It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is ...It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is still unclear.The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma(LUAD).Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies,and through analysis of The Cancer Genome Atlas(TCGA)dataset.Frequent HE4 overexpression was demonstrated in LUAD,but not in lung squamous cell carcinoma(LUSC),indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC.HE4 knockdown significantly inhibited cell growth,colony formation,wound healing,and invasion,and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways.The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells,while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects.Moreover,we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD.Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.展开更多
AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets pre...AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo formulation was achieved by mixing slow- and rapid-of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs68.7%. From release pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67±0.52 h vs9.83±0.98 h and the Cmax being 1 334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn preparations were statistically bioequivalent. Furthermore,percentage absorption in vivo and the cumulative percentage release in vitro.CONCLUSION: The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves.展开更多
AIM: To investigate the permeability characteristics of rebamipide across intestinal mucosa, and examine the effects of some absorption enhancers on the permeability across the colonic tissue. Another purpose is to de...AIM: To investigate the permeability characteristics of rebamipide across intestinal mucosa, and examine the effects of some absorption enhancers on the permeability across the colonic tissue. Another purpose is to demonstrate the colon-specific delivery of rebamipide with or without absorption enhancers using chitosan capsule as a carrier. METHODS: The permeability of rebamipide was evaluated using an in vitro diffusion chamber system, and the effects of some absorption enhancers on the permeability via colon were further investigated. The release of rebamipide from chitosan or gelatin capsule was studied by Japan Pharmacopoeia rotating basket method. The colonic and plasma concentrations were analyzed by high performance liquid chromatography (HPLC) to evaluate colon-targeting action after oral administration of various dosage forms, and rebamipide with absorption enhancers in chitosan dosage forms. RESULTS: The permeability of rebamipide across the jejunal or ileal membranes was higher than the colonic membranes. Both sodium laurate (C12) and labrasol signifi cantly increased permeability across the colon membranes. On the other hand, the release of rebamipide from chitosan capsule was less than 10%totally within 6 h. The area under concentration-time profile of drug in the colon mucosa using chitosan capsules (AUCLI, 1 6011.2 ng·h/g) was 2.5 times and 4.4 times greater than using gelatin capsules and CMC suspension, respectively. Meanwhile, the area under concentration-time profile of drug in the plasma (AUCPL) was 1016.0 ng·h/mL for chitosan capsule, 1887.9 ng·h/mL for CMC suspension p and 2163.5 ng·h/mL for gelatin capsule. Overall, both AUCLI and AUCPL were increased when C12 was co-administrated, but the increase of AUCLI was much greater; the drug delivery index (DDI) was more than 1 compared with simple chitosan capsule group. CONCLUSION: There was a regional difference in the permeability of Rabamipide across the jejunum, ileum and the colon, and passive diffusion seems to be one of the major transport mechanisms of rebamipide. Absorption enhancers can increase the permeability of rebamipide across the colon tissue signifi cantly. In addition, chitosan capsule may be a useful carrier to deliver rebamipide to the colon specifi cally and the co-administration of C12 with rebamipide may also be very useful in local treatment.展开更多
A rapid and sensitive method for quantitative determination of paclitaxel in rat plasmawas developed and validated by using ultra-performance liquid chromatography-tandemmass spectrometry (UPLC-MS/MS). Docetaxel was u...A rapid and sensitive method for quantitative determination of paclitaxel in rat plasmawas developed and validated by using ultra-performance liquid chromatography-tandemmass spectrometry (UPLC-MS/MS). Docetaxel was used as an internal standard anddiethyl ether was the liquideliquid extraction agent. Multiple reaction monitoring (MRM)mode via positive electrospray ionization (ESI) was applied to detect paclitaxel and IS at thetransitions m/z 854 / 286 and m/z 808.48 / 527.3, respectively. This method covered alinearity range from 5 to 5000 ng/ml, with the total run time of 3.0 min. In summary, a highthroughout UPLC-MS/MS method was successfully developed to measure paclitaxel in ratplasma and was applied to pharmacokinetic study after intravenous administration ofpaclitaxel.展开更多
Alkaline phosphatase(ALP)is widely expressed in human tissues.ALP plays an important role in the dephosphorylation of proteins and nucleic acids.Therefore,quantitative analysis of ALP plays a vital role in disease dia...Alkaline phosphatase(ALP)is widely expressed in human tissues.ALP plays an important role in the dephosphorylation of proteins and nucleic acids.Therefore,quantitative analysis of ALP plays a vital role in disease diagnosis and the development of biological detection methods.Terminal deoxynucleotidyl transferase(TdT)catalyzes continuous polymerization of deoxynucleotide triphosphates at the 30-OH end of single-stranded DNA in the absence of a template.In this study,we developed a highly sensitive and selective method based on TdT and endonuclease Ⅳ(Endo Ⅳ)to quantify ALP activity.After ALP hydrolyzes the 30-PO_(4) end of the substrate and generates 30-OH,TdT can effectively elongate the 30-OH end with deoxynucleotide adenine triphosphate(dATP)and produce a poly A tail,which can be detected by the poly T probes.Endo Ⅳ digests the AP site in poly T probes to generate a fluorescent signal and a new 30-OH end,leading to the generation of exponential fluorescence signal amplification.The substrate for TdT elongation was optimized,and a limit of detection of 4.3×10^(-3) U/L was achieved for ALP by the optimized substrate structure.This method can also detect ALP in the cell lysate of a single cell.This work has potential applications in disease diagnosis and biomedical detection.展开更多
Bacillus subtilis is the focus of both academic and industrial research.Previous studies have reported a number of sequence variations in different B.subtilis strains.To uncover the genetic variation and evolutionary ...Bacillus subtilis is the focus of both academic and industrial research.Previous studies have reported a number of sequence variations in different B.subtilis strains.To uncover the genetic variation and evolutionary pressure in B.subtilis strains,we performed whole genome sequencing of two B.subtilis isolates,KM and CGMCC63528.Comparative genomic analyses of these two strains with other B.subtilis strains identified high展开更多
Aqueous and hydro-alcoholic extracts of Achillea fragrantissima L. (Asteraceae) grown in Jordan were screened for their antioxidant, antimicrobial, antiplatelet, anti-proliferative and acetylcholinesterase (AChE) inhi...Aqueous and hydro-alcoholic extracts of Achillea fragrantissima L. (Asteraceae) grown in Jordan were screened for their antioxidant, antimicrobial, antiplatelet, anti-proliferative and acetylcholinesterase (AChE) inhibition efficacy. Total phenols and flavonoids were determined colorimetrically. The radical scavenging activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical scavenging activity assays. High performance liquid chromatography-mass spectrometry (HPLCMS) analysis resulted in the identification of 7 phenolic compounds in the hydro-alcoholic extract and 4 compounds in the aqueous extract;quercetin 3-β-D-glucoside was the main component for both extracts. Antimicrobial activities were determined by antimicrobial susceptibility testing such as agar well-diffusion method, minimum inhibition concentration and minimum bactericidal concentration. Gram positive bacteria showed sensitivity to hydro-alcoholic extract in the agar-well diffusion test. No significant activity was observed against gram negative bacteria and Candida albicans. Hydro-alcoholic extract had a bactericidal activity against Streptococcus pneumoniae and Bacillus cereus at high concentrations (MIC 12.5 mg/ml) rather than inhibitory effect. In vitro antiplatelet activity was tested on human whole blood using an electrical impedance method. At concentrations (50, 100, and 200 μg/ml), no effect on platelet aggregation was noticed. Anti-proliferative activity was investigated using the MTT assay. At concentrations up to 200 μg/ml, extracts did not possess cytotoxic activity against the MCF-7 cells. Acetylcholinesterase (AChE) inhibitory capacity of A. fragrantissima extracts was tested using TLC assay method, and neither aqueous, nor hydroalcoholic extracts showed AChE inhibition. The present investigation supported the traditional use of A. fragrantissima in the Jordanian folk medicine as an antimicrobial active representative of the genus Achillea. A. fragrantissima extracts should be further studied for their potential use in preventing/treating diseases in which oxidative stress is a part of the pathophysiology.展开更多
The influence of bilirubin on mRNA expression of cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) and nuclear receptors in human hepatocytes was investigated. The treatment of the hepatocytes with 40 μg/mL bi...The influence of bilirubin on mRNA expression of cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) and nuclear receptors in human hepatocytes was investigated. The treatment of the hepatocytes with 40 μg/mL bilirubin, which corresponds to hyperbilirubinemia, resulted in 1.7-fold increase of CYP2A6 mRNA compared to the vehicle control while CYP2A6 mRNA did not change after treatment with 1 μg/mL bilirubin, corresponding to physiologically normal level. No significant change of mRNA expression by 40 μg/mL bilirubin treatment was observed for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, UGT1A1, UGT1A3, UGT1A6, UGT2B4, UGT2B7, UGT2B10 and UGT2B15, constitutive androstane receptor (CAR), pregnane X receptor (PXR), retinoid X receptor α (RXRα) and hepatocyte nuclear factor-4α (HNF-4α). The induction profile of bilirubin was different from that of rifampicin, a typical PXR activator. This study demonstrated that CYP2A6 can be induced by bilirubin in a concentration dependent manner.展开更多
Objectives: To explore patient’s perspectives of the role of the community pharmacist in view of other health care professionals (specialist physician, general practitioner, nurse and others (e.g. herbalist)) in Jord...Objectives: To explore patient’s perspectives of the role of the community pharmacist in view of other health care professionals (specialist physician, general practitioner, nurse and others (e.g. herbalist)) in Jordan, UAE and Iraq. The study also investigated patient’s willingness to pay for specialized pharmaceutical care services. Methods: This study followed a single phase cross sectional survey methodology, conducted in three Middle Eastern countries. Data were collected over a period of 6 months on two consecutive years (March to May 2009 and 2010). A questionnaire was designed and validated, then completed by patients walking into community pharmacies. The source of advice (specialist physician, general practitioner, pharmacist, nurse, or herbalist) regarding patient’s medication use and medical management were investigated. Key findings: Patients visiting community pharmacies in Jordan (n = 1000), UAE (n = 1000) and Iraq (n = 968) were recruited into the study (mean age 35.9 ± 13.1, 50.6% males). Significant difference between the three countries was shown, as more patients chose the pharmacist as their primary source of advice on medication use vs. the specialist physician in Jordan (50.8% vs. 37.3%) and Iraq (41.9% vs. 36.7%) compared to UAE (38.0% vs. 40.1%), P < 0.001, Chi-square test. Few agreed to receive paid pharmaceutical care services (Jordan 19.5%;UAE 24.7%;Iraq 2.3%). Conclusion: Current situation resulting in the lower socioeconomic status in Jordan and Iraq seems to lead to patients’ higher reliance on the pharmacist, as compared to the UAE. Majority of patients, regardless of the country of origin, are not willing to pay for specialized pharmaceutical care services. These findings are important for future social pharmacy research in the area.展开更多
Most of the conventional chemotherapeutic agents used for cancer chemotherapy suffer from multidrug resistance of tumor cells and poor antitumor efficacy.Based on physiological differences between the normal tissue an...Most of the conventional chemotherapeutic agents used for cancer chemotherapy suffer from multidrug resistance of tumor cells and poor antitumor efficacy.Based on physiological differences between the normal tissue and the tumor tissue,one effective approach to improve the efficacy of cancer chemotherapy is to develop pH-sensitive polymeric micellar delivery systems.The copolymers with reversible protonationedeprotonation core units or acid-liable bonds between the therapeutic agents and the micelle-forming copolymers can be used to form pH-sensitive polymeric micelles for extracellular and intracellular drug smart release.These systems can be triggered to release drug in response to the slightly acidic extracellular fluids of tumor tissue after accumulation in tumor tissues via the enhanced permeability and retention effect,or they can be triggered to release drug in endosomes or lysosomes by pH-controlled micelle hydrolysis or dissociation after uptake by cells via the endocytic pathway.The pH-sensitive micelles have been proved the specific tumor cell targeting,enhanced cellular internalization,rapid drug release,and multidrug resistance reversal.The multifunctional polymeric micelles combining extracellular pH-sensitivity with receptor-mediated active targeting strategies are of great interest for enhanced tumor targeting.The micelles with receptor-mediated and intracellular pH targeting functions are internalized via receptor-mediated endocytosis followed by endosomal-pH triggered drug release inside the cells,which reverses multidrug resistance.The pH sensitivity strategy of the polymeric micelles facilitates the specific drug delivery with reduced systemic side effects and improved chemotherapeutical efficacy,and is a novel promising platform for tumor-targeting drug delivery.展开更多
Background: Stress index at post-recruitment maneuvers could be a method of positive end-expiratory pressure (PEEP) titration in acute respiratory distress syndrome (ARDS) patients. However, airway pressure (P_a...Background: Stress index at post-recruitment maneuvers could be a method of positive end-expiratory pressure (PEEP) titration in acute respiratory distress syndrome (ARDS) patients. However, airway pressure (P_aw) stress index may not reflect lung mechanics in the patients with high chest wall elastance. This study was to evaluate the P stress index on lung mechanics and the correlation between P stress index and transpulmonary pressure (P_L) stress index in acute respiratory failure (ARF) patients. Methods: Twenty-four ARF patients with mechanical ventilation (MV) were consecutively recruited from July 2011 to April 2013 in Zhongda Hospital, Nanjing, China and Ospedale S. Giovanni Battista-Molinette Hospital, Turin, Italy. All patients underwent MV with volume control (tidal volume 6 ml/kg) for 20 rain. PEEP was set according to the ARDSnet study protocol. The patients were divided into two groups according to the chest wall elastance/respiratory system elastance ratio. The high elastance group (H group, n = 14) had a ratio _〉30%, and the low elastance group (L group, n = 10) had a ratio 〈30%. Respiratory elastance, gas-exchange, P stress index, and Pt stress index were measured. Student's t-test, regression analysis, and Bland-Altman analysis were used for statistical analysis. Results: Pneumonia was the major cause of respiratory failure (71.0%). Compared with the L group, PEEP was lower in the H group (5.7 ± 1.7 cmH,O vs. 9.0 ± 2.3 cmH2O, P 〈 0.01 ). Compared with the H group, lung elastance was higher (20.0 ± 7.8 cmH20/L vs. 11.6 ± 3.6 cmH,O/L, P 〈 0.01), and stress was higher in the L group (7.0 ±1.9 vs. 4.9 ± 1.9, P = 0.02). A linear relationship was observed between the P stress index and the P stress index in H group (x2 = 0.56, P 〈 0.01 ) and L group (x2 = 0.85, P 〈 0.01). Conclusion: In the ARF patients with MV, P,w stress index can substitute for PL to guide ventilator settings.展开更多
Apramycin is unique in the aminoglycoside family due to its octodiose moiety. However, either the biosynthesis process or the precursors involved are largely unknown. Addition of glycine, as well as serine or threonin...Apramycin is unique in the aminoglycoside family due to its octodiose moiety. However, either the biosynthesis process or the precursors involved are largely unknown. Addition of glycine, as well as serine or threonine, to the Streptomyces tenebrabrius UD2 fermentation medium substantially increases the production of apramycin with little effect on the growth of mycelia, indicating that glycine and/or serine might be involved in the biosynthesis of apramycin. The 13C-NMR analysis of [2-13C] glycine-fed (25% enrichment) apramycin showed that glycine specifically and efficiently incorporated into the only N-CH3 substituent of apramycin on the C7′ of the octodiose moiety. We noticed that the in vivo concentration of S-adenosyl methionine increased in parallel with the addition of glycine, while the addition of methione in the fermentation medium significantly decreased the productivity of apra-mycin. Therefore, the methyl donor function of glycine is proposed to be involved in the methionine cycle but methionine itself was proposed to inhibit the methylation and methyl transfer processes as previously reported for the case of rapamycin. The 15N NMR spectra of [2-13C,15N]serine labeled apramycin indicated that serine may also act as a limiting precursor contributing to the ―NH2 substituents of apramycin.展开更多
Bacteria need a high degree of genetic stability to maintain their species identities over long evolutionary times while retaining some mutability to adapt to the changing environment.It is a long unanswered question ...Bacteria need a high degree of genetic stability to maintain their species identities over long evolutionary times while retaining some mutability to adapt to the changing environment.It is a long unanswered question that how bacteria reconcile these seemingly contradictory biological properties.We hypothesized that certain mechanisms must maintain a dynamic balance between genetic stability and mutability for the survival and evolution of bacterial species.To identify such mechanisms,we analyzed bacterial genomes,focusing on the Salmonella mismatch repair(MMR)system.We found that the MMR gene mutL functions as a genetic switch through a slipped-strand mispairing mechanism,modulating and maintaining a dynamic balance between genetic stability and mutability during bacterial evolution.This mechanism allows bacteria to maintain their phylogenetic status,while also adapting to changing environments by acquiring novel traits.In this review,we outline the history of research into this genetic switch,from its discovery to the latest findings,and discuss its potential roles in the genomic evolution of bacteria.展开更多
Amphipathic polymer pullulan acetate (PA)-coated magnetic nanoparticles were prepared and characterized by various physicochemical means. The cytotoxicity and cellular uptake of the magnetic nanoparticles were examine...Amphipathic polymer pullulan acetate (PA)-coated magnetic nanoparticles were prepared and characterized by various physicochemical means. The cytotoxicity and cellular uptake of the magnetic nanoparticles were examined. The hyperthermic effect of the magnetic nanoparticles on tumor cells was evaluated. Transmission electron microscopy (TEM) showed that the PA coated magnetic nanoparticles (PAMNs) had spherical morphology. Dynamic light scattering (DLS) showed that the size distribution of PAMNs was unimodal,with an average diameter of 25.8 nm ± 6.1 nm. The presence of the adsorbed layer of PA on the magnetite surface was confirmed by Fourier transform infrared (FTIR) spectroscopy. Magnetic measurements revealed that the saturation magnetization of the PAMNs reached 51.9 emu/g and the nanoparticles were superparamagnetic. Thermogravimetric analysis (TGA) showed that the Fe_(3)O_(4) particles constituted 75 wt% of the PAMNs. The PAMNs had good heating properties in an alternating magnetic field. Cytotoxicity assay showed that PAMNs exhibited no significant cytotoxicity against L929 cells. TEM results showed that a large number of PAMNs were internalized into KB cells. PAMNs have good hyperthermia effect on KB cells in vitro by magnetic field induced hyperthermia. These novel magnetic nanoparticles have great potential as magnetic hyperthermia mediators.展开更多
基金supported by National Natural Science Foundation of China(82272695)the Key Program of Natural Science Foundation of Zhejiang Province(LZ23H160004)National Undergraduate Training Program for Innovation,and Zhejiang Xinmiao Talents Program,China.
文摘It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is still unclear.The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma(LUAD).Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies,and through analysis of The Cancer Genome Atlas(TCGA)dataset.Frequent HE4 overexpression was demonstrated in LUAD,but not in lung squamous cell carcinoma(LUSC),indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC.HE4 knockdown significantly inhibited cell growth,colony formation,wound healing,and invasion,and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways.The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells,while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects.Moreover,we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD.Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.
文摘AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo formulation was achieved by mixing slow- and rapid-of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs68.7%. From release pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67±0.52 h vs9.83±0.98 h and the Cmax being 1 334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn preparations were statistically bioequivalent. Furthermore,percentage absorption in vivo and the cumulative percentage release in vitro.CONCLUSION: The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves.
基金Research Funding of Medical Association of Japanese-Chinese, Japan
文摘AIM: To investigate the permeability characteristics of rebamipide across intestinal mucosa, and examine the effects of some absorption enhancers on the permeability across the colonic tissue. Another purpose is to demonstrate the colon-specific delivery of rebamipide with or without absorption enhancers using chitosan capsule as a carrier. METHODS: The permeability of rebamipide was evaluated using an in vitro diffusion chamber system, and the effects of some absorption enhancers on the permeability via colon were further investigated. The release of rebamipide from chitosan or gelatin capsule was studied by Japan Pharmacopoeia rotating basket method. The colonic and plasma concentrations were analyzed by high performance liquid chromatography (HPLC) to evaluate colon-targeting action after oral administration of various dosage forms, and rebamipide with absorption enhancers in chitosan dosage forms. RESULTS: The permeability of rebamipide across the jejunal or ileal membranes was higher than the colonic membranes. Both sodium laurate (C12) and labrasol signifi cantly increased permeability across the colon membranes. On the other hand, the release of rebamipide from chitosan capsule was less than 10%totally within 6 h. The area under concentration-time profile of drug in the colon mucosa using chitosan capsules (AUCLI, 1 6011.2 ng·h/g) was 2.5 times and 4.4 times greater than using gelatin capsules and CMC suspension, respectively. Meanwhile, the area under concentration-time profile of drug in the plasma (AUCPL) was 1016.0 ng·h/mL for chitosan capsule, 1887.9 ng·h/mL for CMC suspension p and 2163.5 ng·h/mL for gelatin capsule. Overall, both AUCLI and AUCPL were increased when C12 was co-administrated, but the increase of AUCLI was much greater; the drug delivery index (DDI) was more than 1 compared with simple chitosan capsule group. CONCLUSION: There was a regional difference in the permeability of Rabamipide across the jejunum, ileum and the colon, and passive diffusion seems to be one of the major transport mechanisms of rebamipide. Absorption enhancers can increase the permeability of rebamipide across the colon tissue signifi cantly. In addition, chitosan capsule may be a useful carrier to deliver rebamipide to the colon specifi cally and the co-administration of C12 with rebamipide may also be very useful in local treatment.
基金This work was financially supported from the National Nature Science Foundation of China(No.81173008)from the National Basic Research Program of China(973 Program)No.2009CB930300+1 种基金from Project for Excellent Talents of Liaoning Province(No.LR20110028)from Program for New Century Excellent Talents in University(No.NCET-12-1015).
文摘A rapid and sensitive method for quantitative determination of paclitaxel in rat plasmawas developed and validated by using ultra-performance liquid chromatography-tandemmass spectrometry (UPLC-MS/MS). Docetaxel was used as an internal standard anddiethyl ether was the liquideliquid extraction agent. Multiple reaction monitoring (MRM)mode via positive electrospray ionization (ESI) was applied to detect paclitaxel and IS at thetransitions m/z 854 / 286 and m/z 808.48 / 527.3, respectively. This method covered alinearity range from 5 to 5000 ng/ml, with the total run time of 3.0 min. In summary, a highthroughout UPLC-MS/MS method was successfully developed to measure paclitaxel in ratplasma and was applied to pharmacokinetic study after intravenous administration ofpaclitaxel.
基金financially supported by the National Natural Science Foundation of China(Grant No.:21904045)the Fundamental Research Funds for the Central Universities(HUST:Grant No.:2019kfyXJJS169)Training Program of Innovation and Entrepreneurship for Undergraduates of Hubei Province(Grant No.:S202010487225).
文摘Alkaline phosphatase(ALP)is widely expressed in human tissues.ALP plays an important role in the dephosphorylation of proteins and nucleic acids.Therefore,quantitative analysis of ALP plays a vital role in disease diagnosis and the development of biological detection methods.Terminal deoxynucleotidyl transferase(TdT)catalyzes continuous polymerization of deoxynucleotide triphosphates at the 30-OH end of single-stranded DNA in the absence of a template.In this study,we developed a highly sensitive and selective method based on TdT and endonuclease Ⅳ(Endo Ⅳ)to quantify ALP activity.After ALP hydrolyzes the 30-PO_(4) end of the substrate and generates 30-OH,TdT can effectively elongate the 30-OH end with deoxynucleotide adenine triphosphate(dATP)and produce a poly A tail,which can be detected by the poly T probes.Endo Ⅳ digests the AP site in poly T probes to generate a fluorescent signal and a new 30-OH end,leading to the generation of exponential fluorescence signal amplification.The substrate for TdT elongation was optimized,and a limit of detection of 4.3×10^(-3) U/L was achieved for ALP by the optimized substrate structure.This method can also detect ALP in the cell lysate of a single cell.This work has potential applications in disease diagnosis and biomedical detection.
基金supported by Significant new drugs creation,12th Five-Year plan special science and Technology Major(2013ZX09304101)the National High Technology Research and Development Program of China(863 Program)(2014AA022210)
文摘Bacillus subtilis is the focus of both academic and industrial research.Previous studies have reported a number of sequence variations in different B.subtilis strains.To uncover the genetic variation and evolutionary pressure in B.subtilis strains,we performed whole genome sequencing of two B.subtilis isolates,KM and CGMCC63528.Comparative genomic analyses of these two strains with other B.subtilis strains identified high
文摘Aqueous and hydro-alcoholic extracts of Achillea fragrantissima L. (Asteraceae) grown in Jordan were screened for their antioxidant, antimicrobial, antiplatelet, anti-proliferative and acetylcholinesterase (AChE) inhibition efficacy. Total phenols and flavonoids were determined colorimetrically. The radical scavenging activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical scavenging activity assays. High performance liquid chromatography-mass spectrometry (HPLCMS) analysis resulted in the identification of 7 phenolic compounds in the hydro-alcoholic extract and 4 compounds in the aqueous extract;quercetin 3-β-D-glucoside was the main component for both extracts. Antimicrobial activities were determined by antimicrobial susceptibility testing such as agar well-diffusion method, minimum inhibition concentration and minimum bactericidal concentration. Gram positive bacteria showed sensitivity to hydro-alcoholic extract in the agar-well diffusion test. No significant activity was observed against gram negative bacteria and Candida albicans. Hydro-alcoholic extract had a bactericidal activity against Streptococcus pneumoniae and Bacillus cereus at high concentrations (MIC 12.5 mg/ml) rather than inhibitory effect. In vitro antiplatelet activity was tested on human whole blood using an electrical impedance method. At concentrations (50, 100, and 200 μg/ml), no effect on platelet aggregation was noticed. Anti-proliferative activity was investigated using the MTT assay. At concentrations up to 200 μg/ml, extracts did not possess cytotoxic activity against the MCF-7 cells. Acetylcholinesterase (AChE) inhibitory capacity of A. fragrantissima extracts was tested using TLC assay method, and neither aqueous, nor hydroalcoholic extracts showed AChE inhibition. The present investigation supported the traditional use of A. fragrantissima in the Jordanian folk medicine as an antimicrobial active representative of the genus Achillea. A. fragrantissima extracts should be further studied for their potential use in preventing/treating diseases in which oxidative stress is a part of the pathophysiology.
文摘The influence of bilirubin on mRNA expression of cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) and nuclear receptors in human hepatocytes was investigated. The treatment of the hepatocytes with 40 μg/mL bilirubin, which corresponds to hyperbilirubinemia, resulted in 1.7-fold increase of CYP2A6 mRNA compared to the vehicle control while CYP2A6 mRNA did not change after treatment with 1 μg/mL bilirubin, corresponding to physiologically normal level. No significant change of mRNA expression by 40 μg/mL bilirubin treatment was observed for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, UGT1A1, UGT1A3, UGT1A6, UGT2B4, UGT2B7, UGT2B10 and UGT2B15, constitutive androstane receptor (CAR), pregnane X receptor (PXR), retinoid X receptor α (RXRα) and hepatocyte nuclear factor-4α (HNF-4α). The induction profile of bilirubin was different from that of rifampicin, a typical PXR activator. This study demonstrated that CYP2A6 can be induced by bilirubin in a concentration dependent manner.
文摘Objectives: To explore patient’s perspectives of the role of the community pharmacist in view of other health care professionals (specialist physician, general practitioner, nurse and others (e.g. herbalist)) in Jordan, UAE and Iraq. The study also investigated patient’s willingness to pay for specialized pharmaceutical care services. Methods: This study followed a single phase cross sectional survey methodology, conducted in three Middle Eastern countries. Data were collected over a period of 6 months on two consecutive years (March to May 2009 and 2010). A questionnaire was designed and validated, then completed by patients walking into community pharmacies. The source of advice (specialist physician, general practitioner, pharmacist, nurse, or herbalist) regarding patient’s medication use and medical management were investigated. Key findings: Patients visiting community pharmacies in Jordan (n = 1000), UAE (n = 1000) and Iraq (n = 968) were recruited into the study (mean age 35.9 ± 13.1, 50.6% males). Significant difference between the three countries was shown, as more patients chose the pharmacist as their primary source of advice on medication use vs. the specialist physician in Jordan (50.8% vs. 37.3%) and Iraq (41.9% vs. 36.7%) compared to UAE (38.0% vs. 40.1%), P < 0.001, Chi-square test. Few agreed to receive paid pharmaceutical care services (Jordan 19.5%;UAE 24.7%;Iraq 2.3%). Conclusion: Current situation resulting in the lower socioeconomic status in Jordan and Iraq seems to lead to patients’ higher reliance on the pharmacist, as compared to the UAE. Majority of patients, regardless of the country of origin, are not willing to pay for specialized pharmaceutical care services. These findings are important for future social pharmacy research in the area.
基金This work was financially supported from the National Nature Science Foundation of China(NO.81360483)from the Nature Science Foundation of Ningxia(No.NZ12193).
文摘Most of the conventional chemotherapeutic agents used for cancer chemotherapy suffer from multidrug resistance of tumor cells and poor antitumor efficacy.Based on physiological differences between the normal tissue and the tumor tissue,one effective approach to improve the efficacy of cancer chemotherapy is to develop pH-sensitive polymeric micellar delivery systems.The copolymers with reversible protonationedeprotonation core units or acid-liable bonds between the therapeutic agents and the micelle-forming copolymers can be used to form pH-sensitive polymeric micelles for extracellular and intracellular drug smart release.These systems can be triggered to release drug in response to the slightly acidic extracellular fluids of tumor tissue after accumulation in tumor tissues via the enhanced permeability and retention effect,or they can be triggered to release drug in endosomes or lysosomes by pH-controlled micelle hydrolysis or dissociation after uptake by cells via the endocytic pathway.The pH-sensitive micelles have been proved the specific tumor cell targeting,enhanced cellular internalization,rapid drug release,and multidrug resistance reversal.The multifunctional polymeric micelles combining extracellular pH-sensitivity with receptor-mediated active targeting strategies are of great interest for enhanced tumor targeting.The micelles with receptor-mediated and intracellular pH targeting functions are internalized via receptor-mediated endocytosis followed by endosomal-pH triggered drug release inside the cells,which reverses multidrug resistance.The pH sensitivity strategy of the polymeric micelles facilitates the specific drug delivery with reduced systemic side effects and improved chemotherapeutical efficacy,and is a novel promising platform for tumor-targeting drug delivery.
文摘Background: Stress index at post-recruitment maneuvers could be a method of positive end-expiratory pressure (PEEP) titration in acute respiratory distress syndrome (ARDS) patients. However, airway pressure (P_aw) stress index may not reflect lung mechanics in the patients with high chest wall elastance. This study was to evaluate the P stress index on lung mechanics and the correlation between P stress index and transpulmonary pressure (P_L) stress index in acute respiratory failure (ARF) patients. Methods: Twenty-four ARF patients with mechanical ventilation (MV) were consecutively recruited from July 2011 to April 2013 in Zhongda Hospital, Nanjing, China and Ospedale S. Giovanni Battista-Molinette Hospital, Turin, Italy. All patients underwent MV with volume control (tidal volume 6 ml/kg) for 20 rain. PEEP was set according to the ARDSnet study protocol. The patients were divided into two groups according to the chest wall elastance/respiratory system elastance ratio. The high elastance group (H group, n = 14) had a ratio _〉30%, and the low elastance group (L group, n = 10) had a ratio 〈30%. Respiratory elastance, gas-exchange, P stress index, and Pt stress index were measured. Student's t-test, regression analysis, and Bland-Altman analysis were used for statistical analysis. Results: Pneumonia was the major cause of respiratory failure (71.0%). Compared with the L group, PEEP was lower in the H group (5.7 ± 1.7 cmH,O vs. 9.0 ± 2.3 cmH2O, P 〈 0.01 ). Compared with the H group, lung elastance was higher (20.0 ± 7.8 cmH20/L vs. 11.6 ± 3.6 cmH,O/L, P 〈 0.01), and stress was higher in the L group (7.0 ±1.9 vs. 4.9 ± 1.9, P = 0.02). A linear relationship was observed between the P stress index and the P stress index in H group (x2 = 0.56, P 〈 0.01 ) and L group (x2 = 0.85, P 〈 0.01). Conclusion: In the ARF patients with MV, P,w stress index can substitute for PL to guide ventilator settings.
文摘Apramycin is unique in the aminoglycoside family due to its octodiose moiety. However, either the biosynthesis process or the precursors involved are largely unknown. Addition of glycine, as well as serine or threonine, to the Streptomyces tenebrabrius UD2 fermentation medium substantially increases the production of apramycin with little effect on the growth of mycelia, indicating that glycine and/or serine might be involved in the biosynthesis of apramycin. The 13C-NMR analysis of [2-13C] glycine-fed (25% enrichment) apramycin showed that glycine specifically and efficiently incorporated into the only N-CH3 substituent of apramycin on the C7′ of the octodiose moiety. We noticed that the in vivo concentration of S-adenosyl methionine increased in parallel with the addition of glycine, while the addition of methione in the fermentation medium significantly decreased the productivity of apra-mycin. Therefore, the methyl donor function of glycine is proposed to be involved in the methionine cycle but methionine itself was proposed to inhibit the methylation and methyl transfer processes as previously reported for the case of rapamycin. The 15N NMR spectra of [2-13C,15N]serine labeled apramycin indicated that serine may also act as a limiting precursor contributing to the ―NH2 substituents of apramycin.
基金supported by a Heilongjiang Innovation Endowment Award for graduate studies(YJSCX2012-197HLJ)to Tang Lea grant from the National Natural Science Foundation of China(NSFC30970078)+1 种基金the Natural Science Foundation of Heilongjiang Province to Liu GuiRongthe National Natural Science Foundation of China(NSFC30970119,81030029,81271786,NSFC-NIH 81161120416)to Liu ShuLin
文摘Bacteria need a high degree of genetic stability to maintain their species identities over long evolutionary times while retaining some mutability to adapt to the changing environment.It is a long unanswered question that how bacteria reconcile these seemingly contradictory biological properties.We hypothesized that certain mechanisms must maintain a dynamic balance between genetic stability and mutability for the survival and evolution of bacterial species.To identify such mechanisms,we analyzed bacterial genomes,focusing on the Salmonella mismatch repair(MMR)system.We found that the MMR gene mutL functions as a genetic switch through a slipped-strand mispairing mechanism,modulating and maintaining a dynamic balance between genetic stability and mutability during bacterial evolution.This mechanism allows bacteria to maintain their phylogenetic status,while also adapting to changing environments by acquiring novel traits.In this review,we outline the history of research into this genetic switch,from its discovery to the latest findings,and discuss its potential roles in the genomic evolution of bacteria.
基金This study was supported by the Beijing Municipal Science&Technology Commission(No.Z07000200540704)the China Postdoctoral Science Foundation(No.20090450417)and the Tsinghua Yuyuan Medical Fund.
文摘Amphipathic polymer pullulan acetate (PA)-coated magnetic nanoparticles were prepared and characterized by various physicochemical means. The cytotoxicity and cellular uptake of the magnetic nanoparticles were examined. The hyperthermic effect of the magnetic nanoparticles on tumor cells was evaluated. Transmission electron microscopy (TEM) showed that the PA coated magnetic nanoparticles (PAMNs) had spherical morphology. Dynamic light scattering (DLS) showed that the size distribution of PAMNs was unimodal,with an average diameter of 25.8 nm ± 6.1 nm. The presence of the adsorbed layer of PA on the magnetite surface was confirmed by Fourier transform infrared (FTIR) spectroscopy. Magnetic measurements revealed that the saturation magnetization of the PAMNs reached 51.9 emu/g and the nanoparticles were superparamagnetic. Thermogravimetric analysis (TGA) showed that the Fe_(3)O_(4) particles constituted 75 wt% of the PAMNs. The PAMNs had good heating properties in an alternating magnetic field. Cytotoxicity assay showed that PAMNs exhibited no significant cytotoxicity against L929 cells. TEM results showed that a large number of PAMNs were internalized into KB cells. PAMNs have good hyperthermia effect on KB cells in vitro by magnetic field induced hyperthermia. These novel magnetic nanoparticles have great potential as magnetic hyperthermia mediators.