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1.
Aquat Toxicol ; 269: 106879, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38422927

ABSTRACT

How the particle size and concentration of microplastics impact their toxicity is largely unknown. Herein, the effects of polystyrene microplastics (1 µm, MPs) and nanoplastics (100 nm, NPs) exposed at 1 mg/L (L) and 10 mg/L (H), respectively, on the growth, histopathology, oxidative stress, gut microbiome, and metabolism of rare minnow (Gobiocypris rarus) were investigated by chemical analysis and multi-omics. MPs and NPs inhibited the growth, induced histopathological injury and aggravated oxidative stress markedly with contrasting significance of particle size and concentration. The composition of core gut microbiota changed dramatically especially for the MPs-H. Similarly, gut bacterial communities were reshaped by the MPs and NPs but only NPs-H decreased both richness and Shannon indexes significantly. Co-occurrence network analysis revealed that the potential keystone genera underwent great changes in exposed groups compared to the control. MPs-H increased the network complexity and the frequency of positive interactions which was opposite to other exposed groups. Moreover, the metabolomic profiles associated with amino acid, lipid, unsaturated fatty acid and hormone metabolism were disturbed significantly especially for MPs-H and NPs-H. In conclusion, the toxicity of MPs depends on both the particle size and concentration, and varies with the specific indicators as well.


Subject(s)
Cyprinidae , Cypriniformes , Water Pollutants, Chemical , Animals , Plastics , Polystyrenes/toxicity , Microplastics/toxicity , Particle Size , Water Pollutants, Chemical/toxicity
2.
Nat Biomed Eng ; 2023 Nov 23.
Article in English | MEDLINE | ID: mdl-37996614

ABSTRACT

Retinal prostheses could restore image-forming vision in conditions of photoreceptor degeneration. However, contrast sensitivity and visual acuity are often insufficient. Here we report the performance, in mice and monkeys with induced photoreceptor degeneration, of subretinally implanted gold-nanoparticle-coated titania nanowire arrays providing a spatial resolution of 77.5 µm and a temporal resolution of 3.92 Hz in ex vivo retinas (as determined by patch-clamp recording of retinal ganglion cells). In blind mice, the arrays allowed for the detection of drifting gratings and flashing objects at light-intensity thresholds of 15.70-18.09 µW mm-2, and offered visual acuities of 0.3-0.4 cycles per degree, as determined by recordings of visually evoked potentials and optomotor-response tests. In monkeys, the arrays were stable for 54 weeks, allowed for the detection of a 10-µW mm-2 beam of light (0.5° in beam angle) in visually guided saccade experiments, and induced plastic changes in the primary visual cortex, as indicated by long-term in vivo calcium imaging. Nanomaterials as artificial photoreceptors may ameliorate visual deficits in patients with photoreceptor degeneration.

3.
Ecotoxicol Environ Saf ; 250: 114479, 2023 Jan 15.
Article in English | MEDLINE | ID: mdl-36603484

ABSTRACT

The Dashan Region was a Se-rich region of China. In this study, 131 residents' human hair samples were collected. The concentrations of Se and toxic metals were analyzed, and the health risk was estimated using the concentration data. Cd and As concentrations were significantly higher than in East China. Se and most toxic metal concentrations increased with age (except for the aged people). Furthermore, gender and smoking habits might have a significant impact on toxic metals and Se levels. Multivariable statistics analysis revealed that Se and toxic metals primarily originate in the environment and are then transferred to the human body via the food chain. Dietary habits had an effect on the Se and As concentrations in hair, according to the results of stable isotope analysis. To assess detoxification ability, the Se/ toxic metal molar ratio was used as an indicator. The results demonstrated that the antagonistic effect of Se and Cd, As, Cr, and Hg (molar ratio > 1) could effectively protect residents in the study area from Cd and As pollution in daily life.


Subject(s)
Mercury , Metals, Heavy , Selenium , Humans , Aged , Selenium/analysis , Cadmium/toxicity , Cadmium/analysis , Mercury/analysis , China , Hair/chemistry , Metals, Heavy/toxicity , Metals, Heavy/analysis
4.
Neurooncol Pract ; 9(6): 545-551, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36388415

ABSTRACT

Background: The aim of this study is to retrospectively review the effectiveness and safety of personalized Gamma Knife radiosurgery (GKRS) for cavernous sinus hemangiomas (CSHs) and to summarize experience of personalized GKRS treatment for different volume of CSHs. Methods: 187 CSHs patients who received personalized GKRS treatment in our center from January 1, 2011 to December 31, 2020 were enrolled in this study and classified into small and medium CSHs (<20 ml), large CSHs (20-40 ml) and giant CSHs (≥40 ml) according to tumor volume. The personalized GKRS treatment strategy included single GKRS and staged GKRS. Tumor shrinkage rate, clinical symptoms response, and complications after GKRS were recorded during the follow-up period. Multivariate factors influencing clinical symptoms response were analyzed after personalized GKRS treatment. Results: After a mean follow-up duration of 28 months (range 12-124 months), the tumor control rate was 100%, and the mean shrinkage rate of CSHs was 93.2% (61.3%-100%) in the last follow-up. Of the 115 patients with preexisting symptoms, 43 (37.5%) patients showed symptom disappearance, 17 (14.7%) patients demonstrated improvement, and 55 (47.8%) patients remained with no change. Previous surgical resection of CSHs (OR = 0.025, 95% CI 0.007-0.084, P = .000) was identified to be an independent risk factor for no symptom improvement after GKRS treatment. Conclusions: Personalized GKRS is an effective and safe treatment for different volume of CSHs, which is capable of shrinking the tumor and improving symptoms with extremely low incidence of adverse effects and might be considered as the primary treatment strategy for CSHs.

5.
Ecotoxicol Environ Saf ; 245: 114122, 2022 Oct 15.
Article in English | MEDLINE | ID: mdl-36183425

ABSTRACT

The natural selenium (Se)-rich areas in China are generally characterized by high geological background of cadmium (Cd) which poses potential risks to human health. Therefore, immobilization of Cd is the prerequisite to ensure the safe utilization of natural seleniferous soil resources. A pot experiment was conducted to compare the effects of indigenous earthworm (Amynthas hupeiensis) and its gut bacteria (Citrobacter freundii DS strain) on the remediation of Cd-contaminated seleniferous soil with two traditional chemical amendments. The results indicated that earthworms and DS strain decreased DGT-extractable Cd by 25.52 - 41.53% and reduced Cd accumulation in lettuce leaves by 20.83 - 37.50% compared with control through converting the exchangeable Cd (EX-Cd) into residual Cd (RE-Cd) fractions. Overall, earthworms and DS strain were more effective in Cd immobilization, growth and quality promotion, oxidative stress alleviation, Cd accumulation and bioaccessibility reduction in the soil-lettuce-human continuum than biochar and lime. Moreover, all amendments induced the antagonism between Se and Cd through increasing bioavailable Se/Cd molar ratios in soil. However, all the Cd concentrations in lettuce exceeded the maximum permissible limit of Cd for leaf vegetables, indicating that soil amendment alone could not ensure food safety. This study confirmed that biological amendments were superior to chemical amendments in the remediation of Cd-contaminated seleniferous soil.


Subject(s)
Oligochaeta , Oryza , Selenium , Soil Pollutants , Animals , Bacteria , Cadmium/analysis , Charcoal/chemistry , Humans , Selenium/pharmacology , Soil/chemistry , Soil Pollutants/analysis
6.
Article in English | MEDLINE | ID: mdl-36133791

ABSTRACT

Background: Realgar (REA), a Chinese herbal decoction, has been used to treat various tumors and has produced positive outcomes; however, there is a lack of convincing evidence for the treatment of esophageal cancer. The present study aimed to investigate the effects of REA on esophageal cancer (EC) and explore its mechanism. Methods: EC cells Eca109 and KYSE150 were selected for this study, and different groups of treated cells were set up. We studied the inhibition rate and half inhibition concentration (IC50) by CCK-8 method, the clone formation assay was used to detect the clone formation ability, the scratch assay is used to determine the cell migration ability, the Transwell assay was used to detect the cell invasion ability, the protein expressions of E-cadherin, Slug, N-cadherin, ASK1, p38 MAPK, p-p38 MAPK, and GPX4 were determined using Western blot, the mRNA expressions of ASK1 and p38 MAPK were assessed using qRT-PCR, transmission electron microscopy was used to observe the cellular ultrastructure, Prussian blue staining was used to observe the intracellular iron particle distribution, and biochemical analysis of cellular MDA, SOD, GSH, and GPXS activities, flow cytometric analysis of cellular ROS levels, immunofluorescence staining to detect cellular GPX4 expression, and JC-1 method to detect mitochondrial membrane potential were used. Results: REA inhibited the proliferation of Eca109 and KYSE150 cells in a time- and concentration-dependent manner, and REA significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and activated the cellular ferroptosis and ROS-ASK1-p38 MAPK signaling pathways (P < 0.05). Inhibition of activation of the ROS-ASK1-p38 MAPK signaling pathway promoted the inhibition of proliferation, migration, and invasion of Eca109 and KYSE150 cells and the induction of ferroptosis by REA. Conclusion: REA induced ferroptosis and inhibited the migration of EC cells by activating the ROS-ASK1-p38 MAPK signaling pathway.

7.
PLoS Pathog ; 18(8): e1010787, 2022 08.
Article in English | MEDLINE | ID: mdl-36026486

ABSTRACT

Echovirus 11 (ECHO 11) is a positive-strand RNA virus belonging to the genus Enterovirus of the family Picornaviridae. ECHO 11 infections can cause severe inflammatory illnesses in neonates, including severe acute hepatitis with coagulopathy. The activation of NLRP3 inflammasome is important for host defense against invading viruses, which also contributes to viral pathogenicity. However, whether and how ECHO 11 induces NLRP3 inflammasome activation remains unclear. In this study, we isolated a clinical strain of ECHO 11 from stools of an ECHO 11-infected newborn patient with necrotizing hepatitis. This virus shared 99.95% sequence identity with the previously published ECHO 11 sequence. The clinically isolated ECHO 11 can efficiently infect liver cells and strongly induces inflammation. Moreover, we showed that ECHO 11 induced IL-1ß secretion and pyroptosis in cells and mouse bone marrow-derived macrophages (BMDMs). Furthermore, ECHO 11 infection triggered NLRP3 inflammasome activation, as evidenced by cleavages of GSDMD, pro-IL-1ß and pro-caspase-1, and the release of LDH. ECHO 11 2B protein was required for NLRP3 inflammasome activation via interacting with NLRP3 to facilitate the inflammasome complex assembly. In vivo, expression of ECHO 11 2B also activated NLRP3 inflammasome in the murine liver. Besides, 2Bs of multiple EVs can also interact with NLRP3 and induce NLRP3 inflammasome activation. Together, our findings demonstrate a mechanism by which ECHO 11 induces inflammatory responses by activating NLRP3 inflammasome, providing novel insights into the pathogenesis of ECHO 11 infection.


Subject(s)
Inflammasomes , Pyroptosis , Animals , Enterovirus B, Human , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Macrophages/metabolism , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
8.
Cancer Res ; 82(3): 497-509, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34737211

ABSTRACT

F-box and WD repeat domain containing 7 (FBXW7) is a substrate receptor of the ubiquitin ligase SKP1-Cullin1-F-box complex and a potent tumor suppressor that prevents unregulated cell growth and tumorigenesis. However, little is known about FBXW7-mediated control of cell metabolism and related functions in cancer therapy. Here, we report that FBXW7 expression inversely correlates with the expression levels of the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in patients with glioma and public glioma datasets. Deletion of FBXW7 significantly increased both wild-type (WT) and mutant IDH1 expression, which was mediated by blocking degradation of sterol regulatory element binding protein 1 (SREBP1). The upregulation of neomorphic mutant IDH1 by FBXW7 deletion stimulated production of the oncometabolite 2-hydroxyglutarate at the expense of increasing pentose phosphate pathway activity and NADPH consumption, limiting the buffering ability against radiation-induced oxidative stress. In addition, FBXW7 knockout and IDH1 mutations induced nonhomologous end joining and homologous recombination defects, respectively. In vitro and in vivo, loss of FBXW7 dramatically enhanced the efficacy of radiation treatment in IDH1-mutant cancer cells. Taken together, this work identifies FBXW7 deficiency as a potential biomarker representing both DNA repair and metabolic vulnerabilities that sensitizes IDH1-mutant cancers to radiotherapy. SIGNIFICANCE: Deficiency of FBXW7 causes defects in DNA repair and disrupts NADPH homeostasis in IDH1-mutant glioma cells, conferring high sensitivity to radiotherapy.


Subject(s)
F-Box-WD Repeat-Containing Protein 7 , Glioma , Isocitrate Dehydrogenase , Animals , Humans , Mice , Cell Line, Tumor , Disease Models, Animal , F-Box-WD Repeat-Containing Protein 7/metabolism , Glioma/genetics , Glioma/radiotherapy , Isocitrate Dehydrogenase/metabolism , Mutation
9.
J Neurosurg ; 136(6): 1687-1693, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-34715663

ABSTRACT

OBJECTIVE: Cavernous sinus hemangiomas (CSHs) are rare benign tumors originating from the cavernous sinus. Gamma Knife radiosurgery (GKRS) has been recommended as a primary treatment for small- to medium-sized CSHs. The optimal treatment for giant CSHs is still controversial. In this study, the authors retrospectively reviewed the effectiveness and safety of staged GKRS treatment for giant CSHs. METHODS: Twenty-two patients with giant CSH who received staged GKRS treatment in the Gamma Knife Treatment Center of Henan Province during the period from January 1, 2011, to December 31, 2018, were enrolled in this study. Six patients had received microsurgery before GKRS, the other 16 patients were diagnosed according to clinical symptoms and MR images. All of the enrolled patients received 2-stage GKRS, and the mean interval between the two GKRS treatments was 6.5 months (range 6-12 months). For the first GKRS, the median isodose line was 48% (range 45%-50%), the median marginal dose was 13 Gy (range 11.5-14 Gy), and the median coverage of CSHs was 80% (range 70%-88%). For the second GKRS treatment, the median isodose line was 50% (range 45%-55%), the median marginal dose to the CSHs was 10.5 Gy (range 9-12.5 Gy), and the median coverage of the CSHs was 88% (range 80%-94%). RESULTS: All of the patients received an outpatient review of an enhanced MR image of the head and a clinical physical check every 6 months after the first GKRS treatment. The mean follow-up duration was 52 months (range 24-84 months). The tumor control rate was 100% 24 months after staged GKRS, and at the last follow-up the mean tumor shrinkage rate was 96.7% (range 90.6%-100%) and the mean residual CSH volume was 2.1 ml (range 0-8.5 ml). Twenty patients suffered central nervous system (CNS) injury symptoms to varying degrees before staged GKRS treatment. Complete symptom recovery was found in 11 (55%) patients, improved symptoms in 5 (25%) patients, and no change in 4 (20%) patients after treatment. Only 1 patient suffered temporary preexisting headache aggravation and 1 patient suffered temporary preexisting diplopia aggravation 1 week after receiving the first GKRS treatment. Subacute or chronic complications were not detected after staged GKRS. CONCLUSIONS: Staged GKRS is an effective treatment for giant CSHs. Because of the impressively low incidence of adverse effects, staged GKRS may be considered as a primary treatment for giant CSHs.

10.
Cell Res ; 32(2): 139-156, 2022 02.
Article in English | MEDLINE | ID: mdl-34848869

ABSTRACT

Dopamine (DA) level in the nucleus accumbens (NAc) is critical for reward and aversion encoding. DA released from the ventral mesencephalon (VM) DAergic neurons increases the excitability of VM-projecting D1-dopamine receptor-expressing medium spiny neurons (D1-MSNs) in the NAc to enhance DA release and augment rewards. However, how such a DA positive feedback loop is regulated to maintain DA homeostasis and reward-aversion balance remains elusive. Here we report that the ventral pallidum (VP) projection of NAc D1-MSNs (D1NAc-VP) is inhibited by rewarding stimuli and activated by aversive stimuli. In contrast to the VM projection of D1-MSN (D1NAc-VM), activation of D1NAc-VP projection induces aversion, but not reward. D1NAc-VP MSNs are distinct from the D1NAc-VM MSNs, which exhibit conventional functions of D1-MSNs. Activation of D1NAc-VP projection stimulates VM GABAergic transmission, inhibits VM DAergic neurons, and reduces DA release into the NAc. Thus, D1NAc-VP and D1NAc-VM MSNs cooperatively control NAc dopamine balance and reward-aversion states.


Subject(s)
Dopamine , Nucleus Accumbens , Animals , Mice , Mice, Inbred C57BL , Neurons/metabolism , Nucleus Accumbens/metabolism , Receptors, Dopamine D1/metabolism , Reward
11.
Nanomaterials (Basel) ; 11(12)2021 Dec 03.
Article in English | MEDLINE | ID: mdl-34947629

ABSTRACT

Graphene/poly-(sodium-4-styrene sulfonate)(PSS)/poly-(allylamine hydrochloride) (PAH) composite is a frequently adopted system for fabricating polyelectrolyte multilayer films. Swelling is the bottleneck limiting its applications, and its effects on the conductivity is still controversial. Herein, we report successful swelling of a graphene/PSS/PAH composite in a vapor atmosphere, and the relation with the mass fraction of water is uncovered. The composite was prepared via a layer-by-layer assembly technique and systematically characterized. The results indicated that the average thickness for each bilayer was about 0.95 nm. The hardness and modulus were 2.5 ± 0.2 and 68 ± 5 GPa, respectively, and both were independent of thickness. The sheet resistance decreased slightly with the prolongation of immersion time, but was distinct from that of the water mass fraction. It reduced from 2.44 × 105 to 2.34 × 105 ohm/sq, and the change accelerated as the water mass fraction rose, especially when it was larger than 5%. This could be attributing to the lubrication effect of the water molecules, which sped up the migration of charged groups in the polyelectrolytes. Moreover, molecular dynamics simulations confirmed that a microphase separation occurred when the fraction reached an extreme value owing to the dominated interaction between PSS and PAH. These results provide support for the structural stability of this composite material and its applications in devices.

12.
Neoplasma ; 68(6): 1147-1156, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34427100

ABSTRACT

The cystine/glutamate antiporter xCT (SLC7A11) is frequently upregulated in many cancers, including glioblastoma (GBM). SLC7A11-mediated cystine taken up is reduced to cysteine, a precursor amino acid for glutathione synthesis and antioxidant cellular defense. However, little is known about the biological functions of SLC7A11 and its effect on therapeutic response in GBM. Here, we report that the expression of SLC7A11 is higher in GBM compared with normal brain tissue, but is negatively associated with tumor grades and positively impacts survival in the bioinformatic analysis of TCGA and CGGA database. Additionally, a negative association between SLC7A11 and mismatch repair (MMR) gene expression was identified by Pearson correlation analysis. In the GBM cells with glucose-limited culture conditions, overexpression of SLC7A11 significantly decreased MMR gene expression, including MLH1, MSH6, and EXO1. SLC7A11-overexpressed GBM cells demonstrated elevated double-strand break (DSB) levels and increased sensitivity to radiation treatment. Taken together, our work indicates that SLC7A11 might be a potential biomarker for predicting a better response to radiotherapy in GBM.


Subject(s)
Amino Acid Transport System y+ , DNA Mismatch Repair , Glioblastoma , Amino Acid Transport System y+/genetics , Amino Acid Transport System y+/metabolism , Cell Line, Tumor , Gene Expression , Glioblastoma/genetics , Glioblastoma/radiotherapy , Glucose , Humans
13.
Theranostics ; 11(16): 8008-8026, 2021.
Article in English | MEDLINE | ID: mdl-34335977

ABSTRACT

Rationale: Children usually develop less severe symptoms responding to Coronavirus Disease 2019 (COVID-19) than adults. However, little is known about the molecular alterations and pathogenesis of COVID-19 in children. Methods: We conducted plasma proteomic and metabolomic profilings of the blood samples of a cohort containing 18 COVID-19-children with mild symptoms and 12 healthy children, which were enrolled from hospital admissions and outpatients, respectively. Statistical analyses were performed to identify molecules specifically altered in COVID-19-children. We also developed a machine learning-based pipeline named inference of biomolecular combinations with minimal bias (iBM) to prioritize proteins and metabolites strongly altered in COVID-19-children, and experimentally validated the predictions. Results: By comparing to the multi-omic data in adults, we identified 44 proteins and 249 metabolites differentially altered in COVID-19-children against healthy children or COVID-19-adults. Further analyses demonstrated that both deteriorative immune response/inflammation processes and protective antioxidant or anti-inflammatory processes were markedly induced in COVID-19-children. Using iBM, we prioritized two combinations that contained 5 proteins and 5 metabolites, respectively, each exhibiting a total area under curve (AUC) value of 100% to accurately distinguish COVID-19-children from healthy children or COVID-19-adults. Further experiments validated that all the 5 proteins were up-regulated upon coronavirus infection. Interestingly, we found that the prioritized metabolites inhibited the expression of pro-inflammatory factors, and two of them, methylmalonic acid (MMA) and mannitol, also suppressed coronaviral replication, implying a protective role of these metabolites in COVID-19-children. Conclusion: The finding of a strong antagonism of deteriorative and protective effects provided new insights on the mechanism and pathogenesis of COVID-19 in children that mostly underwent mild symptoms. The identified metabolites strongly altered in COVID-19-children could serve as potential therapeutic agents of COVID-19.


Subject(s)
COVID-19/blood , COVID-19/virology , Adult , COVID-19/epidemiology , COVID-19/immunology , Child , Child, Preschool , China/epidemiology , Female , Hospitalization , Humans , Male , Metabolomics/methods , Middle Aged , Proteomics/methods , SARS-CoV-2/isolation & purification
15.
Ecotoxicol Environ Saf ; 222: 112516, 2021 Oct 01.
Article in English | MEDLINE | ID: mdl-34273847

ABSTRACT

Natural selenium (Se)-rich areas in China are generally characterized by high geological background of cadmium (Cd). However, the interaction between Se and Cd in the soil-rice-human continuum in such areas remains elusive. The concentrations, bioaccessibilities, and biomarkers of Se and Cd in a typical Se-Cd rich area were determined through chemical analysis, in vitro digestion model and cross-sectional study, respectively. The results showed that the molar ratio of available Se/Cd in the soil was averaged at 0.55 and soil Se did not reduce Cd accumulation and transportation in rice. Se bioaccessibility increased from the gastric phase to the intestinal phase, but the opposite was the case for Cd bioaccessibility. Moreover, bioaccessible concentration of Cd was positively correlated to corresponding total concentration in rice but negatively associated with the logarithm of molar ratio of Se/Cd. The risk of Cd-induced nephrotoxicity for the exposure group was not higher than the reference group, which could be ascribed to the mitigative effect of Se. Males and elders were at higher risk of Cd-induced injury owing to higher urinary Cd (U-Cd) and ß2-microglobulin (U-ß2-MG), and lower urinary Se (U-Se). Our results suggested that Cd-induced health risk should be assessed from a soil-rice-human perspective and the interaction between Se and Cd should be taken into account.


Subject(s)
Oryza , Selenium , Soil Pollutants , Aged , Cadmium/analysis , Cadmium/toxicity , Cross-Sectional Studies , Humans , Soil , Soil Pollutants/analysis , Soil Pollutants/toxicity
16.
Front Neurosci ; 15: 617175, 2021.
Article in English | MEDLINE | ID: mdl-34177442

ABSTRACT

Photocoagulation is used for the treatment of retinal ischemic disease. However, due to the invasive nature of photocoagulation and variety of melanin concentrations between individuals, it is challenging to avoid damaging the adjacent photoreceptors and inducing several side effects. Previous studies indicate the role of laser power, duration, and spot size on retinal lesions, but the effect of interspot distance of the laser pulses needs to be considered in panretinal photocoagulation. In this study, we examine different parameters of photocoagulation on lesions of the retina in rabbit, finding that the lesion level of the outer nuclear layer of the retina depended on the pulse duration and laser spot size, and decreasing interspot distance could completely abolish the photoreceptor layer. The degeneration of the photoreceptor by photocoagulation occurred in 24 h and was not restored afterward. We then conducted panretinal photocoagulation in rabbit and found that oxidative stress was decreased in the inner nuclear layer of the retina, and pupillary light reflex and ERG signals were impaired. Our study could provide a rabbit model to explore the mechanism of photoreceptor degeneration and therapies for the side effects after photocoagulation.

17.
J Virol ; 95(12)2021 05 24.
Article in English | MEDLINE | ID: mdl-33789997

ABSTRACT

Enteroviruses belong to the genus Enterovirus of the family Picornaviridae and include four human enterovirus groups (EV-A to -D): the epidemic of enteroviruses such as human enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) is a threat to global public health. Enteroviral protein 2C is the most conserved nonstructural protein among all enteroviruses and possesses RNA helicase activity that plays pivotal roles during enteroviral life cycles, which makes 2C an attractive target for developing antienterovirus drugs. In this study, we designed a peptide, named 2CL, based on the structure of EV-A71 2C. This peptide effectively impaired the oligomerization of EV-A71 2C protein and inhibited the RNA helicase activities of 2C proteins encoded by EV-A71 and CVA16, both of which belong to EV-A, and showed potent antiviral efficacy against EV-A71 and CVA16 in cells. Moreover, the 2CL treatment elicited a strong in vivo protective efficacy against lethal EV-A71 challenge. In addition, the antiviral strategy of targeting the 2C helicase activity can be applied to inhibit the replication of EV-B. Either 2CL or B-2CL, the peptide redesigned based on the 2CL-corresponding sequence of EV-Bs, could exert effective antiviral activity against two important EV-Bs, coxsackievirus B3 and echovirus 11. Together, our findings demonstrated that targeting the helicase activity of 2C with a rationally designed peptide is an efficient antiviral strategy against enteroviruses, and 2CL and B-2CL show promising clinical potential to be further developed as broad-spectrum antienterovirus drugs.IMPORTANCE Enteroviruses are a large group of positive-sense single-stranded RNA viruses and include numerous human pathogens, such as enterovirus A71 (EV-A71), coxsackieviruses, and echoviruses. However, no approved EV antiviral drugs are available. Enteroviral 2C is the most conserved nonstructural protein among all enteroviruses and contains the RNA helicase activity critical for the viral life cycle. Herein, according to the structure of EV-A71 2C, we designed a peptide that effectively inhibited the RNA helicase activities of EV-A71- and coxsackievirus A16 (CVA16)-encoded 2C proteins. Moreover, this peptide exerted potent antiviral effects against EV-A71 and CVA16 in cells and elicited therapeutic efficacy against lethal EV-A71 challenge in vivo Furthermore, we demonstrate that the strategy of targeting the 2C helicase activity can be used for other relevant enteroviruses, including coxsackievirus B3 and echovirus 11. In summary, our findings provide compelling evidence that the designed peptides targeting the helicase activity of 2C could be broad-spectrum antivirals for enteroviruses.


Subject(s)
Antiviral Agents/pharmacology , Carrier Proteins/antagonists & inhibitors , Enterovirus A, Human/drug effects , Enterovirus Infections/drug therapy , Peptides/pharmacology , RNA Helicases/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Carrier Proteins/chemistry , Carrier Proteins/metabolism , Cell Line , Drug Design , Enterovirus A, Human/chemistry , Enterovirus A, Human/physiology , Enterovirus B, Human/drug effects , Enterovirus B, Human/physiology , Enterovirus Infections/virology , Humans , Mice , Mice, Inbred ICR , Peptides/chemistry , Peptides/therapeutic use , RNA Helicases/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
18.
Environ Toxicol ; 35(10): 1091-1099, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32485069

ABSTRACT

Various pollutants co-exist in the aquatic environment such as carbamazepine (CBZ) and copper (Cu), which can cause complex effects on inhabiting organisms. The toxic impacts of the single substance have been studied extensively. However, the studies about their combined adverse impacts are not enough. In the present study, zebrafish were exposed to environmental relevant concentrations of CBZ (1, 10, and 100 µg/L), Cu (0.5, 5, and 10 µg/L) and the mixtures (1 µg/L CBZ + 0.5 µg/L Cu, 10 µg/L CBZ + 5 µg/L Cu, 100 µg/L CBZ + 10 µg/L Cu) for 45 days, the effects on nervous and antioxidant systems of zebrafish were investigated. The results demonstrated that, in comparison with single exposure group, the combined presence of CBZ and Cu exacerbated the effect of antioxidant system (the ability of inhibition of hydroxyl radicals (IHR), superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST)) but not nervous system (Acetylcholinesterase [AChE]). The qPCR results supported the changes of corresponding enzymes activities. Hepatic histopathological analysis verified the results of biomarkers. Our work illustrated that the toxicity of mixed pollutants is very complicated, which cannot simply be inferred from the toxicity of single pollutant, and calls for more co-exposure experiments to better understanding of the co-effects of pollutants on aquatic organisms.


Subject(s)
Antioxidants/metabolism , Carbamazepine/toxicity , Copper/toxicity , Nervous System/drug effects , Oxidative Stress/drug effects , Water Pollutants, Chemical/toxicity , Zebrafish/metabolism , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Animals , Biomarkers/metabolism , Catalase/genetics , Catalase/metabolism , Dose-Response Relationship, Drug , Down-Regulation , Drug Synergism , Gene Expression/drug effects , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Nervous System/enzymology , Nervous System/metabolism , Oxidative Stress/genetics , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism
19.
Bull Environ Contam Toxicol ; 104(4): 545-550, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32179940

ABSTRACT

Soil, rock, potable water, animal food and human hair samples were collected from the Dashan village, a typical selenium (Se)-rich area of China. Se content and fraction distribution were determined to trace the source of soil Se and evaluate the potential health risk to humans. Total Se contents in soils ranged from 0.60 to 10.46 mg kg- 1. The fractions of soil Se followed the order: residual Se (R-Se) > organic-bound Se (O-Se) > acid soluble Se (A-Se) > exchangeable Se (E-Se) > water soluble Se (W-Se). Total Se contents in rocks ranged from 0.07 to 24.8 mg kg- 1. The dietary Se intake of local residents was estimated to be 261.2 µg day- 1 and hair Se content varied from 0.34 to 1.35 mg kg- 1, suggesting that the potential health risk should be concerned. Weathering of carbonaceous rock was speculated to be the primary source of soil Se according to the contents of Se in rocks, the distribution of Se in soil profiles and the relationships between Se and other elements in soils and parent rocks.


Subject(s)
Dietary Exposure/analysis , Drinking Water/chemistry , Environmental Exposure/analysis , Selenium/analysis , Soil Pollutants/analysis , Soil/chemistry , Animals , China , Dietary Exposure/adverse effects , Drinking Water/standards , Hair/chemistry , Humans , Risk Assessment , Rural Population
20.
Environ Sci Pollut Res Int ; 27(14): 16646-16655, 2020 May.
Article in English | MEDLINE | ID: mdl-32130633

ABSTRACT

Diphenylarsinic acid (DPAA) is an emerging phenylarsenic compound derived from chemical warfare agents. It has been suggested that biostimulation of sulfate reduction decreases the concentrations of DPAA in soils. However, biostimulation often induces Fe(III) reduction which may affect the mobility and thereby the transformation of DPAA. Here, a soil incubation experiment was carried out to elucidate the impact of Fe(III) reduction on the mobilization and transformation of DPAA in a biostimulated Acrisol with the addition of sulfate and lactate. DPAA was significantly mobilized and then thionated in the sulfide soil (amended with sulfate and sodium lactate) compared with the anoxic soil (without addition of sulfate or sodium lactate). At the start of the incubation period, 41.8% of the total DPAA in sulfide soil was mobilized, likely by the addition of sodium lactate, and DPAA was then almost completely released into the solution after 2 weeks of incubation, likely due to Fe(III) reduction. The relatively low fraction of oxalate-extractable Fe in Acrisol, which contributes significantly to DPAA sorption and is more active and reduction-susceptible, may explain the observation that only < 40% of the Fe(III) (hydr)oxides were reduced when DPAA was completely released into the solution. A more rapid and final enhanced elimination of DPAA was observed in sulfide soil and the fraction of total DPAA decreased to 60.1 and 91.0%, respectively, at the end of the incubation in sulfide soil and anoxic soil. The difference appears to result from increased DPAA mobilization and sulfate reduction in sulfide soil. On the other hand, the formation of FeS precipitate, a product of Fe and sulfate reduction, may reduce the efficiency of DPAA thionation. Accordingly, the potentially contrasting effects of Fe(III) reduction on DPAA thionation need be considered when planning biostimulated sulfate reduction strategies for DPAA-contaminated soils.


Subject(s)
Arsenicals , Soil Pollutants/analysis , Ferric Compounds , Iron , Oxidation-Reduction
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