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1.
Adv Sci (Weinh) ; : e2402348, 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39331567

RESUMEN

Utilizing rare earth doped ceria in solid oxide cells (SOCs) engineering is indeed a strategy aimed at enhancing the electrochemical devices' durability and activity. Particularly, Gd-doped ceria (GDC) is actively used for barrier layer and catalytic additives in solid oxide fuel cells (SOFCs). In this study, experiments are conducted with La-doped CeO2 (LDC), in which the Ce sites are predominantly occupied by La, to prevent the formation of the Ce-Zr solid solution. This LDC is comparably used as a functional interlayer between the electrolyte and cathode if sintered at lower temperatures to avoid La2Zr2O7 impurity. In addition, the high substitution of La3+ into the ceria lattice improves the oxygen non-stoichiometry of LDC, leading to accelerated electrochemical high performance by the additional role of LDC for oxygen supplier capacitance at high current operation. Thus, it is confirmed that the improved SOFC high performance is achieved at the maximum power density (MPD) of ≈2.15 W cm-2 at 800 °C when the optimized LDC buffer layer is hired at the anode-supported typed-Samsung's SOFC by lowering the sintering temperature to prevent LDC's impurity reaction.

2.
bioRxiv ; 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39314352

RESUMEN

Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood1. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, causing a painful inflammatory disease known as gout. These conditions are associated with many other diseases and affect a significant and increasing proportion of the population2-4. The human urate transporter 1 (URAT1) is responsible for the reabsorption of ~90% of uric acid in the kidneys back into the blood, making it a primary target for treating hyperuricemia and gout5. Despite decades of research and development, clinically available URAT1 inhibitors have limitations because the molecular basis of URAT1 inhibition by gout drugs remains unknown5. Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the novel compound TD-3. Together with functional experiments and molecular dynamics simulations, we reveal that these inhibitors bind selectively to URAT1 in inward-open states. Furthermore, we discover differences in the inhibitor dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia.

3.
Biosens Bioelectron ; 267: 116773, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39277920

RESUMEN

Prostate Imaging Reporting and Data System (PI-RADS) score, a reporting system of prostate MRI cases, has become a standard prostate cancer (PCa) screening method due to exceptional diagnosis performance. However, PI-RADS 3 lesions are an unmet medical need because PI-RADS provides diagnosis accuracy of only 30-40% at most, accompanied by a high false-positive rate. Here, we propose an explainable artificial intelligence (XAI) based PCa screening system integrating a highly sensitive dual-gate field-effect transistor (DGFET) based multi-marker biosensor for ambiguous lesions identification. This system produces interpretable results by analyzing sensing patterns of three urinary exosomal biomarkers, providing a possibility of an evidence-based prediction from clinicians. In our results, XAI-based PCa screening system showed a high accuracy with an AUC of 0.93 using 102 blinded samples with the non-invasive method. Remarkably, the PCa diagnosis accuracy of patients with PI-RADS 3 was more than twice that of conventional PI-RADS scoring. Our system also provided a reasonable explanation of its decision that TMEM256 biomarker is the leading factor for screening those with PI-RADS 3. Our study implies that XAI can facilitate informed decisions, guided by insights into the significance of visualized multi-biomarkers and clinical factors. The XAI-based sensor system can assist healthcare professionals in providing practical and evidence-based PCa diagnoses.

4.
J Korean Med Sci ; 39(36): e246, 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39315441

RESUMEN

BACKGROUND: A decline in masticatory function may indicate brain dysfunction related to dementia, but the relationship between masticatory function and dementia risk remains unclear. This study aimed to investigate whether masticatory function is associated with the risk of cognitive decline and dementia. METHODS: Data were obtained from the nationwide prospective cohort study of randomly sampled community-dwelling Koreans aged ≥ 60 years. The 5,064 non-demented participants, whose number of chewing cycles per bite was assessed by clinical interview, were followed for 8 years with biennial assessments of cognitive performance and clinical diagnoses of all-cause dementia and Alzheimer's disease (AD). Structural brain magnetic resonance imaging was collected from a subset of cohort participants and their spouses for imaging analyses. RESULTS: Males who chewed ≥ 30 cycles/bite had faster decline in global cognition and memory function and were at higher risk for incident all-cause dementia (hazard ratio [HR], 2.91; 95% confidence interval [CI], 1.18-7.18) and AD (HR, 3.22; 95% CI, 1.14-9.11) compared to males with less than 10 cycles/bite. Additionally, increased chewing cycles in males were associated with reduced brain volume, particularly in regions involved in compensatory cognitive control of mastication. There was no significant association between chewing cycles and the risk of dementia or brain volume in females. CONCLUSION: Older men who frequently chew their meals could be considered a notable population at risk for dementia who should be carefully assessed for their cognitive trajectories.


Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Demencia , Imagen por Resonancia Magnética , Masticación , Humanos , Masculino , Femenino , Anciano , Estudios Prospectivos , Factores de Riesgo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Persona de Mediana Edad , Estudios de Cohortes , Modelos de Riesgos Proporcionales , Factores Sexuales , Cognición/fisiología , Disfunción Cognitiva , Anciano de 80 o más Años
5.
Biofabrication ; 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39326447

RESUMEN

Vascular diseases are complex conditions orchestrated by multiple factors, including cellular components, biochemical stimuli, and mechanical forces. Despite the advancement of numerous therapeutic approaches, the global mortality associated with the diseases continues to escalate owing to a lack of understanding of the underlying pathologies. Tissue engineering and computational strategies have been recently developed to investigate diseased blood vessels from multifactorial perspective, enabling more accurate prediction of disease progression and opening new avenues for preclinical advances. This review focuses on in vitro and in silico blood vessel models to elucidate the pathomechanisms of vascular diseases. Following a discussion of biofabrication and computational modeling strategies, the recent research that utilizes the models of various blood vessel diseases, such as atherosclerosis, aneurysms, varicose veins, and thrombosis, are introduced. Finally, current breakthroughs, existing challenges, and outlooks in the field are described.

6.
Nat Commun ; 15(1): 8151, 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39289352

RESUMEN

Simultaneous achievement of lightweight, ultrahigh strength, large fracture strain, and high damping capability is challenging because some of these mechanical properties are mutually exclusive. Here, we utilize self-assembled polymeric carbon precursor materials in combination with scalable nano-imprinting lithography to produce nanoporous carbon nanopillars. Remarkably, nanoporosity induced via sacrificial template significantly reduces the mass density of amorphous carbon to 0.66 ~ 0.82 g cm-3 while the yield and fracture strengths of nanoporous carbon nanopillars are higher than those of most engineering materials with the similar mass density. Moreover, these nanopillars display both elastic and plastic behavior with large fracture strain. A reversible part of the sp2-to-sp3 transition produces large elastic strain and a high loss factor (up to 0.033) comparable to Ni-Ti shape memory alloys. The irreversible part of the sp2-to-sp3 transition enables plastic deformation, leading to a large fracture strain of up to 35%. These findings are substantiated using simulation studies. None of the existing structural materials exhibit a comparable combination of mass density, strength, deformability, and damping capability. Hence, the results of this study illustrate the potential of both dense and nanoporous amorphous carbon materials as superior structural nanomaterials.

7.
Ophthalmol Retina ; 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39293640

RESUMEN

PURPOSE: To assess the correlation between genotype and phenotype severity in X-linked juvenile retinoschisis (XLRS) by examining clinical and genetic features of a cohort of Korean XLRS patients. DESIGN: Retrospective, observational study. PARTICIPANTS: Data from 83 consecutive male patients with molecularly confirmed XLRS were collected retrospectively. METHODS: Clinical evaluation included best-corrected visual acuity (BCVA), fundus photography, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography (ERG). MAIN OUTCOME MEASURES: The phenotypic characteristics of a cohort of pediatric Korean XLRS patients, based on mutation types (truncating versus missense) and secretory profile (secretion versus non-secretion), were assessed. RESULTS: One hundred sixty-six eyes of 83 patients were included. The mean age at diagnosis was 6.1 ± 8.8 years (range, 0.5-20.7 years), with a mean follow-up time of 9.2 ± 7.0 years (range, 0.6-24.3 years). The BCVA at first and last examination ranged from light perception to 0.1 logarithm of the minimum angle of resolution (mean ± SD, 0.75 ± 0.59 and 0.82 ± 0.65, respectively). There were no significant differences in the first and last BCVA measurements between the truncating (0.71 ± 0.51 and 0.75 ± 0.44) and missense (0.77 ± 0.59 and 0.84 ± 0.66) variants (P = 0.678 and 0.551, respectively). Additionally, there were no differences in clinical parameters from fundus photography, SD-OCT, and full-field ERG. However, the BCVA at the first and last measurement were better for patients in the secretion group (0.51 ± 0.24 and 0.61 ± 0.30) compared to patients in the non-secretion group (0.65 ± 0.71 and 0.87 ± 0.81). The last BCVA showed a statistically significant difference between the two groups (P = 0.021). In OCT findings, the frequency of ellipsoid zone disruption was higher in patients with non-secretion variants than those with secretion variants (P = 0.030), with no significant differences in other parameters. CONCLUSIONS: The secretion profile of RS1 could influence the severity of XLRS phenotypes. Patients with RS1-secreted mutants, particularly with intact octamerization, exhibit more homogeneous phenotypes and better visual acuity than the RS1-non-secreted group. This data provides insights for studying genotype and phenotype correlations in both clinical and research fields.

8.
Sci Adv ; 10(31): eadp2211, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39093967

RESUMEN

Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.


Asunto(s)
Frío , Mentol , Canales Catiónicos TRPM , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Humanos , Mentol/farmacología , Simulación de Dinámica Molecular , Adaptación Fisiológica , Microscopía por Crioelectrón , Células HEK293 , Conformación Proteica , Animales
9.
Mol Ther Nucleic Acids ; 35(3): 102257, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39104869

RESUMEN

Mutations in nuclear genes regulating mitochondrial DNA (mtDNA) replication are associated with mtDNA depletion syndromes. Using whole-genome sequencing, we identified a heterozygous mutation (c.272G>A:p.Arg91Gln) in single-stranded DNA-binding protein 1 (SSBP1), a crucial protein involved in mtDNA replisome. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy. This mutation impeded multimer formation and DNA-binding affinity, leading to reduced efficiency of mtDNA replication, altered mitochondria dynamics, and compromised mitochondrial function. To correct this mutation, we tested two adenine base editor (ABE) variants on patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), showed higher editing efficacy (≤30%) and enhanced mitochondrial replication and function, despite off-target editing frequencies; however, risks from bystander editing were limited due to silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (≤10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. Taken together, base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated with SSBP1 mutations.

10.
Small ; : e2404784, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39205546

RESUMEN

Wide-bandgap perovskite solar cells (PSCs) with high open-circuit voltage (Voc) represent a compelling and emerging technological advancement in high-performing perovskite-based tandem solar cells. Interfacial engineering is an effective strategy to enhance Voc in PSCs by tailoring the energy level alignments between the constituent layers. Herein, n-type quinoxaline-phosphine oxide-based small molecules with strong dipole moments is designed and introduce them as effective cathode interfacial layers. Their strong dipole effect leads to appropriate energy level alignment by tuning the work function of the Ag electrode to form an ohmic contact and enhance the built-in potential within the device, thereby improving charge-carrier transport and mitigating charge recombination. The organic interfacial layer-modified wide-bandgap PSCs exhibit a high Voc of 1.31 V (deficit of <0.44 V) and a power conversion efficiency (PCE) of 20.3%, significantly improved from the device without an interface dipole layer (Voc of 1.26 V and PCE of 16.7%). Furthermore, the hydrophobic characteristics of the small molecules contribute to improved device stability, retaining 95% of the initial PCE after 500 h in ambient air.

11.
Tissue Cell ; 90: 102496, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39098256

RESUMEN

Momordica cochinchinensis (MC), commonly known as gac fruit, is a tropical fruit rich in antioxidants and bioactive compounds. This research aimed to elucidate the effect of MC on apoptosis induced by fine particulate matter with a diameter of less than 10 µm (< PM10) in epidermal keratinocyte HaCaT cells. We found that PM10 significantly diminish the viability of HaCaT cells through cytotoxic mechanisms. However, the treatment with MC at a concentration of 10 µg/mL notably restored the cellular viability decreased by PM10. MC reduced the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) by mainly preventing the generation of reactive oxygen species (ROS) in HaCaT cells subjected to PM10. Furthermore, MC exhibited a regulatory effect on the expression of genes associated with apoptosis, including B-Cell Lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), and cleaved caspase-3 by inhibiting the activation of the transcription factor nuclear factor-kappa B (NF-κB). These findings demonstrate that MC aids in neutralizing the apoptotic signaling pathway of free radicals produced by environmental pollutants such as PM10, which have the potential to damage skin cells and accelerate the aging process.


Asunto(s)
Apoptosis , Momordica , Estrés Oxidativo , Material Particulado , Extractos Vegetales , Material Particulado/toxicidad , Estrés Oxidativo/efectos de los fármacos , Humanos , Extractos Vegetales/farmacología , Momordica/química , Apoptosis/efectos de los fármacos , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Supervivencia Celular/efectos de los fármacos , Células HaCaT , Línea Celular
12.
Obstet Gynecol Sci ; 2024 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-39118522

RESUMEN

Ahead of print article withdrawn at the author's request due to administrative errors in the journal's processing of the submission.

13.
PLoS One ; 19(8): e0307975, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39167568

RESUMEN

In a number of species, including humans, perceived outgroup threat can promote ingroup cohesion. However, the distribution and selection history of this association across species with varied intergroup relations remains unclear. Using a sample of 8 captive groups (N = 43 individuals), we here tested whether bonobos, like chimpanzees, show more affiliative ingroup behaviour following perception of outgroup cues (unfamiliar male long-distance vocalisations). We used comparable methods to our previous study of captive chimpanzees, and found that, although weaker, there was an association for more frequent social grooming in response to the outgroup condition than the control condition, alongside more alert posture and increased self-directed behaviour. This provides preliminary evidence for an ancestral origin to the proximate association between outgroup cues and ingroup cohesion, at least prior to the Pan-Homo split, and suggests the presence of intergroup competition in our last common ancestor.


Asunto(s)
Señales (Psicología) , Pan paniscus , Conducta Social , Animales , Pan paniscus/psicología , Pan paniscus/fisiología , Masculino , Femenino , Conducta Animal/fisiología , Vocalización Animal/fisiología
14.
Diagnostics (Basel) ; 14(16)2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39202234

RESUMEN

Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD (n = 38) or autoimmune liver disease (n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8-12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant (n = 19) showed greater CD3+ T-cell infiltration than the cholestatic variant (n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20+, CD38+, or CD68+ cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants (p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant.

15.
Life (Basel) ; 14(8)2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39202704

RESUMEN

Sarcopenia, the age-related decline in muscle mass and function, poses a significant health challenge as the global population ages. Mitochondrial dysfunction is a key factor in sarcopenia, as evidenced by the role of mitochondrial reactive oxygen species (mtROS) in mitochondrial biogenesis and dynamics, as well as mitophagy. Resistance exercise training (RET) is a well-established intervention for sarcopenia; however, its effects on the mitochondria in aging skeletal muscles remain unclear. This review aims to elucidate the relationship between mitochondrial dynamics and sarcopenia, with a specific focus on the implications of RET. Although aerobic exercise training (AET) has traditionally been viewed as more effective for mitochondrial enhancement, emerging evidence suggests that RET may also confer beneficial effects. Here, we highlight the potential of RET to modulate mtROS, drive mitochondrial biogenesis, optimize mitochondrial dynamics, and promote mitophagy in aging skeletal muscles. Understanding this interplay offers insights for combating sarcopenia and preserving skeletal muscle health in aging individuals.

16.
Artículo en Inglés | MEDLINE | ID: mdl-39178158

RESUMEN

Medulloblastoma is the most frequent high-grade tumor of the central nervous system in children but accounts for less than 1% of these tumors in adults. Adolescent and young adult (AYA) patients are between both age groups, and different approaches are used to treat medulloblastoma in this population. We performed a systematic review of studies published between 2007 and 2023 that reported treatment approaches and survival data of AYA patients with medulloblastoma, defined as 15 to 39 years of age at diagnosis. Due to the heterogeneity of data, a meta-analysis was not possible. Except for the omission of chemotherapy after radiotherapy in a few adult studies, the treatment backbone is very similar between studies starting enrolment during childhood and older adolescence or adulthood. Despite indications for a higher rate of early treatment termination due to toxicity in adults, survival data remain comparable between studies starting enrolment earlier or later in life. However, molecular subtyping was missing in most studies, so the survival data must be interpreted cautiously. Nevertheless, pediatric-inspired strategies in the AYA population are feasible, but individual dose adjustments may be necessary during treatment and should be considered upfront. Collaborative studies investigating the best treatment approach for medulloblastoma in the AYA population are needed in the future.

17.
Fish Shellfish Immunol ; 153: 109858, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39187140

RESUMEN

Rock bream (Oplegnathus fasciatus) is one of the highly priced cultured marine fish in Korea. Rock bream iridovirus (RBIV) outbreaks in aquaculture farms may involve environmental factors, co-infection with other pathogenic microorganisms and grounded (raw) fish feed. This study evaluated the effects of RBIV-containing tissue intake on mortality and oral transmission in rock bream. Virus-containing tissues administered to rock bream [50 mg (1.53 × 108/major capsid protein, MCP gene copies) to 2400 mg (7.34 × 109)] held at 23 °C lead to 100 % mortality by 27 days post administration. Interestingly, the mortality rates were not viral dose- or concentration dependent. Further, high MCP gene copy numbers were observed in the gill, liver, intestine, stomach, spleen, heart, kidney, brain and muscle tissues (viral load range of 3.03 × 106 to 4.01 × 107/mg, average viral load 1.70 × 107/mg) of dead rock bream. Moreover, a high viral load was detected in the intestine and stomach, where the virus was directly administered. This indicated that the intake of RBIV-containing tissue feed weakens the intestinal mucosal immunity and increases viral load in the intestine. Moreover, the levels of complete blood cell count (CBC) indicators, such as red blood cell (RBC), hemoglobin (HGB) and hematocrit (HCT) significantly decreased from 15 dpi with red blood cell distribution width (RDW), and white blood cells (lymphocyte, monocyte and granulocyte) significantly increased from the initial to later stage of infection. These results highlight the significance of blood-mediated indicators against RBIV infection in rock bream. We demonstrate the existence of an oral transmission route for RBIV in rock bream. Our findings indicate that pathogen-containing feed is an important risk factor for disease outbreaks in rock bream.


Asunto(s)
Infecciones por Virus ADN , Enfermedades de los Peces , Perciformes , Animales , Perciformes/inmunología , Perciformes/virología , Enfermedades de los Peces/virología , Enfermedades de los Peces/inmunología , Infecciones por Virus ADN/veterinaria , Infecciones por Virus ADN/inmunología , Infecciones por Virus ADN/virología , Iridovirus/fisiología , Alimentación Animal/análisis , Carga Viral , Dieta/veterinaria
18.
Int J Biol Macromol ; 278(Pt 2): 134320, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39084415

RESUMEN

Phytoestrogens are plant-derived compounds that have chemical structures and functions similar to estrogen. Phytoestrogens act as ligand-inducible transcription factors involved in cellular growth by binding to estrogen receptors (ERs), specifically ER alpha (ERα) and beta (ERß). Through this mechanism, phytoestrogens have a physiological function similar to that of the female hormone 17ß-estradiol (E2), which can be useful in treating osteoporosis, cardiovascular disease, and cancer. Furthermore, phytoestrogens have been found to elicit various cellular responses depending on their affinity for ERs; in particular, they show a greater affinity with for ERß. This study aimed to comprehensively analyze the mode of action of eight phytoestrogens, namely kaempferol, coumestrol, glycitein, apigenin, daidzein, genistein, equol, and resveratrol, by evaluating their estrogenic activity as ER ligands. Based on the bioluminescence resonance energy transfer (BRET)-based ER dimerization and transactivation assay results, all the phytoestrogens tested were identified as estrogen agonists by mediating ERα and ERß dimerization. The specific binding and functions of ERα and ERß were distinguished by differentiating between their dimerization activity. In addition, this study contributes to advancing our understanding of the overall mechanism of action involving both ERs.


Asunto(s)
Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Fitoestrógenos , Fitoestrógenos/farmacología , Fitoestrógenos/química , Fitoestrógenos/metabolismo , Humanos , Receptor beta de Estrógeno/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/química , Multimerización de Proteína/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Ligandos , Unión Proteica
19.
Adv Mater ; : e2406179, 2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-39003621

RESUMEN

Hydroxyapatite (HA) exhibits outstanding biocompatibility, bioactivity, osteoconductivity, and natural anti-inflammatory properties. Pure HA, ion-doped HA, and HA-polymer composites are investigated, but critical limitations such as brittleness remain; numerous efforts are being made to address them. Herein, the novel self-crystallization of a polymeric single-stranded deoxyribonucleic acid (ssDNA) without additional phosphate ions for synthesizing deoxyribonucleic apatite (DNApatite) is presented. The synthesized DNApatite, DNA1Ca2.2(PO4)1.3OH2.1, has a repetitive dual phase of inorganic HA crystals and amorphous organic ssDNA at the sub-nm scale, forming nanorods. Its mechanical properties, including toughness and elasticity, are significantly enhanced compared with those of HA nanorod, with a Young's modulus similar to that of natural bone.

20.
Plant Biotechnol J ; 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39016470

RESUMEN

For several decades, a plant-based expression system has been proposed as an alternative platform for the production of biopharmaceuticals including therapeutic monoclonal antibodies (mAbs), but the immunogenicity concerns associated with plant-specific N-glycans attached in plant-based biopharmaceuticals has not been completely solved. To eliminate all plant-specific N-glycan structure, eight genes involved in plant-specific N-glycosylation were mutated in rice (Oryza sativa) using the CRISPR/Cas9 system. The glycoengineered cell lines, PhytoRice®, contained a predominant GnGn (G0) glycoform. The gene for codon-optimized trastuzumab (TMab) was then introduced into PhytoRice® through Agrobacterium co-cultivation. Selected cell lines were suspension cultured, and TMab secreted from cells was purified from the cultured media. The amino acid sequence of the TMab produced by PhytoRice® (P-TMab) was identical to that of TMab. The inhibitory effect of P-TMab on the proliferation of the BT-474 cancer cell line was significantly enhanced at concentrations above 1 µg/mL (****P < 0.0001). P-TMab bound to a FcγRIIIa variant, FcγRIIIa-F158, more than 2.7 times more effectively than TMab. The ADCC efficacy of P-TMab against Jurkat cells was 2.6 times higher than that of TMab in an in vitro ADCC assay. Furthermore, P-TMab demonstrated efficient tumour uptake with less liver uptake compared to TMab in a xenograft assay using the BT-474 mouse model. These results suggest that the glycoengineered PhytoRice® could be an alternative platform for mAb production compared to current CHO cells, and P-TMab has a novel and enhanced efficacy compared to TMab.

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