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1.
Rev Sci Instrum ; 95(4)2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38564326

RESUMEN

Optical thin films with high-reflectivity (HR) are essential for applications in quantum precision measurements. In this work, we propose a coating technique based on reactive magnetron sputtering with RF-induced substrate bias to fabricate HR-optical thin films. First, atomically flat SiO2 and Ta2O5 layers have been demonstrated due to the assistance of radio-frequency plasma during the coating process. Second, a distributed Bragg reflector (DBR) mirror with an HR of ∼99.999 328% centered at 1397 nm has been realized. The DBR structure is air-H{LH}19-substrate, in which the L and H denote a single layer of SiO2 with a thickness of 237.8 nm and a single layer of Ta2O5 with a thickness of 171.6 nm, respectively. This novel coating method would facilitate the development of HR reflectors and promote their wide applications in precision measurements.

2.
Cell Stem Cell ; 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38565140

RESUMEN

Neonatal spinal cord tissues exhibit remarkable regenerative capabilities as compared to adult spinal cord tissues after injury, but the role of extracellular matrix (ECM) in this process has remained elusive. Here, we found that early developmental spinal cord had higher levels of ECM proteins associated with neural development and axon growth, but fewer inhibitory proteoglycans, compared to those of adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserved these differences. DNSCM promoted proliferation, migration, and neuronal differentiation of neural progenitor cells (NPCs) and facilitated axonal outgrowth and regeneration of spinal cord organoids more effectively than DASCM. Pleiotrophin (PTN) and Tenascin (TNC) in DNSCM were identified as contributors to these abilities. Furthermore, DNSCM demonstrated superior performance as a delivery vehicle for NPCs and organoids in spinal cord injury (SCI) models. This suggests that ECM cues from early development stages might significantly contribute to the prominent regeneration ability in spinal cord.

3.
Hepatology ; 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38557414

RESUMEN

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 (HDAC1) and REST co-repressor 1 (RCOR1), components of the co-repressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing HDAC1 and RCOR1 interaction, thus increases the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha (HNF4A), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 (FOXP4) as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to HDAC inhibitors especially in combination with Lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional co-repressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.

4.
Ann Surg ; 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38557705

RESUMEN

BACKGROUND AND AIMS: Surgery is pivotal in the management of neuroblastoma (NB), particularly in patients with Image-Defined Risk Factors (IDRFs). The International Neuroblastoma Surgical Report Form (INSRF) was introduced to enhance surgical reporting quality and analyze the defining role of extensive surgery in NB. This study reports our experience with INSRF and explores new criteria for evaluating the extent of surgical resection. METHODS: INSRF was deployed to critically analyze 166 patients with abdominal or pelvic NB who underwent surgery at our department between October 2021 and June 2023. Patient demographics, clinical characteristics, surgical datasets, and postoperative complications were described in detail. Receiver operating characteristic (ROC) curves were used to explore a new method to evaluate the extent of resection. A questionnaire was formulated to obtain attitudes/feedback and commentary from surgical oncologists with INSRF. RESULTS: 166 neuroblastoma patients with a median disease age 36.50 months. This study collated 320 INSRF reports. Among the 166 index cases, 137 were documented by two surgeons, with a concordance rate of 16.78%. Items with high inconsistency were (i) the extent of tumor resection (29.20%), (ii) renal vein involvement (25.55%), (iii) abdominal aorta encasement (16.79%), and (iv) mesenteric infiltration (17.52%). According to INSRF, the extent of resection was complete excision in 86 (51.81%) patients, minimal residual tumor < 5 cm3 in 67 (40.36%) patients, and incomplete excision > 5 cm3 in 13 (7.83%) patients. In ROC curve analysis, the number of vessels encased by tumors > 3 had a high predictive value in determining that a tumor could not be completely resected (AUC 0.916, sensitivity 0.838, specificity 0.826) using INSRF as the gold standard reference. The questionnaires showed that surgeons agreed that the extent of resection and tumor involvement of organ/vascular structures were important, while the definition and intervention(s) of intraoperative complications were less operational and understandable. CONCLUSIONS: INSRF has significant clinical application in neuroblastoma surgery. The extent of resection can be predicted based on the number of tumor-encased blood vessels. Supplementary information should be considered with the INSRF to aid practitioner reporting. Multicenter studies are needed to explore the defining role of INSRF in NB surgical management.

5.
Artículo en Inglés | MEDLINE | ID: mdl-38561606

RESUMEN

Preeclampsia (PE) is a serious pregnancy complication, and its primary clinical manifestations are gestational hypertension and proteinuria. Trophoblasts are responsible for the basic functions of the placenta during placental development; recent studies have revealed that placental "shallow implantation" caused by the decreased invasiveness of placental trophoblasts plays a crucial role in PE pathogenesis. The interaction between the cells and the extracellular matrix (ECM) plays a crucial role in trophoblast proliferation, differentiation, and invasion. Abnormal ECM function can result in insufficient migration and invasion of placental trophoblasts, thus participating in PE. This article summarizes the recent studies on the involvement of ECM components, including small leucine-rich proteoglycans, syndecans, glypicans, laminins, fibronectin, collagen, and hyaluronic acid, in the development of PE. ECM plays various roles in PE development, most notably by controlling the activities of trophoblasts. The ECM is structurally stable and can serve as a biological diagnostic marker and therapeutic target for PE.

6.
Arch Toxicol ; 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38563870

RESUMEN

The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.

7.
Heliyon ; 10(7): e28638, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38571622

RESUMEN

Background: GLI3 gene mutations can result in various forms of polysyndactyly, such as Greig cephalopolysyndactyly syndrome (GCPS, MIM: #175700), Pallister-Hall syndrome (PHS, MIM: #146510), and isolated polydactyly (IPD, MIM: #174200, #174700). Reports on IPD-associated GLI3 mutations are rare. In this study, a novel GLI3 mutation was identified in a Chinese family with IPD. Results: We report a family with six members affected by IPD. The family members demonstrated several special phenotypes, including sex differences, abnormal finger joint development, and different polydactyly types. We identified a novel frameshift variant in the GLI3 gene (NM_000168.6: c.1820_1821del, NP_000159.3: p.Tyr607Cysfs*9) by whole-exome sequencing. Further analysis suggested that this mutation was the cause of polydactyly in this family. Conclusions: The discovery of this novel frameshift variant in our study further solidifies the relationship between IPD and GLI3 and expands the previously established spectrum of GLI3 mutations and associated phenotypes.

9.
Brain Pathol ; : e13261, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38602336

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

10.
Adv Sci (Weinh) ; : e2400255, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38602431

RESUMEN

Elastomers are widely used in daily life; however, the preparation of degradable and recyclable elastomers with high strength, high toughness, and excellent crack resistance remains a challenging task. In this report, a polycaprolactone-based poly(urethane-urea) elastomer is presented with excellent mechanical properties by optimizing the arrangement of hard segment clusters. It is found that long alkyl chains of the chain extenders lead to small and evenly distributed hard segment clusters, which is beneficial for improving mechanical properties. Together with the multiple hydrogen bond structure and stress-induced crystallization, the obtained elastomer exhibits a high strength of 63.3 MPa, an excellent toughness of 431 MJ m-3 and an outstanding fracture energy of 489 kJ m-2, while maintaining good recyclability and degradability. It is believed that the obtained elastomer holds great promise in various application fields and it contributes to the development of a sustainable society.

12.
Artículo en Inglés | MEDLINE | ID: mdl-38592441

RESUMEN

Owing to the evolution of 5G technology, new energy vehicles, flexible electronics, miniaturization and integration of microelectronic devices, high-frequency and high-power devices, and thermal management of materials must consider additional limitations such as electrical insulation, excellent transverse heat transfer, flexibility, and weight. Boron nitride nanosheets (BNNSs) are ideal insulating materials with high thermal conductivity. However, the problem of the 3D thermal conductivity pathway and toughness strength of nanocomposite paper loaded with inorganic thermal conductivity fillers remains a huge challenge. In this study, we propose a new method for preparing ultrathin, large, and uniformly thick BNNS for quantitative production. Bulk hexagonal boron nitride (hBN) layers were exfoliated using a simple and low-cost hydrothermal reaction, and large-scale fewer-layered BNNSs were efficiently prepared by ball milling with a high yield (up to 80%). Based on the aforementioned step, a flexible insulating composite film with high thermal conductivity and a natural "brick-mud" shell structure was constructed via the sol-gel-film conversion method. After prestretching and hot-pressing treatment, the hydrogels became denser, and the modified BNNS formed a three-dimensional (3D) network structure with an ordered orientation and interconnections in the bacterial cellulose (BC) matrix. After 100 folding cycles, the tensile strength of the nanofiber composite film reached 53 MPa, and the strength retention rate exceeded 42%. By optimizing the modified BNNS content, the thermal conductivity reached 24 W/(m·K). This simple approach has wide application potential in the next-generation electronic devices, providing options for designing thermal interface materials with excellent electrical insulation, high thermal stability, and flexibility.

13.
Can J Ophthalmol ; 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38580215

RESUMEN

OBJECTIVE: Lacrimal sac squamous cell carcinoma (LSSCC) is a rare and poor prognosis malignancy. We aimed to investigate the predictive factors for prognosis and to discuss the optimal treatment mode. METHODS: This retrospective study comprised 84 patients with LSSCC who accepted multidisciplinary treatment. We analyzed the potential prognostic factors and the efficiency of different treatment modes in univariate and multivariate analyses. RESULTS: The 5-year overall survival (OS), progression-free survival (PFS), regional failure-free survival (RFS), and distant metastasis-free survival (DMFS) rates for the entire cohort were 83.7%, 76.3%, 77.2%, and 83.7%, respectively. On univariate analysis, orbital bone erosion, lymph node metastasis, and advanced clinical stage were poor prognostic factors. Multivariate Cox regression analysis showed that orbital bone erosion was a uniquely poor predictor for OS; orbital bone erosion, positive cervical lymph nodes, and old age were poor predictors for PFS. Chemotherapy significantly improved the 5-year OS (90.4% vs. 69.6%, p = 0.03), PFS (82.1% vs. 63.6%, p = 0.036), and DMFS (90.4% vs. 69.6%, p = 0.013), except for RFS (82.5% vs. 65.6%, p = 0.15). Surgery did not improve the 5-year OS (85.6% vs. 79.3%, p = 0.062), PFS (76.0% vs. 76.2%, p = 0.41), RFS (76.1% vs. 79.5%, p = 0.54), and DMFS (85.6% vs. 79.5%, p = 0.096). However, the pre-operative radiotherapy conferred a slightly better OS (p = 0.13) and DMFS (p = 0.16) than post-operative radiotherapy and definitive radiotherapy, but without statistical significance. CONCLUSIONS: Orbital bone erosion and lymph node metastasis were poor prognostic factors in LSSCC. Chemoradiotherapy was vital and effective. Although surgery did not improve survival, multidisciplinary treatment, including surgery, was recommended for LSSCC.

14.
BMC Plant Biol ; 24(1): 258, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38594637

RESUMEN

BACKGROUND: Weed control is essential for agricultural floor management in vineyards and the inter-row mulching is an eco-friendly practice to inhibit weed growth via filtering out photosynthetically active radiation. Besides weed suppression, inter-row mulching can influence grapevine growth and the accumulation of metabolites in grape berries. However, the complex interaction of multiple factors in the field challenges the understanding of molecular mechanisms on the regulated metabolites. In the current study, black geotextile inter-row mulch (M) was applied for two vintages (2016-2017) from anthesis to harvest. Metabolomics and transcriptomics analysis were conducted in two vintages, aiming to provide insights into metabolic and molecular responses of Cabernet Sauvignon grapes to M in a semi-arid climate. RESULTS: Upregulation of genes related to photosynthesis and heat shock proteins confirmed that M weakened the total light exposure and grapes suffered heat stress, resulting in lower sugar-acid ratio at harvest. Key genes responsible for enhancements in phenylalanine, glutamine, ornithine, arginine, and C6 alcohol concentrations, and the downward trend in ε-viniferin, anthocyanins, flavonols, terpenes, and norisoprenoids in M grapes were identified. In addition, several modules significantly correlated with the metabolic biomarkers through weighted correlation network analysis, and the potential key transcription factors regulating the above metabolites including VviGATA11, VviHSFA6B, and VviWRKY03 were also identified. CONCLUSION: This study provides a valuable overview of metabolic and transcriptomic responses of M grapes in semi-arid climates, which could facilitate understanding the complex regulatory network of metabolites in response to microclimate changes.


Asunto(s)
Vitis , Vino , Vitis/metabolismo , Transcriptoma , Antocianinas/metabolismo , Microclima , Granjas , Frutas , Vino/análisis
15.
Sci Adv ; 10(14): eadk6911, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38579000

RESUMEN

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain glycoproteome into networks of coregulated glycoforms and glycans and discovered glycoform and glycan modules associated with AD clinical phenotype, amyloid-ß accumulation, and tau pathology. Our findings provide valuable insights into disease pathogenesis and a rich resource of glycoform and glycan changes in AD and pave the way forward for developing glycosylation-based therapies and biomarkers for AD.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Glicoproteínas/metabolismo , Glicosilación , Polisacáridos/metabolismo , Encéfalo/metabolismo
16.
Water Sci Technol ; 89(7): 1860-1878, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38619908

RESUMEN

The activated persulfate (PS) process could produce sulfate radical (SO4·-) and rapidly degrade organic pollutants. The application of Fe3O4 as a promising PS activator was limited due to the rapid conversion of Fe2+ to Fe3+ on its surface. Mo4+ on MoS2 surface could be used as a reducing site to convert Fe3+ to Fe2+, but the separation and recovery of MoS2 was complex. In this study, MoS2/Fe3O4 was prepared to accelerate the Fe3+/Fe2+ cycle on Fe3O4 surface and achieved efficient separation of MoS2. The results showed that MoS2/Fe3O4 was more effective for PS activation compared to Fe3O4 or MoS2, with a removal efficiency of 91.8% for 20 mg·L-1 tetracycline (TC) solution under the optimal conditions. Fe2+ and Mo4+ on MoS2/Fe3O4 surface acted as active sites for PS activation with the generation of SO4•-, •OH, •O2-, and 1O2. Mo4+ acted as an electron donor to promote the Fe3+/Fe2+ cycling and thus improved the PS activation capability of MoS2/Fe3O4. The degradation pathways of TC were inferred as hydroxylation, ketylation of dimethylamino group and C-N bond breaking. This study provided a promising activated persulfate-based advanced oxidation process for the efficient degradation of TC by employing MoS2/Fe3O4 as an effective activator.


Asunto(s)
Molibdeno , Contaminantes Químicos del Agua , Tetraciclina/análisis , Oxidación-Reducción , Antibacterianos , Fenómenos Magnéticos , Contaminantes Químicos del Agua/química
17.
Mar Environ Res ; 197: 106481, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38593647

RESUMEN

Marine distribution of dimethylsulfoniopropionate (DMSP) and its cleavage product dimethyl sulfide (DMS) is greatly affected by the community structures of bacteria, phytoplankton, and zooplankton. Spatial distributions of dissolved and particulate DMSP (DMSPd,p), and DMS were measured and their relationships with DMSP lyase activity (DLA), abundance of DMSP-consuming bacteria (DCB), and the community structures of phytoplankton, zooplankton, and bacteria were determined during summer in the South China Sea (SCS). The depth distributions of DMSPd,p exhibited a similar trend with Chl a, reaching their maxima in the mixing layer. The DMS concentration was positively correlated with DCB abundance and DLA, indicating that DCB and DMSP lyase had a significant effect on DMS production. High DMS concentrations in the horizontal distribution coincided with high DCB abundance and DLA and may be due to the rapid growth of phytoplankton resulting from the high dissolved inorganic nitrogen concentration brought by the cold vortices. Moreover, the highest copepod abundance at station G3 coincided with the highest DMS concentrations there among stations B4, F2, and G3. These results suggest that copepod may play an important role in DMS production. The bacterial SAR11 clade was positively correlated with DLA, indicating its significant contribution to DMSP degradation in the SCS. These findings contribute to the understanding of the effect of the community assemblage on DMSP/DMS distributions in the SCS dominated by mesoscale vortices.


Asunto(s)
Agua de Mar , Compuestos de Sulfonio , Animales , Agua de Mar/química , Azufre/metabolismo , Compuestos de Sulfonio/química , Compuestos de Sulfonio/metabolismo , Sulfuros/metabolismo , Bacterias/metabolismo , Fitoplancton , China , Zooplancton/metabolismo
18.
J Nanobiotechnology ; 22(1): 144, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38566094

RESUMEN

Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and nanomedicine presents a practical approach for treating epileptic seizures via bypassing the blood-brain barrier. In this study, phenytoin (PHT) loaded layered double hydroxide nanoparticles (BSA-LDHs-PHT) were fabricated via a coprecipitation - hydrothermal method for epileptic seizure control. In this study, we expound on the preparation method and characterization of BSA-LDHs-PHT. In-vitro drug release experiment shows both rapid and continuous drug release from BSA-LDHs-PHT, which is crucial for acute seizure control and chronic epilepsy therapy. In-vivo biodistribution assays after intranasal administration indicate excellent brain targeting ability of BSA-LDHs. Compared to BSA-Cyanine5.5, BSA-LDHs-Cyanine5.5 were associated with a higher brain/peripheral ratio across all tested time points. Following intranasal delivery with small doses of BSA-LDHs-PHT, the latency of seizures in the pentylenetetrazole-induced mouse models was effectively improved. Collectively, the present study successfully designed and applied BSA-LDHs-PHT as a promising strategy for treating epileptic seizures with an enhanced therapeutic effect.


Asunto(s)
Epilepsia , Nanopartículas , Ratones , Animales , Fenitoína/farmacología , Fenitoína/uso terapéutico , Administración Intranasal , Distribución Tisular , Convulsiones/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Nanopartículas/uso terapéutico , Hidróxidos/uso terapéutico
19.
Nat Commun ; 15(1): 2859, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38570500

RESUMEN

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.


Asunto(s)
Diabetes Mellitus Experimental , Factores de Transcripción Forkhead , Ratones , Humanos , Animales , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Transporte Activo de Núcleo Celular , Pez Cebra/metabolismo , Carioferinas/metabolismo
20.
Front Med (Lausanne) ; 11: 1344107, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38576708

RESUMEN

Background: As the most common acute optic neuropathy in older patients, nonarteritic anterior ischemic optic neuropathy (NAION) presents with varying degrees of visual acuity loss and visual field defect. However, there is no generally accepted treatment for NAION. Objectives: To evaluate the efficacy and safety of platelet-rich plasma (PRP) for patients with acute NAION within 2 months. Design: A prospective, nonrandomized controlled trial. Methods: Twenty-five eyes of 25 patients were enrolled. Of them, 13 received anisodine hydrobromide and butylphthalide-sodium chloride injection continuously for 10 days as basic treatment in the control group, and 12 received two tenon capsule injections of PRP on a 10 days interval as an additional treatment in the PRP group. We compared the best-corrected visual acuity (BCVA) and capillary perfusion density (CPD) of radial peripapillary capillaries and the moth-eaten eara of the peripapillary superficial capillary plexus and deep capillary plexus at 1 day (D1) before the first PRP treatment and 7 days (D7), 14 days (D14), and 30 days (D30) after the first PRP injection. Ocular and systemic adverse effects were assessed. Results: In the PRP group, a better BCVA occurred at D30 (adjusted p = 0.005, compared with D1, recovered from 0.67 ± 0.59 to 0.43 ± 0.59), and a significant improvement in CPD was observed at D30 (adjusted p < 0.001, p = 0.027, p = 0.027, compared with D1, D7, D14, in sequence, the value was 35.97 ± 4.65, 38.73 ± 4.61, 39.05 ± 5.26, 42.71 ± 4.72, respectively). CPD at D7 in the PRP group was better than that in the control group (p = 0.043). However, neither BCVA nor the moth-eaten area index were significantly different (all p > 0.5) between the two groups. The main adverse effect was local discomfort resolved within 1 week, and no other systemic adverse events occurred. Conclusion: Tenon capsule injection of PRP was a safe treatment for AION and could improve capillary perfusion of the optic nerve head and might be helpful in increasing short-term vision in patients with acute NAION.

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