In this study, we designed and synthesized 12 novel aloperine derivatives with different core structures. Among them, compound 3 with a ten-membered ring core was obtained through a special ring expansion reaction after γ-H Huffman elimination of quaternary ammonium salt, and the structure was verified by X-single crystal diffraction. Furthermore, their antiviral activity against human β-coronavirus HCoV-OC43 was evaluated by CCK-8 assay. Quaternary ammonium salt 2a and 3 had a good inhibitory effect against HCoV-OC43, and 2a had the highest anti-HCoV-OC43 activity with an EC₅₀ values of 3.77 μmol·L^-1 and a SI value of over 53.1. Schrӧdinger molecular docking results showed that both 2a and 3 might display their anti-HCoV-OC43 activity by directly acting on host TMPRSS2 and SR-B1. The results expanded the structural types of endocyclic aloperine and the function against coronavirus, and provided useful scientific data for the development of pharmaceutical applications of these compounds.

Objective:To evaluate the safety and efficacy of tumor-treating fields (TTFields) and chemoradiation in patients with high-grade glioblastoma.Methods:Clinical data of 38 patients admitted to the Jiangsu Cancer Hospital from September 2021 to May 2023 who were diagnosed with high-grade glioblastoma (36 cases of World Health Organization grade Ⅳ and 2 cases of grade Ⅲ) were retrospectively analyzed. All patients received TTFields combined with concurrent chemoradiation after surgery. Response assessment in neuro-oncology (RANO) criteria was used to evaluate the glioma responses as tumor remission, stable or progression. Common terminology criteria for adverse events v5.0 and TTFields related skin adverse reaction (dAE) criteria were used to evaluate the adverse events. Treatment compliance was assessed by data on the NovoTTF-200A therapeutic device, calculated as a percentage of daily TTFields usage time. Survival analysis was estimated by the Kaplan-Meier method and compared by the log-rank test.Results:The median duration of treatment with TTFields in 38 patients was 20 h (rang: 2.4-22.6 h), and the median treatment compliance was 83% (range: 10%-94%). After 42 days of TTFields combined with concurrent chemoradiation, 12 patients who underwent complete tumor resection were assessed as stable according to RANO criteria. Among the 26 patients who underwent partial tumor resection, 23 (88%) were evaluated as disease remission according to RANO criteria. The 7-, 10-, 13-month progression-free survival rate was 81.0%、64.0%、49.5%, repectively. The common adverse events included grade 1 (45%) and grade 2 (8%) dAE, without grade 3-4 dAE. Typical presentations included contact dermatitis, blisters, lesions or ulcers, and abscesses. The median follow-up time was 10.0 months (range: 1.6-21.3 months). At follow-up as of July 2023, 26 of the 38 patients were stable and 12 had disease progression (8 died).Conclusion:The preliminary results show that TTFields combined with chemoradiation is effective, safe and reliable treatment for high-grade glioblastoma.

Objective:To explore the clinical characteristics,molecular characteristics,treatment and prognosis of pediatric Philadelphia chromosome-like acute lymphoblastic leukemia(Ph-like ALL)with a therapeutic target.Methods:A total of 27 patients of Ph-like ALL with targeted drug target were initially diagnosed in Children's Hospital of Soochow University from December 2017 to June 2021.The data of age,gender,white blood cell(WBC)count at initial diagnosis,genetic characteristics,molecular biological changes,chemotherapy regimen,different targeted drugs were given,and minimal residual disease(MRD)on day 19,MRD on day 46,whether hematopoietic stem cell transplantation(HSCT)were retrospective analyed,and the clinical characteristics and treatment effect were summarized.Survival analysis was performed by Kaplan-Meier method.Results:The intensity of chemotherapy was adjusted according to the MRD level during induced remission therapy in 27 patients,10 patients were treated with targeted drugs during treatment,and 3 patients were bridged with HSCT,1 patient died and 2 patients survived.Among the 24 patients who did not receive HSCT,1 patient developed relapse,and achieved complete remission(CR)after treatment with chimeric antigen receptors T cells(CAR-T).The 3-year overall survival,3-year relapse-free survival and 3-year event-free survival rate of 27 patients were(95.5±4.4)％,(95.0±4.9)％and(90.7±6.3)％respectively.Conclusion:Risk stratification chemotherapy based on MRD monitoring can improve the prognosis of Ph-like ALL in children,combined with targeted drugs can achieve complete remission as soon as possible in children whose chemotherapy response is poor,and sequential CAR-T and HSCT can significantly improve the therapeutic effect of Ph-like ALL in children whose MRD is continuously positive during induced remission therapy.

Aim To investigate the mechanism of treatment of hepatolenticular degeneration with Garde-nia and Rhubarb decoction based on network pharma-cology and animal experiments.Methods The chemi-cal components and target sites of Gardenia and Rhu-barb decoction were retrieved using the Traditional Chi-nese Medicine System Pharmacology Analysis Platform(TCMSP).The disease targets were obtained by searching the databases of DisGeNET,GeneCards.The PPI network of active compound target sites was constructed using the STRING database.GO function and KEGG pathway enrichment analysis were per-formed using the DAVID database to predict the action pathway.A copper-loaded WD rat model was estab-lished by intragastric administration of copper sulfate pentahydrate.A total of 36 rats were randomly divided into the normal group,model group,penicillamine group and the low,medium and high dose groups of gardenia rhubarb.The relevant indicators and patho-logical changes of liver tissue were detected in WD rats.Results Network pharmacology screening identi-fied 68 potential active components of Gardenia and Rhubarb Decoction,30 intersection targets of diseases and drugs,involving key targets such as TNF,IL10,IGF1,IL1B,TP53,CASP3,PPARG,IL6,CXCL8,IL1A,TGFB1,mainly related to signal pathways such as MAPK,AGE-RAGE signaling pathway in diabetic complications.In the animal experiments,compared with the normal group,the urine copper,liver copper,blood copper,liver coefficient,serum and liver ALT,AST,TNF-α,CASP3,P53 levels in the model group rats significantly increased(P＜0.05);hepatocyte swelling,cytoplasm loose reticular appearance,feath-er-like degeneration and reticular necrosis were ob-served in liver tissue pathology;compared with the model group,the urine copper,liver copper,blood copper,liver coefficient,serum and liver ALT,AST,TNF-α,CASP3,P53 levels in the penicillamine group and Gardenia and Rhubarb decoction groups were sig-nificantly reduced(P＜0.05),and the degree of re-ticular necrosis in the rat liver cells in the penicilla-mine group and the Gardenia and Rhubarb decoction group was significantly reduced.Conclusions Garde-nia and Rhubarb decoction has the effect of regulating copper metabolism and reducing liver injury.The mechanism of action may be related to reversing apop-tosis and downregulating protein expression of TNF-α,CASP3,P53 in MAPK signaling pathway.

Objective:To investigate the treatment strategy and prognostic factors of nasopharyngeal necrosis after the first radical radiotherapy for nasopharyngeal carcinoma.Methods:Clinical data of 1020 patients with nasopharyngeal carcinoma undergoing radical intensity-modulated radiotherapy in Jiangsu Cancer Hospital from January 2013 to January 2022 were retrospectively analyzed. Nasopharyngeal necrosis was confirmed by nasopharyngeal MRI, electronic nasopharyngoscopy and biopsy. Patients with nasopharyngeal necrosis were treated with electronic nasopharyngoscope irrigation debridement, combined with systemic anti-infection and nutritional support therapy. Kaplan-Meier method was used to calculate the survival, and Cox regression analysis was used to analyze the relationship between clinical factors and patients' survival.Results:Nasopharyngeal necrosis occurred in 20 cases of 1020 nasopharyngeal carcinoma patients after the first radical intensity-modulated radiotherapy, with an incidence rate of 1.96%. Odd smell and headache were common in nasopharyngeal necrosis patients. All patients had locally advanced nasopharyngeal carcinoma at initial treatment, including 2 (10%) cases of T 3 stage and 18 (90%) cases of T 4 stage. Nasopharyngeal necrosis occurred in the primary nasopharyngeal lesions. According to the stages of nasopharyngeal necrosis, there were 6 (30%) cases of stage I, 14 (70%) cases of stage II and no stage III. The occurrence time of nasopharyngeal necrosis was from 2 to 24 months after radiotherapy, and the median time was 5 months. All 16 cases of nasopharyngeal necrosis were cured clinically after debridement and irrigation under nasopharyngoscope, systemic anti-infection and symptomatic support treatment. Among them, 9 cases had no necrotic cavity and complete healing and 7 cases had residual necrotic cavity. Four patients died of massive nasopharyngeal hemorrhage or due to the inability to nasopharyngeal irrigation. The 5-year survival rates were 37.5% and 85.7% in patients with and without internal carotid artery involvement ( P=0.008), and 25.0% and 77.8% in patients with and without diabetes mellitus ( P=0.016). Univariate Cox regression analysis showed that necrotic lesions involving internal carotid artery ( HR=5.80, 95% CI=1.14-29.38, P=0.034) and diabetes mellitus ( HR=10.24, 95% CI=1.19-88.04, P=0.034) were the influencing factors of overall survival. Conclusions:Nasopharyngoscope irrigation debridement combined with anti-inflammation and nutritional support treatment are effective interventions for nasopharyngeal necrosis after the first radical intensity-modulated radiotherapy in patients with nasopharyngeal carcinoma. The necrosis involving the internal carotid artery and diabetes mellitus are important factors affecting the survival of patients. Vascular invasion caused by vascular rupture is the main cause of death.

OBJECTIVES: Sepsis is a critical dysregulated host response with high mortality and current treatment is difficult to achieve optimal efficacy. Ozone therapy has been revealed to protect infection and inflammation-related diseases due to its role in antibiotic and immunoregulatory effect. Ozonated triglyceride is a key component of ozonated oil that is one of ozone therapy dosage form. However, the potential role of ozonated triglyceride in sepsis remains unclear. This study aims to explore the effect of ozonated triglyceride on septic mouse model and the molecular mechanism. METHODS: Intraperitoneal injection of lipopolysaccharide (LPS), cecal ligation and puncture (CLP) were applied to construct septic mouse model. The mouse serum was obtained for detection of cytokines, and lung tissues were collected for hematoxylin and eosin (HE) staining to evaluate the extent of lung injury in septic mouse with ozonated triglyceride treatment at different time and doses. The survival of septic mice was observed for 96 h and Kaplan-Meier analysis was used to analyze the survival rates. In addition, primary peritoneal macrophages and human acute monocytic-leukemia cell line (THP-1) were treated with inflammasome activators with or without ozonated triglyceride. The level of cytokines was detected by enzyme-linked immunosorbent assay (ELISA). The cleavage of caspase-1 and gasdermin-D (GSDMD) was detected by Western blotting. RESULTS: Ozonated triglyceride at different time and doses reduced the release of inflammasome-related cytokines [interleukin (IL)-1β and IL-18] (all P<0.05) but not pro-inflammatory cytokines such as IL-6 and tumor necrosis factor-α (TNF-α) in septic mice (all P>0.05). Ozonated triglyceride significantly improved the survival rate of septic mice and reduced sepsis-induced lung injury (all P<0.05). Ozonated triglyceride significantly suppressed the canonical and non-canonical activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome (all P<0.05) but not affected absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) inflammasomes in vitro (all P>0.05). Ozonated triglyceride reduced the cleavage of caspase-1 and the downstream GSDMD. CONCLUSIONS Ozonated triglyceride presents a protect effect on sepsis lethality via reducing cytokines release and sepsis-related organ injury. The mechanism is that ozonated triglyceride specifically suppresses the activation of NLRP3 inflammasome. Ozonated triglyceride is a promising candidate for sepsis treatment.
Animals ; Humans ; Mice ; Caspase 1 ; Cytokines ; Disease Models, Animal ; Inflammasomes ; Lung Injury ; NLR Family, Pyrin Domain-Containing 3 Protein ; Ozone/therapeutic use* ; Sepsis/drug therapy*

Objective:To determine the safety of prophylactic irradiation dose CTV 60Gy optimized to CTV 50Gy for II b region in patients with stage N 0-N 1 nasopharyngeal carcinoma (NPC) and the dose advantage and clinical value for parotid gland protection, and to understand the diagnostic value of PET-CT and diffusion-weighted imaging (DWI) for suspicious positive lymph nodes in the neck (5 mm≤maximum short diameter<10 mm). Methods:Clinical data of 157 patients with primary non-metastatic NPC (N 0-N 1) admitted to our hospital from June 2015 to March 2017 were retrospectively analyzed. 104 patients underwent II b clinical target volume optimization guided by multimodal imaging system. Survival analysis was performed by Kaplan - Meier method. Univariate/multivariate regression analysis was performed to analyze the pattern of cervical lymph node recurrence. Paired t-test was used to compare the differences in target volume and parotid gland dose parameters before and after dose optimization. Results:Sixty patients underwent single-neck optimization in stage N 1, 25 patients received double-neck optimization (only those with retropharyngeal lymph node metastasis), and 19 patients underwent double-neck optimization in stage N 0. Three patients had cervical regional recurrence, all in-field. The 5-year overall survival rate was 93.3%. The lymph node recurrence-free survival rate, local recurrence-free survival rate, distant metastasis-free survival rate and disease-free survival rate were 97.1%, 91.3%, 88.5% and 80.8%, respectively. Cervical lymph node recurrence was associated with local recurrence in the nasopharynx, regardless of retropharyngeal lymph node status. Fourteen patients had suspicious positive cervical lymph nodes in II b region, with a mean maximum short diameter of 7.1 (5~9) mm on the largest cross-sectional plane, and 11 of them were positive on PET-CT, with a mean SUV max of 2.96 (2.5~3.3). There was no significant difference in GTV after optimization ( P>0.05). D mean, D max, D 50% and V 26Gy of parotid gland were significantly lower than those of conventional plan (all P<0.01). Conclusions:It is safe to optimize CTV 60Gy to CTV 50Gy in II b region in patients with N 0-N 1 NPC, and the exposure dose to normal tissues around the parotid gland and neck is significantly reduced. For small lymph nodes that do not meet the diagnostic criteria, it needs to be individualized in combination with multimodality imaging systems, such as PET-CT and DWI.

Animals ; Brain Diseases/pathology* ; Cell Cycle ; Interneurons/pathology* ; Median Eminence/pathology* ; Mice

Background/Aims: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. We aimed to investigate the usefulness of a key biomarker, lipocalin-2 (LCN2), for the detection of NASH progression. Methods: A mouse NASH model was established using a high-fat diet and a high-sugar drinking water. Gene expression profile of the NASH model was analyzed using RNA sequencing. Moreover, 360 NAFLD patients (steatosis, 83; NASH, 277), 40 healthy individuals, and 87 patients with alcoholic fatty liver disease were recruited. Results: Inflammatory infiltration, focal necrosis in the leaflets, steatosis, and fibrosis were documented in the mouse liver. In total, 504 genes were differentially expressed in the livers of NASH mice, and showed significant functional enrichment in the inflammation-related category. Upregulated liver LCN2 was found to be significantly interactive with various interleukins and toll-like receptors. Serum LCN2 levels were significantly increased in NAFLD patients. Serum LCN2 levels were correlated with steatosis, intralobular inflammation, semiquantitative fibrosis score, and nonalcoholic fatty liver disease activity score. The area under the curve of serum LCN2 was 0.987 with a specificity of 100% and a sensitivity of 93.5% for NASH diagnosis, and 0.977 with almost the same specificity and sensitivity for steatosis. Conclusions LCN2 might be involved in the transition from NAFL to NASH by mediating inflammation. Serum LCN2 levels might be a novel biomarker for the diagnosis of NASH.

italic>Dendrobium officinale Kimura et Migo is a rare Chinese herbal medicine, while Dendrobium crepidatum Lindl is a local medicine in Yunnan, both of which have the function of nourishing yin and stomach. To reveal the differences in chemical composition between the two species, ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS/MS) was used to analyze the chemical composition of stems and leaves of D. officinale and D. crepidatum. Principal component analysis (PCA) and partial least squares discriminant analysis (OPLS-DA) were used to determine the differences in metabolites between species and parts of Dendrobium. Fifty-eight chemical compounds were identified in the two species. Analysis indicated that the side ring of alkaloids connected with nitrogen was readily cleaved during analysis. The results of PCA analysis showed that the stems and leaves of D. officinale and D. crepidatum could be easily differentiated, and the chemical constituents of D. officinale and D. crepidatum were significantly different. OPLS-DA analysis showed that there were 16 metabolite differences between the stems and 22 differences in metabolites between the leaves of D. officinale and D. crepidatum. The main metabolite differences in components between the two Dendrobium species were dendrocrepidine B, dendrocrepidine C and dendrocrepine. There were 14 differences in metabolites between the stems and leaves of D. crepidatum. In conclusion, the chemical compositions of D. officinale and D. crepidatum are quite different; the small molecular compounds of D. officinale are mainly terpenoids and flavonoids, and the content of alkaloids is low. There is no significant difference between stem and leaf. In contrast, D. crepidatum is mainly composed of alkaloids and terpenoids, with crepidamine and dendrocrepine as its unique components, and there are great differences in the components between stems and leaves. This study provides a theoretical basis for the development and utilization of Dendrobium resources.