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1.
Aging (Albany NY) ; 14(undefined)2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504036

RESUMO

Osteosarcoma (OS) is a common malignant primary tumor of skeleton, especially in children and adolescents, characterized by high lung metastasis rate. Apoptosis has been studied in various tumors, while the prognostic role of apoptosis-related genes in OS has been seldom studied. Three OS related datasets were downloaded from Gene Expression Omnibus (GEO) database. Univariate Cox and LASSO Cox regression analysis identified optimal genes, which were used for building prognostic Risk score. Subsequent multivariate Cox regression analysis and Kaplan-Meier survival analysis determined the independent prognostic factors for OS. The immune cell infiltration was analyzed in CIBERSORT. Basing on 680 apoptosis-related genes, the OS patients could be divided into 2 clusters with significantly different overall survival. Among which, 6 optimal genes were identified to construct Risk score. In both training set (GSE21257) and validation set (meta-GEO dataset), high risk OS patients had significantly worse overall survival compared with the low risk patients. Besides, high Risk score was an independent poor prognostic factor for OS with various ages or genders. Three immune cells were differentially infiltrated between high and low risk OS patients. In conclusion, a six-gene (TERT, TRAP1, DNM1L, BAG5, PLEKHF1 and PPP3CB) based prognostic Risk score signature is probably conducive to distinguish different prognosis of OS patients.

2.
Muscle Nerve ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508598

RESUMO

INTRODUCTION/AIMS: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular junction disorder. Long non-coding RNA (LncRNA) can regulate the expression of mRNA and is involved in the development of autoimmune diseases, but few genetic studies are available. This study aimed to explore the lncRNA and mRNA changes of LEMS. METHODS: Plasma lncRNA and mRNA expression profiles of three LEMS patients with small cell lung cancer (SCLC) and three matched healthy controls were analyzed by microarray. Differentially expressed lncRNAs and adjacent mRNAs were jointly analyzed, and candidates were verified by quantitative real-time polymerase chain reaction (qRT-PCR). The identified genes were subsequently evaluated in 9, 8, and 4 patients with paraneoplastic LEMS, non-tumor LEMS, and SCLC, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine possible functions. RESULTS: A total of 320 lncRNA and 168 mRNAs were differentially expressed in the three LEMS with SCLC compared to healthy controls. Among them, lncRNA LOC338963 and its neighboring mRNA AP3B2 were upregulated jointly, which was confirmed by qRT-PCR. qRT-PCR revealed significant upregulation of the 2 genes in patients with paraneoplastic LEMS compared to non-tumor LEMS or SCLC. GO analysis of AP3B2 identified the enrichment terms anterograde synaptic vesicle transport and establishment of synaptic vesicle localization. KEEG analysis showed that AP3B2 was enriched in lysosomal pathways. DISCUSSION: LOC338963 and AP3B2 were upregulated in patients with paraneoplastic LEMS, suggesting their involvement in pathogenesis. These genes could be targets for exploring the pathomechanism of paraneoplastic LEMS. This article is protected by copyright. All rights reserved.

3.
NPJ Breast Cancer ; 8(1): 64, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538088

RESUMO

Germline mutations in BRCA1 or BRCA2 exist in ~2-7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance.

4.
Biomed Pharmacother ; 151: 113080, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35561427

RESUMO

BACKGROUND: The global prevalence of inflammatory bowel disease (IBD) is increasing, and mucosal healing is the preferred treatment target of IBD. Sodium (aS,9 R)- 3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.12,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) is a novel diarylheptane compound, which is designed to treat IBD. Hence, we investigated the potent therapeutic activity of SDH against IBD and explored the underlying mechanisms, and determined if SDH is a safe and well-tolerated oral therapeutic for IBD treatment. METHODS: We characterized its therapeutic properties in vitro and in vivo using Caco-2 cell monolayer and dextran sodium sulfate (DSS)- or 2,4,6-trinitro-benzene sulfonic acid (TNBS)-induced colitis models. We conducted nonclinical toxicology and safety pharmacology research, including general toxicity, toxicokinetics, pharmacokinetics, metabolism and plasma protein binding, cardiovascular safety pharmacology, central nervous system safety pharmacology, respiratory safety pharmacology, fertility and early embryonic development toxicity, reverse mutation assay, chromosomal aberration assay and micronucleus test. RESULTS: The results showed that SDH promoted expression of tight junction proteins, and protected the integrity and permeability of the epithelial barrier in both cell and animal models. Moreover, lower doses of SDH showed the similar or better efficacy than cyclosporine A (CsA) and mesalazine in DSS- or TNBS-induced colitis animals. Furthermore, our results identified that SDH has satisfactory safety in these studies we tested. In summary, SDH restored the epithelial barrier through tight junction proteins and was expected to be a novel therapeutic agent for the treatment of IBD.

5.
Int J Biol Macromol ; 211: 74-84, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35561856

RESUMO

Small heat shock proteins (sHSPs) help prevent the irreversible aggregation of denatured proteins that occurs in response to organismal stress. In this study, we identified two intron-free genes encoding sHSPs from Frankliniella occidentalis; these were designated FoHSP11.6 and FoHSP28.0 and belonged to an atypical and typical sHSP family, respectively. Both FoHSPs were transcribed in all developmental stages of F. occidentalis with the highest expression levels in pupae and adults and greater expression in males than females. Although the FoHSPs had different temperature-induced expression profiles, they were generally induced by both low and high temperatures and reached maximal expression levels after 0.5-1 h of temperature stress. The FoHSPs expression levels in pupae were induced by drought and high humidity, and higher expression levels were correlated with lower survival rates. The thermotolerance of F. occidentalis decreased when theFoHSPs were silenced by RNA interference. Our results show that FoHSP11.6 and FoHSP28.0 are involved in the response to temperature and drought and may also function in growth and development of F. occidentalis.

6.
Bioorg Med Chem ; 66: 116809, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35569251

RESUMO

To search for novel focal adhesion kinase (FAK) inhibitors for intervention of metastatic triple-negative breast cancer (TNBC), a series of hybrids 7a-s from chloropyramine and cinnamic acid analogs were designed, synthesized and biologically evaluated. The most active compound 7d could potently inhibit the proliferation, invasion and migration of TNBC cells in vitro. The docking analysis of 7d was performed to elucidate its possible binding modes to focal adhesion targeting (FAT) domain of FAK scaffold. Further mechanism studies indicated the ability of 7d in disrupting Y925 autophosphorylation of FAK, reducing formation of focal adhesions (FAs) and stress fibers (SFs) as well as inducing apoptosis of TNBC cells. Together, 7d is a novel FAK inhibitor to inhibit the essential nonkinase scaffolding function of FAK via binding FAT domain and may be worth studying further for intervention of TNBC.

7.
Comput Math Methods Med ; 2022: 7563281, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35529274

RESUMO

The febrile seizure (FS) is a common disease in emergency pediatrics, and about 30% of patients are children aged between 6 months and 5 years. Therefore, we aim to observe the protective impact of liraglutide (LIR) on brain injury in mice with FS and to explore its relevant mechanisms. Male SD mice were selected, and the FS model was established by heat bath method. The behavioral score was performed on mice with Racine grading, and nerve cells in apoptosis in the hippocampus were determined by TUNEL. The content of glutamate was determined by ELISA. mRNA levels and protein expression of GLP-1, GLP-1R, IL-1ß, IL-6, TNF-α, and cleaved-caspase 3 were examined in mice by q-PCR and WB. Protein expression of γ-aminobutyric acid was influenced by WB as well. LIR prolonged the seizure latency and seizure duration in mice with FS. The GLP-1 and GLP-1R in the mouse hippocampus with FS expressed highly and also inhibited the number of nerve cells in apoptosis, decreased glutamate content, and increased γ-aminobutyric acid expression in the mouse hippocampus with FS. In addition, The IL-1ß, IL-6, and TNF-α, in the mouse hippocampus with FS expressed to reduce with LIR. LIR is protective against brain injury in mice with FS and protects brain injury by inhibiting inflammatory factors in mice with FS. Our finding provides a reference for mitigating and delaying the development of FS as well as the prevention and treatment of brain injury caused by FS.


Assuntos
Lesões Encefálicas , Convulsões Febris , Animais , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/prevenção & controle , Peptídeo 1 Semelhante ao Glucagon , Glutamatos , Humanos , Interleucina-6/genética , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Convulsões Febris/tratamento farmacológico , Convulsões Febris/genética , Convulsões Febris/prevenção & controle , Fator de Necrose Tumoral alfa/genética , Ácido gama-Aminobutírico
8.
Bio Protoc ; 12(7): e4372, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35530523

RESUMO

Imaging plays a vital role in the diagnosis and treatment of skin diseases. However, pure optical imaging technique is limited to the visualization of superficial skin tissues. Ultrasonic imaging technique can detect deep tissues, but it lacks detailed information on microscopic pathological structures. Photoacoustic imaging is an advanced technology that bridges the spatial-resolution gap between optical and ultrasonic techniques, by the modes of optical excitation and acoustic detection. Photoacoustic dermoscopy (PAD), based on photoacoustic technology, can noninvasively obtain high-resolution anatomical structures by endogenous absorbers, such as melanin, hemoglobin, lipids, etc. In the past years, PAD has gradually been developed in clinical dermatology for the diagnosis of melanoma, psoriasis, port-wine stains, dermatitis, skin grafting, and testing the efficacy of cosmetics. This protocol provides detailed procedures for PAD construction, including component selection, equipment setup, and system calibration. A step-by-step guide for human skin imaging is provided as an example application. Image reconstruction and troubleshooting procedures are also elaborated. PAD offers the 3D volumetric images of human skin, and quantitatively analyzes the vascular morphology in the dermis. The protocol will provide clinicians with standardized and reasonable guidance in dermatological imaging.

9.
Food Nutr Res ; 662022.
Artigo em Inglês | MEDLINE | ID: mdl-35517847

RESUMO

Background: Resveratrol, a well-known natural compound and nutrient, activates the deacetylation ability of SIRT1, demonstrating p53-dependent apoptosis functions in many diseases. However, the nascent proteomic fluctuation caused by resveratrol is still unclear. Objective: In this study, we investigated the effect of resveratrol on the nascent proteome and transcriptome initiated by SIRT1 activation, and we explored the mechanism of resveratrol in HEK 293T cells. Methods: Bioorthogonal noncanonical amino acid tagging (BONCAT) is a method used to metabolically label nascent proteins. In this strategy, L-azidohomoalanine (AHA) was used to replace methionine (Met) under different conditions. Taking advantage of the click reaction between AHA and terminal alkyne- and disulfide-functionalized agarose resin (TAD resin), we were able to efficiently separate stimulation responsive proteins from the pre-existing proteome. Resveratrol responsive proteins were identified by Liquid Chromatograph-Mass Spectrometer/Mass Spectrometer (LC-MS/MS). Furthermore, changes in mRNA levels were analyzed by transcriptome sequencing. Results: Integrational analysis revealed a resveratrol response in HEK 293T cells and showed that Hsp60 was downregulated at both the nascent protein and mRNA levels. Knockdown of SIRT1 and Hsp60 provides evidence that resveratrol downregulated Hsp60 through SIRT1 and that Hsp60 decreased p53 through the Akt pathway. Conclusions: This study revealed dynamic changes in the nascent proteome and transcriptome in response to resveratrol in HEK 293T cells and demonstrated that resveratrol downregulates Hsp60 by activating SIRT1, which may be a possible mechanism by which resveratrol prevents p53-dependent apoptosis by regulating Hsp60.

10.
Sci Total Environ ; : 155708, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35523329

RESUMO

The spatial distribution of microplastics and the factors influencing their distribution in lakes are important aspects of plastics pollution studies. This study investigated the impacts of lake underwater topography on the spatial distribution of microplastics in Dianchi Lake in China. Data on spatial distribution of microplastics were obtained by pump sampling, microscopic examination, and polymer identification. Parameters of underwater topography were extracted from an isobaths map of Dianchi Lake. The relationships between underwater topography and the abundance of microplastics were analyzed. The results showed that for the northern part of the lake, water depth, slope gradient, relief, roughness and surface curvature have significant relationships with the spatial distribution of microplastics. In the southern part, only roughness showed a significant relationship. The roughness is the only important factor which impacts the microplastics distribution in both parts of the lake and the whole lake. These differences between the northern part and the southern part of the lake are related to the stronger circular currents in the southern part of the lake. These results showed that the impacts of underwater topography manifest themselves well when lake currents are weak, and these impacts are reduced or muted when lake currents are strong. Our research results provide a good reference for understanding distribution and migration principle of microplastics in lakes.

11.
Front Oncol ; 12: 867788, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574406

RESUMO

The application of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer has significantly improved patient survival. However, most patients fail to respond to ICIs or develop drug resistance during treatment. Therefore, novel biomarkers are needed to predict the efficacy of ICIs or provide clues on how to overcome drug resistance. Here, it was revealed that cell division cycle 25C (CDC25C) expression was upregulated in lung adenocarcinoma (LUAD) compared to that of normal lung tissue in multiple databases. This was further verified by q-PCR. Furthermore, higher CDC25C expression was associated with shorter overall survival and worse pathological stage. Most importantly, a higher CDC25C expression was associated with shorter progression-free survival in LUAD patients treated with nivolumab, suggesting the role of the cell cycle in immunotherapy. In addition, CDC25C expression was significantly associated with immune cell infiltration and immune-related signatures in the LUAD tumor microenvironment. Moreover, CDC25C was differentially expressed and correlated with overall survival in multiple tumors, indicating that CDC25C is a broad-spectrum biomarker. Taken together, our study demonstrates that CDC25C is a prognostic biomarker for LUAD patients, especially for patients treated with ICIs. Our study also provides strong evidence for the role of the cell cycle in ICIs therapy and tumor microenvironment.

12.
BMC Genomics ; 23(Suppl 1): 346, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513810

RESUMO

BACKGROUND: The tomato (Solanum lycopersicum L.) is an economically valuable crop grown worldwide. Because the use of sterile males reduces the cost of F1 seed production, the innovation of male sterility is of great significance for tomato breeding. The ABORTED MICROSPORES gene (AMS), which encodes for a basic helix-loop-helix (bHLH) transcription factor, has been previously indicated as an essential gene for tapetum development in Arabidopsis and rice. To determine the function of the SlAMS gene (AMS gene from S. lycopersicum) and verify whether it is a potential candidate gene for generating the male sterility in tomato, we used virus-induced gene silencing (VIGS), CRISPR/Cas9-mediated genome editing and over-expression technology to transform tomato via Agrobacterium infection. RESULTS: Here, the full-length SlAMS gene with 1806 bp from S. lycopersicum (Accession No. MK591950.1) was cloned from pollen cDNA. The results of pollen grains staining showed that, the non-viable pollen proportions of SlAMS-silenced (75%), -knockouted (89%) and -overexpressed plants (60%) were significantly higher than the wild type plants (less than 10%; P < 0.01). In three cases, the morphology of non-viable pollen grains appeared tetragonal, circular, atrophic, shriveled, or otherwise abnormally shaped, while those of wild type appeared oval and plump. Furthermore, the qRT-PCR analysis indicated that SlAMS in anthers of SlAMS-silenced and -knockouted plants had remarkably lower expression than in that of wild type (P < 0.01), and yet it had higher expression in SlAMS-overexpressed plants (P < 0.01). CONCLUSION: In this paper, Our research suggested alternative approaches to generating male sterility in tomato, among which CRISPR/Cas9-mediated editing of SlAMS implied the best performance. We also demonstrated that the downregulation and upregulation of SlAMS both affected the pollen formation and notably led to reduction of pollen viability, suggesting SlAMS might be essential for regulating pollen development in tomato. These findings may facilitate studies on clarifying the SlAMS-associated molecular regulatory mechanism of pollen development in tomato.


Assuntos
Arabidopsis , Infertilidade Masculina , Lycopersicon esculentum , Arabidopsis/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Humanos , Infertilidade Masculina/genética , Masculino , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Pólen , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Sci Total Environ ; 833: 155245, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35429558

RESUMO

Aquaponics is gaining renewed interest to enhance food security. This study aimed to investigate the performance of a novel off-grid aquaponics system with near-zero water and waste discharge, focusing on the carbon cycle and energy recovery that was achieved by the addition of onsite anaerobic treatment of the solid waste streams. Following a stabilization stage, the system was closely monitored for four months. Fish tank water was recirculated via solid and nitrification reactors, from which 66% was recycled to the fish tank directly and 34% indirectly through the hydroponically grown plants. Fish solid waste was anaerobically treated, energy was recovered, and the nutrient-rich supernatant was recycled to the plants to enhance production. Plant waste was also digested anaerobically for further recovery of energy and nutrients. Fish stocking density was 15.3 and over time reached approximately 40 kg/m3 where it was maintained. Feed (45% protein content) was applied daily at 2% of body weight. Typical fish performance was observed with a survival rate >97% and feed conversion ratio of 1.33. Lettuce production was up to 5.65 kg/m2, significantly higher than previous reports, largely because of high nutrients reuse efficiency from the anaerobic supernatant that contained 130 and 34 mg/L N and P, respectively. Of the feed carbon, 24.5% was taken up by fish biomass. Fish solid wastes contained 38.2% carbon, of which 91.9% was recovered as biogas (74.5% CH4). Biogas production was 0.84 m3/kg for fish sludge and 0.67 m3/kg for dry plant material. CO2 sequestration was 1.4 higher than the feed carbon, which reduced the system's carbon footprint by 64%. This study is the first to demonstrate highly efficient fish and plant production with near-zero water and waste discharge and with energy recovery that can potentially supply the system's energy demand.

14.
J Hazard Mater ; 431: 128621, 2022 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-35359113

RESUMO

Nanozymes have been widely utilized in colorimetric sensors and developing nanomaterials with multienzyme functions have more application prospects due to their cascaded catalytic efficiency. Here, a unique organic-inorganic nanocomposite CoFe2O4/H2PPOP was synthesized by depositing CoFe2O4 nanocubes on a fully conjugated porphyrin-based porous organic polymer (H2PPOP) in situ. CoFe2O4/H2PPOP revealed outstanding tetra-enzyme-like activities, namely oxidase-like, peroxidase-like, catalase-like and superoxide dismutase-like activities. Compared with pure CoFe2O4 nanocubes, the catalytic activities of CoFe2O4/H2PPOP were significantly boosted because of the large surface area and extended conjugated structure of H2PPOP, abundant active substances (CoFe2O4) on the surface and the effective electronic transfer between CoFe2O4 and H2PPOP. Based on the oxidase-like activity of CoFe2O4/H2PPOP, a colorimetric platform was constructed for Cr (VI) with a wide linear range (0.6-100 µM) and a low detection limit (26 nΜ). Further utilizing the double oxidase-like and peroxidase-like activities, a more sensitive colorimetric platform with a faster detection speed for Cr (VI) was realized with the LOD as low as 2 nΜ. This work opens up a new way to prepare multi-enzyme active nanozyme and excavates its potential for detecting environmental pollutants.


Assuntos
Colorimetria , Nanocompostos , Catálise , Oxirredutases , Peroxidase
15.
Ecotoxicol Environ Saf ; 236: 113436, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367885

RESUMO

Microcystins (MCs) are the most common and toxic cyanotoxins that are hazardous to human health and ecosystems. Microcystinase is the enzyme in charge of the initial step in the biodegradation of MCs. The characterization, application conditions, and detoxification mechanisms of microcystinase from an indigenous bacterium Sphingopyxis sp. YF1 towards MC-LR were investigated in the current study. The microcystinase gene of strain YF1 was most similar to Sphingomonas sp. USTB-05 and contained a CAAX-family conversed abortive Infection (ABI) domain. The microcystinase was successful obtained and purified by overexpression in Escherichia coli. The highest degradation rate of MC-LR was 1.0 µg/mL/min under the optimal condition of 30 â„ƒ, pH 7, 20 µg/mL MC-LR, and 400 µg/mL microcystinase. The MC-degrading product was identified as linearized MC-LR, which possessed a much lower inhibitory activity against protein phosphatase 2A than MC-LR. Microcystinase interacted with MC-LR via amino acid residues involved in through the formation of conventional Hydrogen Bond, Pi-Pi T-shapes, Van der Waals force, and so on. The optimal MC-degrading condition of pure microcystinase and its detoxification mechanisms against MC-LR were revealed. The toxicity of purified linearized MC-LR was explored for the first time. These findings suggest that pure microcystinase may efficiently detoxify MCs and it is promising in the bioremediation of MC-polluted environments.


Assuntos
Toxinas Marinhas , Sphingomonadaceae , Biodegradação Ambiental , Ecossistema , Humanos , Toxinas Marinhas/metabolismo , Microcistinas/metabolismo , Sphingomonadaceae/metabolismo
16.
Ecotoxicol Environ Saf ; 236: 113454, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367887

RESUMO

Microcystin-leucine arginine (MC-LR), an emerging water pollutant, produced by cyanobacteria, has an acute testicular toxicity. However, little is known about the chronic toxic effects of MC-LR exposure on the testis at environmental concentrations and the underlying molecular mechanisms. In this study, C57BL/6 J mice were exposed to different low concentrations of MC-LR for 6, 9 and 12 months. The results showed that MC-LR could cause testis structure loss, cell abscission and blood-testis barrier (BTB) damage. Long-term exposure of MC-LR also activated RhoA/ROCK pathway, which was accompanied by the rearrangement of α-Tubulin. Furthermore, MC-LR reduced the levels of the adherens junction proteins (N-cadherin and ß-catenin) and the tight junction proteins (ZO-1 and Occludin) in a dose- and time-dependent way, causing BTB damage. MC-LR also reduced the expressions of Occludin, ZO-1, ß-catenin, and N-cadherin in TM4 cells, accompanied by a disruption of cytoskeletal proteins. More importantly, the RhoA inhibitor Rhosin ameliorated these MC-LR-induced changes. Together, these new findings suggest that long-term exposure to MC-LR induces BTB damage through RhoA/ROCK activation: involvement of tight junction and adherens junction changes and cytoskeleton disruption. This study highlights a new mechanism for MC-LR-induced BTB disruption and provides new insights into the cause and treatment of BTB disruption.


Assuntos
Barreira Hematotesticular , beta Catenina , Animais , Caderinas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcistinas/toxicidade , Ocludina/metabolismo
17.
Cancer Imaging ; 22(1): 17, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379339

RESUMO

PURPOSE: The goal of this study is to develop and validate a radiomics nomogram integrating the radiomics features from DCE-MRI and clinical factors for the preoperative diagnosis of axillary lymph node (ALN) metastasis in breast cancer patients. PROCEDURES: A total of 432 patients with breast cancer were enrolled in this retrospective study and divided into a training cohort (n = 296) and a validation cohort (n = 136). Radiomics features were extracted from the second phase of dynamic contrast enhanced (DCE) MRI images. The least absolute shrinkage and selection operator (LASSO) regression method was used to screen optimal features and construct a radiomics signature in the training cohort. Multivariable logistic regression analysis was used to establish a radiomics nomogram model based on the radiomics signature and clinical factors. The predictive performance of the nomogram was quantified with respect to discrimination and calibration, which was further evaluated in the independent validation cohort. RESULTS: Fourteen ALN metastasis-related features were selected to construct the radiomics signature, with an area under the curve (AUC) of 0.847 and 0.805 in the training and validation cohorts, respectively. The nomogram was established by incorporating the histological grade, multifocality, MRI report lymph node status and radiomics signature and showed good calibration and excellent performance for ALN detection (AUC of 0.907 and 0.874 in the training and validation cohorts, respectively). The decision curve, which demonstrated the radiomics nomogram, displayed promising clinical utility. CONCLUSIONS: The radiomics nomogram can be used as a noninvasive and reliable tool to assist clinicians in accurately predicting ALN metastasis in breast cancer preoperatively.


Assuntos
Neoplasias da Mama , Nomogramas , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Linfática , Imageamento por Ressonância Magnética , Estudos Retrospectivos
18.
Bioact Mater ; 16: 47-56, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35386319

RESUMO

In the current global crisis of antibiotic resistance, delivery systems are emerging to combat resistant bacteria in a more efficient manner. Despite the significant advances of antibiotic nanocarriers, many challenges like poor biocompatibility, premature drug release, suboptimal targeting to infection sites and short blood circulation time are still challenging. To achieve targeted drug delivery and enhance antibacterial activity, here we reported a kind of pH-responsive nanoparticles by simply self-assembly of an amphiphilic poly(ethylene glycol)-Schiff-vancomycin (PEG-Schiff-Van) prodrug and free Van in one drug delivery system. The acid-liable Schiff base furnished the PEG-Schiff-Van@Van with good storage stability in the neutral environment and susceptible disassembly in response to faintly acidic condition. Notably, on account of the combination of physical encapsulation and chemical conjugation of vancomycin, these nanocarriers with favorable biocompatibility and high drug loading capacity displayed a programmed drug release behavior, which was capable of rapidly reaching high drug concentration to effectively kill the bacteria at an early period and continuously exerting an bacteria-sensitive effect whenever needed over a long period. In addition, more Schiff-base moieties within the PEG-Schiff-Van@Van nanocarriers may also make great contributions on promoting the antimicrobial activity. Using this strategy, this system was designed to have programmable structural destabilization and sequential drug release due to changes in pH that were synonymous with bacterial infection sites, thereby presenting prominent antibacterial therapy both in vitro and in vivo. This work represents a synergistic strategy on offering important guidance to rational design of multifunctional antimicrobial vehicles, which would be a promising class of antimicrobial materials for potential clinical translation.

19.
Blood Adv ; 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35390147

RESUMO

Hemophilia A and B are hereditary coagulation defects resulting in unstable blood clotting and recurrent bleeding. Current factor replacement therapies have major limitations such as the short half-life of the factors and development of inhibitors. Alternative approaches to rebalance the hemostasis by inhibiting the anticoagulant pathways have recently gained considerable interest. In this study, we tested the therapeutic potential of a monoclonal antibody, HAPC1573, that selectively blocks the anticoagulant activity of human activated protein C (APC). We generated F8-/- or F9-/- hemophilia mice expressing human protein C by genetically replacing the murine Proc gene with the human PROC. The resulting PROC+/+;F8-/- or PROC+/+;F9-/- mice had bleeding characteristics similar to their corresponding F8-/- or F9-/- mice. Pretreating the PROC+/+;F8-/- mice with HAPC1573 shortened the tail bleeding time. HAPC1573 pretreatment significantly reduced mortality and alleviated joint swelling, similar to those treated with either FVIII or FIX, of either PROC+/+;F8-/- or PROC+/+;F9-/- mice in a needle-puncture-induced knee joint bleeding model. Additionally, we found that HAPC1573 significantly improved the thrombin generation of PROC+/+;F8-/- mice but not F8-/- mice, indicating that HAPC1573 enhanced the coagulant activity of hemophilia mice by modulating human APC in vivo. We further documented that HAPC1573 inhibited the APC anticoagulant activity to improve the clotting time of human plasma deficient of FVIII, FIX, FXI, FVII, VWF, FV, or FX. These results demonstrate that selectively blocking the anticoagulant activity of human APC may be an effective therapeutic and/or prophylactic approach for bleeding disorders lacking FVIII, FIX, or other clotting factors.

20.
Pest Manag Sci ; 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35474413

RESUMO

BACKGROUND: Seed mixture strategy can guarantee the compliance of planting non-Bt crops to host the susceptible insects for resistance management. However, pollen movement between Bt and non-Bt corn in the mixed plantings could reduce the efficacy of this strategy for ear-feeding insects. Few studies have evaluated the effects of cross-pollination among non-Bt and pyramided Bt corn in seed mixtures on resistance development of insects possessing multiple resistances. Here, we provided the first study to investigate whether cross-pollination in mixed plantings of pyramided Bt corn producing Cry1A.105 and Cry2Ab2 would increase the dominance of resistance of dual-gene resistant populations of Helicoverpa zea, a target of pyramided Bt corn and cotton in the U.S. RESULTS: We compared the survival and development of susceptible, dual-gene resistant (resistance to both Cry1 and Cry2 proteins), and the heterozygous genotypes of H. zea in the laboratory on non-Bt and pyramided Bt corn ears collected from mixed plantings and structured plantings in the field. We found higher fitness for F1 heterozygous insects than for the susceptible insects of H. zea on both pyramided Bt corn and non-Bt corn in the mixed plantings. CONCLUSION: These results suggest that cross-pollination in mixed plantings will significantly increase the dominance of resistance by supporting survival of heterozygous insects for dual-gene resistant populations of H. zea, and therefore accelerate evolution of resistance to pyramided Bt crops.

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