Integrin α _v β ₃ is overexpressed in various tumor cells and angiogenesis. To date, no drug has been proven to target it for therapy. A first-in-human study was designed to investigate the safety, pharmacokinetics, and dosimetry of ¹⁷⁷Lu-AB-3PRGD2, a novel integrin α _v β ₃-targeting radionuclide drug with an albumin-binding motif to optimize the pharmacokinetics. Ten patients (3 men, 7 women; aged 45 ± 16 years) with integrin α _v β ₃-avid tumors were recruited to accept ¹⁷⁷Lu-AB-3PRGD2 injection in a dosage of 1.57 ± 0.08 GBq (42.32 ± 2.11 mCi), followed by serial scans to obtain its dynamic distribution in the body. Safety tests were performed before and every 2 weeks after the treatment for 6-8 weeks. No adverse event over grade 3 was observed. ¹⁷⁷Lu-AB-3PRGD2 was excreted mainly through the urinary system, with intense radioactivity in the kidneys and bladder. Moderate distribution was found in the liver, spleen, and intestines. The estimated blood half-life was 2.85 ± 2.17 h. The whole-body effective dose was 0.251 ± 0.047 mSv/MBq. The absorbed doses were 0.157 ± 0.032 mGy/MBq in red bone marrow and 0.684 ± 0.132 mGy/MBq in kidneys. This first-in-human study of ¹⁷⁷Lu-AB-3PRGD2 treatment indicates its promising potential for targeted radionuclide therapy of integrin α _v β ₃-avid tumors. It merits further studies in more patients with escalating doses and multiple treatment courses.

OBJECTIVES: To investigate the role of the BNIP3-PI3K/Akt signaling pathway in mediating the inhibitory effect of Buyang Huanwu Decoction (BYHWT) on mitochondrial autophagy in human synovial fibroblasts from rheumatoid arthritis patients (FLS-RA) cultured under a hypoxic condition. METHODS: Forty normal Wistar rats were randomized into two groups (n=20) for daily gavage of BYHWT or distilled water for 7 days to prepare BYHWT-medicated or control sera. FLS-RA were cultured in routine condition or exposed to hypoxia (10% O₂) for 24 h wigh subsequent treatment with IL-1β, followed by treatment with diluted BYHWT-medicated serum (5%, 10% and 20%) or control serum. AnnexinV-APC/7-AAD double staining and T-AOC kit were used for detecting apoptosis and total antioxidant capacity of the cells, and the changes in ROS, ATP level, mitochondrial membrane potential and Ca²⁺ homeostasis were analyzed. The changes in mRNA and protein expressions of BNIP3, PI3K and AKT and mRNA expressions of LC3, Beclin-1 and P62 were detected using RT-qPCR and Western blotting. RESULTS: Treatment with BYHWT-medicated serum dose-dependently lowered apoptosis rate of IL-1β-induced FLS-RA with hypoxic exposure. The treatment significantly decreased T-AOC concentration, increased ROS production, autophagosome formation and ATPase levels, and lowered mitochondrial membrane potential and Ca²⁺ level in the cells. In IL-1β-induced FLS-RA with hypoxic exposure, treatment with BYHWT-medicated serum significantly increased BNIP3 protein expression, decreased the protein expressions of PI3K and AKT, increased the mRNA expressions of BNIP3 and P62, and lowered the mRNA expressions of PI3K, AKT, LC3 and Beclin-1 without significantly affecting Beclin-1 protein expression. The cells treated with 5% and 10% BYHWT-medicated serum showed no significant changes in LC3 expression. CONCLUSIONS BYHWT inhibits mitochondrial autophagy in IL-1β-induced FLS-RA with hypoxic exposure possibly by inhibiting BNIP3-mediated PI3K/AKT signaling pathway.
Drugs, Chinese Herbal/pharmacology* ; Arthritis, Rheumatoid/pathology* ; Animals ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Autophagy/drug effects* ; Humans ; Fibroblasts/cytology* ; Rats, Wistar ; Membrane Proteins/metabolism* ; Rats ; Phosphatidylinositol 3-Kinases/metabolism* ; Mitochondria/metabolism* ; Cells, Cultured ; Proto-Oncogene Proteins/metabolism* ; Apoptosis/drug effects* ; Cell Hypoxia ; Synovial Membrane/cytology* ; Male ; Mitochondrial Proteins

Objective:To explore the correlation between serum 1, 5-anhydroglucitol (1, 5-AG) and mild cognitive impairment (MCI) in elderly patients with type 2 diabetes mellitus (T2DM).Methods:A total of 160 patients with T2DM aged 60-75 years old who visited the First Hospital of Hebei Medical University from May 2021 to July 2022 were selected. According to the Montreal cognitive assessment (MoCA), all patients were divided into T2DM with MCI group (T2DM+ MCI group, n=81) and T2DM without MCI group (T2DM group, n=79). All research subjects were tested for glycated hemoglobin A1c (HbA1c), serum 1, 5-AG, serum β-amyloid peptide 42 (Aβ42), and blood biochemical indicators.SPSS 25.0 statistical software was used for data analysis. The t test, Mann-Whitney U test and χ2 test were used to compare the two groups. Binary Logistic regression analysis was used to examine the relevant influencing factors. Results:(1) Compared with T2DM group, patients in T2DM+ MCI group had significantly higher age, systolic pressure and HbA1c(all P<0.05).The level of 1, 5-AG in T2DM+ MCI group was significantly lower than that in T2DM group( (15.65±2.56 )μg/mL, (18.17±3.72 )μg/mL, P<0.01), and the level of Aβ42 was higher than that of T2DM group (2.95 (3.36) pg/mL, 1.91 (2.48) pg/mL, P<0.05). (2) Binary Logistic regression analysis results showed that HbA1c( β=0.230, OR=1.259, 95% CI=1.010-1.568, P=0.040) and Aβ42( β=0.188, OR=1.206, 95% CI=1.033-1.409, P=0.018) were the independent risk factors for MCI in elderly patients with T2DM, while 1, 5-AG ( β=-0.240, OR=0.786, 95% CI=0.698-0.886, P<0.001) was the protective factor for MCI. Conclusion:There is a positive correlation between serum 1, 5-AG and cognitive function, and the decrease of 1, 5-AG level was associated with the increased risk of MCI in elderly patients with T2DM.

Background and aim:Hepatitis B virus(HBV)-related gestational acute-on-chronic liver failure(ACLF)is a severe condition with limited treatment options.This study aimed to evaluate the efficacy and ideal timing of plasma exchange and continuous renal replacement therapy(CRRT)in managing pregnant women with HBV-related ACLF. Methods:This study retrospectively analyzed 51 eligible patients with HBV-related gestational ACLF between 2009 and 2020.Patients admitted to the study were divided into a conventional treatment group and a new treatment group according to whether they received the new management protocol,which included more aggressive plasma exchange(PE)and CRRT strategies.All 19 pregnant women with hepatic encephalopathy(HE)were divided into an early treatment group and a non-early treatment group according to whether PE therapy was initiated within three days.Our study had two primary objectives.Firstly,we aimed to evaluate the impact of PE and CRRT on puerperal survival.Secondly,we sought to assess the effects of early PE and CRRT regimens on puerperal survival in women with HE. Results:The levels of total bilirubin on the second day postpartum(D3),the third day postpartum(D4),and the fifth day postpartum(D6)were significantly lower in the new treatment group compared to the conventional treatment group(P=0.02,0.01,and 0.02,respectively).The ALT of D3 was significantly elevated in the new treatment group compared to the conventional treatment group(P=0.02).The incidence of HE overall increased from prenatal to postpartum D4,peaked on D4,and then gradually decreased from the fourth day postpartum(D5)(P=0.027).The first week after delivery revealed a significant difference in survival rate between the two groups,the conventional treatment group had statistically higher mortality rates compared to the new treatment group(P=0.002).Similarly,the entire puerperal period mortality rate of the conventional treatment group was statistically higher than the new treatment group(P=0.002).Moreover,among all patients with HE,the non-early treatment group showed significantly higher puerperal mortality rates compared to the early treatment group(P=0.006). Conclusions:Early PE and CRRT conducted within three days post-childbirth,enhance puerperal prog-nosis for HBV-related gestational ACLF.

Objective To explore the application of patient empowerment in early rehabilitation training for patients with lower extremity deep vein thrombosis(DVT)after receiving catheter-directed thrombolysis(CDT).Methods A total of 110 patients with lower extremity DVT,who were scheduled for CDT therapy,were enrolled in this study.Using random digital table method,the patients were divided into control group(n=55)and intervention group(n=55).Routine rehabilitation activities were implemented for patients of the control group,while patient empowerment-based early rehabilitation training program was carried out for patients of the intervention group.The compliance to rehabilitation exercise,difference of upper/lower patella leg circumference,incidence of complications,duration of catheterization and thrombolysis,and length of hospital stay in both groups were calculated.The Self-Efficacy for Managing Chronic Disease,Chinese version of the Readiness for Hospital Discharge Scale,and the VEnous INsufficiency Epidemiological and Economic Study(VEINES)Quality of Life scale were used to evaluate the rehabilitation results of the patients of two groups.Results There were no significant differences in the duration of catheterization and thrombolysis,incidence of complications,and length of hospital stay between the two groups(all P＞0.05).At the time of discharge,the difference of upper/lower patella leg circumference in the intervention group was remarkably smaller than that in the control group,and the compliance with rehabilitation exercise,the self-efficacy,the readiness for discharge,and the quality of life in 3 months after discharge in the intervention group were strikingly better than those in the control group(all P＜0.05).Conclusion The implementation of patient empowerment in early rehabilitation training for patients with lower extremity DVT after receiving CDT therapy can improve the compliance with rehabilitation exercise,self-efficacy,limb swelling,readiness for discharge,and quality of life after discharge from hospital.(J Intervent Radiol,2024,33:554-559)

Objective To investigate the expression level and clinical significance of WW domain-containing E3 ubiquitin protein ligase 1(WWP1)and nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)in patients with heart failure with preserved ejection fraction(HFpEF).Methods A total of 153 patients with HFpEF admitted to Fengfeng General Hospital of North China Medical and Health Group from January 2021 to September 2022 were collected as the observation group.According to the New York Heart Association(NYHA)cardiac function grading of patients,they were grouped into cardiac function grading Ⅰ～Ⅱ group(n=64)and cardiac function grading Ⅲ～Ⅳ group(n=89),while 148 healthy volunteers were collected as the control group.The correlation between serum WWP1 and NLRP3 levels and cardiac function indexes of patients was explored by Pearson analysis.The diagnostic value of serum WWP1 and NLRP3 levels on the severity of heart failure in HFpEF patients was analyzed by the receiver operating characteristic(ROC)curve.Results Compared with the control group,the expression levels of WWP1(1.68±0.35 vs 1.04±0.19)and NLRP3(6.72±1.26 ng/ml vs 4.57±0.84 ng/ml)in the observation group were significantly increased,and the differences were statistically significant(t=19.623,17.359,all P<0.05).Compared with grade Ⅰ to Ⅱ groups,WWP1(1.87±0.39 vs 1.42±0.32)and NLRP3(7.53±1.40 ng/ml vs 5.59±1.18 ng/ml)expression levels in grade Ⅲ to Ⅳ groups were significantly increased and the differences were statistically significant(t=7.744,9.017,all P<0.05).The differences of heart rate,left atrial diameter(LAD),left ventricular end-diastolic diameter(LVEDD),left ventricular end-diastolic diameter(LVEDD),left atrial diameter(LAD),left ventricular end-diastolic diameter(LVEDD),left ventricular end-diastolic posterior wall thickness(LVPWT),left ventricular ejection fraction(LVPWT),left ventricular ejection fraction(LVEF),peak mitral early diastolic velocity(E)/peak late diastolic velocity(A)and the incidence of atrial fibrillation between the cardiac function grade Ⅰ to Ⅱ groups and the grade Ⅲ to Ⅳ groups were significant(t/χ2=2.757～7.069,all P<0.05).Serum WWP1 level in HFpEF patients was positively correlated with LAD,LVEDD and LVPWT(r=0.547,0.471,0.536,all P<0.05),and negatively correlated with LVEF and E/A(r=-0.485,-0.417,all P<0.05).Serum NLRP3 level was positively correlated with LAD,LVEDD and LVPWT(r=0.534,0.494,0.520,all P<0.05),and negatively correlated with LVEF and E/A(r=-0.462,-0.523,all P<0.05).ROC results showed that the area under the curve(AUC)of serum WWP1 and NLRP3 levels alone for diagnosing the severity of heart failure in HFpEF patients was 0.825 and 0.855,respectively,and the AUC(0.924)diagnosed by the combination of the two was significantly greater than that diagnosed by the serum WWP1 alone and the AUC diagnosed by the NLRP3 alone(Z=3.600,P<0.001;Z=3.053,P=0.002).Conclusion The levels of serum WWP1 and NLRP3 were increased in patients with HFpEF,which were closely related to the cardiac function of patients.Serum WWP1 and NLRP3 have certain diagnostic value for the severity of heart failure in patients with HFpEF.

ObjectiveTo observe the effect of tendon clearing combined with Zizhu ointment on the serum levels of nucleotide-binding oligomerization domain-like receptor protein 3 （NLRP3） inflammasomes， interleukin （IL）-1β， and IL-18 in the treatment of non-ischemic diabetic foot ulcers. MethodA total of 106 patients with non-defective diabetic foot ulcers who attended the outpatient clinic and wards of the Vascular Surgery Department of Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine from March 2023 to March 2024 were selected. The patients with non-ischemic diabetic foot ulcers who met the inclusion criteria were assigned with the random number table method into an observation group and a control group， with 53 patients in each group. Patients in both groups received basic treatment. The local ulcers in the observation group received tendon clearing combined with Zizhu ointment， while those in the control group received conventional debridement combined with topical solution of bovine basic fibroblast growth factor. The serum NLRP3， IL-1β， and IL-18 levels， ulcer area， traditional Chinese medicine （TCM） symptom scores， visual analogue scale （VAS） score， and DMIST score were measured and recorded in the two groups before and after treatment. The ulcer healing rate and incidence of adverse reactions were compared between the two groups. ResultThe observation group had higher ulcer healing rate than the control group （P<0.01）. After treatment， both groups showed lowered serum NLRP3， IL-1β， and IL-18 levels， reduced ulcer area， and declined TCM symptom score， VAS score， and DMIST score （P<0.01）. Moreover， these indicators were lower in the observation group than in the control group （P<0.05， P<0.01）. Neither group showed significant changes in the liver and kidney function indicators after treatment. Significant adverse reactions occurred in neither group during the treatment course. ConclusionTendon clearance combined with Zizhu ointment was effective and safe in treating non-ischemic diabetic foot ulcers. It may exert the therapeutic effect by reducing the inflammation of the local ulcers.

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function. In the present study we investigated the contribution of megakaryocytic leukemia 1 (MKL1), a transcriptional modulator, to liver regeneration. We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients. Mice with MKL1 deletion exhibited defective regenerative response in the liver. Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription. MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1. Of interest, phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid (PA). PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure. Finally, PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients. In conclusion, our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration. Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

OBJECTIVE To establish the characteristic chromatogram of the volatile oil in the standard decoction of Qingshang juantong decoction， and preliminarily infer the main active components of volatile oil that affect the clinical therapeutic effect. METHODS The volatile oil in the standard decoction of Qingshang juantong decoction was extracted by steam distillation. The ultra-high performance liquid chromatography （UPLC） characteristic chromatograms of 15 batches of samples were established by the Similarity Evaluation System of TCM Chromatographic Fingerprint （2012 edition）， and the similarity evaluation was carried out. The volatile oil of standard decoction was identified by UPLC coupled with quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF/MS）. Then the volatile oil components were analyzed by GC-MS. RESULTS The similarities of UPLC characteristic chromatograms for volatile oil of 15 batches of Qingshang juantong decoction were between 0.949 and 0.997. A total of 12 common peaks were obtained. According to the UPLC-Q-TOF/MS， the main components were methyl eugenol， E-ligustilide， E-butylidenephthalide and so on. A total of 23 components were identified by GC-MS， which were mainly 3，4，5-trimethoxy- methylbenzene， patchouli alcohol， Z-ligustilide and so on. CONCLUSIONS The characteristic chromatograms of the volatile oil in the standard decoction of Qingshang juantong decoction is established， and it is inferred that methyl eugenol， ligustilide， E- butylidenephthalide， patchouli alcohol， 3，4，5-trimethoxy-methylbenzene might be the main active components affecting the clinical therapeutic effect of the volatile oil of Qingshang juantong decoction.