(±)-Penicithrones A-D (1a/1b-4a/4b), four novel pairs of anthrone-cyclopentenone heterodimers characterized by a distinctive bridged 6/6/6-5 tetracyclic core skeleton, together with three previously identified compounds (5-7), were isolated from the crude extract of the mangrove-derived fungus Penicillium sp., guided by heteronuclear single quantum correlation (HSQC)-based small molecule accurate recognition technology (SMART 2.0) and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based molecular networking. The structural elucidation of new compounds was accomplished through comprehensive spectroscopic analysis, and their absolute configurations were determined using DP4+ ¹³C nuclear magnetic resonance (NMR) calculations and electronic circular dichroism (ECD) calculations. Compounds 1a/1b-4a/4b demonstrated moderate cytotoxicity against three human cancer cell lines HeLa, HCT116 and MCF-7 with half maximal inhibitory concentration (IC₅₀) values ranging from 15.95 ± 1.64 to 28.56 ± 2.59 μmol·L^-1.
Humans ; Penicillium/chemistry* ; Molecular Structure ; Cyclopentanes/isolation & purification* ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology* ; Tandem Mass Spectrometry ; Dimerization ; HeLa Cells ; Magnetic Resonance Spectroscopy

Advanced gastric cancer(AGC)includes locally unresectable gastric cancer(GC),metastatic GC,and postoperative recurrent GC.Due to delayed diagnosis and lack of effective treatment for AGC,the median survival time of AGC patients is only 6-12 months.At present,the main treatment goal of AGC is to improve symptoms and prolong the survival time of patients receiving sequential chemotherapy.Although the therapeutic effect of systemic therapy on AGC is gradually becoming apparent,the patient's prognosis is far from expected.In addition,targeted therapy and novel immunotherapy have drawbacks such as high incidence of drug resistance,high toxic side effects,and heavy economic burden on patients.Therefore,finding new therapeutic targets and developing anti-tumor drugs is a key issue that urgently needs to be addressed.According to reports,abnormal activation of the hepatocyte growth factor(HGF)/cellular-mesenchymal epithelial transition factor(c-MET)pathway plays a crucial role in the progression of GC and the occurrence of multi-line resistance and may be a potential therapeutic target for GC.In recent years,some HGF/c-MET-targeting small molecule tyrosine kinase inhibitors(TKIs)have been found to show good clinical effects in the treatment of GC.Meanwhile,new HGF/c-MET inhibitors(such as monoclonal antibodies,bispecific antibodies,antibody drug conjugates,etc.)have shown good anti-tumor activity in preclinical studies,but they are all at different stages of clinical research,and their efficacy and safety still need further confirmation.This review elaborates on the latest research progress of HGF/c-MET inhibitors in the treatment of AGC and discusses the main reasons and strategies for drug resistance,aiming to provide better guidance for the treatment of AGC and provide reference for future research.

Objective:The effect of Xuan Bi Decoction on inhibition of cyclooxygenase-2(COX-2)pathway on inflammation in rats with acute gouty arthritis(GA).Methods:Sixty SD rats randomly allocated into control group,model group,celecoxib group(20 mg/kg),Xuan Bi Decoction low-dose group(5 g/kg),Xuan Bi Decoction medium-dose group(10 g/kg),Xuan Bi Decoction high-dose group(20 g/kg),with 10 rats in each group.The classic method of Coderre was used to establish a rat gout model and observe the general condition of each group of rats;analysis of rat gait scores and joint swelling of rats;the histopathological growth of rat ankle Sy-novial membrane were observed by HE staining;the levels of inflammatory factors IL-1β,TNF-α,PGE2 and LTB4 in rats joint fluid were detected by ELISA;Western blot detection of PGE2 receptor 2(EP2)and LTB receptor 1(BLT1)expressions in rats ankle syno-vial tissue;qRT-PCR to detect the effect of mRNA expression of COX-2 and 5-lipoxygenase(5-LOX).Results:Rats in the model group had swollen joints,lameness,lusterless fur and mental lethargy;the rats in the celecoxib group and Xuan Bi Decoction low,medium and high dose groups showed effective improvement in related symptoms;compared with control group,the gait score,degree of joint swelling,degree of histopathology,IL-1β,TNF-α,PGE2,LTB4,COX-2,5-LOX,EP2 and BLT1 levels of the rats in the model group were significantly higher(P<0.05);compared with the COX-2 inhibitor celecoxib,Xuan Bi Decoction(20 g/kg)showed better anti-arthritic properties in rats treated with MSU crystals,accompanied by reduced expression of IL-1β,TNF-α,PGE2,LTB4,COX-2,5-LOX,EP2 and BLT1.Conclusion:Dual inhibition of COX-2 and 5-LOX by Xuan Bi Decoction in GA rats to improve MSU crystal-induced inflammation and may serve as a novel therapeutic strategy.

Objective:To explore the protective effect and mechanism of acetate on sepsis-induced acute kidney injury (AKI) in rats.Methods:Male Sprague-Dawley (SD) rats were divided into sham operation group (Sham group), sepsis group caused by cecal ligation and puncture (CLP group), and acetate pretreatment group [NaA group, gavage sodium acetate (NaA) 300 mg/kg twice a day for 7 consecutive days before CLP] using a random number table method, with 7 rats in each group. The blood was taken from the main abdominal artery 24 hours after modeling, and renal tissue was collected from the rats. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and kidney injury molecule-1 (KIM-1). The concentration of serum acetate was determined by high performance liquid chromatography. The level of malondialdehyde (MDA) in renal tissue was detected by thiobarbituric acid method. Myeloperoxidase (MPO) in renal tissue was detected by colorimetric method. Hematoxylin-eosin (HE) staining was used to observe histopathological changes and assess renal tubule injury score. Western blotting was used to detect the protein expressions of G-protein coupled receptor 43 (GPR43) and adenosine monophosphate-activated protein kinase/silence infor-mation regulator 1/peroxlsome proliferator-activated receptor-γ coactlvator-1α (AMPK/SIRT1/PGC-1α) pathway. The positive expressions of GPR43, phosphorylation-AMPK (p-AMPK), SIRT1, PGC-1α were detected by immunohistochemistry.Results:Compared with Sham group, the serum levels of IL-6, TNF-α and KIM-1 were significantly increased in CLP group, the contents of MDA and MPO in renal tissue were increased, and the content of acetate was significantly decreased. HE staining results showed that most of the tubular epithelial cells were denaturated with local necrosis, a large number of brush border injuries and shedding, tubular structure destruction and fragmentation, and more inflammatory cells infiltrated the renal interstitium, the renal tubular injury score significantly increased. The expressions of GPR43, p-AMPK/AMPK, SIRT1, and PGC-1α in renal tissue were significantly reduced, indicating renal injury and increased levels of oxidative stress and inflammation in septic rats. Compared with the CLP group, the serum levels of IL-6, TNF-α and KIM-1 in the NaA group were decreased [IL-6 (ng/L): 126.20±6.23 vs. 161.00±17.37, TNF-α (ng/L): 85.59±7.70 vs. 123.50±17.78, KIM-1 (μg/L): 2.92±0.38 vs. 4.73±0.36, all P < 0.05]. The contents of MDA and MPO in renal tissue were significantly decreased [MDA (μmol/g): 6.56±0.18 vs. 8.53±0.34, MPO (U/g): 2.99±0.20 vs. 3.72±0.29, both P < 0.05]. HE staining showed that kidney injury had been alleviated, with a decrease in renal tubular injury score [1 (1, 2) vs. 3 (2, 3), P < 0.05]. Western blotting showed that the expressions of GPR43 and AMPK/SIRT1/PGC-1α pathway related proteins were significantly increased in renal tissue (GPR43/β-actin: 0.62±0.09 vs. 0.41±0.09, p-AMPK/AMPK: 0.58±0.07 vs. 0.44±0.06, SIRT1/β-actin: 0.85±0.06 vs. 0.73±0.03, PGC-1α/β-actin: 0.79±0.07 vs. 0.62±0.05, all P < 0.05). Immunohistochemistry showed that the positive expressions of GPR43, p-AMPK, SIRT1 and PGC-1α were significantly increased in renal tissue [GPR43 positive area: (33.66±2.62)% vs. (16.21±1.66)%, p-AMPK positive area: (16.64±2.11)% vs. (5.04±1.28)%, SIRT1 positive area: (14.61±2.86)% vs. (7.34±1.00)%, PGC-1α positive area: (15.30±2.39)% vs. (4.84±1.67)%, all P < 0.05], the serum acetate concentration significantly increased (μg/L: 32?479±14?683 vs. 12?935±3?197, P < 0.05). Conclusion:Acetate can ameliorate sepsis-induced AKI, the mechanism may be related to the activation of AMPK/SIRT1/PGC-1α pathway by GPR43.

Objective To study the effects of intramedullary pressure on the fluid flow behavior in bones.Methods Multi-scale models of macro bone tissue and macro-meso osteon groups were established using the COMSOL Multiphysics software.Considering the interrelationship of different pore scales,such as the bone marrow cavity,Haversia canal,and bone lacunar-canaliculus,the pore pressure and flow rate of hollow bone tissues and bone tissues with intramedullary pressure were compared,and the effects of the amplitude and frequency of intramedullary pressure on the pressure and flow velocity of the liquid in the bone were analyzed.Results When intramedullary pressure was considered,the pore pressure in bone tissues with intramedullary pressure was 6.4 kPa higher than that in hollow bone tissues.The flow pressure increased significantly with an increase in the intramedullary pressure amplitude,but the flow velocity remained unchanged.The frequency of intramedullary pressure had little effect on pore pressure and flow velocity.Conclusions The multi-scale pore model established in this study can accurately analyze bone fluid flow behavior.These results are of great significance for an in-depth understanding of force conduction in the bone.

Objective:To carry out a study on the cost analysis of the clinical use of Artificial Intelligence-assisted Diagnosis Technology for Coronary CT Angiography(CCTA-AI)to explore the cost differences and cost effects of Coronary CT Angiography(CCTA)examinations before and after the introduction of Artificial Intelligence(AI),and analyze the impact of the application of AI technology on the high-quality development of public hospitals.Methods:The operation cost method was used to measure the changes in the cost and efficiency of CCTA examinations before and after the application of AI technology in five sample hospitals in Beijing,and diagnostic accuracy was used as the effect value to calculate the cost effect of CCTA-AI diagnosis versus CCTA-manual diagnosis,and to analyze the main factors affecting the unit cost.Results:The average cost of examination in 5 sample hospitals after the application of AI-assisted diagnosis system was 1 074.90 yuan,and 1 266.61 yuan before the application,with a large difference between institutions.The cost-effectiveness analysis based on diagnostic accuracy showed that the AI group had an absolute advantage over the manual group,with a cost of 1 074 900 yuan for the AI group and an effectiveness of 855.05 persons,and a cost of 1 266 610 yuan for the physician group,with an effectiveness of 815.07 persons for the high-year-end physician group,and an effectiveness of 793.40 persons for the low-year-end physician group;0.46 man-hours could be saved for each patient examined;the unit cost of CCTA examination was affected by a number of factors,among which"the number of annual examinations"and"the number of CT units involved in CCTA examination"had the greatest influence on the unit cost of CCTA examination.Conclusion:The application of AI-assisted diagnostic technology can promote the improvement of quality and efficiency in public hospitals in a certain extent,and help optimize the overall distribution of medical resources at the system level.In the future,the cost analysis of AI technology should be further strengthened to comprehensively assess its actual contribution to the healthcare system.

Objective:To carry out a study on the cost analysis of the clinical use of Artificial Intelligence-assisted Diagnosis Technology for Coronary CT Angiography(CCTA-AI)to explore the cost differences and cost effects of Coronary CT Angiography(CCTA)examinations before and after the introduction of Artificial Intelligence(AI),and analyze the impact of the application of AI technology on the high-quality development of public hospitals.Methods:The operation cost method was used to measure the changes in the cost and efficiency of CCTA examinations before and after the application of AI technology in five sample hospitals in Beijing,and diagnostic accuracy was used as the effect value to calculate the cost effect of CCTA-AI diagnosis versus CCTA-manual diagnosis,and to analyze the main factors affecting the unit cost.Results:The average cost of examination in 5 sample hospitals after the application of AI-assisted diagnosis system was 1 074.90 yuan,and 1 266.61 yuan before the application,with a large difference between institutions.The cost-effectiveness analysis based on diagnostic accuracy showed that the AI group had an absolute advantage over the manual group,with a cost of 1 074 900 yuan for the AI group and an effectiveness of 855.05 persons,and a cost of 1 266 610 yuan for the physician group,with an effectiveness of 815.07 persons for the high-year-end physician group,and an effectiveness of 793.40 persons for the low-year-end physician group;0.46 man-hours could be saved for each patient examined;the unit cost of CCTA examination was affected by a number of factors,among which"the number of annual examinations"and"the number of CT units involved in CCTA examination"had the greatest influence on the unit cost of CCTA examination.Conclusion:The application of AI-assisted diagnostic technology can promote the improvement of quality and efficiency in public hospitals in a certain extent,and help optimize the overall distribution of medical resources at the system level.In the future,the cost analysis of AI technology should be further strengthened to comprehensively assess its actual contribution to the healthcare system.

Objective:To carry out a study on the cost analysis of the clinical use of Artificial Intelligence-assisted Diagnosis Technology for Coronary CT Angiography(CCTA-AI)to explore the cost differences and cost effects of Coronary CT Angiography(CCTA)examinations before and after the introduction of Artificial Intelligence(AI),and analyze the impact of the application of AI technology on the high-quality development of public hospitals.Methods:The operation cost method was used to measure the changes in the cost and efficiency of CCTA examinations before and after the application of AI technology in five sample hospitals in Beijing,and diagnostic accuracy was used as the effect value to calculate the cost effect of CCTA-AI diagnosis versus CCTA-manual diagnosis,and to analyze the main factors affecting the unit cost.Results:The average cost of examination in 5 sample hospitals after the application of AI-assisted diagnosis system was 1 074.90 yuan,and 1 266.61 yuan before the application,with a large difference between institutions.The cost-effectiveness analysis based on diagnostic accuracy showed that the AI group had an absolute advantage over the manual group,with a cost of 1 074 900 yuan for the AI group and an effectiveness of 855.05 persons,and a cost of 1 266 610 yuan for the physician group,with an effectiveness of 815.07 persons for the high-year-end physician group,and an effectiveness of 793.40 persons for the low-year-end physician group;0.46 man-hours could be saved for each patient examined;the unit cost of CCTA examination was affected by a number of factors,among which"the number of annual examinations"and"the number of CT units involved in CCTA examination"had the greatest influence on the unit cost of CCTA examination.Conclusion:The application of AI-assisted diagnostic technology can promote the improvement of quality and efficiency in public hospitals in a certain extent,and help optimize the overall distribution of medical resources at the system level.In the future,the cost analysis of AI technology should be further strengthened to comprehensively assess its actual contribution to the healthcare system.

Objective:To carry out a study on the cost analysis of the clinical use of Artificial Intelligence-assisted Diagnosis Technology for Coronary CT Angiography(CCTA-AI)to explore the cost differences and cost effects of Coronary CT Angiography(CCTA)examinations before and after the introduction of Artificial Intelligence(AI),and analyze the impact of the application of AI technology on the high-quality development of public hospitals.Methods:The operation cost method was used to measure the changes in the cost and efficiency of CCTA examinations before and after the application of AI technology in five sample hospitals in Beijing,and diagnostic accuracy was used as the effect value to calculate the cost effect of CCTA-AI diagnosis versus CCTA-manual diagnosis,and to analyze the main factors affecting the unit cost.Results:The average cost of examination in 5 sample hospitals after the application of AI-assisted diagnosis system was 1 074.90 yuan,and 1 266.61 yuan before the application,with a large difference between institutions.The cost-effectiveness analysis based on diagnostic accuracy showed that the AI group had an absolute advantage over the manual group,with a cost of 1 074 900 yuan for the AI group and an effectiveness of 855.05 persons,and a cost of 1 266 610 yuan for the physician group,with an effectiveness of 815.07 persons for the high-year-end physician group,and an effectiveness of 793.40 persons for the low-year-end physician group;0.46 man-hours could be saved for each patient examined;the unit cost of CCTA examination was affected by a number of factors,among which"the number of annual examinations"and"the number of CT units involved in CCTA examination"had the greatest influence on the unit cost of CCTA examination.Conclusion:The application of AI-assisted diagnostic technology can promote the improvement of quality and efficiency in public hospitals in a certain extent,and help optimize the overall distribution of medical resources at the system level.In the future,the cost analysis of AI technology should be further strengthened to comprehensively assess its actual contribution to the healthcare system.

Objective:To carry out a study on the cost analysis of the clinical use of Artificial Intelligence-assisted Diagnosis Technology for Coronary CT Angiography(CCTA-AI)to explore the cost differences and cost effects of Coronary CT Angiography(CCTA)examinations before and after the introduction of Artificial Intelligence(AI),and analyze the impact of the application of AI technology on the high-quality development of public hospitals.Methods:The operation cost method was used to measure the changes in the cost and efficiency of CCTA examinations before and after the application of AI technology in five sample hospitals in Beijing,and diagnostic accuracy was used as the effect value to calculate the cost effect of CCTA-AI diagnosis versus CCTA-manual diagnosis,and to analyze the main factors affecting the unit cost.Results:The average cost of examination in 5 sample hospitals after the application of AI-assisted diagnosis system was 1 074.90 yuan,and 1 266.61 yuan before the application,with a large difference between institutions.The cost-effectiveness analysis based on diagnostic accuracy showed that the AI group had an absolute advantage over the manual group,with a cost of 1 074 900 yuan for the AI group and an effectiveness of 855.05 persons,and a cost of 1 266 610 yuan for the physician group,with an effectiveness of 815.07 persons for the high-year-end physician group,and an effectiveness of 793.40 persons for the low-year-end physician group;0.46 man-hours could be saved for each patient examined;the unit cost of CCTA examination was affected by a number of factors,among which"the number of annual examinations"and"the number of CT units involved in CCTA examination"had the greatest influence on the unit cost of CCTA examination.Conclusion:The application of AI-assisted diagnostic technology can promote the improvement of quality and efficiency in public hospitals in a certain extent,and help optimize the overall distribution of medical resources at the system level.In the future,the cost analysis of AI technology should be further strengthened to comprehensively assess its actual contribution to the healthcare system.