Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

AIM To evaluate the quality of Beidougen Formula Granules.METHODS Fifteen batches of standard decoctions and three batches of formula granules were prepared,after which paste rate and contents,transfer rates of magnoflorine,daurisoline,dauricine were determined.HPLC specific chromatograms were established,and cluster analysis was adopted in chemical pattern recognition.RESULTS For three batches of formula granules,the paste rates were 15.1%-16.6%,the contents of magnoflorine,daurisoline,dauricine were 18.93-19.39,9.42-9.60,6.79-6.85 mg/g with the transfer rates of 34.42%-35.25%,43.81%-44.65%,27.27%-27.51%from decoction pieces to formula granules,respectively,and there were seven characteristic peaks in the specific chromatograms with the similarities of more than 0.95,which demonstrated good consistence with those of standard decoctions and accorded with related limit requirements.Fifteen batches of standard decoctions were clustered into two types,and the medicinal materials produced from Jilin,Hebei,Shangdong could be used for the preparation of formula granules.CONCLUSION This reasonable and reliable method can provide references for the quality control and clinical application of Beidougen Formula Granules.

Humans ; Transcatheter Aortic Valve Replacement ; Aortic Valve/surgery* ; Heart Valve Prosthesis Implantation ; Renal Dialysis ; Aortic Valve Stenosis/surgery* ; Treatment Outcome ; Heart Valve Prosthesis

Humans ; Transcatheter Aortic Valve Replacement ; Aortic Valve/surgery* ; Heart Valve Prosthesis Implantation ; Renal Dialysis ; Aortic Valve Stenosis/surgery* ; Treatment Outcome ; Heart Valve Prosthesis

Objective To explore the therapeutic mechanism of maggot for psoriasis-like lesions in mice from the perspective of immune stress and complement activation regulation.Methods Thirty-six male C57BL/6 mice were randomly divided into control group,model group,maggot(1.25%,2.5%,and 5%)groups,and Benvitimod(1%)group.Psoriasis-like lesions were induced by application of imiquimod cream,and the severity of skin lesions was assessed using the modified Psoriasis Area and Severity Index(MPASI)score.Auricular swelling of the mice was observed,and histopathological changes of the skin lesions were examined with HE staining.Scratching behavior of the mice was observed and the spleen index was calculated.Toluidine blue staining was used to detect mast cells in the skin lesions,and serum levels of IgG,IgM,the complements CH50,C1s,C3,C3a,C5 and C5a,and the inflammatory factors IL-23,IL-17A and TNF-α were determined with ELISA.Results In mice with imiquimod-induced psoriasis-like skin lesions,treatment with the maggot at the 3 doses significantly decreased MPASI score,alleviated auricular swelling and pathologies in the skin lesions,reduced scratching behaviors,spleen index,and the number of mast cells in the lesions.Treatment with high-dose maggot significantly lowered serum levels of IgG,C1s,C3a,C5a,IL-23,IL-17A and TNF-α and the levels of C1s,C3,C3a,C5 and C5a in the lesion tissue,and increased serum levels of CH50,C3,and C5.The therapeutic effect of maggot showed a dose-effect dependence.Conclusion Maggot can alleviate psoriasis-like skin lesions in mice by inhibiting immune stress and complement activation.

Objective To explore the therapeutic mechanism of maggot for psoriasis-like lesions in mice from the perspective of immune stress and complement activation regulation.Methods Thirty-six male C57BL/6 mice were randomly divided into control group,model group,maggot(1.25%,2.5%,and 5%)groups,and Benvitimod(1%)group.Psoriasis-like lesions were induced by application of imiquimod cream,and the severity of skin lesions was assessed using the modified Psoriasis Area and Severity Index(MPASI)score.Auricular swelling of the mice was observed,and histopathological changes of the skin lesions were examined with HE staining.Scratching behavior of the mice was observed and the spleen index was calculated.Toluidine blue staining was used to detect mast cells in the skin lesions,and serum levels of IgG,IgM,the complements CH50,C1s,C3,C3a,C5 and C5a,and the inflammatory factors IL-23,IL-17A and TNF-α were determined with ELISA.Results In mice with imiquimod-induced psoriasis-like skin lesions,treatment with the maggot at the 3 doses significantly decreased MPASI score,alleviated auricular swelling and pathologies in the skin lesions,reduced scratching behaviors,spleen index,and the number of mast cells in the lesions.Treatment with high-dose maggot significantly lowered serum levels of IgG,C1s,C3a,C5a,IL-23,IL-17A and TNF-α and the levels of C1s,C3,C3a,C5 and C5a in the lesion tissue,and increased serum levels of CH50,C3,and C5.The therapeutic effect of maggot showed a dose-effect dependence.Conclusion Maggot can alleviate psoriasis-like skin lesions in mice by inhibiting immune stress and complement activation.

Purpose::Vibrio vulnificus ( V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. Methods::An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. Results::In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival ( p = 0.014), reduced the serum creatinine ( p = 0.002), urea nitrogen ( p = 0.030), aspartate aminotransferase ( p = 0.029), and alanine aminotransferase ( p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1β: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1β, IL-6, TNF-α in liver (IL-1β: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1β: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid ( p = 0.225), liver ( p = 0.186), or kidney ( p = 0.637). Conclusion::Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.