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

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 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.

Objective:To observe the efficacy and safety of subretinal injection of Aflibercept for the treatment of refractory or recurrent polypoidal choroidal vasculopathy (PCV).Methods:A prospective clinical research. From January to June 2022, 18 patients of 18 eyes with PCV diagnosed in The Affiliated Eye Hospital of Nanchang University were included in the study. All patients underwent best corrected visual acuity (BCVA), indocyanine green angiography and optical coherence tomography (OCT). The BCVA examination was performed using the international standard visual acuity chart, which was converted to logarithm of the minimum angle of resolution (logMAR) visual acuity during statistics. The large choroidal vessel thickness (LVCT), central retinal thickness (CRT), sub-foveal choroidal thickness (SFCT) and retinal pigment epithelium detachment (PED) height were measured by enhanced depth imaging technique of OCT. The choroidal vascular index (CVI) was calculated. There were 18 patients of 18 eyes, 11 males of 11 eyes and 7 females of 7 eyes. The age was (64.22±3.86) years old. The disease duration was (5.22±1.80) years. The patient had received intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs for (7.72±1.36) times. The logMAR BCVA of the affected eyes was 1.28±0.25. The SFCT, CRT, LVCT, PED height were (436.56±9.80), (432.44±44.29), (283.78±27.10), (342.44±50.18) μm, respectively, and CVI was 0.65±0.01. All eyes were treated with a single subretinal injection of 40 mg/ml Aflibercept 0.05 ml (including Aflibercept 2.0 mg). According to the results of OCT and BCVA after treatment, the lesions were divided into active type and static type. The active lesions were treated with intravitreal injection of Aflibercept at the same dose as before. Quiescent lesions were followed up. Examinations were performed 1-3, 6, 9 and 12 months after treatment using the same equipment and methods before treatment. The BCVA, LVCT, CRT, SFCT, PED height, CVI, interretinal or subretinal fluid, lesion regression rate, injection times, and complications during and after treatment were observed. The BCVA, SFCT, CRT, LVCT, PED height and CVI before and after treatment were compared by repeated measures analysis of variance.Results:Eighteen eyes received subretinal and/or intravitreal injection of Aflibercept (1.61±0.85) times (1-4 times). At the last follow-up, the polypoid lesions regressed in 4 eyes and PED disappeared in 1 eye. Compared with before treatment, BCVA ( F=50.298) gradually increased, CRT ( F=25.220), PED height ( F=144.16), SFCT ( F=69.77), LVCT ( F=136.69), CVI ( F=72.70) gradually decreased after treatment. The differences were statistically significant ( P<0.001). Macular hole occurred in 1 eye after treatment, and the hole closed spontaneously 3 months after treatment. No serious complications such as retinal tear, retinal detachment, endophthalmitis and vitreous hemorrhage occurred during and after treatment. Conclusion:Subretinal injection of Aflibercept is safe and effective in the treatment of refractory PCV.

Objective:To observe the efficacy and safety of vitrectomy combined with subretinal injection of alteplase (tPA) and intravitreal injection of Conbercept in the treatment of large area submacular hemorrhage (SMH) secondary to polypoidal choroidal vasculopathy (PCV).Methods:A retrospective clinical study. From January to September 2021, 32 eyes of 32 patients with massive SMH secondary to PCV diagnosed in the Affiliated Eye Hospital of Nanchang University were included in the study. Large SMH was defined as hemorrhage diameter ≥4 optic disc diameter (DD). There were 32 patients (32 eyes), 20 males and 12 females. The mean age was (72.36±8.62) years. All patients had unilateral disease.The duration from onset of symptoms to treatment was (7.21±3.36) days. All patients underwent best corrected visual acuity (BCVA) and optical coherence tomography (OCT) examination. BCVA examination was performed using the international standard visual acuity chart, which was converted to the logarithm of the minimum angle of resolution (logMAR) visual acuity during statistics. The central macular thickness (CMT) was measured by spectral domain-OCT. The average size of SMH was (6.82±1.53) DD. The logMAR BCVA 1.73±0.44; CMT was (727.96±236.40) μm. All patients were treated with 23G pars plana vitrectomy combined with subretinal injection of tPA and intravitreal injection of Conbercept. At 1, 3, 6 and 12 months after treatment, the same equipment and methods were used for relevant examinations before treatment. The changes of BCVA and CMT, the clearance rate of macular hemorrhage, and the complications during and after surgery were observed. BCVA and CMT before and after treatment were compared by repeated measures analysis of variance.Results:Compared with before treatment, BCVA gradually increased at 1, 3, 6 and 12 months after treatment, and the differences were statistically significant ( F=77.402, P<0.001). There was no significant difference in BCVA between any two groups at different time points after treatment ( P>0.05). Correlation analysis showed that BCVA at 12 months after treatment was negatively correlated with the course of disease ( r=-0.053, P=0.774). One week after treatment, macular hemorrhage was completely cleared in 30 eyes (93.75%, 30/32). The CMT was (458.56±246.21), (356.18±261.46), (345.82±212.38) and (334.64±165.54) μm at 1, 3, 6 and 12 months after treatment, respectively. Compared with before treatment, CMT decreased gradually after treatment, and the difference was statistically significant ( F=112.480, P<0.001). There were statistically significant differences in different follow-up time before and after treatment ( P<0.001). The number of treatments combined with Conbercept during and after surgery was (4.2±1.8) times. At the last follow-up, there was no recurrence of SMH, retinal interlamellar effusion and other complications. Conclusion:Subretinal injection of tPA combined with intravitreal injection of Conbercept is safe and effective in the treatment of large SMH secondary to PCV, and it can significantly improve the visual acuity of patients.

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.

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.