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1.
BMC Ophthalmol ; 21(1): 16, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413166

RESUMO

BACKGROUND: Ultrasound cycloplasty (UCP) is a non-invasive procedure for glaucoma treatment. Using high-intensity focused ultrasound to work on the ciliary body, the generation of aqueous humor can be reduced and the drainage of aqueous humor through the uveoscleral pathway can be enhanced. Recently, this therapy is gradually gaining clinical recognition. We report a case of a patient with glaucoma who accepted UCP in another hospital, but because of a worsening of a preexistent cataract and an insufficient IOP lowering effect, finally underwent cataract surgery in both eyes in our hospital, during the surgery we observed the unusual opacities probably due to UCP mistreatment. CASE PRESENTATION: Patient was diagnosed as chronic angle closure glaucoma and catacract, accepted UCP on both eyes in another hospital 4 months ago. After the UCP therapy, the pupil was vertical ellipse, the UCP didn't have a sufficient effect on IOP and forced us to do cataract surgery to lower IOP. During the cataract surgery, some unusual white opacities in the peripheral cortex with clear boundary were found. Inaccurate WtW measurement was the most likely cause of the injury, which resulted in the use of the small-size UCP probe and the downward movement of the UCP probe. CONCLUSION: UCP should not be a first line treatment in a patient with cataract and angle closure glaucoma, cataract extraction is a better choice. The appropriate case selection needs to be more strict and the preoperative indexes measurements need to be more accurate.

2.
J Hematol Oncol ; 14(1): 9, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413510

RESUMO

BACKGROUND: Key hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (-) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis. METHODS: NOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2-knockout (Nod2△hep), Rip2-knockout (Rip2△hep), Lamin A/C-knockout (Lamn△hep) and Rip2/Lamin A/C double-knockout (Rip2/Lamn△hep) mice models of diethylnitrosamine (DEN)/CCl4-induced HCC. RESULTS: NOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCC patients. Hepatic NOD2 deletion in vivo decreased DEN/CCl4-induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability. CONCLUSIONS: We reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.

3.
Ecotoxicology ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432457

RESUMO

Ammonia-oxidizing archaea (AOA) and bacteria (AOB) are the crucial players in nitrogen cycle. Both AOA and AOB were examined along a gradient of human activity in a coastal ecosystem from intertidal zone, grassland, and Casuarina equisetifolia forest to farmland. Results showed that the farmland soils had noticeably higher nitrate-N, available P than soils in the other three sites. Generally, AOA and AOB community structures varied across sites. The farmland mainly had Nitrosotalea-like AOA, intertidal zone was dominated by Nitrosopumilus AOA, while grassland and C. equisetifolia forest primarily harbored Nitrososphaera-like AOA. The farmland and C. equisetifolia forest owned Nitrosospira-like AOB, intertidal zone possessed Nitrosomonas-like AOB, and no AOB was detected in the grassland. AOA abundance was significantly greater than AOB in this coastal ecosystem (p < 0.05, n = 8). AOB diversity and abundance in the farmland were significantly higher than those in the other three sites (p < 0.05, n = 2). The biodiversity and abundance of AOA were not significantly correlated with any soil property (p < 0.05, n = 8). However, the diversity of AOB was significantly correlated with pH, available P and total P (p < 0.05, n = 6). The abundance of AOB was significantly correlated with pH, nitrite, available N, available P and total P (p < 0.05, n = 6). This study suggested that the community structures of AOA and AOB vary in the different parts in the bio-engineered coastal ecosystem and agricultural activity appears to influence these nitrifiers.

4.
Cell Prolif ; : e12986, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432610

RESUMO

OBJECTIVES: Mitophagy is considered to be a key mechanism in the pathogenesis of intestinal ischaemic reperfusion (IR) injury. NOD-like receptor X1 (NLRX1) is located in the mitochondria and is highly expressed in the intestine, and is known to modulate ROS production, mitochondrial damage, autophagy and apoptosis. However, the function of NLRX1 in intestinal IR injury is unclear. MATERIALS AND METHODS: NLRX1 in rats with IR injury or in IEC-6 cells with hypoxia reoxygenation (HR) injury were measured by Western blotting, real-time PCR and immunohistochemistry. The function of NLRX1-FUNDC1-NIPSNAP1/NIPSNAP2 axis in mitochondrial homeostasis and cell apoptosis were assessed in vitro. RESULTS: NLRX1 is significantly downregulated following intestinal IR injury. In vivo studies showed that rats overexpressing NLRX1 exhibited resistance against intestinal IR injury and mitochondrial dysfunction. These beneficial effects of NLRX1 overexpression were dependent on mitophagy activation. Functional studies showed that HR injury reduced NLRX1 expression, which promoted phosphorylation of FUN14 domain-containing 1 (FUNDC1). Based on immunoprecipitation studies, it was evident that phosphorylated FUNDC1 could not interact with the mitophagy signalling proteins NIPSNAP1 and NIPSNAP2 on the outer membrane of damaged mitochondria, which failed to launch the mitophagy process, resulting in the accumulation of damaged mitochondria and epithelial apoptosis. CONCLUSIONS: NLRX1 regulates mitophagy via FUNDC1-NIPSNAP1/NIPSNAP2 signalling pathway. Thus, this study provides a potential target for the development of a therapeutic strategy for intestinal IR injury.

6.
Neurosci Bull ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33421025

RESUMO

Ferroptosis is a form of iron-dependent regulated cell death. Evidence of its existence and the effects of its inhibitors on subarachnoid hemorrhage (SAH) is still lacking. In the present study, we found that liproxstatin-1 protected HT22 cells against hemin-induced injury by protecting mitochondrial functions and ameliorating lipid peroxidation. In in vivo experiments, we demonstrated the presence of characteristic shrunken mitochondria in ipsilateral cortical neurons after SAH. Moreover, liproxstatin-1 attenuated the neurological deficits and brain edema, reduced neuronal cell death, and restored the redox equilibrium after SAH. The inhibition of ferroptosis by liproxstatin-1 was associated with the preservation of glutathione peroxidase 4 and the downregulation of acyl-CoA synthetase long-chain family member 4 as well as cyclooxygenase 2. In addition, liproxstatin-1 decreased the activation of microglia and the release of IL-6, IL-1ß, and TNF-α. These data enhance our understanding of cell death after SAH and shed light on future preclinical studies.

7.
Bioinformatics ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33453108

RESUMO

MOTIVATION: Virus integration in the host genome is frequently reported to be closely associated with many human diseases, and the detection of virus integration is a critically challenging task. However, most existing tools show limited specificity and sensitivity. Therefore, the objective of this study is to develop a method for accurate detection of virus integration into host genomes. RESULTS: Herein, we report a novel method termed HIVID2 that is a significant upgrade of HIVID. HIVID2 performs a paired-end combination (PE-combination) for potentially integrated reads. The resulting sequences are then remapped onto the reference genomes, and both split and discordant chimeric reads are used to identify accurate integration breakpoints with high confidence. HIVID2 represents a great improvement in specificity and sensitivity, and predicts breakpoints closer to the real integrations, compared with existing methods. The advantage of our method was demonstrated using both simulated and real data sets. HIVID2 uncovered novel integration breakpoints in well-known cervical cancer-related genes, including FHIT and LRP1B, which was verified using protein expression data. In addition, HIVID2 allows the user to decide whether to automatically perform advanced analysis using the identified virus integrations. By analyzing the simulated data and real data tests, we demonstrated that HIVID2 is not only more accurate than HIVID but also better than other existing programs with respect to both sensitivity and specificity. We believe that HIVID2 will help in enhancing future research associated with virus integration. AVAILABILITY: HIVID2 can be accessed at https://github.com/zengxi-hada/HIVID2/. CONTACT: Xi Zeng (zengxi@mail.hzau.edu.cn), Linghao Zhao (michael_yifan@126.com). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

8.
Bioorg Chem ; 107: 104602, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33453647

RESUMO

The multi-target-directed ligands have been regarded as the promising multifunctional agents for the treatment of Alzheimer's disease (AD). Based on our previous work, a series of genistein-O-alkylamines derivatives was developed to further explore the structure-activity-relationship. The results showed that compound 7d indicated reversible and highly selective hAChE inhibitory activity with IC50 value of 0.53 µM. Compound 7d also displayed good antioxidant activity (ORAC = 1.1 eq.), promising neuroprotective effect and selective metal chelation property. Moreover, compound 7d significantly inhibited self-induced, hAChE-induced and Cu2+-induced Aß aggregation with 39.8%, 42.1% and 74.1%, respectively, and disaggregated Cu2+-induced Aß1-42 aggregation (67.3%). In addition, compound 7d was a potential autophagy inducer and improved the levels of GPX4 protein. Furthermore, compound 7d presented good blood-brain-barrier permeability in vitro. More importantly, compound 7d did not show any acute toxicity at doses of up to 1000 mg/kg and presented good precognitive effect on scopolamine-induced memory impairment. Therefore, compound 7d was a promising multifunctional agent for the development of anti-AD drugs.

9.
Medicine (Baltimore) ; 100(1): e24082, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429773

RESUMO

BACKGROUND: Diabetic foot ulcers are the most common complication among diabetic patients, which may put the patients in a great danger of amputation. Astragalus as a Chinese herbal medicine has been reported in many publications that it has an efficacy toward diabetic foot ulcers. However, the systematic review and meta-analysis of its efficacy and safety are still absent. Therefore, we aim to evaluate the effectiveness and safety of Astragalus for diabetic foot ulcers. METHODS: The following databases will be searched from January 1st, 2010 to September 2020: The Cochrane Library, Pubmed, EMBASE, Web of Science, China National Knowledge Infrastructure, and Wanfang Data. All the English and Chinese publications will be searched without any restriction of countries. Data will be extracted by 2 reviewers independently. RevMan 5.4.1. will be used to perform analysis and synthesis of data. RESULTS: This meta-analysis of randomized controlled trials will evaluate the efficacy and safety of Astragalus for diabetic foot ulcers during the past 10 years. CONCLUSION: This study will provide an evidence to judge whether Astragalus is effective and safe for diabetic patients with foot ulcers. INPLASY REGISTRATION NUMBER: Inplasy protocol 2020110059. (doi:10.37766/inplasy2020.11.00596).

10.
J Rural Stud ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33437114

RESUMO

Governments worldwide have taken unprecedented social distancing and community lockdown measures to halt the COVID-19 epidemic, leaving millions of people restrained in locked-down communities and their mental well-being at risk. This study examines Chinese rural residents' mental health risk under emergency lockdown during the COVID-19 pandemic. It investigates how the environmental, socioeconomic, and behavioral dimensions of community support affect mental health in this emergency context. We also explore whether community support's effectiveness depends on the strictness of lockdown measures implemented and the level of individual perceived COVID-19 infection risk. We collect self-reported mental health risk, community support, and demographics information through a cross-sectional survey of 3892 Chinese rural residents living in small towns and villages. Ordinary least square regressions are employed to estimate the psychological effects of community support. The results suggest that the COVID-19 epidemic and lockdown policies negatively affect psychological well-being, especially for rural females. The capacity for community production has the largest impact on reducing mental health risks, followed by the stability of basic medical services, community cohesion, housing condition, the stability of communications and transportation supply, and the eco-environment. The effectiveness of different community support dimensions depends on the level of lockdown policy implemented and the levels of one's perceived risk of COVID-19 infection. Our study stresses the psychological significance of a healthy living environment, resilient infrastructure and public service system, and community production capacity during the lockdown in rural towns and villages.

11.
Nucleic Acids Res ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33444454

RESUMO

A significant portion of human cancers are due to viruses integrating into human genomes. Therefore, accurately predicting virus integrations can help uncover the mechanisms that lead to many devastating diseases. Virus integrations can be called by analysing second generation high-throughput sequencing datasets. Unfortunately, existing methods fail to report a significant portion of integrations, while predicting a large number of false positives. We observe that the inaccuracy is caused by incorrect alignment of reads in repetitive regions. False alignments create false positives, while missing alignments create false negatives. This paper proposes SurVirus, an improved virus integration caller that corrects the alignment of reads which are crucial for the discovery of integrations. We use publicly available datasets to show that existing methods predict hundreds of thousands of false positives; SurVirus, on the other hand, is significantly more precise while it also detects many novel integrations previously missed by other tools, most of which are in repetitive regions. We validate a subset of these novel integrations, and find that the majority are correct. Using SurVirus, we find that HPV and HBV integrations are enriched in LINE and Satellite regions which had been overlooked, as well as discover recurrent HBV and HPV breakpoints in human genome-virus fusion transcripts.

12.
Food Chem Toxicol ; : 111979, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33450301

RESUMO

Consumption of energy drinks has been associated with adverse cardiovascular effects; however, little is known about the ingredients that may contribute to these effects. We therefore characterized the chemical profiles and in vitro effects of energy drinks and their ingredients on human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, and identified the putative active ingredients using a multivariate prediction model. Energy drinks from 17 widely-available over-the-counter brands were evaluated in this study. The concentrations of six common molecular ingredients (caffeine, taurine, riboflavin, pantothenic acid, adenine, and L-methionine) were quantified by coupling liquid chromatography with a triple quadrupole mass spectrometer for the acquisition of LC-MS/MS spectra. In addition, untargeted analyses for each beverage were performed with a platform combining LC, ion mobility spectrometry and mass spectrometry (LC-IMS-MS) measurements. Approximately 300 features were observed per sample in the untargeted studies, and of these ∼100 were identified. In vitro effects of energy drinks and some of their molecular ingredients were then tested in iPSC-derived cardiomyocytes. Data on the beat rate (positive and negative chronotropy), ion channel function (QT prolongation), and cytotoxicity were collected in a dilution series. We found that some of the energy drinks elicited adverse effects on the cardiomyocytes with the most common being an increase in the beat rate, while QT prolongation was also observed at the lowest concentrations. Finally, concentration addition modeling using quantitative data from the 6 common ingredients and multivariate prediction modeling was used to determine potential molecular ingredients responsible for the adverse effects on the cardiomyocytes. These analyses suggested theophylline, adenine, and azelate as possibly contributing to the in vitro effects of energy drinks on QT prolongation in cardiomyocytes.

13.
Cell Rep ; 34(2): 108603, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33440163

RESUMO

Anterior segment dysgenesis is often associated with cornea diseases, cataracts, and glaucoma. In the anterior segment, the ciliary body (CB) containing inner and outer ciliary epithelia (ICE and OCE) secretes aqueous humor that maintains intraocular pressure (IOP). However, CB development and function remain poorly understood. Here, this study shows that NOTCH signaling in the CB maintains the vitreous, IOP, and eye structures by regulating CB morphogenesis, aqueous humor secretion, and vitreous protein expression. Notch2 and Notch3 function via RBPJ in the CB to control ICE-OCE adhesion, CB morphogenesis, aqueous humor secretion, and protein expression, thus maintaining IOP and eye structures. Mechanistically, NOTCH signaling transcriptionally controls Nectin1 expression in the OCE to promote cell adhesion for driving CB morphogenesis and to directly stabilize Cx43 for controlling aqueous humor secretion. Finally, NOTCH signaling directly controls vitreous protein secretion in the ICE. Therefore, this study provides important insight into CB functions and involvement in eye diseases.

14.
IEEE Trans Med Imaging ; PP2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33395391

RESUMO

Speckle noise is the main cause of poor optical coherence tomography (OCT) image quality. Convolutional neural networks (CNNs) have shown remarkable performances for speckle noise reduction. However, speckle noise denoising still meets great challenges because the deep learning-based methods need a large amount of labeled data whose acquisition is time-consuming or expensive. Besides, many CNNs-based methods design complex structure based networks with lots of parameters to improve the denoising performance, which consume hardware resources severely and are prone to overfitting. To solve these problems, we propose a novel semi-supervised learning based method for speckle noise denoising in retinal OCT images. First, to improve the model's ability to capture complex and sparse features in OCT images, and avoid the problem of a great increase of parameters, a novel capsule conditional generative adversarial network (Caps-cGAN) with small number of parameters is proposed to construct the semi-supervised learning system. Then, to tackle the problem of retinal structure information loss in OCT images caused by lack of detailed guidance during unsupervised learning, a novel joint semi-supervised loss function composed of unsupervised loss and supervised loss is proposed to train the model. Compared with other state-of-the-art methods, the proposed semi-supervised method is suitable for retinal OCT images collected from different OCT devices and can achieve better performance even only using half of the training data.

15.
Cell Biol Toxicol ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33400020

RESUMO

Cholestatic liver injury, a group of diseases characterized with dysregulated bile acid (BA) homeostasis, was partly resulted from BA circulation disorders, which is commonly associated with the damage of hepatocyte barrier function. However, the underlying hepatocyte barrier-protective molecular mechanisms of cholestatic liver injury remain poorly understood. Interestingly, recent studies have shown that sphingosine-1-phosphate (S1P) participated in the process of cholestasis by activating its G protein-coupled receptors S1PRs, regaining the integrity of hepatocyte tight junctions (TJs). Here, we showed that SEW2871, a selective agonist of sphingosine-1-phosphate receptor 1(S1PR1), alleviated ANIT-induced TJs damage in 3D-cultured mice primary hepatocytes. Molecular mechanism studies indicated that AMPK signaling pathways was involved in TJs protection of SEW2871 in ANIT-induced hepatobiliary barrier function deficiency. AMPK antagonist compound C (CC) and agonist AICAR were all used to further identify the important role of AMPK signaling pathway in SEW2871's TJs protection of ANIT-treated mice primary hepatocytes. The in vivo data showed that SEW2871 ameliorated ANIT-induced cholestatic hepatotoxicity. Further protection mechanism research demonstrated that SEW2871 not only regained hepatocyte TJs by the upregulated S1PR1 via AMPK signaling pathway, but also recovered hepatobiliary barrier function deficiency, which was verified by the restored BA homeostasis by using of high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). These results revealed that the increased expression of S1PR1 induced by SEW2871 could ameliorate ANIT-induced cholestatic liver injury through improving liver barrier function via AMPK signaling and subsequently reversed the disrupted BA homeostasis. Our study provided strong evidence that S1PR1 may be a promising therapeutic approach for treating intrahepatic cholestatic liver injury. Graphical abstract.

16.
IEEE Trans Med Imaging ; PP2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33406037

RESUMO

Automatic thoracic disease diagnosis is a rising research topic in the medical imaging community, with many potential applications. However, the inconsistent appearances and high complexities of various lesions in chest X-rays currently hinder the development of a reliable and robust intelligent diagnosis system. Attending to the high-probability abnormal regions and exploiting the priori of a related knowledge graph offers one promising route to addressing these issues. As such, in this paper, we propose two contrastive abnormal attention models and a dual-weighting graph convolution to improve the performance of thoracic multi-disease recognition. First, a left-right lung contrastive network is designed to learn intra-attentive abnormal features to better identify the most common thoracic diseases, whose lesions rarely appear in both sides symmetrically. Moreover, an inter-contrastive abnormal attention model aims to compare the query scan with multiple anchor scans without lesions to compute the abnormal attention map. Once the intra- and inter-contrastive attentions are weighted over the features, in addition to the basic visual spatial convolution, a chest radiology graph is constructed for dual-weighting graph reasoning. Extensive experiments on the public NIH ChestX-ray and CheXpert datasets show that our model achieves consistent improvements over the state-of-the-art methods both on thoracic disease identification and localization.

17.
Methods Mol Biol ; 2153: 59-69, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32840772

RESUMO

DNA double-strand break (DSB) end resection initiates homologous recombination (HR) and is critical for genomic stability. DSB resection has been monitored indirectly in mammalian cells using detection of protein foci or BrdU foci formation, which is dependent on single-stranded DNA (ssDNA) products of resection. Here we describe a quantitative PCR (qPCR)-based assay to directly measure levels of ssDNA intermediates generated by resection at specific DSB sites in human cells, which is more quantitative and precise with respect to the extent and efficiency of resection compared with previous methods. This assay, excluding the time for making the stable cell line expressing the restriction enzyme AsiSI fused to the estrogen receptor hormone-binding domain (ER-AsiSI), can be completed within 3 days.

18.
Methods Mol Biol ; 2188: 259-271, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33119856

RESUMO

Intact and functioning brain enables quantification of neural activities directly associated with real world such as visual and auditory information. In vivo patch clamp can record different types of neuronal activity, such as spiking responses, membrane potential dynamics, and synaptic currents (e.g., EPSC, IPSC) in either anesthetized or awake or even free moving animals. Researchers can not only directly measure these neuronal activities but also quantify and unravel synaptic contribution from excitatory and inhibitory circuits. Here, we describe the requirements and standard protocols to perform in vivo patch clamp recording. The key factors of successful recording based on references and our experiences are also provided.

19.
Toxicol Sci ; 179(1): 108-120, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33165562

RESUMO

Methods to assess environmental exposure to hazardous chemicals have primarily focused on quantification of individual chemicals, although chemicals often occur in mixtures, presenting challenges to the traditional risk characterization framework. Sampling sites in a defined geographic region provide an opportunity to characterize chemical contaminants, with spatial interpolation as a tool to provide estimates for non-sampled sites. At the same time, the use of in vitro bioactivity measurements has been shown to be informative for rapid risk-based decisions. In this study, we measured in vitro bioactivity in 39 surface soil samples collected immediately after flooding associated with Hurricane Harvey in Texas in a residential area known to be inundated with polycyclic aromatic hydrocarbon (PAH) contaminants. Bioactivity data were from a number of functional and toxicity assays in 5 human cell types, such as induced pluripotent stem cell-derived hepatocytes, cardiomyocytes, neurons, and endothelial cells, as well as human umbilical vein endothelial cells. Data on concentrations of PAH in these samples were also available and the combination of data sources offered a unique opportunity to assess the joint spatial variation of PAH components and bioactivity. We found significant evidence of spatial correlation of a subset of PAH contaminants and of cell-based phenotypes. In addition, we show that the cell-based bioactivity data can be used to predict environmental concentrations for several PAH contaminants, as well as overall PAH summaries and cancer risk. This study's impact lies in its demonstration that cell-based profiling can be used for rapid hazard screening of environmental samples by anchoring the bioassays to concentrations of PAH. This work sets the stage for identification of the areas of concern and direct quantitative risk characterization based on bioactivity data, thereby providing an important supplement to traditional individual chemical analyses by shedding light on constituents that may be missed from targeted chemical monitoring.

20.
Pharm Dev Technol ; 26(1): 21-29, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070673

RESUMO

Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by 1H NMR. The nanocarriers TPP-DOX @ HA-PBPE was prepared in a regular shape and particle size of approximately 200 nm. Compared to free DOX, its antitumor activity in vitro and tumor passive targeting in vivo has been enhanced. The ROS-responsive TPP-DOX@HA-PBPE nanocarriers system provide a promising strategy for the reverse of MDR and efficient delivery of doxorubicin derivatives into drug-resistant cancer cells.

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