Search

This study surveyed 183 college and senior high school students' graph-interpretation competence in scientific and daily contexts. Specifically, whether students' graph interpretation in scientific and daily contexts differed across educational levels was investigated. Furthermore, the questions of whether students' graph interpretation competence in scientific contexts might predict their graph interpretation in daily contexts were explored. Other factors including age and gender were also considered and examined to discern significant factor(s) predicting graph interpretation competence in daily contexts. Results indicated that there were statistically significant differences across educational levels in terms of graph interpretation competence in both scientific and daily contexts. Furthermore, the students' graph interpretation competence was related between scientific and daily contexts. The important factors predicting students' graph interpretation in daily contexts include age and graph-interpretation in scientific literacy. Implications are discussed.

Background and Purpose: Metavisualization plays a key role in science and technological learning in which visualization is practiced. We conducted two sequential studies with the purposes to first develop an instrument that allows individuals to report or reflect on their metavisualization, and then validate the instrument and investigate the relationships among the dimensions of metavisualization. Sample: A total of 320 university students participated in this research. Methods: Through exploratory factor analysis (EFA) in the first study and partial least squares -- structural equation modeling (PLS-SEM) in the second study, the validity and reliability of the instrument measuring the four dimensions of metavisualization were reported, and a theoretical model delineating the relationships among the four variables was explored. Findings: It was found that metacognitive skills, rather than metacognitive knowledge, significantly contributed to the demonstration of epistemic knowledge and judgment criteria during visualization. Metacognitive knowledge may also play an indirect role in learners' epistemic performance through its relation with metacognitive skills. Implications: The results provide insights to advance understanding of metavisualization and its relation to metacognition and epistemic practice. The validated instruments may be used for future quantitative or mixed research to advance understanding of the role metavisualization plays in various contexts of learning in science and technological education.

One issue facing teachers who implement model-based instruction within the school system is the tight curricular schedule. The 'lesson objective tension' calls for investigations to address instructional issues such as how to organise modelling-based instruction at the curriculum level which is across multiple units. We investigated the effect of the cyclic curricular design spacing out three modelling-based instruction units with virtual labs over three semesters, each involving 73, 181, and 150 junior high school students, respectively. Results indicate that, overall, the approach of modelling with virtual labs better promoted students' scientific literacy than the traditional instruction did. Specifically, students with low and moderate school science achievements benefitted more as shown in their scientific literacy scores than did the high achievement students. Furthermore, this study found that receiving one unit of modelling-based instruction may not be sufficient to promote students' scientific literacy, whereas the cyclic approach that suggests students receive two or more units of modelling-based instruction with virtual labs spaced over consecutive semesters had significant effects on promoting students' scientific literacy. The results provide insights into when and how modelling-based learning with virtual labs can promote scientific literacy at a curricular level.

Background: Data visualizations transform data into visual representations such as graphs, diagrams, charts and so forth, and enable inquiries and decision-making in many professional fields, as well as in public and economic areas. How students' data visualization literacy (DVL), including constructing, comprehending, and utilizing adequate data visualizations, can be developed is gaining increasing attention in STEM education. As fundamental steps, the purpose of this study was to understand common student difficulties and useful strategies during the process of constructing data visualization so that suggestions and principles can be made for the design of curricula and interventions to develop students' DVL. Methods: This study engaged 57 college and high school students in constructing data visualizations relating to the topic of air quality for a decision-making task. The students' difficulties and strategies demonstrated during the process of data visualization were analyzed using multiple collected data sources including the students' think-aloud transcripts, retrospective interview transcripts, and process videos that captured their actions with the data visualization tool. Qualitative coding was conducted to identify the students' difficulties and strategies. Epistemic network analysis (ENA) was employed to generate network models revealing how the difficulties and strategies co-occurred, and how the college and high school students differed. Results: Six types of student difficulties and seven types of strategies were identified. The strategies were further categorized into non-, basic- and high-level metavisual strategies. About three-quarters of the participants employed basic or high-level metavisual strategies to overcome the technological and content difficulties. The high school students demonstrated a greater need to develop content knowledge and representation skills, whereas the college students needed more support to know how to simplify data to construct the best data visualizations. Conclusions and implications: The study specified metacognition needed for data visualization, which builds on and extends the cognitive model of drawing construction (CMDC) and theoretical perspectives of metavisualization. The results have implications for developing students' data visualization literacy in STEM education by considering the difficulties and trajectories of metacognitive strategy development, and by addressing the different patterns and needs demonstrated by the college and high school students.

Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (β-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol’s potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.

Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast cancer. This study aimed to investigate the involvement of CA9 in the anti-tumor activity of para-toluenesulfonamide (PTS) and elucidate its mechanism of action against breast cancer both in vitro and in vivo. MCF-7 and MDA-MB-231 breast cancer cells were treated with PTS or subjected to hypoxic conditions using cobalt chloride (CoCl2), with acetazolamide serving as a positive control. Additionally, 4T1 breast cancer cell allograft mice were co-treated with PTS and α-programmed cell death 1 (αPD-1) monoclonal antibody for one month. The results demonstrated that PTS effectively reduced cell viability and reversed migration ability in MCF-7 and MDA-MB-231 cells under CoCl2-induced hypoxia. Furthermore, PTS upregulated the expression of apoptosis-related proteins and downregulated CA9, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) proteins, possibly through modulation of p38 MAPK and ERK1/2 phosphorylated proteins. In the animal model, PTS100 inhibited tumor growth and lung metastasis in mammary tumor allograft mice, exhibiting synergistic effects when combined with αPD-1 therapy. Collectively, our findings suggest that PTS inhibits breast cancer growth and metastasis through the p38 MAPK/ERK1/2 pathway. Moreover, PTS may have the potential to prevent the development of resistance to αPD-1 therapy in breast cancer.

Uterine fibroids, the most common benign tumors of the myometrium in women, are characterized by abnormal extracellular matrix deposition and uterine smooth muscle cell neoplasia, with high recurrence rates. Here, we investigated the potential of the marine natural product manzamine A (Manz A), which has potent anti-cancer effects, as a treatment for uterine fibroids. Manz A inhibited leiomyoma cell proliferation in vitro and in vivo by arresting cell cycle progression and inducing caspase-mediated apoptosis. We performed target prediction analysis and identified sterol o-acyltransferases (SOATs) as potential targets of Manz A. Cholesterol esterification and lipid droplet formation were reduced by Manz A, in line with reduced SOAT expression. As a downstream target of SOAT, Manz A also prevented extracellular matrix deposition by inhibiting the β-catenin/fibronectin/metalloproteinases axis and enhanced autophagy turnover. Excessive free fatty acid accumulation by SOAT inhibition led to reactive oxygen species to impair mitochondrial oxidative phosphorylation and trigger endoplasmic reticulum stress via PERK/eIF2α/CHOP signaling. The inhibitory effect of ManzA on cell proliferation was partially restored by PERK knockdown and eliminated by tauroursodeoxycholic acid, suggesting oxidative stress plays a critical role in the mechanism of action of Manz A. These findings suggest that targeting SOATs by Manz A may be a promising therapeutic approach for uterine fibroids.

Abstract Background Age‐related muscle dysfunctions are common disorders resulting in poor quality of life in the elderly. Probiotic supplementation is a potential strategy for preventing age‐related sarcopenia as evidence suggests that probiotics can enhance muscle function via the gut–muscle axis. However, the effects and mechanisms of probiotics in age‐related sarcopenia are currently unknown. In this study, we examined the effects of Lactobacillus casei Shirota (LcS), a probiotic previously reported to improve muscle function in young adult mice. Methods We administered LcS (1 × 108 or 1 × 109 CFU/mouse/day) by oral gavage to senescence‐accelerated mouse prone‐8 mice for 12 weeks (16‐ to 28‐week‐old). Sixteen‐week‐old and 28‐week‐old SMAP8 mice were included as non‐aged and aged controls, respectively. Muscle condition was evaluated using dual‐energy X‐ray absorptiometry for muscle mass, holding impulse and grip strength tests for muscle strength, and oxygen consumption rate, gene expressions of mitochondrial biogenesis, and mitochondrial number assays for mitochondria function. Inflammatory cytokines were determined using enzyme‐linked immunosorbent assay. Gas chromatography–mass spectrometry was utilized to measure the short‐chain fatty acid levels. The gut microbiota was analysed based on the data of 16S rRNA gene sequencing of mouse stool. Results The LcS supplementation reduced age‐related declines in muscle mass (>94.6%, P 66% in holding impulse and >96.3% in grip strength, P 65.9% in the mice given high dose of LcS, P 89.4%, P 2.0] were positively correlated with healthy muscle and physiological condition (P 2.0) were negatively associated with healthy muscle and physiological condition (P

Glutaminase (GLS) serves a critical bioenergetic role for malignant tumor growth and has become a valuable therapeutic target for cancer treatment. Herein, we performed a structure-based virtual screening to discover novel GLS inhibitors and provide information for developing new GLS inhibitors. We identified critical pharmacological interactions in the GLS1 binding site by analyzing the known GLS1 inhibitors and selected potential inhibitors based on their docking score and pharmacological interactions. The inhibitory effects of compounds were further confirmed by enzymatic and cell viability assays. We treated colorectal cancer and triple-negative breast cancer cells with the selected candidates and measured the inhibitory efficacy of hit compounds on cell viability. In total, we identified three GLS1 inhibitors. The compounds identified from our structure-based virtual screening methodology exhibited great anticancer potential as a lead targeting glutamine metabolism.

This study undertakes a comprehensive exploration of the impact of slightly acidic electrolyzed water (SAEW) on Listeria monocytogenes, a common foodborne pathogen, with a particular focus on understanding the molecular mechanisms leading to the viable but nonculturable (VBNC) state. Given the widespread application of SAEW as an effective disinfectant in the food industry, uncovering these molecular pathways is crucial for improving food safety measures. We employed tandem mass tags (TMT), labeling proteomic techniques and LC-MS/MS to identify differentially expressed proteins under two doses of SAEW conditions. We indicated 203 differential expressed proteins (DEPs), including 78 up-regulated and 125 down-regulated DEPs. The functional enrichment analysis of these proteins indicated that ribosomes, biosynthesis of secondary metabolites, and aminoacyl-tRNA biosynthesis were enriched functions affected by SAEW. Further, we delved into the role of protein chlorination, a potential consequence of reactive chlorine species generated during the SAEW production process, by identifying 31 chlorinated peptides from 22 proteins, with a dominant sequence motif of Rxxxxx[cY] and functionally enriched in translation. Our findings suggest that SAEW might prompt alterations in the protein translation process and trigger compensatory ribosome biosynthesis. However, an imbalance in the levels of elongation factors and AARSs could hinder recovery, leading to the VBNC state. This research carries substantial implications for food safety and sanitation, as it adds to our understanding of the SAEW-induced VBNC state in L. monocytogenes and offers potential strategies for its control.

Dysmenorrhea causes pain and inconvenience during menstruation. In addition to medication, natural compounds are widely used to relieve various types of pain. In this study, we aimed to assess the effects of vitamin D (vit. D) supplementation in relieving the symptoms of primary dysmenorrhea. A comprehensive systematic database search of randomized controlled trials (RCTs) was performed. Oral forms of vit. D supplementation were included and compared with a placebo or standard care. The degree of dysmenorrhea pain was measured with a visual analogue scale or numerical rating scale. Outcomes were compared using the standardized mean difference (SMD) and 95% confidence intervals (CIs) in a meta-analysis. RCTs were assessed using the Cochrane risk-of-bias v2 (RoB 2) tool. The meta-analysis included 8 randomized controlled trials involving 695 participants. The results of the quantitative analysis showed a significantly lower degree of pain in the vit. D versus placebo in those with dysmenorrhea (SMD: −1.404, 95% CI: −2.078 to −0.731). The results of subgroup analysis revealed that pain lessened when the average weekly dose of vit. D was over 50,000 IU, in which dysmenorrhea was relieved regardless of whether vit. D was administered for more or less than 70 days and in any dose interval. The results revealed that vit. D treatment substantially reduced the pain level in the primary dysmenorrhea population. We concluded that vit. D supplementation is an alternative treatment for relieving the pain symptoms of dysmenorrhea.

Metastasis is a major challenge in aggressive endometrial cancer treatment accounting for the high recurrence risk and poor prognosis of epithelial–mesenchymal transition (EMT), regulated by the transforming growth factor beta (TGFβ) signaling pathway, facilitates tumor metastasis. Spirulina phycocyanin extract (SPE) and its purified products allophycocyanin (APC) and C-phycocyanin (C-PC), derived from Spirulina platensis, can be considered a nutraceutical compound with the ability to inhibit tumor growth and metastasis. Current study aims to investigate the anti-metastatic potential of SPE, and its purified products APC, and C-PC on endometrial cancer both in vitro and in vivo. Firstly, human endometrial cancer cell lines (HEC-1A and Ishikawa) as an in vitro model. Secondly, HEC-1A cells transfected with luminescence gene were implanted into female nude mice as a xenograft model. MTT assay, transwell migration assay, immunoblotting assay, quantitative real-time polymerase chain reaction assay, and IVIS XRMS analysis techniques were used. The in vitro results showed that SPE and its purified products APC and C-PC inhibited cell migration, and altered the expression of EMT-related phenotypes by reversing the TGFβ/SMADs signaling pathway. The in vivo results indicated that SPE repressed the metastasis of HEC-1A-LUC cells through modulating EMT-related markers expression. Overall, SPE and its efficient components APC and C-PC reversed the EMT through targeting the TGFβ/SMADs signaling pathway, suggesting an effective therapeutic strategy for metastatic endometrial cancer.

Obesity is a cancer progression risk factor; excessive adipocytes increase adipokine secretion. Visfatin, a novel adipokine highly expressed in cancer patients, is related to breast cancer risk. The modulation of nicotinamide adenine dinucleotide (NAD+) metabolism and the induction of a tumorigenic environment plays a vital role in cancer progression. Among cancer cell types, cancer stem-like cells (CSCs) with self-renewal and chemotherapy-resistance abilities could modulate tumor progression and cancer recurrence ability. In this study, we focused on visfatin’s modulation effect on stemness-related properties using the high-malignancy breast cancer cell line MDA-MB-231 in in vitro and in vivo studies. Visfatin treatment significantly increased both the sphere number and sphere diameter and increased the protein expression of NANOG homeobox (NANOG), sex-determining region Y-box 2 (SOX2), and octamer-binding transcription factor 4 (OCT4), as well as SIRT1 protein levels. The serum angiogenesis marker VEGF and extracellular nicotinamide phosphoribosyl transferase (NAMPT, visfatin) were induced after visfatin treatment, increasing the stemness and angiogenesis environment, which were significantly reduced by the visfatin inhibitor FK866. Our results demonstrate that the visfatin-activated SIRT–SOX2 axis promotes triple-negative breast cancer stemness and enriches the tumorigenic microenvironment.

Lupus nephritis (LN) is a common and serious symptom in patients with systemic lupus erythematosus (SLE). Tubular interstitial fibrosis is a common underlying mechanism in the development of lupus nephritis to end-stage renal failure (ESRD). Quercetin is widely proven to prevent tissue fibrosis. Therefore, the purpose of this study is to investigate the beneficial effects of quercetin on the inhibition of fibrosis and inflammation pathways in in vitro and in vivo lupus nephritis models. In the current study, MRL/lpr mice as animal models, and HK-2 human renal tubular epithelial cells were stimulated by interleukin-33 (IL-33) to mimic the cellular model of lupus nephritis. Immunohistochemical staining, immunoblotting assay, immunofluorescence staining, and quantitative real-time polymerase chain reaction assay were used. The in vivo results showed that quercetin improved the renal function and inhibited both fibrosis- and inflammation-related markers in MRL/lpr mice animal models. The in vitro results indicated that quercetin ameliorated the accumulation of fibrosis- and inflammation-related proteins in IL-33-induced HK-2 cells and improved renal cell pyroptosis via the IL33/ST2 pathway. Overall, quercetin can improve LN-related renal fibrosis and inflammation, which may offer an effective potential therapeutic strategy for lupus nephritis.

Type 2 diabetes mellitus is a complex multifactorial disease characterized by poor glucose tolerance and insulin resistance. Rice-husk silica liquid (RHSL) derived from rice husk has the ability to improve the dysfunction of pancreatic β-cells. This study aimed to confirm the potential protective effects of RHSL in streptozotocin (STZ)-induced diabetic mice. Diabetes was induced in male C57BL/6J mice by intraperitoneal administration of STZ (200 mg/kg BW). RHSL, food-grade silica liquid (FDSL), and rosiglitazone (RSG) were administered to diabetic mice for 12 weeks after successful induction of diabetes. During the experiment, fasting blood glucose, serum insulin, and organ weights were measured. The histopathology of liver tissue was evaluated by H&E staining. Western blotting was performed to assess protein expression levels. The results showed that RHSL significantly reversed the serum insulin levels and improved oral glucose tolerance test (OGTT) results (p < 0.05). In addition, liver sections of STZ-induced diabetic mice after RHSL treatment showed neatly arranged and intact hepatocytes. Furthermore, RHSL was more effective than FDSL in increasing the expression of SIRT1 and decreasing the expression of the PPAR-γ and p-NF-κB proteins. Taken together, this study demonstrated that RHSL ameliorated STZ-induced insulin resistance and liver tissue damage in C57BL/6J mice.

Both the annotation and identification of genes in pathogenic parasites are still challenging. Although, as a survival factor, nitric oxide (NO) has been proven to be synthesized in Trichomonas vaginalis (TV), nitric oxide synthase (NOS) has not yet been annotated in the TV genome. We developed a witness-to-suspect strategy to identify incorrectly annotated genes in TV via the Smith–Waterman and Needleman–Wunsch algorithms through in-depth and repeated alignment of whole coding sequences of TV against thousands of sequences of known proteins from other organisms. A novel NOS of TV (TV NOS), which was annotated as hydrogenase in the NCBI database, was successfully identified; this TV NOS had a high witness-to-suspect ratio and contained all the NOS cofactor-binding motifs (NADPH, tetrahydrobiopterin (BH4), heme and flavin adenine dinucleotide (FAD) motifs). To confirm this identification, we performed in silico modeling of the protein structure and cofactor docking, cloned the gene, expressed and purified the protein, performed mass spectrometry analysis, and ultimately performed an assay to measure enzymatic activity. Our data showed that although the predicted structure of the TV NOS protein was not similar to the structure of NOSs of other species, all cofactor-binding motifs could interact with their ligands with high affinities. We clearly showed that the purified protein had high enzymatic activity for generating NO in vitro. This study provides an innovative approach to identify incorrectly annotated genes in TV and highlights a novel NOS that might serve as a virulence factor of TV.

Melissa officinalis (MO), known as lemon balm, is a popular ingredient blended in herbal tea. In recent decades, the bioactivities of MO have been studied in sub-health and pathological status, highlighting MO possesses multiple pharmacological effects. We previously showed that hot water MO extract exhibited anticancer activity in colorectal cancer (CRC). However, the detailed mechanisms underlying MO-induced cell death remain elusive. To elucidate the anticancer regulation of MO extract in colon cancer, a data-driven analysis by proteomics approaches and bioinformatics analysis was applied. An isobaric tandem mass tags-based quantitative proteome analysis using liquid chromatography–coupled tandem mass spectrometry was performed to acquire proteome-wide expression data. The over-representation analysis and functional class scoring method were implemented to interpret the MO-induced biological regulations. In total, 3465 quantifiable proteoforms were identified from 24,348 peptides, with 67 upregulated and 54 downregulated proteins in the MO-treated group. Mechanistically, MO impeded mitochondrial respiratory electron transport by triggering a reactive oxygen species (ROS)-mediated oxidative stress response. MO hindered the mitochondrial membrane potential by reducing the protein expression in the electron transport chain, specifically the complex I and II, which could be restored by ROS scavenger. The findings comprehensively elucidate how MO hot water extract activates antitumor effects in colorectal cancer (CRC) cells.

High-pressure processing (HPP) is a prevailing non-thermal food preservation technology. The inactivation mechanisms of Listeria monocytogenes under HPP at 200 and 400 MPa for 3 min were investigated by label-free quantitative proteomic analysis and functional enrichment analysis in the Kyoto Encyclopedia of Genes and Genomes. HPP treatment at 400 MPa exhibited significant effects on proteins involved in translation, carbon, carbohydrate, lipid and energy metabolism, and peptidoglycan biosynthesis. HPP increased most ribosomal subunits and initiation factors, suggesting it might shift ribosomal biogenesis to translation initiation. However, protein synthesis was impaired by the shortage of proteins responsible for elongation, termination and recycling. HPP stimulated several ATP-dependent Clp proteases, and the global transcriptional regulator Spx, associating with activation of the stress-activated sigma factor Sigma B (σB) and the transcriptional activator positive regulatory factor A (PrfA) regulons. The quantitative proteomics approaches provide fundamental information on L. monocytogenes under different HPP pressures, and provide theoretical support for HPP against Listeriosis illness and for promotion of safer ready-to-eat foods.

The antitumor effects of Coix lacryma-jobi L. var. ma-yuen Stapf. (adlay seed) ethanolic extract have been increasingly shown. This study aimed to investigate the beneficial effects of both the fractions and subfractions of adlay seed ethanolic extract on the human breast (MCF-7) and cervical (HeLa) cancer cell lines, as well as exploring their possible mechanisms of action. The ethanolic extracts were obtained from different parts of adlay seed, including AHE (adlay hull extract), ATE (adlay testa extract), ABE (adlay bran extract) and PAE (polished adlay extract). The results of a 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl- tetrazolium bromide (MTT) assay showed that AHE-Ea and ATE-Ea showed significant growth inhibitory effects in a dose-dependent manner. The results also showed that the AHE-Ea-K, AHE-Ea-L, ATE-Ea-E and ATE-Ea-F subfractions inhibited cell proliferation, induced cell cycle arrest in the G0/G1 phase and decreased CDK4/Cyclin D1 protein expression. Finally, the extract activated caspase-3 activity and PARP protein expression, which induced MCF-7 and HeLa cell apoptosis. We then used liquid chromatography–mass spectrometry (LC/MS) to identify the potential active components., Quercetin showed an anticancer capacity. In conclusion, the AHE-Ea-K, AHE-Ea-L, ATE-Ea-E and ATE-Ea-F subfractions showed antitumor effects through the inhibition of MCF-7 and HeLa cell line viability, as well as inducing apoptosis and cell cycle arrest.

Purpose. To observe and analyze the long-term outcomes of patients with neovascular age-related macular degeneration (nAMD) treated with aflibercept monotherapy under the National Health Insurance (NHI) program in Taiwan. Methods. This retrospective observational study was conducted at Taipei Veterans General Hospital. Patients with naive nAMD who were treated with aflibercept and followed for more than 3 years were reviewed. The better eye was enrolled if both eyes were affected. Visual acuity (VA) and central macular thickness (CMT) were recorded for 3 years. The lost-to-follow-up rate, number of injections, and predictive factors for visual outcomes were analyzed. Results. Ninety-nine eyes in 99 patients were followed up for 3 years. The mean age at onset of nAMD was 82.8 ± 9.26 years, and 65% of the patients were male. Compared with initial visual acuity, 5 (5.1%) of our patients improved their vision for 3 or more lines after 3 years of follow-up, 11 (11.1%) of our patients improved for 1 to 3 lines, 62 (62.6%) patients remained their vision with 1 line or less changes, 15 (15.2%) patients lost their vision for 1 to 3 lines, and 6 (6%) patients lost their vision for 3 or more lines. The CMT was 359 ± 180 µm before treatment and 259 ± 98 after 3 years (p

Small extracellular vesicles (sEVs) are important mediators of cell–cell communication with respect to diverse physiological processes. To further understand their physiological roles, understanding blood sEV homoeostasis in a quantitative manner is desired. In this study, we propose novel kinetic approaches to estimate the secretion and clearance of mouse plasma–derived sEVs (MP-sEVs) based on the hypothesis that blood sEV concentrations are determined by a balance between the secretion and clearance of sEVs. Using our specific and sensitive sEV labelling technology, we succeeded in analysing MP-sEV clearance from the blood after intravenous administration into mice. This revealed the rapid disappearance of MP-sEVs with a half-life of approximately 7 min. Moreover, the plasma sEV secretion rate, which is presently impossible to directly evaluate, was calculated as 18 μg/min in mice based on pharmacokinetic (PK) analysis. Next, macrophage-depleted mice were prepared as a model of disrupted sEV homoeostasis with retarded sEV clearance. MP-sEV concentrations were increased in macrophage-depleted mice, which probably reflected a shift in the balance of secretion and clearance. Moreover, the increased MP-sEV concentration in macrophage-depleted mice was successfully simulated using calculated clearance rate constant, secretion rate constant and volume of distribution, suggesting the validity of our PK approaches. These results demonstrate that blood sEV concentration homoeostasis can be explained by the dynamics of rapid secretion/clearance.

Leiomyoma is the most common benign uterine tumor in reproductive-age women. Increasing numbers of studies are focusing on the effects of environmental exposure on the incidence and progression of tumors. One major step taken in the food industry is the addition of food preservatives to maintain freshness. Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant, which is widely used as an additive to develop fat-soluble characteristics, as well as in cosmetics and rubber. Previous studies also highlighted that BHT may be related to increased fibrosis capacity and carcinogenic effects. In this study, we explored the effects of the commonly used food additive BHT on leiomyoma progression, and the related mechanism. The exposure of the ELT-3 leiomyoma cell line to BHT for 48 h increased the proliferative effect. Since leiomyoma progression is related to increases in extracellular matrix (ECM) accumulation and matrix metalloproteinase (MMP), BHT could effectively increase ECM-related protein expression, as well as MMP-2 and MMP-9 protein expression. This increase in ECM, in response to BHT, may be linked to the activation of the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathway. Through PI3K inhibition, BHT’s effect on leiomyoma progression could be partially modulated. These results suggest the harmful effect of BHT exposure on leiomyoma progression may relate to PI3K modulation. However, an in vivo study is necessary to confirm these findings.

Type 2 diabetes mellitus is a complex multifactorial disease characterized by insulin resistance and dysfunction of pancreatic β-cells. Rice husk silica liquid (RHSL) is derived from rice husks and has not been explored in diabetes mellitus until now. Previous studies showed that rice husk is enriched with silica, and its silica nanoparticles are higher more biocompatible. To investigate the potential protective role of RHSL on pancreatic β cells, we utilized RIN-m5F pancreatic β cells and explored RHSL effect after streptozotocin (STZ)-stimulation. The recovery effects of RHSL were evaluated using flow cytometry, Western blotting, and immunofluorescence analysis. Results of our study showed that RHSL reversed the cell viability, insulin secretion, reactive oxygen species (ROS) production, and the change of mitochondria membrane potential (ΔΨm) in STZ-treated RIN-m5F cells. Moreover, the expression of phospho-receptor-interacting protein 3 (p-RIP3) and cleaved-poly (ADP-ribose) polymerase (PARP), phospho-mammalian target of rapamycin (p-mTOR), and sequestosome-1 (p62/SQSTM1) were significantly decreased, while the transition of light chain (LC)3-I to LC3-II was markedly increased after RHSL treatment in STZ-induced RIN-m5F cells. Interestingly, using autophagy inhibitors such as 3-methyladenine (3-MA) and chloroquine (CQ) both showed an increase in cleaved-PARP protein level, indicating apoptosis induction. Taken together, this study demonstrated that RHSL induced autophagy and alleviated STZ-induced ROS-mediated apoptosis in RIN-m5F cells.

Hinokitiol is a natural tropolone derivative that is present in the heartwood of cupressaceous plants, and has been extensively investigated for its anti-inflammatory, antioxidant, and antitumor properties in the context of various diseases. To date, the effects of hinokitiol on endometrial cancer (EC) has not been explored. The purpose of our study was to investigate the anti-proliferative effects of hinokitiol on EC cells. Cell viability was determined with an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the quantification of apoptosis and reactive oxygen species (ROSs) was performed by using flow cytometry, while protein expression was measured with the Western blotting technique. Hinokitiol significantly suppressed cell proliferation through the inhibition of the expression of cell-cycle mediators, such as cyclin D1 and cyclin-dependent kinase 4 (CDK4), as well as the induction of the tumor suppressor protein p53. In addition, hinokitiol increased the number of apoptotic cells and increased the protein expression of cleaved-poly-ADP-ribose polymerase (PARP) and active cleaved-caspase-3, as well as the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2). Interestingly, except for KLE cells, hinokitiol induced autophagy by promoting the accumulation of the microtubule-associated protein light chain 3B (LC3B) and reducing the sequestosome-1 (p62/SQSTM1) protein level. Furthermore, hinokitiol triggered ROS production and upregulated the phosphorylation of extracellular-signal-regulated kinase (p-ERK1/2) in EC cells. These results demonstrate that hinokitiol has potential anti-proliferative and pro-apoptotic benefits in the treatment of endometrial cancer cell lines (Ishikawa, HEC-1A, and KLE).

5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard of care to treat colorectal cancers (CRCs). As an antimetabolite, 5-FU inhibits thymidylate synthase to disrupt the synthesis and repair of DNA and RNA. However, only a small proportion of patients benefit from 5-FU treatment due to the development of drug resistance. This study applied pharmacogenomic analysis using two public resources, the Genomics of Drug Sensitivity in Cancer (GDSC) and the Connectivity Map, to predict agents overcoming 5-FU resistance in CRC cells based on their genetic background or gene expression profile. Based on the genetic status of adenomatous polyposis coli (APC), the most frequent mutated gene found in CRC, we found that combining a MEK inhibitor with 5-FU exhibited synergism effects on CRC cells with APC truncations. While considering the gene expression in 5-FU resistant cells, we demonstrated that targeting ROCK is a potential avenue to restore 5-FU response to resistant cells with wild-type APC background. Our results reveal MEK signaling plays a pivotal role in loss-of-function, APC-mediated 5-FU resistance, and ROCK activation serves as a signature in APC-independent 5-FU resistance. Through the use of these available database resources, we highlight possible approaches to predict potential drugs for combinatorial therapy for patients developing resistance to 5-FU treatment.

Abstract Background Figs are widely distributed key resources to many tropical-subtropical animals, and flying-foxes are major consumers and seed dispersers of figs. Bat-fig interrelationships, however, may vary among species differing in fruiting traits, i.e., bat- versus bird-dispersed figs. We examined Ryukyu flying-fox foraging dispersion and the relationships with tree species composition and fig abundance in forests of Iriomote Island. Results Bat foraging dispersion showed no spatial patterns with respect to different areas of the island, and was not explained by heterogeneity, density, or basal area (BA) of total trees, nor by relative density or BA of fruiting trees or total fruiting figs among sites. Instead, bat densities were positively dependent on the relative density of total figs, and particularly the relative BA of bat-dispersed figs Ficus septica and F. variegata. Both species were dominant figs in forests, fruiting asynchronously with long crop seasons, and were used as predominant foods. Bats foraged mostly solitarily and the mean density was in a hump-shaped relationship with crop sizes of the dominant bat-figs. These two species and Ficus benguetensis are larger-sized bat-figs, all contained more seeds, higher dry-pulp mass and water mass, but not necessarily water content. By approximate estimation, higher proportions of seeds of these bat-figs would have been removed from fruits through the bat consumption, than that of small-sized bird-figs like F. virgata, F. superba, and F. microcarpa. Conclusions The foraging dispersion of Ryukyu flying-foxes in forests depends on the availability of the most abundant bat-figs that serve as predominant foods. Intermediate levels of crop sizes of theses figs appear most fit with their solitary foraging. Our results suggest that as density and BA coverage of these dominant bat-figs are below a certain level, their effectiveness to attract bats may dwindle and so would their chance of dispersal by bats.

Cardiovascular diseases such as atherosclerosis and aortic valve sclerosis involve inflammatory reactions triggered by various stimuli, causing increased oxidative stress. This increased oxidative stress causes damage to the heart cells, with subsequent cell apoptosis or calcification. Currently, heart valve damage or heart valve diseases are treated by drugs or surgery. Natural antioxidant products are being investigated in related research, such as fucoxanthin (Fx), which is a marine carotenoid extracted from seaweed, with strong antioxidant, anti-inflammatory, and anti-tumor properties. This study aimed to explore the protective effect of Fx on heart valves under high oxidative stress, as well as the underlying mechanism of action. Rat heart valve interstitial cells under H2O2-induced oxidative stress were treated with Fx. Fx improved cell survival and reduced oxidative stress-induced DNA damage, which was assessed by cell viability analysis and staining with propidium iodide. Alizarin Red-S analysis indicated that Fx has a protective effect against calcification. Furthermore, Western blotting revealed that Fx abrogates oxidative stress-induced apoptosis via reducing the expression of apoptosis-related proteins as well as modulate Akt/ERK-related protein expression. Notably, in vivo experiments using 26 dogs treated with 60 mg/kg of Fx in combination with medical treatment for 0.5 to 2 years showed significant recovery in their echocardiographic parameters. Collectively, these in vitro and in vivo results highlight the potential of Fx to protect heart valve cells from high oxidative stress-induced damage.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of