Architecture of ß-Lactoglobulin Coating Modulates Bioinspired Alginate Dialdehyde-Gelatine/Polydopamine Scaffolds for Subchondral Bone Regeneration.

In this study, we developed polydopamine (PDA)-functionalized alginate dialdehyde-gelatine (ADA-GEL) scaffolds for subchondral bone regeneration. These polymeric scaffolds were then coated with ß-Lactoglobulin (ß-LG) at concentrations of 1 mg/ml and 2 mg/ml. Morphological analysis indicated a homogeneous coating of the ß-LG layer on the surface of network-like scaffolds. The ß-LG-coated scaffolds exhibited improved swelling capacity as a function of the ß-LG concentration. Compared to ADA-GEL/PDA scaffolds, the ß-LG-coated scaffolds demonstrated delayed degradation and enhanced biomineralization. Here, a lower concentration of ß-LG showed long-lasting stability and superior biomimetic hydroxyapatite mineralization. According to the theoretical findings, the single-state, representing the low concentration of ß-LG, exhibited homogeneous distribution on the surface of the PDA, while the dimer-state (high concentration) displayed a high likelihood of uncontrolled interactions. ß-LG-coated ADA-GEL/PDA scaffolds with a lower concentration of ß-LG provided a biocompatible substrate that supported adhesion, proliferation, and alkaline phosphatase (ALP) secretion of sheep bone marrow mesenchymal stem cells, as well as increased expression of osteopontin (SPP1) and collagen type 1 (COL1A1) in human osteoblasts. These findings indicate the potential of protein-coated scaffolds for subchondral bone tissue regeneration. STATEMENT OF SIGNIFICANCE: This study addresses a crucial aspect of osteochondral defect repair, emphasizing the pivotal role of subchondral bone regeneration. The development of polydopamine-functionalized alginate dialdehyde-gelatine (ADA-GEL) scaffolds, coated with ß-Lactoglobulin (ß-LG), represents a novel approach to potentially enhance subchondral bone repair. ß-LG, a milk protein rich in essential amino acids and bioactive peptides, is investigated for its potential to promote subchondral bone regeneration. This research explores computationally and experimentally the influence of protein concentration on the ordered or irregular deposition, unravelling the interplay between coating structure, scaffold properties, and in-vitro performance. This work contributes to advancing ordered protein coating strategies for subchondral bone regeneration, providing a biocompatible solution with potential implications for supporting subsequent cartilage repair.

Bovine serum albumin-modified 3D printed alginate dialdehyde-gelatin scaffolds incorporating polydopamine/SiO2-CaO nanoparticles for bone regeneration.

Three-dimensional (3D) printing allows precise manufacturing of bone scaffolds for patient-specific applications and is one of the most recently developed and implemented technologies. In this study, bilayer and multimaterial alginate dialdehyde-gelatin (ADA-GEL) scaffolds incorporating polydopamine (PDA)/SiO2-CaO nanoparticle complexes were 3D printed using a pneumatic extrusion-based 3D printing technology and further modified on the surface with bovine serum albumin (BSA) for application in bone regeneration. The morphology, chemistry, and in vitro bioactivity of PDA/SiO2-CaO nanoparticle complexes were characterized (n = 3) and compared with those of mesoporous SiO2-CaO nanoparticles. Successful deposition of the PDA layer on the surface of the SiO2-CaO nanoparticles allowed better dispersion in a liquid medium and showed enhanced bioactivity. Rheological studies (n = 3) of ADA-GEL inks consisting of PDA/SiO2-CaO nanoparticle complexes showed results that may indicate better injectability and printability behavior compared to ADA-GEL inks incorporating unmodified nanoparticles. Microscopic observations of 3D printed scaffolds revealed that PDA/SiO2-CaO nanoparticle complexes introduced additional topography onto the surface of 3D printed scaffolds. Additionally, the modified scaffolds were mechanically stable and elastic, closely mimicking the properties of natural bone. Furthermore, protein-coated bilayer scaffolds displayed controllable absorption and biodegradation, enhanced bioactivity, MC3T3-E1 cell adhesion, proliferation, and higher alkaline phosphatase (ALP) activity (n = 3) compared to unmodified scaffolds. Consequently, the present results confirm that ADA-GEL scaffolds incorporating PDA/SiO2-CaO nanoparticle complexes modified with BSA offer a promising approach for bone regeneration applications.

ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A1 treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.Abbreviation: ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.

NPC1L1 rs217434 A > G as a Novel Single Nucleotide Polymorphism Related to Dyslipidemia in a Korean Population.

A relationship between cholesterol levels and Niemann-Pick C1-Like 1 (NPC1L1) polymorphisms in diverse populations was found in previous studies. However, relevant research on this association in the Korean population is relatively scarce. Therefore, the current study sought to examine the correlation between the NPC1L1 rs217434 A > G polymorphism and clinical as well as biochemical variables pertaining to dyslipidemia in the Korean population. This cross-sectional single-center study included 1404 Korean subjects aged 20-86 years, grouped based on dyslipidemia presence (normal and dyslipidemia) and genotype (AA or AG). After adjusting for sex and age, it was discovered that the dyslipidemia group's BMI, diastolic blood pressure, glucose-related indicators, lipid profile, high-sensitivity C-reactive protein (hs-CRP), and parameters of oxidative stress were considerably different from the normal group's values. When grouped according to genotype, individuals in the AG group exhibited greater total cholesterol, low-density lipoprotein cholesterol, hs-CRP, and 8-epi-prostaglandin F2α in comparison to those in the AA group. Moreover, individuals with dyslipidemia and the AG genotype exhibited unfavorable outcomes for lipid profiles, markers related to glucose and inflammation, and markers of oxidative stress. This study provided evidence for a relationship between the NPC1L1 rs217434 A > G genotype and dyslipidemia in the Korean population, which highlights the potential of the NPC1L1 rs217434 A > G genotype as an early predictor of dyslipidemia.

Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming ß-propeller.

Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLFWT) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLFD380A) and severe (OLFI499F) disease variants aggregate differently, with rates comparable to OLFWT in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLFWT urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation.

The Possible Effect of Dietary Fiber Intake on the Metabolic Patterns of Dyslipidemia Subjects: Cross-Sectional Research Using Nontargeted Metabolomics.

BACKGROUND: Dyslipidemia is important because of its association with various metabolic complications. Numerous studies have sought to obtain scientific evidence for managing dyslipidemia patients. OBJECTIVES: This study aims to identify differences in the nutritional traits of dyslipidemia subjects based on metabolite patterns. METHODS: Dyslipidemia (n = 73) and control (n = 80) subjects were included. Dyslipidemia was defined as triglycerides ≥200 mg/dL, total cholesterol ≥240 mg/dL, low density lipoprotein cholesterol ≥160 mg/dL, high-density lipoprotein cholesterol <40 mg/dL (men) or 50 mg/dL (women), or lipid-lowering medicine use. Nontargeted metabolomics based on ultra-high performance liquid chromatography-mass spectrometry identified plasma metabolites, and K-means clustering was used to reconstitute groups based on the similarity of metabolomic patterns across all subjects. Then, with eXtreme Gradient Boosting, metabolites significantly contributing to the new grouping were selected. Statistical analysis was conducted to analyze traits demonstrating appreciable differences between the groups. RESULTS: Dyslipidemia subjects were divided into 2 groups based on whether they were (n = 24) or were not (n = 56) in a similar metabolic state as the controls by K-means clustering. The considerable contribution of 4 metabolites (3-hydroxybutyrylcarnitine, 2-octenal, 1,3,5-heptatriene, and 5ß-cholanic acid) to this new subset of dyslipidemia was confirmed by eXtreme Gradient Boosting. Furthermore, fiber intake was significantly higher in dyslipidemia subjects whose metabolic state was similar to that of the control than in the dissimilar group (P = 0.002). Moreover, significant correlations were observed between the 4 metabolites and fiber intake. Regression analysis determined that the ideal cutoff for fiber intake was 17.28 g/d. CONCLUSIONS: Dyslipidemia patients who consume 17.28 g/d or more of dietary fiber may maintain similar metabolic patterns to healthy individuals, with substantial effects on the changes in the concentrations of 4 metabolites. Our findings could be applied to developing dietary guidelines for dyslipidemia patients.

Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans.

Enavogliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor approved for clinical use in South Korea. As SGLT2 inhibitors are a treatment option for patients with diabetes, enavogliflozin is expected to be prescribed in various populations. Physiologically based pharmacokinetic (PBPK) modelling can rationally predict the concentration-time profiles under altered physiological conditions. In previous studies, one of the metabolites (M1) appeared to have a metabolic ratio between 0.20 and 0.25. In this study, PBPK models for enavogliflozin and M1 were developed using published clinical trial data. The PBPK model for enavogliflozin incorporated a non-linear urinary excretion in a mechanistically arranged kidney model and a non-linear formation of M1 in the liver. The PBPK model was evaluated, and the simulated pharmacokinetic characteristics were in a two-fold range from those of the observations. The pharmacokinetic parameters of enavogliflozin were predicted using the PBPK model under pathophysiological conditions. PBPK models for enavogliflozin and M1 were developed and validated, and they seemed useful for logical prediction.

Comparison of factors associated with postpartum depression from two cohorts of nurses: the Korea Nurses' Health Study and the Nurses' Health Study 3.

OBJECTIVES: This study aimed to identify whether differences exist in postpartum depression (PPD) in US and Korean nurses and its related factors. Identifying occupational and personal factors that underlie potential differences will be helpful for women's occupational health. METHODS: Baseline and postpartum survey data from employed nurses in the Korea Nurses' Health Study and Nurses' Health Study 3 (1244 Korean; 2742 US nurses) were analysed. Postpartum data collection was done via online survey. PPD was analysed based on cultural validation from prior studies using the Edinburgh Postnatal Depression Scale (cut-off of 10 for Korea and 13 for USA); depressive symptoms prior to pregnancy and childbirth, general characteristics and sleep satisfaction were also measured. Descriptive statistics, χ2 tests and t-tests and multivariate ordinal logistic regression analysis were performed. RESULTS: 45.9% of Korean participants had clinical symptoms of PPD (≥10), whereas US participants presented with 3.4% (≥13). Prior depressive symptoms were also higher in Korean participants (22.5%) compared with their US counterparts (4.5%). Prior depressive symptoms and poor sleep satisfaction were significant risk factors of PPD in both cohort groups, and vaginal birth was an additional influencing factor in Korean participants. CONCLUSIONS: Differences in PPD rates and related factors suggest the role of stress, cultural variation and differing work systems. Nurses and other women shift-workers noted to have depressive symptoms before and during pregnancy and exhibit PPD symptoms should especially be followed closely and offered supportive mental health services that include greater flexibility in returning to work.

MoS2 Passivated Multilayer Graphene Membranes for Li-Ion Extraction From Seawater.

Abundant Li resources in the ocean are promising alternatives to refining ore, whose supplies are limited by the total amount and geopolitical imbalance of reserves in Earth's crust. Despite advances in Li+ extraction using porous membranes, they require screening other cations on a large scale due to the lack in precise control of pore size and inborn defects. Herein, MoS2 nanoflakes on a multilayer graphene membrane (MFs-on-MGM) that possess ion channels comprising i) van der Waals interlayer gaps for optimal Li+ extraction and ii) negatively charged vertical inlets for cation attraction, are reported. Ion transport measurements across the membrane reveal ≈6- and 13-fold higher selectivity for Li+ compared to Na+ and Mg2+ , respectively. Furthermore, continuous, stable Li+ extraction from seawater is demonstrated by integrating the membrane into a H2 and Cl2 evolution system, enabling more than 104 -fold decrease in the Na+ concentration and near-complete elimination of other cations.

Mussel-inspired polydopamine decorated alginate dialdehyde-gelatin 3D printed scaffolds for bone tissue engineering application.

This study utilized extrusion-based 3D printing technology to fabricate calcium-cross-linked alginate dialdehyde-gelatin scaffolds for bone regeneration. The surface of polymeric constructs was modified with mussel-derived polydopamine (PDA) in order to induce biomineralization, increase hydrophilicity, and enhance cell interactions. Microscopic observations revealed that the PDA layer homogeneously coated the surface and did not appear to induce any distinct change in the microstructure of the scaffolds. The PDA-functionalized scaffolds were more mechanically stable (compression strength of 0.69 ± 0.02 MPa) and hydrophilic (contact angle of 26) than non-modified scaffolds. PDA-decorated ADA-GEL scaffolds demonstrated greater durability. As result of the 18-days immersion in simulated body fluid solution, the PDA-coated scaffolds showed satisfactory biomineralization. Based on theoretical energy analysis, it was shown that the scaffolds coated with PDA interact spontaneously with osteocalcin and osteomodulin (binding energy values of -35.95 kJ mol-1 and -46.39 kJ mol-1, respectively), resulting in the formation of a protein layer on the surface, suggesting applications in bone repair. PDA-coated ADA-GEL scaffolds are capable of supporting osteosarcoma MG-63 cell adhesion, viability (140.18% after 7 days), and proliferation. In addition to increased alkaline phosphatase secretion, osteoimage intensity also increased, indicating that the scaffolds could potentially induce bone regeneration. As a consequence, the present results confirm that 3D printed PDA-coated scaffolds constitute an intriguing novel approach for bone tissue engineering.

Selective TnsC recruitment enhances the fidelity of RNA-guided transposition.

Bacterial transposons are pervasive mobile genetic elements that use distinct DNA-binding proteins for horizontal transmission. For example, Escherichia coli Tn7 homes to a specific attachment site using TnsD1, whereas CRISPR-associated transposons use type I or type V Cas effectors to insert downstream of target sites specified by guide RNAs2,3. Despite this targeting diversity, transposition invariably requires TnsB, a DDE-family transposase that catalyses DNA excision and insertion, and TnsC, a AAA+ ATPase that is thought to communicate between transposase and targeting proteins4. How TnsC mediates this communication and thereby regulates transposition fidelity has remained unclear. Here we use chromatin immunoprecipitation with sequencing to monitor in vivo formation of the type I-F RNA-guided transpososome, enabling us to resolve distinct protein recruitment events before integration. DNA targeting by the TniQ-Cascade complex is surprisingly promiscuous-hundreds of genomic off-target sites are sampled, but only a subset of those sites is licensed for TnsC and TnsB recruitment, revealing a crucial proofreading checkpoint. To advance the mechanistic understanding of interactions responsible for transpososome assembly, we determined structures of TnsC using cryogenic electron microscopy and found that ATP binding drives the formation of heptameric rings that thread DNA through the central pore, thereby positioning the substrate for downstream integration. Collectively, our results highlight the molecular specificity imparted by consecutive factor binding to genomic target sites during RNA-guided transposition, and provide a structural roadmap to guide future engineering efforts.

Effects of Spore-Displayed p75 Protein from Lacticaseibacillus rhamnosus GG on the Transcriptional Response of HT-29 Cells.

A Lacticaseibacillus rhamnosus GG-derived protein, p75, is one of the key molecules exhibiting probiotic activity. However, the molecular mechanism and transcriptional response of p75 in human intestinal epithelial cells are not completely understood. To gain a deeper understanding of its potential probiotic action, this study investigated genome-wide responses of HT-29 cells to stimulation by spore-displayed p75 (CotG-p75) through a transcriptome analysis based on RNA sequencing. Analysis of RNA-seq data showed significant changes of gene expression in HT-29 cells stimulated by CotG-p75 compared to the control. A total of 189 up-regulated and 314 down-regulated genes was found as differentially expressed genes. Gene ontology enrichment analysis revealed that a large number of activated genes was involved in biological processes, such as epithelial cell differentiation, development, and regulation of cell proliferation. A gene-gene interaction network analysis showed that several DEGs, including AREG, EREG, HBEGF, EPGN, FASLG, GLI2, CDKN1A, FOSL1, MYC, SERPINE1, TNFSF10, BCL6, FLG, IVL, SPRR1A, SPRR1B, SPRR3, and MUC5AC, might play a critical role in these biological processes. RNA-seq results for selected genes were verified by reverse transcription-quantitative polymerase chain reaction. Overall, these results provide extensive knowledge about the transcriptional responses of HT-29 cells to stimulation by CotG-p75. This study showed that CotG-p75 can contribute to cell survival and epithelial development in human intestinal epithelial cells.

A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells.

Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer and the leading cause of global cancer-related mortality. Despite the earlier identification of membrane-proximal cleavage of cell adhesion molecule 1 (CADM1) in cancers, the role of the membrane-bound fragment of CAMD1 (MF-CADM1) is yet to be clearly identified. In this study, we first isolated MF-CADM1-specific fully human single-chain variable fragments (scFvs) from the human synthetic scFv antibody library using the phage display technology. Following the selected scFv conversion to human immunoglobulin G1 (IgG1) scFv-Fc antibodies (K103.1-4), multiple characterization studies, including antibody cross-species reactivity, purity, production yield, and binding affinity, were verified. Finally, via intensive in vitro efficacy and toxicity evaluation studies, we identified K103.3 as a lead antibody that potently promotes the death of human SCLC cell lines, including NCI-H69, NCI-H146, and NCI-H187, by activated Jurkat T cells without severe endothelial toxicity. Taken together, these findings suggest that antibody-based targeting of MF-CADM1 may be an effective strategy to potentiate T cell-mediated SCLC death, and MF-CADM1 may be a novel potential therapeutic target in SCLC for antibody therapy.

Early Prediction for Prediabetes and Type 2 Diabetes Using the Genetic Risk Score and Oxidative Stress Score.

We aimed to use a genetic risk score (GRS) constructed with prediabetes and type 2 diabetes-related single nucleotide polymorphisms (SNPs) and an oxidative stress score (OSS) to construct an early-prediction model for prediabetes and type 2 diabetes (T2DM) incidence in a Korean population. The study population included 549 prediabetes and T2DM patients and 1036 normal subjects. The GRS was constructed using six prediabetes and T2DM-related SNPs, and the OSS was composed of three recognized oxidative stress biomarkers. Among the nine SNPs, six showed significant associations with the incidence of prediabetes and T2DM. The GRS was profoundly associated with increased prediabetes and T2DM (OR = 1.946) compared with individual SNPs after adjusting for age, sex, and BMI. Each of the three oxidative stress biomarkers was markedly higher in the prediabetes and T2DM group than in the normal group, and the OSS was significantly associated with increased prediabetes and T2DM (OR = 2.270). When BMI was introduced to the model with the OSS and GRS, the area under the ROC curve improved (from 69.3% to 70.5%). We found that the prediction model composed of the OSS, GRS, and BMI showed a significant prediction ability for the incidence of prediabetes and T2DM.

Anti-Obesity and Anti-Adipogenic Effects of Administration of Arginyl-Fructose-Enriched Jeju Barley (Hordeum vulgare L.) Extract in C57BL/6 Mice and in 3T3-L1 Preadipocytes Models.

In our previous study, we reported that arginyl-fructose (AF), one of the Amadori rearrangement compounds (ARCs) produced by the heat processing of Korean ginseng can reduce carbohydrate absorption by inhibiting intestinal carbohydrate hydrolyzing enzymes in both in vitro and in vivo animal models. This reduced absorption of carbohydrate might be helpful to control body weight gain due to excessive carbohydrate consumption and support induced calorie restriction. However, the weight management effect, except for the effect due to anti-hyperglycemic action, along with the potential mechanism of action have not yet been determined. Therefore, the efforts of this study are to investigate and understand the possible weight management effect and mechanism action of AF-enriched barley extracts (BEE). More specifically, the effect of BEE on lipid accumulation and adipogenic gene expression, body weight gain, body weight, plasma lipids, body fat mass, and lipid deposition were evaluated using C57BL/6 mice and 3T3-L1 preadipocytes models. The formation of lipid droplets in the 3T3-L1 treated with BEE (500 and 750 µg/mL) was significantly blocked (p < 0.05 and p < 0.01, respectively). Male C57BL/6 mice were fed a high-fat diet (30% fat) for 8 weeks with BEE (0.3 g/kg-body weight). Compared to the high fat diet control (HFD) group, the cells treated with BEE significantly decreased in intracellular lipid accumulation with concomitant decreases in the expression of key transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (CEBP/α), the mRNA expression of downstream lipogenic target genes such as fatty acid binding protein 4 (FABP4), fatty acid synthase (FAS), and sterol regulatory element-binding protein 1c (SREBP-1c). Supplementation of BEE effectively lowered the body weight gain, visceral fat accumulation, and plasma lipid concentrations. Compared to the HFD group, BEE significantly suppressed body weight gain (16.06 ± 2.44 g vs. 9.40 ± 1.39 g, p < 0.01) and increased serum adiponectin levels, significantly, 1.6-folder higher than the control group. These results indicate that AF-enriched barley extracts may prevent diet-induced weight gain and the anti-obesity effect is mediated in part by inhibiting adipogenesis and increasing adiponectin level.

Effect of cardioplegic arrest and reperfusion on left and right ventricular proteome/phosphoproteome in patients undergoing surgery for coronary or aortic valve disease.

Our earlier work has shown inter­disease and intra­disease differences in the cardiac proteome between right (RV) and left (LV) ventricles of patients with aortic valve stenosis (AVS) or coronary artery disease (CAD). Whether disease remodeling also affects acute changes occuring in the proteome during surgical intervention is unknown. This study investigated the effects of cardioplegic arrest on cardiac proteins/phosphoproteins in LV and RV of CAD (n=6) and AVS (n=6) patients undergoing cardiac surgery. LV and RV biopsies were collected during surgery before ischemic cold blood cardioplegic arrest (pre) and 20 min after reperfusion (post). Tissues were snap frozen, proteins extracted, and the extracts were used for proteomic and phosphoproteomic analysis using Tandem Mass Tag (TMT) analysis. The results were analysed using QuickGO and Ingenuity Pathway Analysis softwares. For each comparision, our proteomic analysis identified more than 3,000 proteins which could be detected in both the pre and Post samples. Cardioplegic arrest and reperfusion were associated with significant differential expression of 24 (LV) and 120 (RV) proteins in the CAD patients, which were linked to mitochondrial function, inflammation and cardiac contraction. By contrast, AVS patients showed differential expression of only 3 LV proteins and 2 RV proteins, despite a significantly longer duration of ischaemic cardioplegic arrest. The relative expression of 41 phosphoproteins was significantly altered in CAD patients, with 18 phosphoproteins showing altered expression in AVS patients. Inflammatory pathways were implicated in the changes in phosphoprotein expression in both groups. Inter­disease comparison for the same ventricular chamber at both timepoints revealed differences relating to inflammation and adrenergic and calcium signalling. In conclusion, the present study found that ischemic arrest and reperfusion trigger different changes in the proteomes and phosphoproteomes of LV and RV of CAD and AVS patients undergoing surgery, with markedly more changes in CAD patients despite a significantly shorter ischaemic period.

Echocardiographic Assessment of Patients with Pulmonary Tumor Thrombotic Microangiopathy First Diagnosed in the Emergency Department.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal disease that obstructs pulmonary vessels, leading to pulmonary hypertension (PH) and right-sided heart failure causing rapid progressive dyspnea in patients with cancer. This retrospective chart review involved nine patients with PTTM who were first clinically diagnosed in a tertiary emergency department (ED) between January 2015 and June 2021. They underwent laboratory tests, chest radiography, chest computed tomography (CT), and echocardiography. All patients presented with severe and rapidly progressive dyspnea within a few days, a high oxygen demand. The right ventricle (RV): left ventricle ratio was >1 on chest CT, and no life-threatening pulmonary thromboembolism (PTE) was observed. Echocardiographic findings indicated that all patients had moderate-to-severe RV dilatation with a D-shaped LV. The median tricuspid regurgitation maximum velocity was 3.8 m/s, and the median RV systolic pressure was 63 mmHg, indicating severe PH. The median value of tricuspid annular plane systolic excursion was 15 mm, showing a decrease in RV systolic function, and McConnell's sign was observed in five patients. Two patients immediately underwent chemotherapy and are currently alive. PTTM should be suspected and evaluated using echocardiography in patients with cancer presenting to the ED with acute dyspnea and RV failure without PTE.

A curcumin analog CA-5f inhibits urokinase-type plasminogen activator and invasive phenotype of triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is one of the most aggressive types of breast cancer with poor outcomes. Patients with TNBC cannot benefit from targeted therapies such as Tamoxifen and Herceptin. The aim of the present study was to seek a preventive or therapeutic agent with a potential inhibitory effect on aggressive progression of TNBC. Anticancer effect of a natural compound curcumin have been demonstrated, however, development of more effective curcumin analogs with better bioavailability is needed. We investigated if a curcumin analog CA-5f could inhibit the invasive phenotype of TNBC cell lines in the present study. Treatment with CA-5f inhibited the viability of MDA­MB­231 and Hs578T TNBC cells, possible by inducing apoptosis. The invasive phenotypes of these cells were inhibited by CA-5f in a concentration-dependent manner. Protein expression of urokinase-type plasminogen activator (uPA), a serine protease known to degrade the extracellular matrix and lead to invasion, was markedly decreased by CA-5f in Hs578T cells. However, mRNA level of uPA was not altered by CA-5f, implicating that the effect of CA-5f was not through transcriptional regulation. Of note, CA-5f upregulated plasminogen activator inhibitor type (PAI)-1, which is known to inhibit uPA by interacting with urokinase-type plasminogen receptor, in TNBC cells. Taken together, these results demonstrated that CA-5f significantly inhibited the invasive phenotype of TNBC cells, possibly by decreasing the protein level of uPA through upregulating PAI-1. Our results may provide useful information on developing CA-5f as a potential therapeutic agent against malignant progression of TNBC.

Adiponectin and 8-epi-PGF2α as intermediate influencing factors in weight reduction after legume consumption: a 12-week randomised controlled trial.

Legumes are rich sources of essential nutrients, and their potential health benefits were reported in many studies. Several studies showed a positive effect of legumes on obesity, but randomised clinical trials are limited in the Korean population. The present intervention study investigated the impact of legumes on body weight in obese Korean subjects. A total of 400 participants (BMI ≥ 25 kg/m2) were randomised into two groups. The legume-enriched diet (LD) group replaced one-third of their refined rice consumption with legumes three times per day as a carbohydrate source. In contrast, the usual diet (UD) group consumed their UD. The mean weight loss at 12 weeks was 2·87 (sem 0·21) kg and 0·17 (sem 0·11) kg in the LD and UD, respectively, which was significantly different between the groups (P < 0·001). HDL-cholesterol and adiponectin levels were increased, and levels of glucose, insulin, TAG, and 8-epi-PGF2α and the homoeostasis model assessment of insulin resistance (IR) index value decreased at 12 weeks compared with baseline in the LD. The consumption of legumes may accelerate weight loss accompanied by regulation of adiponectin and 8-epi-PGF2α in obese subjects. In particular, legumes seemed to induce significant changes in BMI by increasing adiponectin in females. Additionally, increases in plasma adiponectin due to greater substantial weight loss may be related to the improvement in IR.

Usefulness of cyclic thermal therapy and red blood cell scintigraphy in patients with chemotherapy-induced peripheral neuropathy.

BACKGROUND: Pharmacological and non-pharmacological therapies have been used to treat patients with chemotherapy-induced peripheral neuropathy (CIPN). However, the effect of therapies in cancer patients has yet to be investigated comprehensively. We hypothesized that cyclic thermal therapy would improve blood flow and microcirculation and improve the symptoms driven by CIPN. METHODS: The criteria of assessment were blood volume in region of interest (ROI) in the images, and European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 questionnaire scores. The blood volume was quantified by using red blood cell (RBC) scintigraphy. All patients were treated 10 times during 10 days. The thermal stimulations, between 15° and 41°, were repeatedly delivered to the patient's hands. RESULTS: The total score of the questionnaires, the score of questions related to the upper limbs, the score of questions closely related to the upper limbs, and the score excluding the upper limbs questions was decreased. The blood volume was decreased, and the variance of blood volume was decreased. During cooling stimulation, the blood volume was decreased, and its variance was decreased. During warming stimulation, the blood volume was decreased, and its variance was decreased. CONCLUSIONS: We suggest that cyclic thermal therapy is useful to alleviate CIPN symptoms by blood circulation improvement. RBC scintigraphy can provide the quantitative information on blood volume under certain conditions such as stress, as well as rest, in peripheral tissue.