In this study, araucarene diterpenes, characterized by a pimarene skeleton with a variably oxidized side chain at C-13, were investigated. A total of 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara, including 11 previously unreported compounds: dammaradione (1), dammarones D-G (2, 5, 14, 15), dammaric acids B-F (8-12), and dammarol (16). The structures of these new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and one-dimensional/two-dimensional (1D/2D) nuclear magnetic resonance (NMR), while their absolute configurations were determined through the electronic circular dichroism (ECD) exciton chirality method and Snatzke's method. The hypoglycemic activity of all isolated compounds was evaluated using a transgenic zebrafish model, and a structure-activity relationship (SAR) analysis was conducted. Araucarone (3) and dammaric acid C (9), serving as representative compounds, demonstrated significant hypoglycemic effects on zebrafish. The primary mechanism involves the promotion of pancreatic β cell regeneration and glucose uptake. Specifically, these compounds enhance the differentiation of pancreatic endocrine precursor cells (PEP cells) into β cells in zebrafish.
Zebrafish ; Animals ; Diterpenes/isolation & purification* ; Insulin-Secreting Cells/cytology* ; Glucose/metabolism* ; Hypoglycemic Agents/isolation & purification* ; Molecular Structure ; Structure-Activity Relationship ; Plant Extracts/pharmacology* ; Regeneration/drug effects*

OBJECTIVE:There are many kinds of biological agents for the treatment of rheumatoid arthritis in clinic,but the differences in therapeutic efficacy and safety are still unclear.The purpose of this study is to compare the differences in effectiveness and safety of different biological agents for the treatment of rheumatoid arthritis. METHODS:CNKI,VIP,WanFang,China Biomedical Literature System,PubMed,Cochrane Library,Web of Science,and Embase databases were searched to collect the randomized controlled trials on biological agents for rheumatoid arthritis that meet the requirements from inception to October 1,2022.The literature was selected by EndNote software,and the quality of the included literature was evaluated by RevMan 5.3 software.The software Stata 14.2 was used for direct meta-analysis and network meta-analysis of ACR20(American College of Rheumatology 20%response),ACR50(American College of Rheumatology 50%response),ACR70(American College of Rheumatology 70%response),erythrocyte sedimentation rate,and adverse reactions. RESULTS:Totally 39 articles were included,including 5 low-risk articles,4 high-risk articles,and the remaining 30 articles contained unknown risk bias,with a total of 13 treatment measures.The results of network meta-analysis:(1)In ACR20,infliximab combined with methotrexate(OR=5.54,95%CI:1.33-23.01,P<0.05),abatacept+methotrexate tablets(OR=3.21,95%CI:1.13-9.10,P<0.05),and tocilizumab(OR=2.95,95%CI:1.61-5.44,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR20 was:infliximab+methotrexate tablets>abatacept+methotrexate tablets>tocilizumab>certlizumab>etanercept+methotrexate tablets.(2)In the aspect of ACR50,etanercept combined with methotrexate tablets(OR=4.04,95%CI:2.13-7.66,P<0.05),infliximab combined with methotrexate tablets(OR=4.79,95%CI:1.19-19.26,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.54,95%CI:1.36-9.22,P<0.05)had better therapeutic effects than methotrexate tablets.The probabilistic ranking of ACR50 was:etanercept+methotrexate tablets>infliximab+methotrexate tablets>tocilizumab+methotrexate tablets>tocilizumab>certlizumab+methotrexate tablets.(3)In terms of ACR70,the therapeutic effects of infliximab combined with methotrexate tablets(OR=8.00,95%CI:2.31-27.69,P<0.05),etanercept combined with methotrexate tablets(OR=4.26,95%CI:2.51-7.21,P<0.05),and tocilizumab combined with methotrexate tablets(OR=3.51,95%CI:1.82-6.80,P<0.05)were better than methotrexate tablets.The probabilistic ranking of ACR70 was infliximab+methotrexate tablets>etanercept+methotrexate tablets>tocilizumab+methotrexate tablets>certlizumab>adalimumab+methotrexate tablets.(4)In erythrocyte sedimentation rate,etanercept combined with methotrexate tablets(SMD=-9.23,95%CI:-16.55 to-1.92,P<0.05)was better than etanercept and methotrexate tablets(SMD=14.59,95%CI:7.28-21.91,P<0.05).The probabilistic ranking of erythrocyte sedimentation rate was etanercept+methotrexate tablets>infliximab+methotrexate tablets>etanercept>adalimumab+methotrexate tablets>methotrexate tablets.(5)In terms of adverse reactions,placebo(OR=0.62,95%CI:0.39-0.99,P<0.05)was better than infliximab and certlizumab(OR=0.44,95%CI:0.25-0.78,P<0.05).The probabilistic ranking of adverse reactions was placebo>infliximab>etanercept+methotrexate tablets>certlizumab>etanercept. CONCLUSION:Based on evidence from 39 randomized controlled trials,infliximab combined with methotrexate tablets(highly recommended)can be the first choice in clinic,and etanercept combined with methotrexate tablets(highly recommended)can be the second choice in terms of good effectiveness and safety.

The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.

Adhesive intestinal obstruction is the most common type of ileus, and conserva-tive treatment serves as its preferred treatment option. In the course of conservative treatment, gastrointestinal decompression will relieve symptoms, prevent ileus progression and promote gas-trointestinal function recovery, which has significant clinical effects. Currently, decompression effects of nasointestinal tubes and nasogastric tubes are controversial. There is a previous Meta-analysis evaluating decompression effects of these two methods, but this analysis includes non-randomized controlled trial and lacks research about Chinese patients. Therefore, the authors con-duct a Meta-analysis to evaluate decompression effects of nasointestinal tubes versus nasogastric tubes for adhesive intestinal obstruction.

Objective:To evaluate the therapeutic effect and safety of microwave ablation plus curettage.Methods:Clinical data of a single group of 12 patients admitted to our hospital from June 2015 to June 2019 who underwent microwave ablation for bone metastasis were retrospectively analyzed. There were 7 males and 5 females, with an average age of 59.5±10.1 (range from 43 to 79) years old. Curettage plus bone cement after microwave ablation was performedand when the lesion involved the sacroiliac joint surface and impaired the bearing arch, the internal fixation was performed with plate and screws. 8 among the 12 patients underwent curettage, bone cement and metal internal fixation after microwave ablation. After microwave ablation, and 4 patients underwent curettage and reconstruction with bone cement alone. The patients were followed up aftersurgery. The observational indicators included: patient survival rate, local recurrence rate, perioperative complications, Operation time, intraoperative blood loss, VAS score, SF-36 score, and MSTS function score. VAS scores and SF-36 scores were recorded before surgery, 1 week after surgery and 3 months after surgery.Results:12 patients were followed up for 4-27 months, with an average follow-up time of 14.2 months and a median follow-up time of 9 months. During the follow-up, 7 patients died and 5 survived, with a 6-month survival rate of 81.8%, a 1-year survival rate of 40.9% and a 2-year survival rate of 27.3%. The mean survival time of the dying patients was 8.8 months (5-18 months), and the median survival time was 7 months. Operation time was 101±21 min and intraoperative blood loss was 295±108 ml. During the follow-up period, local recurrence rate was 8.3% (1/12), and the average postoperative time to recurrence was 4 months. There were no complications such as wound nonunion, wound infection, deep infection, vascular nerve heat injury and internal fixation failure. VAS score before surgery was 7.5 (7, 8) points, VAS score 1 week after surgery was 5 (4, 5) points, and VAS score 3 months after surgery was 5 (4, 5.75) points ( P<0.05). Preoperative SF-36 score was 23 (21, 24.75) points, 1 week after surgery SF-36 score was 47 (46, 54) points, and 3 months after surgery SF-36 score was 50.5 (47, 55.25) points ( P<0.05). 3 months after the operation, the MSTS score was 20.5 (16.25, 21.75) points, of which excellent 16.7% (2/12), good 50% (6/12), medium 16.7% (2/12), poor 16.7% (2/12), and the overall excellent and good rate was 66.7% (8/12). Conclusion:Microwave ablation plus curettage for pelvic metastasis of malignant tumor can significantly relieve local pain, rebuild limb function and improve patients' quality of life, and it`s an alternative treatment for pelvic metastases.

Aberrant crypt foci(ACF)is highly similar to colorectal cancer(CRC)in phenotypic and molecular changes,and is positively correlated with the risk of CRC. It is considered as precancerous lesion of CRC. Many compounds have therapeutic effects on ACF,inhibiting their occurrence and malignant transformation,which can be regarded as a preventive effect on CRC. In this paper,we will review the treatment of ACF by various compounds in different ways in recent years.

Objective    To explore the efficacy of a novel detection technique of circulating tumor cells (CTCs) to identify benign and malignant lung nodules. Methods     Nanomagnetic CTC detection based on polypeptide with epithelial cell adhesion molecule (EpCAM)-specific recognition was performed on enrolled patients with pulmonary nodules. There were 73 patients including 48 patients with malignant lesions as a malignant group and 25 patients with benign lesion as a benign group. There were 13 males and 35 females at age of 57.0±11.9 years in the malignant group and 11 males and 14 females at age of 53.1±13.2 years in the benign group. e calculated the differential diagnostic efficacy of CTC count, and conducted subgroup analysis according to the consolidation-tumor ratio, while compared with PET/CT on the efficacy. Results     CTC count of the malignant group was significantly higher than that of the benign group  (0.50/ml vs. 0.00/ml, P<0.05). Subgroup analysis according to consolidation tumor ratio (CTR) revealed that the difference was statistically significant in pure ground glass (pGGO) nodules 1.00/ml vs. 0.00/ml, P<0.05), but not in part-solid or pure solid nodules. For pGGO nodules, the area under the receiver operating characteristic (ROC) curve of CTC count was 0.833, which was significantly higher than that of maximum of standardized uptake value (SUVmax) (P<0.001). Its sensitivity and specificity was 80.0% and 83.3%, respectively. Conclusion     The peptide-based nanomagnetic CTC detection system can differentiate malignant tumor and benign lesions in pulmonary nodules presented as pGGO. It is of great clinical potential as a noninvasive, nonradiating method to identify malignancies in pulmonary nodules.

This study aimed at preparing the chemical reference substance of garcinol.A preparative high-speed countercurrent chromatography (HSCCC) was adopted for the isolation of garcinol from the twigs of Garcinia multifiora Champ,G.esculenta Y.H.Li and the fruits of G.xanthochymus Hook.f.ex T.Anders.The crude extracts were separated by HSCCC with two phase solvent systems composed of n-hexane-ethyl acetate-95％ ethanol-water (8∶8∶12∶4,volume ratio) using the upper stationary phase and the lower mobile phase.Under the conditions of a flow rate of 2.0 and 4.0 mL· min-1,and the apparatus rotation at 850 rpm,the column temperature at 25℃ and the detection wavelength at 254 nm,the fraction containing garcinol was purified by the Sephadex LH20 chromatography.The purity test in the extracts was determined by high-performance liquid chromatography.As a result,the contents of garcinol were 45,281 and 4080mg respectively separated from 104.765 g twigs of G.multiflora Champ,105.270 g G.esculenta Y.H.Li and 102.318 g the fruits of G.xanthochymus Hook.f.ex T.with the purity of 98.72％,98.36％ and 98.42％.Compared with the sample pretreatments and separation efficiency of the three plants,it was found that the fat-soluble extracts rapidly and efficiently extracted using n-hexane-ethyl acetate-95％ ethanol-water (5∶5∶5∶5,volume ratio) contained abundant garcinol taking fruits of G.xanthochymus Hook.f.ex T as the raw material with the combination of HSCCC and Sephadex LH-20 chromatography.In conclusion,it was indicated that the combination method is efficient with high operability and large preparation quantity.

Objective To investigate the effect of hyperthermic intraperitoneal perfusion and cisplatinon apoptosis in human ovarian cancer cells.Methods Two human ovarian cancer cells (OVCAR-3,A2780) were divided into control group,cisplatin group,hyperthermia group and thermo-chemotherapy group;microscopy was used to observe the morphological changes of the four groups;AO/GV stain and flow cytometry(FCM) was used to analyze cell apoptosis;Apoptosis related genes caspase7,caspase8 and Bax in ovarian cancer cells were detected by fluorescence quantitative PCR.Results Inverted microscopy observeed that the ovarian cancer cells retracted and suspended partially in the cisplatin group and hyperthermia group,especially in the thermo-chemotherapy group.After AO/GV staining,the apoptotic cells were increased in the cisplatin group and hyperthermia group compared with the control group,and the thermo-chemotherapy group was more than cisplatin group and hyperthermia group.FCM results indicated that the proportion of cells apoptosis were higher in the cisplatin group and hyperthermiagroup,the thermo-chemotherapy group is the higher than the all other groups(P＜0.05).q-PCR results showed that in the thermo-treatment group the expression of pro-apoptotic genes,including caspase3,caspase6,caspase7,caspase8,caspase9,Bax,Bak and Bid,was significantly higher than other groups,apoptosis inhibitory gennes,such as Bcl-2,Bcl-xL,Mcl-1,c-FLIP,was significantly decreased than the others.Conclusions Cisplatin plus hyperthermia can promote the apoptosis in ovarian cancer cells.

Background It has not been reported that if the visual cortex M receptor changed during the development of myopia and how it changed if given acupuncture treatment.Objective The aim of this study was to observe the effect of electroacupuncture stimulation on the expression of acetylcholine receptors M1 (AchRM1) in visual cortex of guinea with lens-induced myopia (LIM).Methods Forty-eight three-week-old healthy guinea pigs were randomized into the normal control group,the LIM model group and the LIM electroacupuncture group.The right eyes of the guinea pigs were selected as the experimental eyes.LIM was created by monocularly wearing of-10 D lens for 4 weeks in the right eyes in the LIM model group and LIM electroacupuncture group,and then the acupuncture at the temple and hegu point was performed for 30 minutes per day for consequent 4 weeks,in the LIM electroacupuncture group.The fellow eyes of the guinea pigs were used as the self-control eyes.The refractive power and axial length were examined with retinoscopy and A-type sonography before and 4 weeks after modeling,respectively.The animals were sacrificed by excessive anesthesia at the fourth week after acupuncture and visual vertex tissue was obtained.The expression of M1 receptor mRNA in visual vertex was detected by fluorescence quantitative PCR,and the content of M1 receptor protein in visual vertex was assyed by ELISA.The study protocal was approved by Animal Ethic Committee of Shandong University of Traditional Chinese Medicine,and the use and care complied with Statement of the Association for Research in Vision and Ophthalmology.Results At the fourth week after modeling,the mean diopters were (-3.24±0.28) D and (-3.30±0.45) D in the LIM model group and the LIM eleetroacupuncture group,which were significantly higher than (0.83 ±0.86)D in the normal control group (both at P=0.000),and there was no significant difference in the diopter between the LIM model group and the LIM electroacupuncture group (t =0.200,P =0.659).The mean axial lengths were (8.67 ±0.14) mm and (8.60±0.06) mm in the LIM model group and the LIM electroacupuncture group,which were considerably increased in comparison with (8.33±0.08)mm in the normal control group (both at P＜0.05).The relative expression levels of AchRM1 mRNA in visual cortex were 0.79±0.18,1.36±0.23 and 1.13±0.13 in the normal control group,LIM model group and LIM electroacupuncture group,and the relative expression level of AchRM1 mRNA in the LIM electroacupuncture group was significantly higher than that of the normal control group and lower than that of the LIM model group (both at P＜0.05).In addition,the contents of AchRM1 receptor protein in the visual cortex were 248.00±33.31,455.17±42.40 and 396.17±47.57 in the normal control group,LIM model group and the LIM electroacupuncture group,with a similar pattern among the groups (both at P＜0.05).Conclusions A electroacupuncture stimmulation do not affect the myopic diopter and axial length in LIM model.The AchRM1 and AchRM1 receptor in the visual cortex up-regulate in LIM eyes,infering that electroacupuncture stimmulation can improve vision by decreasing the level of AchRM1 receptor in visual cortex in LIM eyes in guinea pigs.