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1.
Cell Res ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670290

RESUMO

Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.

2.
Mol Biol Rep ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653729

RESUMO

BACKGROUND: Enterovirus A71 (EV-A71)is a prevalent infection in severe hand, foot and mouth disease HFMD and can induce acute central nervous system seizures. The three EV-A71 vaccines now circulating in the market are produced for a single subtype. While EV-A71 is constantly evolving and the vaccine's efficacy is gradually reducing, no specialized anti-EV-A71 medication has yet been developed. Therefore, it is crucial to consistently develop new anti-EV-A71 medications. METHOD: Ebselen, an organoselenium molecule with glutathione oxidase-like activity, is resistant to a range of viruses. In this investigation, we used the Cell counting kit-8 (CCK-8 kit) assay in a Vero cell model to confirm the effectiveness of ebselen against EV-A71 infection. Later, to examine ebselen's anti-EV-A71 mechanism, we measured the apoptosis level of cells in different treatment groups through Annexin V, JC-1, and cell cycle assays, as well as the intracellular reactive oxygen species (ROS) concentration. Ebselen may have an impact on the apoptotic signaling pathway caused by EV-A71 infection, according to the results of a caspase-3 activity experiment. RESULT: The results showed that Ebselen protected cell damage from ROS generation, decreased the frequency of EV-A71-induced apoptosis, and inhibited caspase-3-mediated apoptosis by lowering caspase-3 activity. CONCLUSION: To summarize, ebselen is a promising anti-EV-A71 medication.

3.
J Neuropsychol ; 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36642964

RESUMO

Emotions affects moral judgements, and controlled cognitive processes regulate those emotional responses during moral decision making. However, the neurobiological basis of this interaction is unclear. We used a graph theory measurement called participation coefficient ('PC') to quantify the resting-state functional connectivity within and between four meta-analytic groupings (MAGs) associated with emotion generation and regulation, to test whether that measurement predicts individual differences in moral foundations-based values. We found that the PC of one of the MAGs (MAG2) was positively correlated with one of the five recognized moral foundations-the one based on harm avoidance. We also found that increased inter-module connectivity between the ventromedial prefrontal cortex, dorsolateral prefrontal cortex and middle temporal gyrus with other nodes in the four MAGs was likewise associated with higher endorsement of the Harm foundation. These results suggest that individuals' sensitivity to harm is associated with functional integration of large-scale brain networks of emotional regulation. These findings add to our knowledge of how individual variations in our moral values could be reflected by intrinsic brain network organization and deepen our understanding of the relationship between emotion and cognition during evaluations of moral values.

4.
Int J Biol Sci ; 19(2): 521-536, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632461

RESUMO

Neuropeptide Y (NPY) is produced by the nerve system and may contribute to the progression of CKD. The present study found the new protective role for NPY in AKI in both patients and animal models. Interestingly, NPY was constitutively expressed in blood and resident kidney macrophages by co-expressing NPY and CD68+ markers, which was lost in patients and mice with AKI-induced by cisplatin. Unexpectedly, NPY was renoprotective in AKI as mice lacking NPY developed worse renal necroinflammation and renal dysfunction in cisplatin and ischemic-induced AKI. Importantly, NPY was also a therapeutic agent for AKI because treatment with exogenous NPY dose-dependently inhibited cisplatin-induced AKI. Mechanistically, NPY protected kidney from AKI by inactivating M1 macrophages via the Y1R-NF-κB-Mincle-dependent mechanism as deleting or silencing NPY decreased Y1R but increased NF-κB-Mincle-mediated M1macrophage activation and renal necroinflammation, which were reversed by addition of NPY or by silencing Mincle but promoted by blocking Y1R with BIBP 3226. Thus, NPY is renoprotective and may be a novel therapeutic agent for AKI. NPY may act via Y1R to protect kidney from AKI by blocking NF-κB-Mincle-mediated M1 macrophage activation and renal necroinflammation.


Assuntos
Injúria Renal Aguda , NF-kappa B , Camundongos , Animais , Neuropeptídeo Y/efeitos adversos , Cisplatino/uso terapêutico , Rim , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Macrófagos
5.
Artigo em Inglês | MEDLINE | ID: mdl-36689154

RESUMO

Acupuncture point specificity has been recognized as a key scientific issue in traditional Chinese medicine (TCM), but there is limited clinical trial or animal study to verify the characteristics of PC6, BL15, and ST36 in the protection from myocardial injury. We aimed to compare the effects among these three acupoints on the acute myocardial infarction mice model and to explore possible mechanisms for the first time. We found that PC6 is the most appropriate acupoint to deliver efficacy and safety to treat acute MI in mice. BL15 stimulation improved the systolic function, but increased the risk of arrhythmia. ST36 only slightly attenuated systolic function and had no effect on arrhythmia during MI. RNA profiles of skin tissue in local acupoints demonstrated that the most altered DEGs and related pathways may partly support its best effects of PC6 treatment on MI injury, and support the observed phenomenon of the acupoint specificity.

6.
CNS Neurosci Ther ; 29(2): 619-632, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36575865

RESUMO

BACKGROUND: Motor imagery training (MIT) has been widely used to improve hemiplegic upper limb function in stroke rehabilitation. The effectiveness of MIT is associated with the functional neuroplasticity of the motor network. Currently, brain activation and connectivity changes related to the motor recovery process after MIT are not well understood. AIM: We aimed to investigate the neural mechanisms of MIT in stroke rehabilitation through a longitudinal intervention study design with task-based functional magnetic resonance imaging (fMRI) analysis. METHODS: We recruited 39 stroke patients with moderate to severe upper limb motor impairment and randomly assigned them to either the MIT or control groups. Patients in the MIT group received 4 weeks of MIT therapy plus conventional rehabilitation, while the control group only received conventional rehabilitation. The assessment of Fugl-Meyer Upper Limb Scale (FM-UL) and Barthel Index (BI), and fMRI scanning using a passive hand movement task were conducted on all patients before and after treatment. The changes in brain activation and functional connectivity (FC) were analyzed. Pearson's correlation analysis was conducted to evaluate the association between neural functional changes and motor improvement. RESULTS: The MIT group achieved higher improvements in FM-UL and BI relative to the control group after the treatment. Passive movement of the affected hand evoked an abnormal bilateral activation pattern in both groups before intervention. A significant Group × Time interaction was found in the contralesional S1 and ipsilesional M1, showing a decrease of activation after intervention specifically in the MIT group, which was negatively correlated with the FM-UL improvement. FC analysis of the ipsilesional M1 displayed the motor network reorganization within the ipsilesional hemisphere, which correlated with the motor score changes. CONCLUSIONS: MIT could help decrease the compensatory activation at both hemispheres and reshape the FC within the ipsilesional hemisphere along with functional recovery in stroke patients.


Assuntos
Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , Extremidade Superior
7.
Accid Anal Prev ; 180: 106926, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36543079

RESUMO

Automated driving technology has constantly been maturing; however, how to ensure automated vehicle (AV) safety has not yet been effectively solved, functional safety assessment remains an important part of the development of automated driving technology. To compensate for the lack of multidimensional evaluation indicators, this paper proposes a safety evaluation method in multi-logical scenarios (SEMMS) for AVs' functional safety based on naturalistic driving trajectory (NDT) in order to evaluate the comprehensive performance of the tested AV in a diversity of scenarios simultaneously. The potential field method is used to describe the quantified danger level of an AV in a single concrete scenario that considers the dangerous situation of the scenario and AV test results. Combined with the internal probability distribution of the logical scenario parameter space obtained by NDT, the safety performance of an AV in logical scenario is calculated by integrating the two indexes. With the information entropy and relative frequency of different logical scenarios, the relative weights of logical scenarios are obtained, and the safety performance evaluation results of the tested AV in the multi-logical scenarios can be determined based on the weighting danger level in different logical scenarios. During the actual application of the method, the HighD database was used as the input source of NDT, and a black-box automated driving algorithm was subjected to traversal tests in three logical scenarios. The test results of the automated driving algorithm were evaluated using the SEMMS, and the results show that the SEMMS could well evaluate the performance of the tested automated driving algorithm in multiple kinds of logical scenarios simultaneously, indicating that it is an effective solution to the problem of automated driving algorithm safety evaluation.


Assuntos
Acidentes de Trânsito , Condução de Veículo , Humanos , Acidentes de Trânsito/prevenção & controle , Veículos Autônomos , Automação , Tecnologia , Segurança
8.
Antiviral Res ; 209: 105507, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36565755

RESUMO

The Omicron variant is sweeping the world, which displays striking immune escape potential through mutations at key antigenic sites on the spike protein, making broad-spectrum SARS-CoV-2 prevention or therapeutical strategies urgently needed. Previously, we have reported a hACE2-targeting neutralizing antibody 3E8, which could efficiently block both prototype SARS-CoV-2 and Delta variant infections in prophylactic mouse models, having the potential of broad-spectrum to prevent SARS-CoV-2. However, preparation of monoclonal neutralizing antibodies is severely limited by the time-consuming process and the relative high cost. Here, we utilized a modified VEEV replicon with two subgenomic (sg) promoters engineered to express the light and heavy chains of the 3E8 mAb. The feasibility and protective efficacy of replicating mRNA encoding 3E8 against Omicron infection in the hamster were demonstrated through the lung targeting delivery with the help of VEEV-VRP. Overall, we developed a safe and cost-effective platform of broad-spectrum to prevent SARS-CoV-2 infection.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Cricetinae , Camundongos , SARS-CoV-2/genética , COVID-19/prevenção & controle , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes , RNA Mensageiro , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Antivirais
9.
Adv Sci (Weinh) ; : e2202448, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36453576

RESUMO

The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.

10.
Wei Sheng Yan Jiu ; 51(6): 947-952, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36539873

RESUMO

OBJECTIVE: To explore the relationship between the duration of sleep and hypertension among residents aged 60 and above in 15 provinces of China. METHODS: Based on the China Health and Nutrition Survey in 2015, 4078 residents aged 60 and above who provided complete diagnostic information on sleep duration and blood pressure were selected as subjects by stratified multi-stage cluster random sampling. RESULTS: The average age of participants aged 60 and above in 15 provinces was 68.41 years old, with 1915 were male, 2163 were female, 1683 urban participants and 2464 rural participants. After adjusting for gender, age, education, and economic confounding factors, Model 2 found that subjects who slept less than 7 h/d and those who slept more than 8 h/d had an increased risk of developing hypertension compared with the recommended sleep duration, the ORs were 1.24(95%CI 1.03-1.51) and 1.38(95%CI 1.15-1.65). Adding the sitting time, smoking, drinking and obesity to the Model 2, compared with the recommended sleep duration, subjects who slept less than 7 h/d and those who slept more than 9 h/d had an increased risk of hypertension. The ORs values were 1.27(95%CI 1.04-1.56) and 1.40(95%CI 1.16-1.70). CONCLUSION: The proportion of the elder aged 60 and older who sleep less than 7 h/d or more than 9 h/d has increased hypertension.


Assuntos
Hipertensão , Idoso , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Hipertensão/epidemiologia , Sono/fisiologia , China/epidemiologia
11.
Sci Rep ; 12(1): 21472, 2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36509804

RESUMO

Xinjiang is an important power production base in China, and its electric energy production needs not only meet the demand of Xinjiang's electricity consumption, but also make up for the shortage of electricity in at least 19 provinces or cities in China. Therefore, it is of great significance to know ahead of time the electric energy production of Xinjiang in the future. In such terms, accurate electric energy production forecasts are imperative for decision makers to develop an optimal strategy that includes not only risk reduction, but also the betterment of the economy and society as a whole. According to the characteristics of the historical data of monthly electricity generation in Xinjiang from January 2001 to August 2020 , the suitable and widely used SARIMA (Seasonal autoregressive integrated moving mean model) method and Holt-winter method were used to construct the monthly electric energy production in Xinjiang for the first time. The results of our analysis showed that the established SARIMA((1,2,3,4,6,7,11),2,1)(1,0,1)12 model had higher prediction accuracy than that of the established Holt-Winters' multiplicative model. We predicted the monthly electric energy production from August 2021 to August 2022 by the SARIMA((1,2,3,4,6,7,11),2,1)(1,0,1)12 model, and errors are very small compared to the actual values, indicating that our model has a very good prediction performance. Therefore, based on our study, we provided a simple and easy scientific tool for the future power output prediction in Xinjiang. Our research methods and research ideas can also provide scientific reference for the prediction of electric energy production elsewhere.

13.
JAMA Netw Open ; 5(11): e2242343, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36409497

RESUMO

Importance: With a shortfall in fellowship-trained breast radiologists, mammography screening programs are looking toward artificial intelligence (AI) to increase efficiency and diagnostic accuracy. External validation studies provide an initial assessment of how promising AI algorithms perform in different practice settings. Objective: To externally validate an ensemble deep-learning model using data from a high-volume, distributed screening program of an academic health system with a diverse patient population. Design, Setting, and Participants: In this diagnostic study, an ensemble learning method, which reweights outputs of the 11 highest-performing individual AI models from the Digital Mammography Dialogue on Reverse Engineering Assessment and Methods (DREAM) Mammography Challenge, was used to predict the cancer status of an individual using a standard set of screening mammography images. This study was conducted using retrospective patient data collected between 2010 and 2020 from women aged 40 years and older who underwent a routine breast screening examination and participated in the Athena Breast Health Network at the University of California, Los Angeles (UCLA). Main Outcomes and Measures: Performance of the challenge ensemble method (CEM) and the CEM combined with radiologist assessment (CEM+R) were compared with diagnosed ductal carcinoma in situ and invasive cancers within a year of the screening examination using performance metrics, such as sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). Results: Evaluated on 37 317 examinations from 26 817 women (mean [SD] age, 58.4 [11.5] years), individual model AUROC estimates ranged from 0.77 (95% CI, 0.75-0.79) to 0.83 (95% CI, 0.81-0.85). The CEM model achieved an AUROC of 0.85 (95% CI, 0.84-0.87) in the UCLA cohort, lower than the performance achieved in the Kaiser Permanente Washington (AUROC, 0.90) and Karolinska Institute (AUROC, 0.92) cohorts. The CEM+R model achieved a sensitivity (0.813 [95% CI, 0.781-0.843] vs 0.826 [95% CI, 0.795-0.856]; P = .20) and specificity (0.925 [95% CI, 0.916-0.934] vs 0.930 [95% CI, 0.929-0.932]; P = .18) similar to the radiologist performance. The CEM+R model had significantly lower sensitivity (0.596 [95% CI, 0.466-0.717] vs 0.850 [95% CI, 0.766-0.923]; P < .001) and specificity (0.803 [95% CI, 0.734-0.861] vs 0.945 [95% CI, 0.936-0.954]; P < .001) than the radiologist in women with a prior history of breast cancer and Hispanic women (0.894 [95% CI, 0.873-0.910] vs 0.926 [95% CI, 0.919-0.933]; P = .004). Conclusions and Relevance: This study found that the high performance of an ensemble deep-learning model for automated screening mammography interpretation did not generalize to a more diverse screening cohort, suggesting that the model experienced underspecification. This study suggests the need for model transparency and fine-tuning of AI models for specific target populations prior to their clinical adoption.


Assuntos
Neoplasias da Mama , Mamografia , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Inteligência Artificial , Neoplasias da Mama/diagnóstico por imagem , Estudos Retrospectivos , Detecção Precoce de Câncer
14.
Cell Death Differ ; 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396719

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has become a growing public health problem. However, the complicated pathogenesis of NAFLD contributes to the deficiency of effective clinical treatment. Here, we demonstrated that liver-specific loss of Arid2 induced hepatic steatosis and this progression could be exacerbated by HFD. Mechanistic study revealed that ARID2 repressed JAK2-STAT5-PPARγ signaling pathway by promoting the ubiquitination of JAK2, which was mediated by NEDD4L, a novel E3 ligase for JAK2. ChIP assay revealed that ARID2 recruited CARM1 to increase H3R17me2a level at the NEDD4L promoter and activated the transcription of NEDD4L. Moreover, inhibition of Jak2 by Fedratinib in liver-specific Arid2 knockout mice alleviated HFD-induced hepatic steatosis. Downregulation of ARID2 and the reverse correlation between ARID2 and JAK2 were also observed in clinical samples. Therefore, our study has revealed an important role of ARID2 in the development of NAFLD and provided a potential therapeutic strategy for NAFLD.

15.
Orthop Surg ; 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411506

RESUMO

OBJECTIVE: Although pedicle screws are widely used to reconstruct the stability of the spine, screw loosening is a common complication after spine surgery. The main objective of this study was to investigate whether the application of the hollow lateral hole structure had the potential to improve the stability of the pedicle screw by comparing the biomechanical properties of the novel lateral hole pedicle screws (LHPSs) with those of the solid pedicle screws (SPSs) in beagle dogs. METHODS: The cancellous bone of the distal femur, proximal femur, distal tibia, and proximal tibia were chosen as implantation sites in beagle dogs. In each of 12 dogs, four LHPSs, and four SPSs were implanted into both lower limbs. At 1, 2, and 3 months after surgery, four dogs were randomly sampled and sacrificed. The LHPS group and SPS group were subdivided into four subgroups according to the length of their duration of implantation (0, 1, 2, 3 months). The biomechanical properties of both pedicle screws were evaluated by pull-out and the cyclic bending tests. RESULTS: The results of the study showed that no significant difference was found between LHPSs (276.62 ± 50.11 N) and SPSs (282.47 ± 42.98 N) in pull-out tests at time 0 (P > 0.05). At the same time point after implantations, LHPSs exhibited significantly higher maximal pullout strength than SPSs (month 1: 360.51 ± 25.63 vs 325.87 ± 28.11 N; month 2: 416.59 ± 23.78 vs 362.12 ± 29.27 N; month 3: 447.05 ± 38.26 vs 376.63 ± 32.36 N) (P < 0.05). Moreover, compared with SPSs, LHPSs withstood more loading cycles (month 2: 592 ± 21 vs 534 ± 48 times; month 3: 596 ± 10 vs 543 ± 59 times), and exhibiting less displacement before loosening at month 2 (1.70 ± 0.17 vs 1.96 ± 0.10 mm) and 3 (1.69 ± 0.19 vs 1.92 ± 0.14 mm) (P < 0.05), but no significant difference in time 0 and month 1 (P > 0.05). CONCLUSIONS: The pedicle screw with the hollow lateral hole structure could allow bone to grow into the inner architecture, which improved biomechanical properties by extending the contact area between screw and bone tissue after implantation into the cancellous bone. It indicated that LHPS could reduce loosening of the pedicle screws in long term after surgery.

16.
Artigo em Inglês | MEDLINE | ID: mdl-36429355

RESUMO

Heavy metal contamination in agricultural soils has attracted increasing attention in recent years. In this study, 1999 agricultural soil samples were collected from 11 cities in Zhejiang Province from 2016 to 2020, and the spatial and temporal variation characteristics of 3 of the most important heavy metals, i.e., lead (Pb), cadmium (Cd), and chromium (Cr) were analyzed. The results showed that Cd had a slightly higher sample over-standard rate of 12.06%. Spatial distribution and temporal trends showed that the Pb concentrations overall increased from 2016 to 2020 and mainly accumulated in southern Zhejiang. In addition, multiple exposure routes were evaluated for human health risks. Children are more susceptible to the adverse effects of heavy metals in agricultural soils, and oral ingestion was the major exposure route. Cr poses higher human health risks to humans than Pb and Cd in agricultural soils. Therefore, more rigid environmental monitoring and related soil remediation counter-measures for some sites with high concentrations of heavy metals are necessary to limit the potential threat to human health.


Assuntos
Metais Pesados , Poluentes do Solo , Criança , Humanos , Solo , Poluentes do Solo/análise , Cádmio , Chumbo , Metais Pesados/análise , Medição de Risco , Cromo
17.
Sci China Life Sci ; 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36271982

RESUMO

DNMT1 is a DNA methyltransferase that catalyzes and maintains methylation in CpG dinucleotides. It blocks the entrance of DNA into the catalytic pocket via the replication foci targeting sequence (RFTS) domain. Recent studies have shown that an H3-tail-conjugated two-mono-ubiquitin mark (H3Ub2) activates DNMT1 by binding to the RFTS domain. However, the activation mechanism of DNMT1 remains unclear. In this work, we combine various sampling methods of extensive simulations, including conventional molecular dynamics, Gaussian-accelerated molecular dynamics, and coarse-grained molecular dynamics, to elucidate the activation mechanism of DNMT1. Geometric and energy analyses show that binding of H3Ub2 to the RFTS domain of DNMT1 results in the bending of the α4-helix in the RFTS domain at approximately 30°-35°, and the RFTS domain rotates ∼20° anti-clockwise and moves ∼3 Å away from the target recognition domain (TRD). The hydrogen-bonding network at the RFTS-TRD interface is significantly disrupted, implying that the RFTS domain is dissociated from the catalytic core, which contributes to activating the auto-inhibited conformation of DNMT1. These results provide structural and dynamic evidence for the role of H3Ub2 in regulating the catalytic activity of DNMT1.

18.
Front Cell Dev Biol ; 10: 959518, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36247016

RESUMO

Cryptotanshinone (CT), a natural compound derived from Salvia miltiorrhiza Bunge that is also known as the traditional Chinese medicine Danshen, exhibits antitumor activity in various cancers. However, it remains unclear whether CT has a potential therapeutic benefit against ovarian cancers. The aim of this study was to test the efficacy of CT in ovarian cancer cells in vitro and using a xenograft model in NSG mice orthotopically implanted with HEY A8 human ovarian cancer cells and to explore the molecular mechanism(s) underlying CT's antitumor effects. We found that CT inhibited the proliferation, migration, and invasion of OVCAR3 and HEY A8 cells, while sensitizing the cell responses to the chemotherapy drugs paclitaxel and cisplatin. CT also suppressed ovarian tumor growth and metastasis in immunocompromised mice orthotopically inoculated with HEY A8 cells. Mechanistically, CT degraded the protein encoded by the oncogene c-Myc by promoting its ubiquitination and disrupting the interaction with its partner protein Max. CT also attenuated signaling via the nuclear focal adhesion kinase (FAK) pathway and degraded FAK protein in both cell lines. Knockdown of c-Myc using lentiviral CRISPR/Cas9 nickase resulted in reduction of FAK expression, which phenocopies the effects of CT and the c-Myc/Max inhibitor 10058-F4. Taken together, our studies demonstrate that CT inhibits primary ovarian tumor growth and metastasis by degrading c-Myc and FAK and attenuating the FAK signaling pathway.

19.
Inorg Chem ; 61(42): 16805-16813, 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36223409

RESUMO

Developing non-noble metal-based core-shell heterojunction electrocatalysts with high catalytic activity and long-lasting stability is crucial for the oxygen evolution reaction (OER). Here, we prepared novel core-shell Fe,V-NiSe2@NiFe(OH)x heterostructured nanoparticles on hydrophilic-treated carbon paper with high electronic transport and large surface area for accelerating the oxygen evolution rate via high-temperature selenization and electrochemical anodic oxidation procedures. Performance testing shows that Fe,V-NiSe2@NiFe(OH)x possesses the highest performance for OER compared to as-prepared diselenide core-derived heterojunctions, which only require an overpotential of 243 mV at 10 mA cm-2 and a low Tafel slope of 91.6 mV decade-1 under basic conditions. Furthermore, X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) confirm the morphology and elementary stabilities of Fe,V-NiSe2@NiFe(OH)x after long-term chronopotentiometric testing. These advantages are largely because of the strong synergistic effect between the Fe,V-NiSe2 core with high conductivity and the amorphous NiFe(OH)x shell with enriched defects and vacancies. This study also presents a general approach to designing and synthesizing more active core-shell heterojunction electrocatalysts for OER.

20.
Anat Rec (Hoboken) ; 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36300612

RESUMO

Acupuncture plays a vital anti-inflammatory action in sepsis by activating autonomic nerve anti-inflammatory pathways, such as sympathoadrenal medullary pathway, but the mechanism remains unclear. This study aims to explore the optimum parameter of electroacupuncture (EA) stimulation in regulating the sympathoadrenal medullary pathway and evaluate EA's anti-inflammatory effect on sepsis. To determine the optimum parameter of EA at homotopic acupoint on adrenal sympathetic activity, the left adrenal sympathetic nerve firing rate evoked by different intensities of single shock electrical stimulation (ES) at ST25 in healthy male Sprague-Dawley rats were evaluated by in vivo electrophysiological recording, and the levels of norepinephrine (NE) and its metabolites normetanephrine (NMN) were also examined using mass spectrometry. To verify the role of EA at ST25 in sepsis, the rats were given an intraperitoneal injection of lipopolysaccharide (LPS) to induce sepsis model, and survival rate, clinical score, and the level of interleukin (IL)-6, IL-1ß, and IL-10 were evaluated after EA application. We observed that 3 mA is the optimal intensity for activating adrenal sympathetic nerve, which significantly elevated the level of NE in the peripheral blood. For LPS-treated rats, EA at the ST25 apparently increased the survival rate and improved the clinical score compared to the control group. Furthermore, 3 mA EA at ST25 significantly decreased pro-inflammatory cytokines IL-6 and IL-1ß and upregulated anti-inflammatory cytokine IL-10 compared to the LPS-treated group. Overall, our data suggested that 3 mA is the optimal EA intensity at ST25 to activate the sympathoadrenal medullary pathway and exert an anti-inflammatory effect in sepsis.

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