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1.
J Nanosci Nanotechnol ; 20(3): 1873-1877, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492355

RESUMO

The structure and anisotropic magnetization of One-dimensional (1D) Nd/Co/PA66 coaxial nanocables prepared by a low cost physical infiltration and electrodeposition methods are investigated. The preparation of Co nanotubes, Co/PA66 two-layer nanotubes and Nd/Co/PA66 three-layer nanocales is described, respectively. The structure, chemical composition and magnetic properties of various nanomaterials were investigated. The results show that the magnetic properties were affected by the rare earth metal Nd and the structural properties. The residual magnetization ratio of Nd/Co/PA66 nanocables is the biggest due to the synergistic effect of Nd and Co. In addition, the magnetization processes of the nanostructure were discussed in detail. We believe that these methods may provide an idea for ferromagnetic alloys and permanent magnet material and suitable for future applications in perpendicular recording media.

2.
Sheng Li Xue Bao ; 71(5): 792-798, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646333

RESUMO

Aberrant oxidative metabolism in cells is one of the hallmarks of cancer. Overproduction of reactive species promotes carcinogenesis by inducing genetic mutations and activating oncogenic pathways, and thus, antioxidant therapy is considered as an important strategy for cancer prevention and treatment. Caveolin-1 (Cav-1), a constituent protein of caveolae, is involved in not only the formation of the caveolae, vesicular transport, maintaining cholesterol homeostasis directly, but also many cellular physiological and pathological processes including growth, regulation of mitochondrial antioxidant level, apoptosis and carcinomas by interacting with a lot of signaling molecules through caveolin scaffolding domain. Cav-1 has also been shown to mediate tumor genesis and progression through oxidative stress modulation, while Cav-1-targeted treatment could scavenge the reactive species. Intracellular reactive species could modulate the expression, degradation, post-translational modifications and membrane trafficking of Cav-1. More importantly, emerging evidence has indicated that multiple antioxidants could exert antitumor activities in cancer cells by modulating the signaling of Cav-1. This paper reviewed the research progresses on the roles of Cav-1 and oxidative stress in tumorigenesis and development, and would provide new insights on designing strategies for cancer prevention or treatment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31569796

RESUMO

BACKGROUND: A few studies have explored the association between meteorological factors and hand, foot, and mouth disease (HFMD) with inconsistent results. Besides, studies about the effects of air pollutants on HFMD are very limited. METHODS: Daily HFMD cases among children aged 0-14 years in Shenzhen were collected from 2009 to 2017. A distributed lag nonlinear model (DLNM) model was fitted to simultaneously assess the nonlinear and lagged effects of meteorological factors and air pollutants on HFMD incidence, and to further examine the differences of the effect across different subgroups stratified by gender, age and childcare patterns. RESULTS: The cumulative relative risk (cRR) (median as reference) of HFMD rose with the increase of daily temperature and leveled off at about 30 °C (cRR: 1.40, 95%CI: 1.29, 1.51). There was a facilitating effect on HFMD when relative humidity was 46.0% to 88.8% (cRR at 95th percentile: 1.18, 95%CI: 1.11, 1.27). Short daily sunshine duration (5th vs. 50th) promoted HFMD (cRR: 1.07, 95%CI: 1.02, 1.11). The positive correlation between rainfall and HFMD reversed when it exceeded 78.3 mm (cRR: 1.41, 95% CI: 1.22, 1.63). Ozone suppressed HFMD when it exceeded 104 µg /m3 (cRR at 99th percentile: 0.85, 95%CI: 0.76, 0.94). NO2 promoted HFMD among infants and the cRR peaked at lag 9 day (cRR: 1.47, 95%CI: 1.02, 2.13) (99th vs. 50th). Besides, children aged below one year, males and scattered children were more vulnerable to high temperature, high relative humidity, and short sunshine duration. CONCLUSIONS: Temperature, relative humidity, sunshine duration, rainfall, ozone and NO2 were significantly associated with HFMD, and such effects varied with gender age and childcare patterns. These findings highlight the need for more prevention effort to the vulnerable populations and may be helpful for developing an early environment-based warning system for HFMD.

4.
Nanoscale ; 11(42): 19729-19735, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31617545

RESUMO

Helical nanostructures are important nanoscale building blocks. While only a few methods are available for synthesizing helical metal nanostructures, those involving collective twisting behaviour are even fewer. Here, we report a solution synthesis of Au nanowire bundles with hierarchical helical constructions. Ultrathin nanowires with diameters of only about 10 nm formed huge ribbon bundles that have a width of 0.5-1 µm and thickness of a few hundreds of nanometres. These bundles extended to hundreds of micrometres and curled into helices. Mechanism studies revealed that the white floccules formed by Au(i) and a thiol ligand are of critical importance for both the nanowire growth and helical bundle formation. The nanowire growth took place in the floccules following the previously reported active surface growth mode, and the bundle formation was due to the splitting of the active surface. Most importantly, the floccules assisted the strain-induced curling process that yielded helices. As the length of the bundles keeps increasing and they break out from the surrounding floccules, they would have to pass through the pores of the floccules. The imbalanced squeezing at the pore caused the bundles to curl into helices.

5.
BMC Nephrol ; 20(1): 384, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646979

RESUMO

BACKGROUND: The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS). METHODS: The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3. RESULTS: In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups. CONCLUSIONS: CsA is an effective and safe agent in the therapy of patients with SRNS.

6.
J Radiat Res ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31665488

RESUMO

Intestinal injury is the primary toxicity of radiotherapy for pelvic and abdominal tumors, and it is also one of the common acute complications of radiotherapy. At present, there are no effective drugs to prevent intestinal injury in the clinic. Zingerone is a natural product with radioprotective effects. In this study, a novel compound (thiazolidine hydrochloride, TZC01) was synthesized by structural modification of zingerone. The effects of TZC01 on preventing intestinal injury from radiation were further investigated in this study. C57BL/6N mice were exposed to a lethal dose of abdominal irradiation (ABI) with and without TZC01 treatments. The morphological changes of the intestine and various makers of intestinal crypt cells were investigated. Treatment with TZC01 improved the survival rate of mice exposed to 12 Gy ABI. Moreover, TZC01 protected the intestinal morphology of mice, decreased the apoptotic rate of intestinal crypt cells, maintained cell regeneration and promoted crypt cell proliferation and differentiation. This study suggests that TZC01 has preventive and therapeutic effects on radiation enteritis by promoting the proliferation and differentiation of crypt cells to protect the small intestine from the toxic effects of ionizing radiation. Furthermore, the study of TCZ01 lays a strong foundation for developing novel radioprotectors with multiple properties.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31638768

RESUMO

Bio-inspired by the aligned structure and building blocks of bone, this work mineralized the aligned bacterial cellulose (BC) through in-situ mineralization using CaCl2 and K2HPO4 solutions. The cellulose nanofibers were aligned by a scalable stretching process. The aligned and mineralized bacterial cellulose (AMBC) homogeneously incorporates hydroxyapatite (HAP) with high mineral content and exhibits excellent mechanical strength. The ordered three-dimensional structure allows the AMBC composite to achieve high elastic modulus and hardness and developed a similar nanostructure as natural bone. The AMBC composite exhibits elastic modulus of 10.91 ± 3.26 GPa and hardness of 0.37 ± 0.18 GPa. Compared to nonaligned mineralized bacterial cellulose (NMBC) composite with mineralized crystals of HAP randomly distributed into BC scaffolds, the AMBC composite possesses 210 % higher elastic modulus and 95 % higher hardness. The obtained AMBC composite has excellent mechanical properties by mimicking the natural structure of bone, which indicates that the aligned BC is a promising template for biomimetic mineralization.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31635235

RESUMO

In this study, we characterize the body of knowledge of groundwater remediation from 1950 to 2018 by employing scientometric techniques and CiteSpace software, based on the Science Citation Index Expanded (SCI-E) databases. The results indicate that the United States and China contributed 56.4% of the total publications and were the major powers in groundwater remediation research. In addition, the United States, Canada, and China have considerable capabilities and expertise in groundwater remediation research. Groundwater remediation research is a multidisciplinary field, covering water resources, environmental sciences and ecology, environmental sciences, and engineering, among other fields. Journals such as Environmental Science and Technology, Journal of Contaminant Hydrology, and Water Research were the major sources of cited works. The research fronts of groundwater remediation were transitioning from the pump-and-treat method to permeable reactive barriers and nanoscale zero­valent iron particles. The combination of new persulfate ion­activation technology and nanotechnology is receiving much attention. Based on the visualized networks, the intelligence base was verified using a variety of metrics. Through landscape portrayal and developmental trajectory identification of groundwater remediation research, this study provides insight into the characteristics of, and global trends in, groundwater remediation, which will facilitate the identification of future research directions.

9.
Chem Commun (Camb) ; 55(87): 13120-13123, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31616884

RESUMO

Histone H3.3 was identified as an arsenic-binding protein of S-dimethylarsino-glutathione (ZIO-101, darinaparsin®) in leukemia cells by GE-ICP-MS. Such a binding results in TRAIL-induced apoptosis. We further validate histone H3.3 as a vital target for ZIO-101, offering new information on the mode of action of arsenic-based anticancer agents.

10.
Crit Care ; 23(1): 300, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484582

RESUMO

RATIONALE: Our pilot study suggested that noninvasive ventilation (NIV) reduced the need for intubation compared with conventional administration of oxygen on patients with "early" stage of mild acute respiratory distress syndrome (ARDS, PaO2/FIO2 between 200 and 300). OBJECTIVES: To evaluate whether early NIV can reduce the need for invasive ventilation in patients with pneumonia-induced early mild ARDS. METHODS: Prospective, multicenter, randomized controlled trial (RCT) of NIV compared with conventional administration of oxygen through a Venturi mask. Primary outcome included the numbers of patients who met the intubation criteria. RESULTS: Two hundred subjects were randomized to NIV (n = 102) or control (n = 98) groups from 21 centers. Baseline characteristics were similar in the two groups. In the NIV group, PaO2/FIO2 became significantly higher than in the control group at 2 h after randomization and remained stable for the first 72 h. NIV did not decrease the proportion of patients requiring intubation than in the control group (11/102 vs. 9/98, 10.8% vs. 9.2%, p = 0.706). The ICU mortality was similar in the two groups (7/102 vs. 7/98, 4.9% vs. 3.1%, p = 0.721). Multivariate analysis showed minute ventilation greater than 11 L/min at 48 h was the independent risk factor for NIV failure (OR, 1.176 [95% CI, 1.005-1.379], p = 0.043). CONCLUSIONS: Treatment with NIV did not reduce the need for intubation among patients with pneumonia-induced early mild ARDS, despite the improved PaO2/FIO2 observed with NIV compared with standard oxygen therapy. High minute ventilation may predict NIV failure. TRIAL REGISTRATION: NCT01581229 . Registered 19 April 2012.

11.
Aging Clin Exp Res ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520334

RESUMO

AIM: The aim of this systematic review was to understand the exergames that can be applied to the pre-frail and frail elderly people, to evaluate whether these games have a positive impact on physical outcomes in pre-frail and frail older adults, and to explore user's subjective feelings and compliance. METHODS: PubMed, EMBASE, CINAHL, Web of Science, and the Cochrane Library were searched until January 15, 2019. Only randomized controlled trials published in English for human beings were eligible. The review included studies which examined the effects of exergames on physical outcomes, feasibility and/or subjective feelings of pre-frail and frail older adults. Two researchers assessed the risk bias of all articles independently using the Cochrane collaboration's tool for assessing risk of bias. RESULTS: Seven randomized controlled trials with 243 pre-frail and frail older adults met inclusion criteria and were included in this review. Results of the studies were heterogeneous. Physical outcomes (included muscle strength, balance ability, mobility function, gait and falls), subjective feeling outcomes, feasibility, attendance and some other functional outcomes were reported. CONCLUSION: Exergames improved balance and mobility function of frail elderly, and it showed a tendency to increase muscle strength when combined with resistance training. As far as the limited evidence was concerned, exergames were feasible and generally accepted by participants.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31520390

RESUMO

We studied the effects of mutual grafting on cadmium (Cd) accumulation characteristics on the first post-generations of the Cd-hyperaccumulator plants Bidens pilosa L. and Galinsoga parviflora Cav. The seeds from scions and rootstocks of B. pilosa and G. parviflora were collected and planted in Cd-contaminated soil in pot and field experiments. In the pot experiment, rootstock treatment increased the shoot biomass of B. pilosa post-grafting generations, compared with ungrafted B. pilosa, but decreased the Cd content in shoots and Cd extraction by shoots of post-grafting generations; scion treatment decreased or had no significant effect. Mutual grafting resulted in no significant differences to the photosynthetic pigment contents in B. pilosa post-grafting generations. Compared with ungrafted G. parviflora, scion treatment increased the shoot biomass, photosynthetic pigment content, and Cd extraction by shoots of G. parviflora post-grafting generations, but rootstock treatment did not lead to significant differences. Mutual grafting resulted in no significant differences to the Cd contents in shoots of G. parviflora post-grafting generations. In the field experiment, only rootstock treatment increased the shoot biomass of B. pilosa post-grafting generations, and only scion treatment increased the shoot biomass and the Cd extraction by shoots of G. parviflora post-grafting generations. Therefore, mutual grafting of scions may enhance the phytoremediation ability of G. parviflora first post-grafting generations.

13.
World J Gastroenterol ; 25(33): 4921-4932, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543683

RESUMO

BACKGROUND: The potential role of chronic inflammation in the development of cancer has been widely recognized. However, there has been little research fully and thoroughly exploring the molecular link between hepatitis B virus (HBV) and hepatocellular carcinoma (HCC). AIM: To elucidate the molecular links between HBV and HCC through analyzing the molecular processes of HBV-HCC using a multidimensional approach. METHODS: First, maladjusted genes shared between HBV and HCC were identified by disease-related differentially expressed genes. Second, the protein-protein interaction network based on dysfunctional genes identified a series of dysfunctional modules and significant crosstalk between modules based on the hypergeometric test. In addition, key regulators were detected by pivot analysis. Finally, targeted drugs that have regulatory effects on diseases were predicted by modular methods and drug target information. RESULTS: The study found that 67 genes continued to increase in the HBV-HCC process. Moreover, 366 overlapping genes in the module network participated in multiple functional blocks. It could be presumed that these genes and their interactions play an important role in the relationship between inflammation and cancer. Correspondingly, significant crosstalk constructed a module level bridge for HBV-HCC molecular processes. On the other hand, a series of non-coding RNAs and transcription factors that have potential pivot regulatory effects on HBV and HCC were identified. Among them, some of the regulators also had persistent disorders in the process of HBV-HCC including microRNA-192, microRNA-215, and microRNA-874, and early growth response 2, FOS, and Kruppel-like factor 4. Therefore, the study concluded that these pivots are the key bridge molecules outside the module. Last but not least, a variety of drugs that may have some potential pharmacological or toxic side effects on HBV-induced HCC were predicted, but their mechanisms still need to be further explored. CONCLUSION: The results suggest that the persistent inflammatory environment of HBV can be utilized as an important risk factor to induce the occurrence of HCC, which is supported by molecular evidence.

14.
ACS Infect Dis ; 5(10): 1693-1697, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31475514

RESUMO

Gallium nitrate (Ganite) is a potential drug for the treatment of Pseudomonas aeruginosa infection. CRISPR/Cas9-based gene mutagenesis studies reveal that siderophore pyochelin-facilitated uptake and an ABC transporter are two major Ga3+ internalization pathways in Pseudomonas aeruginosa (P. aeruginosa). Crystal structures reveal that Ga3+ and Fe3+ occupy exactly the same metal site of HitA, a periplasmic iron-binding protein of the ABC transporter system. The study provides a molecular basis for Ga3+ internalization by P. aeruginosa and facilitates gallium-based antimicrobial drug development.

15.
Sci Total Environ ; 697: 134051, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31487586

RESUMO

BACKGROUND: The intricate association of mortality risk with ambient air pollution and temperature is of growing concern. Little is known regarding effect of changes in season and temperature on daily cardiovascular mortality associated with air pollutant nitrogen dioxide (NO2). OBJECTIVES: Our study aimed to assess the effect of NO2 on cardiovascular mortality modified by season and daily air temperature in the effect, and further to identify the population highly susceptible to cardiovascular mortality associated with NO2 and air temperature. METHODS: We collected daily cause-specific death data, weather conditions, and air pollutant concentrations in Shenzhen from 2013 to 2017. Distributed-lag linear models were employed to analyze the effect of season on the NO2-associated mortality. Furthermore, generalized additive models were combined with stratification parametric analysis to estimate the interaction effect of NO2 with air temperature on cardiovascular mortality. RESULTS: In the cold season, the percentage increase in daily mortality for every 10 µg/m3 increment in NO2 concentration over lags of 0-2 days was 4.45% (95% CI: 2.71-6.21%). However, no statistically significant effect of NO2 was observed in the warm season. Compared with high-temperature days (>median temperature), a 3.51% increase in mortality (95% CI: 2.04-5.01%) over low-temperature days (≤median temperature) for the same increase in NO2 was significant. Air temperature modified the effect of NO2 on daily mortality by 4.08% (95% CI: 2.28-5.91%) for the elderly (age ≥ 65 years) on low-temperature days vs. -0.82% (95% CI: -3.88-2.34%) on high-temperature days, and 3.38% (95% CI: 1.50-5.29%) for males on low-temperature days vs. -0.73% (95% CI: -3.83-2.47%) on high air temperature days. CONCLUSIONS: The cold season and low temperatures could significantly enhance the effect of NO2 on cardiovascular mortality. The elderly and males suffering from cardiovascular disease should take precautions against low temperature and NO2 air pollution.

16.
J Food Biochem ; 43(9): e12968, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31489675

RESUMO

A computational DFT B3LYP method with 6-311G (d,p) basis set, the in vitro chemical-based and cellular antioxidant activity (CAA) assays were applied in this study to explain the structure-antioxidant activity relationships of delphinidin and petunidin. The compound molecular structures, spectral properties, frontier orbital energy, and transition state of delphinidin and petunidin were compared. In transition state, the result of the active site (O21-H32 and O22-H33) was consistent with the result of bond length. The frontier orbital theory results indicated that the probable antioxidant activity order was petunidin (0.09126 a.u.) > delphinidin (0.09175 a.u.), which agreed well with the cell-based antioxidant activity determined by CAA. However, the order of ABTS•+ and DPPH radical scavenging activity was delphinidin > petunidin. Our study could help to provide a rational approach for the investigation of antioxidant activity of phytochemicals. PRACTICAL APPLICATIONS: As anthocyanins, delphinidin and petunidin with great antioxidant activity are widely found in various fruits and vegetables. However, there are many kinds of methods used to measure their antioxidant activity and the antioxidant mechanism which are not concrete and clear. Therefore, it is crucial to study the antioxidant actvity of anthocyanins utilizing the DFT method combined with in vitro chemical-based and cell-based assays. Our study could contribute not only to the elucidation of chemical mechanism of antioxidants and exploration the structural features in essence, but also to promote the further development of phytochemicals in the field of food chemistry and pharmacy.

17.
Qual Life Res ; 28(11): 2859-2870, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471814

RESUMO

PURPOSE: To identify the effects of whole body vibration (WBV) on health-related quality of life (HRQOL) in patients with chronic conditions. METHODS: Five databases (the Cochrane Library, PubMed, Medline, EBSCO, and Web of science) were searched (from inception until April 30, 2019) for original articles. All studies were randomized controlled trials reporting the effects of WBV on HRQOL. Two independent reviewers extracted trial data and assessed the risk of bias using the risk of bias tool recommended by the Cochrane Back Review Group. RESULTS: Of the 349 articles that were screened, 17 articles, including 763 participants with various chronic conditions, met the inclusion criteria. Six studies reported significant improvements in HRQOL. No evidence was observed to suggest that WBV was more effective than other types of exercises. The study participants, exercise protocols, HRQOL instruments, study duration, and frequency as well as amplitude of WBV varied across the studies. Meta-analysis was not conducted due to the heterogeneity of study designs and outcome measures. CONCLUSIONS: This study has demonstrated that WBV may improve HRQOL in patients with chronic conditions. However, the evidence was not strong enough to warrant recommendation and thus further high-quality studies with larger sample sizes and longer intervention durations are needed.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31487566

RESUMO

ShenMai Injection (SMI) is a traditional Chinese medicine that has been extensively applied in the treatment of coronary artery disease and tumor for many years. However, there is still lack of deep research on the behaviors of SMI in vivo. In this study, a reliable, specific, and sensitive method was developed for simultaneous determination of sixteen saponins found in SMI using liquid chromatography tandem mass spectrometry (LC-MS/MS). This method was successfully applied to investigate the pharmacokinetics, tissue distribution and excretion of sixteen active compounds after a single intravenous administration of SMI. These compounds included seven protopapaxdiol (PPD-type) ginsenosides (ginsenosides Rb1, Rb2, Rb3, Rc, Rd, S-Rg3, R-Rg3), six protopapaxtriol (PPT-type) ginsenosides (notoginsenoside R1, ginsenosides Re, Rf, Rg1, S-Rg2, R-Rg2), one oleanolic acid type ginsenoside (ginsenoside Ro) and two ophiopogonins (ophiopogonin D (MD-D) and ophiopogonin D' (MD-D')). Connection of the C-20 hydroxyl group to the glycoside and the chiral configuration of C-20 might significantly impact the pharmacokinetic behaviors in vivo of ginsenosides, particularly PPD-type ginsenosides. PPD-type ginsenosides were usually eliminated slowly in serum and tissues, but S/R-Rg3 bearing a free hydroxyl group at C-20 exhibited quick elimination, and R-Rg3 underwent quicker elimination than S-Rg3. The PPT-type ginsenosides, oleanolic acid type ginsenoside and ophiopogonins underwent a fast elimination from serum and tissues. There were 10 ginsenosides that could penetrate the blood-brain barrier. In contrast to other saponins, the distributions of S-Rg2, R-Rg2, S-Rg3, R-Rg3, MD-D and MD-D' in liver were higher than in kidney. Several PPD-type ginsenosides were found to have a long-term accumulation risk in some tissues, especially Rd in kidney. In the excretion study, Rg1, S-Rg2 and MD-D were mainly excreted in a prototype and other saponins were mainly excreted in the form of metabolites. Prototypes of S-Rg2, R-Rg2, S-Rg3, R-Rg3, MD-D and MD-D' exhibited higher distribution in the liver than kidney, were excreted mainly in the feces, whereas prototypes of the remaining saponins were primarily excreted via urine. To best our knowledge, this is the first study to quantitatively evaluate the tissue distribution and excretion of SMI in rats. Our research provides novel insight into the behaviors in vivo of PPD-type ginsenosides and delivers valuable information for further drug development of SMI.

19.
Drug Metab Dispos ; 47(10): 1111-1121, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387871

RESUMO

The identification of nonopioid alternatives to treat chronic pain has received a great deal of interest in recent years. Recently, the engineering of a series of Nav1.7 inhibitory peptide-antibody conjugates has been reported, and herein, the preclinical efforts to identify novel approaches to characterize the pharmacokinetic properties of the peptide conjugates are described. A cryopreserved plated mouse hepatocyte assay was designed to measure the depletion of the peptide-antibody conjugates from the media, with a correlation being observed between percentage remaining in the media and in vivo clearance (Pearson r = -0.5525). Physicochemical (charge and hydrophobicity), receptor-binding [neonatal Fc receptor (FcRn)], and in vivo pharmacokinetic data were generated and compared with the results from our in vitro hepatocyte assay, which was hypothesized to encompass all of the aforementioned properties. Correlations were observed among hydrophobicity; FcRn binding; depletion rates from the hepatocyte assay; and ultimately, in vivo clearance. Subsequent studies identified potential roles for the low-density lipoprotein and mannose/galactose receptors in the association of the Nav1.7 peptide conjugates with mouse hepatocytes, although in vivo studies suggested that FcRn was still the primary receptor involved in determining the pharmacokinetics of the peptide conjugates. Ultimately, the use of the cryopreserved hepatocyte assay along with FcRn binding and hydrophobic interaction chromatography provided an efficient and integrated approach to rapidly triage molecules for advancement while reducing the number of in vivo pharmacokinetic studies. SIGNIFICANCE STATEMENT: Although multiple in vitro and in silico tools are available in small-molecule drug discovery, pharmacokinetic characterization of protein therapeutics is still highly dependent upon the use of in vivo studies in preclinical species. The current work demonstrates the combined use of cryopreserved hepatocytes, hydrophobic interaction chromatography, and neonatal Fc receptor binding to characterize a series of Nav1.7 peptide-antibody conjugates prior to conducting in vivo studies, thus providing a means to rapidly evaluate novel protein therapeutic platforms while concomitantly reducing the number of in vivo studies conducted in preclinical species.

20.
Drug Des Devel Ther ; 13: 2305-2330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371924

RESUMO

Introduction: The efficacy of cyclosporine A (CsA) in the treatment of idiopathic membranous nephropathy (IMN) is unclear. This meta-analysis was conducted to assess the efficacy and the safety of CsA in the treatment of IMN in Asians. Methods: We searched the Pubmed, China Biomedical Database, CNKI, Wanfang Data, VIP, and EMBASE (November 30, 2018) systematically to identify the appropriate randomized controlled trials (RCTs) reporting the efficacy and the safety of CsA and glucocorticoid (GC) treatment vs other immunosuppressants and GC on patients with IMN in Asian populations. Results: The CsA treated group entered complete remission (CR) faster (3 months) than a cyclophosphamide (CTX) group. While the CsA group lower inefficacy rates and higher total remission (TR, CR, or partial remission) than the CTX group in the total treatment (3 months, 6 months, and 12 months), it had a higher relapse rate. As for the CsA group vs the tacrolimus (TAC) group, the TAC had a significant effect in increasing the CR and the TR, with decreased no remission. With the therapeutic regimens of CsA+GC vs CTX+GC, the CsA exhibited better efficacy in lowering the proteinuria levels only at 12 months, not at 3 months or 6 months. Severe events like leucopenia, hemorrhagic cystitis, and alopecia were observed in the CTX group. Gingival hyperplasia, hirsutism, and elevated blood pressure were reported only in the CsA group. Gastrointestinal syndrome, liver function lesion, happened more frequently in the CTX group, and elevated uric acid was more common in the CsA group. Conclusions: In brief, the CsA has better efficacy than the CTX group in the Asian population, with mild adverse effects but higher relapse rates in short-term treatment.

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