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1.
Artigo em Inglês | MEDLINE | ID: mdl-34623273

RESUMO

Mobile molecular communication via diffusion (MCvD) has attracted lots of attentions due to its time-varying channels. In this paper, we investigate a mobile two-way MCvD model, which consists of two mobile source nanomachines and a mobile relay nanomachine. The amplify-and-forward (AF) relaying and analog network coding (ANC) are utilized to implement the exchange of information between two source nanomachines in this model. To explore the performance of the mobile two-way MCvD system, we first adopt the depleted molecule shift keying (D-MoSK) modulation, and then the mathematical expressions of symbol error probability (SEP) and mutual information are derived by using AF and ANC scheme on the basis of maximum a posteriori (MAP) probability detection. Finally, we present the numerical and simulation results. Compared with the AF-No-ANC scheme which is without use of ANC scheme, the scheme of combining AF and ANC can significantly improve the performance of SEP and mutual information. Moreover, the D-MoSK modulation outperforms the molecule shift keying (MoSK) modulation for this mobile two-way MCvD system. In addition, we propose the evaluation and discussion about the impacts of several important parameters on the performance of this system. These results can be used to design mobile two-way MCvD system with lower SEP and higher mutual information.

3.
Dalton Trans ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523633

RESUMO

A new beryllium-free zincoborate, BaZn3(BO3)2F2, with a KBBF-type structure has been synthesized for the first time. The electrostatic force of interaction in BaZn3(BO3)2F2 provides better linkage in neighboring [ZnBO3F]∞ single layers. BaZn3(BO3)2F2 is the first case of borates with both [ZnO3F] tetrahedra and [ZnO6] octahedra, enriching the structural chemistry of borate system. All the coplanar [BO3] triangles align in the same direction with a high density, which endows BaZn3(BO3)2F2 with a large birefringence of cal. 0.076 at 1064 nm. This work is of great significance to design beryllium-free borates with a KBBF-type structure.

4.
Int J Biol Sci ; 17(13): 3343-3355, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512151

RESUMO

Mesangial cell (MC) proliferation and matrix expansion are basic pathological characteristics of IgA nephropathy (IgAN). However, the stepwise mechanism of MC proliferation and the exact set of related signaling molecules remain largely unclear. In this study, we found a significant upregulation of miR-214-3p in the renal cortex of IgAN mice by miRNA sequencing. In situ hybridization analysis showed that miR-214-3p expression was obviously elevated in MCs in the renal cortex in IgAN. Functionally, knockdown of miR-214-3p alleviated mesangial hypercellularity and renal lesions in IgAN mice. In vitro, the inhibition of miR-214-3p suppressed MC proliferation and arrested G1-S cell cycle pSrogression in IgAN. Mechanistically, a luciferase reporter assay verified PTEN as a direct target of miR-214-3p. Downregulation of miR-214-3p increased PTEN expression and reduced p-JNK and p-c-Jun levels, thereby inhibiting MC proliferation and ameliorating renal lesions in IgAN. Moreover, these changes could be attenuated by co-transfection with PTEN siRNA. Collectively, these results illustrated that miR-214-3p accelerated MC proliferation in IgAN by directly targeting PTEN to modulate JNK/c-Jun signaling. Therefore, miR-214-3p may represent a novel therapeutic target for IgAN.

5.
J Transl Med ; 19(1): 393, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530846

RESUMO

BACKGROUND: Sphingosine Kinase (SphK) that catalyzes sphingosine (Sph) to sphingosine 1-phosphate (S1P), plays a key role in both sphingolipid metabolism and cellular signaling. While SphK has been implicated in type 2 diabetes mellitus (T2DM), it is unexplored in humans. Herein, we investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort. METHODS: Levels of SphK-related sphingolipid metabolites, including Sph, S1P, dihydrosphingosine (dhSph) and dihydro-S1P (dhS1P) in serum were measured by targeted-lipidomic analyses. By accessing to an established prospective cohort that involves a total of 2486 non-diabetic adults at baseline, 100 subjects who developed T2DM after a mean follow-up of 4.2-years, along with 100 control subjects matched strictly with age, sex, BMI and fasting glucose, were randomly enrolled for the present study. RESULTS: Comparison with the control group, medians of serum dhS1P and dhS1P/dhSph ratio at baseline were elevated significantly prior to the onset of T2DM. Each SD increment of dhS1P and dhS1P/dhSph ratio was associated with 53.5% and 54.1% increased risk of incident diabetes, respectively. The predictive effect of circulating dhS1P and dhS1P/dhSph ratio on T2DM incidence was independent of conventional risk factors in multivariate regression models. Furthermore, combination of serum dhS1P and dhS1P/dhSph ratio with conventional clinical indices significantly improved the accuracy of T2DM prediction (AUROC, 0.726), especially for normoglycemic subjects (AUROC, 0.859). CONCLUSION: Circulating levels of dhS1P and dhS1P/dhSph ratio are strongly associated with increased risk of T2DM, and could serve as a useful biomarker for prediction of incident T2DM in normoglycemic populations.

6.
Clin Appl Thromb Hemost ; 27: 10760296211044722, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34559016

RESUMO

BACKGROUND: Novel oral anticoagulants and warfarin are widely used for stroke prevention in patients with atrial fibrillation. The anticoagulation status of patients receiving warfarin or rivaroxaban has been studied. In this study, we aimed to evaluate the effect of dabigatran and warfarin on preventing thrombin generation (TG). METHODS: This retrospective study enrolled 237 nonvalvular atrial fibrillation (NVAF) subjects treated with 110 mg dabigatran etexilate twice daily and 224 NVAF patients received adjusted-dose warfarin (international normalized ratio [INR] of 2 to 3)). Coagulation assays, prothrombin fragment 1 + 2 (F1+2), calibrated automated thrombogram, and thrombin-antithrombin complex (TAT) were detected at the steady state. RESULTS: Activated partial thromboplastin time (APTT), antithrombin III activity, fibrinogen, and lag time showed no difference between the two groups. Compared to the dabigatran group, prothrombin time and INR values were higher in the warfarin group (all P < .001). Thrombin time, endogenous thrombin potential, peak TG (Cmax), F1+2, and TAT were lower in the warfarin group. The inhibition of TG was still stronger in the warfarin group when the patients were divided into subgroups. CONCLUSION: Conventional coagulation assays are suboptimal for assessing the coagulation status of dabigatran. TG could be used as supplementary assays to evaluate the anticoagulation effect of oral anticoagulants. Our results suggest that warfarin may inhibit TG more aggressively than dabigatran in patients regardless of age and kidney function.

7.
Signal Transduct Target Ther ; 6(1): 300, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381015

RESUMO

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks' continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.


Assuntos
COVID-19/genética , Diabetes Mellitus/genética , MicroRNAs/genética , Glicoproteína da Espícula de Coronavírus/genética , Adulto , Fatores Etários , Idoso , COVID-19/sangue , COVID-19/patologia , COVID-19/virologia , China , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Estudos de Coortes , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Diabetes Mellitus/virologia , Exercício Físico , Exossomos/genética , Exossomos/metabolismo , Exossomos/virologia , Feminino , Regulação da Expressão Gênica , Células HEK293 , Interações Hospedeiro-Patógeno/genética , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , SARS-CoV-2/genética , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/sangue , Replicação Viral
8.
Nat Immunol ; 22(9): 1127-1139, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34413521

RESUMO

Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of TFH cell survival remains unclear. Here we report that TFH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for TFH cell survival. The deletion of GPX4 in T cells selectively abrogated TFH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased TFH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.


Assuntos
Ferroptose/fisiologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/farmacologia , Células T Auxiliares Foliculares/fisiologia , Adolescente , Adulto , Animais , Sobrevivência Celular/imunologia , Criança , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Imunidade Humoral/imunologia , Vacinas contra Influenza/imunologia , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/fisiologia , Ovalbumina , Células T Auxiliares Foliculares/imunologia , Vacinação , Adulto Jovem
9.
Aging (Albany NY) ; 13(14): 18310-18330, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34270461

RESUMO

Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.

10.
Dig Endosc ; 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233037

RESUMO

OBJECTIVES: Patients with advanced ampullary carcinoma (AC) who are unsuitable for surgery are most likely to have poor outcomes. The role of endoscopic radiofrequency ablation (RFA) in this population has not been fully defined. We aimed to assess the short- and long-term outcomes of RFA in a large cohort of AC patients. METHODS: In this retrospective study, data of consecutive patients with pathologically proven AC who underwent successful endobiliary RFA and/or stent placement were collected. All patients did not undergo surgical resection. The primary outcome was overall survival (OS). The secondary outcomes included clinical success and adverse events. RESULTS: A total of 85 patients, 50 in the RFA plus stenting group and 35 in the stenting alone group, were identified. The median OS was significantly longer in the RFA group than in the stenting alone group (16.9 vs. 9.8 months, P < 0.001). In multivariable Cox analysis, RFA (hazards ratio 0.408; 95% confidence interval 0.235-0.706; P = 0.001) was the only independent OS predictor. Eight patients with stage II tumors, exclusively from the RFA group, survived for more than 3 years. Clinical success was comparable between the two groups (96% vs. 100%, P = 0.231). Early adverse events between the two groups were similar (10% vs. 2.9%, P = 0.206); however, late biliary/pancreatic stenoses occurred in three RFA patients who were successfully managed with endoscopic interventions. CONCLUSIONS: Endoscopic RFA appears to prolong patients' survival with acceptable safety; it may therefore be a feasible treatment option for patients with inoperable ampullary cancers.

11.
Aging (Albany NY) ; 13(12): 16316-16340, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34148031

RESUMO

The drug response sensitivity and related prognosis of prostate cancer varied from races, while the original mechanism remains rarely understood. In this study, the comprehensive signature including transcriptomics, epigenome and single nucleotide polymorphisms (SNPs) of 485 PCa cases- including 415 Whites, 58 Blacks and 12 Asians from the TCGA database were analyzed to investigate the drug metabolism differences between races. We found that Blacks and Whites had a more prominent drug metabolism, cytotoxic therapy resistance, and endocrine therapy resistance than Asians, while Whites were more prominent in drug metabolism, cytotoxic therapy resistance and endocrine therapy resistance than Blacks. Subsequently, the targeted regulation analysis indicated that the racial differences in cytotoxic therapy resistance, endocrine therapy resistance, might originate from drug metabolisms, and 19 drug metabolism-related core genes were confirmed in the multi-omics network for subsequent analysis. Furthermore, we verified that CYP1A1, CYP3A4, CYP2B6, UGT2B17, UGT2B7, UGT1A8, UGT2B11, GAS5, SNHG6, XIST significantly affected antineoplastic drugs sensitivities in PCa cell lines, and these genes also showed good predictive efficiency of drug response and treatment outcomes for PCa in this cohort of patients. These findings revealed a comprehensive signature of drug metabolism differences for the Whites, Blacks and Asians, and it may provide some evidence for making individualized treatment strategies.


Assuntos
Afro-Americanos , Antineoplásicos/metabolismo , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Neoplasias da Próstata/metabolismo , Área Sob a Curva , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Epigenoma , Grupos Étnicos , Genômica , Humanos , Concentração Inibidora 50 , Masculino , Redes e Vias Metabólicas/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Transcriptoma/genética , Resultado do Tratamento
12.
Oncoimmunology ; 10(1): 1929726, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34104546

RESUMO

Adoptive cell therapy using TCR-engineered T cells (TCR-T cells) represents a promising strategy for treating relapsed and metastatic cancers. We previously established methods to identify neoantigen-specific TCRs based on patients' PBMCs. However, in clinical practice isolation of PBMCs from advanced-stage cancer patients proves to be difficult. In this study, we substituted blood-derived T cells for tumor-infiltrating lymphocytes (TILs) and used an HLA-matched cell line of antigen-presenting cells (APCs) to replace autologous dendritic cells. Somatic mutations were determined in head and neck squamous cell carcinoma resected from two patients. HLA-A*02:01-restricted neoantigen libraries were constructed and transferred into HLA-matched APCs for stimulation of patient TILs. TCRs were isolated from reactive TIL cultures and functionality was tested using TCR- T cells in vitro and in vivo. To exemplify the screening approach, we identified the targeted neoantigen leading to recognition of the minigene construct that stimulated the strongest TIL response. Neoantigen peptides were used to load MHC-tetramers for T cell isolation and a TCR was identified targeting the KIAA1429D1358E mutation. TCR-T cells were activated, exhibited cytotoxicity, and secreted cytokines in a dose-dependent manner, and only when stimulated with the mutant peptide. Furthermore, comparable to a neoantigen-specific TCR that was isolated from the patient's PBMCs, KIAA1429D1358E-specific TCR T cells destroyed human tumors in mice. The established protocol provides the required flexibility to methods striving to identify neoantigen-specific TCRs. By using an MHC-matched APC cell line and neoantigen-encoding minigene libraries, autologous TILs can be stimulated and screened when patient PBMCs and/or tumor material are not available anymore. Abbreviations: Head and neck squamous cell carcinoma (HNSCC); adoptive T cell therapy (ACT); T cell receptor (TCR); tumor-infiltrating lymphocytes (TIL); cytotoxic T lymphocyte (CTL); peripheral blood mononuclear cell (PBMC); dendritic cell (DC); antigen-presenting cells (APC).


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T , Transferência Adotiva , Animais , Humanos , Linfócitos do Interstício Tumoral , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia
13.
Asian J Surg ; 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34147329

RESUMO

BACKGROUND: Current management guidelines for gallbladder polyps (GBPs) focus on a diameter more than 1 cm as an indication for cholecystectomy. Since most GBPs are not malignant, unnecessary cholecystectomies can lead to unnecessary complications and costs. We developed a score to identify true polyps focusing on their cross-sectional area (CSA). METHODS: We retrospectively analyzed the demographic, clinical, laboratory, and sonographic characteristics of 522 patients with GBPs who had undergone cholecystectomy at our hospital between January 2010 and July 2020 (reference group). We used univariate analysis to compare these parameters between 88 true polyps and 434 pseudopolyps and multivariate logistic regression analysis to identify parameters to include in our scoring model. Receiver operating characteristics and area under the curve were used to identify cut-off values. The model was tested on a validation group of 98 patients. RESULTS: In the multivariate analysis, a CSA >123 mm2, positive blood flow signal, age >55.5 years, alanine aminotransferase (ALT) levels > 50 U/L, and an ALT/aspartate aminotransferase ratio > 0.77 were significantly associated with true polyps (odds ratio 6.528, 2.377, 2.617, 2.445, and -0.372, respectively). A prediction model based on cut-off values was used to distinguish a low-risk and high-risk GBP group; true polyps accounted for 6.54% and 58.72%, respectively (p < 0.001). In the low-risk and high-risk validation groups, true polyps comprised 12.35% and 82.35%, respectively (p < 0.001). CONCLUSIONS: Our scoring system shows high accuracy and specificity in identifying true polyps and helps determine the need for surgical resection.

14.
Ecotoxicol Environ Saf ; 220: 112366, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34058679

RESUMO

Exposure to many kinds of bisphenols (BPs) is common, and the effects of BP mixtures may differ from those of individual BPs. Therefore, evaluating combined exposure effects is necessary. Our study evaluated the individual and combined exposure effects of bisphenol A (BPA), bisphenol S (BPS) and bisphenol AF (BPAF) on embryonic development using an embryonic stem cell test (EST) and a concentration additive (CA) model at relatively high doses to uncover the interaction model of the three BPs. Environmentally relevant concentrations were then used to evaluate the possible effects of the individual and combined BPs at actual human exposure levels. Exposure to relatively high-dose BPA, BPS and BPAF inhibited embryonic stem cell differentiation into cardiomyocytes and exhibited weak embryo toxicity. Individually, BPA, BPS and BPAF inhibited endoderm, mesoderm and ectoderm marker expression but enhanced pluripotency marker expression. Combined exposure to BPs had an additive effect on cardiomyocyte differentiation and embryonic stem cell proliferation based on the CA model. Environmentally relevant individual or combined BP doses (10 ng/ml individual BPA, BPS and BPAF doses or 1 ng/ml and 10 ng/ml BP mixture doses) failed to cause oxidative stress, DNA damage or apoptosis changes in stem cell differentiation. The cardiomyocyte differentiation ratio also did not change significantly. Individual and combined exposure to environmentally relevant BP doses led to a significant increase in collagen expression. BPAF and the combination of BPs increased the type 1 collagen level, while the combination also increased the type 3 collagen level, which may be related to p38 pathway activation. The p38 pathway inhibitor SB203580 inhibited the increase in collagen during cardiomyocyte differentiation caused by low-dose BPs. These results suggest that relatively high-dose BPs in combination have an additive effect on cardiomyocyte differentiation. Low-dose BPs individually and in combination may affect cardiomyocyte collagen through the p38 pathway.


Assuntos
Compostos Benzidrílicos/toxicidade , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Apoptose , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Dano ao DNA , Sinergismo Farmacológico , Células-Tronco Embrionárias/citologia , Poluentes Ambientais/toxicidade , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miócitos Cardíacos/citologia , Estresse Oxidativo
15.
Emerg Microbes Infect ; 10(1): 1191-1199, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34049471

RESUMO

The ongoing COVID-19 pandemic has led to more than 159 million confirmed cases with over 3.3 million deaths worldwide, but it remains mystery why most infected individuals (∼98%) were asymptomatic or only experienced mild illness. The same mystery applies to the deadly 1918 H1N1 influenza pandemic, which has puzzled the field for a century. Here we discuss dual potential properties of the 1918 H1N1 pandemic viruses that led to the high fatality rate in the small portion of severe cases, while about 98% infected persons in the United States were self-limited with mild symptoms, or even asymptomatic. These variations now have been postulated to be impacted by polymorphisms of the sialic acid receptors in the general population. Since coronaviruses (CoVs) also recognize sialic acid receptors and cause severe acute respiratory syndrome epidemics and pandemics, similar principles of influenza virus evolution and pandemicity may also apply to CoVs. A potential common principle of pathogen/host co-evolution of influenza and CoVs under selection of host sialic acids in parallel with different epidemic and pandemic influenza and coronaviruses is discussed.


Assuntos
COVID-19/patologia , Influenza Humana/patologia , Receptores de Superfície Celular/genética , Receptores Virais/genética , Ácidos Siálicos/metabolismo , Doenças Assintomáticas , Evolução Biológica , COVID-19/mortalidade , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/patogenicidade , Subtipo H7N9 do Vírus da Influenza A/genética , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Influenza Humana/mortalidade , Receptores de Superfície Celular/metabolismo , Receptores Virais/metabolismo , SARS-CoV-2/genética , Saliva/metabolismo , Saliva/virologia
16.
Chemistry ; 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33939211

RESUMO

Herein, a new congruently melting mixed-anion compound Cs4 B4 O3 F10 has been characterized as the first fluorooxoborate with [BF4 ] involving heteroanionic units. Compound Cs4 B4 O3 F10 possesses two highly fluorinated anionic clusters and therefore its formula can be expressed as Cs3 (B3 O3 F6 ) ⋅ Cs(BF4 ). The influence of [BF4 ] units on micro-symmetry and structural evolution was discussed based on the parent compound. More importantly, Cs4 B4 O3 F10 shows the lowest melting point among all the available borates and thus sets a new record for such system. This work is of great significance to enrich and tailor the structure of borates using perfluorinated [BF4 ] units.

17.
Int J Pharm ; 601: 120553, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33794325

RESUMO

Pancreatic cancer (PC) is an aggressive form of cancer with dense stroma and immune-suppressive microenvironment, which are the major barriers for treatment. To address such barriers, this study aimed to develop a sequential receptor-mediated mixed-charge targeted delivery system for PC based on 2-(3-((S)-5-amino-1-carboxypentyl)-ureido) pentanedioate (ACUPA-) and triphenylphosphonium (TPP+) modified nanomicelles containing ingenol-3-mebutate (I3A), which was named ACUPA-/TPP+-I3A or ACUPA/TPP-I3A. ACUPA/TPP-I3A induced immunogenic cell death (ICD), which significantly increased the number of tumor-infiltrating T lymphocytes, activated adaptive immunity, and achieved superior survival time. I3A, a novel anticancer drug, could induce PC cell necrosis to release damage-associated molecular patterns, thereby activating adaptive immunity. With certain ratios of negatively (ACUPA-) and positively (TPP+) charged ligands, ACUPA/TPP-I3A acquired a negative charge in plasma (pH 7.4, to inhibit aggregation and uptake in the circulation) and was neutral in the acidic tumor microenvironment (pH 5.0-6.0, to overcome electrostatic hindrances and facilitate transcytosis). Furthermore, neovascular endothelium-specific ACUPA enabled rapid transcytosis of ACUPA/TPP-I3A across tumor vessel walls, entering into endosome/lysosomes (pH 4.5-5.0, its charge became positive and exhibited lysosome escape). Then, ACUPA/TPP-I3A selectively targeted mitochondria, which correlated with TPP-mediated effect. Finally, I3A was released to induce ICD that activated adaptive immunity and achieved superior survival time. Therefore, reshaping of the tumor microenvironment and potentiating antitumor immunity using ACUPA-/TPP+-I3A constituted a novel strategy to prolong the survival time.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Humanos , Morte Celular Imunogênica , Nanomedicina , Neoplasias Pancreáticas/tratamento farmacológico , Microambiente Tumoral
18.
Signal Transduct Target Ther ; 6(1): 145, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33859168

RESUMO

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus with high fatality and an expanding endemic. Currently, effective anti-SFTSV intervention remains unavailable. Favipiravir (T-705) was recently reported to show in vitro and in animal model antiviral efficacy against SFTSV. Here, we conducted a single-blind, randomized controlled trial to assess the efficacy and safety of T-705 in treating SFTS (Chinese Clinical Trial Registry website, number ChiCTR1900023350). From May to August 2018, laboratory-confirmed SFTS patients were recruited from a designated hospital and randomly assigned to receive oral T-705 in combination with supportive care or supportive care only. Fatal outcome occurred in 9.5% (7/74) of T-705 treated patients and 18.3% (13/71) of controls (odds ratio, 0.466, 95% CI, 0.174-1.247). Cox regression showed a significant reduction in case fatality rate (CFR) with an adjusted hazard ratio of 0.366 (95% CI, 0.142-0.944). Among the low-viral load subgroup (RT-PCR cycle threshold ≥26), T-705 treatment significantly reduced CFR from 11.5 to 1.6% (P = 0.029), while no between-arm difference was observed in the high-viral load subgroup (RT-PCR cycle threshold <26). The T-705-treated group showed shorter viral clearance, lower incidence of hemorrhagic signs, and faster recovery of laboratory abnormities compared with the controls. The in vitro and animal experiments demonstrated that the antiviral efficacies of T-705 were proportionally induced by SFTSV mutation rates, particularly from two transition mutation types. The mutation analyses on T-705-treated serum samples disclosed a partially consistent mutagenesis pattern as those of the in vitro or animal experiments in reducing the SFTSV viral loads, further supporting the anti-SFTSV effect of T-705, especially for the low-viral loads.

19.
Angew Chem Int Ed Engl ; 60(26): 14650-14656, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-33871912

RESUMO

The generated light can be tuned to cover almost the entire spectral range from deep-ultraviolet to terahertz wavelengths by utilizing the nonlinear optical crystals with a simple frequency doubling process. Among them, the discovery of novel candidates for the production of deep-ultraviolet light is by extension a great challenge toward realizing the vast potential. Actually, the availability for this process mainly depends on whether the critical performance can be well coexisted in one practical crystal. Herein, the first magnesium fluorooxoborate MgB5 O7 F3 was synthesized as a new competitive candidate for deep-ultraviolet nonlinear optical application. It has a sufficiently large nonlinearity and a deep-ultraviolet phase matching wavelength, indicating that it holds great potential for the production of coherent light below 200 nm. The critical performance enhancement of MgB5 O7 F3 when compared with its isomorphic phases was demonstrated and discussed. More importantly, we proposed that fluorooxoborate system with the general formula of MB5 O7 F3 (M=divalent metal) possesses stable fluorine terminated framework, which makes them tend to retain their crystallized space groups unchanged.

20.
Ecotoxicol Environ Saf ; 217: 112259, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33910067

RESUMO

Surgical smoke is widespread in operating rooms, and fine particles are the main toxic components. However, the effect of fine particles in surgical smoke on embryonic development has not yet been studied. This study evaluated the effect of fine particles in surgical smoke on embryonic development and compared it with that of atmospheric fine particles. Afterwards, differentiated cardiomyocytes were purified, and the effect of exposure to fine particles in surgical smoke on cardiomyocyte differentiation was evaluated. Fine particles in surgical smoke exhibited weak embryotoxicity toward an embryonic stem cell test model, and their inhibitory effect on cardiomyocyte differentiation was slightly stronger than that of atmospheric fine particles. Fine particles in surgical smoke specifically inhibited the differentiation of the mesoderm lineage and promoted the differentiation of the ectoderm lineage. Furthermore, fine particles in surgical smoke reduced the beating rate of purified cardiomyocytes, promoted mitophagy, reduced ATP production and increased the reactive oxygen species (ROS) content. Antioxidants attenuated the inhibition of cardiomyocyte differentiation and the reduction in the cardiomyocyte beating rate caused by fine particles in surgical smoke and simultaneously restored mitophagy and other processes to the control levels. However, mitophagy inhibitors treatment blocked only the inhibition of cardiomyocyte differentiation caused by fine particles in surgical smoke; it had little effect on other changes caused by fine particles. Based on the results described above, we propose that fine particles in surgical smoke and atmospheric fine particles exhibit similar levels of toxicity toward embryonic development. Fine particles in surgical smoke potentially affect the beating of cardiomyocytes by damaging mitochondria and increasing oxidative stress.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Cirurgia Geral , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Material Particulado/toxicidade , Animais , Antioxidantes/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Mitocôndrias , Mitofagia/fisiologia , Miócitos Cardíacos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Fumaça , Tabaco
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