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1.
Protein Expr Purif ; 166: 105520, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31644959

RESUMO

An affibody is a 58 amino acids peptide derived from the Z domain of staphylococcal protein A and generally applied in areas such as imaging diagnosis, clinical therapeutics and biotechnology research. To screen for an affibody targeting the immune checkpoint PD-L1, a combinatorial affibody library was generated in yeast using degenerate overlap PCR primers and In-fusion technology. Z-j1 and Z-j2 affibodies targeting the Ig-like V domain of PD-L1 were screened and identified from this combinatorial library using the yeast two hybrid system. The Z-j1 and Z-j2 recombinant affibody proteins were over produced in E.coli and purified. ELISA and GST pull-down assays showed that recombinant Z-j1 and Z-j2 affibody proteins bound with high affinity to PD-L1 and inhibited the interaction of PD-1/PD-L1. Thus, novel affibodies targeting the immune checkpoint PD-1/PD-L1 were identified and produced in this study and have the potential to be used in cancer immunotherapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31685470

RESUMO

Mammalian serum amyloid A (SAA) is a major acute phase protein that shows a massive increase in plasma concentration during inflammation. In the current study, we demonstrate that the expression of mouse SAA1 in serum was increased when infected with Candida albicans, a major human fungal pathogen, in a systemic infection model. We then set out to investigate the antifungal activity of SAA proteins against C. albicans. Recombinant human and mouse SAA1 (rhSAA1 and rmSAA1) were expressed and purified in E. coli. Both rhSAA1 and rmSAA1 exhibited a potent antifungal activity against C. albicans. We further demonstrate that rhSAA1 binds to the cell surface of C. albicans, disrupts cell membrane integrity and induces rapid fungal cell death in C. albicans Our finding expands the known functions of SAA1 and provides new insight into host-Candida interactions during fungal infection.

3.
Int J Nanomedicine ; 14: 8345-8360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695371

RESUMO

Background: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect. Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging. Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of -6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium. Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.

4.
Dev Cell ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31735664

RESUMO

Neurons convert synaptic or sensory inputs into cellular outputs. It is not well understood how a single neuron senses, processes multiple stimuli, and generates distinct neuronal outcomes. Here, we describe the mechanism by which the C. elegans PVD neurons sense two mechanical stimuli: external touch and proprioceptive body movement. These two stimuli are detected by distinct mechanosensitive DEG/ENaC/ASIC channels, which trigger distinct cellular outputs linked to mechanonociception and proprioception. Mechanonociception depends on DEGT-1 and activates PVD's downstream command interneurons through its axon, while proprioception depends on DEL-1, UNC-8, and MEC-10 to induce local dendritic Ca2+ increase and dendritic release of a neuropeptide NLP-12. NLP-12 directly modulates neuromuscular junction activity through the cholecystokinin receptor homolog on motor axons, setting muscle tone and movement vigor. Thus, the same neuron simultaneously uses both its axon and dendrites as output apparatus to drive distinct sensorimotor outcomes.

5.
Chin Med J (Engl) ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31764172

RESUMO

OBJECTIVE: Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application. DATA SOURCES: Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis. CONCLUSIONS: We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.

6.
J Pharm Sci ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31622601

RESUMO

The effect of vapor sorption on the free volume of drug-polymer spray-dried dispersions (SDDs) was investigated, along with the crystallization propensity of drug molecules in SDDs after exposure to humidity. Subsequently, the correlation of free volume change and relaxation time with drug recrystallization was examined. Four polymers, including polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropyl cellulose, and hydroxypropyl methylcellulose acetate succinate, and 2 drugs (indomethacin and ketoconazole) were selected for preparing SDDs. Free volume data of the exposed SDDs were obtained with positron annihilation lifetime spectroscopy, while the relaxation time was measured using a TA rheometer. Additionally, the crystallization propensity of active pharmaceutical ingredients (APIs) in the exposed SDDs was assessed using both polarized light microscopy and powder X-ray diffraction, followed by relating API crystallization inclination with expansion of holes and relaxation time. Finally, Cohen and Turnbull molecular transport model, along with its extensions by Vrentas and Duda, was qualitatively utilized for interpreting the recrystallization propensity of API molecules. In conclusion, API recrystallization is closely related to free volume change upon moisture sorption and relaxation time, but system dependent; overall, drug-hydroxypropyl methylcellulose acetate succinate SDDs appear physically stable against recrystallization due to less increase in free volume.

7.
Chem Res Toxicol ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31664825

RESUMO

The artemisinin class of anticancer compounds is well known for oxidative DNA-damage-mediated growth arrest, followed by cell death. However, the nature of this genotoxic stress for cancer therapeutics remains elusive. Here we show that artesunate (Art), a water-soluble artemisinin analog, triggers inducible anticancer responses directly implicated in the DNA-damage-intended therapy. We observed that the level of the antiviral enzyme APOBEC3C (apolipoprotein-B mRNA-editing catalytic polypeptide-like 3C (A3C)) preferentially increased upon the treatment with Art against tumor xenografts of p53-deficient H1299 cells. Using gain-of-function experiments, A3C could improve the therapeutic efficacy of Art, as determined by cell proliferation and colony formation assays. Furthermore, elevated A3C provoked a minor accumulation of γH2AX foci and the phosphorylation of RPA32 and Chk1, which strongly sensitized H1299 cells to Art. The employment of A3C also caused an increase in the synergistic interaction between Art and Chk1 inhibition. Besides, A3C overexpression delayed the cell cycle at the S phase, accompanied by attenuated G2/M arrest in the presence of Art. The enzymatic inactivation of A3C by the mutation of zinc-coordinating residues (C97S and C100S) indicated that A3C sensitized Art in a deaminase-dependent manner. Furthermore, we showed that using small interfering RNA against A3C can induce the chemoresistance of Art. These studies combine to suggest that upregulated A3C is involved in the Art-induced DNA damage response as a consequent event to improve the overall cytotoxic responses of Art.

8.
Medicine (Baltimore) ; 98(40): e17360, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577732

RESUMO

In neonates, congenital factor VII deficiency (FVIID) is characterized by central nervous system bleeding and gastrointestinal hemorrhage, often resulting in poor prognosis and high mortality.To improve understanding of FVIID in neonates in Asia, we retrospectively analyzed the clinical manifestations, diagnosis, treatment, clinical course, and genetic diagnosis of 2 cases of neonatal FVIID in the Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou, China, from January 2007 to December 2017 and performed a review of the relevant literature.Both neonates were female and presented with severe gastrointestinal tract and intracranial hemorrhage. The laboratory findings were characterized by repeated and non-vitamin K1-dependent prolonged of the prothrombin time (PT), Factor VII (FVII) activity was 1.5% and 3%, respectively. Both neonates died of severe intracranial hemorrhage, at 31 days and 6 months after birth, respectively. Gene sequencing results revealed a homozygous mutation in the FVII gene splice site (IVS7+1G>T) in both cases. Upon review of relevant literature published since 1996, we identified 19 cases of neonatal FVIID. The patients were full-term neonates with onset of symptoms mostly within 7 days after birth (73.7%), which included gastrointestinal bleeding (blood stool, vomiting blood; 31.6%), nervous system signs (drowsiness, convulsions, poor response; 26.3%), severe intracranial hemorrhage (84.2%), significantly prolonged PT with significantly decreased FVII activity (89.5%), high mortality, and disability (68.4%). Gene sequencing was performed in 9 of the 19 children evaluated and revealed a mutation in the FVII gene in all cases.FVIID can be clinically diagnosed based on the presence of prolonged PT that is difficult to correct and significantly decreased FVII activity (≤5%). As mutations in some sites are associated with severe bleeding, genetic diagnosis represents a useful tool for prenatal diagnosis of FVIID. In brief, we should pay great attention to the FVIID onset of the neonatal period, although it is rare but result in life-threatening bleeding with poor prognosis.


Assuntos
Deficiência do Fator VII/genética , Deficiência do Fator VII/patologia , China , Fator VII/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Tempo de Protrombina , Estudos Retrospectivos
9.
Chin Med J (Engl) ; 132(19): 2315-2324, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31567376

RESUMO

BACKGROUND: Nucleos(t)ide analog (NA) in combination with peginterferon (PegIFN) therapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) shows better effectiveness than NA monotherapy in hepatitis B surface antigen loss, termed "functional cure," based on previous published studies. However, it is not known which strategy is more cost-effective on functional cure. The aim of this study was to analyze the cost-effectiveness of first-line monotherapies and combination strategies in HBeAg-positive CHB patients in China from a social perspective. METHODS: A Markov model was developed with functional cure and other five states including CHB, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and death to assess the cost-effectiveness of seven representative treatment strategies. Entecavir (ETV) monotherapy and tenofovir disoproxil fumarate (TDF) monotherapy served as comparators, respectively. RESULTS: In the two base-case analysis, compared with ETV, ETV generated the highest costs with $44,210 and the highest quality-adjusted life-years (QALYs) with 16.78 years. Compared with TDF, treating CHB patients with ETV and NA - PegIFN strategies increased costs by $7639 and $6129, respectively, gaining incremental QALYs by 2.20 years and 1.66 years, respectively. The incremental cost-effectiveness ratios were $3472/QALY and $3692/QALY, respectively, which were less than one-time gross domestic product per capita. One-way sensitivity analysis and probabilistic sensitivity analyses showed the robustness of the results. CONCLUSION: Among seven treatment strategies, first-line NA monotherapy may be more cost-effective than combination strategies in HBeAg-positive CHB patients in China.

10.
Molecules ; 24(19)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569766

RESUMO

Gastric cancer is the fifth most common tumor and has the third-highest mortality rate among various malignant tumors, and the survival rate of patients is low. Celastrus orbiculatus extract has been shown to inhibit the activity of a variety of tumors. This study explored the inhibitory effect of the oleanane-type triterpenoid acid 28-hydroxy-3-oxoolean-12-en-29-oic acid molecule from Celastrus orbiculatus extract on gastric cancer cell invasion and metastasis and determined its mechanism. 28-Hydroxy-3-oxoolean-12-en-29-oic acid was first diluted to various concentrations and then used to treat SGC-7901 and BGC-823 cells. Cell proliferation was assessed by an MTT (thiazole blue) assay. Transwell and wound healing assays were used to assess cell invasion and migration. High-content imaging technology was used to further observe the effects of the drug on cell invasion and migration. Western blotting was used to assess the effects on the expression of matrix metalloproteinases (MMPs) and the effects on epithelial-mesenchymal transition (EMT)-related proteins and phosphorylation-related proteins. We found that 28-Hydroxy-3-oxoolean-12-en-29-oic acid inhibited the migration and invasion of SGC-7901 and BGC-823 gastric cancer cells in a dose-dependent manner. Consequently, 28-hydroxy-3-oxoolean-12-en-29-oic acid decreased the expression of EMT-related proteins and MMPs in gastric cancer cells and reduced protein phosphorylation, inhibiting the migration and invasion of gastric cancer cells.

11.
J Nat Prod ; 82(10): 2925-2930, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31490677

RESUMO

A pyridone alkaloid, asperpyridone A (1), which possesses an unusual pyrano[3,2-c]pyridine scaffold, was isolated from solid cultures of the endophytic fungus Aspergillus sp. TJ23. Its structure, including its absolute configuration, was determined using a combination of nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, quantum chemical calculations (electronic circular dichroism), and X-ray crystallography. In vitro bioassays demonstrated that asperpyridone A (1) could function as a potential hypoglycemic agent, which exhibited pronounced glucose uptake effect in liver HepG2 cells, under both normal and insulin-resistant conditions, with higher efficacy than metformin. The underlying mechanism of asperpyridone A was elucidated by analyzing the genes expressed, the Gene Ontology (GO) function enrichment, the protein interaction network, and real-time quantitative reverse transcription polymerase chain reaction, which suggested that asperpyridone A exhibits hypoglycemic activity by activating the insulin signaling pathway. Moreover, on the basis of the hypoglycemic potency, fibroblast growth factor 21 (FGF21) was determined to be a potential target for asperpyridone A.

12.
Chin J Nat Med ; 17(7): 498-505, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31514981

RESUMO

The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections (XNJ) on cerebral ischemia injury and blood-brain barrier (BBB) disruption. Middle cerebral artery occlusion (MCAO) method was applicated to establish the model of cerebral ischemia/reperfusion (I/R) injury in rats. BBB permeability after I/R injury was assessed with the leaking amount of Evans Blue and the expression of occludin and ZO-1. The expression of NOD-like receptor family, pyrin domain containing (NLRP3) was checked to explore the inhibition of inflammation by XNJ. The results showed that XNJ could significantly increase the survival percent, decrease the infarct area and ameliorate neurological deficits and brain damage after I/R injury. Leaking amount of Evans Blue was reduced by XNJ, and the expression of tight junction protein, occludin and ZO-1 was also up-regulated by XNJ, which showed a role of protection on BBB disruption. The expression of NLRP3 was inhibited after exposure of XNJ, which was associated with inhibition of the inflammatory response. In summary, XNJ could suppress NLRP3 inflammasomes and improve BBB disruption and brain damage in rats after cerebral I/R injury, which provided a beneficial insight to further explore XNJ.

13.
Int J Surg Pathol ; : 1066896919873078, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31526158

RESUMO

Dedifferentiated liposarcoma rarely occurs in the esophagus. It always has atypical clinical manifestations and different pathologic features, which usually lead to misdiagnosis and mistreatment. Given its poor prognosis, early and accurate diagnosis is of the utmost importance. The accumulation of similar cases is critical for surgeons and pathologists to raise awareness of such tumors. This report aims to discuss the diagnosis and provide a reference for the clinical diagnosis and treatment for pathologists and clinicians.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31548180

RESUMO

BACKGROUND: This study uses a novel geographic approach to summarize the distribution of breast cancer in San Francisco and aims to identify the neighborhoods and racial/ethnic groups that are disproportionately affected by this disease. METHODS: Nine geographic groupings were newly defined on the basis of racial/ethnic composition and neighborhood socioeconomic status. Distribution of breast cancer cases from the Greater Bay Area Cancer Registry in these zones were examined. Multivariable logistic regression models were used to determine neighborhood associations with stage IIB+ breast cancer at diagnosis. Cox proportional hazards regression was used to estimate the hazard ratios for all-cause and breast cancer-specific mortality. RESULTS: A total of 5,595 invasive primary breast cancers were diagnosed between January 1, 2006 and December 31, 2015. We found neighborhood and racial/ethnic differences in stage of diagnosis, molecular subtype, survival, and mortality. Patients in the Southeast (Bayview/Hunter's Point) and Northeast (Downtown, Civic Center, Chinatown, Nob Hill, Western Addition) areas were more likely to have stage IIB+ breast cancer at diagnosis, and those in the East (North Beach, Financial District, South of Market, Mission Bay, Potrero Hill) and Southeast were more likely to be diagnosed with triple-negative breast cancers (TNBC). Compared with other racial/ethnic groups, Blacks/African Americans (B/AA) experienced the greatest disparities in breast cancer-related outcomes across geographic areas. CONCLUSIONS: San Francisco neighborhoods with lower socioeconomic status and larger minority populations experience worse breast cancer outcomes. IMPACT: Our findings, which reveal breast cancer disparities at sub-county geographic levels, have implications for population-level health interventions.

15.
BMB Rep ; 52(9): 566-571, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401980

RESUMO

Lymphoma is one of the most curable types of cancer. However, drug resistance is the main challenge faced in lymphoma treatment. Peroxisomal acyl-CoA oxidase 1 (ACOX1) is the rate-limiting enzyme in fatty acid ß-oxidation. Deregulation of ACOX1 has been linked to peroxisomal disorders and carcinogenesis in the liver. Currently, there is no information about the function of ACOX1 in lymphoma. In this study, we found that upregulation of ACOX1 promoted proliferation in lymphoma cells, while downregulation of ACOX1 inhibited proliferation and induced apoptosis. Additionally, overexpression of ACOX1 increased resistance to doxorubicin, while suppression of ACOX1 expression markedly potentiated doxorubicin-induced apoptosis. Interestingly, downregulation of ACOX1 promoted mitochondrial location of Bad, reduced mitochondrial membrane potential and provoked apoptosis by activating caspase-9 and caspase-3 related apoptotic pathway. Overexpression of ACOX1 alleviated doxorubicin-induced activation of caspase-9 and caspase-3 and decrease of mitochondrial membrane potential. Importantly, downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. Also, overexpression of ACOX1 significantly reduced stability of p73 protein thereby reducing p73 expression. Thus, our study indicated that suppression of ACOX1 could be a novel and effective approach for treatment of lymphoma. [BMB Reports 2019; 52(9): 566-571].

16.
Org Biomol Chem ; 17(35): 8234-8242, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31441489

RESUMO

Chemical investigation of the extracts of the aerial parts of Hypericum przewalskii Maxim. resulted in the isolation and identification of six new epoxychromene-containing polycyclic polyprenylated acylphloroglucinols (PPAPs), named przewalcyrones A-F (1-6), and one known analogue (7). All of the structures were determined based on extensive spectroscopic analyses, X-ray crystallographic analysis, modified Mosher's method, [Rh2(OCOCF3)4]-induced ECD, and electronic circular dichroism (ECD) comparison. Structurally, przewalcyrones A-F represent the first examples of PPAPs containing an unexpected 8,8-dimethyl-3,9-epoxychromene moiety. All these compounds were evaluated for the immunosuppressive activity in anti-CD3/anti-CD28 monoclonal antibody (mAb)-stimulated human T cells. Among them, przewalcyrones C and D exhibited potential in vitro immunosuppressive activity, with IC50 values of (5.01 ± 0.52) µM and (5.26 ± 0.56) µM, respectively, highlighting those compounds as a promising starting point for the development of new immunosuppressive agents.

17.
Aging Clin Exp Res ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363931

RESUMO

BACKGROUND: The purpose of this study is to determine whether new-onset postoperative atrial fibrillation (NOPAF) among patients after hip arthroplasty can predict 1-year mortality. METHODS: All patients over 65 years who underwent hip arthroplasty from January 2013 to December 2017 in a Chinese tertiary hospital were retrospectively analyzed. Patients with paroxysmal and persistent atrial fibrillation were ruled out. 2438 patients were identified to be eligible. The primary endpoint was 1-year mortality after the arthroplasty. RESULTS: Among the 2438 patients, 101 (4.1%) had NOPAF and 2337 (95.9%) had not. Only the current use of beta blocker could predict the occurrence of NOPAF after hip arthroplasty. 1-year mortality for patients with NOPAF was significantly higher than that for patients without NOPAF (70.3% vs 19.0%; p < 0.001). Anti-arrhythmic and anticoagulant treatments were related to 1-year mortality, respectively. With multivariate analysis, NOPA was the most significant variable related to 1-year mortality (hazard ratio 7.8, 95% CI 2.9-24.6). CONCLUSIONS: Among elderly patients after hip arthroplasty, 1-year mortality is increased significantly for patients with NOPAF.

18.
J Pharm Sci ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31469998

RESUMO

Isomerization of surface-exposed aspartic acid (Asp) in the complementarity-determining regions of therapeutic proteins could potentially impact their target binding affinity because of the sensitive location, and often requires complex analytical tactics to understand its effect on structure-function and stability. Inaccurate quantitation of Asp-isomerized variants, especially the succinimide intermediate, presents major challenge in understanding Asp degradation kinetics, its stability, and consequently establishing a robust control strategy. As a practical solution to this problem, a comprehensive analytical tool kit has been developed, which provides a solution to fully characterize and accurately quantify the Asp-related product variants. The toolkit offers a combination of 2 steps, an ion-exchange chromatography method to separate and enrich the isomerized variants in the folded structure for structure-function evaluation and a novel focused peptide mapping method to quantify the individual complementarity-determining region isomerization components including the unmodified Asp, succinimide, and isoaspartate. This novel procedure allowed an accurate quantification of each Asp-related variant and a comprehensive assessment of the functional impact of Asp isomerization, which ultimately helped to establish an appropriate control strategy for this critical quality attribute.

19.
Angew Chem Int Ed Engl ; 58(44): 15895-15903, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31452306

RESUMO

2,5-Furandicarboxylic acid was obtained from the electrooxidation of 5-hydroxymethylfurfural (HMF) with non-noble metal-based catalysts. Moreover, combining the biomass oxidation with the hydrogen evolution reaction (HER) increased the energy conversion efficiency of an electrolyzer and also generated value-added products at both electrodes. Here, the reaction pathway on the surface of a carbon-coupled nickel nitride nanosheet (Ni3 N@C) electrode was evaluated by surface-selective vibrational spectroscopy using sum frequency generation (SFG) during the electrochemical oxidation. The Ni3 N@C electrode shows catalytic activities for HMF oxidation and the HER. As the first in situ SFG study on transition-metal nitride for the electrooxidation upgrade of HMF, this work not only demonstrates that the reaction pathway of electrochemical oxidation but also provides an opportunity for nonprecious metal nitrides to simultaneously upgrade biomass and produce H2 under ambient conditions.

20.
J Cardiothorac Surg ; 14(1): 152, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439013

RESUMO

BACKGROUND: Pericardiectomy is the final treatment for constrictive pericarditis. However, this greatest surgical approach is still very controversial. This study pursued to assess the outcomes in patients with recurrent chronic constrictive pericarditis undergoing reoperated pericardiectomy via median sternotomy versus left anterolateral thoracotomy and to explain which surgical approaches might be better for recurrent chronic constrictive pericarditis. METHODS: A total of 24 patients were identified with recurrent chronic constrictive pericarditis and underwent reoperation with pericardiectomy between July 2003 and July 2015. The decision for this surgical approach was mainly dependent on the operating surgeon's preference. Out of 20 patients, 16 patients underwent pericardiectomy via median sternotomy and 8 patients via left anterolateral thoracotomy pericardiectomy. Their data were obtained retrospectively from the case notes. RESULTS: Both groups of patients were similar in age, gender between two operations, and also in peripheral venous pressure, cardiac rhythm and New York Heart Association (NYHA) class distribution. The mortality rates were similar in both groups with one death (12.5%) due to low cardiac output syndrome in the left anterolateral thoracotomy group and two deaths (12.5%) in the median sternotomy group. All the deaths were associated with cardiac complications and happened in the perioperative period. NYHA functional class status enhanced in most of the patients. Patients in both groups had a similar and significant improvement in their NYHA status that improved from 3.4 ± 0.7 to 1.8 ± 0.1 (P = 0.001) in the left anterolateral thoracotomy group and reduced from 3.3 ± 0.6 to 1.9 ± 0.4 (P = 0.001) in the median sternotomy group. There was a significantly greater rate of pulmonary infection in the thoracotomy group than in the median sternotomy group (50% versus 25%, P = 0.02). Nevertheless, there was a significantly greater occurrence of wound infections in the median sternotomy group in 3 patients versus in one patient of the left anterolateral thoracotomy group (18.8% versus 12.5%, P = 0.02). CONCLUSIONS: Left thoracotomy incision was preferred to sternotomy in the current setting of this situation and was done safely without CPB. It avoided life-threatening sternal infection and it also has showed an equal as well las significant enhancement of NYHA status of the patients.


Assuntos
Pericardiectomia/métodos , Pericardite Constritiva/cirurgia , Reoperação , Esternotomia/métodos , Toracotomia/métodos , Adolescente , Adulto , Baixo Débito Cardíaco/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pericardiectomia/efeitos adversos , Pericardiectomia/mortalidade , Pericardite Constritiva/mortalidade , Pericardite Constritiva/fisiopatologia , Período Perioperatório , Pneumonia/etiologia , Recidiva , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/etiologia , Adulto Jovem
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