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Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer;hence,new and efficient strategies are necessary.In this study,a supramolecular nanoreactor(DOC@TA-Fe3+)based on tannic acid(TA),iron ion(Fe3+),and docetaxel(DOC)with microtubule inhibition,reactive oxygen species(ROS)generation,and glutathione peroxidase 4(GPX4)inhibition,is prepared for ferroptosis/apoptosis treatment.After internalization by CT26 cells,the DOC@TA-Fe3+nanoreactor escapes from the lysosomes to release payloads.The subsequent Fe3+/Fe2+conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration.Additionally,Fe3+can consume gluta-thione to repress the activity of GPX4 to induce ferroptosis.Meanwhile,the released DOC controls microtubule dynamics to activate the apoptosis pathway.The superior in vivo antitumor efficacy of DOC@TA-Fe3+nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model.Therefore,the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.
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In recent years， neurotoxicity caused by traditional Chinese medicine （TCM） has frequently occurred and has become one of the important factors restricting the development and application of TCM. TCM contains active components and its dosage-effect relationship is the key to determine its pharmacological activity and toxic effects. Among them， the endogenous toxic components include alkaloids， glycosides， diterpenoids， animal and plant toxic proteins and heavy metals， and so on； exogenous toxic components mainly refer to some harmful elements and pesticide residues during the cultivation， processing， transportation and storage of medicinal materials that are not synthesized by themselves. Effect on the processes such as oxidative stress， inflammation， ion exchange， and energy metabolism may be important mechanisms of TCM-induced neurotoxicity. Neural cells， myelin cells， axons and neurotransmitter systems are common targets of TCM-induced neurotoxicity. In the future， we can use modern research methods and big data mining means to establish a safety evaluation mode of “toxic symptoms-poisoning dose-toxic original agent-detoxification scheme” with the basic component group of toxic substances as the core， so as to provide support for development and clinical intervention of neurotoxic traditional Chinese medicine.
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Objective:To evaluate the effects of different depths of anesthesia on CD4 + T cell function in the patients undergoing radical resection for malignant tumor. Methods:Forty-two American Society of Anesthesiologists physical status Ⅱ patients, aged 36-64 yr, weighing 49-95 kg, undergoing elective radical surgery for malignant tumor, were divided into 2 groups ( n=21 each) using a random number table method: light anesthesia group (L group) and deep anesthesia group (D group). The AAI values were maintained at 30-40 and 20-29 during operation in L group and D group, respectively.The time to eye opening, extubation time and consumption of propofol were recorded.The peripheral venous blood samples were collected immediately before induction of anesthesia (T 0), at 2 h of operation (T 1) and at 4, 24, and 72 h after operation (T 2-4) for determination of serum interferon (IFN)-γ and interleukin-4 (IL-4) concentrations (by enzyme-linked immunosorbent assay), and IFN-γ/IL-4 ratio was calculated. Results:Compared with the baseline value at T 0, the serum IFN-γ concentrations were significantly increased at T 3, 4, the serum IL-4 concentrations were decreased at T 1-4, and IFN-γ /IL-4 ratio was increased in group D ( P<0.05). Compared with group L, the serum IFN-γ concentrations were significantly increased at T 3, 4, the serum IL-4 concentrations were decreased at T 1-4, IFN-γ/IL-4 ratio was increased, the consumption of propofol was increased, and the extubation time was prolonged in group D ( P<0.05), and no significant change was found in the time to eye opening between the two groups ( P>0.05). Conclusion:Deep anesthesia can improve CD4 + T cell function in the patients undergoing radical resection for malignant tumor.
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Objective To analyze the incidence and risk factors of hypocalcemia after total parathyroidectomy without autotransplantation. Methods A total of 783 maintenance hemodialysis patients who underwent TPTX in the Second Affiliated Hospital of Nanjing Medical University from September 2008 to September 2017 were included in the study. The preoperative blood biochemical examination, preoperative iPTH, total mass of parathyroid gland (M) and postoperative iPTH and electrolyte results were collected. The incidence of severe hypocalcemia after TPTX were analyzed retrospectively. Binary logistic regression model was used to analyze the risk factors of severe hypocalcemia after TPTX. Results The age of 783 patients with TPTX was (46.90±10.78) years old, and the average dialysis age was (91.36±41.75) months. Postoperative severe hypocalcemia occurred in 235 cases (30.01％). Binary logistic regression analysis showed that higher preoperative blood iPTH (OR=7.56, 95％CI: 1.55-36.79, P=0.01), higher blood alkaline phosphatase (OR=36.71, 95％CI:14.75-91.36, P<0.01), blood phosphorus (OR=1.74, 95％CI: 1.11-2.71, P=0.02) and greater mass of resected glands (OR=1.18, 95％ CI: 1.06-1.31, P<0.01) were the risk factors for post-hypocalcemia. The higher preoperative serum calcium can reduce the risk of postoperative hypocalcemia (OR=0.02,95％CI: 0.01-0.07, P<0.01). Conclusions The incidence of hypocalcemia after TPTX treatment for SHPT is very high. Blood iPTH, alkaline phosphatase, phosphorus, and total mass of intraoperative parathyroid gland excision are the independent risk factors for severe hypocalcemia after surgery.
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Objective · To compare urine sample collection methods for measuring urinary concentrations of phenolic endocrine disrupting chemicals including bisphenol A (BPA),triclosan (TCS),and 4-n-nonylphenol (4-n-NP) in pregnant women.Methods· Urine samples were collected from women at late pregnancy by two methods:urine catheter and collection bag (n=176),urine collecting containers made of polypropylene (PP) (n=642).Urinary concentrations of BPA,TCS and 4-n-NP were measured with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)method.Confirmation experiment used PP containers,urine catheter and collection bags,as well as low-density polyethylene (LDPE) tubes and glass containers as both negative controls to collect urine samples from each of the 5 women.Results · Geometric mean (GM) of urinary BPA concentration collected by urine catheter and collection bags was 82.5 ng/mL (95％ CI 71.4-95.4 ng/mL),which was 63 times higher than that from PP containers (GM 1.3 ng/mL;95％ CI 1.3-1.5 ng/mL).Concentrations of urinary 4-n-NP and creatinine were similar between two collection methods.Confirmation experiment showed that urinary BPA concentration collected by urine catheter and collection bags was much higher than those collected by other three methods.Conclusion· In collection of urine samples for measuring phenolic chemicals,PP urine collection container as well as LDPE containers are adequate for use in epidemiologic studies,but urine catheter and collection bag is not.
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A lot of basic and clinical studies have proved that limb remote ischemic preconditioning (RIPre) is a safe and effective means reducing perioperative myocardial reperfusion injury .However ,RIPre possesses specific protec‐tive window .Therefore ,researchers used repeated limb RIPre to prolong the protective window in order to explore a new prevention and rehabilitation measure for cardiovascular diseases .
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_ Objective_ To study whether quinoid dihydropteridine reductase ( QDPR ) expression level change can affect oxidative stress of NRK-52E renal tubular cells in a high glucose environment. Methods The NRK-52E model of overexpression, knockdown QDPR gene and respective control were constructed by lentivirus. All groups were given 5. 4 mmol/L and 30 mmol/L glucose culture medium respectively to imitate normal and high glucose condition. The level of superoxide anion ( O-2 ) was detected by flow cytometer dihydroethidium method. The protein expression level of superoxide dismutase 1 (SOD1)was tested by Western blot. Results QDPR over-expression can decrease O-2(P<0. 01)and SOD1(P<0. 05)levels in high glucose condition;QDPR knockdown increases O-2(P<0. 01) and does not change SOD1. Conclusion Under high glucose condition, overexpression of QDPR gene decreases NRK-52E cell oxidative stress. Knockdown QDPR gene increases NRK-52E cell oxidative stress. QDPR gene may influence the development of diabetic nephropathy by oxidative stress.
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<p><b>OBJECTIVE</b>To explore the influence of relapse and survival by chronic graft versus host disease (cGVHD) in patients with acute myeloid leukemia (AML) after allogeneic hematopoietics stem cell transplantation (allo-HSCT).</p><p><b>METHODS</b>Fifty-five AML patients received allo-HSCT were retrospectively reviewed. Relapse rate and overall survival (OS) were analyzed according to cGVHD.</p><p><b>RESULTS</b>cGVHD significantly decreased the relapse rate of AML patients after transplantation within 2 years when compared with those without cGVHD (8.7% vs 38.6%, P=0.019), however, cGVHD had no effect on the long-term relapse rate (22.8% vs 5.9%, P=0.217). cGVHD had no effect on OS within 2 years (78.3% vs 61.0%, P=0.155) but could decrease the rate of long-term survival (63.7% vs 100%,P=0.01). cGVHD also could reduce the rate of relapse (8.3% vs 46.2%, P=0.044) and enhanced the rate of survival (83.3% vs 47.2%, P=0.045) in patients with high risk AML after allo-HSCT in 2 years, while it had no effect on the relapse rate and OS in patients with low and intermediated risk AML in early and late phase. Moreover, compared with the rate of relapse(38.6%) in patients without cGVHD, the rate of relapse were lower in patients with limited cGVHD and intensive cGVHD (27.3% and 31.3%, respectively) but the long-term survival was significantly lower (53.3%, P=0.001) in those patients with intensive cGVHD after all-HSCT.</p><p><b>CONCLUSION</b>The benefit effect of cGVHD mainly took place within 2 years after allo-HSCT in AML patients especially in those with high risk, while in late phase after allo-HSCT, cGVHD especially intensive cGVHD had an effect on reducing long-term survival.</p>
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Humanos , Doença Crônica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Recidiva , Estudos Retrospectivos , Transplante HomólogoRESUMO
The enzymes involved in riboflavin biosynthesis are considered to be potential anti-bacterial drug targets because these proteins are essential in bacterial pathogens but are absent in humans. 3,4-dihydroxy-2-butanone-4-phosphate synthase (DHBPS) is one of the key enzymes in the biosynthesis of riboflavin. DHBPS catalyzes the conversion of ribulose-5-phosphate (Ru5P) to 3,4-Dihydroxy-2-butanone-4-phosphate (DHBP) and formate. The purified SpDHBPS enzyme, in the presence of Mg(2+) ion, catalyzed the conversion of Ru5P to DHBP at a rate of 109nmolmin(-1)mg(-1) with an apparent Km value of 181µM at 37°C. Surprisingly, our experiments first revealed that DHBPS showed activity in the presence of the trivalent metal ion, Fe(3+). Furthermore, we determined the crystal structure of DHBPS from Gram-positive bacteria, Streptococcus pneumoniae, with 2.0Å resolution. The overall architecture of SpDHBPS was similar to its homologs, which comprise one ß-sheet (five-stranded) and eight α-helices, adopting a three-layered α-ß-α sandwich fold. Similar to the homologs, gel-filtration experiments verified that the enzyme was arranged as a dimer. Although the overall fold of DHBPS was similar, the significant structural differences between the species at the active site region may be utilized to develop antibacterial agents that are species-specific.
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Proteínas de Bactérias/química , Transferases Intramoleculares/química , Streptococcus pneumoniae/enzimologia , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Sistemas de Liberação de Medicamentos , Estabilidade Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Transferases Intramoleculares/genética , Transferases Intramoleculares/isolamento & purificação , Transferases Intramoleculares/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Multimerização Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Alinhamento de Sequência , Streptococcus pneumoniae/genéticaRESUMO
The aim of the present study was to obtain the crystal of transcription factor LytR of streptococcus pneumoniae for X-ray crystal structure and function analysis. The LytR gene of D39 strains from Streptococcus pneumoniae (S. pn) was cloned into the prokaryotic expression vector pET32a(+), then overexpression was obtained in the E. coli BL21 (DE3) through transformation of the recombinant plasmid that had been verified by colony PCR and sequencing. Soluble fusion protein with His-tag highly expressed by the induction of 0.5 mmol/L IPTG and was purified by a three step procedure, the purity of the purified LytR recombinant protein was over 90%. Preliminary screening of crystallization conditions was performed using the hanging-drop vapour-diffusing method with Hampton Crystal screen and PEG screen kits. The protein crystals X-ray diffraction data were collected from a single crystal and more stick crystals whose X-ray diffraction reached 4.0 A were obtained. These works laid the foundation for further research on the 3D structure of putative transcription factor LytR and its biological aspects.
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Proteínas de Bactérias , Genética , Escherichia coli , Genética , Metabolismo , Proteínas Recombinantes , Genética , Streptococcus pneumoniae , Genética , Metabolismo , Fatores de Transcrição , GenéticaRESUMO
Objective The aim of the study was to analyze the psychological problems and psychological needs of the odinopoeia patients with stillbirth or fetal malformation.Methods From May to August 2012,25 patients with stillbirth or fetal malformation were collected and 40 normal patients were selected as control in the targeted hospital,their psychological conditions were compared.The socio-demographics of patients were survey,the Symptom Check List 90(SCL-90) was applied to assess the two groups' psychological conditions,and Impact of Event Scale Revised (IES-R) was applied to assess the post traumatic stress disorder (PTSD),moreover,the associated factors with PTSD was also analyzed.Results The symptom factor scores of the cases were significantly higher in odinopoeia patients than the controls.The age,education levels,having or no offsprings and the support of spouse were greatly associated with PTSD of patients with stillbirth or fetal malformation.The patients with stillbirth or fetal malformation demanded to understand some prenatal care knowledge and the reasons for stillbirth or fetal malformation.Conclusions The patients with stillbirth or fetal malformation had low levels of psychological health,so the medical workers and family members must pay much attention to the psychological conditions of patients with stillbirth or fetal malformation,and provide them the psychological counseling in order to eliminate the patients' suffering from stillbirth or fetal malformation and improve their mental health.
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Objective Although aspirin resistance has been recognized to occur in patients with diabetes mellitus, the prevalence and related risk factors for aspirin resistance in elderly patients with diabetes mellitus have not been reported yet. The purpose of the present study was to evaluate the prevalence and potential risk factors for aspirin resistance in elderly patients with type 2 diabetes.Methods The 140 elderly patients [aged from 60 to 92 years, mean age (73.8±8. 0) years] with type 2 diabetes receiving daily aspirin therapy (≥ 75 mg) over one month were recruited. Platelet aggregation was measured by light transmittance aggregometry (LTA) and thrombelastograph (TEG)platelet mapping assay. Results By LTA, 6 patients (4.3%) of the diabetic patients were found to be resistant to aspirin therapy, 44 patients (31.4 %) were semi-responders. By TEG, 31 patients (22. 1%) were aspirin resistant. Among the 31 patients who were aspirin resistant by TEG, 3 were aspirin resistant by LTA. In the multivariate logistic regression analysis, female gender (OR= 5. 54,95%CI: 1.17-27.47, P=0.036) and homocysteine level (OR=1.15, 95%CI: 1.00-1.35, P=0. 043) were statistically significant risk factors for aspirin resistance by TEG. Conclusions The prevalence of aspirin resistance in elderly patients with type 2 diabetes is considerably higher in elderly female patients and in elderly patients with higher serum homocysteine level.
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Objective To investigate the changes of sex hormone and androgen receptor levels and evaluate the relationship of the sex hormones and androgen receptor with coronary heart disease (CHD) in elderly men. Methods A cross-sectional study was performed in 539 elderly men, including 400 healthy people aged 62-92 years and 139 CHD patients aged 60-88 years. The plasma concentrations of total testosterone (TT), free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. The androgen receptor (AR) level was tested by flow cytometry. Results The fluorescence intensity of DHEAS, TT, SHBG, FT and AR were significantly lower in CHD group than in healthy group (P<0.01);however, FSH and E2 in CHD group were higher(P(0.01). Age was negatively correlated with TT(r=-0.28,P<0.01) and FT (r=-0.17,P<0.05), and positively correlated with SHBG(r=0.14,P<0.05) and E2 (r=0.33, P<0.01). AR fluorescence intensity was negatively correlated with systolic blood pressure (r=-0.12,P<0.01). Logistic regression analysis indicated that TT (OR=1.065,9% CI: 1.012～1.121,P<0.05), SHBG(OR=0.994,95% CI:0.990～0.998,P<0.01) and AR (OR=0.971,95%CI:0.956～0.986, P<0.01)were significantly associated with CHD in elderly male patients. Conclusions The levels of DHEAS, TT, SHBG, FT and AR are lower in elderly men with CHD than in elderly healthy men;however, the FSH and E2 concentrations are higher. Low levels of TT, SHBG and AR may be the independent risk factors for CHD in elderly men.
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Objective To evaluate endothelium-dependent dilation (flow-mediated dilation, FMD) and endothelium-independent dilation(nitroglycerin-mediated dilation, NMD) of the brachial and superficial arteries in elderly patients with atherosclerotic disease(LEASD) of the lower extremity, and to evaluate the correlation between brachial and superficial femoral FMD and NMD and their characteristics. Methods Both FMD and NMD of the brachial artery and the superficial femoral artery were determined in 33 old LEASD patients with the high-resolution ultrasound, and the results were compared with that of 40 healthy elderly controls and 30 non-LEASD elderly patients with cardiovascular risk factors, respectively. Results Both FMD and NMD of the brachial artery and the superficial femoral artery were significantly lower in 33 elderly LEASD patients compared with those of 40 healthy elderly controls and 30 non-LEASD elderly patients but with cardiovascular risk factors (P
