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1.
Nat Commun ; 15(1): 568, 2024 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-38278791

RESUMEN

Microbes can decompose biodegradable plastics on land, rivers and seashore. However, it is unclear whether deep-sea microbes can degrade biodegradable plastics in the extreme environmental conditions of the seafloor. Here, we report microbial decomposition of representative biodegradable plastics (polyhydroxyalkanoates, biodegradable polyesters, and polysaccharide esters) at diverse deep-sea floor locations ranging in depth from 757 to 5552 m. The degradation of samples was evaluated in terms of weight loss, reduction in material thickness, and surface morphological changes. Poly(L-lactic acid) did not degrade at either shore or deep-sea sites, while other biodegradable polyesters, polyhydroxyalkanoates, and polysaccharide esters were degraded. The rate of degradation slowed with water depth. We analysed the plastic-associated microbial communities by 16S rRNA gene amplicon sequencing and metagenomics. Several dominant microorganisms carried genes potentially encoding plastic-degrading enzymes such as polyhydroxyalkanoate depolymerases and cutinases/polyesterases. Analysis of available metagenomic datasets indicated that these microorganisms are present in other deep-sea locations. Our results confirm that biodegradable plastics can be degraded by the action of microorganisms on the deep-sea floor, although with much less efficiency than in coastal settings.


Asunto(s)
Plásticos Biodegradables , Polihidroxialcanoatos , ARN Ribosómico 16S/genética , Biodegradación Ambiental , Poliésteres/metabolismo , Polisacáridos
2.
Mar Pollut Bull ; 199: 115466, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37806825

RESUMEN

Understanding microplastic (MP) behavior in oceans is crucial for reducing marine plastic pollution. However, the complex process underlying MP transportation to the deep seafloor remains unknown despite the deep sea being considered its major sink. We focused on MP distribution in Sagami Bay (adjacent to highly populated areas of Japan), the plate triple junction connected through the Sagami Trough, and the abyssal plain immediately below the Kuroshio Extension. We observed the highest number of MPs in the abyssal stations, more than previously reported. The polymer types and aspect ratio of MPs in the abyssal stations significantly differed from those in the bathyal/hadal stations. The study suggests that MPs accumulated in the open ocean surface layer sink to the abyssal plains immediately below it, while MPs from land sources accumulate in the bathyal depth and are transported to the hadal depth near the coast through turbidity currents along the submarine canyon.


Asunto(s)
Microplásticos , Contaminantes Químicos del Agua , Plásticos , Sedimentos Geológicos , Ecosistema , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente
3.
MethodsX ; 11: 102489, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38053623

RESUMEN

With the high number of microplastic-like particles captured by net hauls including manta or neuston nets, it is often required to subsample in order to decrease sample volume for microplastic enumeration and analysis. Plankton splitter is commonly used to divide microplastic samples. However, current devices such as Folsom plankton splitter and Motoda box splitter have accuracy issues in separating highly buoyant microplastics, namely expanded polystyrene (EPS) as they tend to adhere to the inner walls. Inspired by an apple cutter, we have developed a simple radial splitter made of stainless steel that efficiently divides EPS microplastic samples into precise aliquots. With this simple device, we uniformly divided EPS microplastic samples from marine environments into eight aliquots with no significant differences. The device is a versatile tool to partition all buoyant microplastics including polypropylene and polyethylene microplastics.•The method developed facilitates the precise division of buoyant microplastics into equal aliquots.•The method is specifically effective in splitting expanded polystyrene particles with high buoyancy.

4.
Commun Biol ; 6(1): 1105, 2023 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-37907640

RESUMEN

In the brain, many regions work in a network-like association, yet it is not known how durable these associations are in terms of activity and could survive without structural connections. To assess the association or similarity between brain regions with a generating approach, this study evaluated the similarity of activities of neurons within each region after disconnecting between regions. The "generation" approach here refers to using a multi-layer LSTM (Long Short-Term Memory) model to learn the rules of activity generation in one region and then apply that knowledge to generate activity in other regions. Surprisingly, the results revealed that activity generation from one region to disconnected regions was possible with similar accuracy to generation between the same regions in many cases. Notably, firing rates and synchronization of firing between neuron pairs, often used as neuronal representations, could be reproduced with precision. Additionally, accuracies were associated with the relative angle between brain regions and the strength of the structural connections that initially connected them. This outcome enables us to look into trends governing non-uniformity of the cortex based on the potential to generate informative data and reduces the need for animal experiments.


Asunto(s)
Encéfalo , Neuronas , Animales , Neuronas/fisiología , Corteza Cerebral , Aprendizaje
5.
eNeuro ; 10(10)2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37903612

RESUMEN

The brain is an organ that functions as a network of many elements connected in a nonuniform manner. In the brain, the neocortex is evolutionarily newest and is thought to be primarily responsible for the high intelligence of mammals. In the mature mammalian brain, all cortical regions are expected to have some degree of homology, but have some variations of local circuits to achieve specific functions performed by individual regions. However, few cellular-level studies have examined how the networks within different cortical regions differ. This study aimed to find rules for systematic changes of connectivity (microconnectomes) across 16 different cortical region groups. We also observed unknown trends in basic parameters in vitro such as firing rate and layer thickness across brain regions. Results revealed that the frontal group shows unique characteristics such as dense active neurons, thick cortex, and strong connections with deeper layers. This suggests the frontal side of the cortex is inherently capable of driving, even in isolation and that frontal nodes provide the driving force generating a global pattern of spontaneous synchronous activity, such as the default mode network. This finding provides a new hypothesis explaining why disruption in the frontal region causes a large impact on mental health.


Asunto(s)
Neocórtex , Neuronas , Animales , Neuronas/fisiología , Lóbulo Frontal/fisiología , Cabeza , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiología , Imagen por Resonancia Magnética , Mamíferos
6.
Biopsychosoc Med ; 17(1): 30, 2023 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-37612759

RESUMEN

BACKGROUND: This study aimed to conduct a preliminary evaluation of the effects of 6-methylsulfinylhexyl isothiocyanate (6-MSITC) contained in wasabi rhizomes on fatigue and sleep and to examine its safety through overdose study. METHODS: A total of 20 healthy volunteers who were experiencing daily fatigue were given powder containing 6-MSITC (4.8 mg/day of 6-MSITC) extracted from wasabi for 4 weeks. Then, fatigue, sleep, autonomic nervous functioning, stress, and immunity were evaluated. In addition, an overdose safety study of the extract powder (up to 16 mg/day of 6-MSITC for 4 weeks) was performed with 30 healthy volunteers in a double-blind, placebo-controlled method. RESULTS: The powder containing 6-MSITC did not improve fatigue after a mental task, but fatigue before the mental task, sleep, and mood were improved significantly after 4 weeks intake. No changes were observed in the autonomic nerve function, stress, or immune markers. In the overdose safety study, no changes in the parameters ​​or side effects were observed, and the results showed that high doses of the extract powder containing 6-MSITC is safe. CONCLUSION: This study confirmed the possibility that this powder extracted from wasabi that contains 6-MSITC might improve fatigue and sleep. However, because the effectiveness evaluation in this study was a single-arm, open-label study and there was no placebo control group, these points must be considered when interpreting the results. Safety was confirmed in an overdose study of more than three times the amount compared to that in the efficacy evaluation study. In the future, further research should be conducted on its effectiveness for treating fatigue and sleep problems. TRIAL REGISTRATION: UMIN clinical trial registration system, UMIN000049913. Registered 27 December 2022 Retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000056818.

7.
iScience ; 26(7): 107054, 2023 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-37534189

RESUMEN

The accumulation of polybrominated diphenyl ethers (PBDEs) and benzotriazole UV stabilizers (BZT-UVs) were examined in the hadal amphipod Hirondellea gigas caught from a near-land trench off the Japan island (9200 m). H. gigas were collected from two distinct sites: one is located at the outlet of submarine canyons directly connected to land and the other is apart from the outlet and geographically isolated from the first site. The level of the PBDEs in H. gigas at the canyon outlet (mean 219 ng/g lipid weight (l.w.)) was significantly higher than that in the isolated site (mean 42 ng/g l.w.) and BZT-UVs were only detected within the first site (mean 1.5 ng/g wet weight). In addition to vertical transport from the surface water, near-land trenches associated with submarine canyons and troughs may have more complex influx of contaminants through horizontal transportation from the land, resulting in more severe contamination.

8.
J Toxicol Sci ; 48(2): 65-73, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36725022

RESUMEN

Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, induces various biological reactions in vivo. Our previous study suggested that LPS administration disrupts respiratory chain complex activities, enhances reactive oxygen species production, especially in the liver mitochondria, and sensitizes mitochondrial permeability transition (MPT) pore opening in rats. However, it is unknown whether LPS-induced MPT pore opening in rats is similarly observed in mice and whether the mechanism is the same. LPS administration to mice increased not only cyclosporin A-sensitive swelling (MPT pore opening) susceptibility, but also induced cyclosporin A-insensitive basal swelling, unlike in rats. In addition, respiratory activity observed after adding ADP was significantly decreased. Based on these results, we further investigated the role of adenine nucleotide translocase (ANT). Carboxyatractyloside (CATR; an ANT inhibitor) treatment decreased respiratory activity after ADP was added in vehicle-treated mitochondria similarly to LPS administration. Additionally, CATR treatment increased MPT pore opening susceptibility in LPS-treated mitochondria compared to that of vehicle-treated mitochondria. Our study shows that ANT maintained a c-state conformation upon LPS administration, which increased MPT pore opening susceptibility in mice. These results suggest that LPS enhances MPT pore opening susceptibility across species, but the mechanism may differ between rat and mouse.


Asunto(s)
Mitocondrias Hepáticas , Translocasas Mitocondriales de ADP y ATP , Poro de Transición de la Permeabilidad Mitocondrial , Animales , Ratones , Calcio/metabolismo , Ciclosporina/farmacología , Lipopolisacáridos/toxicidad , Hígado/metabolismo , Mitocondrias Hepáticas/metabolismo , Permeabilidad
9.
Chem Commun (Camb) ; 59(28): 4162-4165, 2023 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-36853596

RESUMEN

A new organic superconductor (TEA)(HEDO-TTF-dc)2·2(H2C2O4) (H2EDO-TTF-dc = ethylenedioxy-tetrathiafulvalene dicarboxylic acids) with an onset TC of 4.0 K, was successfully obtained using oxalic acid and HEDO-TTF-dc anion donor. The crystal structure analysis indicated that strong π-π overlaps and very strong intra- and inter-molecular hydrogen-bonding interactions exist between the HEDO-TTF-dc anion donors and oxalic acid molecules.

10.
Anal Bioanal Chem ; 415(5): 775-785, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36504284

RESUMEN

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme essential for energy production. Recently, associations between NAD+ and aging-related diseases have been reported, and NAD+ precursors that increase NAD+ concentration in the body have been acknowledged as anti-aging supplements. However, there have been only a few studies on the link between aging or aging-related diseases and human blood NAD+ concentration because NAD+ and its precursors are unstable in blood and difficult to measure. Therefore, we aimed to construct a quantitative NAD+ measurement method that is simpler than the existing methods. The calibration standards of NAD+ showed good linearity (0.9936 to 0.9990) in the range of 0.25 to 200 µM, and the lower limit of quantification was 0.5 to 2 µM. We found that QIAcard FTA DMPK-B maintained NAD+ stability of 85% or more for at least 2 weeks at 4 °C and 1 week at room temperature using the dried blood spot method. Additionally, NAD+ stability in the blood extraction solution was more than 90% for 2 months. To our knowledge, there has been no report on a quantitative NAD+ measurement method in human whole blood that can be performed with as little as 5 µL of blood and can be easily implemented at both medical clinics and private homes. Our simple and convenient method has the potential to become the gold standard for NAD+ measurement in blood. It is expected to contribute to the acceleration of research on the correlation between aging or aging-related diseases and NAD+ concentration in human blood.


Asunto(s)
Envejecimiento , NAD , Humanos
11.
Sci Total Environ ; 855: 159564, 2023 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-36332720

RESUMEN

The recent influx of microplastics into the Arctic Ocean may increase environmental stress on the western Arctic marine ecosystem, which is experiencing significant sea-ice loss due to global warming. Quantitative data on microplastics in the western Arctic Ocean are very limited, and the microplastic budget of the water column is completely unknown. To fill in gaps in our knowledge of Arctic microplastics, we observed surface concentrations (number of particles per unit volume of seawater) of meso- and microplastics using a neuston net, and we observed wind speeds and significant wave heights in the Chukchi Sea, Bering Strait, and Bering Sea. From these observations, we estimated the total number (particle inventory) and mass (mass inventory) of microplastics in the entire water column by taking into account the effect of vertical mixing. The particle inventory of microplastics in the Chukchi Sea ranged from 0 to 18,815 pieces km-2 with a mean and standard deviation of 5236 ± 6127 pieces km-2. The mass inventory ranged from 0 to 445 g km-2 with a mean and standard deviation of 124 ± 145 g km-2. Mean particle inventories for the Chukchi Sea were one-thirtieth of those for the Arctic Ocean on the Atlantic side and less than one-tenth of the average for the global ocean, suggesting that the Chukchi Sea is less polluted. However, the annual flux of microplastics from the Pacific Ocean into the Chukchi Sea, estimated from microplastic concentrations in the Bering Strait, was about 5.5 times greater than the total amount of microplastic in the entire Chukchi Sea water. This suggests that microplastic inflows from the Pacific Ocean are accumulating in large amounts in reservoirs other than the Chukchi Sea water (e.g., sea ice and seafloor sediments) or in the downstream regions of the Pacific-origin water.


Asunto(s)
Microplásticos , Agua , Plásticos , Ecosistema , Océano Pacífico
12.
Biopsychosoc Med ; 16(1): 26, 2022 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-36510244

RESUMEN

BACKGROUND: Wasabi (Eutrema japonicum) is a common pungent spice used in Japan. 6-Methylsulfinylhexyl isothiocyanate (6-MSITC) found in the rhizome of wasabi has been shown to have anti-inflammatory and antioxidant effects, as well as improve neuroinflammation and memory. Therefore, we hypothesized that these effects would be beneficial for treating myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was conducted to investigate the effectiveness of wasabi extract containing 6-MSITC on ME/CFS in an open-label trial. METHODS: Fifteen patients (3 males, 12 females, 20-58 years old) were orally administered wasabi extract (9.6 mg of 6-MSITC/day) for 12 weeks. The following parameters and test results were compared pre- and post-treatment: performance status (PS), self-rating questionnaires, pressure pain threshold (PPT) on the occiput, Trail Making test-A (TMT-A), and hemodynamic patterns determined by an active standing test. RESULTS: After treatment with 6-MSITC, PS improved significantly (p = 0.001). Although the scores on the 11-item Chalder Fatigue scale (CFS-11) and numerical rating scale (NRS) of fatigue did not show significant changes, subjective symptoms improved significantly, including headache frequency (4.1 to 3.0 times/week, p = 0.001) and myalgia (4.1 to 2.4 times/week, p = 0.019), NRS brain fog scores (5.7 to 4.5, p = 0.011), difficulty finding appropriate words (4.8 to 3.7, p = 0.015), photophobia (4.8 to 3.5, p = 0.008), and the Profile of Mood Status vigor score (46.9 to 50.0, p = 0.045). The PPT of the right occiput (17.3 to 21.3 kPa, p = 0.01) and TMT-A scores (53.0 to 38.1 s, p = 0.007) also changed, suggesting reduced pain sensitivity, and improved cognitive function, respectively. Orthostatic patterns determined by a standing test did not show remarkable changes. There were no serious adverse reactions. CONCLUSION: This study suggests that 6-MSITC improves PS as well as subjective symptoms such as pain and cognitive dysfunction, and psychological vitality of patients with ME/CFS. It also improved cognitive performance and increased pain thresholds in these patients. 6-MSITC may be a promising therapeutic option especially for improving cognitive dysfunction associated with ME/CFS.

13.
Biomacromolecules ; 23(10): 4220-4229, 2022 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-36084927

RESUMEN

Chitin is a key component of hard parts in many organisms, but the biosynthesis of the two distinctive chitin allomorphs, α- and ß-chitin, is not well understood. The accurate determination of chitin allomorphs in natural biomaterials is vital. Many chitin-secreting living organisms, however, produce poorly crystalline chitin. This leads to spectrums with only broad lines and imprecise peak positions under conventional analytical methods such as X-ray diffraction (XRD), Fourier-transform infrared spectroscopy, and solid-state nuclear magnetic resonance spectroscopy, resulting in inconclusive identification of chitin allomorphs. Here, we developed a novel method for discerning chitin allomorphs based on their different complexation capacity and guest selectivity, using ethylenediamine (EDA) as a complexing agent. From the peak shift observed in XRD profiles of the chitin/EDA complex, the chitin allomorphs can be clearly discerned. By testing this method on a series of samples with different chitin allomorphs and crystallinity, we show that the sensitivity is sufficiently high to detect the chitin allomorphs even in near-amorphous, very poorly crystalline samples. This is a powerful tool for determining the chitin allomorphs in phylogenetically important chitin-producing organisms and will pave the way for clarifying the evolution and mechanism of chitin biosynthesis.


Asunto(s)
Materiales Biocompatibles , Quitina , Quitina/química , Etilenodiaminas , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X
14.
Front Cardiovasc Med ; 9: 844626, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35571222

RESUMEN

Acute myocarditis is a rare but serious complication associated with mRNA-based coronavirus disease 2019 (COVID-19) vaccination. In this article, four COVID-19 mRNA vaccination induced myocarditis cases managed at our tertiary Medical Center have been discussed. Three patients had typical myocarditis. One patient suffered from atrioventricular block and heart failure, which required more intensive treatment, but eventually improved. Additionally, a review of cardiac magnetic resonance imaging (MRI) features related to the diagnosis of myocarditis showed that COVID-19 mRNA vaccine-associated myocarditis tend to have more late-gadolinium enhancement (LGE) accumulation in the inferior lateral wall direction. According to a report by the U.S. Centers for Disease Control and Prevention (CDC), the diagnosis of COVID-19 mRNA vaccine-associated myocarditis is based on clinical symptoms, altered myocardial enzymes, cardiac MRI finding, or histopathology. Cardiac MRI is relatively less invasive than myocardial biopsy and plays an important role in the diagnosis of myocarditis. This review may aid in the diagnosis of COVID-19 mRNA vaccine-associated myocarditis.

15.
Mar Pollut Bull ; 176: 113427, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35150990

RESUMEN

Few studies have investigated the prevalence of polybrominated diphenyl ethers (PBDEs) in deep-sea sharks. In this study, the levels and profiles of PBDEs were determined in liver samples of eight different species of deep-sea sharks collected in Suruga Bay, Japan. Widespread contamination of PBDEs in the deep-sea environment was reconfirmed in this study as these persistent organic pollutants (POPs) were detected in all specimens analyzed. Mean ΣPBDE levels in the deep-sea sharks ranged from 7 to 517 ng/g of lipid weight. The distribution patterns of BDE homologues were similar in all species where tetra-BDEs provided the dominant contribution to total PBDEs (46%). PBDEs levels were similar to, or higher than, those seen in other deep-sea sharks from different regions. The levels of PBDEs were likely to reflect their feeding preferences as higher PBDE levels were seen in species with higher trophic positions.


Asunto(s)
Tiburones , Contaminantes Químicos del Agua , Animales , Bahías , Monitoreo del Ambiente , Éteres Difenilos Halogenados/análisis , Japón , Contaminantes Químicos del Agua/análisis
16.
Anal Methods ; 13(19): 2215-2222, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-33908466

RESUMEN

Hyperspectral data in the near infrared range were examined for nine common types of plastic particles of 1 mm and 100-500 µm sizes on dry and wet glass fiber filters. Weaker peak intensities were detected for small particles compared to large particles, and the reflectances were weaker at longer wavelengths when the particles were measured on a wet filter. These phenomena are explainable due to the effect of the correlation between the particle size and the absorption of infrared light by water. We constructed robust classification models that are capable of classifying polymer types, regardless of particle size or filter conditions (wet vs. dry), based on hyperspectral data for small particles measured on wet filters. Using the models, we also successfully classified the polymer type of polystyrene beads covered with microalgae, which simulates the natural conditions of microplastics in the ocean. This study suggests that hyperspectral imaging techniques with appropriate classification models allow the identification of microplastics without the time- and labor-consuming procedures of drying samples and removing biofilms, thus enabling more rapid analyses.


Asunto(s)
Microplásticos , Contaminantes Químicos del Agua , Monitoreo del Ambiente , Plásticos , Polímeros , Contaminantes Químicos del Agua/análisis
17.
Mar Pollut Bull ; 166: 112188, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33795148

RESUMEN

The abyss (3500-6500 m) covers the bulk of the deep ocean floor yet little is known about the extent of plastic debris on the abyssal seafloor. Using video imagery we undertook a quantitative assessment of the debris present on the abyssal seafloor (5700-5800 m depth) beneath the Kuroshio Extension current system in the Northwest Pacific. This body of water is one of the major transit pathways for the massive amounts of debris that are entering the North Pacific Ocean from Asia. Shallower sites (1400-1500 m depth) were also investigated for comparison. The dominant type of debris was single-use plastics - mainly bags and food packaging. The density of the plastic debris (mean 4561 items/km2) in the abyssal zone was the highest recorded for an abyssal plain suggesting that the deep-sea basin in the Northwest Pacific is a significant reservoir of plastic debris.


Asunto(s)
Monitoreo del Ambiente , Plásticos , Asia , Océano Pacífico , Residuos/análisis
18.
Sci Total Environ ; 768: 144537, 2021 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-33736296

RESUMEN

Plastic waste has become a growing concern in terms of marine pollution, but little information is available on plastic debris and its possible risks of chemical additives exposure in the deep-sea. This study focused on identification of polymer type and additive concentrations in 21 plastic debris collected from deep-sea of Sagami Bay, Japan and West Pacific Ocean under the Kuroshio Extension and its recirculation gyre (KERG) zone (water depth: 1388-5819 m). Polyethylene (PE) was dominant polymer (57% of the total) in samples, followed by polyvinylchloride (PVC), epoxy resin, polyester (PES), and polypropylene. In plastic additives, bis (2-ethylhexyl) phthalate (DEHP) was detected to be contained in a PVC sheet at concentration of 48%. Butylated hydroxytoluene (BHT) was also detected in PE plastic debris with median concentration of 12,000 ng/g. PES clothes were detected to contain dyeing mixtures, 1,2,4-trichlorobenzene (1,2,4-TCB), up to 42,000 ng/g. Knowing the estimated number of plastic debris under KE current, the minimum burden of chemical additives were estimated that 720 kg of dibutyl phthalate, 570 kg of BHT, 230 kg of DEHP, and 160 kg of 1,2,4-TCB exist on the seabed of KERG zone. This result strongly suggests that enormous amount of hazardous additives lie within plastic debris on abyssal level of the ocean.

19.
Bioorg Med Chem Lett ; 36: 127786, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33493627

RESUMEN

The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.


Asunto(s)
Caproatos/farmacología , Descubrimiento de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Animales , Caproatos/química , Caproatos/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Relación Estructura-Actividad
20.
J Clin Med ; 10(2)2021 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-33477425

RESUMEN

The comparative severity of patent foramen ovale (PFO)-related stroke in patients without atrial fibrillation (AF) and AF-related stroke in patients without PFO is unknown. Therefore, we compared the severity of PFO-related stroke and AF-related stroke. Twenty-six patients who underwent transesophageal echocardiography (TEE) were diagnosed with cardioembolic stroke from July 2018 to March 2020. Cases with AF detected by electrocardiograms or thrombus in the left atrium or left atrial appendage on TEE were included in the AF-related stroke group. Cases with a positive microbubble test on the Valsalva maneuver during TEE, and with no other factors that could cause stroke, were included in the PFO-related stroke group. This study was designed as a single-center, small population pilot study. The stroke severity of the two groups by the National Institute of Health Stroke Scale (NIHSS) score was compared by statistical analysis. Of the 26 cases, five PFO-related stroke patients and 21 AF-related stroke patients were analyzed. The NIHSS score was 2.2 ± 2.8 and 11.5 ± 9.2 (p-value < 0.01), the rate of hypertension was 20.0% and 85.7% (p-value = 0.01), and the HbA1c value was 5.5 ± 0.2% and 6.3 ± 1.3% (p-value = 0.02) in the PFO-related and AF-related stroke groups, respectively. Compared with AF-related stroke patients, stroke severity was low in PFO-related stroke patients.

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