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1.
Front Psychol ; 15: 1387847, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38993345

RESUMO

Introduction: This study aimed to determine the effectiveness of group therapy on the stress coping skills of Chinese students in Korea using a pre-test post-test control group design. Methods: Thirty participants were randomly placed into an experimental group (EG; n = 15) and a control group (CG; n = 15). The EG completed eight 120-min sessions of group art therapy. The Person-in-the-Rain (PITR) drawing test was conducted with both groups before and after the EG completed art therapy. Results: The test revealed that EG members demonstrated lower stress and significantly higher stress resources and coping abilities than the CG members after the intervention. The group art therapy program improved the EG participants' ability to deal with stress. Discussion: This study's findings may offer insights useful for determining how best to provide psychological and emotional support to international students who have left their home countries and are continuing their academic journeys abroad.

2.
J Prosthodont ; 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822528

RESUMO

PURPOSE: Bilayered restorations have both the strength of the substructure material and the esthetics of the veneer material; however, they should have appropriate bonding between the two materials. This study aimed to evaluate the shear bond strength (SBS) according to the substructure material and veneering technique used in bilayered restorations. MATERIALS AND METHODS: The experimental group was divided into four groups (n = 15 per group) based on the substructure materials (cobalt-chromium [Co-Cr] alloy and 3 mol% yttrium-stabilized tetragonal zirconia polycrystal [3Y-TZP]) and veneering techniques (pressing and layering). Veneering was performed with disk shape (diameter: 5 mm, height: 2 mm) on a substructure using each veneering technique. Shear stress was applied to the interface of the substructure and the veneering ceramic using a universal testing machine. The shear bond strength, according to the substructure and veneering technique, was analyzed using a two-way analysis of variance with a post-hoc Tukey's honestly significant difference test. The failure mode was observed, and the surface was analyzed using a scanning electron microscope and energy-dispersive spectroscopy. RESULTS: The shSBS of the Co-Cr alloy and 3Y-TZP substructure was not different (p > 0.05); however, the pressing technique showed a higher SBS than the layering technique (p < 0.05). The SBS did not differ depending on the veneering technique in the Co-Cr alloys (p > 0.05), whereas the SBS in the pressing technique was higher than that in the layering technique for 3Y-TZP (p < 0.05). In the layering technique, the Co-Cr alloy showed a higher SBS than 3Y-TZP (p < 0.05). In the failure mode, mixed failure occurred most frequently in all groups. Extensive elemental interdiffusion was observed through the opaque layer in the Co-Cr alloy, regardless of the veneering technique. In 3Y-TZP, a wider range of elemental interdiffusion was observed in the pressing technique than in the layering technique. CONCLUSIONS: In bilayered restorations with a 3Y-TZP substructure, the pressing technique yielded higher bonding strength than layering. Using the layering technique, 3Y-TZP showed a lower SBS than the Co-Cr alloy. In bilayered restorations using 3Y-TZP as a substructure, the veneering technique and thermal compatibility of the materials must be considered.

3.
iScience ; 27(5): 109795, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38741711

RESUMO

Despite the promising outcomes of immune checkpoint inhibitors (ICIs), resistance to ICI presents a new challenge. Therefore, selecting patients for specific ICI applications is crucial for maximizing therapeutic efficacy. Herein, we curated 69 human esophageal squamous cell cancer (ESCC) patients' tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC. Integrative analyses of the cellular network and transcriptional signatures of T cells and myeloid cells define distinct ESCC subtypes characterized by T cell exhaustion, and interleukin (IL) and interferon (IFN) signaling. Furthermore, this approach classifies ESCC patients into ICI responders and non-responders, as validated by whole tumor transcriptomes and liquid biopsy-based single-cell transcriptomes of anti-PD-1 ICI responders and non-responders. Our study stratifies ESCC patients based on TME transcriptional network, providing novel insights into tumor niche remodeling and potentially predicting ICI responses in ESCC patients.

4.
STAR Protoc ; 5(2): 103067, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38748883

RESUMO

Single-cell RNA sequencing (scRNA-seq) provides high resolution of cell-to-cell variation in gene expression and offers insights into cell heterogeneity, differentiating dynamics, and disease mechanisms. However, technical challenges such as low capture rates and dropout events can introduce noise in data analysis. Here, we present a deep learning framework, called the dynamic batching adversarial autoencoder (DB-AAE), for denoising scRNA-seq datasets. First, we describe steps to set up the computing environment, training, and tuning. Then, we depict the visualization of the denoising results. For complete details on the use and execution of this protocol, please refer to Ko et al.1.


Assuntos
Aprendizado Profundo , RNA-Seq , Análise de Célula Única , Análise de Célula Única/métodos , RNA-Seq/métodos , Humanos , Análise de Sequência de RNA/métodos , Análise da Expressão Gênica de Célula Única
5.
Cell Rep ; 43(6): 114286, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38796854

RESUMO

Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, some lung adenocarcinoma (LUAD) cells transform into neuroendocrine (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD (capping protein inhibiting regulator of actin dynamics), a capping protein inhibitor, is frequently inactivated in cancers. CRACD knockout (KO) is sufficient to de-repress NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE cell plasticity is associated with cell de-differentiation and stemness-related pathway activation. The single-cell transcriptomic analysis of LUAD patient tumors recapitulates that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with impaired actin remodeling. This study reveals the crucial role of CRACD in restricting NE cell plasticity that induces cell de-differentiation of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Plasticidade Celular , Neoplasias Pulmonares , Células Neuroendócrinas , Animais , Humanos , Camundongos , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo
6.
Medicina (Kaunas) ; 60(5)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38792971

RESUMO

Background and Objectives: Patella baja is a common complication after operative treatment for patellar fracture. This study aimed to investigate (1) the serial changes in patellar height and (2) the potential predictive factors for patellar height changes after tension band wiring (TBW) for patellar fractures. Materials and Methods: Forty-one patients who underwent TBW for patellar fracture between March 2019 and September 2022 were enrolled. To identify serial changes in patellar height, modified Blackburne-Peel index (mBPI) was assessed at just after surgery, at 3 months, at 6 months, at 1 year and at the final follow-up. Multiple regression analysis was conducted to identify factors correlated with mBPI difference between the contralateral side (considered as preoperative status) and injured side. Results: The postoperative mBPI exhibited a decline over time (mean mBPI immediately post operation/3 months/6 months/1 year/final follow-up: 0.69/0.63/0.63/0.62/0.61) Specifically, mBPI showed a significant reduction immediately post operation to 3 months (p < 0.001), although comparisons at other time points did not reveal significant differences. A lower position of the fracture was associated with a decrease in patellar height after surgery. Conclusions: Patellar height was mainly decreased from immediately post operation to 3 months. A fracture in a lower position of associated with decreased patellar height after the TBW of the transverse patellar fracture.


Assuntos
Fraturas Ósseas , Patela , Humanos , Patela/lesões , Masculino , Feminino , Adulto , Fraturas Ósseas/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fios Ortopédicos/efeitos adversos , Fixação Interna de Fraturas/métodos , Fixação Interna de Fraturas/efeitos adversos
7.
Sci Rep ; 14(1): 7787, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565933

RESUMO

This retrospective study aimed to determine risk factors associated with post-operative bleeding after dentoalveolar surgery in patients taking anticoagulants. Patients taking anticoagulants who were planned to undergo periodontal flap operation, tooth extraction or implant surgery were included. Patients were divided into two subgroups according to the maintenance of anticoagulants following medical consultation: (1) maintenance group and (2) discontinuation group. The analysed patient-related factors included systemic diseases, maintenance of anticoagulants and types of anticoagulant. Intra- and post-operative treatment-related factors, haemostatic methods and post-operative bleeding were collected for statistical analyses. There were 35 post-operative bleeding complications (6.5%) in the 537 included patients: 21 (8.6%) in maintenance group and 14 (4.8%) in discontinuation group. The type of anticoagulant (p = 0.037), tooth extraction combined with bone grafting (p = 0.016) and type of implant surgery (p = 0.032) were significantly related to the post-operative bleeding rate. In the maintenance group, atrial fibrillation [odds ratio (OR) = 6.051] and vitamin K inhibitors (OR = 3.679) were associated with a significantly higher bleeding risk. From this result, it can be inferred that the decision to continue anticoagulants should be made carefully based on the types of anticoagulant and the characteristics of dentoalveolar surgeries performed: extraction with bone grafting, multiple implantations and involvement of maxillary arch.


Assuntos
Anticoagulantes , Fibrilação Atrial , Humanos , Anticoagulantes/efeitos adversos , Estudos de Coortes , Estudos Retrospectivos , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/induzido quimicamente , Extração Dentária/efeitos adversos , Fibrilação Atrial/complicações , Administração Oral
8.
Genes Dev ; 38(3-4): 151-167, 2024 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-38453480

RESUMO

By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that a branch of glycolysis, the serine biosynthesis pathway (SBP), is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSC activation and expansion of myogenic progenitors through production of the metabolite α-ketoglutarate (α-KG) and α-KG-generated glutamine. Psat1 ablation resulted in defective expansion of MuSCs and impaired regeneration. Psat1, α-KG, and glutamine were reduced in MuSCs of old mice. α-KG or glutamine re-established appropriate muscle regeneration of adult conditional Psat1 -/- mice and of old mice. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest α-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.


Assuntos
Células-Tronco Adultas , Ácidos Cetoglutáricos , Camundongos , Animais , Ácidos Cetoglutáricos/metabolismo , Glutamina/metabolismo , Envelhecimento/fisiologia , Músculos , Músculo Esquelético
9.
J Prosthet Dent ; 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38443239

RESUMO

Mandibular condyle fracture malunion and tooth loss can cause functional and esthetic problems. A patient with restricted mouth opening associated with muscle atrophy required prosthetic rehabilitation. Since the remaining teeth had a poor prognosis and the patient had difficulty adapting to the interim denture, complete mouth rehabilitation with implants was chosen. The implants were placed by using nerve lateralization and an autogenous bone graft. Prosthetic rehabilitation combines digital diagnosis and conventional prosthetic restorations. The definitive prosthesis was fabricated to ensure adequate oral hygiene and functional adaptation of the orofacial structures. Treatment resulted in stable masticatory function, occlusion, and esthetics and restored the function of the atrophied lips and restricted mouth opening.

10.
J Pediatr Orthop ; 44(5): e411-e418, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38477319

RESUMO

BACKGROUND: The aim of this study was to investigate factors determining the final outcomes of hemipercutaneous epiphysiodesis using transphyseal screw (PETS) for the genu valgum, especially focusing on postoperative courses after screw removal. METHODS: Fifty-five patients with idiopathic genu valgum treated with hemi-PETS were included. The mechanical lateral distal femoral angle (mLDFA) and medial proximal tibial angle (MPTA) were measured to calculate the degree of correction and rebound. Regarding factors related to surgical techniques, the number of screw threads beyond the physis, the moment arm of the screw, and screw insertion angles were measured. RESULTS: In 54 femoral segments (randomly selected in bilateral cases), hemi-PETS was performed with a growth remaining of 2.0±0.6 years. The screw was removed after 6.5±2.1 months, and the degree of correction was 5.0±1.5 degrees. The mean rebound angle was -0.4±2.4 (the negative value means further correction after screw removal). A late time of surgery and an extreme peripheral position of a screw were associated with the growth inhibition. In 50 tibial segments (also randomly selected in bilateral cases), a screw was inserted with a growth remaining of 2.0±0.6 years and removed after 6.3±1.9 months. The degree of correction was 2.9±1.7 degrees during the interval, and the rebound angle was 0.8±1.7 degrees. An earlier time of surgery and a greater correction angle before screw removal were associated with the rebound phenomenon. CONCLUSIONS: Growth inhibition of >1.6 degrees was observed in about one-fourth of femoral segments. An extreme peripheral position of a screw should be avoided when performing hemi-PETS at the distal femur. We also recommend not performing hemi-PETS at distal femur with too short a period of growth remaining. LEVEL OF EVIDENCE: Level III-retrospective comparative series.


Assuntos
Geno Valgo , Humanos , Geno Valgo/cirurgia , Estudos Retrospectivos , Fêmur/cirurgia , Tíbia/cirurgia , Extremidade Inferior
11.
Int J Prosthodont ; 0(0): 1-17, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38373057

RESUMO

PURPOSE: To determine whether food texture affects chewing side preference (CSP) and to investigate the relationship between CSP and masticatory factors such as occlusal contact area, bite force, and masticatory performance. MATERIALS AND METHODS: Forty-seven adults (20 women and 27 men; mean age, 24 years) participated in this study. Three types of food (chewing gum, beef jerky, and peanuts) were provided to assess CSP. Occlusal contact area was measured at various ranges of interocclusal distance, and the bite force was measured. Masticatory performance was assessed according to the median particle size. Asymmetry indices of each measurement were calculated and analyzed using Pearson's correlation coefficient (α = .05). RESULTS: The CSP for beef jerky and peanuts were significantly correlated with each other, whereas the CSP for chewing gum was not correlated with other food. The proportion of participants who chewed equally on both sides was higher for chewing gum than for beef jerky. There was a significant correlation between the CSP for beef jerky and occlusal contact area, especially at interocclusal distance ranges of 0-89 and 0-109 µm (r = 0.41). Bite force and masticatory performance were not significantly correlated with CSP. CONCLUSION: Food texture seemed to affect chewing side preference and masticatory laterality was greater for tough foods. Moreover, CSP for tough food was closely related to the occlusal contact area at about 0.1mm interocclusal distance level.

12.
J Exp Med ; 221(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38411616

RESUMO

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.


Assuntos
Ascite , Carcinogênese , Humanos , Animais , Camundongos , Carcinogênese/genética , Transformação Celular Neoplásica , Estômago , Caderinas/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética
13.
iScience ; 27(3): 109027, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38361616

RESUMO

By providing high-resolution of cell-to-cell variation in gene expression, single-cell RNA sequencing (scRNA-seq) offers insights into cell heterogeneity, differentiating dynamics, and disease mechanisms. However, challenges such as low capture rates and dropout events can introduce noise in data analysis. Here, we propose a deep neural generative framework, the dynamic batching adversarial autoencoder (DB-AAE), which excels at denoising scRNA-seq datasets. DB-AAE directly captures optimal features from input data and enhances feature preservation, including cell type-specific gene expression patterns. Comprehensive evaluation on simulated and real datasets demonstrates that DB-AAE outperforms other methods in denoising accuracy and biological signal preservation. It also improves the accuracy of other algorithms in establishing pseudo-time inference. This study highlights DB-AAE's effectiveness and potential as a valuable tool for enhancing the quality and reliability of downstream analyses in scRNA-seq research.

14.
J Esthet Restor Dent ; 36(3): 445-452, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37671774

RESUMO

OBJECTIVE: This in vitro study aimed to evaluate the flexural strength (FS) and translucency parameter (TP) of resin nanoceramics (RNCs) with barium silicate for additive manufacturing. MATERIALS AND METHODS: An RNC slurry was prepared by mixing a barium silicate filler and resin monomer. For the FS tests, specimens with three filler contents (0, 50, and 63 wt%) were designed according to ISO6872 for dental ceramics and ISO10477 for dental polymers. These specimens were then formed into discs with thicknesses of 1 and 2 mm for TP measurement. RESULTS: In the specimens prepared according to ISO6872, the FS increased significantly depending on the filler content. However, in the case of ISO10477, there was no significant difference between the FSs of the specimens with 0 and 50 wt% filler contents. The increase in thickness affected translucency, and the lowest translucency was obtained at a filler content of 63 wt%. The filler distribution was dense in the specimen with 63 wt% filler and uniform but relatively sparse in the specimen with 50 wt% filler. More voids were observed in the specimen with 63 wt% filler. The thickness and filler content of the specimen affected its TP. The TP of the specimen with 63 wt% filler was similar to that of human enamel. CONCLUSION: The FS was significantly higher at a filler content of 63 wt%. The lowest translucency was obtained at a filler content of 63 wt% for all tested thicknesses. CLINICAL SIGNIFICANCE: Increasing the filler content was advantageous for the mechanical properties of the RNCs. A high filler content led to low translucency in the RNCs. Therefore, the esthetics of human teeth can be reproduced if layering according to the filler content is performed in areas where esthetic characteristics are required.


Assuntos
Porcelana Dentária , Resistência à Flexão , Humanos , Bário , Teste de Materiais , Silicatos , Propriedades de Superfície , Cerâmica
16.
J Prosthodont ; 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38115183

RESUMO

PURPOSE: The purpose of this in vitro study was to compare the tensile bond strength (TBS) of resin nanoceramics (RNC), zirconia, and lithium disilicate (LS2) restorations cemented to titanium abutments before and after thermomechanical aging. MATERIALS AND METHODS: Twelve specimens per group were fabricated to determine the TBS between a titanium abutment and four types of crown materials (2 RNCs, LS2, and translucent zirconia crowns for the maxillary molar). After milling, the abutments and crowns were cemented with resin cement after air-particle abrasion. In addition, thermomechanical aging (200,000 cycles, 50 N, 2 Hz) was applied to half of the specimens by using a mastication simulator. TBS was measured by using a universal testing machine. The interface between the crown and the cement was observed by using scanning electron microscopy (SEM). Two-way ANOVA was performed to analyze the effects of crown materials and thermomechanical aging. Failure-mode and interface analyses were also conducted. RESULTS: After thermomechanical aging, the TBS decreased in the LS2 specimens and increased in RNCs (p < 0.001). The ratio of mixed failure and debonding with the hole-sealing resin increased in the RNC group. SEM images showed the reduced gap between the crown and the resin cement after thermomechanical aging in the RNC group. CONCLUSIONS: Differences in TBS were affected by the crown materials after thermomechanical aging. After thermomechanical aging, the RNC crowns showed increased TBS, whereas LS2 and zirconia crowns exhibited decreased or similar TBS.

17.
Front Psychol ; 14: 1263754, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37928585

RESUMO

Background: Although China and South Korea share a similar East Asian culture, owing to major social and cultural differences, international students encounter several difficulties, which can lead to various psychological problems. Objective: To explore the experiences of eight Chinese doctoral students in South Korea participating in mandala-based art therapy. Method: Data for this phenomenological study were gathered through individual interviews and visual art from April 5 to 20, 2022. The MAXQDA software program was used for data analysis. Results: The data analysis results yielded 355 codes, 53 subcategories, and 17 categories. Five final themes emerged: (a) sealed lips by others' eyes, (b) inner exploration and outward expression, (c) healing power of the mandala, (d) filling the inner space together, and (e) opportunities to understand art therapy. Conclusion: The researchers hope that completing this intervention will enable participants to complete their studies more effectively and achieve their ideals as well as future career goals, helping them ultimately return home safely with both personal and academic growth.

18.
Light Sci Appl ; 12(1): 280, 2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-37996413

RESUMO

Transition metal dichalcogenide (TMD) layered semiconductors possess immense potential in the design of photonic, electronic, optoelectronic, and sensor devices. However, the sub-bandgap light absorption of TMD in the range from near-infrared (NIR) to short-wavelength infrared (SWIR) is insufficient for applications beyond the bandgap limit. Herein, we report that the sub-bandgap photoresponse of MoS2/Au heterostructures can be robustly modulated by the electrode fabrication method employed. We observed up to 60% sub-bandgap absorption in the MoS2/Au heterostructure, which includes the hybridized interface, where the Au layer was applied via sputter deposition. The greatly enhanced absorption of sub-bandgap light is due to the planar cavity formed by MoS2 and Au; as such, the absorption spectrum can be tuned by altering the thickness of the MoS2 layer. Photocurrent in the SWIR wavelength range increases due to increased absorption, which means that broad wavelength detection from visible toward SWIR is possible. We also achieved rapid photoresponse (~150 µs) and high responsivity (17 mA W-1) at an excitation wavelength of 1550 nm. Our findings demonstrate a facile method for optical property modulation using metal electrode engineering and for realizing SWIR photodetection in wide-bandgap 2D materials.

19.
Front Cardiovasc Med ; 10: 1212174, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37781317

RESUMO

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The "response-to-injury" model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain poorly understood. This article aims to provide mechanistic insights into this association and propose future directions to better comprehend this complex interplay.

20.
Res Sq ; 2023 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-37790313

RESUMO

Background: Stroke is a major cause of morbidity and mortality, and its incidence increases with age. While acute therapies for stroke are currently limited to intravenous thrombolytics and endovascular thrombectomy, recent studies have implicated an important role for the gut microbiome in post-stroke neuroinflammation. After stroke, several immuno-regulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, become activated. AHR is a master regulatory pathway that mediates neuroinflammation. Among various cell types, microglia (MG), as the resident immune cells of the brain, play a vital role in regulating post-stroke neuroinflammation and antigen presentation. Activation of AHR is dependent on a dynamic balance between host-derived and microbiota-derived ligands. While previous studies have shown that activation of MG AHR by host-derived ligands, such as kynurenine, is detrimental after stroke, the effects of post-stroke changes in microbiota-derived ligands of AHR, such as indoles, is unknown. Our study builds on the concept that differential activation of MG AHR by host-derived versus microbiome-derived metabolites affects outcomes after ischemic stroke. We examined the link between stroke-induced dysbiosis and loss of essential microbiota-derived AHR ligands. We hypothesize that restoring the balance between host-derived (kynurenine) and microbiota-derived (indoles) ligands of AHR is beneficial after stroke, offering a new potential avenue for therapeutic intervention in post-stroke neuroinflammation. Method: We performed immunohistochemical analysis of brain samples from stroke patients to assess MG AHR expression after stroke. We used metabolomics analysis of plasma samples from stroke and non-stroke control patients with matched comorbidities to determine the levels of indole-based AHR ligands after stroke. We performed transient middle cerebral artery occlusion (MCAO) in aged (18 months) wild-type (WT) and germ-free (GF) mice to investigate the effects of post-stroke treatment with microbiota-derived indoles on outcome. To generate our results, we employed a range of methodologies, including flow cytometry, metabolomics, and 16S microbiome sequencing. Results: We found that MG AHR expression is increased in human brain after stroke and after ex vivo oxygen-glucose deprivation and reperfusion (OGD/R). Microbiota-derived ligands of AHR are decreased in the human plasma at 24 hours after ischemic stroke. Kynurenine and indoles exhibited differential effects on aged WT MG survival after ex vivoOGD/R. We found that specific indole-based ligands of AHR (indole-3-propionic acid and indole-3-aldehyde) were absent in GF mice, thus their production depends on the presence of a functional gut microbiota. Additionally, a time-dependent decrease in the concentration of these indole-based AHR ligands occurred in the brain within the first 24 hours after stroke in aged WT mice. Post-stroke treatment of GF mice with a cocktail of microbiota-derived indole-based ligands of AHR regulated MG-mediated neuroinflammation and molecules involved in antigen presentation (increased CD80, MHC-II, and CD11b). Post-stroke treatment of aged WT mice with microbiota-derived indole-based ligands of AHR reduced both infarct volume and neurological deficits at 24 hours. Conclusion: Our novel findings provide compelling evidence that the restoration of a well-balanced pool of host-derived kynurenine-based and microbiota-derived indole-based ligands of AHR holds considerable therapeutic potential for the treatment of ischemic stroke.

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