RESUMEN

Elevated blood cholesterol and triglyceride levels induced by secondary causes are frequently observed. The identification and appropriate handling of these causes are essential for secondary dyslipidemia treatment. Major secondary causes of hypercholesterolemia and hypertriglyceridemia include an unhealthy diet, diseases and metabolic conditions affecting lipid levels, and therapeutic side effects. It is imperative to correct secondary causes prior to initiating conventional lipid-lowering therapy. Guideline-based lipid therapy can then be administered based on the subsequent lipid levels.

Asunto(s)

Consenso , Dislipidemias , Hipolipemiantes , Humanos , Hipolipemiantes/uso terapéutico , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/tratamiento farmacológico , Dislipidemias/terapia , Biomarcadores/sangre , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/sangre , Hipertrigliceridemia/terapia , Factores de Riesgo , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/tratamiento farmacológico , Resultado del Tratamiento , Triglicéridos/sangre

RESUMEN

Our previous study suggested that the Mono-ADP ribosylhydrolase 2 (MACROD2) rs6110695 A>G polymorphism is significantly associated with white blood cell (WBC) count in the Korean population. The present study aimed to evaluate the clinical relevance of the MACROD2 rs6110695 A>G polymorphism for predicting WBC count by utilizing plasma metabolites and a single-nucleotide polymorphism (SNP). Two groups were characterized by MACROD2 rs6110695 A>G SNP genotypes among 139 healthy subjects based on the genetic information provided in our previous work: rs6110695 AA genotype group (n = 129) and rs6110695 AG genotype group (n = 10). Plasma global metabolic profiling was performed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). To estimate the predictive abilities of WBC count models using the rs6110695 genotype and/or significant differential metabolites, multiple linear regression analysis and receiver operating characteristic (ROC) curve analysis were conducted. The AG genotype had greater WBC-to-apolipoprotein (apo) A-I ratios; counts of WBCs, lymphocytes, monocytes, and granulocytes; monocyte-to-lymphocyte ratio (MLR); and monocyte-to-platelet ratio (MPR) than the AA genotype. In terms of metabolic profile, indoleacetic acid, and butyrylcarnitine levels were considerably distinct between the two groups, and these metabolites were considered to be meaningful prognostic variables for the rs6110695 genotype. Finally, ROC curve analysis demonstrated that the model containing the rs6110695 genotype and the two main metabolites was reliable. The present study revealed that individuals carrying the rs6110695 AG genotype with high plasma indoleacrylic acid and butyrylcarnitine levels might have elevated WBC counts. The rs6110695 genotype and the concentrations of indoleacrylic acid and butyrylcarnitine could contribute to reducing the risk of chronic diseases in the future.

RESUMEN

Nanobodies derived from camelids and sharks offer unique advantages in therapeutic applications due to their ability to bind to epitopes that were previously inaccessible. Traditional methods of nanobody development face challenges such as ethical concerns and antigen toxicity. Our study presents a synthetic, phagedisplayed nanobody library using trinucleotide-directed mutagenesis technology, which allows precise amino acid composition in complementarity-determining regions (CDRs), with a focus on CDR3 diversity. This approach avoids common problems such as frameshift mutations and stop codon insertions associated with other synthetic antibody library construction methods. By analyzing FDA-approved nanobodies and Protein Data Bank sequences, we designed sub-libraries with different CDR3 lengths and introduced amino acid substitutions to improve solubility. The validation of our library through the successful isolation of nanobodies against targets such as PD-1, ATXN1 and STAT3 demonstrates a versatile and ethical platform for the development of high specificity and affinity nanobodies and represents a significant advance in biotechnology.

RESUMEN

The objective of the present case series was to investigate the various computed tomography findings of six dogs diagnosed with extraskeletal osteosarcoma (exOSA) at several locations. Among the tumors evaluated, four were subcutaneous, one was mammary, and one involved the intestinal tract. Intralesional mineralization was observed in all six dogs. Most of the tumors were moderately calcified, exhibited amorphous mineralization, and were heterogeneous on post-contrast imaging. Three of the tumors were peripherally enhanced, and regional lymphadenopathy was identified in two of the dogs, which was presumed to be metastatic. No lymph node calcification was reported. Although the presence of intralesional mineralization is not a pathognomonic finding, it was consistently identified in the present case series. Therefore, exOSA should be considered in the differential diagnosis when mineralization occurs in a mass unrelated to osseous structures.

RESUMEN

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 a 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.

Asunto(s)

Alginatos , Regeneración Ósea , Materiales Biocompatibles Revestidos , Gelatina , Indoles , Lactoglobulinas , Polímeros , Andamios del Tejido , Alginatos/química , Alginatos/farmacología , Indoles/química , Indoles/farmacología , Andamios del Tejido/química , Animales , Polímeros/química , Polímeros/farmacología , Regeneración Ósea/efectos de los fármacos , Gelatina/química , Ovinos , Lactoglobulinas/química , Lactoglobulinas/farmacología , Materiales Biocompatibles Revestidos/farmacología , Materiales Biocompatibles Revestidos/química , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Aldehídos/química , Proliferación Celular/efectos de los fármacos

RESUMEN

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.

Asunto(s)

Indoles , Nanopartículas , Polímeros , Andamios del Tejido , Humanos , Andamios del Tejido/química , Alginatos/química , Gelatina/química , Albúmina Sérica Bovina , Dióxido de Silicio , Regeneración Ósea , Impresión Tridimensional , Ingeniería de Tejidos/métodos , Osteogénesis

RESUMEN

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.

Asunto(s)

Amiloide , Glaucoma , Humanos , Amiloide/metabolismo , Glaucoma/genética , Mutación , Péptidos beta-Amiloides/genética , Proteínas Amiloidogénicas/genética , Pliegue de Proteína

RESUMEN

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.

Asunto(s)

Anexina A2 , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Autofagia/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Factores de Transcripción del Choque Térmico/genética , Anexina A2/genética , Línea Celular Tumoral , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Doxorrubicina , Sirolimus

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Dislipidemias , Masculino , Humanos , Femenino , Estudios Transversales , Metabolómica , HDL-Colesterol , Fibras de la Dieta

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Depresión Posparto , Enfermeras y Enfermeros , Embarazo , Humanos , Femenino , Depresión Posparto/epidemiología , Depresión Posparto/psicología , Depresión/epidemiología , Depresión/etiología , Periodo Posparto , Factores de Riesgo , República de Corea/epidemiología

RESUMEN

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.

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Adenosina Trifosfatasas , Elementos Transponibles de ADN , Proteínas de Unión al ADN , Proteínas de Escherichia coli , ARN Bacteriano , Adenosina Trifosfatasas/metabolismo , Secuenciación de Inmunoprecipitación de Cromatina , Elementos Transponibles de ADN/genética , ADN Bacteriano/química , ADN Bacteriano/metabolismo , Proteínas de Unión al ADN/metabolismo , Escherichia coli/enzimología , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , ARN Bacteriano/genética , ARN Bacteriano/metabolismo , Especificidad por Sustrato , Transposasas/metabolismo

RESUMEN

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.

Asunto(s)

Neoplasias Pulmonares , Anticuerpos de Cadena Única , Carcinoma Pulmonar de Células Pequeñas , Molécula 1 de Adhesión Celular/genética , Técnicas de Visualización de Superficie Celular , Humanos , Anticuerpos de Cadena Única/farmacología

RESUMEN

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.

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Fármacos Antiobesidad , Hordeum , Obesidad , Células 3T3-L1 , Adipocitos , Adipogénesis , Adiponectina/metabolismo , Animales , Fármacos Antiobesidad/farmacología , Arginina/análogos & derivados , Peso Corporal , Metabolismo de los Hidratos de Carbono , Fructosa/análogos & derivados , Hordeum/química , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Extractos Vegetales/farmacología

RESUMEN

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.

Asunto(s)

Enfermedad de la Válvula Aórtica , Estenosis de la Válvula Aórtica , Estenosis de la Válvula Aórtica/cirugía , Humanos , Inflamación , Fosfoproteínas , Proteoma , Proteómica , Reperfusión