Objective INF2 is a member of the formins family.Abnormal expression and regulation of INF2 have been associated with the progression of various tumors,but the expression and role of INF2 in hepatocellular carcinoma(H...Objective INF2 is a member of the formins family.Abnormal expression and regulation of INF2 have been associated with the progression of various tumors,but the expression and role of INF2 in hepatocellular carcinoma(HCC)remain unclear.HCC is a highly lethal malignant tumor.Given the limitations of traditional treatments,this study explored the expression level,clinical value and potential mechanism of INF2 in HCC in order to seek new therapeutic targets.Methods In this study,we used public databases to analyze the expression of INF2 in pan-cancer and HCC,as well as the impact of INF2 expression levels on HCC prognosis.Quantitative real time polymerase chain reaction(RT-qPCR),Western blot,and immunohistochemistry were used to detect the expression level of INF2 in liver cancer cells and human HCC tissues.The correlation between INF2 expression and clinical pathological features was analyzed using public databases and clinical data of human HCC samples.Subsequently,the effects of INF2 expression on the biological function and Drp1 phosphorylation of liver cancer cells were elucidated through in vitro and in vivo experiments.Finally,the predictive value and potential mechanism of INF2 in HCC were further analyzed through database and immunohistochemical experiments.Results INF2 is aberrantly high expression in HCC samples and the high expression of INF2 is correlated with overall survival,liver cirrhosis and pathological differentiation of HCC patients.The expression level of INF2 has certain diagnostic value in predicting the prognosis and pathological differentiation of HCC.In vivo and in vitro HCC models,upregulated expression of INF2 triggers the proliferation and migration of the HCC cell,while knockdown of INF2 could counteract this effect.INF2 in liver cancer cells may affect mitochondrial division by inducing Drp1 phosphorylation and mediate immune escape by up-regulating PD-L1 expression,thus promoting tumor progression.Conclusion INF2 is highly expressed in HCC and is associated with poor prognosis.High expression of INF2 may promote HCC progression by inducing Drp1 phosphorylation and up-regulation of PD-L1 expression,and targeting INF2 may be beneficial for HCC patients with high expression of INF2.展开更多
A bearing fault diagnosis method based on the Markov transitionfield(MTF)and SEnet(SE)-IShufflenetV2 model is proposed in this paper due to the problems of complex working conditions,low fault diagnosis accuracy,and poo...A bearing fault diagnosis method based on the Markov transitionfield(MTF)and SEnet(SE)-IShufflenetV2 model is proposed in this paper due to the problems of complex working conditions,low fault diagnosis accuracy,and poor generalization of rolling bearing.Firstly,MTF is used to encode one-dimensional time series vibration sig-nals and convert them into time-dependent and unique two-dimensional feature images.Then,the generated two-dimensional dataset is fed into the SE-IShufflenetV2 model for training to achieve fault feature extraction and classification.This paper selects the bearing fault datasets from Case Western Reserve University and Paderborn University to experimentally verify the effectiveness and superiority of the proposed method.The generalization performance of the proposed method is tested under the variable load condition and different signal-to-noise ratios(SNRs).The experimental results show that the average accuracy of the proposed method under different working conditions is 99.2%without adding noise.The accuracy under different working conditions from 0 to 1 HP is 100%.When the SNR is 0 dB,the average accuracy of the proposed method can still reach 98.7%under varying working conditions.Therefore,the bearing fault diagnosis method proposed in this paper is characterized by high accuracy,strong anti-noise ability,and generalization.Moreover,the proposed method can also overcome the influence of variable working conditions on diagnosis accuracy,providing method support for the accurate diagnosis of bearing faults under strong noise and variable working conditions.展开更多
BACKGROUND At present,the existing internal medicine drug treatment can alleviate the high glucose toxicity of patients to a certain extent,to explore the efficacy of laparoscopic jejunoileal side to side anastomosis ...BACKGROUND At present,the existing internal medicine drug treatment can alleviate the high glucose toxicity of patients to a certain extent,to explore the efficacy of laparoscopic jejunoileal side to side anastomosis in the treatment of type 2 diabetes,the report is as follows.AIM To investigate the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes mellitus(T2DM).METHODS We retrospectively analyzed the clinical data of 78 patients with T2DM who were treated via jejunoileal lateral anastomosis.Metabolic indicators were collected preoperatively,as well as at 3 and 6 months postoperative.The metabolic indicators analyzed included body mass index(BMI),systolic blood pressure(SBP),diastolic blood pressure(DBP),fasting blood glucose(FBG),2-hour blood glucose(PBG),glycated hemoglobin(HbA1c),fasting C-peptide,2-hour C-peptide(PCP),fasting insulin(Fins),2-hour insulin(Pins),insulin resistance index(HOMA-IR),βCellular function index(HOMA-β),alanine aminotransferase,aspartate aminotransferase,serum total cholesterol(TC),low-density lipoprotein cholesterol(L DL-C),triglycerides(TG),high-density lipoprotein,and uric acid(UA)levels.RESULTS SBP,DBP,PBG,HbA1c,LDL-C,and TG were all significantly lower 3 months postoperative vs preoperative values;body weight,BMI,SBP,DBP,FBG,PBG,HbA1c,TC,TG,UA,and HOMA-IR values were all significantly lower 6 months postoperative vs at 3 months;and PCP,Fins,Pins,and HOMA-βwere all significantly higher 6 months postoperative vs at 3 months(all P<0.05).CONCLUSION Side-to-side anastomosis of the jejunum and ileum can effectively treat T2DM and improve the metabolic index levels associated with it.展开更多
The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findin...The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.展开更多
The chloride penetration resistance of cement-based grout materials was improved by nano-silica emulsion.Specimens of mixtures containing different nano-silica particles or emulsions were exposed in sodium chloride so...The chloride penetration resistance of cement-based grout materials was improved by nano-silica emulsion.Specimens of mixtures containing different nano-silica particles or emulsions were exposed in sodium chloride solutions of specific concentrations with different test ages.Hardened properties of the mixes were assessed in terms of weight loss and compressive strength.X-ray diffraction(XRD)and scanning electron microscopy(SEM)of mixes were performed to analysis the phase evolution and microstructure.The results demonstrated that the introduction of nano-SiO_(2) emulsion significantly decreased the compressive strength loss and calcium hydroxide(CH)crystal content of hydration production,and then enhanced the resistance of cement-based grouting materials to chloride ion penetration.This improvement derives from the filling and pozzolanic effects of nano-SiO_(2) particles,which were incorporated via an emulsion and attributed to a well dispersion in grouting matrix.展开更多
A series of multi-hydroxyl bis-(quaternary ammonium)ionic liquids(Ils1‒7)was prepared as bifunctional catalysts for the chemical fixation of CO_(2).All these ionic liquid compounds were efficient for the catalytic syn...A series of multi-hydroxyl bis-(quaternary ammonium)ionic liquids(Ils1‒7)was prepared as bifunctional catalysts for the chemical fixation of CO_(2).All these ionic liquid compounds were efficient for the catalytic synthesis of cyclic carbonates and oxazolidinones via the cycloaddition reactions between CO_(2) and epoxides or aziridines with excellent yield and high selectivity in the absence of co-catalyst,metal and solvent.Due to the synergistic effects of hydroxyl groups and halogen anion,the cycloaddition reactions proceeded smoothly either at atmospheric pressure or room temperature.The selectivity for substituted oxazolidinones at 5-and 4-positions can be tuned via changing the reaction conditions.Finally,possible mechanisms including the activation of both CO_(2) and epoxide or aziridines were proposed based on the literatures and experimental results.展开更多
The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain functio...The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.展开更多
Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autoph...Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.展开更多
AIM:To explore the neuroprotective effects of high mobility group box 2(HMGB2)knockdown on retinal ganglion cells(RGCs)in the retinal ischemia-reperfusion injury(RIRI).METHODS:Oxygen-glucose deprivation(OGD)-injured R...AIM:To explore the neuroprotective effects of high mobility group box 2(HMGB2)knockdown on retinal ganglion cells(RGCs)in the retinal ischemia-reperfusion injury(RIRI).METHODS:Oxygen-glucose deprivation(OGD)-injured RGCs from postnatal three-day C57BL/6 mice pups and high intraocular pressure(IOP)-induced RIRI mice were used as cellular and animal models of RIRI.The expression of HMGB2 in the retina of RIRI mice and OGD-injured RGCs was detected through reverse transcription-polymerase chain reaction(RT-qPCR)and Western blotting.The effects of HMGB2 silencing on the morphological changes,RGCs survival,and cell apoptosis in mouse retinal tissues were observed through H&E staining,immunofluorescence staining with RNA-binding protein with multiple splicing(RBPMS)antibody,and TUNEL staining,respectively.RGC viability and apoptosis were examined by CCK-8 and flow cytometry assays.The levels of proteins associated with NOD-like receptor thermal protein domain associated protein 3(NLRP3)-mediated pyroptosis[NLRP3,Caspase-1,GSDMD-N,interleukin(IL)-1β,IL-18]in vivo and in vitro were measured by Western blotting.RESULTS:HMGB2 protein and NLRP3 were upregulated in the retina of RIRI mice and OGD-injured RGCs(P<0.001).The retina was edematous,accompanied by disorganized cell arrangement and decreased thickness of all layers,and obvious vacuoles in ganglion cell layer.HMGB2 silencing alleviated the reduction in total retinal thickness and the severity of retinal tissue damage as well as suppressed RGC loss and retinal cell apoptosis in RIRI mice.OGD-induced RGC apoptosis was ameliorated after downregulation of HMGB2 in vitro.Intravitreal injection of the AAV-sh-HMGB2 and si-HMGB2 resulted in significantly decrease of NLRP3,Caspase-1,GSDMD-N,IL-1β,and IL-18 protein levels in the retinal tissues of RIRI mice and OGD-injured RGCs,respectively(all P<0.001).CONCLUSION:HMGB2 knockdown protects against RGC apoptosis and pyroptosis after RIRI through suppressing NLRP3 inflammasome activation.展开更多
Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Her...Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.展开更多
An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease prog...An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.展开更多
文摘Objective INF2 is a member of the formins family.Abnormal expression and regulation of INF2 have been associated with the progression of various tumors,but the expression and role of INF2 in hepatocellular carcinoma(HCC)remain unclear.HCC is a highly lethal malignant tumor.Given the limitations of traditional treatments,this study explored the expression level,clinical value and potential mechanism of INF2 in HCC in order to seek new therapeutic targets.Methods In this study,we used public databases to analyze the expression of INF2 in pan-cancer and HCC,as well as the impact of INF2 expression levels on HCC prognosis.Quantitative real time polymerase chain reaction(RT-qPCR),Western blot,and immunohistochemistry were used to detect the expression level of INF2 in liver cancer cells and human HCC tissues.The correlation between INF2 expression and clinical pathological features was analyzed using public databases and clinical data of human HCC samples.Subsequently,the effects of INF2 expression on the biological function and Drp1 phosphorylation of liver cancer cells were elucidated through in vitro and in vivo experiments.Finally,the predictive value and potential mechanism of INF2 in HCC were further analyzed through database and immunohistochemical experiments.Results INF2 is aberrantly high expression in HCC samples and the high expression of INF2 is correlated with overall survival,liver cirrhosis and pathological differentiation of HCC patients.The expression level of INF2 has certain diagnostic value in predicting the prognosis and pathological differentiation of HCC.In vivo and in vitro HCC models,upregulated expression of INF2 triggers the proliferation and migration of the HCC cell,while knockdown of INF2 could counteract this effect.INF2 in liver cancer cells may affect mitochondrial division by inducing Drp1 phosphorylation and mediate immune escape by up-regulating PD-L1 expression,thus promoting tumor progression.Conclusion INF2 is highly expressed in HCC and is associated with poor prognosis.High expression of INF2 may promote HCC progression by inducing Drp1 phosphorylation and up-regulation of PD-L1 expression,and targeting INF2 may be beneficial for HCC patients with high expression of INF2.
基金supported by Hebei Natural Science Foundation under Grant No.E2024402079Key Laboratory of Intelligent Industrial Equipment Technology of Hebei Province(Hebei University of Engineering)under Grant No.202206.
文摘A bearing fault diagnosis method based on the Markov transitionfield(MTF)and SEnet(SE)-IShufflenetV2 model is proposed in this paper due to the problems of complex working conditions,low fault diagnosis accuracy,and poor generalization of rolling bearing.Firstly,MTF is used to encode one-dimensional time series vibration sig-nals and convert them into time-dependent and unique two-dimensional feature images.Then,the generated two-dimensional dataset is fed into the SE-IShufflenetV2 model for training to achieve fault feature extraction and classification.This paper selects the bearing fault datasets from Case Western Reserve University and Paderborn University to experimentally verify the effectiveness and superiority of the proposed method.The generalization performance of the proposed method is tested under the variable load condition and different signal-to-noise ratios(SNRs).The experimental results show that the average accuracy of the proposed method under different working conditions is 99.2%without adding noise.The accuracy under different working conditions from 0 to 1 HP is 100%.When the SNR is 0 dB,the average accuracy of the proposed method can still reach 98.7%under varying working conditions.Therefore,the bearing fault diagnosis method proposed in this paper is characterized by high accuracy,strong anti-noise ability,and generalization.Moreover,the proposed method can also overcome the influence of variable working conditions on diagnosis accuracy,providing method support for the accurate diagnosis of bearing faults under strong noise and variable working conditions.
文摘BACKGROUND At present,the existing internal medicine drug treatment can alleviate the high glucose toxicity of patients to a certain extent,to explore the efficacy of laparoscopic jejunoileal side to side anastomosis in the treatment of type 2 diabetes,the report is as follows.AIM To investigate the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes mellitus(T2DM).METHODS We retrospectively analyzed the clinical data of 78 patients with T2DM who were treated via jejunoileal lateral anastomosis.Metabolic indicators were collected preoperatively,as well as at 3 and 6 months postoperative.The metabolic indicators analyzed included body mass index(BMI),systolic blood pressure(SBP),diastolic blood pressure(DBP),fasting blood glucose(FBG),2-hour blood glucose(PBG),glycated hemoglobin(HbA1c),fasting C-peptide,2-hour C-peptide(PCP),fasting insulin(Fins),2-hour insulin(Pins),insulin resistance index(HOMA-IR),βCellular function index(HOMA-β),alanine aminotransferase,aspartate aminotransferase,serum total cholesterol(TC),low-density lipoprotein cholesterol(L DL-C),triglycerides(TG),high-density lipoprotein,and uric acid(UA)levels.RESULTS SBP,DBP,PBG,HbA1c,LDL-C,and TG were all significantly lower 3 months postoperative vs preoperative values;body weight,BMI,SBP,DBP,FBG,PBG,HbA1c,TC,TG,UA,and HOMA-IR values were all significantly lower 6 months postoperative vs at 3 months;and PCP,Fins,Pins,and HOMA-βwere all significantly higher 6 months postoperative vs at 3 months(all P<0.05).CONCLUSION Side-to-side anastomosis of the jejunum and ileum can effectively treat T2DM and improve the metabolic index levels associated with it.
文摘The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.
基金Funded by a Science and Technology Project from the Ministry of Housing and Urban-Rural Development of the People’s Republic of China(No.2019-K-047)Yangzhou Government-Yangzhou University Cooperative Platform Project for Science and Technology Innovation(No.YZ2020262)。
文摘The chloride penetration resistance of cement-based grout materials was improved by nano-silica emulsion.Specimens of mixtures containing different nano-silica particles or emulsions were exposed in sodium chloride solutions of specific concentrations with different test ages.Hardened properties of the mixes were assessed in terms of weight loss and compressive strength.X-ray diffraction(XRD)and scanning electron microscopy(SEM)of mixes were performed to analysis the phase evolution and microstructure.The results demonstrated that the introduction of nano-SiO_(2) emulsion significantly decreased the compressive strength loss and calcium hydroxide(CH)crystal content of hydration production,and then enhanced the resistance of cement-based grouting materials to chloride ion penetration.This improvement derives from the filling and pozzolanic effects of nano-SiO_(2) particles,which were incorporated via an emulsion and attributed to a well dispersion in grouting matrix.
文摘A series of multi-hydroxyl bis-(quaternary ammonium)ionic liquids(Ils1‒7)was prepared as bifunctional catalysts for the chemical fixation of CO_(2).All these ionic liquid compounds were efficient for the catalytic synthesis of cyclic carbonates and oxazolidinones via the cycloaddition reactions between CO_(2) and epoxides or aziridines with excellent yield and high selectivity in the absence of co-catalyst,metal and solvent.Due to the synergistic effects of hydroxyl groups and halogen anion,the cycloaddition reactions proceeded smoothly either at atmospheric pressure or room temperature.The selectivity for substituted oxazolidinones at 5-and 4-positions can be tuned via changing the reaction conditions.Finally,possible mechanisms including the activation of both CO_(2) and epoxide or aziridines were proposed based on the literatures and experimental results.
基金supported by the National Natural Science Foundation of China,Nos.32371070 (to JT),31761163005 (to JT),32100824 (to QX)the Shenzhen Science and Technology Program,Nos.RCBS20210609104606024 (to QX),JCY20210324101813035 (to DL)+4 种基金the Guangdong Provincial Key S&T Program,No.2018B030336001 (to JT)the Key Basic Research Program of Shenzhen Science and Technology Innovation Commission,Nos.JCYJ20200109115405930 (to JT),JCYJ20220818101615033 (to DL),JCYJ20210324115811031 (to QX),JCYJ20200109150717745 (to QX)Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases,No.ZDSYS20220304163558001 (to JT)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior,No.2023B1212060055 (to JT)the China Postdoctoral Science Foundation,No.2021M693298 (to QX)。
文摘The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.
基金the National Natural Science Foundation of China(Nos.22307009,82374155,82073997,82104376)the Sichuan Science and Technology Program(Nos.2023NSFSC1108,2024NSFTD0023)+1 种基金the Postdoctoral Research Project of Sichuan Provincethe Xinglin Scholar Research Promotion Project of Chengdu University of TCM.
文摘Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.
基金Supported by Science and Technology Research Project of Hubei Provincial Department of Education(No.B2021108).
文摘AIM:To explore the neuroprotective effects of high mobility group box 2(HMGB2)knockdown on retinal ganglion cells(RGCs)in the retinal ischemia-reperfusion injury(RIRI).METHODS:Oxygen-glucose deprivation(OGD)-injured RGCs from postnatal three-day C57BL/6 mice pups and high intraocular pressure(IOP)-induced RIRI mice were used as cellular and animal models of RIRI.The expression of HMGB2 in the retina of RIRI mice and OGD-injured RGCs was detected through reverse transcription-polymerase chain reaction(RT-qPCR)and Western blotting.The effects of HMGB2 silencing on the morphological changes,RGCs survival,and cell apoptosis in mouse retinal tissues were observed through H&E staining,immunofluorescence staining with RNA-binding protein with multiple splicing(RBPMS)antibody,and TUNEL staining,respectively.RGC viability and apoptosis were examined by CCK-8 and flow cytometry assays.The levels of proteins associated with NOD-like receptor thermal protein domain associated protein 3(NLRP3)-mediated pyroptosis[NLRP3,Caspase-1,GSDMD-N,interleukin(IL)-1β,IL-18]in vivo and in vitro were measured by Western blotting.RESULTS:HMGB2 protein and NLRP3 were upregulated in the retina of RIRI mice and OGD-injured RGCs(P<0.001).The retina was edematous,accompanied by disorganized cell arrangement and decreased thickness of all layers,and obvious vacuoles in ganglion cell layer.HMGB2 silencing alleviated the reduction in total retinal thickness and the severity of retinal tissue damage as well as suppressed RGC loss and retinal cell apoptosis in RIRI mice.OGD-induced RGC apoptosis was ameliorated after downregulation of HMGB2 in vitro.Intravitreal injection of the AAV-sh-HMGB2 and si-HMGB2 resulted in significantly decrease of NLRP3,Caspase-1,GSDMD-N,IL-1β,and IL-18 protein levels in the retinal tissues of RIRI mice and OGD-injured RGCs,respectively(all P<0.001).CONCLUSION:HMGB2 knockdown protects against RGC apoptosis and pyroptosis after RIRI through suppressing NLRP3 inflammasome activation.
基金supported by the National Key Research and Development Program of China,No.2022YFC2402701(to WC)Key International(Regional)Joint Research Program of the National Natural Science Foundation of China,No.81820108009(to SY)+5 种基金the National Natural Science Foundation of China,Nos.81970890(to WC)and 82371148(to WG)Fujian Provincial Healthcare Young and Middle-aged Backbone Talent Training Project,No.2023GGA035(to XC)Spring City Planthe High-level Talent Promotion and Training Project of Kunming,No.2022SCP001(to SY)the Natural Science Foundation of Hainan Province of China,No.824MS052(to XS)the Sixth Medical Center of Chinese PLA General Hospital Innovation Cultivation,No.CXPY202116(to LX)。
文摘Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.
基金supported by a grant from Ministry of Science,Technological Development and Innovation,Serbia,No.451-03-68/2022-14/200178(to NN)University of Defence,No.MFVMA/02/22-24(to MN)。
文摘An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.
