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1.
Anticancer Res ; 41(10): 4957-4968, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593443

RESUMO

BACKGROUND/AIM: Cancer stem cells (CSCs) have been suggested playing a crucial role in the tumorigenesis and tumor progression. Clinically, concurrent chemoradiotherapy (CCRT) after transurethral resection of the bladder is the widely accepted treatment option for high-grade bladder urothelial carcinoma (UC); however, a proportion of bladder UC patients still suffer from recurrence and metastasis. In the present study, we investigated the stemness properties of bladder UC cells with respect to various disease stages. The metastatic capability and epithelial-mesenchymal transition (EMT) of the parental cells and the CSC cells of bladder UC, after chemotherapy with cisplatin alone or CCRT were also studied, respectively. MATERIALS AND METHODS: The aldehyde dehydrogenase (ALDH)-positive cells were analyzed by a flow cytometer. The inhibitory effects of radiation in combination with cisplatin on the cell viability, migration, invasion and EMT characteristics were also examined. RESULTS: We found that the proportion of ALDH+-CSCs of bladder UC cells and the disease grading were independent. Furthermore, cisplatin alone significantly (p<0.05) enhanced the migration of both grade-III T24 cells and advanced-stage HT1197 cells, while CCRT treatment significantly (p<0.05) inhibited the T24 cell migration capability, compared to the cisplatin alone group. Interestingly, we found that the cell invasion capability was obviously increased upon the treatment with CCRT in both T24 and HT1197 CSCs. Furthermore, cisplatin played a promoting role in EMT whether in the presence or absence of irradiation. CONCLUSION: CSCs as well as EMT signaling might contribute to the resistance and metastasis of one-shot CCRT in malignant bladder cancer.


Assuntos
Quimiorradioterapia/métodos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias da Bexiga Urinária/terapia , Apoptose , Proliferação de Células , Humanos , Metástase Neoplásica , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/patologia
2.
Thorac Cancer ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623764

RESUMO

C-ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement has been detected in patients with advanced non-small cell lung cancer (NSCLC). Although ROS1 tyrosine kinase inhibitors (TKIs) provide a survival benefit for patients with ROS1-rearranged advanced NSCLC, subsequent therapy remains limited. Small cell transformation is an important mechanism of drug resistance in epidermal growth factor receptor-mutant NSCLC. However, its significance in mediating ROS1 resistance has not been determined yet. Here, we present the case of a 63-year-old man with ROS1-rearranged advanced NSCLC who had disease progression with small cell transformation of the mediastinal lymph node after 8 months of treatment with crizotinib. More importantly, fluorescence in situ hybridization of post-progression tumor biopsy demonstrated retention of ROS1 rearrangement. Tissue biopsy remains indispensable for patients who acquire resistance to ROS1 TKIs.

3.
Appl Opt ; 60(22): 6487-6494, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34612884

RESUMO

Photonic time-stretch (PTS) has been extensively studied due to its great potential in analog-to-digital converters. Here, we propose and demonstrate a PTS system based on phase modulation for sub-octave applications. Different from the PTS system using a Mach-Zehnder modulator (MZM), the PTS system, which uses a phase modulator (PM), has an operation bandwidth within an octave and is more suitable for preprocessing of sub-octave signals. Within the sub-octave band, the system is free of all second-order spurious signals. Because there is no direct current bias in a PM, the problem of bias drift, as well as the nonlinear distortion caused by it, can be thoroughly avoided. In addition, based on phase modulation and direct detection, the proposed PTS system has higher stability and a more simplified structure than that based on coherent detection. An exact analytical model has been established, and some compact expressions have been derived to fully characterize all frequency components of the PM-based PTS system. System properties, including the power transfer function, 3-dB bandwidth, and nonlinear distortion have been discussed, and numerical and experimental results on the performance of the PM-based PTS have been presented. In addition, a dual-channel PTS that employs a PM and a push-pull MZM has been proposed to extend the operation bandwidth to multi-octave.

4.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3034-3042, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467693

RESUMO

To explore the mechanism of anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium based on network pharmacology and inflammatory or pain mouse models. The effective components of Zanthoxyli Pericarpium were screened out by TCMSP database. And their potential corresponding targets were predicted by PharmMapper software. The possible targets relating to inflammation and pain were mainly collected through DrugBank, TTD and DisGeNET databases. The "active ingredient-gene-disease" network diagram was constructed by Cytoscape 3.7.0 software. The network pharmacology results showed 5 potential effective compounds, which were related to 29 targets; 132 targets relating to inflammation and pain were screened out in the DrugBank, TTD and DisGeNET databases. The network analysis results indicated that the phosphatidylinositol 3-kinase catalytic subunit gamma isoform(PIK3 CG) gene may be the key to the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium. The anti-inflammatory and analgesic effects of essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium were explored through the mouse model of inflammation induced by xylene or carrageenan and the mouse model of pain induced by acetic acid or formalin. The experimental results showed that essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium could reduce xylene-induced ear swelling and carrageenan-induced paw swelling and decrease the number of writhing responses in mice induced by acetic acid and the licking foot time of mice in phase Ⅱ induced by formalin. Western blot results showed that Zanthoxyli Pericarpium extract could inhibit the expressions of PIK3 CG, phosphonated nuclear factor kappaB(p-NF-κB) and phosphonated p38(p-p38 MAPK) protein. The present study showed the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium through multiple components and targets, so as to provide a pharmacodynamic basis for the study of Zanthoxyli Pericarpium and its mechanism.


Assuntos
Medicamentos de Ervas Chinesas , Óleos Voláteis , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/genética , Camundongos , Extratos Vegetais
5.
Artigo em Inglês | MEDLINE | ID: mdl-34519002

RESUMO

In order to reduce the dust pollution caused by the coal mining process, a novel composite environmental dust suppressant for coal dust control was synthesized by corn straw, sodium carboxymethyl cellulose (CMC), and additives. This study focused on the preparation conditions of the dust suppressant, and the performances of which were investigated systematically. Response surface method (RSM) was used to optimize the raw material formulation and preparation parameters. The optimum mass ratio of straw, CMC, and alkali of the dust suppression was 65:20:15 (m/m), which was prepared under the conditions of the reaction time being 1.5 h and the rotation speed being 300 r/min. The pH of the dust suppressant was 8.0, and the state of which was suspension. Additives were benefited to enhance the suppressant performance, and the surface tension and the contact angle could decrease to 32.4 mN/m and 32.0°. The suppressant has a maximum viscosity of 363.6 mPa·s, and the compressive strength could be up to 200 kPa. The hygroscopic rate could reach more than 4%. The wind erosion resistance could be up to 99 % at the wind speed of 14 m/s. After spraying the dust suppressant, the gap between particles was filled with dust suppressant, and the adjacent particles were bound by strong mechanical action.

6.
Exp Eye Res ; 212: 108767, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34534542

RESUMO

Limbal stem cells (LSCs) are the stem cell reservoir for corneal epithelium. The protocol to isolate LSCs from human cornea has been examined and optimized. However, the isolation protocol has not been optimized for mouse cornea, which is crucial for the downstream cell analysis. Here we compared four different isolation methods evolved from the previous reports to obtain mouse limbal epithelial cells which are heterogeneous and contain LSCs in a single-cell suspension: (1) the dissected limbal rim was cut into pieces and digested by 10-cycle incubation in trypsin; (2) after the removal of corneal epithelium by a rotating bur, the remaining eyeball was incubated in dispase at 4 °C for overnight to obtain limbal epithelial sheet, followed by trypsin digestion into a single-cell suspension; (3) same as method 2 except that the incubation was in dispase at 37 °C for 2h and an additional collagenase incubation at 37 °C for 20 min; (4) same as method 3 except that the corneal epithelium was punctured by a 1.5 mm trephine instead of being removed by a rotating bur. Method 1 showed the lowest cell yield, the lowest percentage of single cells, and the lowest number of limbal epithelial stem/progenitor cells in the harvested cells among the four methods, thus not a recommended protocol. Method 2, 3, and 4 isolated a comparable number of K14+ and p63α-bright stem/progenitor cells per eye. The remaining eye globe after cell collection in the three methods showed a complete removal of limbal epithelium albeit different extent of corneal and limbal stromal digestion. Among the three methods, method 2 showed a higher cell viability than method 4; method 3 yielded the lowest cell number; method 4 led to the highest percentage of single cells in cell suspension. Results suggest that method 2, 3, and 4 are preferred methods to isolate heterogeneous-LSCs from mouse corneas.

7.
Medicine (Baltimore) ; 100(36): e27137, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516505

RESUMO

RATIONALE: Malakoplakia and xanthogranulomatous pyelonephritis are chronic inflammatory conditions of the kidney characterized by the infiltration of inflammatory cells. PATIENT CONCERNS: An 82-year-old female patient had a history of hypertension, type 2 diabetes mellitus, dyslipidemia, and end-stage renal disease under hemodialysis. She was admitted repeatedly 4 times within 4 months due to urosepsis. DIAGNOSIS: The enlarged right kidney with a low-density lesion at the right middle calyx, and a well-enhanced ureter were noted on the computed tomography scan. Therefore, xanthogranulomatous inflammation was suspected. Semi-rigid ureteroscopy with biopsy was performed, and xanthogranulomatous inflammation of the ureter was confirmed on the pathology report. INTERVENTIONS: After right open radical nephrectomy was performed, the final pathology report revealed malakoplakia with xanthogranulomatous pyelonephritis. OUTCOMES: After the surgery, she has no longer suffered from urosepsis for 8 months, and there were no adverse event or recurrence noted. LESSONS: With this case report, we aim to emphasize that these 2 diseases are not mutually exclusive, but they may exist simultaneously in the same patient.


Assuntos
Falência Renal Crônica , Malacoplasia/diagnóstico , Pielonefrite Xantogranulomatosa/diagnóstico , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Malacoplasia/diagnóstico por imagem , Malacoplasia/cirurgia , Nefrectomia , Pielonefrite Xantogranulomatosa/diagnóstico por imagem , Pielonefrite Xantogranulomatosa/cirurgia , Tomografia Computadorizada por Raios X
8.
Int J Mol Sci ; 22(18)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34576152

RESUMO

Aryl hydrocarbon receptor (AHR) genomic pathway has been well-characterized in a number of respiratory diseases. In addition, the cytoplasmic AHR protein may act as an adaptor of E3 ubiquitin ligase. In this study, the physiological functions of AHR that regulate cell proliferation were explored using the CRISPR/Cas9 system. The doubling-time of the AHR-KO clones of A549 and BEAS-2B was observed to be prolonged. The attenuation of proliferation potential was strongly associated with either the induction of p27Kip1 or the impairment in mitogenic signal transduction driven by the epidermal growth factor (EGF) and EGF receptor (EGFR). We found that the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a repressor of EGFR, was induced in the absence of AHR in vitro and in vivo. The LRIG1 tends to degrade via a proteasome dependent manner by interacting with AHR in wild-type cells. Either LRIG1 or a disintegrin and metalloprotease 17 (ADAM17) were accumulated in AHR-defective cells, consequently accelerating the degradation of EGFR, and attenuating the response to mitogenic stimulation. We also affirmed low AHR but high LRIG1 levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients. This might partially elucidate the sluggish tissue repairment and developing inflammation in COPD patients.


Assuntos
Receptores ErbB/metabolismo , Glicoproteínas de Membrana/metabolismo , Mitógenos/metabolismo , Proteólise , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Células A549 , Proteína ADAM17/metabolismo , Animais , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Fator de Crescimento Epidérmico/farmacologia , Humanos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteólise/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Regulação para Cima/efeitos dos fármacos
9.
JMIR Med Inform ; 9(8): e23230, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34463639

RESUMO

BACKGROUND: The International Classification of Diseases (ICD) code is widely used as the reference in medical system and billing purposes. However, classifying diseases into ICD codes still mainly relies on humans reading a large amount of written material as the basis for coding. Coding is both laborious and time-consuming. Since the conversion of ICD-9 to ICD-10, the coding task became much more complicated, and deep learning- and natural language processing-related approaches have been studied to assist disease coders. OBJECTIVE: This paper aims at constructing a deep learning model for ICD-10 coding, where the model is meant to automatically determine the corresponding diagnosis and procedure codes based solely on free-text medical notes to improve accuracy and reduce human effort. METHODS: We used diagnosis records of the National Taiwan University Hospital as resources and apply natural language processing techniques, including global vectors, word to vectors, embeddings from language models, bidirectional encoder representations from transformers, and single head attention recurrent neural network, on the deep neural network architecture to implement ICD-10 auto-coding. Besides, we introduced the attention mechanism into the classification model to extract the keywords from diagnoses and visualize the coding reference for training freshmen in ICD-10. Sixty discharge notes were randomly selected to examine the change in the F1-score and the coding time by coders before and after using our model. RESULTS: In experiments on the medical data set of National Taiwan University Hospital, our prediction results revealed F1-scores of 0.715 and 0.618 for the ICD-10 Clinical Modification code and Procedure Coding System code, respectively, with a bidirectional encoder representations from transformers embedding approach in the Gated Recurrent Unit classification model. The well-trained models were applied on the ICD-10 web service for coding and training to ICD-10 users. With this service, coders can code with the F1-score significantly increased from a median of 0.832 to 0.922 (P<.05), but not in a reduced interval. CONCLUSIONS: The proposed model significantly improved the F1-score but did not decrease the time consumed in coding by disease coders.

10.
J Immunother Cancer ; 9(8)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34341130

RESUMO

BACKGROUND: The abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood. METHODS: Combined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA. RESULTS: THADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer. CONCLUSIONS: Our data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.

11.
Biomed Pharmacother ; 142: 112061, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34449313

RESUMO

CRISPR/Cas9 system has been used as the most powerful gene editing tool for precision medicine and advanced gene therapy. However, its wide applications are limited by the poor biosafety of lentivirus delivery vectors though with high-efficiency transduction. To construct a safer vector and promote genome integration, the CRISPR/Cas9 gene is cloned into a plasmid-based non-viral safe vector Sleeping-Beauty (SB) transposon in this study to obtain pT2SpCas9. Meanwhile, PDA/DEX-PEI@HA (PDPH) nanoparticles are constructed to facilitate the precise CRISPR/Cas9 targeting delivery, by using polydopamine (PDA) as the carrier, hyaluronic acid (HA) as the cell-targeting ligand and dexamethasone (DEX) as the nuclear localization signal (NLS). The results showed that PDPH could deliver pDNA efficiently into the cell and further into the nucleus. The transfection efficiency of PDPH is much higher than that of NPs without HA and DEX. Remarkably, the cytotoxicity of PDPH is negligible in comparison to PEI25k and PEI10k. Western blots showed that after the transfection of PDPH/pT2SpCas9-Nanog/SB11, Nanog protein in HeLa cells is knocked out, and the proliferation and migration abilities of tumor cells are significantly decreased. This study demonstrates that PDA/DEX-PEI25k@HA/pT2SpCas9 (PDPH25 K/pT2SpCas9) has the great potential as a non-viral gene vector for CRISPR/Cas9 delivery and clinical medication.

12.
Sci Rep ; 11(1): 15830, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349157

RESUMO

The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia-reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3-/- mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3.

13.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299636

RESUMO

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.


Assuntos
Movimento Celular , Células Epiteliais/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Luz , Neovascularização Retiniana/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Células Epiteliais/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Células HeLa , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/química , Humanos , Masculino , Camundongos , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/patologia , Epitélio Pigmentado da Retina/irrigação sanguínea , Epitélio Pigmentado da Retina/patologia
14.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204423

RESUMO

The exploration of nonhazardous nanoparticles to fabricate a template-driven superhydrophobic surface is of great ecological importance for oil/water separation in practice. In this work, nano-hydroxyapatite (nano-HAp) with good biocompatibility was easily developed from discarded oyster shells and well incorporated with polydimethylsiloxane (PDMS) to create a superhydrophobic surface on a polyurethane (PU) sponge using a facile solution-immersion method. The obtained nano-HAp coated PU (nano-HAp/PU) sponge exhibited both excellent oil/water selectivity with water contact angles of over 150° and higher absorption capacity for various organic solvents and oils than the original PU sponge, which can be assigned to the nano-HAp coating surface with rough microstructures. Moreover, the superhydrophobic nano-HAp/PU sponge was found to be mechanically stable with no obvious decrease of oil recovery capacity from water in 10 cycles. This work presented that the oyster shell could be a promising alternative to superhydrophobic coatings, which was not only beneficial to oil-containing wastewater treatment, but also favorable for sustainable aquaculture.


Assuntos
Exoesqueleto/química , Durapatita/química , Recuperação e Remediação Ambiental/métodos , Exoesqueleto/metabolismo , Animais , Carbonato de Cálcio/química , Dimetilpolisiloxanos/química , Durapatita/isolamento & purificação , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/química , Óleos/química , Ostreidae/metabolismo , Poluição por Petróleo/análise , Poluição por Petróleo/prevenção & controle , Solventes , Propriedades de Superfície , Água/química , Purificação da Água/métodos
15.
Am J Transplant ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34254428

RESUMO

The relevance of Tregs in the induction of tolerance against corneal allografts has been well established. Although it is well known that the conversion of Tregs into effector-like cells contributes to the loss of corneal immune privilege, the underlying mechanism is still not fully understood. Using heterologous penetrating keratoplasty model, we found that Tregs from corneal allograft rejected mice (inflam-Tregs) exhibit impaired function and characteristics of effector T cells. Further study showed that the expression of NF-κB c-Rel, a key mediator of effector T cell function, was significantly increased in inflam-Tregs. Mechanistic study revealed that elevated NF-κB c-Rel level in inflam-Tregs impaired Treg function through the promotion of inflammatory cytokine production and glycolysis. More importantly, we demonstrated that targeting NF-κB c-Rel was able to improve the immune suppressive function of inflam-Tregs in vitro and enhance the potential of them to suppress corneal transplantation rejection. Therefore, our current study identified NF-κB c-Rel as a key mediator of the conversion of Tregs into effector-like cells when under inflammatory environment.

16.
Cell Res ; 31(8): 847-860, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34112954

RESUMO

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Assuntos
Antivirais/metabolismo , COVID-19/patologia , Proteínas do Envelope de Coronavírus/metabolismo , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/química , Antivirais/uso terapêutico , Apoptose , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteínas do Envelope de Coronavírus/antagonistas & inibidores , Proteínas do Envelope de Coronavírus/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Meia-Vida , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidade , Baço/metabolismo , Baço/patologia , Carga Viral , Virulência
17.
Int Urogynecol J ; 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34132863

RESUMO

INTRODUCTION AND HYPOTHESIS: The association of vitamin D deficiency with female urinary incontinence is unclear. METHODS: A systematic review of English and non-English articles was conducted. All observational studies in databases including PubMed, EMBASE, the Cochrane Library Trials Register, and Google Scholar were searched until 5 October 2020. Additional studies were identified by contacting clinical experts and searching the bibliographies and abstracts of the compiled articles. Search terms included urinary incontinence and vitamin D. Article data, including study quality indicators, were independently extracted by two authors using predefined data fields. RESULTS: Two cohort studies, four case-control studies and five cross-sectional studies were included in the qualitative synthesis. Two cohort studies and one cross-sectional study, with a total of 2501 females, were included in the meta-analysis. Heterogeneity among the three studies was not observed (I2 = 0.0%, P = 0.69). All pooled analyses were based on fixed-effects models. No difference in vitamin D level was observed between the urinary incontinence group and the control group (mean difference 0.07 ng/ml; 95% confidence interval [CI] -0.57-0.72, P = 0.81, I2 = 0%). CONCLUSIONS: Our meta-analysis revealed that adult females with urinary incontinence did not have lower serum vitamin D levels than control females.

18.
Artigo em Inglês | MEDLINE | ID: mdl-34002913

RESUMO

A planar dibenzo-peri-hexacene derivative (2) was synthesized via FeCl3 -mediated Scholl reaction from a cyclopenta-fused perylene (CP) based polyphenylene precursor (1). However, an unexpected octagon-containing, negatively curved molecule (3) was obtained in nearly quantitative yield when 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and methanesulfonic acid (MeSO3 H) were used. Similar results were observed when two smaller-sized precursors containing one (4) or two CP units (5) were tested. X-ray crystallographic analysis also revealed that there is no close π-π stacking between neighboring π-conjugated skeletons. DFT calculations suggest a radical cation mechanism in the presence of FeCl3 while an arenium ion pathway for the DDQ/MeSO3 H mediated Scholl reaction, which can well explain the selective formation of hexagons and octagons under different conditions. The obtained compounds showed tunable optical and electrochemical properties.

19.
PLoS One ; 16(4): e0249522, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33798238

RESUMO

After a violent earthquake, the supply of medical services may fall short of the rising demand, leading to overcrowding in hospitals, and, consequently, a collapse in the healthcare system. This paper takes the emergency care system in Taiwan as the research context, where first-aid hospitals are ranked to three levels, advanced, intermediate, and general, and, currently, emphasizes on a general emergency responsibility hospital. Having limited capacity and capability, a general emergency responsibility hospital treats minor and moderate injuries, from which the majority of earthquake-induced casualties suffer. The purpose of this study is to analyze the impact of this group of earthquake-induced non-urgent patients on the performance of a hospital. A patient flow model was built to represent patients' paths throughout emergency care. Based on the model, discrete event simulation was applied to simulate patients' trajectories and states of a hospital under four seismic scenarios, where patient visits are 1.4, 1.6, 1.9, and 2.3 times the normal number. A healthcare performance index, Crowdedness Index (CI), is proposed to measure crowdedness on a daily basis, which is defined as the ratio of the average waiting time for treatment to the recommended maximal waiting time. Results of simulations rendered the establishment of empirical equations, describing the relation between the maximum CIs and the patient growth ratios. In the most severe case in this study, the maximum CI exceeds 92 and it takes 10 days to recover from the quality drop. This highlights the problem a general emergency responsibility hospital may encounter if no emergency response measure is implemented. Findings are provided pertaining to the predication of a recovery curve and the alarming level of patient increase, which are supportive information for preparedness planning as well as response measure formulation to improve resilience.


Assuntos
Aglomeração , Atenção à Saúde/organização & administração , Atenção à Saúde/normas , Terremotos , Serviços Médicos de Emergência/normas , Serviço Hospitalar de Emergência/normas , Primeiros Socorros , Humanos
20.
Anal Chem ; 93(17): 6594-6598, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33885279

RESUMO

Lysine acylations are important post-translational modifications that are present in both eukaryotes and prokaryotes and regulate diverse cellular functions. Our knowledge of the microbiome lysine acylation remains limited due to the lack of efficient analytical and bioinformatics methods for complex microbial communities. Here, we show that the serial enrichment using motif antibodies successfully captures peptides containing lysine acetylation, propionylation, and succinylation from human gut microbiome samples. A new bioinformatic workflow consisting of an unrestricted database search confidently identified >60,000 acetylated, and ∼20,000 propionylated and succinylated gut microbial peptides. The characterization of these identified modification-specific metaproteomes, i.e., meta-PTMomes, demonstrates that lysine acylations are differentially distributed in microbial species with different metabolic capabilities. This study provides an analytical framework for the study of lysine acylations in the microbiome, which enables functional microbiome studies at the post-translational level.


Assuntos
Microbioma Gastrointestinal , Acetilação , Acilação , Humanos , Lisina/metabolismo , Processamento de Proteína Pós-Traducional
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