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1.
Small ; : e2000793, 2020 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-32227454

RESUMO

DNA origami has rapidly emerged as a powerful technique to fabricate user-defined DNA nanostructures. However, the ability to custom-make patterns on DNA origami template is hampered by the heavy workload and high cost of changing staple DNA (up to several hundred strands per set). Here, a scaffold-decorated DNA origami method is developed by prescribing the pattern information to the scaffold DNA. For each pixel of an origami, a designed "pixel strand" (P-strand) is hybridized to the scaffold, strongly preoccupying a specific position and competing with invading staples in a mild origami assembly. To fabricate a new origami pattern, the P-strand set needs to be replaced with a universal staple set. The yield of thus-fabricated DNA origami patterns is comparable to a conventional DNA origami with canonical method. One-pot fabrication of three different nanopatterns in a single test-tube is further demonstrated. Also, dynamic switch of the pattern is shown. This method provides a generic approach and offers large flexibility for scaling up the nanofabrication with DNA origami by kinetically modulating the reaction pathway of the staples with the scaffold DNA, which represents a novel route in the self-assembly of complex biomolecular systems.

2.
Dev Cell ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32197067

RESUMO

Understanding of NAD+ metabolism provides many critical insights into health and diseases, yet highly sensitive and specific detection of NAD+ metabolism in live cells and in vivo remains difficult. Here, we present ratiometric, highly responsive genetically encoded fluorescent indicators, FiNad, for monitoring NAD+ dynamics in living cells and animals. FiNad sensors cover physiologically relevant NAD+ concentrations and sensitively respond to increases and decreases in NAD+. Utilizing FiNad, we performed a head-to-head comparison study of common NAD+ precursors in various organisms and mapped their biochemical roles in enhancing NAD+ levels. Moreover, we showed that increased NAD+ synthesis controls morphofunctional changes of activated macrophages, and directly imaged NAD+ declines during aging in situ. The broad utility of the FiNad sensors will expand our mechanistic understanding of numerous NAD+-associated physiological and pathological processes and facilitate screening for drug or gene candidates that affect uptake, efflux, and metabolism of this important cofactor.

3.
Tree Physiol ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32159803

RESUMO

Remorins (REMs) play an important role in the ability of plants to adapt to adverse environments. PeREM6.5, a protein of the REM family in Populus euphratica (salt-resistant poplar), was induced by NaCl stress in callus, roots and leaves. We cloned the full-length PeREM6.5 from P. euphratica and transformed it into Escherichia coli and Arabidopsis thaliana. PeREM6.5 recombinant protein significantly increased the H+-ATPase hydrolytic activity and H+ transport activity in P. euphratica plasma membrane (PM) vesicles. Yeast two-hybrid assay showed that P. euphratica REM6.5 interacted with RPM1-interacting protein 4 (PeRIN4). Notably, the PeREM6.5-induced increase in PM H+-ATPase activity was enhanced by PeRIN4 recombinant protein. Overexpression of PeREM6.5 in Arabidopsis significantly improved salt tolerance in transgenic plants in terms of survival rate, root growth, electrolyte leakage, and malondialdehyde content. Arabidopsis plants overexpressing PeREM6.5 retained high PM H+-ATPase activity in both in vivo and in vitro assays. PeREM6.5-transgenic plants had reduced accumulation of Na+ due to the Na+ extrusion promoted by the H+-ATPases. Moreover, the H+ pumps caused hyperpolarization of the plasma membrane, which reduced the K+ loss mediated by the depolarization-activated channels in the PM of salinized roots. Therefore, we conclude that PeREM6.5 regulated H+-ATPase activity in the PM, thus enhancing the plant capacity to maintain ionic homeostasis under salinity.

4.
J Appl Toxicol ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170788

RESUMO

ET-26 hydrochloride (ET-26HCl), a novel analog of etomidate, induces as effective sedation, with good cardiac and respiratory stability, as etomidate but with mild adrenocortical suppression. The objective of this study was to evaluate the potential adverse effects of ET-26HCl in rats. In a single-dose toxicity study, abnormal urine color (red) was observed in all groups: control (100%), 8 mg/kg (10%), 16 mg/kg (50%), and 20 mg/kg (70%) ET-26HCl, which returned to normal on the day of dosing. There were no mortalities or serious toxicological signs; the maximum tolerable dose of ET-26HCl was 20 mg/kg. In the repeated-dose toxicity study, deaths occurred in the 12- (13.33% of males) and 16-mg/kg/day (20% of males and 3.33% of females) groups. Abnormal urine color (red or brown) was detected in the control group (10%) and all treatment groups (30%, 46.67%, and 40% at 8, 12 and 16 mg/kg/day, respectively), at a frequency of 1.43% in the control group, 4.76% in 8 mg/kg/day, 7.62% in 12 mg/kg/day, and 4.29% in 16 mg/kg/day. Increases in neutrophils and plasma fibrinogen were temporary and recoverable effects. Macroscopic and histopathologic changes were found only at the injection sites: abnormal skin color, scabbing, thrombus, ulceration, and inflammation. During the recovery period, there was evidence of reversibility, including fibroblast proliferation and vessel recanalization. The no-observed-adverse-effect level of ET-26HCl was 8 mg/kg/day. Toxicokinetic variables of ET-26HCl, except the calculated initial concentration in females on Day 1, showed a dose-dependent increase to exposure, with no gender difference and no evidence of accumulation.

5.
Minerva Anestesiol ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32162897

RESUMO

INTRODUCTION: It remains unclear whether intraoperative use of volatile anesthetics has a positive effect on postoperative clinical outcomes in patients undergoing coronary artery bypass grafting (CABG). Therefore, we aimed to systematically analyze the long- and short-term mortality rates and the clinical outcomes of volatile anesthesia compared to those of total intravenous anesthesia (TIVA) in patients undergoing CABG. EVIDENCE ACQUISITION: We queried the MEDLINE, Embase, and CENTRAL databases from inception to October 2019 for relevant randomized clinical trials (RCTs) on the intraoperative use of volatile anesthetics in patients undergoing CABG. EVIDENCE SYNTHESIS: We pooled and analyzed 36 eligible RCTs with 10,308 patients and found that there was no significant difference in the long- and short-term mortality rate between the use of volatile anesthesia and TIVA during CABG. 30-day mortality, volatile group (39/2,824, 1.4%) vs TIVA group (35/2,786, 1.3%), RR=1.11, 95% CI [0.70, 1.74], P-value for effect = 0.66, I2 =0%, moderate-certainty evidence; One-year mortality, volatile group (77/2,749, 2.8%) vs TIVA group (78/2,731, 2.9%), RR=0.98, 95% CI [0.72, 1.34], P-value for effect = 0.90, I2 =0%, moderate- certainty evidence. Mechanical ventilation time was reduced in volatile group (MD -0.65, 95% CI [-1.07, -0.24], P-value for effect = 0.002, I2 = 26%). CONCLUSIONS: There is no difference in the long- and short-term mortality and clinical outcomes between intraoperative use of volatile anesthetics and TIVA during CABG. However, volatile anesthetics may shorten the mechanical ventilation time. There is a need for high-quality multicenter RCTs that specifically assess factors that influence mortality and clinical outcomes.

6.
J Am Chem Soc ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32176498

RESUMO

Several important micropeptides encoded by noncoding RNAs have been identified in recent years; however, there have never been any reports of micropeptides in head and neck squamous cell carcinoma (HNSCC). Here we report the discovery and characterization of a human endogenous peptide named micropeptide inhibiting actin cytoskeleton (MIAC). Comprehensive analysis of the TCGA (The Cancer Genome Atlas) database (n = 500), clinical fresh samples (n = 94), and tissue microarrays (n = 60) revealed that lower MIAC expression is correlated with poor overall survival of HNSCC patients. Meanwhile, RNA-sequencing analysis of 9657 human tissues across 32 cancer types from TCGA cohorts found that MIAC is significantly associated with the progression of 5 other different tumors. Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. Collectively, the mechanism investigation and evaluation of MIAC activity in vivo and in vitro highlights that MIAC plays an important role in HNSCC tumorigenesis.

7.
Oncogene ; 39(14): 2877-2889, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32042113

RESUMO

Aiming to identify immune molecules with a novel function in cancer pathogenesis, we found the cluster of differentiation 177 (CD177), a known neutrophil antigen, to be positively correlated with relapse-free, metastasis-free, or overall survival in breast cancer. In addition, CD177 expression is correlated with good prognosis in several other solid cancers including prostate, cervical, and lung. Focusing on breast cancer, we found that CD177 is expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Loss of CD177 leads to hyperproliferative mammary epithelium and contributes to breast cancer pathogenesis. Mechanistically, we found that CD177-deficiency is associated with an increase in ß-catenin signaling. Here we identified CD177 as a novel regulator of mammary epithelial proliferation and breast cancer pathogenesis likely via the modulation of Wnt/ß-catenin signaling pathway, a key signaling pathway involved in multiple cancer types.

8.
Sci Rep ; 10(1): 2083, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034198

RESUMO

Anti-PD-1/PD-L1 inhibitors provide a survival advantage over conventional therapies for treatment of advanced or metastatic cancer. However, the factors determining which patients benefit the most from anti-PD-1/PD-L1 inhibitors are unknown, making treatment-related decisions difficult. We performed a systematic review and meta-analysis of acquired data to assess the efficacy and toxicity of anti-PD-1/PD-L1 inhibitors in advanced and metastatic cancer. A thorough search strategy was applied to identify randomised controlled trials (RCTs) in Pubmed, Embase, Cochrane, and major conferences. Studies meeting predefined selection criteria were selected, and two independent investigators performed data extraction; overall survival (OS), progression-free survival (PFS), and overall response rate were compared between anti-PD-1/PD-L1 inhibitors and control therapies. We calculated the pooled response rate and 95% CIs of all-grade and high-grade (≥3) adverse effects and evaluated the within-study heterogeneity using subgroup, sensitivity, and meta-regression analyses. In final, we included eligible 35 RCTs (21047 patients). The main estimated hazard ratios (HRs) for OS and PFS were 0.76 (0.71-0.82) and 0.81 (0.73-0.89) in a random-effects model. The anti-PD-1/PD-L1 inhibitor group had a significantly high risk for all-grade immune-related adverse events. Anti-PD-1/PD-L1 inhibitors were identified as a preferable treatment option for advanced or metastatic cancer patients who are male, aged < 65 years, current or former smokers, had no CNS or liver metastasis, had not EGFR mutation, and had high PD-L1 expression.

9.
J Agric Food Chem ; 68(6): 1588-1595, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31994388

RESUMO

The discovery of new, safe, and effective pesticides is one of the main means for modern crop protection and parasitic disease control. During the search for new insecticidal secondary metabolites from endophytes in Stemona sessilifolia (a traditional Chinese medicine with a long history as an insecticide), 10 new insecticidal endostemonines A-J (1-10) were identified from an endophytic Streptomyces sp. BS-1. Their structures were determined by comprehensive spectroscopic analysis. Endostemonines A-J represent the first reported naturally occurring pyrrole-2-carboxylic ester derivatives, which consisted of different fatty acid chains at the C-2 of pyrrole ring were produced by traditional Chinese medicine endophytic microbes. All new tested compounds exhibited strong lethal activity against Aphis gossypii (LC50 value range of 3.55-32.00 mg/L after 72 h). This research highlighted the discovery of pesticide natural products from insecticidal medicinal plant endophytes for the first time, paving a new pathway for the development of pest control.


Assuntos
Endófitos/química , Compostos Heterocíclicos com 3 Anéis/metabolismo , Inseticidas/metabolismo , Stemonaceae/microbiologia , Streptomyces/química , Streptomyces/metabolismo , Animais , Afídeos/efeitos dos fármacos , Endófitos/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/toxicidade , Inseticidas/química , Inseticidas/toxicidade , Metabolismo Secundário
10.
J Exp Bot ; 71(4): 1527-1539, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31680166

RESUMO

Plasma membrane proton pumps play a crucial role in maintaining ionic homeostasis in salt-resistant Populus euphratica under saline conditions. High levels of NaCl (200 mM) induced PeHA1 expression in P. euphratica roots and leaves. We isolated a 2022 bp promoter fragment upstream of the translational start of PeHA1 from P. euphratica. The promoter-reporter construct PeHA1-pro::GUS was transferred to tobacco plants, demonstrating that ß-glucuronidase activities increased in root, leaf, and stem tissues under salt stress. DNA affinity purification sequencing revealed that PeWRKY1 protein targeted the PeHA1 gene. We assessed the salt-induced transcriptional response of PeWRKY1 and its interaction with PeHA1 in P. euphratica. PeWRKY1 binding to the PeHA1 W-box in the promoter region was verified by a yeast one-hybrid assay, EMSA, luciferase reporter assay, and virus-induced gene silencing. Transgenic tobacco plants overexpressing PeWRKY1 had improved expression of NtHA4, which has a cis-acting W-box in the regulatory region, and improved H+ pumping activity in both in vivo and in vitro assays. We conclude that salt stress up-regulated PeHA1 transcription due to the binding of PeWRKY1 to the W-box in the promoter region of PeHA1. Thus, we conclude that enhanced H+ pumping activity enabled salt-stressed plants to retain Na+ homeostasis.

11.
Cell Death Differ ; 27(1): 379-395, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31217502

RESUMO

DC-SIGN is previously focused on its physiologic and pathophysiologic roles in immune cells. Little is known about whether DC-SIGN is expressed in malignant epithelial cells and how DC-SIGN participates in tumor progression. Here we showed that DC-SIGN expression was increased in metastatic colorectal cancer (CRC) cell lines and patient tissues. The overall survival in CRC patients with positive DC-SIGN was remarkably reduced. Gain of DC-SIGN function facilitated the CRC metastases both in vitro and in vivo, and this effect was reversed by miR-185. DC-SIGN and Lyn interacted physically, and Lyn maintained the stability of DC-SIGN in cells. DC-SIGN activation recruited Lyn and p85 to form the DC-SIGN-Lyn-p85 complex, which promoted CRC metastasis by increasing PI3K/Akt/ß-catenin signaling in tyrosine kinase Lyn-dependent manner. Furthermore, activation of DC-SIGN promoted the transcription of MMP-9 and VEGF by increasing PI3K/Akt/ß-catenin signaling, and induced TCF1/LEF1-mediated suppression of miR-185. Our findings reveal the presence of the DC-SIGN-TCF1/LEF1-miR-185 loop in cancer cells with metastatic traits, implying that it may represent a new pathogenic mechanism of CRC metastasis. This character of the loop promises to provide new targets for blocking CRC invasive and metastatic activity.

12.
J Hazard Mater ; 384: 121255, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31590087

RESUMO

Polychlorinated dibenzo-p-dioxins (PCDDs), characterized by their high persistency and bioaccumulation, are widely detected in the environment. In this study, high-performance g-C3N4/NiO heterojunctions were fabricated to degrade 2-chlorodibenzo-p-dioxin (2-CDD) under ultraviolet-visible (UV-vis) light illumination. Experiments revealed that the pure g-C3N4 and range of g-C3N4/NiO heterojunctions were synthesized by the mixing and heating method, and then were characterized by XRD, TEM, XPS and PL etc. The composites exhibited enhanced dechlorination activities under anoxic conditions. After comparison, the g-C3N4/NiO (4:6) showed optimal dechlorination performance such that 70.4% of 2-CDD was removed within 8 h and 52.3% of 2-CDD was transformed to dibenzo-p-dioxin (DD), about fourfold higher than the pristine g-C3N4. The transformation of 2-CDD was accompanied by the resale of Cl ion, and the additional oxygen was proven to be able to consume electrons and hydrogen ions, thus greatly inhibiting the degradation of PCDD in systems. The g-C3N4/NiO (4:6) can be reused at least seven times, and the mechanism was proposed in detail to promote photoinduced electrohole separation and provide active sites. This study extends the use range of g-C3N4/NiO heterojunctions and develops a new technology to degrade PCDDs with striking activity and stability.

13.
Chemistry ; 26(11): 2478-2485, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31756008

RESUMO

Antibiotic resistance poses severe health threats throughout the world. Exploring new antibiotics is widely recognized as an effective strategy to counter antibiotic resistance, but new antibiotics will eventually lead to further antibiotic resistance when new drugs are misused or overused. An alternative tactic may be antibacterial regulation on demand. Here, we show experimentally and theoretically that unstable black phosphorus nanosheets (BPNs) can function as antibacterial agents without causing antibiotic resistance. This antibacterial strategy relies on an unprecedented synergism: The BPNs use reactive oxygen species, are not toxic towards nonbacterial cells within a wide range of BPN concentration (0.01-2.0 mg mL-1 ), and are chemically degradable on demand. BPNs thus offer a promising approach to fighting bacterial infections without causing antibiotic resistance. We believe this proposed strategy offers new insights into instability-guided antibacterial therapy in clinical applications and indicates a new direction for fighting antibiotic resistance.

14.
Nat Commun ; 10(1): 5469, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784537

RESUMO

Biomolecular cryptography exploiting specific biomolecular interactions for data encryption represents a unique approach for information security. However, constructing protocols based on biomolecular reactions to guarantee confidentiality, integrity and availability (CIA) of information remains a challenge. Here we develop DNA origami cryptography (DOC) that exploits folding of a M13 viral scaffold into nanometer-scale self-assembled braille-like patterns for secure communication, which can create a key with a size of over 700 bits. The intrinsic nanoscale addressability of DNA origami additionally allows for protein binding-based steganography, which further protects message confidentiality in DOC. The integrity of a transmitted message can be ensured by establishing specific linkages between several DNA origamis carrying parts of the message. The versatility of DOC is further demonstrated by transmitting various data formats including text, musical notes and images, supporting its great potential for meeting the rapidly increasing CIA demands of next-generation cryptography.

15.
Nat Commun ; 10(1): 5597, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811136

RESUMO

The inherent specificity of DNA sequence hybridization has been extensively exploited to develop bioengineering applications. Nevertheless, the structural potential of DNA has been far less explored for creating non-canonical DNA-based reactions. Here we develop a DNA origami-enabled highly localized metallization reaction for intrinsic metallization patterning with 10-nm resolution. Both theoretical and experimental studies reveal that low-valence metal ions (Cu2+ and Ag+) strongly coordinate with DNA bases in protruding clustered DNA (pcDNA) prescribed on two-dimensional DNA origami, which results in effective attraction within flexible pcDNA strands for site-specific pcDNA condensation. We find that the metallization reactions occur selectively on prescribed sites while not on origami substrates. This strategy is generically applicable for free-style metal painting of alphabet letters, digits and geometric shapes on all-DNA substrates with near-unity efficiency. We have further fabricated single- and double-layer nanoscale printed circuit board (nano-PCB) mimics, shedding light on bio-inspired fabrication for nanoelectronic and nanophotonic applications.

16.
Opt Express ; 27(21): 30909-30918, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31684332

RESUMO

Aluminum (Al) plasmonic nanostructures have recently demonstrated remarkable optical nonlinear phenomena, such as enhanced second harmonic (SH) generation. However, the relatively weak field enhancement resulted from large optical losses associated with aluminum nanostructures in combination with the difficulties in controlling the emission polarization pose as a challenge for SH enhancement and tuning. In this paper, we show that the SH emission of aluminum nanostructures can be efficiently enhanced with the polarization properties simultaneously tunable by using metal-insulator-metal (MIM) nanostructures, constituting of Al cross nanoantenna arrays on top of Al mirrors with a SiO2 spacing layer. Specifically, femtosecond laser beam with a linear polarization parallel to one arm illuminates on the structure while the orthogonal arms were physically modified by the laser-induced photothermal reshaping technique to control the SH radiation by the plasmonic resonances. Under the resonance at the SH wavelength, we observed one order of magnitude larger emission enhancement compared to that at the off-resonant condition. Interestingly, the polarization states can be well manipulated simultaneously by controlling the resonances of the orthogonal arms. The enhanced SH conversion and tunable polarization states pave the way for the development of nonlinear optical sources and advanced functional metasurfaces.

17.
Age Ageing ; 49(1): 88-95, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711096

RESUMO

BACKGROUND: post-operative delirium (POD) is a common complication in older patients, though a possible link between metabolic changes and POD development has yet to be investigated. METHODS: older patients with hip fracture who underwent hemi-arthroplasty were recruited, and delirious states were assessed for 3 days after surgery using the confusion assessment method-Chinese revision. Simultaneously, fasting blood samples were collected on the morning of surgery and on the first post-operative day. Ultimately, 244 older patients who met the inclusion and exclusion criteria were assessed. Blood samples from 60 patients with POD and 60 matched controls were analysed using metabolomics platforms. RESULTS: sixty patients (24.6%) developed POD. Principal component analysis scores plot and cross-validated scores plots from orthogonal partial least squares-discriminant analysis were implemented to visualise the differences in metabolites between the two groups before and after surgery (P < 0.05). Our data indicate that levels of ω3 and ω6 fatty acids were lower in the POD group than in the NPOD (non-POD) group both before and after surgery; tricarboxylic cycle intermediate levels were lower in the POD group than in the NPOD group, but glycolysis products were higher in the POD group than in the NPOD group after surgery. Furthermore, the branched-chain amino acid (BCAA)/aromatic amino acid ratio was lower in the POD group than in the NPOD group after surgery. CONCLUSIONS: metabolic abnormalities, including deficiencies in ω3 and ω6 fatty acids, perturbations in tricarboxylic cycle and oxidative stress and metabolic imbalances in BCAA and AAA might contribute to POD development.

18.
Medicine (Baltimore) ; 98(48): e18165, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770263

RESUMO

RATIONALE: Crossed renal ectopia (CRE) is a rare congenital anomaly that is frequently associated with gastrointestinal, cardiovascular, genital and bone malformations. To the best of our knowledge, only 35 cases of crossed renal ectopia involving calculi and 30 cases of CRE associated with renal carcinoma have been reported to date. PATIENT CONCERNS: Here, we present 2 cases of crossed renal ectopia. A 59-year-old woman with diabetes presented to our hospital with abdominal pain. The second patient was a 24-year-old woman who complained with abdominal pain with a duration of 1 day. DIAGNOSES: On the basis of abdominal ultrasonography, we suspected a solitary kidney both in the two patients. Combined with retrograde pyelography and 3D computed tomography, case 1 was diagnosed as an S-shaped right-to-left crossed-fused ectopic kidney with many stones in the left (normal) renal pelvis and case 2 was confirmed to have lump right-to-left crossed-fused renal ectopia with two 3-mm stones in the renal pelvis of the 2 kidneys. INTERVENTIONS: Case 1 underwent percutaneous nephrolithotomy while case 2 refused to undergo surgery and underwent conservative treatment for pain relief. OUTCOMES: Two patients have been followed up and have no stones recurrence. LESSONS: Crossed fused renal ectopia is easily misdiagnosed as a solitary kidney. CRE is so rare that the recognition of the disease needs to be improved and effective treatment should be taken timely. According to the two cases and literature review, minimally invasive surgery has become increasingly common to treat CRE with stones and carcinoma.


Assuntos
Dor Abdominal , Rim Fundido , Cálculos Renais , Rim , Nefrolitotomia Percutânea/métodos , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Adulto , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Feminino , Rim Fundido/complicações , Rim Fundido/diagnóstico , Rim Fundido/fisiopatologia , Humanos , Rim/anormalidades , Rim/diagnóstico por imagem , Rim/cirurgia , Cálculos Renais/complicações , Cálculos Renais/diagnóstico , Cálculos Renais/fisiopatologia , Cálculos Renais/cirurgia , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Ultrassonografia/métodos , Urografia/métodos
19.
Chem Sci ; 10(32): 7641-7648, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31583069

RESUMO

A divergent modular strategy for the enantioselective total synthesis of 12 naturally-occurring griseusin type pyranonaphthoquinones and 8 structurally-similar analogues is described. Key synthetic highlights include Cu-catalyzed enantioselective boration-hydroxylation and hydroxyl-directed C-H olefination to afford the central pharmacophore followed by epoxidation-cyclization and maturation via diastereoselective reduction and regioselective acetylation. Structural revision of griseusin D and absolute structural assignment of 2a,8a-epoxy-epi-4'-deacetyl griseusin B are also reported. Subsequent mechanistic studies establish, for the first time, griseusins as potent inhibitors of peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3). Biological evaluation, including comparative cancer cell line cytotoxicity and axolotl embryo tail inhibition studies, highlights the potential of griseusins as potent molecular probes and/or early stage leads in cancer and regenerative biology.

20.
EBioMedicine ; 48: 478-490, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31628020

RESUMO

BACKGROUND: Urea, the end product of protein metabolism, has been considered to have negligible toxicity for a long time. Our previous study showed a depression phenotype in urea transporter (UT) B knockout mice, which suggests that abnormal urea metabolism may cause depression. The purpose of this study was to determine if urea accumulation in brain is a key factor causing depression using clinical data and animal models. METHODS: A meta-analysis was used to identify the relationship between depression and chronic diseases. Functional Magnetic Resonance Imaging (fMRI) brain scans and common biochemical indexes were compared between the patients and healthy controls. We used behavioural tests, electrophysiology, and molecular profiling techniques to investigate the functional role and molecular basis in mouse models. FINDINGS: After performing a meta-analysis, we targeted the relevance between chronic kidney disease (CKD) and depression. In a CKD mouse model and a patient cohort, depression was induced by impairing the medial prefrontal cortex. The enlarged cohort suggested that urea was responsible for depression. In mice, urea was sufficient to induce depression, interrupt long-term potentiation (LTP) and cause loss of synapses in several models. The mTORC1-S6K pathway inhibition was necessary for the effect of urea. Lastly, we identified that the hydrolysate of urea, cyanate, was also involved in this pathophysiology. INTERPRETATION: These data indicate that urea accumulation in brain is an independent factor causing depression, bypassing the psychosocial stress. Urea or cyanate carbamylates mTOR to inhibit the mTORC1-S6K dependent dendritic protein synthesis, inducing impairment of synaptic plasticity in mPFC and depression-like behaviour. CKD patients may be able to attenuate depression only by strict management of blood urea.

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