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1.
Neural Regen Res ; 16(2): 312-318, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32859790

RESUMO

Cattle encephalon glycoside and ignotin (CEGI) injection is known as a multi-target neuroprotective drug that contains numerous liposoluble molecules, such as polypeptides, monosialotetrahexosyl ganglioside (GM-1), free amino acids, hypoxanthine and carnosine. CEGI has been approved by the Chinese State Food and Drug Administration and widely used in the treatments of various diseases, such as stroke and Alzheimer's disease. However, the neuroprotective effects of CEGI beyond the time window of thrombolysis (within 4.5 hours) on acute ischemic stroke remain unclear. This study constructed a rat middle cerebral artery occlusion model by suture-occluded method to simulate ischemic stroke. The first daily dose was intraperitoneally injected at 8 hours post-surgery and the CEGI treatments continued for 14 days. Results of the modified five-point Bederson scale, beam balance test and rotameric test showed the neurological function of ischemic stroke rats treated with 4 mL/kg/d CEGI improved significantly, but the mortality within 14 days did not change significantly. Brain MRI and 2,3,5-triphenyltetrazolium chloride staining confirmed that the infarct size in the 4 mL/kg/d CEGI-treated rats was significantly reduced compared with ischemic insult only. The results of transmission electron microscopy and double immunofluorescence staining showed that the hippocampal neuronal necrosis in the ischemic penumbra decreased whereas the immunopositivity of new neuronal-specific protein doublecortin and the percentage of Ki67/doublecortin positive cells increased in CEGI-treated rats compared with untreated rats. Our results suggest that CEGI has an effective neuroprotective effect on ischemic stroke when administered after the time window of thrombolysis. The study was approved by the Animal Ethics Committee of The Third Military Medical University, China.

2.
Protein Expr Purif ; 177: 105762, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32971297

RESUMO

For recombinant antibody purification, removal of product-related impurities usually relies on the two polishing steps post Protein A chromatography. A certain impurity may bind weaker or tighter to a particular type of column than the target antibody, and this forms the basis for separation. For impurities that bind weaker, they can be removed by pre-elution wash under appropriate conditions. For impurities that bind stronger, they can be separated by using a suitable condition that selectively elutes the product. In this study, with a bispecific antibody case, we compared the relative robustness of byproduct removal by wash and by elution using two different types of chromatography. The data suggest that elution-enabled byproduct clearance is more robust than wash-enabled clearance, and the former approach provides consistent impurity clearance over a relatively wide range of loading density.

3.
Talanta ; 221: 121607, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33076137

RESUMO

Drug-induced liver injury (DILI) has been a hot issue of public health, owing to its unpredictability and serious harm to public health. Peroxynitrite (ONOO-) is an important biomarker for the assessment and diagnosis of DILI. In this article, based on a kind of rhodamine analogue with a near-infrared (NIR) emission (610 nm-800 nm) and a two-photon absorption cross section (54 GM), a two-photon excited NIR fluorescence probe (NIR-ONOO) for ONOO- was developed. With a high selectivity and a high sensitivity to ONOO-, NIR-ONOO has a linear range for detection of ONOO- from 5.0 × 10-8 to 1.0 × 10-5 M, a good detection limit (15 nM) and a large fluorescence enhancement (340-fold). In addition, NIR-ONOO has been used to monitor ONOO- in cells with satisfactory results. Because of its two-photon excied NIR emission, NIR-ONOO also showed excellent performances for imaging ONOO- including low autofluorescence, stable and persistent fluorescence, and a deep penetration (204 µm). Finally, NIR-ONOO was successfully employed to image ONOO- in inflammatory mouse, drug-induced hepatotoxicity in cells and its remediation. All the results indicated that NIR-ONOO is a powerful chemical tool to image ONOO- and assay drug-induced hepatotoxicity.

4.
Acta Biomater ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33035698

RESUMO

Injection of urethral bulking agents is a low-risk, minimally invasive surgical procedure to treat stress urinary incontinence (SUI). In this study, we developed a promising injectable bulking agent comprising extracellular matrix fragments of adipose-derived stem cell sheets (ADSC ECM) and investigated its effectiveness in urethral bulking therapy. The structural integrity and proteins of ADSC sheet ECM were well retained in decellularized ADSC ECM fragments. To locate transplanted ADSC ECM fragments, they were labeled with ultrasmall super-paramagnetic iron oxide nanoparticles, which enabled in vivo monitoring after implantation in a SUI rat model for up to 4 weeks. When ADSC ECM fragments were injected into the rat urethra, they became fully integrated with the surrounding tissue within 1 week. Four weeks after transplantation, host cells had regenerated within the ADSC ECM fragment injection area. Moreover, new smooth muscle tissue had formed around the ADSC ECM fragments, as confirmed by positive staining of myosin. These results indicate that injection of ECM fragments may be a promising minimally invasive approach for treating SUI.

5.
J Am Soc Nephrol ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051360

RESUMO

BACKGROUND: Epsins, a family of evolutionarily conserved membrane proteins, play an essential role in endocytosis and signaling in podocytes. METHODS: Podocyte-specific Epn1, Epn2, Epn3 triple-knockout mice were generated to examine downstream regulation of serum response factor (SRF) by cell division control protein 42 homolog (Cdc42). RESULTS: Podocyte-specific loss of epsins resulted in increased albuminuria and foot process effacement. Primary podocytes isolated from these knockout mice exhibited abnormalities in cell adhesion and spreading, which may be attributed to reduced activation of cell division control protein Cdc42 and SRF, resulting in diminished ß 1 integrin expression. In addition, podocyte-specific loss of Srf resulted in severe albuminuria and foot process effacement, and defects in cell adhesion and spreading, along with decreased ß 1 integrin expression. CONCLUSIONS: Epsins play an indispensable role in maintaining properly functioning podocytes through the regulation of Cdc42 and SRF-dependent ß 1 integrin expression.

7.
FASEB J ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33047380

RESUMO

Intrauterine growth restriction (IUGR) leads to offspring obesity. In a maternal food restriction (MFR) during pregnancy-related IUGR rat model, bone marrow stem cells showed enhanced adipogenic programming; however, the effect of IUGR on white adipose tissue (WAT) progenitors is unknown. Here, by mRNA and functional profiling, we determined sex-specific adipogenic programming of WAT progenitors isolated from pups on the postnatal day (PND) 1 and 21. On PND1, PPARγ and Pref-1 expression was significantly downregulated in preadipocytes of both MFR males and females; however, at PND21, preadipocytes of MFR males showed upregulation in these genes. Even following adipogenic induction, both male and female MFR adipocytes exhibited lower PPARγ, ADRP, and adiponectin levels at PND1; however, at PND21 MFR male adipocytes showed an upward trend in the expression of these genes. An adipogenesis-specific RT-PCR array showed that male MFR adipocytes were programmed to exhibit stronger adipogenic propensity than females. Last, serum sex hormone and adipocyte estrogen/testosterone receptor expression profiles provide preliminary insights into the possible mechanism underlying sex-specific adipogenic programming in the IUGR offspring. In summary, IUGR programs WAT preadipocytes to greater adipogenic potential in males. Although the altered adipogenic programming following MFR was detectable at PND1, the changes were more pronounced at PND21, suggesting a potential role of postnatal nutrition in facilitating the sex-specific adipogenic programming in the IUGR offspring.

9.
Food Funct ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33057513

RESUMO

Peptides extracted from Xuanwei ham (XHP) can prevent free radical-induced diseases. The aim of the present study was to isolate and identify bioactive peptides from Xuanwei hams that rescue the oxidative stress damage induced by alcohol in HHL-5 hepatocytes. Alcohol-treated HHL-5 human hepatocytes were utilized as the alcohol-induced hepatocyte damage model to evaluate the effects of XHP on amounts of aminotransferase (ALT), aspartate aminotransferase (AST) and malondialdehyde (MDA). The result showed that XHP could significantly reduce ALT, AST and MDA, the major biomarkers of liver damage. The crude XHP was separated by size exclusion chromatography, followed by the evaluation of respective activities. Then, the most active components were further separated by RP-HPLC, and their activities were evaluated according to the above method. The peptide was identified as a hexapeptide with the sequence of Asn-Pro-Pro-Lys-Phe-Asp (NPPKFD) through LC-MS/MS. Further, the molecular mechanisms by which NPPKFD prevents alcohol-induced oxidative stress damage were revealed. Results showed that the hexapeptide could downregulate CYP2E1 expression, reduce generation of ROS and enhance oxidant defense systems via the activation of NrF2/HO-1 pathway. The findings suggest that Xuanwei ham can be used as a new source of bioactive peptides for protection from alcohol-induced liver damage.

10.
Dalton Trans ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021307

RESUMO

Discrete supertetrahedral clusters of metal chalcogenides are rare because of the difficulty involved in meeting global charge matching between the negative charge of the skeleton and counterion. We present herein the third type of a discrete chalcogenide cluster with a double T3 structure in the compound (HDBN)6[In20S33(DBN)6] (DBN = 1,5-diazabicyclo [4.3.0]-5-nonene), the anion of which features quasi-D3 symmetrical double-T3 In20S33 supertetrahedra with six cornered indium atoms coordinated by DBN molecules. DFT theory calculations of the interaction between host and guest show that this compound may have high kinetic stability and low photoelectric reactivity.

11.
J Recept Signal Transduct Res ; : 1-5, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045879

RESUMO

Coronary no-reflow damage is caused by endothelial cell damage although little drug is available to intervene in coronary no-reflow. Liraglutide is a kind of anti-diabetic drug and its cardioprotective role has been widely reported. In this study, we explored the role of liraglutide in regulating coronary endothelial cell damage. We used hydrogen peroxide to mimic coronary no-reflow damage in vitro. After exposure to hydrogen peroxide, endothelial cells' viability was significantly reduced, an effect that was followed by an increase in cell apoptosis. Interestingly, liraglutide treatment obviously upregulated endothelial cell viability and thus prevented cell apoptosis. Further, we also found that liraglutide inhibited the activation of caspase-3 in hydrogen peroxide-treated endothelial cells. Besides, cellular metabolism, as reflected by mitochondrial membrane potential, was disrupted by hydrogen peroxide and reversed to normal levels with liraglutide. Further, we found that the ERK pathway is a potential downstream effector of liraglutide. Administration of liraglutide significantly promoted the activation of ERK and this effect may contribute to endothelial cell survival. Altogether, our results illustrated that hydrogen peroxide-mediated endothelial cell damage could be attenuated by liraglutide through modulation of the MAPK/ERK signaling pathway. This finding will pave a novel road for the intervention of coronary no-reflow damage in patients suffering from myocardial infarction.

12.
Nat Med ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046869

RESUMO

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3-5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.

13.
Hum Cell ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33047284

RESUMO

This study aimed to investigate the role of long non-coding RNA (lncRNA) taurine up-regulated 1 (TUG1) in the development of ulcerative colitis (UC) and to explore the underlying mechanisms. A murine model of UC was induced by dextran sodium sulfate (DSS) exposure. The colonic epithelial YAMC cells were treated with TNF-α to simulate the inflammatory environment of intestinal epithelial cells (IECs). RNA pull-down and RIP assays were performed to analyze the interaction between TUG1 and HuR. Luciferase activity assay was conducted to evaluate the interaction between TUG1 and miR-29b-3p. Cell proliferation was evaluated by MTT assay. Cell apoptosis was assessed by flow cytometry and western blot analysis of apoptosis-related proteins. TUG1 overexpression promoted cell proliferation and inhibited cell apoptosis in the TNF-α-stimulated YAMC cells. The mechanistic analysis showed that TUG1 positively regulated the HuR/c-myc axis via its interaction with HuR, leading to upregulation of c-myc expression; meanwhile, TUG1 negatively regulated the miR-29b-3p/CDK2 signaling via binding to miR-29b-3p, leading to derepression of CDK2 expression. Further animal experiments showed that TUG1 overexpression attenuated UC progression in the DSS-induced UC in mice. Collectively, TUG1 inhibits IEC apoptosis and UC progression by regulating the balance of HuR and miR-29b-3p.

14.
Cancer Res ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023946

RESUMO

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the interleukin (IL)-1ß inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue Of Somatic Mutations In Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS lung cancer patients, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n=29) versus without (n=38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (p=0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL-6, IL-18, IL-1 receptor antagonist, tumor necrosis factor-α, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL-6, both downstream of IL-1ß signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL-1ß pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL-1ß-mediated pro-tumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer.

15.
Biotechnol Bioeng ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33017042

RESUMO

Liver is fed by nutrition via diffusion across the vascular wall from blood flow. However, hepatocytes in liver models are directly exposed to the perfusion culture medium, where the shear stress reduces the cell viability and liver-specific functions. By mimicking the mass transfer and structural features of hepatic lobule, we designed a microfluidic liver-on-a-chip based on the di-acrylated pluronic F127 hydrogel. In the hydrogel chip, hepatocellular carcinoma HepG2 and human hepatic stellate cell LX-2 were statically cultured inside the microwells on the outer channel. These hepatic cells were fed by the diffused medium from the adjacent but separated inner channel with endothelial cell monolayers, which was perfused by the medium with physiologically relevant shear stress. As found, the hepatic cells in the liver-on-a-chip rapidly formed spheroids within 1-day incubation and expressed about one to two-fold higher viability/liver-specific functions than the corresponding static culture for at least 8 days. Moreover, the presence of endothelial cells also contributed to the expression of liver-specific functions in the liver-on-a-chip. Therefore, the proposed liver-on-a-chip provides a new concept for construction of 3D liver models in vitro, and shows the potential value for a variety of applications including bio-artificial livers and drug toxicity screening.

16.
Mol Ther ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-33002420

RESUMO

Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors.

17.
West J Nurs Res ; : 193945920967674, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33089754

RESUMO

This meta-analysis was conducted to identify maternal risk factors for lactational mastitis. Studies published in English or Chinese were retrieved from Medline (PubMed), Embase, Cochrane Library, Web of Science, CNKI, WANFANG, and VIP databases according to predefined inclusion and exclusion criteria. Study quality was assessed by the Newcastle-Ottawa Scale. A random-effects model was used for data pooling and I2 tests to assess study heterogeneity. Pooled data from 8 cohorts and 10 case-control studies identified previous mastitis during breastfeeding (P<0.00001), cesarean section (P=0.001), breast trauma (P<0.001), anemia (P=0.0001), latch problems ≤ 8 weeks post-delivery (P=0.003), milk overproduction (P=0.002), blocked duct (P<0.0001), cracked nipple (especially ≤ 4 weeks post-delivery) (P=0.0001), use of nipple shields (P<0.00001), nipple cream (P<0.0001), brassieres (P<0.0001), and breast pumps (P<0.00001), and breastfeed duration > 30 min (P=0.008) as significant risk factors. Washing nipples before breastfeeding decreased lactational mastitis risk. Identification of these risk factors may facilitate the development of nursing care protocols for reducing lactational mastitis.

18.
Food Chem ; 341(Pt 1): 128241, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038774

RESUMO

A strategy was developed to distinguish and quantitate nonfumigated ginger (NS-ginger) and sulfur-fumigated ginger (S-ginger), based on Fourier transform near infrared spectroscopy (FT-NIR) and chemometrics. FT-NIR provided a reliable method to qualitatively assess ginger samples and batches of S-ginger (41) and NS-ginger (39) were discriminated using principal component analysis and orthogonal partial least squares discriminant analysis of FT-NIR data. To generate quantitative methods based on partial least squares (PLS) and counter propagation artificial neural network (CP-ANN) from the FT-NIR, major gingerols were quantified using high performance liquid chromatography (HPLC) and the data used as a reference. Finally, PLS and CP-ANN were deployed to predict concentrations of target compounds in S- and NS-ginger. The results indicated that FT-NIR can provide an alternative to HPLC for prediction of active components in ginger samples and was able to work directly on solid samples.

19.
Transl Psychiatry ; 10(1): 348, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051440

RESUMO

To study the acute psychological effects of Coronavirus Disease 2019 (COVID-19) outbreak among healthcare workers (HCWs) in China, a cross-sectional survey was conducted among HCWs during the early period of COVID-19 outbreak. The acute psychological effects including symptoms of depression, anxiety, and post-traumatic stress disorder (PTSD) were assessed using the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder (GAD-7) questionnaire, and the Impact of Event Scale-Revised (IES-R). The prevalence of depression, anxiety, and PTSD was estimated at 15.0%, 27.1%, and 9.8%, respectively. Having an intermediate technical title, working at the frontline, receiving insufficient training for protection, and lacking confidence in protection measures were significantly associated with increased risk for depression and anxiety. Being a nurse, having an intermediate technical title, working at the frontline, and lacking confidence in protection measures were risk factors for PTSD. Meanwhile, not worrying about infection was a protective factor for developing depression, anxiety, and PTSD. Psychological interventions should be implemented among HCWs during the COVID-19 outbreak to reduce acute psychological effects and prevent long-term psychological comorbidities. Meanwhile, HCWs should be well trained and well protected before their frontline exposure.

20.
Surg Today ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33104877

RESUMO

PURPOSE: We used five machine-learning algorithms to predict cancer-specific mortality after surgical resection of primary non-metastatic invasive breast cancer. METHODS: This study was a secondary analysis of data for 1661 women with primary non-metastatic invasive breast cancer. The overall patient population was divided into a training group and a test group at a ratio of 8:2 and python was used for machine learning to establish the prognosis model. RESULTS: The machine-learning Gbdt algorithm for cancer-specific death caused by various factors showed the five most important factors, ranked from high to low as follows: the number of regional lymph node metastases, LDH, triglyceride, plasma fibrinogen, and cholesterol. Among the five algorithm models in the test group, the highest accuracy rate was by DecisionTree (0.841), followed by the gbm algorithm (0.838). Among the five algorithms, the AUC values from high to low were GradientBoosting (0.755), gbm (0.755), Logistic (0.733), Forest (0.715), and DecisionTree (0.677). CONCLUSION: Machine learning can predict cancer-specific mortality after surgery for patients with primary non-metastatic invasive breast.

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