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1.
Acta Pharmacol Sin ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937930

RESUMO

Etimicin (ETM), a fourth-generation aminoglycosides (AGs), is now widely clinically used in China due to its high efficacy and low toxicity. However, the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear. In the present study we compared the antibacterial and toxicity profiles of etimicin, gentamicin (GM, a second-generation AG), and amikacin (AMK, a third-generation AG), and investigated their pharmacokinetic properties in the toxicity target organs (kidney and inner ear) and subcellular compartments. We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK, and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration. Then, we conducted pharmacokinetic studies in rats, showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups. Furthermore, we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells, and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation; they not only directly inhibited the activity of mitochondrial complexes IV and V but also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway; ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis. Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function. These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.

2.
BMC Plant Biol ; 20(1): 5, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900117

RESUMO

BACKGROUND: In strawberry cultivation, continuous cropping (CC) obstacles seriously threaten production. A patented soil amendment (SA) can effectively relieve the CC obstacles to strawberry cultivation, but knowledge of the recovery mechanisms underlying this phenomenon is limited. RESULTS: In this study, transcriptomic profiling of strawberry roots in soil with and without the SA was conducted using RNA-Seq technology to reveal gene expression changes in response to SA treatment. In total, 188 differentially expressed genes (DEGs), including 144 upregulated and 44 downregulated DEGs, were identified. SA treatment resulted in genotype-dependent responses, and the response pattern, including an overall increase in the expression of nutrient transport genes and a decrease in the expression of defense response genes, may be a possible mechanism underlying recovery strategies in strawberry roots after the application of the SA to CC soil. We also found that 9 Hsp genes involved in plant defense pathways were all downregulated in the SA-treated roots. CONCLUSIONS: This research indicated that strawberry plants reallocated defense resources to development when SA treatment alleviated the stress caused by a CC soil environment. The present study provides an opportunity to reveal the fundamental mechanisms of the tradeoff between growth and defense in strawberry.

3.
J Asian Nat Prod Res ; 22(1): 91-97, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30661391

RESUMO

Tetradium trichotomum Lour., is a plant species endemic to tropical South East Asia with particular medicinal importance. However, very little analysis in this plant has been studied up to now from a phytochemical viewpoint. One new amide alkaloid (wuchuyuamide V, 1), as well as two known amide alkaloids-wuchuyuamide III (2), and wuchuyuamide I (3) were obtained from the fruits of T. trichotomum for the first time. The structures of wuchuyuamide V (1) and wuchuyuamide III (2) were unambiguously elucidated by 1D and 2D-NMR spectra, mass spectrometry, and single-crystal X-ray diffraction.

4.
Angew Chem Int Ed Engl ; 59(4): 1711-1717, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31763728

RESUMO

Functional coatings are of considerable interest because of their fundamental implications for interfacial assembly and promise for numerous applications. Universally adherent materials have recently emerged as versatile functional coatings; however, such coatings are generally limited to catechol, (ortho-diphenol)-containing molecules, as building blocks. Here, we report a facile, biofriendly enzyme-mediated strategy for assembling a wide range of molecules (e.g., 14 representative molecules in this study) that do not natively have catechol moieties, including small molecules, peptides, and proteins, on various surfaces, while preserving the molecule's inherent function, such as catalysis (≈80 % retention of enzymatic activity for trypsin). Assembly is achieved by in situ conversion of monophenols into catechols via tyrosinase, where films form on surfaces via covalent and coordination cross-linking. The resulting coatings are robust, functional (e.g., in protective coatings, biological imaging, and enzymatic catalysis), and versatile for diverse secondary surface-confined reactions (e.g., biomineralization, metal ion chelation, and N-hydroxysuccinimide conjugation).

5.
Angew Chem Int Ed Engl ; 59(1): 275-280, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31646700

RESUMO

The manipulation of interfacial properties has broad implications for the development of high-performance coatings. Metal-phenolic networks (MPNs) are an emerging class of responsive, adherent materials. Herein, host-guest chemistry is integrated with MPNs to modulate their surface chemistry and interfacial properties. Macrocyclic cyclodextrins (host) are conjugated to catechol or galloyl groups and subsequently used as components for the assembly of functional MPNs. The assembled cyclodextrin-based MPNs are highly permeable (even to high molecular weight polymers: 250-500 kDa), yet they specifically and noncovalently interact with various functional guests (including small molecules, polymers, and carbon nanomaterials), allowing for modular and reversible control over interfacial properties. Specifically, by using either hydrophobic or hydrophilic guest molecules, the wettability of the MPNs can be readily tuned between superrepellency (>150°) and superwetting (ca. 0°).

6.
Bioorg Chem ; 94: 103392, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669093

RESUMO

The key functions of microtubules and the mitotic spindle in cell division make them attractive targets for cancer therapy. In this study, a series of 1-(benzofuran-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole derivatives was synthesized, and their antiproliferative activities against HCT116, HeLa, HepG2, and A549 cells were evaluated. 6-Methoxy-N-phenyl-3-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)benzofuran-2-carboxamide (17g) exhibited the strongest antiproliferative activities, with IC50 values ranging from 0.57 to 5.7 µM. Mechanistic studies showed that 17g inhibited tubulin polymerization, leading to the disruption of mitotic spindle formation, cell cycle arrest in the G2/M phase, and apoptosis of A549 cells. A docking study indicated that 17g was a good molecular fit at the colchicine binding site of tubulin. These results showed that 17g is a potential anticancer compound that is worthy of further development as a tubulin polymerization inhibitor.

7.
J Ovarian Res ; 12(1): 118, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783885

RESUMO

Ovarian cancer (OC) is a type of gynaecological malignancy with high mortality in females. Serous ovarian cancer (SOC) is a distinct subtype of OC with poor early diagnosis. Given the limitations of traditional therapies, such as chemotherapy, targeted treatment is therefore a promising therapy to improve the survival rate of SOC patients. Cyclophilin A (CYPA) is a member of Cyclophilin family and thought to participates in multiple cellular processes such as cell transduction and immune modulation. Recently, various of studies indicated that CYPA has critical impact on cancer progression. CYPA could regulate cell proliferation, invasion, and chemoresistance of multiple types of cancers. However, it is still unclear whether it could affect ovarian cancer. In this study, we demonstrated that CYPA was highly expressed in SOC tissues compared with adjacent tissues. Further, CYPA was significantly associated with clinical stage and lymphnode metastasis of SOC patients. Additionally, data indicated that knockdown of CYPA by its shRNA dramatically reduces migration and invasion capacity of SOC cells in vitro and blocks tumor metastasis in vivo. Our study investigates the involvement of CYPA in the progression and metastasis of SOC, and therefore provides CYPA as a promising therapeutic target for SOC treatment.

8.
Mediators Inflamm ; 2019: 6248197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827377

RESUMO

During organ culture of intact vessels, endothelin receptors (ETRs) were upregulated in vascular smooth muscle cells (VSMCs) by various stimuli, but whether inflammation alters ETR expression in vivo remains unclear. We aimed to explore the effects of lipopolysaccharide (LPS) challenge on ETR expression in the VSMC in vivo. Male Sprague-Dawley rats received a single intraperitoneal injection of LPS (5 mg/kg body weight) or normal saline (NS) for 6 hrs. The function and expression of ETR type A (ETA) and type B (ETB) were evaluated in the mesenteric arteries without endothelium, by using myograph system, real-time quantitative PCR, Western blot, and immunohistochemical staining, respectively. Serum tumor necrosis factor-α (TNF-α) level was assessed by using enzyme-linked immunosorbent assay. The results showed that, compared to control (NS) group, LPS treatment potently enhanced the vasoconstriction mediated by ETA or ETB in rat mesenteric artery, with elevated maximum effects. ETA and ETB expressions in the VSMC were increased at both mRNA and protein levels after LPS treatment, paralleled with activation of the NF-κB pathway and augmented serum TNF-α level. Conclusively, in the rat model of immediate systemic inflammation induced by LPS, ETA and ETB expressions were increased in the mesenteric arterial VSMC, paralleled with enhanced receptor-mediated vasoconstriction and activation of the NF-κB pathway. Our data has for the first time demonstrated the upregulation of ETRs in VSMCs by LPS-induced immediate inflammation in vivo.

9.
J Asian Nat Prod Res ; : 1-16, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31833411

RESUMO

Chrysin amino acid derivatives were synthesized to evaluate for their antiproliferative activities. Among them, N-(7-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)valeryl)-L-leucine (8c) displayed the most remarkable inhibitory activities against MCF-7 cells with IC50 values of 16.6 µM. Preliminary mechanistic studies showed that 8c could inhibit the colony formation and migration of MCF-7 cells. Flow cytometry analysis demonstrated that 8c mediated cell apoptosis and the prolongation of cell cycle progression in G1/S-phase against MCF-7 cells. Besides, 8c displayed the moderate inhibition against EGFR. Western blot assay suggested that 8c significantly inhibited EGFR phosphorylation. Molecular docking showed that 8c can bind the EGFR kinase well.

10.
ACS Nano ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31715098

RESUMO

Single-molecule magnets (SMMs), exhibiting magnetic bistability and a large energy barrier to the magnetization relaxation, are attractive candidates for realizing efficient spintronic devices such as ultra-high-density memories and quantum computers. Here, we demonstrate robust spin-polarization of a quintessential SMM, the double-decker bis(phthalocyaninato)terbium(III) (TbPc2) molecules, adsorbed on the bilayer Co islands on Au(111) using spin-polarized scanning tunneling microscopy, visualizing the switching of the SMM spin with submolecular resolution. Our results reveal that molecular spins of TbPc2 are antiferromagnetically coupled to the magnetization of the Co island, irrespective of the bonding configuration of the molecule. Stable spin-polarization is inferred from the substantial hysteresis observed in the magnetization curves measured over the molecules. This is in contrast to the reports of near-zero remanence for the bulk TbPc2 crystals and the TbPc2 molecules on a nonmagnetic substrate. The observation of a significant hysteretic opening can be attributed to the large magnetic anisotropy barrier of the molecule and the suppression of the quantum tunneling process. We anticipate that our approach of using the substrate to control and enhance the properties of a TbPc2 SMM will accelerate further research toward realization of SMM-based functional spintronic devices.

11.
Adv Sci (Weinh) ; 6(21): 1901846, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31728297

RESUMO

Droplet bouncing on repellent solid surfaces (e.g., the lotus leaf effect) is a common phenomenon that has aroused interest in various fields. However, the scenario of a droplet bouncing off another droplet (either identical or distinct chemical composition) while moving on a solid material (i.e., ricocheting droplets, droplet billiards) is scarcely investigated, despite it having fundamental implications in applications including self-cleaning, fluid transport, and heat and mass transfer. Here, the dynamics of bouncing collisions between liquid droplets are investigated using a friction-free platform that ensures ultrahigh locomotion for a wide range of probing liquids. A general prediction on bouncing droplet-droplet contact time is elucidated and bouncing droplet-droplet collision is demonstrated to be an extreme case of droplet bouncing on surfaces. Moreover, the maximum deformation and contact time are highly dependent on the position where the collision occurs (i.e., head-on or off-center collisions), which can now be predicted using parameters (i.e., effective velocity, effective diameter) through the concept of an effective interaction region. The results have potential applications in fields ranging from microfluidics to repellent coatings.

12.
Pest Manag Sci ; 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31762173

RESUMO

BACKGROUD: Volatile terpenes can act as ecological signals to affect insect behavior. It has been proposed that the manipulation of terpenes in plants can help to control herbivore pests. In order to investigate the potential pest management function of (E)-ß-caryophyllene in cotton plants, the (E)-ß-caryophyllene synthase gene (GhTPS1) was inserted into Gossypium hirsutum variety R15 to generate overexpression lines. RESULTS: Four GhTPS1-transgenic lines were generated, and GhTPS1 expression in transgenic L18 and L46 lines was 3-5-fold higher than in R15 plants. The transgenic L18 and L46 lines also emitted significantly more (E)-ß-caryophyllene than R15. In laboratory bioassays, L18 and L46 plants reduced pests Apolygus lucorum, Aphis gossypii and Helicoverpa armigera, and attracted parasitoids Peristenus spretus and Aphidius gifuensis, but not Microplitis mediator. In open-field trials, L18 and L46 plants reduced A. lucorum, Adelphocoris suturalis and H. armigera, but had no significant effects on predators. CONCLUSION: Our findings suggest that L18 and L46 plants reduce several major hemipteran and lepidopteran cotton pests, whereas, two parasitoids P. spretus and A. gifuensis, were attracted by L18 and L46 plants. This study shows that overexpressing GhTPS1 in cotton may help to improve pest management in cotton fields. © 2019 Society of Chemical Industry.

13.
Medicine (Baltimore) ; 98(39): e17180, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574824

RESUMO

BACKGROUND: ATPase family, AAA+ domain containing 2 (ATAD2) is also known as AAA+ nuclear coregulator cancer-associated protein or PRO2000. ATAD2 has been reported as a prognostic factor in different cancer types, but the association between ATAD2 high expression and survival is still unclear. Thereby, this meta-analysis was performed to evaluate the prognostic value of ATAD2 high expression in human cancers. METHODS: All of the studies included were retrieved from PubMed, EMBASE, and Cochrane Library electronic databases. The clinical outcomes were evaluated by calculating hazard ratio (HR) with their 95% confidence interval (CI). RESULTS: Thirteen studies including 2689 patients were eligible for this analysis. The pooled results showed that ATAD2 over-expression was significantly associated with shorter overall survival (OS) (HR = 2.32, 95% CI = 1.77-3.02), as well as shorter recurrence-free survival (RFS), disease-free survival (DFS), and disease-specific survival (DSS) (HR = 1.83, 95% CI = 1.51-2.23) among human cancers. Subgroup analyses for OS were implemented in terms of region, tumor type, and sample size and the results were coincident with overall pooled results. Begg funnel plot and Egger test showed the presence of publication bias for OS. Sensitivity analysis indicated that both results were not affected for removing any study. CONCLUSION: ATAD2 would be likely to act as a prognostic biomarker for the patients of different cancer types and provide a guide on clinical treatment. Prospective clinical studies are needed to support these findings.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/análise , Adenosina Trifosfatases/análise , Proteínas de Ligação a DNA/análise , Neoplasias/enzimologia , Neoplasias/mortalidade , Intervalo Livre de Doença , Humanos , Prognóstico , Modelos de Riscos Proporcionais
14.
Sensors (Basel) ; 19(19)2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569346

RESUMO

An optical waveguide (OWG) sensor was developed for real-time detection of diethyl chlorophosphate (DCP) vapor, which is a typical simulant for organophosphorus pesticides and chemical weapon agents. Silica gel, crystal violet (CV), and potassium ion-exchange (PIE) OWG were used to fabricate the sensor's device. In the real-time detection of the DCP vapor, the volume fraction of DCP vapor was recorded to be as low as 1.68 × 10-9. Moreover, the detection mechanism of CV-SiO2 gel film coated the PIE OWG sensor for DCP, which was evaluated by absorption spectra. These results demonstrated that the change of output light intensity of the OWG sensor significantly increased with the augment of the DCP concentration. Repeatability as well as selectivity of the sensors were tested using 0.042 × 10-6 and 26.32 × 10-6 volume fraction of the DCP vapor. No clear interference with the DCP detection was observed in the presence of other common solvents (e.g., acetone, methanol, dichloromethane, dimethylsulfoxide, and tetrahydrofuran), benzene series (e.g., benzene, toluene, chlorobenzene, and aniline), phosphorus-containing reagents (e.g., dimethyl methylphosphonate and trimethyl phosphate), acid, and basic gas (e.g., acetic acid and 25% ammonium hydroxide), which demonstrates that the OWG sensor could provide real-time, fast, and accurate measurement results for the detection of DCP.

15.
J Am Chem Soc ; 141(45): 17995-17999, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31647653

RESUMO

Hydrogen is regarded as an attractive alternative energy carrier due to its high gravimetric energy density and only water production upon combustion. However, due to its low volumetric energy density, there are still some challenges in practical hydrogen storage and transportation. In the past decade, using chemical bonds of liquid organic molecules as hydrogen carriers to generate hydrogen in situ provided a feasible method to potentially solve this problem. Research efforts on liquid organic hydrogen carriers (LOHCs) seek practical carrier systems and advanced catalytic materials that have the potential to reduce costs, increase reaction rate, and provide a more efficient catalytic hydrogen generation/storage process. In this work, we used methanol as a hydrogen carrier to release hydrogen in situ with the single-site Pt1/CeO2 catalyst. Moreover, in this reaction, compared with traditional nanoparticle catalysts, the single site catalyst displays excellent hydrogen generation efficiency, 40 times higher than 2.5 nm Pt/CeO2 sample, and 800 times higher compared to 7.0 nm Pt/CeO2 sample. This in-depth study highlights the benefits of single-site catalysts and paves the way for further rational design of highly efficient catalysts for sustainable energy storage applications.

16.
Oncol Lett ; 18(4): 3792-3802, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31579409

RESUMO

The present study focused on exploring the inhibitory mechanism of microRNA (miR)-23a in endometrial cancer. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to investigate miR-23a expression in endometrial tissues and endometrial cancer cells. A colony formation assay using crystal violet staining was performed to compare cell proliferation, while wound-healing and Transwell assays were performed to compare cell migration and invasion. Subsequently, bioinformatics and a luciferase reporter gene assay were used to investigate the effect of miR-23a on sine oculis homeobox homolog 1 (SIX1) expression, and the biological function of SIX1 was analyzed. Additionally, a nude mouse tumorigenicity assay was performed to test the inhibitory effect of miR-23a and Taxol® therapy in endometrial cancer. Finally, immunohistochemistry and RT-qPCR were used to explore the association between miR-23a and SIX1 expression in endometrial cancer tissues. miR-23a was underexpressed in endometrial cancer tissues compared with in para-carcinoma tissues, and the overexpression of miR-23a inhibited proliferation and invasion of endometrial cancer cells. Furthermore, SIX1 was demonstrated to be a downstream target of miR-23a, and miR-23a reduced SIX1 expression. Additionally, SIX1 inversely promoted cell proliferation, migration and invasion. In addition, the effects of reduced cell proliferation and increased cell invasion following miR-23a overexpression could be reversed by adding SIX1 to in vitro culture. Furthermore, the inhibitory effect of miR-23a and Taxol therapy, which reduced SIX1 expression in endometrial cancer, was demonstrated in vivo. Finally, a negative association between miR-23a and SIX1 expression was demonstrated in endometrial cancer tissues. The results of the present study revealed that miR-23a may inhibit endometrial cancer development by targeting SIX1.

17.
Surg Oncol ; 31: 67-74, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31541909

RESUMO

The molecular mechanisms governing the metastasis of colorectal cancer (CRC) are incompletely understood. In the present study, we found NOVA1 to be expressed at higher levels in CRC cell lines and tissue samples, and this upregulation was positively correlated with TNM stage (p = 0.034), poor differentiation (p = 0.001), and lymph node metastasis (p = 0.008). Both overall survival (OS) and relapse-free survival (RFS) were both significantly decreased in patients with high NOVA1 expression relative to those with low expression. Through a multivariate analysis, we determined that NOVA1 independently predicted poor outcomes in those with CRC. In further functional studies, we found that NOVA1 expression controlled the proliferation and invasive characteristics of CRC cells via a mechanism wherein NOVA1 bound and stabilized the IL6 mRNA, enhancing IL-6/JAK2/STAT3 signaling to in turn upregulate matrix metalloproteinases (MMPs) 2, 7, and 9. NOVA1 therefore plays key functional roles in regulating CRC progression, and our results further indicate that it serve as a valuable prognostic biomarker and potentially a target for therapeutic treatment in individuals with CRC.

18.
Appl Opt ; 58(25): 6942-6948, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31503666

RESUMO

A colorful surface plasmon resonance imaging (SPRi) sensor with the hue-based enhanced sensitivity has been developed by using sputtered AuAg alloy thin film as the sensing layer. The condition for optimizing the hue-based sensitivity of the SPRi sensor was achieved, that is, the initial resonance wavelength is in the range from 595 to 610 nm. Under this condition, the hue-based refractive index sensitivity of the SPRi sensor was measured as high as Δhue/Δnc=29879/RIU. This sensitivity is 8 times higher than that obtained with a gold-layer SPRi sensor (Δhue/Δnc=3658/RIU) and 7.7 times as high in magnitude as the spectral sensitivity of the same sensor (ΔλR/Δnc=3897.6 nm/RIU). After functionalization of the AuAg alloy film with the monoclonal antibody, the sensor was used for quantitative immunodetection of highly carcinogenic benzo[a]pyrene (BaP) in water. According to the experimental results, the average hue of the SPR color image (300 pixels×300 pixels) experiences an initial rapid increase and then stabilizes 15 min after exposure of the functionalized AuAg alloy film to an aqueous BaP solution sample. The variation of average hue obtained at the equilibrium of surface immunoreaction is a linear function of BaP concentration with the slope being Δhue/Δc=132.2/(µg·L-1). A cooled CCD camera is able to distinguish a change of Δhue=1, offering the colorful SPRi sensor the BaP detection limit of 0.01 µg·L-1. The comparative measurements of the sensor's responses indicate that the hue variation obtained with 0.1 µg·L-1 of BaP is equal to that obtained either with 5 µg·L-1 of benzanthracene or with 5 µg·L-1 of benzofluoranthene, revealing the sensor's excellent specificity to BaP. The work demonstrated that the AuAg alloy film-based colorful SPRi sensor can be used not only for visualized analysis of molecular interaction at the surface but also for quantitative trace detection of small-molecule analytes.

19.
Biomacromolecules ; 20(9): 3425-3434, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31411865

RESUMO

Supraparticles (SPs) assembled from smaller colloidal nanoparticles can serve as depots of therapeutic compounds and are of interest for long-term, sustained drug release in biomedical applications. However, a key challenge to achieving temporal control of drug release from SPs is the occurrence of an initial rapid release of the loaded drug (i.e., "burst" release) that limits sustained release and potentially causes burst release-associated drug toxicity. Herein, a biocoating strategy is presented for silica-SPs (Si-SPs) to reduce the extent of burst release of the loaded model protein lysozyme. Specifically, Si-SPs were coated with a fibrin film, formed by enzymatic conversion of fibrinogen into fibrin. The fibrin-coated Si-SPs, FSi-SPs, which could be loaded with 7.9 ± 0.9 µg of lysozyme per SP, released >60% of cargo protein over a considerably longer period of time of >20 days when compared with the uncoated Si-SPs that released the same amount of the cargo protein, however, within the first 3 days. Neurotrophins that support the survival and differentiation of neurons could also be loaded at ∼7.3 µg per SP, with fibrin coating also delaying neurotrophin release (only 10% of cargo released over 21 days compared with 60% from Si-SPs). In addition, the effects of incorporating a hydrogel-based system for surgical delivery and the opportunity to control drug release kinetics were investigated-an alginate-based hydrogel scaffold was used to encapsulate FSi-SPs. The introduction of the hydrogel further extended the initial release of the encapsulated lysozyme to ∼40 days (for the same amount of cargo released). The results demonstrate the increasing versatility of the SP drug delivery platform, combining large loading capacity with sustained drug release, that is tailorable using different modes of controlled delivery approaches.

20.
Genes Dev ; 33(17-18): 1191-1207, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371435

RESUMO

The vast majority of eukaryotes possess two DNA recombinases: Rad51, which is ubiquitously expressed, and Dmc1, which is meiosis-specific. The evolutionary origins of this two-recombinase system remain poorly understood. Interestingly, Dmc1 can stabilize mismatch-containing base triplets, whereas Rad51 cannot. Here, we demonstrate that this difference can be attributed to three amino acids conserved only within the Dmc1 lineage of the Rad51/RecA family. Chimeric Rad51 mutants harboring Dmc1-specific amino acids gain the ability to stabilize heteroduplex DNA joints with mismatch-containing base triplets, whereas Dmc1 mutants with Rad51-specific amino acids lose this ability. Remarkably, RAD-51 from Caenorhabditis elegans, an organism without Dmc1, has acquired "Dmc1-like" amino acids. Chimeric C. elegans RAD-51 harboring "canonical" Rad51 amino acids gives rise to toxic recombination intermediates, which must be actively dismantled to permit normal meiotic progression. We propose that Dmc1 lineage-specific amino acids involved in the stabilization of heteroduplex DNA joints with mismatch-containing base triplets may contribute to normal meiotic recombination.


Assuntos
Aminoácidos/metabolismo , Rad51 Recombinase/química , Rad51 Recombinase/metabolismo , Recombinases/química , Recombinases/metabolismo , Recombinação Genética/genética , Aminoácidos/genética , Animais , Pareamento Incorreto de Bases , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Sequência Conservada , Mutação , Rad51 Recombinase/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Recombinases/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
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