Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor b...Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor biology and immune responses;however,its specific roles in HCC progression and macrophage-mediated regulation remain unclear.This study aimed to elucidate the biological functions of DNASE1L3 in HCC and to determine how it modulates tumor behavior and immune interactions.Methods:Bioinformatics analyses of the GSE41804 and Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC)datasets were used to identify hub genes.Functional assays assessed the impact of DNASE1L3 on HCC cell proliferation,migration,invasion,and cell cycle progression.The effects of DNASE1L3 on macrophage polarization and the Wnt/β-catenin signaling pathway were examined using a co-culture system.An HCC organoid model was established to further validate its regulatory function.Results:Eight prognostic signature genes were identified,with deoxyribonuclease I-like 3(DNase I-like 3)selected as the hub gene.DNASE1L3 overexpression suppressed HCC cell growth,inhibited migration and invasion,induced G1 arrest,and modulated epithelial-mesenchymal transition(EMT)markers.DNASE1L3 knockdown promoted M2-like macrophage polarization.Mechanistically,DNASE1L3 interacted withβ-catenin to enhance its ubiquitination and degradation,thereby inhibiting Wnt/β-catenin signaling and reducing PD-L1 expression.DNASE1L3 overexpression similarly restricted organoid growth and suppressed pathway activity.Conclusion:DNASE1L3 acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression,thereby influencing both tumor cell behavior and macrophage-mediated immune responses.展开更多
As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HI...As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.展开更多
Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase...Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.展开更多
目的探讨抗逆转录病毒治疗(antiretroviral treatment,ART)对HIV-1感染者(people living with HIV-1,PLWH)CD3^(+)T细胞PD-1和CD160表达及其活化凋亡水平的影响。方法收集66例慢性HIV-1感染患者,根据是否接受ART治疗,将PLWH分为non-ART...目的探讨抗逆转录病毒治疗(antiretroviral treatment,ART)对HIV-1感染者(people living with HIV-1,PLWH)CD3^(+)T细胞PD-1和CD160表达及其活化凋亡水平的影响。方法收集66例慢性HIV-1感染患者,根据是否接受ART治疗,将PLWH分为non-ART组(39例)和ART组(27例),并设置HIV-1阴性对照组(30例)。采用流式细胞术检测3组外周血CD4计数及CD3^(+)T细胞中PD-1、CD160、CD95、CD38和HLA-DR的表达,并分析3组间不同指标的差异性。结果non-ART组CD3^(+)T细胞百分比和PD-1^(+)T细胞百分比与ART组相比差异无统计学意义(P=0.8141,P>0.9999),而其CD160^(+)CD3^(+)T细胞百分比显著高于ART组(P=0.0162)。共表达分析显示,non-ART组PD-1^(+)CD160^(+)CD3^(+)T细胞百分比显著高于ART组(P=0.0121),而在单阳的CD3^(+)T性细胞(CD160^(+)PD-1^(-)和PD-1^(+)CD160-)细胞群,ART组和non-ART组差异均无统计学意义(P=0.3382,P>0.9999)。在PD-1^(+)CD160^(+)CD3^(+)T细胞CD38方面,non-ART组显著高于ART组和HIV-1阴性对照组(P=0.0005,P=0.0015),HIV-1阴性对照组和ART组差异无统计学意义(P>0.9999)。结论ART对PLWH中PD-1^(+)CD160^(+)CD3^(+)T细胞百分比及其CD38的表达具有调节作用。展开更多
Aim To investigate the effects of FDP on different liver injury models to explore the possibility of FDP used as an oral liver protective agent. Methods Chronic liver injury model in rats was induced by carbon tetrach...Aim To investigate the effects of FDP on different liver injury models to explore the possibility of FDP used as an oral liver protective agent. Methods Chronic liver injury model in rats was induced by carbon tetrachloride （ CCl4 ） ; Acute liver injury model in mice was induced by aminogalactose （GAIN） or lipopolysaccharide （LPS）. Results In CCl4-induced chronic liver injury model, FDP （1 , 4 g·kg^-1·d^-1, q.d., for 10 weeks） significantly lowered ALT, AST,γ-glutamyl transpeptidase （γ-GT）, alkaline phosphatase （ALP）, and total bilirubin （T-BIL） in serum compared with vehicle; simultaneously it evidently elevated abnormal total protein （TP）, albumin （ALB） and total cholesterol （ T-CHO ） levels in serum; it also dose-dependently reduced hydroxyproline contents in hepatic tissue. 4 g·kg^-1·d^-1 of FDP apparently decreased incidence of hepatic cirrhosis, and alleviated pathological changes of liver tissue. In GaiN-induced model, 1.0 - 4. 0 g·kg^-1·d^-1 of FDP （ bid, for 3 d ） significantly lowered alanine aminotransferase （ ALT ） and aspartate aminotransferase （ AST ） levels in serum ; it also decreased liver coefficient. 4. 0 g·kg^-1·d^-1 of FDP significantly alleviated pathological changes of cell ultra-structures. In LPS-induced model, only high dose of FDP （4. 0 g·kg^-1·d^-1, bid, for 12 d） significantly decreased ALT level in serum. Conclusion This study first demonstrated the protective effect of oral FDP on chronic liver injury caused by CCl4, and confirmed its effect on acute liver injury at the same time, suggesting that Long-term oral FDP is efficacious against liver injury induced by different factors and can be used as an oral liver protective agent in clinic.展开更多
The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disr...The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.展开更多
We study the localized coherent structures ofa generally nonintegrable (2+ 1 )-dimensional KdV equation via a variable separation approach. In a special integrable case, the entrance of some arbitrary functions leads ...We study the localized coherent structures ofa generally nonintegrable (2+ 1 )-dimensional KdV equation via a variable separation approach. In a special integrable case, the entrance of some arbitrary functions leads to abundant coherent structures. However, in the general nonintegrable case, an additional condition has to be introduced for these arbitrary functions. Although the additional condition has been introduced into the solutions of the nonintegrable KdV equation, there still exist many interesting solitary wave structures. Especially, the nonintegrable KdV equation possesses the breather-like localized excitations, and the similar static ring soliton solutions as in the integrable case. Furthermor,in the integrable case, the interaction between two travelling ring solitons is elastic, while in the nonintegrable case we cannot find even the single travelling ring soliton solution.展开更多
Measurements from geomagnetic satellites continue to underpin advances in geomagnetic field models that describe Earth's internally generated magnetic field.Here,we present a new field model,MSCM,that integrates v...Measurements from geomagnetic satellites continue to underpin advances in geomagnetic field models that describe Earth's internally generated magnetic field.Here,we present a new field model,MSCM,that integrates vector and scalar data from the Swarm,China Seismo-Electromagnetic Satellite(CSES),and Macao Science Satellite-1(MSS-1)missions.The model spans from 2014.0 to 2024.5,incorporating the core,lithospheric,and magnetospheric fields,and it shows characteristics similar to other published models based on different data.For the first time,we demonstrate that it is possible to successfully construct a geomagnetic field model that incorporates CSES vector data,albeit one in which the radial and azimuthal CSES vector components are Huber downweighted.We further show that data from the MSS-1 can be integrated within an explicitly smoothed,fully time-dependent model description.Using the MSCM,we identify new behavior of the South Atlantic Anomaly,the broad region of low magnetic field intensity over the southern Atlantic.This prominent feature appears split into a western part and an eastern part,each with its own intensity minimum.Since 2015,the principal western minimum has undergone only modest intensity decreases of 290 nT and westward motion of 20 km per year,whereas the recently formed eastern minimum has shown a 2–3 times greater intensity drop of 730 nT with no apparent east-west motion.展开更多
基金funded by Shanghai Science and Technology Innovation Action Plan Project(22140901100)Shanghai Key Laboratory of Molecular Imaging(18DZ2260400)Shanghai University of Medicine and Health Science Seed Fund(SSF-24-21-01).
文摘Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor biology and immune responses;however,its specific roles in HCC progression and macrophage-mediated regulation remain unclear.This study aimed to elucidate the biological functions of DNASE1L3 in HCC and to determine how it modulates tumor behavior and immune interactions.Methods:Bioinformatics analyses of the GSE41804 and Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC)datasets were used to identify hub genes.Functional assays assessed the impact of DNASE1L3 on HCC cell proliferation,migration,invasion,and cell cycle progression.The effects of DNASE1L3 on macrophage polarization and the Wnt/β-catenin signaling pathway were examined using a co-culture system.An HCC organoid model was established to further validate its regulatory function.Results:Eight prognostic signature genes were identified,with deoxyribonuclease I-like 3(DNase I-like 3)selected as the hub gene.DNASE1L3 overexpression suppressed HCC cell growth,inhibited migration and invasion,induced G1 arrest,and modulated epithelial-mesenchymal transition(EMT)markers.DNASE1L3 knockdown promoted M2-like macrophage polarization.Mechanistically,DNASE1L3 interacted withβ-catenin to enhance its ubiquitination and degradation,thereby inhibiting Wnt/β-catenin signaling and reducing PD-L1 expression.DNASE1L3 overexpression similarly restricted organoid growth and suppressed pathway activity.Conclusion:DNASE1L3 acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression,thereby influencing both tumor cell behavior and macrophage-mediated immune responses.
基金supported by the Natural Science Foundation of Zhejiang Province (Y. 4090578)
文摘As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.
文摘Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.
文摘目的探讨抗逆转录病毒治疗(antiretroviral treatment,ART)对HIV-1感染者(people living with HIV-1,PLWH)CD3^(+)T细胞PD-1和CD160表达及其活化凋亡水平的影响。方法收集66例慢性HIV-1感染患者,根据是否接受ART治疗,将PLWH分为non-ART组(39例)和ART组(27例),并设置HIV-1阴性对照组(30例)。采用流式细胞术检测3组外周血CD4计数及CD3^(+)T细胞中PD-1、CD160、CD95、CD38和HLA-DR的表达,并分析3组间不同指标的差异性。结果non-ART组CD3^(+)T细胞百分比和PD-1^(+)T细胞百分比与ART组相比差异无统计学意义(P=0.8141,P>0.9999),而其CD160^(+)CD3^(+)T细胞百分比显著高于ART组(P=0.0162)。共表达分析显示,non-ART组PD-1^(+)CD160^(+)CD3^(+)T细胞百分比显著高于ART组(P=0.0121),而在单阳的CD3^(+)T性细胞(CD160^(+)PD-1^(-)和PD-1^(+)CD160-)细胞群,ART组和non-ART组差异均无统计学意义(P=0.3382,P>0.9999)。在PD-1^(+)CD160^(+)CD3^(+)T细胞CD38方面,non-ART组显著高于ART组和HIV-1阴性对照组(P=0.0005,P=0.0015),HIV-1阴性对照组和ART组差异无统计学意义(P>0.9999)。结论ART对PLWH中PD-1^(+)CD160^(+)CD3^(+)T细胞百分比及其CD38的表达具有调节作用。
文摘Aim To investigate the effects of FDP on different liver injury models to explore the possibility of FDP used as an oral liver protective agent. Methods Chronic liver injury model in rats was induced by carbon tetrachloride （ CCl4 ） ; Acute liver injury model in mice was induced by aminogalactose （GAIN） or lipopolysaccharide （LPS）. Results In CCl4-induced chronic liver injury model, FDP （1 , 4 g·kg^-1·d^-1, q.d., for 10 weeks） significantly lowered ALT, AST,γ-glutamyl transpeptidase （γ-GT）, alkaline phosphatase （ALP）, and total bilirubin （T-BIL） in serum compared with vehicle; simultaneously it evidently elevated abnormal total protein （TP）, albumin （ALB） and total cholesterol （ T-CHO ） levels in serum; it also dose-dependently reduced hydroxyproline contents in hepatic tissue. 4 g·kg^-1·d^-1 of FDP apparently decreased incidence of hepatic cirrhosis, and alleviated pathological changes of liver tissue. In GaiN-induced model, 1.0 - 4. 0 g·kg^-1·d^-1 of FDP （ bid, for 3 d ） significantly lowered alanine aminotransferase （ ALT ） and aspartate aminotransferase （ AST ） levels in serum ; it also decreased liver coefficient. 4. 0 g·kg^-1·d^-1 of FDP significantly alleviated pathological changes of cell ultra-structures. In LPS-induced model, only high dose of FDP （4. 0 g·kg^-1·d^-1, bid, for 12 d） significantly decreased ALT level in serum. Conclusion This study first demonstrated the protective effect of oral FDP on chronic liver injury caused by CCl4, and confirmed its effect on acute liver injury at the same time, suggesting that Long-term oral FDP is efficacious against liver injury induced by different factors and can be used as an oral liver protective agent in clinic.
基金supported by the National Natural Science Foundation of China (No. 30472166)the Tianjin Commission of Science and Technology (06YFGZSH07000)
文摘The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.
文摘We study the localized coherent structures ofa generally nonintegrable (2+ 1 )-dimensional KdV equation via a variable separation approach. In a special integrable case, the entrance of some arbitrary functions leads to abundant coherent structures. However, in the general nonintegrable case, an additional condition has to be introduced for these arbitrary functions. Although the additional condition has been introduced into the solutions of the nonintegrable KdV equation, there still exist many interesting solitary wave structures. Especially, the nonintegrable KdV equation possesses the breather-like localized excitations, and the similar static ring soliton solutions as in the integrable case. Furthermor,in the integrable case, the interaction between two travelling ring solitons is elastic, while in the nonintegrable case we cannot find even the single travelling ring soliton solution.
基金supported by the National Natural Science Foundation of China(Grant No.42274003)PWL was supported by Swarm DISC(Swarm Data,Innovation,and Science Cluster)+2 种基金funded by the European Space Agency(ESAContract No.4000109587)HFR acknowledges funding from the UK Natural Environment Research Council(Grant No.NE/V010867/1)。
文摘Measurements from geomagnetic satellites continue to underpin advances in geomagnetic field models that describe Earth's internally generated magnetic field.Here,we present a new field model,MSCM,that integrates vector and scalar data from the Swarm,China Seismo-Electromagnetic Satellite(CSES),and Macao Science Satellite-1(MSS-1)missions.The model spans from 2014.0 to 2024.5,incorporating the core,lithospheric,and magnetospheric fields,and it shows characteristics similar to other published models based on different data.For the first time,we demonstrate that it is possible to successfully construct a geomagnetic field model that incorporates CSES vector data,albeit one in which the radial and azimuthal CSES vector components are Huber downweighted.We further show that data from the MSS-1 can be integrated within an explicitly smoothed,fully time-dependent model description.Using the MSCM,we identify new behavior of the South Atlantic Anomaly,the broad region of low magnetic field intensity over the southern Atlantic.This prominent feature appears split into a western part and an eastern part,each with its own intensity minimum.Since 2015,the principal western minimum has undergone only modest intensity decreases of 290 nT and westward motion of 20 km per year,whereas the recently formed eastern minimum has shown a 2–3 times greater intensity drop of 730 nT with no apparent east-west motion.
