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.

Oral and maxillofacial malignant tumors threaten the life and health of patients, and seriously affect their swallowing, language function and face. 125I seeds brachytherapy for oral and maxillofacial malignant tumors has been widely concerned and studied because of its advantages such as less surgical trauma, large and uniform dose distribution in the target tissue, little damage to the surrounding normal tissue, and reducing radiation exposure of medical staff. Low-dose brachytherapy with 125I seeds can effectively reduce the tumor volume and prolong the survival time of patients. This article reviews the clinical application of 125I seeds brachytherapy in oral and maxillofacial malignant tumors.

This article systematically elaborates on the origin and development of natural orifice specimen extraction surgery(NOSES)in the treatment of colorectal tumors.By analyzing several retrospective studies,we summarize the scientific basis,feasibility,and clinical advantages of applying NOSES in the treatment of colorectal tumors.Additionally,the article points out certain limitations in terms of operational techniques and the selection of indications for NOSES,which require continuous optimization and improvement.Advancements in technology have enabled NOSES to become increasingly integrated with new technologies.Accordingly,its application prospects in colorectal surgery and across multiple disciplines are broadened.

[Objective]People infected with Hepatitis B are often divided into hepatitis B carriers and hepatitis B patients based on whether ALT is normal or not,and ALT ≥ 2UNL is one of the indications for clinical antiviral treatment,but no sufficient evidence to justify this. In order to explore the theoretical basis,the paper investigated the effects of hepatitis B virus(HBV) on hepatic stellate cells(HSCs).[Methods]A total of 132 chronic hepatitis B patients with different viral loads and ALT levels were randomly selected as the study subjects. Of these patients,those with ALT≥2UNL were treated with antiviral therapy and followed up for 24 weeks. The effects of HBV on HSCs before and after the treatment were compared and analyzed. HSCs proliferation was detected by MTT method,HSCs cell cycle by flow cytometry,and expression of TGF-β1,Smad3,Smad7,α-SMA,collagen Ⅰ,collgen Ⅲ mRNAs and corresponding proteins by RT-PCR and Western blotting,respectively.[Results]At the normal ALT level,HBV with different viral loads had no significant effect on the proliferation,cell cycle and cell secretion of the HSCs. At the abnormal ALT level,especially when ALT ≥ 2UNL,with the increase of virus loads,HSCs proliferation accelerated;cells in the G0/G1 phase decreased significantly and cells in the S and G2/M phases increased significantly;the expression of TGF-β1,Smad3,α-SMA,collagen Ⅰ,collgen Ⅲ mRNAs and corresponding proteins increased significantly,but Smad7 mRNA and protein expression decreased significantly,the differences were statistically significant. HBV showed a significantly lower effect on HSCs after the antiviral therapy than before.[Conclusions]This paper reveals the differential effects of HBV on HSCs at different ALT levels and presents a comparative analysis of the effects before and after the antiviral therapy,which provides a theroretical basis for identifying the ALT level as an indication for HBV antiviral therapy.

Objective:To investigate the value of implantable cardiac monitor (ICM) in the diagnosis and treatment of patients over 60 years old with unexplained syncope.Methods:This was a multi-center, prospective cohort study. Between June 2018 and April 2021, patients over the age of 60 with unexplained syncope at Beijing Hospital, Fuwai Hospital, Beijing Anzhen Hospital and Puren Hospital were enrolled. Patients were divided into 2 groups based on their decision to receive ICM implantation (implantation group and conventional follow-up group). The endpoint was the recurrence of syncope and cardiogenic syncope as determined by positive cardiac arrhythmia events recorded at the ICM or diagnosed during routine follow-up. Kaplan‐Meier survival analysis was used to compare the differences of cumulative diagnostic rate between the 2 groups. A multivariate Cox regression analysis was performed to determine independent predictors of diagnosis of cardiogenic syncope in patients with unexplained syncope.Results:A total of 198 patients with unexplained syncope, aged (72.9±8.25) years, were followed for 558.0 (296.0,877.0) d, including 98 males (49.5%). There were 100 (50.5%) patients in the implantation group and 98 (49.5%) in the conventional follow-up group. Compared with conventional follow-up group, patients in the implantation group were older, more likely to have comorbidities, had a higher proportion of first degree atrioventricular block indicated by baseline electrocardiogram, and had a lower body mass index (all P<0.05). During the follow-up period, positive cardiac arrhythmia events were recorded in 58 (58.0%) patients in the ICM group. The diagnosis rate (42.0% (42/100) vs. 4.1% (4/98), P<0.001) and the intervention rate (37.0% (37/100) vs. 2.0% (2/98), P<0.001) of cardiogenic syncope in the implantation group were higher than those in the conventional follow-up group (all P<0.001). Kaplan-Meier survival analysis showed that the cumulative diagnostic rate of cardiogenic syncope was significantly higher in the implantation group than in the traditional follow-up group ( HR=11.66, 95% CI 6.49-20.98, log-rank P<0.001). Multivariate analysis indicated that ICM implantation, previous atrial fibrillation, diabetes mellitus or first degree atrioventricular block in baseline electrocardiogram were independent predictors for cardiogenic syncope (all P<0.05). Conclusions:ICM implantation improves the diagnosis and intervention rates in patients with unexplained syncope, and increases diagnostic efficiency in patients with unexplained syncope.

Objective:To evaluate the effect of the right stellate ganglion block (SGB) on the acute lung injury induced by hind limb ischemia-reperfusion (I/R) in rats.Methods:Twenty-seven SPF healthy male Sprague-Dawley rats, aged 7-8 weeks, weighing 200-250 g, were divided into 3 groups ( n=9 each) by the random number table method: sham operation group (Sham group), hind limb I/R group (I/R group) and right SGB+ hind limb I/R group (SGB+ I/R group). The right hind limb I/R injury model was developed in anesthetized rats in I/R and SGB+ I/R groups, and the right SGB was performed with 0.2% ropivacaine 0.5 ml before the right hind limb ischemia in SGB+ I/R group. The pathological changes of lung tissues were observed with a light microscope, the wet/dry lung weight ratio, PaO 2 and PaCO 2 were determined, and the oxygenation index was calculated. The concentrations of serum malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) were determined using enzyme-linked immunosorbent assay. Results:Compared with Sham group, the wet/dry lung weight ratio, PaO 2, oxygenation index, and GSH-Px concentrations were significantly decreased, and the concentrations of serum MDA were increased in I/R and SGB+ I/R groups ( P<0.05). Compared with I/R group, the wet/dry lung weight ratio, PaO 2, oxygenation index, and GSH-Px concentrations were significantly increased, the concentrations of serum MDA were decreased ( P<0.05), and the pathological changes of lung tissues were significantly attenuated in SGB+ I/R group. There was no significant difference in PaCO 2 among the 3 groups ( P>0.05). Conclusions:The right SGB can alleviate the acute lung injury induced by hind limb I/R, and the mechanism may be related to the inhibition of oxidative stress responses in rats.

OBJECTIVE: To explore the mechanism underlying the inhibitory effect of quercetin against testicular oxidative damage induced by a mixture of 3 commonly used phthalates (MPEs) in rats. METHODS: Forty male Sprague-Dawley rats were randomly divided into control group, MPEs exposure group, and MPEs with low-, median- and high-dose quercetin treatment groups. For MPEs exposure, the rats were subjected to intragastric administration of MPEs at the daily dose of 900 mg/kg for 30 consecutive days; Quercetin treatments were administered in the same manner at the daily dose of 10, 30, and 90 mg/kg. After the treatments, serum levels of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testicular malondialdeyhde (MDA), catalase (CAT) and superoxide dismutase (SOD) were detected, and testicular pathologies of the rats were observed with HE staining. The expressions of nuclear factor-E2-related factor 2 (Nrf2), Kelch-like ECH2 associated protein 1 (Keap1) and heme oxygenase 1 (HO-1) in the testis were detected using immunofluorescence assay and Western blotting. RESULTS: Compared with the control group, the rats with MPEs exposure showed significant reductions of the anogenital distance, weight of the testis and epididymis, and the coefficients of the testis and epididymis with lowered serum testosterone, LH and FSH levels (P < 0.05). Testicular histological examination revealed atrophy of the seminiferous tubules, spermatogenic arrest, and hyperplasia of the Leydig cells in MPEs-exposed rats. MPEs exposure also caused significant increments of testicular Nrf2, MDA, SOD, CAT and HO-1 expressions and lowered testicular Keap1 expression (P < 0.05). Treatment with quercetin at the median and high doses significantly ameliorated the pathological changes induced by MPEs exposure (P < 0.05). CONCLUSION Quercetin treatment inhibits MPEs-induced oxidative testicular damage in rats possibly by direct scavenging of free radicals to lower testicular oxidative stress and restore the regulation of the Nrf2 signaling pathway.
Rats ; Male ; Animals ; Testis ; Quercetin/pharmacology* ; Rats, Sprague-Dawley ; NF-E2-Related Factor 2/metabolism* ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Oxidative Stress ; Testosterone/pharmacology* ; Superoxide Dismutase/metabolism* ; Follicle Stimulating Hormone ; Luteinizing Hormone

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the canonical type IV exporter fold. Herein, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, or ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the transmembrane domains (TMDs), and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-electron microscopy (Cryo-EM) structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB. Moreover, the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle. This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.
Siderophores/metabolism* ; Iron/metabolism* ; Mycobacterium tuberculosis/metabolism* ; Cryoelectron Microscopy ; Adenosine Triphosphate/metabolism* ; ATP-Binding Cassette Transporters

Heme/metabolism* ; Cryoelectron Microscopy ; Membrane Transport Proteins ; Escherichia coli Proteins/metabolism*