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1.
Cancer Lett ; 604: 217240, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39265800

RESUMO

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of the MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFß mRNA upregulation, as well as invasion. Moreover, the cleavage under targets and release using nuclease (CUT&RUN) assay coupled with next-generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor regions of genes encoding TGFß and its signaling pathway members in cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1 and this study offers new therapeutic strategies to treat Bcl-xL-overexpressing cancer.

2.
Cell Death Dis ; 15(8): 589, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138148

RESUMO

It is still challenging to predict the efficacy of cisplatin-based therapy, particularly in relation to the activation of macroautophagy/autophagy in oral squamous cell carcinoma (OSCC). We studied the effect of selected chromatin remodeling genes on the cisplatin resistance and their interplay with autophagy in 3-dimensional tumor model and xenografts. We analyzed gene expression patterns in the cisplatin-sensitive UMSCC1, and a paired cisplatin-resistant UM-Cis cells. Many histone protein gene clusters involved in nucleosome assembly showed significant difference of expression. Gain- and loss-of-function analyses revealed an inverse correlation between cisplatin resistance and HIST1H3D expression, while a positive correlation was observed with HIST3H2A or HIST3H2B expression. In UM-Cis, HIST3H2A- and HIST3H2B-mediated chromatin remodeling upregulates autophagy status, which results in cisplatin resistance. Additionally, knockdown of HIST3H2A or HIST3H2B downregulated autophagy-activating genes via chromatin compaction of their promoter regions. MiTF, one of the key autophagy regulators upregulated in UM-Cis, negatively regulated transcription of HIST1H3D, suggesting an interplay between chromatin remodeling-dependent cisplatin resistance and autophagy. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, protein expression pattern of the selected histone protein genes were matched with the in vitro data. By examining the relationship between autophagy and chromatin remodeling genes, we identified a set of candidate genes with potential use as markers predicting chemoresistance in OSCC biopsy samples.


Assuntos
Autofagia , Carcinoma de Células Escamosas , Montagem e Desmontagem da Cromatina , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Neoplasias Bucais , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Humanos , Autofagia/efeitos dos fármacos , Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Histonas/metabolismo , Camundongos Nus , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Ophthalmic Epidemiol ; : 1-19, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865606

RESUMO

PURPOSE: Amidst the global aging population and an increasing prevalence of visual impairment across all age groups, this study aims to investigate the current state of research on sleep health in visually impaired populations. METHODS: A scoping review was conducted to synthesize the existing literature on sleep health and visual impairment. We employed conceptual mapping to identify key research topics, analyzing data from four databases: PubMed (n = 290), CINAHL (n = 81), Scopus (n = 117), and PsycInfo (n = 96). A total of 83 peer-reviewed articles, published from 1977 to August 2023, were included in the review. RESULTS: Our analysis identified 11 distinct eye health conditions including blindness, glaucoma, diabetic retinopathy, low vision, cataract, retinitis pigmentosa, macular degeneration, optic neuropathy, visual field defects, ocular hypertension, and retinal vein occlusion. Additionally, 8 major sleep problems were recognized: abnormal sleep duration, daytime sleepiness, insomnia, Non-24-Hour Sleep Wake Disorder, sleep apnea, sleep disorders, sleep disturbances, and sleep disordered breathing. The dominant research themes were (1) poor sleep quality in individuals with visual impairments and ophthalmic diseases, (2) high prevalence of sleep issues in patients with ophthalmic diseases, (3) sleep apnea in patients with ophthalmic conditions, and (4) circadian rhythm disruptions in blind individuals. CONCLUSION: This review highlights research gaps that, when addressed, could greatly enhance our comprehension of the interplay between visual impairment and sleep health. Bridging these gaps promises to lead to more holistic care strategies, potentially improving vision functioning and rehabilitation outcomes for individuals with visual impairments.

4.
Bioengineering (Basel) ; 11(6)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38927853

RESUMO

The significant growth of the global protein drug market, including fusion proteins, emphasizes the crucial role of optimizing amino acid sequences to enhance the productivity and bioefficacy. Among these fusion proteins, RBP-IIIA-IB, comprising retinol-binding protein in conjunction with the albumin domains, IIIA and IB, has displayed efficacy in alleviating liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs). This study aimed to address the issue of the low productivity in RBP-IIIA-IB. To induce structural changes, the linking sequence, EVDD, between domain IIIA and IB in RBP-IIIA-IB was modified to DGPG, AAAA, and GGPA. Among these, RBP-IIIA-AAAA-IB demonstrated an increase in yield (>4-fold) and a heightened inhibition of HSC activation. Furthermore, we identified amino acid residues that could form disulfide bonds when substituted with cysteine. Through the mutation of N453S-V480S in RBP-IIIA-AAAA-IB, the productivity further increased by over 9-fold, accompanied by an increase in anti-fibrotic activity. Overall, there was a more than 30-fold increase in the fusion protein's yield. These findings demonstrate the effectiveness of modifying linker sequences and introducing extra disulfide bonds to improve both the production yield and biological efficacy of fusion proteins.

5.
Sci Rep ; 14(1): 13694, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871983

RESUMO

We present quad-layered reflective structural color filters generating vivid additive primary colors by controlling a mode number in a Fabry-Perot (FP) cavity and an anti-reflective (AR) coating layer, thus accomplishing high spectral contrast which is highly demanded in creating sharp colors. The reflection brightness of fabricated structural color filters is over 78% and a color gamut is comparable to the standard color gamut (sRGB). Higher-order resonant modes are exploited yielding a narrow passband with strong suppression of the reflection at shorter and longer wavelength ranges for a green color, while red and blue colors are produced by employing fundamental resonant modes. Besides, the structural color filters maintain both high brightness and high color purity at oblique incidence angles up to 40° due to a small angle of refraction by a cavity medium with high refractive index. Moreover, a large-scale fabrication is enabled owing to the simplicity of a device structure, where thin film deposition is used. The scheme presented in this work may open the door to a number of applications, such as reflective displays, imaging devices, colored photovoltaics, and decorations.

6.
Mhealth ; 10: 17, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38689610

RESUMO

Background: Mobile health (mHealth) applications (apps) are crucial in delivering health information and services to older adults. Despite their importance, blind and visually impaired (BVI) older individuals often face significant challenges in app accessibility and usability. This study delves into the design preferences and expectations of BVI older users and underscores the necessity of user-centered design for inclusive mHealth apps. Methods: Conducted in September 2023, the study comprised six focus group interviews. Each session involved two to four participants who began with self-introductions, followed by discussions centered on three open-ended interview questions. Results: The study involved 14 participants: four with severe low vision and 10 totally blind. The primary design principles highlighted were "customizability" and "simplicity". The participants stressed the importance of intuitively designed main pages aligning with user patterns. Further, the participants articulated the following mHealth app feature or menu recommendations: editable profiles, emergency contact access, adaptable data presentation, data exportation, audible color details, customizable colors for varying visual needs, audible error feedback, feasible data input methods, toolbars, and habit-establishing reminders. Discussions also touched on the vital role of clear health data visualizations and comprehensible app-based health information. Conclusions: The findings illuminate paths for software developers and health scientists working towards more inclusive mHealth solutions. It is essential during the development phase to prioritize app learnability to accommodate a broad range of users, ensuring that even those with disabilities can effectively use technological innovations to address health disparities.

7.
JMIR Form Res ; 8: e48783, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38598285

RESUMO

BACKGROUND: College students with disabilities need to transition from pediatric-centered care to adult care. However, they may become overwhelmed by multiple responsibilities, such as academic activities, peer relationships, career preparation, job seeking, independent living, as well as managing their health and promoting healthy behaviors. OBJECTIVE: As the use of smartphones and wearable devices for collecting personal health data becomes popular, this study aimed to compare the characteristics of self-tracking health practices between college students with disabilities and their counterparts. In addition, this study examined the relationships between disability status, self-tracking health practices, eHealth literacy, and subjective well-being among college students. METHODS: The web-based questionnaire was designed using Qualtrics for the cross-sectional online survey. The survey data were collected from February 2023 to April 2023 and included responses from 702 participants. RESULTS: More than 80% (563/702, 80.2%) of the respondents participated voluntarily in self-tracking health practices. College students with disabilities (n=83) showed significantly lower levels of eHealth literacy and subjective well-being compared with college students without disabilities (n=619). The group with disabilities reported significantly lower satisfaction (t411=-5.97, P<.001) and perceived efficacy (t411=-4.85, P<.001) when using smartphone health apps and wearable devices. Finally, the study identified a significant correlation between subjective well-being in college students and disability status (ß=3.81, P<.001), self-tracking health practices (ß=2.22, P=.03), and eHealth literacy (ß=24.29, P<.001). CONCLUSIONS: Given the significant relationships among disability status, self-tracking health practices, eHealth literacy, and subjective well-being in college students, it is recommended to examine their ability to leverage digital technology for self-care. Offering learning opportunities to enhance eHealth literacy and self-tracking health strategies within campus environments could be a strategic approach to improve the quality of life and well-being of college students.

8.
J Infect ; 88(6): 106159, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38641139

RESUMO

OBJECTIVE: To diagnose invasive pulmonary aspergillosis (IPA), galactomannan (GM) detection in serum or bronchoalveolar lavage fluid (BALF) is widely used. However, the utility of proximal airway GM test (from induced sputum or tracheal aspirate) has not been well elucidated. METHODS: In this retrospective cohort study, we evaluated the diagnostic performance of proximal airway GM in diagnosis of IPA including COVID-19 associated pulmonary aspergillosis (CAPA). Between January 2022 and January 2023, patients who had been tested for GM with clinical suspicion or for surveillance from any specimen (serum, induced sputum, tracheal aspirate, and BALF) were screened. IPA was diagnosed using EORTC/MSGERC criteria, and CAPA was diagnosed following the 2020 ECMM/ISHAM consensus criteria. RESULTS: Of 624 patients with GM results, 70 met the criteria for proven/probable IPA and 427 had no IPA. The others included possible IPA and chronic form of aspergillosis. The sensitivities and specificities of serum, proximal airway, and BALF GM for proven/probable IPA versus no IPA were 78.9% and 70.6%, 93.1% and 78.7%, and 78.6% and 91.0%, respectively. Areas under the receiver operating characteristic curve (AUCs) were 0.742 for serum GM, 0.935 for proximal airway GM, and 0.849 for BALF GM (serum GM vs proximal airway GM, p = 0.014; proximal airway GM vs BALF GM, p = 0.334; serum GM vs BALF GM, p = 0.286). CONCLUSION: This study demonstrates that the performance of GM test from non-invasive proximal airway samples is comparable or even better than those from serum and distal airway sample (BALF).


Assuntos
Líquido da Lavagem Broncoalveolar , Galactose , Aspergilose Pulmonar Invasiva , Mananas , Sensibilidade e Especificidade , Humanos , Galactose/análogos & derivados , Mananas/sangue , Mananas/análise , Aspergilose Pulmonar Invasiva/diagnóstico , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/microbiologia , Idoso , COVID-19/diagnóstico , Escarro/microbiologia , Adulto , SARS-CoV-2/isolamento & purificação , Curva ROC
9.
Cereb Cortex ; 34(3)2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38517178

RESUMO

Cognitive decline with aging involves multifactorial processes, including changes in brain structure and function. This study focuses on the role of white matter functional characteristics, as reflected in blood oxygenation level-dependent signals, in age-related cognitive deterioration. Building on previous research confirming the reproducibility and age-dependence of blood oxygenation level-dependent signals acquired via functional magnetic resonance imaging, we here employ mediation analysis to test if aging affects cognition through white matter blood oxygenation level-dependent signal changes, impacting various cognitive domains and specific white matter regions. We used independent component analysis of resting-state blood oxygenation level-dependent signals to segment white matter into coherent hubs, offering a data-driven view of white matter's functional architecture. Through correlation analysis, we constructed a graph network and derived metrics to quantitatively assess regional functional properties based on resting-state blood oxygenation level-dependent fluctuations. Our analysis identified significant mediators in the age-cognition relationship, indicating that aging differentially influences cognitive functions by altering the functional characteristics of distinct white matter regions. These findings enhance our understanding of the neurobiological basis of cognitive aging, highlighting the critical role of white matter in maintaining cognitive integrity and proposing new approaches to assess interventions targeting cognitive decline in older populations.


Assuntos
Disfunção Cognitiva , Substância Branca , Humanos , Idoso , Substância Branca/diagnóstico por imagem , Reprodutibilidade dos Testes , Mapeamento Encefálico , Envelhecimento , Encéfalo/diagnóstico por imagem , Cognição , Imageamento por Ressonância Magnética , Disfunção Cognitiva/diagnóstico por imagem
10.
Microbiol Res ; 283: 127692, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38508088

RESUMO

NADP/NADPH plays an indispensable role in cellular metabolism, serving as a pivotal cofactor in numerous enzymatic processes involved in anabolic pathways, antioxidant defense, and the biosynthesis of essential cellular components. NAD/NADH kinases (NADKs) phosphorylate NAD/NADH, constituting the sole de novo synthetic pathway for NADP/NADPH generation. Despite the pivotal role of NADP/NADPH in cellular functions, the physiological role of NADK remains largely unexplored in filamentous fungi. In this study, we identified three putative NADKs in Fusarium graminearum-FgNadk1, FgNadk2, and FgNadk3-responsible for NAD/NADH phosphorylation. NADK-mediated formation of intracellular NADPH proved crucial for vegetative growth, sexual reproduction, and virulence. Specifically, FgNadk2, the mitochondrial NADK, played a role in oxidative stress resistance and the maintenance of mitochondrial reactive oxygen species levels. Moreover, the deletion of FgNADK2 resulted in arginine auxotrophy, contributing to the reduced fungal virulence. These findings underscore the necessity of mitochondrial NADK in fungal virulence in F. graminearum, revealing its involvement in mitochondrial redox homeostasis and the arginine biosynthetic pathway. This study provides critical insights into the interconnectedness of metabolic pathways essential for fungal growth, stress response, and pathogenicity.


Assuntos
Fusarium , NAD , Virulência , NAD/metabolismo , NADP/metabolismo , Estresse Oxidativo , Oxirredução , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo
11.
Gerontol Geriatr Med ; 10: 23337214241237097, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455642

RESUMO

This study explored the daily challenges and emotional reactions experienced by older adults living with various disabilities, employing both traditional and text mining approaches to ensure rigorous interpretation of qualitative data. In addition to employing a traditional qualitative data analysis method, such as thematic analysis, this paper also leveraged a text mining approach. By utilizing topic modeling and sentiment analysis, the study attempted to mitigate potential researcher bias and diminishes subjectivity in interpreting qualitative data. The findings indicated that older adults with visual impairments predominantly encountered challenges related to navigation, technology utilization, and online shopping. Individuals with hearing impairments chiefly struggled with communicating with healthcare providers, while those with mobility impairments face significant barriers in public participation and managing personal hygiene, such as showering. A prevailing sentiment of negative emotional states was identifiable among all participant groups, with those having visual impairments exhibiting more pronounced negative language patterns. The challenges perceived by participants varied depending on the types of disabilities they have. This study can serve as a valuable reference for researchers interested in a mixed-method strategy that combines conventional qualitative analysis with machine-assisted text analysis, illuminating the varied daily experiences and needs of the older adult population with disabilities.

12.
Methods Cell Biol ; 181: 109-125, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38302234

RESUMO

The process of senescence impairs the function of cells and can ultimately be a key factor in the development of disease. With an aging population, senescence-related diseases are increasing in prevalence. Therefore, understanding the mechanisms of cellular senescence within the central nervous system (CNS), including the retina, may yield new therapeutic pathways to slow or even prevent the development of neuro- and retinal degenerative diseases. One method of probing the changing functions of senescent retinal cells is to observe retinal microglial cells. Their morphological structure may change in response to their surrounding cellular environment. In this chapter, we show how microglial cells in the retina, which are implicated in aging and diseases of the CNS, can be identified, quantified, and classified into five distinct morphotypes using image processing and supervised machine learning algorithms. The process involves dissecting, staining, and mounting mouse retinas, before image capture via fluorescence microscopy. The resulting images can then be classified by morphotype using a support vector machine (SVM) we have recently described showing high accuracy. This SVM model uses shape metrics found to correspond with qualitative descriptions of the shape of each morphotype taken from existing literature. We encourage more objective and widespread use of methods of quantification such as this. We believe automatic delineation of the population of microglial cells in the retina, could potentially lead to their use as retinal imaging biomarkers for disease prediction in the future.


Assuntos
Microglia , Retina , Camundongos , Animais , Microglia/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Envelhecimento/fisiologia , Aprendizado de Máquina Supervisionado
13.
NMR Biomed ; 37(5): e5111, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38297919

RESUMO

Deoxygenation-based dynamic susceptibility contrast (dDSC) MRI uses respiratory challenges as a source of endogenous contrast as an alternative to gadolinium injection. These gas challenges induce T2*-weighted MRI signal losses, after which tracer kinetics modeling was applied to calculate cerebral perfusion. This work compares three gas challenges, desaturation (transient hypoxia), resaturation (transient normoxia), and SineO2 (sinusoidal modulation of end-tidal oxygen pressures) in a cohort of 10 healthy volunteers (age 37 ± 11 years; 60% female). Perfusion estimates consisted of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Calculations were computed using a traditional tracer kinetics model in the time domain for desaturation and resaturation and in the frequency domain for SineO2. High correlations and limits of agreement were observed among the three deoxygenation-based paradigms for CBV, although MTT and CBF estimates varied with the hypoxic stimulus. Cross-modality correlation with gadolinium DSC was lower, particularly for MTT, but on a par with agreement between the other perfusion references. Overall, this work demonstrated the feasibility and reliability of oxygen respiratory challenges to measure brain perfusion. Additional work is needed to assess the utility of dDSC in the diagnostic evaluation of various pathologies such as ischemic strokes, brain tumors, and neurodegenerative diseases.


Assuntos
Meios de Contraste , Gadolínio , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética , Encéfalo/patologia , Oxigênio , Circulação Cerebrovascular/fisiologia
14.
Sci Adv ; 10(4): eadi0616, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38277462

RESUMO

Correlations between magnetic resonance imaging (MRI) blood oxygenation level-dependent (BOLD) signals from pairs of gray matter areas are used to infer their functional connectivity, but they are unable to describe how white matter is engaged in brain networks. Recently, evidence that BOLD signals in white matter are robustly detectable and are modulated by neural activities has accumulated. We introduce a three-way correlation between BOLD signals from pairs of gray matter volumes (nodes) and white matter bundles (edges) to define the communication connectivity through each white matter bundle. Using MRI images from publicly available databases, we show, for example, that the three-way connectivity is influenced by age. By integrating functional MRI signals from white matter as a third component in network analyses, more comprehensive descriptions of brain function may be obtained.


Assuntos
Substância Branca , Substância Branca/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Imageamento por Ressonância Magnética , Mapeamento Encefálico/métodos
15.
Adapt Phys Activ Q ; 41(3): 450-474, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38218179

RESUMO

This study evaluated physical activity interventions designed for individuals with visual impairments and sought to guide health intervention scientists aiming to promote physical activity in this demographic. We delved into the specifics of participants' visual impairments, intervention features, accommodation approaches, and replicability prospects. The search spanned four databases, namely PubMed, CINAHL, SportDiscus, and Scopus, providing a wide scope and diversity of potential studies. There were no restrictions on publication years. We reviewed 13 studies, totaling 15 interventions. A consensus on visual-impairment definitions remains elusive, and the intervention dosages displayed variability. Notably, 66.7% (n = 7) integrated behavior-change techniques to amplify physical activity levels. Multiple studies employed audio descriptions as an accommodation method. While most studies provided adequate information for potential replication, detailed study protocols were frequently absent. It is essential for developed interventions to be persistently evaluated and fine-tuned to optimize results.


Assuntos
Exercício Físico , Transtornos da Visão , Humanos , Pessoas com Deficiência Visual
16.
Theranostics ; 14(2): 460-479, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169528

RESUMO

Rationale: Platinum-based chemotherapy is commonly used for treating solid tumors, but drug resistance often limits its effectiveness. Cancer-associated fibroblast (CAF)-derived extracellular vesicle (EV), which carry various miRNAs, have been implicated in chemotherapy resistance. However, the molecular mechanism through which CAFs modulate cisplatin resistance in oral squamous cell carcinoma (OSCC) is not well understood. We employed two distinct primary CAF types with differential impacts on cancer progression: CAF-P, representing a more aggressive cancer-promoting category, and CAF-D, characterized by properties that moderately delay cancer progression. Consequently, we sought to investigate whether the two CAF types differentially affect cisplatin sensitivity and the underlying molecular mechanism. Methods: The secretion profile was examined by utilizing an antibody microarray with conditioned medium obtained from the co-culture of OSCC cells and two types of primary CAFs. The effect of CAF-dependent factors on cisplatin resistance was investigated by utilizing conditioned media (CM) and extracellular vesicle (EVs) derived from CAFs. The impacts of candidate genes were confirmed using gain- and loss-of-function analyses in spheroids and organoids, and a mouse xenograft. Lastly, we compared the expression pattern of the candidate genes in tissues from OSCC patients exhibiting different responses to cisplatin. Results: When OSCC cells were cultured with conditioned media (CM) from the two different CAF groups, cisplatin resistance increased only under CAF-P CM. OSCC cells specifically expressed insulin-like growth factor binding protein 3 (IGFBP3) after co-culture with CAF-D. Meanwhile, IGFBP3-knockdown OSCC cells acquired cisplatin resistance in CAF-D CM. IGFBP3 expression was promoted by GATA-binding protein 1 (GATA1), a transcription factor targeted by miR-876-3p, which was enriched only in CAF-P-derived EV. Treatment with CAF-P EV carrying miR-876-3p antagomir decreased cisplatin resistance compared to control miRNA-carrying CAF-P EV. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, there was a positive correlation between IGFBP3 and GATA1 expression and cisplatin sensitivity in OSCC tissues from patients. Conclusion: These results provide insights for overcoming cisplatin resistance, especially concerning EVs within the tumor microenvironment. Furthermore, it is anticipated that the expression levels of GATA1 and miR-876-3p, along with IGFBP3, could aid in the prediction of cisplatin resistance.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma de Células Escamosas , Vesículas Extracelulares , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , Humanos , Animais , Camundongos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Meios de Cultivo Condicionados/farmacologia , Meios de Cultivo Condicionados/metabolismo , Proliferação de Células , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Linhagem Celular Tumoral , Microambiente Tumoral/genética
17.
mBio ; 15(1): e0240123, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38112432

RESUMO

IMPORTANCE: Fusarium graminearum is a destructive fungal pathogen that causes Fusarium head blight (FHB) on a wide range of cereal crops. To control fungal diseases, it is essential to comprehend the pathogenic mechanisms that enable fungi to overcome host defenses during infection. Pathogens require an oxidative stress response to overcome host-derived oxidative stress. Here, we identify the underlying mechanisms of the Fgbzip007-mediated oxidative stress response in F. graminearum. ChIP-seq and subsequent genetic analyses revealed that the role of glutathione in pathogenesis is not dependent on antioxidant functions in F. graminearum. Altogether, this study establishes a comprehensive framework for the Fgbzip007 regulon on pathogenicity and oxidative stress responses, offering a new perspective on the role of glutathione in pathogenicity.


Assuntos
Fusarium , Virulência/genética , Estresse Oxidativo , Enxofre , Doenças das Plantas/microbiologia
18.
J Cell Physiol ; 239(1): 112-123, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38149778

RESUMO

Lipid biosynthesis is recently studied its functions in a range of cellular physiology including differentiation and regeneration. However, it still remains to be elucidated in its precise function. To reveal this, we evaluated the roles of lysophosphatidic acid (LPA) signaling in alveolar bone formation using the LPA type 2 receptor (LPAR2) antagonist AMG-35 (Amgen Compound 35) using tooth loss without periodontal disease model which would be caused by trauma and usually requires a dental implant to restore masticatory function. In this study, in vitro cell culture experiments in osteoblasts and periodontal ligament fibroblasts revealed cell type-specific responses, with AMG-35 modulating osteogenic differentiation in osteoblasts in vitro. To confirm the in vivo results, we employed a mouse model of tooth loss without periodontal disease. Five to 10 days after tooth extraction, AMG-35 facilitated bone formation in the tooth root socket as measured by immunohistochemistry for differentiation markers KI67, Osteocalcin, Periostin, RUNX2, transforming growth factor beta 1 (TGF-ß1) and SMAD2/3. The increased expression and the localization of these proteins suggest that AMG-35 elicits osteoblast differentiation through TGF-ß1 and SMAD2/3 signaling. These results indicate that LPAR2/TGF-ß1/SMAD2/3 represents a new signaling pathway in alveolar bone formation and that local application of AMG-35 in traumatic tooth loss can be used to facilitate bone regeneration and healing for further clinical treatment.


Assuntos
Lisofosfolipídeos , Osteogênese , Receptores de Lisofosfolipídeos , Perda de Dente , Animais , Camundongos , Diferenciação Celular/fisiologia , Lisofosfolipídeos/metabolismo , Osteoblastos/metabolismo , Ligamento Periodontal/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Receptores de Lisofosfolipídeos/metabolismo
19.
JMIR Form Res ; 7: e52410, 2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-38145472

RESUMO

BACKGROUND: Current mobile health (mHealth) technology is predominantly designed with a visual orientation, often resulting in user interfaces that are inaccessible to visually impaired users. While mHealth technology offers potential for facilitating chronic illness management and enhancing health behaviors among visually impaired older populations, understanding its usage remains limited. OBJECTIVE: This qualitative research aimed to explore the mHealth technology experiences of middle-aged and older individuals with visual impairments including the accessibility and usability issues they faced. METHODS: The qualitative exploration was structured using the mHealth for Older Users framework. Cross-sectional interviews were conducted via Zoom between June 1 and July 31, 2023, using an interview protocol for data collection. A thematic analysis approach was employed to analyze the transcribed interview scripts. RESULTS: Of the 7 participants who took part in the Zoom interviews, 3 were men and 4 were women, with ages ranging from 53 to 70 years. Most participants adopted mHealth apps and wearable devices for promoting health. They exhibited 3 distinct adoption patterns. Seven themes were emerged from the perceived challenges in using mHealth technologies: (1) a scarcity of accessible user manuals, (2) user interfaces that are not visually impaired-friendly, (3) health data visualizations that are not accessible, (4) unintuitive arrangement of app content, (5) health information that is challenging to comprehend, (6) cognitive overload caused by an excess of audible information, and (7) skepticism regarding the accuracy of health records. mHealth technologies seem to positively affect the health and health management of participants. CONCLUSIONS: Design considerations for mHealth technologies should consider individuals' disabilities and chronic conditions and should emphasize the importance of providing accessible manuals and training opportunities when introducing new mHealth solutions.

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