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1.
J Trace Elem Med Biol ; 86: 127517, 2024 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-39270538

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy. The aim of this research was to develop a ferroptosis and cuproptosis related novel prognostic signature associated with AML. METHODS: The ferroptosis and cuproptosis related genes correlated with the prognosis of AML were identified by univariate Cox analysis. The consistent cluster analysis was performed for 150 AML patients in TCGA dataset. The key module genes associated with GSVA score of ferroptosis and cuproptosis were identified by WGCNA. univariate Cox and LASSO regression analysis were adopted to build a ferroptosis and cuproptosis AML prognostic signature. Finally, the expression of five prognostic genes in clinical tissue samples were verified by RT-qPCR. RESULTS: A grand total of 27 FCRGs associated with AML prognosis were identified.Then, two AML sub-types with significantly different survival were obtained. We found 3 significantly differential expressed immune cells (naive CD4 cells, regulatory T cells and resting mast cells) between two risk sub-groups. Meanwhile, 'IL6 JAK STAT3 signaling' and 'P53 pathway' were enriched in low-risk group. A ferroptosis and cuproptosis related prognostic signature was build based on 8 prognostic genes. RT-qPCR results indicated that there was no significant difference in the expression of OLFML2A and CD109 between AML and normal samples. However, compared to the control group, LGALS1, SOCS1, and RHOC showed significantly lower expression in the AML group. CONCLUSION: The prognostic signature comprised of OLFML2A, LGALS1, ABCB11, SOCS1, RHOC, CD109, RD3L and PTPN13 based on ferroptosis and cuproptosis was established, which provided theoretical basis for the research of AML.

2.
J Transl Med ; 22(1): 788, 2024 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-39183280

RESUMO

Vascular dementia (VaD) is a prevalent form of dementia resulting from chronic cerebral hypoperfusion (CCH). However, the pathogenic mechanisms of VaD and corresponding therapeutic strategies are not well understood. Sirtuin 6 (SIRT6) has been implicated in various biological processes, including cellular metabolism, DNA repair, redox homeostasis, and aging. Nevertheless, its functional relevance in VaD remains unexplored. In this study, we utilized a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the role of SIRT6. We detected a significant decrease in neuronal SIRT6 protein expression following CCH. Intriguingly, neuron-specific ablation of Sirt6 in mice exacerbated neuronal damage and cognitive deficits after CCH. Conversely, treatment with MDL-800, an agonist of SIRT6, effectively mitigated neuronal loss and facilitated neurological recovery. Mechanistically, SIRT6 inhibited excessive mitochondrial fission by suppressing the CCH-induced STAT5-PGAM5-Drp1 signaling cascade. Additionally, the gene expression of monocyte SIRT6 in patients with asymptomatic carotid stenosis showed a correlation with cognitive outcomes, suggesting translational implications in human subjects. Our findings provide the first evidence that SIRT6 prevents cognitive impairment induced by CCH, and mechanistically, this protection is achieved through the remodeling of mitochondrial dynamics in a STAT5-PGAM5-Drp1-dependent manner.


Assuntos
Disfunção Cognitiva , Dinaminas , Dinâmica Mitocondrial , Fator de Transcrição STAT5 , Sirtuínas , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Isquemia Encefálica/metabolismo , Estenose das Carótidas/complicações , Estenose das Carótidas/metabolismo , Doença Crônica , Disfunção Cognitiva/patologia , Dinaminas/metabolismo , Dinaminas/genética , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo , Sirtuínas/genética , Fator de Transcrição STAT5/metabolismo
3.
Adv Healthc Mater ; : e2401981, 2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-39073014

RESUMO

Conventional phototherapeutic agents are typically used in either photodynamic therapy (PDT) or photothermal therapy (PTT). However, efficacy is often hindered by hypoxia and elevated levels of heat shock proteins in the tumor microenvironment (TME). To address these limitations, a formylated, near-infrared (NIR)-absorbing and heavy-atom-free Aza-BODIPY dye is presented that exhibits both type-I and type-II PDT actions with a high yield of reactive oxygen species (ROS) and manifests efficient photothermal conversion by precise adjustments to the conjugate structure and electron distribution, leading to a large amount of ROS production even under severe hypoxia. To improve biosafety and water solubility, the dye with an amphiphilic triblock copolymer (Pluronic F-127), yielding BDP-6@F127 nanoparticles (NPs) is coated. Furthermore, inspired by the fact that phototherapy triggers the release of tumor-associated antigens, a strategy that leverages potential immune activation by combining PDT/PTT with immune checkpoint blockade (ICB) therapy to amplify the systemic immune response and achieve the much-desired abscopal effect is developed. In conclusion, this study presents a promising molecular design strategy that integrates multimodal therapeutics for a precise and effective approach to cancer therapy.

4.
Colloids Surf B Biointerfaces ; 242: 114109, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39047644

RESUMO

Photoimmunotherapy represents an innovative approach to enhancing the efficiency of immunotherapy in cancer treatment. This approach involves the fusion of immunotherapy and phototherapy (encompassing techniques like photodynamic therapy (PDT) and photothermal therapy (PTT)). Boron-dipyrromethene (BODIPY) has the potential to trigger immunotherapy owing to its excellent PD and PT efficiency. However, the improvements in water solubility, bioavailability, PD/PT combined efficiency, and tumor tissue targeting of BODIPY require introduction of suitable carriers for potential practical application. Herein, a disulfide bond-based hollow mesoporous organosilica (HMON) with excellent biocompatibility and GSH-responsive degradation properties was used as a carrier to load a bithiophene Aza-BODIPY dye (B5), constructing a sample chemotherapy reagent-free B5@HMON nanoplatform achieving triple-synergistic photoimmunotherapy. HMON, involving disulfide bond, is utilized to improve water solubility, tumor tissue targeting, and PD efficiency by depleting GSH and enhancing host-guest interaction between B5 and HMO. The study reveals that HMON's large specific surface area and porous properties significantly enhance the light collection and oxygen adsorption capacity. The HMON's rich mesoporous structure and internal cavity achieved a loading rate of B5 at 11 %. It was found that the triple-synergistic nanoplatform triggered a stronger anti-tumor immune response, including tumor invasion, cytokine production, calreticulin translocation, and dendritic cell maturation, eliciting specific tumor-specific immunological responses in vivo and in vitro. The BALB/c mouse model with 4T1 tumors was used to assess tumor suppression efficiency in vivo, showing that almost all tumors in the B5@HMON group disappeared after 14 days. Such a simple chemotherapy reagent-free B5@HMON nanoplatform achieved triple-synergistic photoimmunotherapy.


Assuntos
Compostos de Boro , Glutationa , Imunoterapia , Animais , Compostos de Boro/química , Compostos de Boro/farmacologia , Camundongos , Imunoterapia/métodos , Glutationa/química , Glutationa/metabolismo , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Camundongos Endogâmicos BALB C , Humanos , Tamanho da Partícula , Tiofenos/química , Tiofenos/farmacologia , Propriedades de Superfície , Fotoquimioterapia , Nanopartículas/química , Fototerapia/métodos , Linhagem Celular Tumoral , Feminino , Proliferação de Células/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Porosidade
5.
Small ; : e2403941, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058224

RESUMO

Photo-responsive materials have garnered significant interest for their ability to react to non-contact stimuli, though achieving self-healing under gentle conditions remains an elusive goal. In this research, an innovative and straightforward approach for synthesizing silicone elastomers is proposed that not only self-heal at room temperature but also possess unique photochromic properties and adjustable mechanical strength, along with being both transparent and reprocessable. Initially, aldehyde-bifunctional dithiophene-ethylene molecules with dialdehyde groups (DTEM) and isocyanurate (IPDI) is introduced into the aminopropyl-terminated polydimethylsiloxane (H2N-PDMS-NH2) matrix. Subsequently, palladium is incorporated to enhance coordination within the matrix. These silicone elastomers transition to a blue state under 254 nm UV light and revert to transparency under 580 nm light. Remarkably, they demonstrate excellent thermal stability at temperatures up to 100 °C and show superior fatigue resistance. The optical switching capabilities of the silicone elastomers significantly affect both their mechanical characteristics and self-healing abilities. Notably, the PDMS-DTEM-IPDI-@Pd silicone elastomer, featuring closed-loop photo-switching molecules, exhibits a fracture toughness that is 1.3 times greater and a room temperature self-healing efficiency 1.4 times higher than its open-loop counterparts. This novel photo-responsive silicone elastomer offers promising potential for applications in data writing and erasure, UV protective coatings, and micro-trace development.

6.
Haemophilia ; 30(4): 959-969, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38853005

RESUMO

INTRODUCTION: Reduced doses of emicizumab improve the affordability among patients in developing countries. However, the relationship between variant dose selection and efficacy in the real world of China is still unclear. AIM: This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real-world setting. METHODS: We carried out a multicentre study from 28 hospitals between June 2019 and June 2023 in China and retrospectively analysed the characteristics including demographics, diagnosis, treatment, bleeding episodes, and surgical procedures. RESULTS: In total, 127 patients with haemophilia A, including 42 with inhibitors, were followed for a median duration of 16.0 (IQR: 9.0-30.0) months. Median age at emicizumab initiation was 2.0 (IQR: 1.0-4.0) years. Median (IQR) consumption for loading and maintenance was 12.0 (8.0-12.0) and 4.2 (3.0-6.0) mg/kg/4 weeks, respectively. While on emicizumab, 67 (52.8%) patients had no bleeds, whereas 60 (47.2%) patients had any bleeds, including 26 with treated bleeds. Compared to previous treatments, patients on emicizumab had significantly decreased annualized bleeding rate, annualized joint bleeding rate, target joints and intracerebral haemorrhage. Different dosages had similar efficacy except the proportion of patients with treated spontaneous bleeds and target joints. Adverse events were reported in 12 (9.4%) patients. Postoperative excessive bleeding occurred following two of nine procedures. CONCLUSION: This is the largest study describing patients with HA receiving emicizumab prophylaxis on variant dose regimens in China. We confirmed that nonstandard dose is efficacious and can be considered where full-dose emicizumab is ill affordable.


Assuntos
Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Hemofilia A , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , China , Hemofilia A/tratamento farmacológico , Masculino , Estudos Retrospectivos , Pré-Escolar , Feminino , Resultado do Tratamento , Lactente , Hemorragia , Criança , Relação Dose-Resposta a Droga
7.
ACS Appl Mater Interfaces ; 16(15): 18252-18267, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38581365

RESUMO

Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Fosfatidiletanolaminas , Polietilenoglicóis , Doxorrubicina/farmacologia , Óxido Nítrico , Fototerapia , Nanopartículas/uso terapêutico , Mitocôndrias , Lipídeos , Linhagem Celular Tumoral
8.
Int J Ophthalmol ; 17(2): 311-316, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38371258

RESUMO

AIM: To describe the clinical, electrophysiological, and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant. METHODS: The patient underwent a complete ophthalmologic examination including best-corrected visual acuity, anterior segment and dilated fundus, visual field, spectral-domain optical coherence tomography (OCT) and electroretinogram (ERG). The retinal disease panel genes were sequenced through chip capture high-throughput sequencing and Sanger sequencing was used to confirm the result. Then we reviewed the characteristics of the patients reported with the same variant. RESULTS: A 30-year male presented with severe early retinal degeneration who complained night blindness, decreased visual acuity, vitreous floaters and amaurosis fugax. The best corrected vision was 0.04 OD and 0.12 OS, respectively. The fundus photo and OCT showed bilateral macular atrophy but larger areas of macular atrophy in the left eye. Autofluorescence shows bilateral symmetrical hypo-autofluorescence. ERG revealed that the amplitudes of a- and b-wave were severely decreased. Multifocal ERG showed decreased amplitudes in the local macular area. A homozygous missense variant c.146C>T (chr14:68191267) was found. The clinical characteristics of a total of 13 patients reported with the same pathologic variant varied. CONCLUSION: An unusual patient with a homozygous pathogenic variant in the c.146C>T of RDH12 which causes late-onset and asymmetric retinal degeneration are reported. The clinical manifestations of the patient with multimodal retinal imaging and functional examinations have enriched our understanding of this disease.

9.
Int J Mol Sci ; 25(3)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38338791

RESUMO

Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks), essential enzymes in the phosphatidylinositol signaling pathway, are crucial for the abiotic stress responses and the overall growth and development of plants. However, the GhPIP5Ks had not been systematically studied, and their function in upland cotton was unknown. This study identified a total of 28 GhPIP5Ks, and determined their chromosomal locations, gene structures, protein motifs and cis-acting elements via bioinformatics analysis. A quantitative real-time PCR (qRT‒PCR) analysis showed that most GhPIP5Ks were upregulated under different stresses. A virus-induced gene silencing (VIGS) assay indicated that the superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities were significantly decreased, while malondialdehyde (MDA) content were significantly increased in GhPIP5K2- and GhPIP5K22-silenced upland cotton plants under abiotic stress. Furthermore, the expression of the stress marker genes GhHSFB2A, GhHSFB2B, GhDREB2A, GhDREB2C, GhRD20-1, GhRD29A, GhBIN2, GhCBL3, GhNHX1, GhPP2C, GhCBF1, GhSnRK2.6 and GhCIPK6 was significantly decreased in the silenced plants after exposure to stress. These results revealed that the silencing of GhPIP5K2 and GhPIP5K22 weakened the tolerance to abiotic stresses. These discoveries provide a foundation for further inquiry into the actions of the GhPIP5K gene family in regulating the response and resistance mechanisms of cotton to abiotic stresses.


Assuntos
Gossypium , Estresse Fisiológico , Gossypium/metabolismo , Estresse Fisiológico/genética , Sequências Reguladoras de Ácido Nucleico , Transdução de Sinais , Biologia Computacional , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia
10.
Mol Genet Genomic Med ; 12(2): e2393, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38407575

RESUMO

BACKGROUND: Brachydactyly type E (BDE) is a general term characterized by variable shortening of metacarpals and metatarsals, with phalanges affected frequently. It can occur as an isolated form or part of syndromes and manifest a high degree of phenotypic variability. In this study, we have identified the clinical characteristics and pathogenic causes of a four-generation pedigree with 10 members affected by BDE and short stature. METHODS: After the informed consent was signed, clinical data and peripheral blood samples were collected from available family members. Karyotype analysis, array-CGH, next-generation sequencing, and Sanger sequencing were employed to identity the pathogenic candidate gene. RESULTS: No translocation or microdeletion/duplication was found in karyotype analysis and array-CGH; hence, a novel heterozygous mutation, c.146dupA. p.S50Vfs*22, was detected by next-generation sequencing in PTHLH gene, leading to a premature stop codon. Subsequently, the mutation was confirmed by Sanger sequencing and co-segregation analysis. CONCLUSION: In this study, we described a novel heterozygous mutation (c.146dupA. p.S50Vfs*22) of gene PTHLH in a Chinese family. The mutation could induce a premature stop codon leading to a truncation of the protein. Our study broadened the mutation spectrum of PTHLH in BDE.


Assuntos
Braquidactilia , Nanismo , Humanos , Braquidactilia/genética , Códon sem Sentido , Mutação , Proteína Relacionada ao Hormônio Paratireóideo/genética
11.
Sci Rep ; 14(1): 1696, 2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-38242895

RESUMO

Psoraleae Fructus (PF) is a widely-used herb with diverse pharmacological activities, while its related hepatic injuries have aroused public concerns. In this work, a systematic approach based on RNA sequencing (RNA-seq), high-content screening (HCS) and molecular docking was developed to investigate the potential mechanism and identify major phytochemicals contributed to PF-induced hepatotoxicity. Animal experiments proved oral administration of PF water extracts disturbed lipid metabolism and promoted hepatic injuries by suppressing fatty acid and cholesterol catabolism. RNA-seq combined with KEGG enrichment analysis identified mitochondrial oxidative phosphorylation (OXPHOS) as the potential key pathway. Further experiments validated PF caused mitochondrial structure damage, mtDNA depletion and inhibited expressions of genes engaged in OXPHOS. By detecting mitochondrial membrane potential and mitochondrial superoxide, HCS identified bavachin, isobavachalcone, bakuchiol and psoralidin as most potent mitotoxic compounds in PF. Moreover, molecular docking confirmed the potential binding patterns and strong binding affinity of the critical compounds with mitochondrial respiratory complex. This study unveiled the underlying mechanism and phytochemicals in PF-induced liver injuries from the view of mitochondrial dysfunction.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Psoralea , Animais , Medicamentos de Ervas Chinesas/química , Simulação de Acoplamento Molecular , Psoralea/química , RNA-Seq , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Compostos Fitoquímicos/farmacologia
12.
World Neurosurg ; 178: e777-e790, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37562682

RESUMO

OBJECTIVE: The anterior clinoid process (ACP) is surrounded by nerves and vessels that, together, constitute an intricate anatomical structure with variations that challenges the performance of individualized anterior clinoidectomy in treating lesions with different extents of invasion. In the present study, we established a 6-surface system for the ACP based on anatomical landmarks and analyzed its value in guiding ACP drilling and resection of paraclinoid meningiomas. METHODS: Using the anatomical characteristics of 10 dry skull specimens, we set 9 anatomical landmarks to delineate the ACP into 6 surfaces. Guided by our 6-surface system and eggshell technique, 5 colored silicone-injected anatomical specimens were dissected via a frontotemporal craniotomy to perform anterior clinoidectomy. Next, 3 typical cases of paraclinoid meningioma were selected to determine the value of using our 6-surface system in tumor resection. RESULTS: Nine points (A-H and T) were proposed to delineate the ACP surface into frontal, temporal, optic nerve, internal carotid artery, cranial nerve III, and optic strut surfaces according to the adjacent tissues. Either intradurally or extradurally, the frontal and temporal surfaces could be identified and drilled into depth, followed by skeletonization of the optic nerve, cranial nerve III, internal carotid artery, and optic strut surfaces. After the residual bone was removed, the ACP was drilled off. In surgery of paraclinoid meningiomas, our 6-surface system provided great benefit in locating the dura, nerves, and vessels, thus, increasing the safety of opening the optic canal and relaxing the oculomotor or optic nerves and allowing for individualized ACP drilling for meningioma removal. CONCLUSIONS: Our 6-surface system adds much anatomical information to the classic Dolenc triangle and can help neurosurgeons, especially junior ones, to increase their understanding of the paraclinoid spatial structure and accomplish individualized surgical procedures with high safety and minimal invasiveness.


Assuntos
Aneurisma Intracraniano , Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Aneurisma Intracraniano/cirurgia , Base do Crânio/cirurgia , Osso Esfenoide/cirurgia , Osso Esfenoide/anatomia & histologia , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia
13.
Front Immunol ; 14: 1172334, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37614235

RESUMO

Microglial activation and subsequent inflammatory responses are critical processes in aggravating secondary brain injury after intracerebral hemorrhage (ICH). Pterostilbene (3', 5'-dimethoxy-resveratrol) features antioxidant and anti-inflammation properties and has been proven neuroprotective. In this study, we aimed to explore whether Pterostilbene could attenuate neuroinflammation after experimental ICH, as well as underlying molecular mechanisms. Here, a collagenase-induced ICH in mice was followed by intraperitoneal injection of Pterostilbene (10 mg/kg) or vehicle once daily. PTE-treated mice performed significantly better than vehicle-treated controls in the neurological behavior test after ICH. Furthermore, our results showed that Pterostilbene reduced lesion volume and neural apoptosis, and alleviated blood-brain barrier (BBB) damage and brain edema. RNA sequencing and subsequent experiments showed that ICH-induced neuroinflammation and microglial proinflammatory activities were markedly suppressed by Pterostilbene treatment. With regard to the mechanisms, we identified that the anti-inflammatory effects of Pterostilbene relied on remodeling mitochondrial dynamics in microglia. Concretely, Pterostilbene reversed the downregulation of OPA1, promoted mitochondrial fusion, restored normal mitochondrial morphology, and reduced mitochondrial fragmentation and superoxide in microglia after OxyHb treatment. Moreover, conditionally deleting microglial OPA1 in mice largely countered the effects of Pterostilbene on alleviating microglial inflammation, BBB damage, brain edema and neurological impairment following ICH. In summary, we provided the first evidence that Pterostilbene is a promising agent for alleviating neuroinflammation and brain injury after ICH in mice, and uncovered a novel regulatory relationship between Pterostilbene and OPA1-mediated mitochondrial fusion.


Assuntos
Edema Encefálico , Lesões Encefálicas , Animais , Camundongos , Doenças Neuroinflamatórias , Microglia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Inflamação/tratamento farmacológico , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Hemorragia Cerebral/tratamento farmacológico
14.
Biochem Biophys Res Commun ; 671: 58-66, 2023 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-37300943

RESUMO

Clinical progress in the treatment of traumatic brain injury (TBI) is hindered by the poor understanding of the molecular mechanisms that underlie secondary brain injury (SBI). USP30, a mitochondrial deubiquitinase, has been implicated in the pathological progress of various diseases. However, the precise role of USP30 in TBI-induced SBI remains unclear. In this study, we found that USP30 was differentially upregulated after TBI in humans and mice. Immunofluorescence staining further revealed that the enhanced USP30 mainly localized in neurons. Neuron-specific knockout of USP30 reduced lesion volumes, mitigated brain edema, and attenuated neurological deficits after TBI in mice. Additionally, we found that USP30 deficiency effectively suppressed oxidative stress and neuronal apoptosis in TBI. Those protective effects of USP30 loss may be attributed, at least partially, to the reduction of TBI-induced impairment of mitochondrial quality control, including mitochondrial dynamics, function, and mitophagy. Collectively, our findings identify a previously undisclosed role of USP30 in the pathophysiology of TBI and lay a preliminary foundation for future research in this field.


Assuntos
Lesões Encefálicas Traumáticas , Humanos , Camundongos , Animais , Mitocôndrias/metabolismo , Estresse Oxidativo , Apoptose , Mitofagia/fisiologia
15.
Adv Sci (Weinh) ; 10(14): e2300328, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36935367

RESUMO

The fact that multidrug resistance (MDR) could induce medical device-related infections, along with the invalidation of traditional antibiotics has become an intractable global medical issue. Therefore, there is a pressing need for innovative strategies of antibacterial functionalization of medical devices. For this purpose, a multimodal antibacterial coating that combines photothermal and photodynamic therapies (PTT/PDT) is developed here based on novel heavy atom-free photosensitizer compound, BDP-6 (a kind of boron-dipyrromethene). The photothermal conversion efficiency of BDP-6 is of 55.9%, which could improve biocompatibility during PTT/PDT process by reducing the exciting light power density. Furthermore, BDP-6, together with oxidized hyaluronic acid, is crosslinked with a natural polymer, gelatin, to fabricate a uniform coating (denoted as polyurethane (PU)-GHB) on the surface of polyurethane. PU-GHB has excellent synergistic in vitro PTT/PDT antibacterial performance against both susceptible bacteria and MDR bacteria. The antibacterial mechanisms are revealed as that hyperthermia could reduce the bacterial activity and enhance the permeability of inner membrane to reactive oxygen species by disturbing cell membrane. Meanwhile, in an infected abdominal wall hernia model, the notable anti-infection performance, good in vivo compatibility, and photoacoustic imaging property of PU-GHB are verified. A promising strategy of developing multifunctional antibacterial coatings on implanted medical devices is provided here.


Assuntos
Infecções Bacterianas , Fotoquimioterapia , Oxibato de Sódio , Humanos , Fotoquimioterapia/métodos , Polímeros , Poliuretanos , Infecções Bacterianas/tratamento farmacológico , Antibacterianos/farmacologia
16.
Oxid Med Cell Longev ; 2023: 7857760, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36819779

RESUMO

Intracerebral hemorrhage (ICH) is lethal but lacks effective therapies. Nicotinamide adenine dinucleotide (NAD+) is a central metabolite indispensable for a broader range of fundamental intracellular biological functions. Reduction of NAD+ usually occurs after acute brain insults, and supplementation of NAD+ has been proven neuroprotective. P7C3-A20 is a novel compound featuring its ability to facilitate the flux of NAD+. In this study, we sought to determine the potential therapeutic value of P7C3-A20 in ICH. In collagenase-induced ICH mouse models, we found that P7C3-A20 treatment could diminish lesion volume, reduce blood-brain barrier (BBB) damage, mitigate brain edema, attenuate neural apoptosis, and improve neurological outcomes after ICH. Further, RNA sequencing and subsequent experiments revealed that ICH-induced neuroinflammation and microglial proinflammatory activities were significantly suppressed following P7C3-A20 treatment. Mitochondrial damage is an important trigger of inflammatory response. We examined mitochondrial morphology and function and found that P7C3-A20 could attenuate OxyHb-induced impairment of mitochondrial dynamics and functions in vitro. Mechanistically, Sirt3, an NAD+-dependent deacetylase located in mitochondria, was then found to play a vital role in the protection of P7C3-A20 against mitochondrial damage and inflammatory response. In rescue experiments, P7C3-A20 failed to exert those protective effects in microglia-specific Sirt3 conditional knockout (CKO) mice. Finally, preclinical research revealed a correlation between the plasma NAD+ level and the neurological outcome in ICH patients. These results demonstrate that P7C3-A20 is a promising therapeutic agent for neuroinflammatory injury after ICH and exerts protective actions, at least partly, in a Sirt3-dependent manner.


Assuntos
Lesões Encefálicas , Sirtuína 3 , Animais , Camundongos , Lesões Encefálicas/metabolismo , Hemorragia Cerebral/patologia , Inflamação , Microglia/metabolismo , NAD/metabolismo
17.
Adv Mater ; 35(18): e2207546, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36398522

RESUMO

The use of boron dipyrromethene (BODIPY) in biomedicine is reviewed. To open, its synthesis and regulatory strategies are summarized, and inspiring cutting-edge work in post-functionalization strategies is highlighted. A brief overview of assembly model of BODIPY is then provided: BODIPY is introduced as a promising building block for the formation of single- and multicomponent self-assembled systems, including nanostructures suitable for aqueous environments, thereby showing the great development potential of supramolecular assembly in biomedicine applications. The frontier progress of BODIPY in biomedical application is thereafter described, supported by examples of the frontiers of biomedical applications of BODIPY-containing smart materials: it mainly involves the application of materials based on BODIPY building blocks and their assemblies in fluorescence bioimaging, photoacoustic imaging, disease treatment including photodynamic therapy, photothermal therapy, and immunotherapy. Lastly, not only the current status of the BODIPY family in the biomedical field but also the challenges worth considering are summarized. At the same time, insights into the future development prospects of biomedically applicable BODIPY are provided.


Assuntos
Nanopartículas , Medicina de Precisão , Boro/química , Indicadores e Reagentes , Nanopartículas/química
18.
Micromachines (Basel) ; 13(11)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36363965

RESUMO

In this paper, we combine the dielectric metasurface with monolayer graphene to realize a high quality(Q)-factor quasi-BIC-based optical modulator, and the corresponding modulation performances are investigated by using the finite-difference time-domain (FDTD) method, which can be well fitting by the Fano formula based on the temporal couple-mode theory. The results demonstrate that bound states in the continuum (BIC) will turn into the quasi-BIC with high Q-factor by breaking the symmetry of every unit of the metasurface. Meanwhile, the amplitude and bandwidth of transmission based on the quasi-BIC mode can be efficiently adjusted by changing the Fermi energy (EF) of monolayer graphene, and the maximum difference in transmission up to 0.92 is achieved. Moreover, we also discuss the influence of the asymmetry degree to further investigate the modulation effect of graphene on the quasi-BIC mode.

19.
Nanotechnology ; 34(4)2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36265458

RESUMO

Exploration of high-performance photoanodes is considered as an essential challenge in photoelectrochemical (PEC) water splitting due to the complex four-electron reaction in water oxidation. Herein, the nano-structured WO3-Se heterojunction decorated by organic Nafion layer is designed. The optimized WO3-Se200-0.05Nafion photoanode shows a remarkable photocurrent of 1.40 mA cm-2at 1.23 V versus reversible hydrogen electrode, which is 2.5-fold higher than that of pure WO3nanosheets (WO3NS) photoelectrode. Remarkably, the photocurrent increments of WO3-Se200-0.05Nafion is larger than the increment sum of WO3-Se200 and WO3-0.05Nafion, which affirming the synergistic effect of Se nanospheres and Nafion layer. The improved PEC performances are attributed to the quick charge separation and transfer, the increased electric conductivity, and the excellent kinetics of oxygen evolution, which is derived from the strong interaction among WO3, Se and Nafion. Meanwhile, the better visible-light harvesting from Se nanospheres as photosensitizer and the induction of transparent Nafion as a passivation layer can explain this synergy. It hopes this heterostructure design with organic Nafion decoration can inspire to exploit outstanding performance photoanodes for PEC water splitting.

20.
Materials (Basel) ; 15(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36234119

RESUMO

In our previous work, epitaxial Ba(Zr0.2Ti0.8)O3 thick films (~1-2 µm) showed an excellent energy storage performance with a large recyclable energy density (~58 J/cc) and a high energy efficiency (~92%), which was attributed to a nanoscale entangled heterophase polydomain structure. Here, we propose a detailed analysis of the structure-property relationship in these film materials, using an annealing process to illustrate the effect of nanodomain entanglement on the energy storage performance. It is revealed that an annealing-induced stress relaxation led to the segregation of the nanodomains (via detailed XRD analyses), and a degraded energy storage performance (via polarization-electric field analysis). These results confirm that a nanophase entanglement is an origin of the high-energy storage performance in the Ba(Zr0.2Ti0.8)O3 thick films.

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