Long-term hypertension causes excessive vascular remodeling and leads to adverse cardiovascular events. Balance of ubiquitination and deubiquitination has been linked to several chronic conditions, including pathological vascular remodeling. In this study, we discovered that the expression of ubiquitin-specific protease 25 (USP25) is significantly up-regulated in angiotensin II (Ang II)-challenged mouse aorta. Knockout of Usp25 augments Ang II-induced vascular injury such as fibrosis and endothelial to mesenchymal transition (EndMT). Mechanistically, we found that USP25 interacts directly with Forkhead box O3 (FOXO3) and removes the K63-linked ubiquitin chain on the K258 site of FOXO3. We also showed that this USP25-mediated deubiquitination of FOXO3 increases its binding to light chain 3 beta isoform and autophagosomic-lysosomal degradation of FOXO3. In addition, we further validated the biological function of USP25 by overexpressing USP25 in the mouse aorta with AAV9 vectors. Our studies identified FOXO3 as a new substrate of USP25 and showed that USP25 may be a potential therapeutic target for excessive vascular remodeling-associated diseases.

This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
Animals ; Male ; Mice ; Aquatic Organisms/chemistry* ; Biological Availability ; Cytochrome P-450 Enzyme System/metabolism* ; Glucuronosyltransferase/metabolism* ; Microsomes, Liver/metabolism* ; Molecular Structure ; Biological Products/pharmacokinetics* ; Pyridines/pharmacokinetics*

Objective To explore the mechanism of Danggui Sini Decoction in treating knee osteoarthritis(KOA)by using network pharmacology,combined with in vitro experimental verification.Methods The active components of Danggui Sini Decoction were retrieved and screened through TCMSP,CNKI and PubMed databases,and their corresponding targets were predicted using the SwissTarget Prediction platform.KOA related targets were retrieved from GeneCards and OMIM databases.Intersection of drug targets and KOA targets was obtained,and key components,core targets,and their related biological mechanisms were identified through network topology analysis,GO and KEGG pathway enrichment analysis.Molecular docking was used to verify the degree of binding between key components and core targets.Danggui Sini Decoction containing serum was prepared,and an in vitro KOA model was constructed by inducing rat articular chondrocytes with lipopolysaccharide.The CCK-8 method was used to screen for the optimal concentration of drug containing serum intervention,fluorescent probes were used to detect intracellular ROS content,immunofluorescence was used to detect NF-κB p65 nuclear translocation,RT-qPCR was used to detect the expressions of IL-6,IL-1β and TNF-α mRNA,Western blot was used to detect the expression of Toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),NF-κB p65 and p-NF-κB p65 proteins.Results The results of network pharmacology analysis indicated that the treatment of KOA with Danggui Sini Decoction may involve regulating Toll like receptors,MAPK,TNF,apoptosis and other inflammatory and aging signaling pathways,compounds such as quercetin,kaempferol and glycyrrhizin may play important roles.Core targets included IL6,IL1B,TNF,TLR4,NFKB1,JUN,MAPK1,RELA.In vitro experiments showed that compared with the blank group,the ROS content in chondrocytes of the model group significantly increased(P<0.01),NF-κB p65 protein was significantly nuclear translocation(P<0.01),and mRNA expressions of IL-6,IL-1β,TNF-α mRNA and protein expressions of TLR4,MyD88 and p-NF-κB p65 significantly increased(P<0.01);compared with the model group,the intervention of Danggui Sini Decoction containing serum could significantly reduce intracellular ROS content(P<0.05),inhibit NF-κB p65 nuclear translocation(P<0.01),and reduce the expression of inflammatory factor mRNA and related proteins(P<0.05,P<0.01).Conclusion Danggui Sini Decoction can significantly reduce the inflammatory response of rat articular chondrocytes induced by lipopolysaccharide and exert therapeutic effects on KOA.Its mechanism may be related to the inhibition of TLR4/MyD88/NF-κB pathway.

Objective To investigate the diagnostic efficacy of targeted biopsy(TB)combined with ipsilateral hemiglandular systematic biopsy(SB)of the dominant lesion,so as to explore a novel reduced-core biopsy strategy.Methods A retrospective analysis was conducted on the clinical data of 299 patients treated in our hospital during Sep.1,2022,and Feb.28,2023,who had a Prostate Imaging Reporting and Data System(PI-RADS)score ≥3 and underwent combined TB and SB.The dominant lesion was defined as the lesion with the highest PI-RADS score on multi-parametric magnetic resonance imaging(mpMRI);in cases of identical scores,the largest was designated as the dominant.SB was categorized as ipsilateral(ipsi-SB)or contralateral(contra-SB)to the dominant lesion.The consistency in detecting clinically significant prostate cancer(csPCa)was compared between TB with ipsi-SB(TB+ipsi-SB),TB with contra-SB(TB+contra-SB),and TB with SB(TB+SB).Subgroup analyses were performed based on PI-RADS score,prostate-specific antigen(PSA)level,prostate volume(PV),and mpMRI lesion distribution to evaluate csPCa detection rates across different variables.Results TB+ipsi-SB demonstrated comparable detection rate to TB+SB(46.2％vs.46.8％).The K values for TB+ipsi-SB and TB+contra-SB relative to TB+SB were 0.987(95％CI:0.969-1.000,P＜0.01)and 0.933(95％CI:0.892-0.974,P＜0.01),respectively.Across all subgroups,TB+ipsi-SB showed the highest agreement with TB+SB.Notably,in subgroups with PI-RADS 3 and 5,PSA＞0-20 ng/mL,PV＜25 mL,bilateral or multiple mpMRI lesions,TB+ipsi-SB achieved complete concordance with TB+SB in csPCa detection[K=1.000(95％CI:1.000-1.000),P＜0.01].Conclusion For patients with PI-RADS score ≥3,TB+ipsi-SB exhibits near-perfect consistency with TB+SB in csPCa detection while requiring fewer biopsy cores.TB+ipsi-SB represents a promising refinement of the TB+SB approach.

Objective:To investigate the treatment approaches and outcomes of early hepatic artery thrombosis (E-HAT) in adult recipients following orthotopic liver transplantation (OLT).Methods:A retrospective analysis was conducted on clinical data of E-HAT cases after adult OLT at the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to June 2022. Clinical characteristics, treatment methods, therapeutic outcomes, long-term survival of recipients and grafts, and the incidence of long-term complications were summarized. The Kaplan-Meier method was utilized to calculate recipient survival rates.Results:Among 1 016 OLT recipients, 22 cases (2.2%) developed postoperative E-HAT. There were 19 males and 3 females, with a age of 44.81±9.98 years. E-HAT was diagnosed via angiography at a median of 3.5 (1.0, 7.0) days post-OLT. Twenty recipients underwent vascular intervention therapy, achieving clinical success in 14 cases (70.0%) with a mean thrombolysis duration of 5.1±3.2 days. Twelve cases (60.0%) experienced complications, including abdominal bleeding (10 cases), gastrointestinal bleeding (1 case), catheter-related infection (1 case), subcutaneous bleeding (1 case), and hepatic artery dissection (1 case). Five recipients underwent hepatic artery re-anastomosis, including two initial cases and three following failed interventional therapy. Surgery was performed at a median of 5.0 (1.0, 15.3) days post OLT, with 4 successful cases. Through combined interventional and surgical treatment, 81.8% (18/22) of grafts were salvaged. However, the success rate was significantly lower in cases with marked transaminase (AST, ALT) and total bilirubin elevation (16/18 vs 2/4). Nineteen E-HAT survivors were followed for a median of 22 (5, 52) months. During follow-up, 2 cases experienced thrombus recurrence, and 12 cases developed biliary complications, including ischemic biliary stenosis (11 cases), extensive liver necrosis (1 case), localized liver abscess (1 case), and biliary anastomotic stenosis (1 case). Seven recipients died due to graft failure. The 1-year, 3-year and 5-year cumulative survival rates were 67.2%, 60.5% and 34.5%, respectively.Conclusions:Combined interventional and surgical treatment demonstrates a high success rate for managing E-HAT, particularly when addressed before significant graft damage. Ischemic biliary stenosis remains the most common long-term complication.

Objective To explore the mechanism through which dexmedetomidine(Dex)alleviates doxorubicin(Adr)-induced myo-cardial injury via regulating nuclear factor κB(NF-κB)expression.Methods Sprague-Dawley rats were divided into control,Adr,and Adr+Dex groups.Theirs hearts were harvested for hematoxylin and eosin(HE)staining,immunohistochemical staining,real-time polymerase chain reaction(PCR),and Western blotting anlyses.The rat primary cardiomyocytes,breast cancer cell line MDA-MB-23,lung cancer cell line H226,gastric cancer cell line AGS,and bladder cancer cell line 5637 were cultured and divided into control,Adr,Adr+Dex,Dex,and Adr+Dex+NF-κBi groups.CCK-8 and immunofluorescence staining were performed to detect the reactive oxygen species(ROS)contents.Results The myocardial arrangement of the rats in the Adr group was disordered,myocardial cell activity was lower,the mitochondrial membrane potential was lower,ROS production was higher,and NF-κB mRNA and protein contents were sub-stantially lower than those in the control group.The cardiomyocyte morphology was improved,cell activity was higher,mitochondrial mem-brane potential was increased,ROS production decreased,and NF-κB expression significantly increased in the Adr+Dex group compared with those in the control group.The mitochondrial membrane potential in the Adr+Dex+NF-κBi group was lower,and ROS generation was increased compared with the control group.The activity of the tumor cells in the Adr group was lower,and no statistically significant diffe-rences were found compared with that in the Adr+Dex group.Conclusion Treatment with Dex may not affect the chemotherapeutic effects of Adr.Dex administration may increase the myocardial mitochondrial membrane potential and reduce ROS generation by regu-lating NF-κB levels,thereby reducing Adr-induced myocardial damage.

The number of patients with eye diseases in China is enormous,and the negative effects of these conditions,such as impaired visual function,psychological burdens,and restricted social participation,are becoming increasingly severe.Due to the limited and unevenly distributed ophthalmic resources,and the significant limitations of traditional diagnostic and therapeutic approaches in terms of accuracy and efficiency,there is an urgent need for more sensitive and efficient modalities.With the rapid advancement of artificial intelligence technology,ophthalmic diagnosis has entered a new stage of intelligent transformation.Facial photos,as a noninvasive and convenient medium,show unique advantages in eye disease diagnosis.Artificial intelligence systems based on facial photo analysis have been applied to the screening and diagnosis of conditions such as myopia,strabismus,ptosis,and thyroid eye disease,showing promising results.This review introduces the workflow of intelligent diagnosis for ocular diseases based on facial photographs,with a focus on recapitulating relevant research findings both domestically and internationally in recent years.It summarizes the innovative features and application advantages of intelligent diagnosis systems for eye diseases based on facial photos,analyzes the current technical bottlenecks and challenges in application,proposes corresponding countermeasures,and discusses future development directions,aiming to provide references and new insights for the intelligent screening and diagnosis of eye diseases.

Objective To investigate the diagnostic efficacy of targeted biopsy(TB)combined with ipsilateral hemiglandular systematic biopsy(SB)of the dominant lesion,so as to explore a novel reduced-core biopsy strategy.Methods A retrospective analysis was conducted on the clinical data of 299 patients treated in our hospital during Sep.1,2022,and Feb.28,2023,who had a Prostate Imaging Reporting and Data System(PI-RADS)score ≥3 and underwent combined TB and SB.The dominant lesion was defined as the lesion with the highest PI-RADS score on multi-parametric magnetic resonance imaging(mpMRI);in cases of identical scores,the largest was designated as the dominant.SB was categorized as ipsilateral(ipsi-SB)or contralateral(contra-SB)to the dominant lesion.The consistency in detecting clinically significant prostate cancer(csPCa)was compared between TB with ipsi-SB(TB+ipsi-SB),TB with contra-SB(TB+contra-SB),and TB with SB(TB+SB).Subgroup analyses were performed based on PI-RADS score,prostate-specific antigen(PSA)level,prostate volume(PV),and mpMRI lesion distribution to evaluate csPCa detection rates across different variables.Results TB+ipsi-SB demonstrated comparable detection rate to TB+SB(46.2％vs.46.8％).The K values for TB+ipsi-SB and TB+contra-SB relative to TB+SB were 0.987(95％CI:0.969-1.000,P＜0.01)and 0.933(95％CI:0.892-0.974,P＜0.01),respectively.Across all subgroups,TB+ipsi-SB showed the highest agreement with TB+SB.Notably,in subgroups with PI-RADS 3 and 5,PSA＞0-20 ng/mL,PV＜25 mL,bilateral or multiple mpMRI lesions,TB+ipsi-SB achieved complete concordance with TB+SB in csPCa detection[K=1.000(95％CI:1.000-1.000),P＜0.01].Conclusion For patients with PI-RADS score ≥3,TB+ipsi-SB exhibits near-perfect consistency with TB+SB in csPCa detection while requiring fewer biopsy cores.TB+ipsi-SB represents a promising refinement of the TB+SB approach.

Objective To explore the mechanism of Danggui Sini Decoction in treating knee osteoarthritis(KOA)by using network pharmacology,combined with in vitro experimental verification.Methods The active components of Danggui Sini Decoction were retrieved and screened through TCMSP,CNKI and PubMed databases,and their corresponding targets were predicted using the SwissTarget Prediction platform.KOA related targets were retrieved from GeneCards and OMIM databases.Intersection of drug targets and KOA targets was obtained,and key components,core targets,and their related biological mechanisms were identified through network topology analysis,GO and KEGG pathway enrichment analysis.Molecular docking was used to verify the degree of binding between key components and core targets.Danggui Sini Decoction containing serum was prepared,and an in vitro KOA model was constructed by inducing rat articular chondrocytes with lipopolysaccharide.The CCK-8 method was used to screen for the optimal concentration of drug containing serum intervention,fluorescent probes were used to detect intracellular ROS content,immunofluorescence was used to detect NF-κB p65 nuclear translocation,RT-qPCR was used to detect the expressions of IL-6,IL-1β and TNF-α mRNA,Western blot was used to detect the expression of Toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),NF-κB p65 and p-NF-κB p65 proteins.Results The results of network pharmacology analysis indicated that the treatment of KOA with Danggui Sini Decoction may involve regulating Toll like receptors,MAPK,TNF,apoptosis and other inflammatory and aging signaling pathways,compounds such as quercetin,kaempferol and glycyrrhizin may play important roles.Core targets included IL6,IL1B,TNF,TLR4,NFKB1,JUN,MAPK1,RELA.In vitro experiments showed that compared with the blank group,the ROS content in chondrocytes of the model group significantly increased(P<0.01),NF-κB p65 protein was significantly nuclear translocation(P<0.01),and mRNA expressions of IL-6,IL-1β,TNF-α mRNA and protein expressions of TLR4,MyD88 and p-NF-κB p65 significantly increased(P<0.01);compared with the model group,the intervention of Danggui Sini Decoction containing serum could significantly reduce intracellular ROS content(P<0.05),inhibit NF-κB p65 nuclear translocation(P<0.01),and reduce the expression of inflammatory factor mRNA and related proteins(P<0.05,P<0.01).Conclusion Danggui Sini Decoction can significantly reduce the inflammatory response of rat articular chondrocytes induced by lipopolysaccharide and exert therapeutic effects on KOA.Its mechanism may be related to the inhibition of TLR4/MyD88/NF-κB pathway.

The number of patients with eye diseases in China is enormous,and the negative effects of these conditions,such as impaired visual function,psychological burdens,and restricted social participation,are becoming increasingly severe.Due to the limited and unevenly distributed ophthalmic resources,and the significant limitations of traditional diagnostic and therapeutic approaches in terms of accuracy and efficiency,there is an urgent need for more sensitive and efficient modalities.With the rapid advancement of artificial intelligence technology,ophthalmic diagnosis has entered a new stage of intelligent transformation.Facial photos,as a noninvasive and convenient medium,show unique advantages in eye disease diagnosis.Artificial intelligence systems based on facial photo analysis have been applied to the screening and diagnosis of conditions such as myopia,strabismus,ptosis,and thyroid eye disease,showing promising results.This review introduces the workflow of intelligent diagnosis for ocular diseases based on facial photographs,with a focus on recapitulating relevant research findings both domestically and internationally in recent years.It summarizes the innovative features and application advantages of intelligent diagnosis systems for eye diseases based on facial photos,analyzes the current technical bottlenecks and challenges in application,proposes corresponding countermeasures,and discusses future development directions,aiming to provide references and new insights for the intelligent screening and diagnosis of eye diseases.