, metastasis, and proliferation of cancer cells. Recently, a point-mutated variant of IL-32θ was discovered in breast cancer tissues, which suppressed migration and proliferation through intracellular pathways. Although the relationship between cancer and IL-32 has been previously studied, the effects of IL-32θ on TAMs remain elusive. Recombinant human IL-32θ (rhIL-32θ) was generated using an Escherichia coli expression system. To induce M0 macrophage polarization, THP-1 cells were stimulated with PMA. After PMA treatment, the cells were cultured with IL-4 and IL-13, or rhIL-32θ. The mRNA level of M1 macrophage markers (IL-1ß, TNFα, inducible nitric oxide synthase) were increased by rhIL-32θ in M0 macrophages. On the other hand, the M2 macrophage markers (CCL17, CCL22, TGFß, CD206) were decreased by rhIL-32θ in M2 macrophages. rhIL-32θ induced nuclear translocation of the NF-κB via regulation of the MAPK (p38) pathway. In conclusion, point-mutated rhIL-32θ induced the polarization to M1-like macrophages through the MAPK (p38) and NF-κB (p65/p50) pathways.

Effect of atractylenolide III on zearalenone-induced Snail1-mediated epithelial-mesenchymal transition in porcine intestinal epithelium.

BACKGROUND: The intestinal epithelium performs essential physiological functions, such as nutrient absorption, and acts as a barrier to prevent the entry of harmful substances. Mycotoxins are prevalent contaminants found in animal feed that exert harmful effects on the health of livestock. Zearalenone (ZEA) is produced by the Fusarium genus and induces gastrointestinal dysfunction and disrupts the health and immune system of animals. Here, we evaluated the molecular mechanisms that regulate the effects of ZEA on the porcine intestinal epithelium. RESULTS: Treatment of IPEC-J2 cells with ZEA decreased the expression of E-cadherin and increased the expression of Snai1 and Vimentin, which induced Snail1-mediated epithelial-to-mesenchymal transition (EMT). In addition, ZEA induces Snail-mediated EMT through the activation of TGF-ß signaling. The treatment of IPEC-J2 cells with atractylenolide III, which were exposed to ZEA, alleviated EMT. CONCLUSIONS: Our findings provide insights into the molecular mechanisms of ZEA toxicity in porcine intestinal epithelial cells and ways to mitigate it.

Tripartite motif-containing protein 21 is involved in IFN-γ-induced suppression of hepatitis B virus by regulating hepatocyte nuclear factors.

The antiviral role of the tripartite motif-containing (TRIM) protein family , a member of the E3-ubiquitin ligase family, has recently been actively studied. Hepatitis B virus (HBV) infection is a major contributor to liver diseases; however, the host factors regulated by cytokine-inducible TRIM21 to suppress HBV remain unclear. In this study, we showed the antiviral efficacy of TRIM21 against HBV in hepatoma cell lines, primary human hepatocytes isolated from patient liver tissues, and mouse model. Using TRIM21 knock-out cells, we confirmed that the antiviral effects of interferon-gamma, which suppress HBV replication, are diminished when TRIM21 is deficient. Northern blot analysis confirmed a reduction of HBV RNA levels by TRIM21. Using Luciferase reporter assay, we also discovered that TRIM21 decreases the activity of HBV enhancers, which play a crucial role in covalently closed circular DNA transcription. The participation of the RING domain and PRY-SPRY domain in the anti-HBV effect of TRIM21 was demonstrated through experiments using deletion mutants. We identified a novel interaction between TRIM21 and hepatocyte nuclear factor 4α (HNF4α) through co-immunoprecipitation assay. More specifically, ubiquitination assay revealed that TRIM21 promotes ubiquitin-mediated proteasomal degradation of HNF4α. HNF1α transcription is down-regulated as a result of the degradation of HNF4α, an activator for the HNF1α promoter. Therefore, the reduction of key HBV enhancer activators, HNF4α and HNF1α, by TRIM21 resulted in a decline in HBV transcription, ultimately leading to the inhibition of HBV replication.IMPORTANCEDespite extensive research efforts, a definitive cure for chronic hepatitis B remains elusive, emphasizing the persistent importance of this viral infection as a substantial public health concern. Although the risks associated with hepatitis B virus (HBV) infection are well known, host factors capable of suppressing HBV are largely uncharacterized. This study elucidates that tripartite motif-containing protein 21 (TRIM21) suppresses HBV transcription and consequently inhibits HBV replication by downregulating the hepatocyte nuclear factors, which are host factors associated with the HBV enhancers. Our findings demonstrate a novel anti-HBV mechanism of TRIM21 in interferon-gamma-induced anti-HBV activity. These findings may contribute to new strategies to block HBV.

Smartphone-based gaze estimation for in-home autism research.

Atypical gaze patterns are a promising biomarker of autism spectrum disorder. To measure gaze accurately, however, it typically requires highly controlled studies in the laboratory using specialized equipment that is often expensive, thereby limiting the scalability of these approaches. Here we test whether a recently developed smartphone-based gaze estimation method could overcome such limitations and take advantage of the ubiquity of smartphones. As a proof-of-principle, we measured gaze while a small sample of well-assessed autistic participants and controls watched videos on a smartphone, both in the laboratory (with lab personnel) and in remote home settings (alone). We demonstrate that gaze data can be efficiently collected, in-home and longitudinally by participants themselves, with sufficiently high accuracy (gaze estimation error below 1° visual angle on average) for quantitative, feature-based analysis. Using this approach, we show that autistic individuals have reduced gaze time on human faces and longer gaze time on non-social features in the background, thereby reproducing established findings in autism using just smartphones and no additional hardware. Our approach provides a foundation for scaling future research with larger and more representative participant groups at vastly reduced cost, also enabling better inclusion of underserved communities.

Effects of sports therapy on improvement of menopausal symptoms, psychological status, and body morphology in perimenopausal women.

OBJECTIVE: The aim of this study was to increase the treatment rate of perimenopausal women by providing evidence-based nonpharmaceutical treatments through developing scientific evidence-based sports therapy and verifying its effectiveness. METHODS: In a cross-over design, a total of 33 women were assigned to two different sequences of intervention: sports therapy and telephone intervention (n = 17) or telephone intervention and sports therapy (n = 16). A self-reported clinical symptom survey was conducted before and after the experimental and control periods using the following measures: the Menopause Rating Scale, Patient Health Questionnaire 9, and Patient Health Questionnaire 15. RESULTS: There were significant differences in the changes in the scores for Menopause Rating Scale total (exercise phase, 17.8 ± 5.5 at baseline [B] and 13.5 ± 4.2 at follow-up [F]; control phase, 15.9 ± 6.0 [B] and 15.4 ± 5.3 [F]; P < 0.01), somatic symptoms (exercise phase, 9.5 ± 2.6 [B] and 6.6 ± 2.0 [F]; control phase, 8.5 ± 2.8 [B] and 8.0 ± 1.3 [F], P < 0.01), and urogenital symptoms (exercise phase, 4.9 ± 1.7 [B] and 4.1 ± 1.4 [F]; control phase, 4.3 ± 1.6 [B] and 4.4 ± 1.5 [F]; P < 0.01) between the exercise and control phases. There were also significant differences in the changes in the scores for PHQ-9 (exercise phase, 4.6 ± 4.4 [B] and 3.6 ± 3.3 [F]; control phase, 4.5 ± 3.8 [B] and 5.5 ± 4.6 [F]; P = 0.008) and PHQ-15 (exercise phase, 7.2 ± 4.4 [B] and 5.5 ± 3.5 [F]; control phase, 6.8 ± 4.4 [B] and 7.2 ± 4.9 [F]; P = 0.009) between the two phases. CONCLUSIONS: Sports therapy would improve menopause symptoms, especially somatic and urogenital symptoms. In addition, sports therapy would improve depressive moods in perimenopausal women.

The clinical relevance of a polygenic risk score for type 2 diabetes mellitus in the Korean population.

The clinical utility of a type 2 diabetes mellitus (T2DM) polygenic risk score (PRS) in the East Asian population remains underexplored. We aimed to examine the potential prognostic value of a T2DM PRS and assess its viability as a clinical instrument. We first established a T2DM PRS for 5490 Korean individuals using East Asian Biobank data (269,487 samples). Subsequently, we assessed the predictive capability of this T2DM PRS in a prospective longitudinal study with baseline data and data from seven additional follow-ups. Our analysis showed that the T2DM PRS could predict the transition of glucose tolerance stages from normal glucose tolerance to prediabetes and from prediabetes to T2DM. Moreover, T2DM patients in the top-decile PRS group were more likely to be treated with insulin (hazard ratio = 1.69, p value = 2.31E-02) than were those in the remaining PRS groups. T2DM PRS values were significantly high in the severe diabetes subgroup, characterized by insulin resistance and ß -cell dysfunction (p value = 0.0012). The prediction models with the T2DM PRS had significantly greater Harrel's C-indices than did corresponding models without it. By utilizing prospective longitudinal study data and extensive clinical risk factor information, our analysis provides valuable insights into the multifaceted clinical utility of the T2DM PRS.

Synergistic Effect of Electrical and Biochemical Stimulation on Human iPSC-Derived Neural Differentiation in a Microfluidic Electrode Array Chip.

Neural differentiation is crucial for advancing our understanding of the nervous system and developing treatments for neurological disorders. The advanced methods and the ability to manipulate the alignment, proliferation, and differentiation of stem cells are essential for studying neuronal development and synaptic interactions. However, the utilization of human induced pluripotent stem cells (iPSCs) for disease modeling of neurodegenerative conditions may be constrained by the prolonged duration and uncontrolled cell differentiation required for functional neural cell differentiation. Here, we developed a microfluidic chip to enhance the differentiation and maturation of specific neural lineages by placing aligned microelectrodes on the glass surface to regulate the neural differentiation of human iPSCs. The utilization of electrical stimulation (ES) in conjunction with neurotrophic factors (NF) significantly enhanced the efficiency in generating functional neurons from human iPSCs. We also observed that the simultaneous application of NF and ES to human iPSCs promoted their differentiation and maturation into functional neurons while increasing synaptic interactions. Our research demonstrated the effect of combining NF and ES on human iPSC-derived neural differentiation.

Incorporating functional annotation with bilevel continuous shrinkage for polygenic risk prediction.

BACKGROUND: Genetic variants can contribute differently to trait heritability by their functional categories, and recent studies have shown that incorporating functional annotation can improve the predictive performance of polygenic risk scores (PRSs). In addition, when only a small proportion of variants are causal variants, PRS methods that employ a Bayesian framework with shrinkage can account for such sparsity. It is possible that the annotation group level effect is also sparse. However, the number of PRS methods that incorporate both annotation information and shrinkage on effect sizes is limited. We propose a PRS method, PRSbils, which utilizes the functional annotation information with a bilevel continuous shrinkage prior to accommodate the varying genetic architectures both on the variant-specific level and on the functional annotation level. RESULTS: We conducted simulation studies and investigated the predictive performance in settings with different genetic architectures. Results indicated that when there was a relatively large variability of group-wise heritability contribution, the gain in prediction performance from the proposed method was on average 8.0% higher AUC compared to the benchmark method PRS-CS. The proposed method also yielded higher predictive performance compared to PRS-CS in settings with different overlapping patterns of annotation groups and obtained on average 6.4% higher AUC. We applied PRSbils to binary and quantitative traits in three real world data sources (the UK Biobank, the Michigan Genomics Initiative (MGI), and the Korean Genome and Epidemiology Study (KoGES)), and two sources of annotations: ANNOVAR, and pathway information from the Kyoto Encyclopedia of Genes and Genomes (KEGG), and demonstrated that the proposed method holds the potential for improving predictive performance by incorporating functional annotations. CONCLUSIONS: By utilizing a bilevel shrinkage framework, PRSbils enables the incorporation of both overlapping and non-overlapping annotations into PRS construction to improve the performance of genetic risk prediction. The software is available at https://github.com/styvon/PRSbils .

Effect of gut microbiota-derived metabolites and extracellular vesicles on neurodegenerative disease in a gut-brain axis chip.

A new perspective suggests that a dynamic bidirectional communication system, often referred to as the microbiome-gut-brain axis, exists among the gut, its microbiome, and the central nervous system (CNS). This system may influence brain health and various brain-related diseases, especially in the realms of neurodevelopmental and neurodegenerative conditions. However, the exact mechanism is not yet understood. Metabolites or extracellular vesicles derived from microbes in the gut have the capacity to traverse the intestinal epithelial barrier or blood-brain barrier, gaining access to the systemic circulation. This phenomenon can initiate the physiological responses that directly or indirectly impact the CNS and its function. However, reliable and controllable tools are required to demonstrate the causal effects of gut microbial-derived substances on neurogenesis and neurodegenerative diseases. The integration of microfluidics enhances scientific research by providing advanced in vitro engineering models. In this study, we investigated the impact of microbe-derived metabolites and exosomes on neurodevelopment and neurodegenerative disorders using human induced pluripotent stem cells (iPSCs)-derived neurons in a gut-brain axis chip. While strain-specific, our findings indicate that both microbial-derived metabolites and exosomes exert the significant effects on neural growth, maturation, and synaptic plasticity. Therefore, our results suggest that metabolites and exosomes derived from microbes hold promise as potential candidates and strategies for addressing neurodevelopmental and neurodegenerative disorders.

Unveiling Neurocognitive Disparities in Encoding and Retrieval between Paper and Digital Tablet-Based Learning.

The widespread use of mobile devices and laptops has replaced traditional paper-based learning and the question of how the brain efficiency of digital tablet-based learning differs from that of paper-based learning remains unclear. The purpose of this study was to investigate the difference in brain efficiency for learning between paper-based and digital tablet-based learning by measuring activity in the prefrontal cortex (PFC) using functional near-infrared spectroscopy. Thirty-two subjects were randomly assigned to the paper-based learning or the digital tablet-based learning group. Subjects in each group performed a memory task that required memorizing a three-minute novel (encoding phase) on a paper or digital tablet, followed by a test in which they answered four multiple-choice questions based on the novel's content. To compare both groups, behavioral performance on the test (retrieval phase) and activity in the PFC were measured. As a result, no significant difference in behavioral performance between both groups was observed (p > 0.05). However, the paper-based learning group showed significantly lower activity in the PFC in the encoding phase than the digital tablet-based learning group (p < 0.05) but not in the retrieval phase. The current study demonstrated that brain efficiency in encoding is higher in subjects with paper-based learning than those with digital tablet-based learning. This finding has important implications for education, particularly in terms of the pros and cons of electronic document-based learning.

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.

(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.

Smartphone-based iontophoresis transdermal drug delivery system for cancer treatment.

Cancer is a leading cause of the death worldwide. However, the conventional cancer therapy still suffers from several limitations, such as systemic side effects, poor efficacy, and patient compliance due to limited accessibility to the tumor site. To address these issues, the localized drug delivery system has emerged as a promising approach. In this study, we developed an iontophoresis-based transdermal drug delivery system (TDDS) controlled by a smartphone application for cancer treatment. Iontophoresis, a low-intensity electric current-based TDDS, enhances drug permeation across the skin to provide potential for localized drug delivery and minimize systemic side effects. The fundamental mechanism of our system was modeled using finite element analysis and its performance was corroborated through the flow-through skin permeation tests using a plastic-based microfluidic chip. The results of in vitro cell experiments and skin deposition tests successfully demonstrated that our smartphone-controlled iontophoresis system significantly enhanced the drug permeation for cancer treatment. Therefore, this hand-held smartphone-based iontophoresis TDDS could be a powerful tool for self-administrated anticancer drug delivery applications.

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.

Health-related quality of life in long-term early-stage breast cancer survivors compared to general population in Korea.

PURPOSE: This study assessed health-related quality of life (HRQoL) of long-term breast cancer (BC) survivors diagnosed at early stages and compare with cancer-free, age-matched women. METHODS: The study population included BC survivors diagnosed with ductal carcinoma in situ (DCIS) or breast cancer stages I-II, who had undergone lumpectomy/mastectomy, with time since diagnosis ranging from 9 to 16 years. Survey was conducted at two tertiary hospitals in 2020. Data for cancer-free female controls was randomly drawn from a population-based survey and age-, education-matched with 1 case: 3 controls ratio. Self-reported HRQoL was assessed using EQ-5D with five dimentions. EQ-5D utility index score was calculated. Difference in EQ-5D score was evaluated using the Tobit regression model with adjustment for other covariates. RESULTS: Of 273 survivors. 88% and 12% underwent mastectomy and lumpectomy, respectively. The mean (standard deviation, SD) age at survey was 57.3 (8.5) years old. BC survivors reported significantly more problems performing daily activities (11% vs. 5%, p < 0.001), pain/discomfort (46% vs. 23%, p < 0.001), and anxious/depressed feelings (44% vs. 8%, p < 0.001) relative to the controls. Difference in EQ-5D score between BC survivors and the general population was higher in older age groups. The overall EQ-5D score of BC survivors was statistically lower than that of the control subjects (adjusted [Formula: see text]=0.117, p < 0.001). CONCLUSION: Long-term BC survivors who survived beyond ten years post-diagnosis experience more pain, anxiety, and distress, leading to an overall poorer HRQoL. IMPLICATIONS FOR CANCER SURVIVORS: This study suggest the importance of follow-up care, particularly focusing on pain, anxiety, and distress management to enhance the HRQoL of long-term BC survivors.