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*

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.

Background/Aims: Crohn’s disease (CD) primarily affects young female adults of reproductive age. Few studies have been conducted on this population’s ovarian reserve status. The aim of study was to investigate potential risk factors associated with low ovarian reserve, as reflected by serum anti-Müllerian hormone (AMH) in women of reproductive age with CD. Methods: This was a case-control study. Cases included 87 patients with established CD, and healthy controls were matched by age, height and weight in a 1:1 ratio. Serum AMH levels were measured by enzyme-linked immunosorbent assay. Results: The average serum AMH level was significantly lower in CD patients than in control group (2.47±2.08 ng/mL vs. 3.87±1.96 ng/mL, respectively, P<0.001). Serum AMH levels were comparable between CD patients and control group under 25 years of age (4.41±1.52 ng/mL vs. 3.49±2.10 ng/mL, P=0.06), however, serum AMH levels were significantly lower in CD patients over 25 years of age compared to control group (P<0.05). Multivariable analysis showed that an age greater than 25 (odds ratio [OR], 10.03; 95% confidence interval [CI], 1.90–52.93, P=0.007), active disease state (OR, 27.99; 95% CI, 6.13–127.95, P<0.001) and thalidomide use (OR, 15.66; 95% CI, 2.22–110.65, P=0.006) were independent risk factors associated with low ovarian reserve (serum AMH levels <2 ng/mL) in CD patients. Conclusions Ovarian reserve is impaired in young women of reproductive age with CD. Age over 25 and an active disease state were both independently associated with low ovarian reserve. Thalidomide use could result in impaired ovarian reserve.

Objective To explore the Cep70 by adjusting the stability of acetylated alpha tubulin,participate in breast cancer drug resistance mechanisms.Methods (1) In order to induce taxol drug resistance cell line Michigan cancer foundation-7 (MCF-7)/pac,high-dose shock treatments taxol MCF-7 was used for 6 months,until the cells can grow in 3.5 μmol/L of paclitaxel.(2) The 3-(4,5-dimenthylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) method was used to detect inhibition rate by taxol to MCF-7 and MCF-7/pac cell.(3) Immunofluorescence and Western blot were used to test acetylated alpha-tubulin and Cep70 expression levels in MCF-7 and MCF-7/pac cells.(4) Chemical intervention was used to acetylate apha-tubulin expression,Western blot and polymerase chain reaction (PCR) were used to detect the change of acetylated alpha-tubulin and Cep70 in MCF-7 and MCF-7/pac groups.Flow cytometry and Western blot were used to detect the change of cell cycle.Results (1) IC50 of MCF-7 and MCF-7/pac was 22.47 μ mol/L and 31.38 μmol/L,respectively.(2) Immunofluorescence and Western blot results showed that the expression of acetylation of alpha-tubulin in resistant MCF-7 cell/pac was obviously decreased.(3) Real time polymerase chain reaction (RT-PCR) and Western blot showed Cep70 expression was consistent of acetylation of alpha-tubulin.(4) After incubation with paclitaxel for 24 hours,the expressions of acetylation of alpha-tubulin and Cep70 in MCF-7 and MCF-7/pac were increased,but the extent of MCF-7 cell was much higher.Instead,incubation with nocodazole after 24 hours,the acetylation of alpha-tubulin and Cep70 in MCF-7 and MCF-7/pac cells were obviously lowered.(5) After paclitaxel intervention,compared to the same group MCF-7 cells,the G2 phase ratio in MCF-7/pac cells was lower.In addition,given nocodazole after the intervention,compared to the same group MCF-7 cells,the ratio of G2 phase in MCF-7 cell/pac was significantly decreased.Conclusions Cep70 decreased the expression of the acetylated alpha-tubulin,reduced the stability of microtubules,which could be an important mechanism of taxol drug resistance.

Objective To reveal acetylated a-tubulin acts as pressure sensors,sensing the changes in extracellular matrix to impact on the invasion and metastasis of breast cancer.Methods The acetylated alpha microtubule protein expressions were detected,and its relationship with invasion and metastasis in breast cancer clinical specimens and different molecular subtypes of breast cancer cell lines were analyzed.The expression of acetylated a-tubulin was interfered through chemical methods,and cell morphology and the change of the invasion and metastasis ability were detected under the condition of different matrix hardness.Results The expression of acetylated a-tubulin was highest in basal-like breast cancer tissue and cell lines,and was lowest expressed in the luminal B breast cancer tissue and the breast cancer cell lines.The expression of acetylated a-microtubule was positively correlated with the occurrence of breast cancer.Under the condition of soft substrate cultivation,cell polarization was declined,becoming the circular or oval shape.The acetylated a-tubulin caused reduction in cell polarity,accompanied with less invasion and metastasis ability.Conclusions The acetylated a-tubulin acts as pressure sensors,sensing the sclerosis of extracellular matrix in the process of tumorigenesis,promoting invasion and metastasis of breast cancer.

BACKGROUND:Studies have shown that anterolateral approach for repairing the hip joint capsule has great effects on dislocation after hip replacement, but it remains unclear at present. OBJECTIVE: To study the impact of anterolateral approach for repairing the hip joint capsule on dislocation after artificial hip joint replacement. METHODS: 480 patients, who received artificial hip joint replacement in the First People’s Hospital of Qinzhou from January 2010 to January 2014, were enroled in this study. They were divided into the control group (January 2010 to January 2012) and the observation group (February 2012 to January 2014) according to the order of their admission, each of 240 cases. The control group was subdivided into the total hip replacement group (A1 group) and the femoral head replacement group (A2 group), each of 120 cases; and the observation group was also subdivided into the total hip replacement group (B1group) and the femoral head replacement group (B2 group), each of 120 cases. A1group and A2 group were subjected to artificial hip joint replacementvia anterolateral approach. B1 group and B2 group were subjected to artificial hip joint replacementvia anterolateral approach and the repair of the joint capsule. The postoperative early dislocation rate was analyzed in patients of A1 group and B1 group. Postoperative early dislocation rate was analyzed in patients of A2 group and B2 group. RESULTS AND CONCLUSION: The rate of early postoperative dislocation was 6.7% in A1 group, and 0.8% in the B1 group. The rate of early postoperative dislocation was significantly higher in the A1group than in the B1 group (P < 0.05). The rate of early postoperative dislocation was 3.3% in the A2 group and 0.8% in the B2 group. No significant difference was found between the A2 and B2 groups (P > 0.05). Results showed that anterolateral approach in repairing the hip joint capsule can effectively reduce the incidence of postoperative dislocation after the total hip replacement, but does not obviously impact postoperative dislocation.

Objective To investigate the risk factors for neurological complications after deep hypothermic ciculatory arrest (DHCA) operation.Methods From January 2009 to October 2013, 70 patients who were diagnosed as aortic dissection or aortic an-eurysm underwent aortic operations under DHCA .According to the occurrence of neurological complications after surgery , patients were divided into neurological complication group (26 patients) and normal group (44 patients).Risk factors of neurological complications after surgery were evaluated by univariate analysis and multivariate logistic regression analysis .Results Central neurological compli-cations occurred in 26 patients (37.14%) , including 18 patients with temporary neurological dysfunction and 7 patients with perma-nent neurological dysfunction , 1 patient with paraplegia , 1 patient died of cerebral infarction .Univariate analysis showed that hyperten-sion disease( P =0.001), emergency surgery within 72 hours( P =0.009),cardiopulmonary bypass time ( P =0.015),antegrade se-lective cerebral perfusion ( ASCP) ( P =0.005 ) , hemodilution degree ( P =0.001 ) , erythrocyte ( P =0.033 ) and plasma ( P =0.034 ) transfusion volume in the perioperative period , oxygen index <200 mmHg in 4 hours postoperatively ( P =0.043 ) , arterial blood pressure instability ( P =0.037 ) and hypernatremia in 24 hours postoperatively ( P =0.001 ) , and the Acute Physiology And Chronic Health Evaluation II (APACHE II) score are the risk factors for central neurological complication .Hypertension disease( P =0.017 ) , emergency surgery within 72 hours ( P =0.048 ) , ASCP ( P =0.015 ) , hypernatremia in 24 hours postoperatively ( P =0.008 ) were independent determinats for central neurological complication .Conclusions A series of procedure including evaluating patients condition correctly before operation , controlling hypertension effectively in the perioperative period , applying the ASCP and the suitable hemodilution degree in operation , maintaining electrolyte balance , and correcting hypernatremia timely in the postoperative pe-riod maybe reduce the incidence of neurological complications after DHCA operation .

Objective To explore the therapeutic effect influencing factors of intra-aortic balloon pump(IABP) support during cardiac surgery perioperative period and countermeasures.Methods Clinical data of 42 patients using IABP in the cardiac surgery was analyzed retrospectively.The patients were classified into 2 groups:living group (32 patients) and died group (10 patients).The time of IABP implantation,preoperative cardiac function,the duration of cardiopulmonary bypass(CPB) and aorta block,mean arterial pressure (MAP) and inotropic score (IS) before using IABP and postoperative complications were recorded and compared.Results In died group,2 patients were used IABP preoperatively,1 patient was used intraoperatively,7 patients were used postoperatively,8 patients were in NYHA cardiac function class Ⅲ or Ⅳ preoperative,the duration of CPB and aorta block were (144.43 ± 49.03),(97.29 ± 39.99)min respectively,MAP and IS before using IABP were (57.34 ±7.25) mm Hg (1 mm Hg =0.133 kPa) and (28.22 ±17.72) scores,IABP time was (86.00 ±52.31) min.Compared with living group,all above comparisons showed significant difference [(100.43 ± 35.03) min,(60.45 ± 20.55) min,(69.34 ± 8.05)mm Hg,(10.82 ± 15.75) scores,(49.00 ± 25.23) min] (P ＜ 0.05).Postoperative complications in died group included 7 patients of ventilator dependency,6 patients of acute renal failure,5 patients of refractory metabolic acidosis,2 patients of malignant arrhythmia,1 patient of acute myocardial infarction,significantly higher than those in living group (0,4,2,0,0) (P ＜ 0.05).Conclusions Erroneously choose the timing of using IABP,poor preoperative cardiac function,prolonging CPB and aorta block time,MAP less than 60 mm Hg and high dose positive inotropic agent before using IABP,and postoperative complications are main influencing factors for clinical outcomes of IABP in cardiac surgery.Reasonably choosing adaptive indication and timing of IABP,preventing and treating postoperative complications effectively can improve effects of IABP in cardiac surgery.

Objective To study the mechanism of pulmonary injury and protective effect of modified ultrafiltration on lung function in infant open heart surgery.Methods According to the wishes of parents,40 cases of congenital heart disease were divided into without modified ultrafiltration control group (C) and modified ultrafiltration group (M),and parents signed informed consent.The cardiopulmonary bypass (CPB) was used without ultrafiltration in Group C,while with modified ultrafiltration in group M.The pneumodynamic parameters and C3a,C5a,TXA2,LT were measured at specific time points.Results The static pulmonary compliance (Cstat) and oxygen index (OI) were lower,and alveolar-arteria oxygen difference (AaDO2) was higher after CPB in the two groups(P ＜ 0.05).At T3,T4 and T5 time points,the Cstat and OI in Group M was higher than that in Group C; AaDO2 in Group M was lower than that in Group C (P ＜0.05).The levels of C3a and C5a were lower after CPB in the two groups; levels of TXA2,LT were higher after CPB in the C groups.At T2,T3,T4 and T5 time points,the TXA2 and LT in Group M were lower than that in Group C(P ＜0.05).Conclusions The pulmonary injury in pediatric open heart surgery may be concerned with the the alexin(C3a,C5a) activation and I/R.The level of C3a and C5a was considered earlier index of inflammatory reaction and pulmonary injury.Modified ultrafiltration improves pulmonary function due to elevating coloid osmotic pressure and degrading the plasma level of TXA2,LT.

The signal analysis of heart rate variability (HRV) has been very significant for heart disease of aided diagnosis, monitoring and evaluation. We proposed a new method of HRV signal analysis based on the Hilbert spectrum entropy dividing frequency range. According to Hilbert spectrum characteristics of the multi-resolution and the characteristic of HRV signal frequency spectrum, the Hilbert time-frequency spectrum entropy of HRV signal in different frequency range and the full frequency Hilbert time-frequency spectrum entropy with weighting factor were calculated. This approach was analyzed after the appropriate separation for various physiological factors based on the frequency range and it is more conducive to reflect the physiological and the pathological characteristics. Applying the new approach to the actual HRV signal of the MIT-BIH standard database, we obtained the results which showed that this method could effectively differentiate from the sample group for the young, the elder and the patients with atrial fibrillation, and for the sample group for the healthy persons and CHF patients, the performance in statistical analysis was superior to those of the general time-frequency entropy method. The approach could provide an effective analysis method for clinical HRV signal.
Algorithms ; Electrocardiography ; methods ; Entropy ; Heart Rate ; physiology ; Humans ; Signal Processing, Computer-Assisted