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MOTIVATION: Protein-ligand binding affinity prediction is a central task in drug design and development. Cross-modal attention mechanism has recently become a core component of many deep learning models due to its potential to improve model explainability. Non-covalent interactions (NCIs), one of the most critical domain knowledge in binding affinity prediction task, should be incorporated into protein-ligand attention mechanism for more explainable deep drug-target interaction models. We propose ArkDTA, a novel deep neural architecture for explainable binding affinity prediction guided by NCIs. RESULTS: Experimental results show that ArkDTA achieves predictive performance comparable to current state-of-the-art models while significantly improving model explainability. Qualitative investigation into our novel attention mechanism reveals that ArkDTA can identify potential regions for NCIs between candidate drug compounds and target proteins, as well as guiding internal operations of the model in a more interpretable and domain-aware manner. AVAILABILITY: ArkDTA is available at https://github.com/dmis-lab/ArkDTA. CONTACT: kangj@korea.ac.kr.
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Sistemas de Liberación de Medicamentos , Diseño de Fármacos , LigandosRESUMEN
AIM: Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects. METHODS: In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing. RESULTS: Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated. CONCLUSION: The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.
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Etnicidad , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Masculino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Estudios Cruzados , Área Bajo la Curva , Interacciones Alimento-Droga , Voluntarios Sanos , Administración Oral , República de Corea , ChinaRESUMEN
Mixed-lineage protein kinase 3 (MLK3) is implicated in several human cancers and neurodegenerative diseases. A series of 3H-imidazo[4,5-b]pyridine derivatives were designed, synthesized and evaluated as novel MLK3 inhibitors. A homology model of MLK3 was developed and all designed compounds were docked to assess their binding pattern and affinity toward the MLK3 active site. Based on this knowledge, we synthesized and experimentally evaluated the designed compounds. Majority of the compounds showed significant inhibition of MLK3 in the enzymatic assay. In particular, compounds 9a, 9e, 9j, 9 k, 12b and 12d exhibited IC50 values of 6, 6, 8, 11, 14 and 14 nM, respectively. Furthermore, compounds 9a, 9e, 9 k and 12b exhibited favorable physicochemical properties among these compounds.
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Proteina Quinasa Quinasa Quinasa 11 Activada por Mitógeno , Piridinas , Humanos , Relación Estructura-Actividad , Piridinas/química , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/químicaRESUMEN
Expression and function of odorant receptors (ORs), which account for more than 50% of G protein-coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumor-derived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage-tumor axis. Using Olfr78+/+ and Olfr78-/- bone marrow-derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78-lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.
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Proteínas de Ciclo Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Odorantes/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Animales , Proteínas de Ciclo Celular/fisiología , Línea Celular Tumoral , Femenino , Humanos , Ácido Láctico/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenotipo , Receptores Acoplados a Proteínas G/fisiología , Receptores Odorantes/fisiología , Transducción de Señal , Microambiente Tumoral , Macrófagos Asociados a Tumores/fisiologíaRESUMEN
The circadian rhythm is a 24 h internal clock within the body that regulates various factors, including sleep, body temperature, and hormone secretion. Circadian rhythm disruption is an important risk factor for many diseases including neurodegenerative illnesses. The central and peripheral oscillators' circadian clock network controls the circadian rhythm in mammals. The clock genes govern the central clock in the suprachiasmatic nucleus (SCN) of the brain. One function of the circadian clock is regulating lipid metabolism. However, investigations of the circadian regulation of lipid metabolism-associated apolipoprotein genes in the brain are lacking. This review summarizes the rhythmic expression of clock genes and lipid metabolism-associated apolipoprotein genes within the SCN in Mus musculus. Nine of the twenty apolipoprotein genes identified from searching the published database (SCNseq and CircaDB) are highly expressed in the SCN. Most apolipoprotein genes (ApoE, ApoC1, apoA1, ApoH, ApoM, and Cln) show rhythmic expression in the brain in mice and thus might be regulated by the master clock. Therefore, this review summarizes studies on lipid-associated apolipoprotein genes in the SCN and other brain locations, to understand how apolipoproteins associated with perturbed cerebral lipid metabolism cause multiple brain diseases and disorders. This review describes recent advancements in research, explores current questions, and identifies directions for future research.
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Relojes Circadianos , Metabolismo de los Lípidos , Ratones , Animales , Metabolismo de los Lípidos/genética , Encéfalo/metabolismo , Ritmo Circadiano/genética , Núcleo Supraquiasmático/metabolismo , Relojes Circadianos/genética , Apolipoproteínas/genética , Apolipoproteínas/metabolismo , Mamíferos/metabolismoRESUMEN
Composites based on carbon nanotubes (CNTs) are promising patternable materials that can be engineered to incorporate the outstanding properties of CNTs into various applications via printing technologies. However, conventional printing methods for CNTs require further improvement to overcome the major drawbacks that limit the patterning resolution and target substrate. Herein, an intaglio contact printing method based on a CNT/paraffin composite is presented for realizing highly precise CNT network patterns without restrictions on the substrate. In this method, the CNT/paraffin composite can be patterned with a high resolution (<10 µm) and neatly transferred onto various substrates with a wide range of surface energies, including human skin. The patterned composite exhibits high durability against structural deformations, and structural damage caused by fatigue accumulation can be cured in a few seconds. In addition, miniaturized sensing and energy-harvesting applications are demonstrated with high performances. The present method facilitates the rapid fabrication of highly precise interdigitated electrodes via one-step printing, enabling high-performance operation and miniaturization of the devices. It is anticipated that these results will not only spur the further development of various applications of CNTs but also contribute to advances in soft lithography methods applicable to many fields of science and engineering.
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Nanotubos de Carbono , Electrodos , Humanos , Nanotubos de Carbono/química , Impresión TridimensionalRESUMEN
Tumor-derived extracellular vesicles (EVs) have emerged as a promising source of circulating biomarkers for liquid biopsies. However, understanding the heterogeneous physical and biochemical properties of EVs originating from multiple complex biogenesis pathways remains a major challenge. Here, we introduce EV-Ident for preparation of subpopulations of EVs in three different size fractions: large EVs (EV200 nm; 200-1â¯000 nm), medium EVs (EV100 nm; 100-200 nm), and small EVs (EV20 nm; 20-100 nm). Furthermore, this technology enables the in situ labeling of fluorescence markers for the protein profiling of individual EVs. As a proof-of-concept, we analyzed the presence of human epidermal growth factor receptor 2 (HER2) and prostate-specific membrane antigen (PSMA) in breast cancer and prostate cancer cell-derived EVs, respectively, using three different size fractions at the single-EV level. By reducing the complexity of EV heterogeneity in each size fraction, we found that HER2-positive breast cancer cells showed the greatest expression of HER2 in EV20 nm, whereas PSMA expression was the highest in EV200 nm derived from PSMA-expressing prostate cancer cells. This increase in HER2 expression in EV20 nm and PSMA expression in EV200 nm was further confirmed in plasma-derived nanoparticles (PNPs) obtained from breast and prostate cancer patients, respectively. Our study demonstrates that single-EV analysis using EV-Ident provides a practical way to understand EV heterogeneity and to successfully identify potent subpopulation of EVs for breast and prostate cancer, which has promising translational implications for cancer theranostics. Furthermore, these findings have the potential to address fundamental questions surrounding the biology and clinical applications of EVs.
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Antígenos de Superficie/sangre , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Vesículas Extracelulares/química , Glutamato Carboxipeptidasa II/sangre , Neoplasias de la Próstata/sangre , Receptor ErbB-2/sangre , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Masculino , Tamaño de la Partícula , Neoplasias de la Próstata/diagnóstico , Propiedades de SuperficieRESUMEN
Odorant receptors are the largest subfamily of G protein-coupled receptors and were recently suggested to play critical roles in nonolfactory tissues. However, the expression and function of odorant receptors in astrocytes, the most abundant cells in the brain, are not well known. We demonstrate that Olfr920 is highly expressed and propose that it functions as a short-chain fatty acid sensor in primary cortical astrocytes. The short-chain fatty acid isobutyric acid (IBA) was identified via a luciferase assay as an Olfr920 ligand. We show that IBA activates the Gs protein-adenylyl cyclase-cAMP pathway via Olfr920 in primary cortical astrocytes by using cAMP and knockdown analyses. In addition, IBA reduces lipopolysaccharide-induced glial fibrillary acidic protein expression in reactive astrocytes. These results suggest that astrocytic Olfr920 is a potential novel target for increased reactive astrocytes.
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Astrocitos/metabolismo , Isobutiratos/farmacología , Receptores Odorantes/agonistas , Animales , Astrocitos/efectos de los fármacos , Células Cultivadas , AMP Cíclico/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones Endogámicos C57BL , Receptores Odorantes/metabolismoRESUMEN
Colorectal cancer (CRC) is the second-highest cause of cancer-associated mortality among both men and women worldwide. One of the risk factors for CRC is obesity, which is correlated with a high-fat diet prevalent in Western dietary habits. The association between an obesogenic high-fat diet and CRC has been established for several decades; however, the mechanisms by which a high-fat diet increases the risk of CRC remain unclear. Recent studies indicate that gut microbiota strongly influence the pathogenesis of both high-fat diet-induced obesity and CRC. The gut microbiota is composed of hundreds of bacterial species, some of which are implicated in CRC. In particular, the expansion of facultative anaerobic Enterobacteriaceae, which is considered a microbial signature of intestinal microbiota functional imbalance (dysbiosis), is associated with both high-fat diet-induced obesity and CRC. Here, we review the interaction between the gut microbiome and its metabolic byproducts in the context of colorectal cancer (CRC) during high-fat diet-induced obesity. In addition, we will cover how a high-fat diet can drive the expansion of genotoxin-producing Escherichia coli by altering intestinal epithelial cell metabolism during gut inflammation conditions.
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Neoplasias Colorrectales , Dieta Alta en Grasa , Disbiosis , Microbioma Gastrointestinal , Obesidad , Dieta Alta en Grasa/efectos adversos , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/etiología , Humanos , Obesidad/microbiología , Animales , Disbiosis/microbiología , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/genética , Bacterias/aislamiento & purificación , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismoRESUMEN
The selected strain, TAP041, showing an excellent ability to reduce the glyoxal and methylglyoxal levels, was identified by 16S rRNA gene-based phylogenetic analysis as Pediococcus pentosaceus. It demonstrated probiotic properties, including acid, bile salt, pancreatin, lysozyme tolerance, gut adhesion, and auto/coaggregation. In RAW264.7 macrophages, both live and heat-killed strains induced nitric oxide production and activated inducible nitric oxide synthase. RAW264.7 treated with P. pentosaceus TAP041 increased the expression level of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and cyclooxygenase-2, and regulated the expression of c-Jun amino-terminal kinase, p38, and extracellular signal-regulated kinase. These findings suggest that both live and heat-killed P. pentosaceus TAP041 can be used as potential immunostimulatory agents in functional food additives. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01530-2.
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The current challenge in using extracellular vesicles (EVs) as drug delivery vehicles is to precisely control their membrane permeability, specifically in the ability to switch between permeable and impermeable states without compromising their integrity and functionality. Here, we introduce a rapid, efficient, and gentle loading method for EVs based on tonicity control (TC) using a lab-on-a-disc platform. In this technique, a hypotonic solution was used for temporarily permeabilizing a membrane ("on" state), allowing the influx of molecules into EVs. The subsequent isotonic washing led to an impermeable membrane ("off" state). This loading cycle enables the loading of different cargos into EVs, such as doxorubicin hydrochloride (Dox), ssDNA, and miRNA. The TC approach was shown to be more effective than traditional methods such as sonication or extrusion, with loading yields that were 4.3-fold and 7.2-fold greater, respectively. Finally, the intracellular assessments of miRNA-497-loaded EVs and doxorubicin-loaded EVs confirmed the superior performance of TC-prepared formulations and demonstrated the impact of encapsulation heterogeneity on the therapeutic outcome, signifying potential opportunities for developing novel exosome-based therapeutic systems for clinical applications.
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Exosomas , Vesículas Extracelulares , MicroARNs , Comunicación Celular , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodosRESUMEN
The development of pressure sensors with high sensitivity and effectiveness that exhibit linearity over a wide pressure range is crucial for wearable devices. In this study, we fabricated a novel ionic liquid (IL)/polymer composite with a convex and randomly wrinkled microstructure in a cost-effective and facile manner using an opaque glass and stretched polydimethylsiloxane template. The fabricated IL/polymer composite was used as the dielectric layer in a capacitive pressure sensor. The sensor exhibited a high linear sensitivity of 56.91 kPa-1 owing to the high interfacial capacitance formed by the electrical double layer of the IL/polymer composite over a relatively wide range (0-80 kPa). We also demonstrated the sensor performance for various applications such as a glove-attached sensor, sensor array, respiration monitoring mask, human pulse, blood pressure measurement, human motion detection, and a wide range of pressure sensing. It would be expected that the proposed pressure sensor has sufficient potential for use in wearable devices.
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Cancer immunotherapy has been acknowledged as a new paradigm for cancer treatment, with notable therapeutic effects on certain cancer types. Despite their significant potential, clinical studies over the past decade have revealed that cancer immunotherapy has low response rates in the majority of solid tumors. One of the key causes for poor responses is known to be the relatively low immunogenicity of solid tumors. Because most solid tumors are immune desert 'cold tumors' with antitumor immunity blocked from the onset of innate immunity, combination therapies that combine validated T-based therapies with approaches that can increase tumor-immunogenicity are being considered as relevant therapeutic options. This review paper focuses on immunogenic cell death (ICD) as a way of enhancing immunogenicity in tumor tissues. We will thoroughly review how ICDs such as necroptosis, pyroptosis, and ferroptosis can improve anti-tumor immunity and outline clinical trials targeting ICD. Finally, we will discuss the potential of ICD inducers. as an adjuvant for cancer immunotherapy.[BMB Reports 2023; 56(5): 275-286].
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Antineoplásicos , Neoplasias , Humanos , Muerte Celular , Muerte Celular Inmunogénica , Inmunoterapia , Antineoplásicos/farmacologíaRESUMEN
Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. In a recent phase I study, Venetoclax (ABT-199) targeting Bcl-2 also exhibited disappointing response rates in patients with relapsed/refractory DLBCL, suggesting that targeting only Bcl-2 is not sufficient for achieving successful efficacy due to the concurrent oncogenic function of c-Myc expression and drug resistance following an increase in Mcl-1. Therefore, co-targeting c-Myc and Mcl-1 could be a key combinatorial strategy to enhance the efficacy of Venetoclax. In this study, BR101801 a novel drug for DLBCL, effectively inhibited DLBCL cell growth/proliferation, induced cell cycle arrest, and markedly inhibited G0/G1 arrest. The apoptotic effect of BR101801 was also observed by increased Cytochrome C, cleaved PARP, and Annexin V-positive cell populations. This anti-cancer effect of BR101801 was confirmed in animal models, where it effectively inhibited tumor growth by reducing the expression of both c-Myc and Mcl-1. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL.
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Medullary thyroid cancer originates from parafollicular C-cells in the thyroid. Despite successful thyroidectomy, localizing remnant cancer cells in patients with elevated calcitonin and carcinoembryonic antigen levels remains a challenge. Extranasal odorant receptors are expressed in cells from non-olfactory tissues, including C-cells. This study evaluates the odorant receptor signals from parafollicular C-cells, specifically, the presence of olfactory marker protein, and further assesses the ability of the protein in localizing and treating medullary thyroid cancer. We used immunohistochemistry, immunofluorescent staining, Western blot, RNA sequencing, and real time-PCR to analyze the expression of odorant receptors in mice thyroids, thyroid cancer cell lines, and patient specimens. We used in vivo assays to analyze acetate binding, calcitonin secretion, and cAMP pathway. We also used positron emission tomography (PET) to assess C11-acetate uptake in medullary thyroid cancer patients. We investigated olfactory marker protein expression in C-cells in patients and found that it co-localizes with calcitonin in C-cells from both normal and cancer cell lines. Specifically, we found that OR51E2 and OR51E1 were expressed in thyroid cancer cell lines and human medullary thyroid cancer cells. Furthermore, we found that in the C-cells, the binding of acetate to OR51E2 activates its migration into the nucleus, subsequently resulting in calcitonin secretion via the cAMP pathway. Finally, we found that C11-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C11-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C11-acetate PET, we identified recurrence sites in post-operative medullary thyroid cancer patients. Therefore, OR51E2 may be a novel diagnostic and therapeutic target for medullary thyroid cancer.
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Odorant receptors (ORs), the largest subfamily of G protein-coupled receptors, detect odorants in the nose. In addition, ORs were recently shown to be expressed in many nonolfactory tissues and cells, indicating that these receptors have physiological and pathophysiological roles beyond olfaction. Many ORs are expressed by tumor cells and tissues, suggesting that they may be associated with cancer progression or may be cancer biomarkers. This review describes OR expression in various types of cancer and the association of these receptors with various types of signaling mechanisms. In addition, the clinical relevance and significance of the levels of OR expression were evaluated. Namely, levels of OR expression in cancer were analyzed based on RNA-sequencing data reported in the Cancer Genome Atlas; OR expression patterns were visualized using t-distributed stochastic neighbor embedding (t-SNE); and the associations between patient survival and levels of OR expression were analyzed. These analyses of the relationships between patient survival and expression patterns obtained from an open mRNA database in cancer patients indicate that ORs may be cancer biomarkers and therapeutic targets. [BMB Reports 2022;55(2): 72-80].
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Neoplasias , Receptores Odorantes , Biomarcadores de Tumor/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Odorantes , Receptores Acoplados a Proteínas G , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , OlfatoRESUMEN
The development of hepatic insulin resistance (IR) is a critical factor in developing type 2 diabetes (T2D), where insulin fails to inhibit hepatic glucose production but retains its capacity to promote hepatic de novo lipogenesis leading to hyperglycemia and hypertriglyceridemia. Improving insulin sensitivity can be effective in preventing and treating T2D. However, selective control of glucose and lipid synthesis has been difficult. It is known that excess white adipose tissue is detrimental to insulin sensitivity, whereas brown adipose tissue transplantation can restore it in diabetic mice. However, challenges remain in our understanding of liver-adipose communication because the confounding effects of hypothalamic regulation of metabolic function cannot be ruled out in previous studies. There is a lack ofin vitromodels that use primary cells to study cellular-crosstalk under insulin resistant conditions. Building upon our previous work on the microfluidic primary liver and adipose organ-on-chips, we report for the first time, the development of an integrated insulin resistant liver-adipose (white and brown) organ-on-chip. The design of the microfluidic device was carried out using computational fluid dynamics; the experimental studies were conducted by carrying out detailed biochemical analysis RNA-seq analysis on both cell types. Further, we tested the hypothesis that brown adipocytes (BAC) regulated both hepatic insulin sensitivity and de novo lipogenesis. Our results show that BAC effectively restored insulin sensitivity and supressed hepatic glucose production and de novo lipogenesis suggesting that the experimental platform could be useful for identifying potential therapeutics to treat IR and diabetes.
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Adipocitos Marrones , Adipocitos Blancos , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Análisis de Matrices Tisulares , Adipocitos Marrones/citología , Adipocitos Marrones/metabolismo , Adipocitos Blancos/citología , Adipocitos Blancos/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Dispositivos Laboratorio en un Chip , Lipogénesis/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Análisis de Matrices Tisulares/instrumentación , Análisis de Matrices Tisulares/métodosRESUMEN
A triboelectric nanogenerator (TENG) is an energy generator that converts mechanical energy into electrical energy using triboelectricity at a nanoscale. Given their potential application as power sources in electronic devices, various attempts have been made to improve their output performance. Here, we present an eco-friendly, low-cost, and facile fabrication method to enhance TENG characteristics with keratin protein additives. Keratin sources, human and cat hair, are processed into powder and added to the friction layer, which increases their positive charge affinity, thereby boosting the output performance of the TENG. The output performances of the keratin-added TENG (K-TENG) are measured in the vertical contact-separation mode, with both additives having the highest output values at 5 wt % load. The K-TENG generates more output voltage and current values than the pristine TENG by 90 and 208%, respectively. Hence, we conclude that this method would potentially promote TENG as a strong candidate for a competitive "green" energy harvesting device in future electronics applications.
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Queratinas , Polímeros , Humanos , Citoesqueleto , Suministros de Energía Eléctrica , ElectrónicaRESUMEN
Pseudomonas aeruginosa (P. aeruginosa) is a well-known Gramnegative opportunistic pathogen. Neutrophils play key roles in mediating host defense against P. aeruginosa infection. In this study, we identified a metabolite derived from P. aeruginosa that regulates neutrophil activities. Using gas chromatography-mass spectrometry, a markedly increased level of 2-undecanone was identified in the peritoneal fluid of P. aeruginosa-infected mice. 2-Undecanone elicited the activation of neutrophils in a Gαi-phospholipase C pathway. However, 2-undecanone strongly inhibited responses to lipopolysaccharide and bactericidal activity of neutrophils against P. aeruginosa by inducing apoptosis. Our results demonstrate that 2-undecanone from P. aeruginosa limits the innate defense activity of neutrophils, suggesting that the production of inhibitory metabolites is a strategy of P. aeruginosa for escaping the host immune system. [BMB Reports 2022; 55(8): 395-400].
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Infecciones por Pseudomonas , Pseudomonas aeruginosa , Animales , Cetonas , Ratones , Neutrófilos/metabolismo , Infecciones por Pseudomonas/metabolismoRESUMEN
Exopolysaccharide (EPS)-producing Lacticaseibacillus paracasei EPS DA-BACS was isolated from healthy human feces and its probiotic properties, as well as the structure and prebiotic activity of the EPS from this strain were examined. EPS from L. paracasei EPS DA-BACS had a ropy phenotype, which is known to have potential health benefits and is identified as loosely cell-bounded glucomannan-type EPS with a molecular size of 3.7 × 106 Da. EPS promoted the acid tolerance of L. paracasei EPS DA-BACS and provided cells with tolerance to gastrointestinal stress. The purified EPS showed growth inhibitory activity against Clostridium difficile. L. paracasei EPS DA-BACS cells completely inhibited the growth of Bacillus subtilis, Pseudomonas aeruginosa, and Aspergillus brasiliensis, as well as showed high growth inhibitory activity against Staphylococcus aureus and Escherichia coli. Treatment of lipopolysaccharide-stimulated RAW 264.7 cells with heat-killed L. paracasei EPS DA-BACS cells led to a decrease in the production of nitric oxide, indicating the anti-inflammatory activity of L. paracasei EPS DA-BACS. Purified EPS promoted the growth of Lactobacillus gasseri, Bifidobacterium bifidum, B. animalis, and B. faecale which showed high prebiotic activity. L. paracasei EPS DA-BACS harbors no antibiotic resistance genes or virulence factors. Therefore, L. paracasei EPS DA-BACS exhibits anti-inflammatory and antimicrobial activities with high gut adhesion ability and gastrointestinal tolerance and can be used as a potential probiotic.