OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

ObjectiveTo explore the mechanism of Astragali Radix-Aconiti Lateralis Radix Praeparata in the treatment of heart failure and substance basis based on ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometer （UPLC-Q-TOF-MS） and network pharmacology. MethodThe chemical components of Astragali Radix-Aconiti Lateralis Radix Praeparata solution was analyzed by UPLC-Q-TOF-MS， and the active components and targets were screened out by the PubChem database. The targets related to heart failure disease were retrieved from Comparative Toxicogenomics Database（CTD）， Online Mendelian Inheritance in Man （OMIM）， and GeneCard databases， and the common targets were obtained by Venn analysis. The target protein-protein interactions （PPI） were analyzed using the STRING database. Gene ontology （GO） functional enrichment analysis and Kyoto encyclopedia of genes and genomes （KEGG） pathway enrichment analysis were performed using the Metascape database， and molecular docking verification of key targets and active components was performed using SYBYL-X 2.1.1. Experimental validation of key targets was carried out using the rat model of heart failure. ResultThere were 202 chemical components identified in Astragali Radix-Aconiti Lateralis Radix Praeparata solution， of which 64 active components were predicted to act on 183 targets for the treatment of heart failure. The important active components were caffeic acid， L-arginine， biochanin A， adenine， nicotinic acid， trans-ferulic acid， p-coumaric acid， riboflavin， calycosin， etc. The main targets were interleukin （IL）-6， cysteine aspartic acid specific protease （Caspase）-3， vascular endothelial growth factor A （VEGFA）， protein kinase B1 （Akt1）， tumor necrosis factor （TNF）， IL-1B， matrix metallopeptidase （MMP）-9， etc. The main signaling pathways involved hypoxia-inducible factor （HIF）-1 signaling pathway， TNF signaling pathway， phosphatidylinositol 3-kinase （PI3K）/Akt signaling pathway， Toll-like receptor signaling pathway， mitogen-activated protein kinase （MAPK） signaling pathway， forkhead box O （FoxO） signaling pathway， etc. The molecular docking results showed that the active components in Astragali Radix-Aconiti Lateralis Radix Praeparata solution had a good binding ability with HIF-1α， VEGFA， Akt1， Caspase-3， and IL-6， which were the key proteins in the HIF-1 signaling pathway. Animal experiments showed that Astragali Radix-Aconiti Lateralis Radix Praeparata solution significantly improved the hemodynamic indexes， reduced the serum atrial natriuretic peptide （ANP）， brain natriuretic peptide （BNP）， and IL-6 levels， improved the myocardial histopathological changes， protected the mitochondrial morphology of cardiomyocytes， down-regulated the expression of HIF-1α， VEGFA and phosphorylation（p）-Akt， and reduced the activation of Caspase-3 in the myocardial tissue of rats with heart failure. ConclusionAstragali Radix-Aconiti Lateralis Radix Praeparata treats heart failure in a multi-component， multi-target， and multi-pathway manner. The experimental validation indicates that it treats heart failure by improving myocardial histopathological changes and regulating HIF-1 signaling pathway， which provides references for the subsequent pharmacodynamic substance research.

ObjectiveTo explore the risk factors of stroke， and to provide reference for the prevention and health management of stroke. MethodsFrom February 2022 to March 2022， four community residents over 60 years old with stroke in Shanghai were randomly selected as the case group （n=100）， and non-stroke residents were selected as the control group （n=100）. The survey was in the form of questionnaires to record and compare the age， body mass index （BMI）， blood lipids， blood pressure-related indicators， family history of other diseases， living habits， mood and sleep conditions of all subjects. The value of predicting the incidence of stroke among the elderly in Shanghai community was analyzed by receiver operating characteristic （ROC）， and the influencing factors of stroke were analyzed by logistic model. ResultsBMI， hypertension， heart disease， diabetes， transient ischemic attack （TIA）， dyslipidemia， family history of stroke， smoking， lack of exercise or only light physical labor， SBP， DBP， TG levels were significantly higher in the case group （P<0.05）. The level of HDL-C was significantly lower than that in the control group （P<0.05）. BMI， SBP， DBP， TG， HDL-C predicted the incidence of stroke by ROC analysis （P<0.05）. Logistic regression analysis showed that BMI≥23.820 kg·m^-2， heart disease， diabetes， TIA， dyslipidemia， family history of stroke， smoking， lack of exercise or only light physical labor， SBP≥139.535 mmHg， DBP≥89.605 mmHg， TG≥1.565 mmol·L^-1 and HDL-C≤1.105 mmol·L^-1 were risk factors for stroke （P<0.05）. ConclusionPhysical health status including blood lipids and blood pressure， family history of certain diseases， and living habits could be important risk factors for stroke in the elderly in Shanghai community. Preventive intervention measures for the above factors have important clinical significance.

Objective: To investigate the efficacy of the first-day suspension method for improving the success rate of construction of nasopharyngeal carcinoma-patient derived organoids (NPC-PDO). Methods: The tumor samples of 14 nasopharyngeal carcinoma(NPC) patients, i.e.,13 males and 1 female, with a mean age of 43.0±12.0 years old, were collected from the Affiliated Tumor Hospital of Guangxi Medical University and the First Affiliated Hospital of Guangxi Medical University from January 2022 to July 2022. The tumor samples of 3 patients were digested into single cell suspension and divided into 2 groups, for comparing the efficacy of NPC-PDO construction by the direct inoculation method and the first-day suspension method. The remaining 11 patients were randomized to receive either the direct inoculation method or the first-day suspension method for NPC-PDO construction. The diameter and the number of spheres of NPC-PDO constructed by the two methods were compared by optical microscope; the 3D cell viability detection kit was used to compare the cell viability; the survival rates were compared by trypan blue staining; the success rates of the two construction methods were compared; the number of cases which could be successfully passaged for more than 5 generations and were consistent with the original tissue by pathological examination was counted; and the dynamic changes of cells in suspension overnight were observed by live cell workstation. The independent sample t-test was applied to compare the measurement data of the two groups, and the chi-square test was used to compare the classification data. Results: Compared with the direct inoculation, the diameter and the number of spheres of NPC-PDO constructed by the first-day suspension method were increased, with a higher cell activity, and the success rate of construction was obviously improved (80.0% vs 16.7%, χ²=4.41, P<0.05). In the suspension state, some of the cells aggregated and increased their ability to proliferate. Conclusion: The first-day suspension method can improve the success rate of NPC-PDO construction, especially for those whose original tumor sample size is small.
Male ; Humans ; Female ; Adult ; Middle Aged ; Nasopharyngeal Carcinoma ; China ; Microscopy ; Organoids ; Nasopharyngeal Neoplasms

【Objective】 To explore the emergency treatment of penoscrotal avulsion injury based on the American Association for Surgery and Trauma (AAST) penoscrotal injury grade. 【Methods】 Data of 30 patients with penoscrotal avulsion injury treated in our hospital with in-situ suture, skin grafting or skin flap during Oct.2003 and Dec.2017 were reviewed. 【Results】 Among the 30 patients, 29 received emergency surgery, including in-situ suturein 15 grade Ⅰ-Ⅲ cases, skin graft in 8 grade Ⅳ-Ⅴ cases, and skin flap in 6 cases;1 case received delayed operation due to wound infection on admission. In the perioperative period,25 cases had more than 90% wound healing, 3 cases had 70% wound healing after wound dressing change, and 2 cases had complete necrosis. Second-stage skin graft yielded satisfactory penoscrotal appearance. 【Conclusion】 According to the specific conditions of patients, reasonable surgical methods can be selected. For grade Ⅰ-Ⅲ patients, in-situ suture can be used, while for grade Ⅳ-Ⅴ patients, wound condition, age, fertility and other factors should be taken into consideration so as to preserve the function of testis to the maximum extent.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Long-segment lichen sclerosus (LS) urethral stricture is a challenge for urologists. Limited data are available for surgeons to make a surgical decision between Kulkarni and Asopa urethroplasty. In this retrospective study, we investigated the outcomes of these two procedures in patients with LS urethral stricture. Between January 2015 and December 2020, 77 patients with LS urethral stricture underwent Kulkarni and Asopa procedures for urethroplasty in the Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China). Of the 77 patients, 42 (54.5%) underwent the Asopa procedure and 35 (45.5%) underwent the Kulkarni procedure. The overall complication rate was 34.2% in the Kulkarni group and 19.0% in the Asopa group, and no difference was observed ( P = 0.105). Among the complications, no statistical difference was observed in the incidence of urethral stricture recurrence ( P = 0.724) or glans dehiscence ( P = 0.246) except for postoperative meatus stenosis ( P = 0.020). However, the recurrence-free survival rate between the two procedures was significantly different ( P = 0.016). Cox survival analysis showed that antiplatelet/anticoagulant therapy use ( P = 0.020), diabetes ( P = 0.003), current/former smoking ( P = 0.019), coronary heart disease ( P < 0.001), and stricture length ( P = 0.028) may lead to a higher hazard ratio of complications. Even so, these two techniques can still provide acceptable results with their own advantages in the surgical treatment of LS urethral strictures. The surgical alternative should be considered comprehensively according to the patient characteristics and surgeon preferences. Moreover, our results showed that antiplatelet/anticoagulant therapy use, diabetes, coronary heart disease, current/former smoking, and stricture length may be contributing factors of complications. Therefore, patients with LS are advised to undergo early interventions for better therapeutic effects.
Male ; Humans ; Urethral Stricture/etiology* ; Retrospective Studies ; Constriction, Pathologic/surgery* ; Lichen Sclerosus et Atrophicus/surgery* ; Treatment Outcome ; Urologic Surgical Procedures, Male/methods* ; China ; Urethra/surgery* ; Postoperative Complications/etiology* ; Mouth Mucosa ; Diabetes Mellitus/etiology* ; Anticoagulants ; Coronary Disease

Objective:To analyze the prognostic factors and evaluate the accuracy of existing survival prediction models in patients with lung cancer-derived spinal metastases who have undergone open surgery.Methods:According to the inclusion criteria, the data of 76 patients with spinal metastasis of lung cancer who underwent open surgery in the department of Orthopedics in Guangdong Provincial People's Hospital were collected from January 2019 to November 2021. The relationship between the number of bone metastasis, pathological type, visceral metastasis, epidermal growth factor receptor mutation, serum alkaline phosphatase (ALP), hemoglobin (Hb), Frankel grade and postoperative survival time in 76 cases was analyzed by Cox logical regression analysis and Kaplan-Meier method to determine the potential prognostic factors. The accuracy of Tomita score, Tokuhashi revised score, Katagiri New score, New England Spinal Metastasis Score score (NESMS) and Skeletal Oncology Research Group (SORG) machine learning algorithm in predicting postoperative survival time was verified by drawing receiver operating characteristic (ROC) curve.Results:The median follow-up time of the patients was 18.0 months (2.3-36.0 months). The median survival time was 12.6 months [95% CI (10.8, 14.4)]. The survival rates at 6 and 12 months after operation were 71.6% and 52.0%, respectively. Multivariate regression analysis showed that ALP [ HR=0.23, 95% CI (0.11, 0.48), P<0.001], Hb [ HR=4.48, 95% CI (2.07, 9.70), P< 0.001] and EGFR mutation [ HR=2.22, 95% CI (1.04, 4.76), P=0.040] were independent predictors of prognosis. The accuracy of Tomita score, Tokuhashi revised score (2005), Katagiri New score and NESMS score in predicting 1-year mortality was 58.7%, 65.7%, 70.5% and 65% respectively, and the accuracy in predicting 6-month mortality was 63.7%, 62.2%, 61.2% and 56.8% respectively. The accuracy of SORG machine learning algorithm in predicting 1-year and 90 d mortality was 81.1%, 67.5%, respectively. Conclusion:No EGFR mutation, ALP>164 U/L and Hb≤125 g/L were risk factors affecting the survival of patients with spinal metastasis of lung cancer. SORG machine learning algorithm has good accuracy in predicting the postoperative survival rate of patients with lung cancer spinal metastasis.

Taking lipophagy as the breakthrough point, we explored the mechanism of Zexie Decoction(ZXD) in improving lipid metabolism in the hepatocyte model induced by palmitic acid(PA) and in the animal model induced by high-fat diet(HFD) on the basis of protein kinase B(Akt)/transcription factor EB(TFEB) signaling pathway. Co-localization was carried out for the microtubule-associated protein light chain 3(LC3) plasmid labeled with green fluorescent protein(GFP) and lipid droplets(LDs), and immunofluorescence co-localization for liver LC3 of HFD mice and perilipin 2(PLIN2). The results showed that ZXD up-regulated the expression of LC3, reduced lipid accumulation in hepatocytes, and increased the co-localization of LC3 and LDs, thereby activating lipo-phagy. Western blot results confirmed that ZXD increased autophagy-related protein LC3Ⅱ/LC3Ⅰ transformation ratio and lysosome-associated membrane protein 2(LAMP2) in vivo and in vitro and promoted the degradation of sequestosome-1(SQSTM1/p62)(P<0.05). The results above jointly explained that ZXD regulated lipophagy. Furthermore, ZXD activated TFEB expression(P<0.05) and reversed the PA-and HFD-induced decrease of TFEB nuclear localization in hepatocytes(P<0.05). Meanwhile, ZXD activated liver TFEB to up-regulate the expression of the targets Lamp2, Lc3 B, Bcl2, and Atg5(P<0.05). Additionally, ZXD down-regulated the protein level of p-Akt upstream of TFEB in vivo and in vitro. In conclusion, ZXD may promote lipophagy by regulating the Akt/TFEB pathway.
Animals ; Mice ; Autophagy/drug effects* ; Hepatocytes/metabolism* ; Microtubule-Associated Proteins/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Signal Transduction ; Drugs, Chinese Herbal/pharmacology*