Soft tissue repair and regeneration present a significant clinical challenge.Soft hydrogels have emerged as a promising solution for promoting stem cell differentiation and facilitating soft tissue formation[1].Variou...Soft tissue repair and regeneration present a significant clinical challenge.Soft hydrogels have emerged as a promising solution for promoting stem cell differentiation and facilitating soft tissue formation[1].Various materials,including synthetic polymers like polydimethyl siloxane and natural polymers like proteins,have been be used as hydrogel matrix for hydrogel preparation[2,3].However,the limited biodegradability,inhomogeneous network structure,and inadequate mechanical properties of these hydrogels hinder their long-term application in complex environments in vivo.Inspired by the nanostructure of collagen fibrils,Li et al.developed a strategy for creating injectable nanofibrillar hydrogels by combining self-assembly and chemical crosslinking of nanoparticles[4].Moreover,injectable hydrogels offer advantages as implantable materials,including better defect filling and reduced risk of infection compared to prefabricated hydrogels[5].展开更多
Although the advent of antibiotics has significantly improved the quality of life of infected patients,bacterial infections continue to pose a serious threat to public health[1,2].According to a recent report,within t...Although the advent of antibiotics has significantly improved the quality of life of infected patients,bacterial infections continue to pose a serious threat to public health[1,2].According to a recent report,within the next 30 years,bacterial infections are projected to surpass cancer in terms of lethality rates,resulting in an alarming 10 million deaths annually by 2050 due to the development of bacterial resistance[3].Moreover,the formation of bacterial biofilms hampers the penetration of antibacterial agents and inhibits the host immune response,making biofilm infections extremely challenging to treat[4-7].Hence,the development of innovative antimicrobial biofilm therapeutics is imperative.展开更多
The administration of antibiotics has been the primary strategy for combating bacterial infections[1,2].However,the widespread and excessive use of antibiotics has resulted in the alarming rise of bacterial resistance...The administration of antibiotics has been the primary strategy for combating bacterial infections[1,2].However,the widespread and excessive use of antibiotics has resulted in the alarming rise of bacterial resistance,posing a significant threat to human health[3–5].Therefore,it is imperative to exploit innovative treatment strategy.展开更多
Microbubbles(MBs)are gas-filled micrometer-scale spheres that are commonly formed by the gas core encapsulated with stabilizing shells,including polymers,surfactants,proteins,or liposomes shells.Clinically,MBs were or...Microbubbles(MBs)are gas-filled micrometer-scale spheres that are commonly formed by the gas core encapsulated with stabilizing shells,including polymers,surfactants,proteins,or liposomes shells.Clinically,MBs were originally used as contrast agents for enhanced ultrasound(US)imaging and diagnostics.Nowadays,MBs were given expectations that they can be alternative platforms for drug delivery owing to their unique acoustic properties.MBs can respond to the US by cavitation effect which refers to a series of complex dynamic processes,such as oscillation,expansion,contraction,and implosion[1].Drug molecules or therapeutic agents can be associated with the MB shells by means of van-der-Waals forces,electrostatic or hydrophobic interactions,or merely by physical encapsulation[2].Therefore,strategies are emerging which take advantages of US-mediated MBs drug delivery systems,mainly focusing on sonothrombolysis,cancer therapy and central nervous system(CNS)pathologies[3].Nevertheless,several researchers have apperceived the promising potential of US-responsive MBs in antibacterial therapy.Here,we aimed to paint an overview of the latest published papers on MBs for antibacterial therapy,hoping to help understand the perspectives that the field may offer emerging generations of antibacterial agents.展开更多
AIM: To investigate the expression of programmed death (PD)-1,PD ligand 1 (PD-L1) and PD-L2 in liver tissues in the context of chronic hepatitis and hepatocellular carcinoma (HCC).METHODS: Liver biopsies and HCC speci...AIM: To investigate the expression of programmed death (PD)-1,PD ligand 1 (PD-L1) and PD-L2 in liver tissues in the context of chronic hepatitis and hepatocellular carcinoma (HCC).METHODS: Liver biopsies and HCC specimens from patients were collected and histologically examined.The expression of PD-1,PD-L1,and PD-L2 in biopsy specimens of chronic hepatitis and HCC specimens was evaluated by immunohistochemical staining.The association between the expression level of PD-1,PD-L1,and PD-L2 and clinical and pathological variables was analyzed statistically.RESULTS: Expression of PD-1 was found in liverinfiltrating lymphocytes.In contrast,PD-L1 and PD-L2 were expressed in non-parenchyma liver cells and tumor cells.The expression of PD-L1 was significantly correlated with hepatitis B virus infection (1.42 ± 1.165 vs 0.50 ± 0.756,P = 0.047) and with the stage of HCC (7.50 ± 2.121 vs 1.75 ± 1.500 vs 3.00 ± 0.001,P = 0.018).PD-1 and PD-Ls were significantly up-regulated in HCC specimens (1.40 ± 1.536 vs 5.71 ± 4.051,P = 0.000;1.05 ± 1.099 vs 4.29 ± 3.885,P = 0.004;1.80 ± 1.473 vs 3.81 ± 3.400,P = 0.020).CONCLUSION: PD-L1 may contribute to negative regulation of the immune response in chronic hepatitis B.PD-1 and PD-Ls may play a role in immune evasion of tumors.展开更多
AIM:To develop models to predict hepatitis B e antigen(HBe Ag)seroconversion in response to interferon(IFN)-αtreatment in chronic hepatitis B patients.METHODS:We enrolled 147 treatment-nave HBe Agpositive chronic h...AIM:To develop models to predict hepatitis B e antigen(HBe Ag)seroconversion in response to interferon(IFN)-αtreatment in chronic hepatitis B patients.METHODS:We enrolled 147 treatment-nave HBe Agpositive chronic hepatitis B patients in China and analyzed variables after initiating IFN-α1b treatment.Patients were tested for serum alanine aminotransferase(ALT),hepatitis B virus-DNA,hepatitis B surface antigen(HBs Ag),antibody to hepatitis B surface antigen,HBe Ag,antibody to hepatitis B e antigen(anti-HBe),and antibody to hepatitis B core antigen(anti-HBc)at baseline and 12 wk,24 wk,and 52 wk after initiating treatment.We performed univariate analysis to identify response predictors among the variables.Multivariate models to predict treatment response were constructed at baseline,12 wk,and 24 wk.RESULTS:At baseline,the 3 factors correlating most with HBe Ag seroconversion were serum ALT level>4×the upper limit of normal(ULN),HBe Ag≤500 S/CO,and anti-HBc>11.4 S/CO.At 12 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤250 S/CO,decline in HBe Ag>1 log10 S/CO,and anti-HBc>11.8 S/CO.At 24 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤5 S/CO,anti-HBc>11.4 S/CO,and decline in HBe Ag>2 log10 S/CO.Each variable was assigned a score of1,a score of 0 was given if patients did not have any of the 3 variables.The 3 factors most strongly correlating with HBe Ag seroconversion at each time point were used to build models to predict the outcome after IFN-αtreatment.When the score was 3,the response rates at the 3 time points were 57.7%,83.3%,and 84.0%,respectively.When the score was 0,the response rates were 2.9%,0.0%,and 2.1%,respectively.CONCLUSION:Models with good negative and positive predictive values were developed to calculate the probability of response to IFN-αtherapy.展开更多
Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus(HBV) worldwide. Current antiviral therapies,including interferon and nucleot(s)ide analogues,rarely cure ...Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus(HBV) worldwide. Current antiviral therapies,including interferon and nucleot(s)ide analogues,rarely cure chronic hepatitis B. Animal models are very crucial for understanding the pathogenesis of chronic hepatitis B and developing new therapeutic drugs or strategies. HBV can only infect humans and chimpanzees, with the use of chimpanzees in HBV research strongly restricted. Thus, most advances in HBV research have been gained using mouse models with HBV replication or infection or models with HBV-related hepadnaviral infection. This review summarizes the animal models currently available for the study of HBV infection.展开更多
AIM: To establish a cell model harboring replicative clinical hepatitis B virus (HBV) isolates and evaluate its application in individualized selection of anti-HBV agents for chronic hepatitis B (CHB) patients. METHOD...AIM: To establish a cell model harboring replicative clinical hepatitis B virus (HBV) isolates and evaluate its application in individualized selection of anti-HBV agents for chronic hepatitis B (CHB) patients. METHODS: The full-length HBV genomic DNA from 8 CHB patients was amplified by polymerase chain reaction (PCR). All the patients were treated with lamivudine for at least seven months and finally became resistant to lamivudine. The amplified HBV DNA fragments were inserted into pHY106 vectors by Sap Ⅰ?digestion. The recombinant plasmids containing 1.1 copies of HBV genome were transiently transfected into Huh7 cell line, and the levels of HBsAg, HBeAg and intercellular HBV replicative intermediates were determined by ELISA and Southern blot analysis, respectively, with or without lamivudine and adefovir treatment. The antiviral treatment with adefovir was administered to the patients and analyzed in parallel. RESULTS: A total of 25 independent HBV isolateswere obtained from the sera of 8 patients, each patient had at least two isolates. One isolate from each individual was selected and subcloned into pHY106 vector, including 5 isolates with YVDD mutation and 3 isolates with YIDD mutation. All recombinant plasmids harboring HBV isolates were transfected into Huh7 cells. The results indicated that HBV genome carried in HBV replicons of clinical HBV isolates could effectively replicate and express in Huh7 cells. Adefovir, but not lamivudine, inhibited HBV replication both in vitro and in vivo, and in vitro inhibition was dose-dependent. CONCLUSION: The novel method described herein enables individualized selection of anti-HBV agents in clinic and is useful in future studies of antiviral therapy for CHB.展开更多
Objective:Ascites in patients with hepatic cirrhosis is caused by cirrhosis in most cases.For most malignant ascites,the primary malignancy could be readily identified using conventional imaging methods,e.g.,computer ...Objective:Ascites in patients with hepatic cirrhosis is caused by cirrhosis in most cases.For most malignant ascites,the primary malignancy could be readily identified using conventional imaging methods,e.g.,computer tomography(CT)and magnetic resonance imaging(MRI).However,in a small fraction of the patients,the primary malignancy remains occult even with these examinations.In this retrospective study,we assessed the usefulness of18F-FDG PET/CT in patients with hepatic cirrhosis and malignant ascites of otherwise unknown origin.Methods:Twenty-eight patients with malignant ascites of unknown primary sites after CT,MRI and ultrasound during the period of five years between January 2008 and December 2012 had received18F-FDG PET/CT.Medical records of these patients were reviewed and analyzed.Results:Elevated18F-FDG absorption was found in 23 of 28 cases in the following sites:gastrointestinal tract(n=10,43.5%),prostate(n=5,21.7%),peritoneum(n=4,13.3%),and ovary(n=4,13.3%).Cancer was confirmed by pathology in 20 cases after open or laparoscopic surgeries.Five patients were found to have benign ascites,among which,3 were found to be false positive due to tuberculosis.SUV values were significantly higher for tumors than for benign lesions(mean values,6.95 vs.2.94;P=0.005).Conclusions:The18F-FDG PET/CT can be as a powerful imaging tool in identifying tissue origin in liver cirrhosis patients suspected of cancers or with cancers of unknown primary sites.展开更多
AIM: To investigate the expressions of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma (HCC) and their significance. METHODS: The expressions of PTEN, PPM1A and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues...AIM: To investigate the expressions of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma (HCC) and their significance. METHODS: The expressions of PTEN, PPM1A and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues and 13 non-tumor liver tissues were detected by using Envision immunohistochemical technique. RESULTS: The positive expression (64.52%) and staining intensity (4.19 ± 3.31) of PTEN in the cytoplasm of HCC were significantly lower and weaker than those in the adjacent or non-tumor liver tissues (97.37%, 7.88 ± 0.93; 100%, 7.77 ± 0.93, respectively) (P < 0.05), and its staining intensity in the cytoplasm of HCC, which belongs to Edmondson pathologic grades Ⅱ-Ⅲ and above, was also lower than that of gradeⅠandⅠ-Ⅱ. Furthermore, its location in the nucleus or cytoplasm of liver cells was negatively correlated with the progression of liver disease (r = -0.339, P = 0.002); most of PPM1A might be only expressed in the nucleus of adjacent liver tissues, non-HCC tissues or Edmondson gradeⅠandⅠ-Ⅱ HCC, but it was mainly expressed in the cytoplasm of HCC with Edmondson grade ≥Ⅱ, weakly or negatively expressed in the nucleus (P < 0.05), and its location was negatively correlated with the progression of liver disease (r = -0.45, P = 0.0000). P-Smad2, which was mostly located in the nucleus and cytoplasm of gradeⅠ andⅠ-Ⅱ HCC, surrounding or non-tumor liver tissues, was only in the nucleus of HCC with Edmondson grade Ⅱ and above (P < 0.001), and its location was positively correlated with the disease progression (r = 0.224, P = 0.016). Spearman correlation analysis revealed that P-Smad2 was significantly negatively correlated with PTEN and PPM1A (r = -0.748, P = 0.000; r = -0.366, P = 0.001, respectively); and PTEN and PPM1A were positively correlated with HCC carcinogenesis (r = 0.428, P = 0.000). CONCLUSION: The aberrant location of expression and staining intensity of PTEN, PPM1A and P-Smad2 in HCC and their relationship might have an impact on the pathogenesis of HCC.展开更多
AIM: To investigate the role of mi R-125 b in regulating monocyte immune responses induced by hepatitis C virus(HCV) core protein.METHODS: Monocytic THP-1 cells were treated with various concentrations of recombinant ...AIM: To investigate the role of mi R-125 b in regulating monocyte immune responses induced by hepatitis C virus(HCV) core protein.METHODS: Monocytic THP-1 cells were treated with various concentrations of recombinant HCV core protein, and cytokines and mi R-125 b expression in these cells were analyzed. The requirement of Tolllike receptor 2(TLR2) or My D88 gene for HCV core protein-induced immune responses was determined by the transfection of THP-1 cells with gene knockdown vectors expressing either TLR2 si RNA or My D88 si RNA. The effect of mi R-125 b overexpression on TLR2/My D88 signaling was examined by transfecting THP-1 cells with mi R-125 b mimic RNA oligos.RESULTS: In response to HCV core protein stimulation, cytokine production was up-regulated and mi R-125 b expression was down-regulated in THP-1 cells. The modulatory effect of HCV core protein on cellular events was dose-dependent and required functional TLR2 or My D88 gene. Forced mi R-125 b expression abolished the HCV core protein-induced enhancement of tumor necrosis factor-α, interleukin(IL)-6, and IL-10 expression by 66%, 54%, and 66%, respectively(P < 0.001), by inhibiting My D88-mediated signaling, including phosphorylation of NF-k Bp65, ERK, and P38.CONCLUSION: The inverse correlation between mi R-125 b and cytokine expression after HCV core challenge suggests that mi R-125 b may negatively regulate HCVinduced immune responses by targeting TLR2/My D88 signaling in monocytes.展开更多
AIM: To investigate the effect of human apolipoprotein B mRNA-editing enzyme catalytic-polypeptide 3G (APOBEC3G) and its N-terminal or C-terminal cytosine deaminase domain-mediated antiviral activity against hepatitis...AIM: To investigate the effect of human apolipoprotein B mRNA-editing enzyme catalytic-polypeptide 3G (APOBEC3G) and its N-terminal or C-terminal cytosine deaminase domain-mediated antiviral activity against hepatitis B virus (HBV) in vitro and in vivo. METHODS: The mammalian hepatoma cells HepG2 and HuH7 were cotransfected with APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain expression vector and 1.3-fold-overlength HBV DNA as well as the linear monomeric HBV of genotype B and C. For in vivo study, an HBV vector-based mouse model was used in which APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain expression vectors were co-delivered with 1.3-fold-overlength HBV DNA via high-volume tail vein injection. Levels of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) in the media of the transfected cells and in the sera of mice were determined by ELISA.The expression of hepatitis B virus core antigen (HBcAg) in the transfected cells was determined by Western blot analysis. Core-associated HBV DNA was examined by Southern blot analysis. Levels of HBV DNA in the sera of mice as well as HBV core-associated RNA in the liver of mice were determined by quantitative PCR and quantitative RT-PCR analysis, respectively. RESULTS: Human APOBEC3G exerted an anti-HBV activity in a dose-dependent manner in HepG2 cells, and comparable suppressive effects were observed on genotype B and C as that of genotype A. Interestingly, the N-terminal or C-terminal cytosine deaminase domain alone could also inhibit HBV replication in HepG2 cells as well as Huh7 cells. Consistent with in vitro results, the levels of HBsAg in the sera of mice were dramatically decreased, with more than 50 times decrease in the levels of serum HBV DNA and core-associated RNA in the liver of mice treated with APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain as compared to the controls. CONCLUSION: Our findings provide probably the first evidence showing that APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain could suppress HBV replication in vitro and in vivo.展开更多
Guanylate binding protein-1(GBP-1)is an interferon-induced protein.To observe its antiviral effect against Hepatitis B virus(HBV)and Coxsackie virus B3(CVB3),we constructed an eukaryotic expression vector of human GBP...Guanylate binding protein-1(GBP-1)is an interferon-induced protein.To observe its antiviral effect against Hepatitis B virus(HBV)and Coxsackie virus B3(CVB3),we constructed an eukaryotic expression vector of human GBP-1(hGBP-1).Full-length encoding sequence of hGBP-1 was amplified by long chain RT-PCR and inserted into a pCR2.1 vector,then subcloned into a pCDNA3.1(-)vector.Recombinant hGBP-1 plasmids and pHBV1.3 carrying 1.3-fold genome of HBV were contransfected into HepG2 cells,and inhibition effect of hGBP-1 against HBV replication was observed.Hela cells transfected with recombinant hGBP-1 plasmids were challenged with CVB3,and viral yield in cultures were detected.The results indicated that recombinant eukaryotic expression plasmid of hGBP-1 was constructed successfully and the hGBP-1 gene carried in this plasmid could be efficiently expressed in HepG2 cells and Hela cells.hGBP-1 inhibit CVB3 but not HBV replication in vitro.These results demonstrate that hGBP-1 mediates an antiviral effect against CVB3 but not HBV and perhaps plays an important role in the interferon-mediated antiviral response against CVB3.展开更多
The structural phase transitions of bismuth under rapid compression has been investigated in a dynamic diamond anvil cell using time-resolved synchrotron x-ray diffraction. As the pressure increases, the transformatio...The structural phase transitions of bismuth under rapid compression has been investigated in a dynamic diamond anvil cell using time-resolved synchrotron x-ray diffraction. As the pressure increases, the transformations from phase I,to phase II, to phase III, and then to phase V have been observed under different compression rates at 300 K. Compared with static compression results, no new phase transition sequence appears under rapid compression at compression rate from 0.20 GPa/s to 183.8 GPa/s. However, during the process across the transition from phase III to phase V, the volume fraction of product phase as a function of pressure can be well fitted by a compression-rate-dependent sigmoidal curve.The resulting parameters indicate that the activation energy related to this phase transition, as well as the onset transition pressure, shows a compression-rate-dependent performance. A strong dependence of over-pressurization on compression rate occurs under rapid compression. A formula for over-pressure has been proposed, which can be used to quantify the over-pressurization.展开更多
Previous studies have shown that expression of the interferon-sensitive gene (ISG)15 protease UBP43 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-α therapy. We hypothes...Previous studies have shown that expression of the interferon-sensitive gene (ISG)15 protease UBP43 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-α therapy. We hypothesized that UBP43 might hinder the ability of IFN to inhibit HBV replication. In this study, we investigated whether vector-based siRNA promoted by H1 (psiUBP43) could enhance IFN inhibiting HBV replication in cell culture. UBP43 was specifically silenced using shRNA. In HepG2.2.15 cells, the HBeAg and HBV DNA levels were significantly reduced by IFN after transfection of shRNA, imphicated that vector-based siRNA promoted by H1 (psiUBP43) could enhance IFN inhibiting HBV replication in cell culture. These data suggest that UBP43 modulates the anti-HBV type I IFN response, and is a possible therapeutic target for the treatment of HBV infection.展开更多
Emerging data indicated that HCV subverts the antiviral activity of interferon(IFN);however,whether HCV core protein contributes to the process remains controversial.In the present study,we examined the effect of HCV ...Emerging data indicated that HCV subverts the antiviral activity of interferon(IFN);however,whether HCV core protein contributes to the process remains controversial.In the present study,we examined the effect of HCV core protein on interferon-induced antiviral gene expression and whether the effect is involved in the activation and negative regulation of the Jak/STAT signaling pathway.Our results showed that,following treatment with IFN-α,the transcription of PKR,MxA and 2'-5'OAS were down-regulated in HepG2 cells expressing the core protein.In the presence of HCV core protein,ISRE-dependent luciferase activity also decreased.Further study indicated that the core protein could inhibit the tyrosine phosphorylation of STAT1,whereas the level of STAT1 expression was unchanged.Accordingly,SOCS3,the negative regulator of the Jak/STAT pathway,was induced by HCV core protein.These results suggests that HCV core protein may interfere with the expression of some interferon-induced antiviral genes by inhibiting STAT1 phosphorylation and induction of SOCS3.展开更多
Objective:To investigate the significance of computed tomography findings in diffuse malignant peritoneal mesothelioma(DMPeM),tuberculous peritonitis(TBP),and peritoneal carcinomatosis(PC)to differentiate the three di...Objective:To investigate the significance of computed tomography findings in diffuse malignant peritoneal mesothelioma(DMPeM),tuberculous peritonitis(TBP),and peritoneal carcinomatosis(PC)to differentiate the three diseases.Methods:The clinical manifestation and computed tomography scans of 147 patients with diffuse malignant peritoneal mesothelioma(n=60),tuberculous peritonitis(n=32),and peritoneal carcinomatosis(n=55)were retrospectively reviewed,while taking into account of ascites,pleural plaques,viscera infiltration;abnormalities in the peritoneum;involvement of the mesentery and omentum;as well as the presence and location of enlarged lymph nodes.Results:There was no significant difference among all three groups in terms of clinical manifestation,peritoneum,omentum,and mesentery involvement,ascites,as well as the presence and location of enlarged lymph nodes.The study found that 95%of DMPeM patients had been exposed to asbestos in the past.The patients showed significant differences in the following aspects:(1)irregular peritoneum thickening,caked omentum thickening,pleural plaques,visceral infiltration,and asbestos exposure were more common in peritoneal mesothelioma patients;(2)nodular peritoneum thickening and visceral metastasis were more common in patients with peritoneal carcinomatosis;(3)smooth peritoneal thickening,pleural effusion,and extraperitoneal tuberculosis were more common in patients with tuberculous peritonitis.Conclusion:A combination of computed tomography findings could improve our ability in differentiating the three diseases.展开更多
文摘Soft tissue repair and regeneration present a significant clinical challenge.Soft hydrogels have emerged as a promising solution for promoting stem cell differentiation and facilitating soft tissue formation[1].Various materials,including synthetic polymers like polydimethyl siloxane and natural polymers like proteins,have been be used as hydrogel matrix for hydrogel preparation[2,3].However,the limited biodegradability,inhomogeneous network structure,and inadequate mechanical properties of these hydrogels hinder their long-term application in complex environments in vivo.Inspired by the nanostructure of collagen fibrils,Li et al.developed a strategy for creating injectable nanofibrillar hydrogels by combining self-assembly and chemical crosslinking of nanoparticles[4].Moreover,injectable hydrogels offer advantages as implantable materials,including better defect filling and reduced risk of infection compared to prefabricated hydrogels[5].
基金supported by the Natural Science Foundation of Jiangsu Province(BK20230117)the Natural Science Research Project of Nanjing Polytechnic Institute(NJPI-2023-04).
文摘Although the advent of antibiotics has significantly improved the quality of life of infected patients,bacterial infections continue to pose a serious threat to public health[1,2].According to a recent report,within the next 30 years,bacterial infections are projected to surpass cancer in terms of lethality rates,resulting in an alarming 10 million deaths annually by 2050 due to the development of bacterial resistance[3].Moreover,the formation of bacterial biofilms hampers the penetration of antibacterial agents and inhibits the host immune response,making biofilm infections extremely challenging to treat[4-7].Hence,the development of innovative antimicrobial biofilm therapeutics is imperative.
基金supported by the Natural Science Foundation of Jiangsu Province(BK20200710).
文摘The administration of antibiotics has been the primary strategy for combating bacterial infections[1,2].However,the widespread and excessive use of antibiotics has resulted in the alarming rise of bacterial resistance,posing a significant threat to human health[3–5].Therefore,it is imperative to exploit innovative treatment strategy.
基金financially supported by“3456”Cultivation Program for Junior Talents of Nanjing Stomatological Hospital,Medical School of Nanjing University(No.0222R212)Natural Science Foundation of Jiangsu Province(No.BK20200710).
文摘Microbubbles(MBs)are gas-filled micrometer-scale spheres that are commonly formed by the gas core encapsulated with stabilizing shells,including polymers,surfactants,proteins,or liposomes shells.Clinically,MBs were originally used as contrast agents for enhanced ultrasound(US)imaging and diagnostics.Nowadays,MBs were given expectations that they can be alternative platforms for drug delivery owing to their unique acoustic properties.MBs can respond to the US by cavitation effect which refers to a series of complex dynamic processes,such as oscillation,expansion,contraction,and implosion[1].Drug molecules or therapeutic agents can be associated with the MB shells by means of van-der-Waals forces,electrostatic or hydrophobic interactions,or merely by physical encapsulation[2].Therefore,strategies are emerging which take advantages of US-mediated MBs drug delivery systems,mainly focusing on sonothrombolysis,cancer therapy and central nervous system(CNS)pathologies[3].Nevertheless,several researchers have apperceived the promising potential of US-responsive MBs in antibacterial therapy.Here,we aimed to paint an overview of the latest published papers on MBs for antibacterial therapy,hoping to help understand the perspectives that the field may offer emerging generations of antibacterial agents.
基金Supported by Grants from the National Mega Research Program of China,No.2008ZX10002-011the National Key Basic Research Program of China,No.2001CB510008,2005CB522901,2007CB512804 and 2009CB522500the Deutsche Forschun-gsgemeinschaft (SFB/Transregio 60)
文摘AIM: To investigate the expression of programmed death (PD)-1,PD ligand 1 (PD-L1) and PD-L2 in liver tissues in the context of chronic hepatitis and hepatocellular carcinoma (HCC).METHODS: Liver biopsies and HCC specimens from patients were collected and histologically examined.The expression of PD-1,PD-L1,and PD-L2 in biopsy specimens of chronic hepatitis and HCC specimens was evaluated by immunohistochemical staining.The association between the expression level of PD-1,PD-L1,and PD-L2 and clinical and pathological variables was analyzed statistically.RESULTS: Expression of PD-1 was found in liverinfiltrating lymphocytes.In contrast,PD-L1 and PD-L2 were expressed in non-parenchyma liver cells and tumor cells.The expression of PD-L1 was significantly correlated with hepatitis B virus infection (1.42 ± 1.165 vs 0.50 ± 0.756,P = 0.047) and with the stage of HCC (7.50 ± 2.121 vs 1.75 ± 1.500 vs 3.00 ± 0.001,P = 0.018).PD-1 and PD-Ls were significantly up-regulated in HCC specimens (1.40 ± 1.536 vs 5.71 ± 4.051,P = 0.000;1.05 ± 1.099 vs 4.29 ± 3.885,P = 0.004;1.80 ± 1.473 vs 3.81 ± 3.400,P = 0.020).CONCLUSION: PD-L1 may contribute to negative regulation of the immune response in chronic hepatitis B.PD-1 and PD-Ls may play a role in immune evasion of tumors.
基金Supported by Specialized Research Fund for the Doctoral Program of Higher Education of China,No.20093420120005National Science Foundation of China,No.30771907
文摘AIM:To develop models to predict hepatitis B e antigen(HBe Ag)seroconversion in response to interferon(IFN)-αtreatment in chronic hepatitis B patients.METHODS:We enrolled 147 treatment-nave HBe Agpositive chronic hepatitis B patients in China and analyzed variables after initiating IFN-α1b treatment.Patients were tested for serum alanine aminotransferase(ALT),hepatitis B virus-DNA,hepatitis B surface antigen(HBs Ag),antibody to hepatitis B surface antigen,HBe Ag,antibody to hepatitis B e antigen(anti-HBe),and antibody to hepatitis B core antigen(anti-HBc)at baseline and 12 wk,24 wk,and 52 wk after initiating treatment.We performed univariate analysis to identify response predictors among the variables.Multivariate models to predict treatment response were constructed at baseline,12 wk,and 24 wk.RESULTS:At baseline,the 3 factors correlating most with HBe Ag seroconversion were serum ALT level>4×the upper limit of normal(ULN),HBe Ag≤500 S/CO,and anti-HBc>11.4 S/CO.At 12 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤250 S/CO,decline in HBe Ag>1 log10 S/CO,and anti-HBc>11.8 S/CO.At 24 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤5 S/CO,anti-HBc>11.4 S/CO,and decline in HBe Ag>2 log10 S/CO.Each variable was assigned a score of1,a score of 0 was given if patients did not have any of the 3 variables.The 3 factors most strongly correlating with HBe Ag seroconversion at each time point were used to build models to predict the outcome after IFN-αtreatment.When the score was 3,the response rates at the 3 time points were 57.7%,83.3%,and 84.0%,respectively.When the score was 0,the response rates were 2.9%,0.0%,and 2.1%,respectively.CONCLUSION:Models with good negative and positive predictive values were developed to calculate the probability of response to IFN-αtherapy.
基金supported by the Chinese National Key Technology R&D Program(2015BAI09B06)the National Science and Technology Major Project for Infectious Diseases of China(2012ZX10004503,2017ZX10304402-002-005)the National Natural Science Foundation of China(81461130019)
文摘Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus(HBV) worldwide. Current antiviral therapies,including interferon and nucleot(s)ide analogues,rarely cure chronic hepatitis B. Animal models are very crucial for understanding the pathogenesis of chronic hepatitis B and developing new therapeutic drugs or strategies. HBV can only infect humans and chimpanzees, with the use of chimpanzees in HBV research strongly restricted. Thus, most advances in HBV research have been gained using mouse models with HBV replication or infection or models with HBV-related hepadnaviral infection. This review summarizes the animal models currently available for the study of HBV infection.
基金Supported by the National Natural Science Foundation of China, No. 30271170 and 30571646 the National Key Basic Research Program of China, No. 20014CB510008
基金National Mega Research Program of China(2008ZX10002-011)National Natural Science Foundation of China(30700701)National High Tech-nology Research and Development program of China(2006AA02Z128)
基金The National Natural Science Foundation of China, No. 30271170the Ph.D. Program Fund of Chinese Ministry of Education, No. 20070487152
文摘AIM: To establish a cell model harboring replicative clinical hepatitis B virus (HBV) isolates and evaluate its application in individualized selection of anti-HBV agents for chronic hepatitis B (CHB) patients. METHODS: The full-length HBV genomic DNA from 8 CHB patients was amplified by polymerase chain reaction (PCR). All the patients were treated with lamivudine for at least seven months and finally became resistant to lamivudine. The amplified HBV DNA fragments were inserted into pHY106 vectors by Sap Ⅰ?digestion. The recombinant plasmids containing 1.1 copies of HBV genome were transiently transfected into Huh7 cell line, and the levels of HBsAg, HBeAg and intercellular HBV replicative intermediates were determined by ELISA and Southern blot analysis, respectively, with or without lamivudine and adefovir treatment. The antiviral treatment with adefovir was administered to the patients and analyzed in parallel. RESULTS: A total of 25 independent HBV isolateswere obtained from the sera of 8 patients, each patient had at least two isolates. One isolate from each individual was selected and subcloned into pHY106 vector, including 5 isolates with YVDD mutation and 3 isolates with YIDD mutation. All recombinant plasmids harboring HBV isolates were transfected into Huh7 cells. The results indicated that HBV genome carried in HBV replicons of clinical HBV isolates could effectively replicate and express in Huh7 cells. Adefovir, but not lamivudine, inhibited HBV replication both in vitro and in vivo, and in vitro inhibition was dose-dependent. CONCLUSION: The novel method described herein enables individualized selection of anti-HBV agents in clinic and is useful in future studies of antiviral therapy for CHB.
文摘Objective:Ascites in patients with hepatic cirrhosis is caused by cirrhosis in most cases.For most malignant ascites,the primary malignancy could be readily identified using conventional imaging methods,e.g.,computer tomography(CT)and magnetic resonance imaging(MRI).However,in a small fraction of the patients,the primary malignancy remains occult even with these examinations.In this retrospective study,we assessed the usefulness of18F-FDG PET/CT in patients with hepatic cirrhosis and malignant ascites of otherwise unknown origin.Methods:Twenty-eight patients with malignant ascites of unknown primary sites after CT,MRI and ultrasound during the period of five years between January 2008 and December 2012 had received18F-FDG PET/CT.Medical records of these patients were reviewed and analyzed.Results:Elevated18F-FDG absorption was found in 23 of 28 cases in the following sites:gastrointestinal tract(n=10,43.5%),prostate(n=5,21.7%),peritoneum(n=4,13.3%),and ovary(n=4,13.3%).Cancer was confirmed by pathology in 20 cases after open or laparoscopic surgeries.Five patients were found to have benign ascites,among which,3 were found to be false positive due to tuberculosis.SUV values were significantly higher for tumors than for benign lesions(mean values,6.95 vs.2.94;P=0.005).Conclusions:The18F-FDG PET/CT can be as a powerful imaging tool in identifying tissue origin in liver cirrhosis patients suspected of cancers or with cancers of unknown primary sites.
基金sub-projects of National Key Basic Research Program of China (973), No. 2005CB522901
文摘AIM: To investigate the expressions of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma (HCC) and their significance. METHODS: The expressions of PTEN, PPM1A and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues and 13 non-tumor liver tissues were detected by using Envision immunohistochemical technique. RESULTS: The positive expression (64.52%) and staining intensity (4.19 ± 3.31) of PTEN in the cytoplasm of HCC were significantly lower and weaker than those in the adjacent or non-tumor liver tissues (97.37%, 7.88 ± 0.93; 100%, 7.77 ± 0.93, respectively) (P < 0.05), and its staining intensity in the cytoplasm of HCC, which belongs to Edmondson pathologic grades Ⅱ-Ⅲ and above, was also lower than that of gradeⅠandⅠ-Ⅱ. Furthermore, its location in the nucleus or cytoplasm of liver cells was negatively correlated with the progression of liver disease (r = -0.339, P = 0.002); most of PPM1A might be only expressed in the nucleus of adjacent liver tissues, non-HCC tissues or Edmondson gradeⅠandⅠ-Ⅱ HCC, but it was mainly expressed in the cytoplasm of HCC with Edmondson grade ≥Ⅱ, weakly or negatively expressed in the nucleus (P < 0.05), and its location was negatively correlated with the progression of liver disease (r = -0.45, P = 0.0000). P-Smad2, which was mostly located in the nucleus and cytoplasm of gradeⅠ andⅠ-Ⅱ HCC, surrounding or non-tumor liver tissues, was only in the nucleus of HCC with Edmondson grade Ⅱ and above (P < 0.001), and its location was positively correlated with the disease progression (r = 0.224, P = 0.016). Spearman correlation analysis revealed that P-Smad2 was significantly negatively correlated with PTEN and PPM1A (r = -0.748, P = 0.000; r = -0.366, P = 0.001, respectively); and PTEN and PPM1A were positively correlated with HCC carcinogenesis (r = 0.428, P = 0.000). CONCLUSION: The aberrant location of expression and staining intensity of PTEN, PPM1A and P-Smad2 in HCC and their relationship might have an impact on the pathogenesis of HCC.
基金Supported by National Natural Science Foundation of China, No. 81202321 and No. 81461130019Transregio-SFB (TRR) of the Deutsche Forschungsgemeinschaft (DFG), No. TRR60
文摘AIM: To investigate the role of mi R-125 b in regulating monocyte immune responses induced by hepatitis C virus(HCV) core protein.METHODS: Monocytic THP-1 cells were treated with various concentrations of recombinant HCV core protein, and cytokines and mi R-125 b expression in these cells were analyzed. The requirement of Tolllike receptor 2(TLR2) or My D88 gene for HCV core protein-induced immune responses was determined by the transfection of THP-1 cells with gene knockdown vectors expressing either TLR2 si RNA or My D88 si RNA. The effect of mi R-125 b overexpression on TLR2/My D88 signaling was examined by transfecting THP-1 cells with mi R-125 b mimic RNA oligos.RESULTS: In response to HCV core protein stimulation, cytokine production was up-regulated and mi R-125 b expression was down-regulated in THP-1 cells. The modulatory effect of HCV core protein on cellular events was dose-dependent and required functional TLR2 or My D88 gene. Forced mi R-125 b expression abolished the HCV core protein-induced enhancement of tumor necrosis factor-α, interleukin(IL)-6, and IL-10 expression by 66%, 54%, and 66%, respectively(P < 0.001), by inhibiting My D88-mediated signaling, including phosphorylation of NF-k Bp65, ERK, and P38.CONCLUSION: The inverse correlation between mi R-125 b and cytokine expression after HCV core challenge suggests that mi R-125 b may negatively regulate HCVinduced immune responses by targeting TLR2/My D88 signaling in monocytes.
基金Supported by the National Natural Science Foundation of China, No. 30271170 and 30571646, and the National Key Basic Research Program of China, No. 20014CB510008 and 2005CB522900
文摘AIM: To investigate the effect of human apolipoprotein B mRNA-editing enzyme catalytic-polypeptide 3G (APOBEC3G) and its N-terminal or C-terminal cytosine deaminase domain-mediated antiviral activity against hepatitis B virus (HBV) in vitro and in vivo. METHODS: The mammalian hepatoma cells HepG2 and HuH7 were cotransfected with APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain expression vector and 1.3-fold-overlength HBV DNA as well as the linear monomeric HBV of genotype B and C. For in vivo study, an HBV vector-based mouse model was used in which APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain expression vectors were co-delivered with 1.3-fold-overlength HBV DNA via high-volume tail vein injection. Levels of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) in the media of the transfected cells and in the sera of mice were determined by ELISA.The expression of hepatitis B virus core antigen (HBcAg) in the transfected cells was determined by Western blot analysis. Core-associated HBV DNA was examined by Southern blot analysis. Levels of HBV DNA in the sera of mice as well as HBV core-associated RNA in the liver of mice were determined by quantitative PCR and quantitative RT-PCR analysis, respectively. RESULTS: Human APOBEC3G exerted an anti-HBV activity in a dose-dependent manner in HepG2 cells, and comparable suppressive effects were observed on genotype B and C as that of genotype A. Interestingly, the N-terminal or C-terminal cytosine deaminase domain alone could also inhibit HBV replication in HepG2 cells as well as Huh7 cells. Consistent with in vitro results, the levels of HBsAg in the sera of mice were dramatically decreased, with more than 50 times decrease in the levels of serum HBV DNA and core-associated RNA in the liver of mice treated with APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain as compared to the controls. CONCLUSION: Our findings provide probably the first evidence showing that APOBEC3G and its N-terminal or C-terminal cytosine deaminase domain could suppress HBV replication in vitro and in vivo.
基金National Natural Science Foundation (No.30271170,No.30170889).
文摘Guanylate binding protein-1(GBP-1)is an interferon-induced protein.To observe its antiviral effect against Hepatitis B virus(HBV)and Coxsackie virus B3(CVB3),we constructed an eukaryotic expression vector of human GBP-1(hGBP-1).Full-length encoding sequence of hGBP-1 was amplified by long chain RT-PCR and inserted into a pCR2.1 vector,then subcloned into a pCDNA3.1(-)vector.Recombinant hGBP-1 plasmids and pHBV1.3 carrying 1.3-fold genome of HBV were contransfected into HepG2 cells,and inhibition effect of hGBP-1 against HBV replication was observed.Hela cells transfected with recombinant hGBP-1 plasmids were challenged with CVB3,and viral yield in cultures were detected.The results indicated that recombinant eukaryotic expression plasmid of hGBP-1 was constructed successfully and the hGBP-1 gene carried in this plasmid could be efficiently expressed in HepG2 cells and Hela cells.hGBP-1 inhibit CVB3 but not HBV replication in vitro.These results demonstrate that hGBP-1 mediates an antiviral effect against CVB3 but not HBV and perhaps plays an important role in the interferon-mediated antiviral response against CVB3.
基金supported by the Joint Fund of the National Natural Science Foundation of China and the China Academy of Engineering Physics(NSAF)(Grant No.U1530134)the Foundation of National Key Laboratory of Shock Wave and Detonation Physics,China(Grant No.6142A0306010817)the Chinese Academy of Sciences(Grant Nos.KJCX2-SW-N20 and KJCX2-SW-N03)
文摘The structural phase transitions of bismuth under rapid compression has been investigated in a dynamic diamond anvil cell using time-resolved synchrotron x-ray diffraction. As the pressure increases, the transformations from phase I,to phase II, to phase III, and then to phase V have been observed under different compression rates at 300 K. Compared with static compression results, no new phase transition sequence appears under rapid compression at compression rate from 0.20 GPa/s to 183.8 GPa/s. However, during the process across the transition from phase III to phase V, the volume fraction of product phase as a function of pressure can be well fitted by a compression-rate-dependent sigmoidal curve.The resulting parameters indicate that the activation energy related to this phase transition, as well as the onset transition pressure, shows a compression-rate-dependent performance. A strong dependence of over-pressurization on compression rate occurs under rapid compression. A formula for over-pressure has been proposed, which can be used to quantify the over-pressurization.
基金National Science Foundation of China (30271170National Hish Technology Research and Douelopment program of China (2006AA02Z128)
文摘Previous studies have shown that expression of the interferon-sensitive gene (ISG)15 protease UBP43 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-α therapy. We hypothesized that UBP43 might hinder the ability of IFN to inhibit HBV replication. In this study, we investigated whether vector-based siRNA promoted by H1 (psiUBP43) could enhance IFN inhibiting HBV replication in cell culture. UBP43 was specifically silenced using shRNA. In HepG2.2.15 cells, the HBeAg and HBV DNA levels were significantly reduced by IFN after transfection of shRNA, imphicated that vector-based siRNA promoted by H1 (psiUBP43) could enhance IFN inhibiting HBV replication in cell culture. These data suggest that UBP43 modulates the anti-HBV type I IFN response, and is a possible therapeutic target for the treatment of HBV infection.
文摘Emerging data indicated that HCV subverts the antiviral activity of interferon(IFN);however,whether HCV core protein contributes to the process remains controversial.In the present study,we examined the effect of HCV core protein on interferon-induced antiviral gene expression and whether the effect is involved in the activation and negative regulation of the Jak/STAT signaling pathway.Our results showed that,following treatment with IFN-α,the transcription of PKR,MxA and 2'-5'OAS were down-regulated in HepG2 cells expressing the core protein.In the presence of HCV core protein,ISRE-dependent luciferase activity also decreased.Further study indicated that the core protein could inhibit the tyrosine phosphorylation of STAT1,whereas the level of STAT1 expression was unchanged.Accordingly,SOCS3,the negative regulator of the Jak/STAT pathway,was induced by HCV core protein.These results suggests that HCV core protein may interfere with the expression of some interferon-induced antiviral genes by inhibiting STAT1 phosphorylation and induction of SOCS3.
文摘Objective:To investigate the significance of computed tomography findings in diffuse malignant peritoneal mesothelioma(DMPeM),tuberculous peritonitis(TBP),and peritoneal carcinomatosis(PC)to differentiate the three diseases.Methods:The clinical manifestation and computed tomography scans of 147 patients with diffuse malignant peritoneal mesothelioma(n=60),tuberculous peritonitis(n=32),and peritoneal carcinomatosis(n=55)were retrospectively reviewed,while taking into account of ascites,pleural plaques,viscera infiltration;abnormalities in the peritoneum;involvement of the mesentery and omentum;as well as the presence and location of enlarged lymph nodes.Results:There was no significant difference among all three groups in terms of clinical manifestation,peritoneum,omentum,and mesentery involvement,ascites,as well as the presence and location of enlarged lymph nodes.The study found that 95%of DMPeM patients had been exposed to asbestos in the past.The patients showed significant differences in the following aspects:(1)irregular peritoneum thickening,caked omentum thickening,pleural plaques,visceral infiltration,and asbestos exposure were more common in peritoneal mesothelioma patients;(2)nodular peritoneum thickening and visceral metastasis were more common in patients with peritoneal carcinomatosis;(3)smooth peritoneal thickening,pleural effusion,and extraperitoneal tuberculosis were more common in patients with tuberculous peritonitis.Conclusion:A combination of computed tomography findings could improve our ability in differentiating the three diseases.
