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1.
Aging (Albany NY) ; 112019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31721726

RESUMO

Cellular senescence is a well-established defensive mechanism for tumor suppression, and is also proposed to play a crucial role in embryonic development, wound repair, aging and age-related diseases. Senescent cell is characterized by the marked morphological changes and active metabolism along with a distinctive senescence associated secretion phenotype (SASP). Cellular senescence is triggered by multiple endogenous and exogenous stressors, which collectively induce three types of senescence. It is believed that senescence represents a programmed phenomenon to facilitate ß cell functional maturation and, therefore, senescence has been suggested to be involved in ß cell regeneration, insulin secretion and diabetes development. Nevertheless, despite past extensive studies, the exact impact of senescence on ß cell viability, regeneration and functionality, and its relevance to the development of diabetes are yet to be fully addressed. In this review, we will summarize the recent progress in ß cell senescence, through which we intend to spark more instructive discussion and perspective with regard to the mechanisms underlying ß cell senescence and their links to the pathogenesis of diabetes and the development of therapeutic strategies.

2.
Nat Commun ; 10(1): 4860, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649273

RESUMO

Membrane fouling is a considerable challenge for the stable operation of anaerobic membrane-based bioreactors. Membrane used as a cathode is a common measure to retard fouling growth in anaerobic electrochemical membrane bioreactors (AnEMBR), which; however, cannot avoid the fouling growth. Here we report a strategy using the membrane as an anode to resist membrane fouling in an AnEMBR. Although aggravating in the initial stage, the fouling on the anode membrane is gradually alleviated by the anode oxidation with enriching exoelectrogens to finally achieve a dynamic equilibrium between fouling growth and decomposition to maintain the operation stable. A mesh-like biofilter layer composed of cells with less extracellular polymeric substance (EPS) is formed on the membrane surface to lower the trans-membrane pressure and promote the interception of the anode membrane. The membrane has high electron storage and transfer capacities to accelerate the oxidation of the intercepted fouling materials, especially, the redundant EPSs of the biofilter layer.

3.
Fungal Genet Biol ; 133: 103282, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31629081

RESUMO

Candida albicans is an important opportunistic fungal pathogen, and hyphal polarized growth is critical for its invasive infection to the host. Both the vacuolar transient receptor potential (TRP) Ca2+ channel Yvc1 and the NADPH oxidase Fre8-governed reactive oxygen species (ROS) gradient are involved in hyphal development, but the relationship between Yvc1 and Fre8 during hyphal polarized growth remains to be investigated. Herein, we found that deletion of YVC1 led to dispersed distribution of ROS along the germ tube, while it was concentrated at the hyphal tip in WT cells. Moreover, Fre8 localization was altered as YVC1 was disrupted. Besides, similar to deletion of YVC1, addition of the Ca2+ chelating agent EGTA caused depolarization of Fre8-GFP in the wild-type cells, indicating the critical role of Yvc1-maintained Ca2+ gradient in polarized distribution of Fre8-GFP and consequent disruption of tip ROS gradient. By constructing a series of GFP-tagged polarized growth-related proteins, including Bud6, Exo70 and Lifeact, we found that these proteins, similar to Fre8 and ROS, had depolarized localization in yvc1Δ/Δ. Thus, our work provides a mechanic explanation of Yvc1-governed and ROS-related hyphal polarized growth, and shed a novel light on the role of Ca2+ signaling in maintenance of redox homeostasis and morphogenesis in the fungal pathogens.

4.
Mycopathologia ; 184(5): 573-583, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473908

RESUMO

Candida albicans is one of the most important fungal pathogens. Hyphal development is required for the virulence of this pathogen. Our previous study has revealed that Spf1, an ER P-type calcium pump, plays an important role in hyphal development. However, the detailed mechanisms by which this protein functions in this process remain to be investigated. In this study, we found that loss of Spf1 led to decreased growth biomass under the hypha-inducing condition, suggesting a role of this protein in maintaining hyphal growth rate. Actin staining further revealed that the spf1Δ/Δ mutant showed attenuated tip-localization of actin patches and the defect in transport of both the chitin synthase Chs3 and the hypha-related factor Hwp1, implying that Spf1 functions in polarized growth of the hyphae by regulating actin organization and consequent polarized transport of morphogenesis-associated factors. Moreover, deletion of SPF1 led to abnormal vacuolar morphology under the hypha-inducing condition, which may also contribute to the defect of hyphal development in the spf1Δ/Δ mutant. This study revealed the pleiotropic role of Spf1-regulated calcium homeostasis in controlling hyphal development in C. albicans.

5.
Chemistry ; 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31539175

RESUMO

Water splitting as a greatly desired technology to produce clean renewable energy, but is hampered by the sluggish oxygen evolution reaction. So, the development of highly active and durable water oxidation electrocatalysts is of primarily significance for energy conversion. Here, a facial strategy to synthesize FeCoNi nanohybrids with adjustable morphological structures by using fluorine is introduced. The morphology and electrocatalytic activity of the sample is determined by the innovative introduction of fluorine. Among them, the overpotential at 10 mA cm-2 of the best sample is approximately 97 mV lower than the commercial RuO2 toward the oxygen evolution reaction in 1 m KOH. Additionally, the catalysts also have low Tafel slopes and remarkable stability.

6.
Chem Commun (Camb) ; 55(81): 12200-12203, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31549132

RESUMO

ß-Cyclodextrin (CD)-grafted graphene oxide (GO) is an emerging drug carrier for human diseases therapy. Herein, we report two-dimensional nano-supramolecular assemblies to specifically target and disrupt tumor cell mitochondria in a photocontrollable manner. Moreover, the nanoassemblies displayed extremely high near-infrared-induced photothermal efficiency.

7.
Mol Immunol ; 114: 314-322, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442915

RESUMO

Hematopoietic development occurs in the bone marrow, and this process begins with hematopoietic stem cells (HSCs). Ubc9 is a unique E2-conjugating enzyme required for SUMOylation, an evolutionarily conserved post-translational modification system. We herein show that a conditional Ubc9 deletion in the hematopoietic system caused decreased thymus weight and reduced lymphocyte to myeloid cell ratio. Importantly, Ubc9 deletion in the hematopoietic system only selectively impaired the development of common lymphoid progenitors (CLPs) in the bone marrow and perturbed their potential to differentiate into lymphocytes, thereby decreasing the number of T/B cells in the periphery. Ubc9 was found to be required for CLP viability, and therefore, Ubc9 deficiency rendered CLPs to undergo apoptosis and attenuated their proliferation. Thus, Ubc9 plays a critical role in the regulation of CLP function during hematopoietic development in the bone marrow.

8.
Bioresour Technol ; 291: 121858, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31377515

RESUMO

The improved performances during anaerobic degradation of phenol to methane with Fe(OH)3 were usually inapparent, due to its lower solubility (unaccessible to dissimilatory iron reduction) and more positive reduction potential of Fe(III)/Fe(II) (unfavorable for enriching Fe(III)-reducing bacteria [IRBs]). In this study, citrate, the organic chelates, were used to solubilize Fe(III) with the aim of improving the phenol degradation and declining the reduction potential of Fe(III)/Fe(II). Results showed that, in the co-occurrence of citrate and Fe(OH)3, the degradation rates of phenol were about 1.3-fold rapider than that with sole Fe(OH)3. Analysis of cyclic voltammetry demonstrated that the reduction potential of Fe(III)/Fe(II) in the form of Fe(OH)3 (-0.41 to -0.28 V vs Ag/AgCl) declined to -0.61 to -0.41 V. As a result, the Fe(III)-reducing genera, such as Petrimonas and Shewanella, which held a great potential of proceeding syntrophic metabolism via direct interspecies electron transfer (DIET), were significantly enriched.


Assuntos
Quelantes/farmacologia , Compostos Férricos/metabolismo , Ferro/metabolismo , Metano/metabolismo , Fenol/metabolismo , Anaerobiose , Bacteroides/efeitos dos fármacos , Bacteroides/metabolismo , Transporte de Elétrons , Oxirredução , Fenóis/metabolismo , Shewanella/efeitos dos fármacos , Shewanella/metabolismo
9.
Biochem Biophys Res Commun ; 516(4): 1152-1158, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31284951

RESUMO

Candida albicans is an important opportunistic pathogenic fungus in the human body. It is a common microbe inhabiting on the mucosa surfaces of healthy individuals, but may cause infections when the host immune system is weak. Autophagy is a "self-eating" process in eukaryotes, which can recover and utilize damaged organelles and misfolded proteins. Here we investigated the role of the autophagy-related protein Atg11 in C. albicans. Deletion of ATG11 led to the defect in growth under the nitrogen starvation condition. Western blotting and GFP localization further revealed that the transport and degradation of Atg8 was blocked in the atg11Δ/Δ mutant under both the nitrogen starvation and hypha-inducing conditions. Moreover, degradation of both Lap41 (the indicator of the cytoplasm-to-vacuole pathway) and Csp37 (the indicator of mitophagy) was also thoroughly suppressed in this mutant under nitrogen starvation. These results indicated that Atg11 plays an essential role in both non-selective and selective autophagy in C. albicans.

10.
Angew Chem Int Ed Engl ; 58(31): 10553-10557, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31165539

RESUMO

Tunable protein assemblies not only hold a dominant position in vital biological events but are also a significant theme in supramolecular chemistry. Herein, we demonstrated that the intertubular aggregation of microtubules (MTs) could be efficiently regulated by a synergistic polypeptide-tubulin interaction and host-guest complexation. The benzylimidazolium-modified antimitotic peptide (BP) could recognize the MTs and concurrently form stable inclusion complexes with avirulent cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) in different binding stoichiometries. The self-assembling morphology of MTs was converted from fibrous to nanoparticulate aggregates via extensive BP⊂CB[8] cross-linkage, leading to significant cell apoptosis and tumor ablation in vivo. The targeted (BP⊂CB[8])@MT ternary assembly provides a facile supramolecular method to enhance the protein-protein interactions, which may be developed as a therapy for degenerative diseases, such as cancer.

11.
Chem Commun (Camb) ; 55(56): 8138-8141, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31240296

RESUMO

A 2D polypseudorotaxane-type assembly was constructed using cucurbit[8]uril and styrylpyridinium-bearing triphenylamine. In addition, tunable non-covalent to covalent transition was achieved by [2+2] photodimerization of styrylpyridinium units. Thus, a more stable 2D polyrotaxane-type nanoarchitecture was obtained, which could capture [60]fullerene and further exhibit an excellent photodynamic therapy effect.

12.
iScience ; 15: 223-233, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31079026

RESUMO

Biofunctional supramolecular assemblies that combine macrocyclic receptors and amphiphiles are potent drug delivery systems, but optimization and implementation challenges remain. We herein describe a cooperative drug displacement strategy exemplified by the use of cyclodextrin-liposome supramolecular nanoassemblies as a therapy for acute liver injury. The hepatoprotective drug silibinin was solubilized in phosphotyramine-modified ß-cyclodextrin, and subsequent encapsulation of the silibinin-cyclodextrin complex in phosphatidylcholine liposomes gave uniformly sized and stable nanoassemblies that accumulated preferentially in the liver of mice. Enzymatic cleavage of the phosphate ester of the ß-cyclodextrin resulted in rapid release of the encapsulated silibinin. Significantly, silibinin could be readily displaced by cytotoxic bile acids, thus leading to the removal of excess bile acids from the bodies of mice and the recovery of liver function. Our results demonstrate that cyclodextrin-based nanoassemblies with a dual role of solubilizing a drug and removing toxins constitute a promising therapy for hepatic injury.

13.
Chem Commun (Camb) ; 55(30): 4343-4346, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30911744

RESUMO

A carbazole derivative (G) was synthesized as a photosensitizer to complex with cucurbit[8]uril, resulting in a nanocube with emission at 662 nm for lysosome cell imaging. Furthermore, the alkyl chain on G was included by α-cyclodextrine-modified hyaluronic acid for further assembly, affording a system targeted to cancer cells.


Assuntos
Carbazóis/química , Compostos Macrocíclicos/química , Imagem Molecular/métodos , Polissacarídeos/química , Células HEK293 , Humanos , alfa-Ciclodextrinas/química
14.
Chem Commun (Camb) ; 55(21): 3148-3151, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30801078

RESUMO

Supramolecular assembly with tumor-targeting properties or photodynamic therapy (PDT) ability has recently become a focus of interest in biomaterial field because of its high therapeutic efficacy against tumor cells. Herein, we reported a new type of targeted supramolecular nanoparticles for photodynamic therapy of tumor cells constructed using adamantane-functionalized transferrin protein (Ad-TRF) and a ß-cyclodextrin-functionalized ruthenium complex (Ru-HOP-CD), wherein Ad-TRFs acted as the targeted sites for tumor cells, the coordinated Ru(ii) centers acted as the PDT active sites, and the biocompatible polysaccharide ß-cyclodextrins acted as the non-covalent linkers. Significantly, the resultant Ru/polysaccharide/protein exhibited not only specific targeting properties towards tumor cells but also high PDT ability under the irradiation of visible light. Furthermore, the assembly showed selective killing towards tumor cells along with negligible toxicity towards normal cells.


Assuntos
Adamantano/análogos & derivados , Complexos de Coordenação/administração & dosagem , Sistemas de Liberação de Medicamentos , Fármacos Fotossensibilizantes/administração & dosagem , Rutênio/administração & dosagem , Transferrina/análogos & derivados , beta-Ciclodextrinas/química , Células A549 , Linhagem Celular , Complexos de Coordenação/farmacologia , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Rutênio/farmacologia
15.
Ecotoxicol Environ Saf ; 167: 301-308, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30343144

RESUMO

Cerium oxide (CeO2) nanomaterials (NMs) have wide applications in biomedicine and are also detected with increasing bioaccumulation in various biological and environmental media. Thus, a system was developed to evaluate the chemosensitization effect of CeO2 NMs. Herein, we discovered that low doses of CeO2 NMs could trigger reactive oxygen species (ROS) production and decrease mitochondrial membrane potential (MMP) without causing severe toxicity to cancer cells, while pretreatment of the cells with CeO2 NMs enhanced the toxicity of the chemotherapeutic agent doxorubicin (DOX). The reduced efflux of DOX was mainly attributed to adenosine triphosphate (ATP) depletion, followed by attenuation of exocytosis and enhancement of DOX retention. Further investigations revealed that CeO2 NM-induced ROS production caused depletion of intracellular glutathione (GSH) and consequent impairment of DOX detoxification. Moreover, CeO2 NMs were found to enhance the chemosensitization of cancer cells rather than normal cells. Thus, this study uncovered the underlying application potential of CeO2 NMs in cancer therapy by enhancing the efficacy of chemotherapeutic agent, which is associated with disruption of mitochondrial function and impairment of drug detoxification.


Assuntos
Cério/farmacologia , Inativação Metabólica , Nanoestruturas/química , Células A549 , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Glutationa/metabolismo , Humanos , Potencial da Membrana Mitocondrial , Ratos , Espécies Reativas de Oxigênio/metabolismo
16.
Biophys J ; 115(10): 2003-2013, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30389091

RESUMO

Actomyosin contractility regulates various biological processes, including cell migration and cytokinesis. The cell cortex underlying the membrane of eukaryote cells exhibits dynamic contractile behaviors facilitated by actomyosin contractility. Interestingly, the cell cortex shows reversible aggregation of actin and myosin called "pulsed contraction" in diverse cellular phenomena, such as embryogenesis and tissue morphogenesis. Although contractile behaviors of actomyosin machinery have been studied extensively in several in vitro experiments and computational studies, none of them successfully reproduced the pulsed contraction observed in vivo. Recent experiments have suggested the pulsed contraction is dependent upon the spatiotemporal expression of a small GTPase protein called RhoA. This only indicates the significance of biochemical signaling pathways during the pulsed contraction. In this study, we reproduced the pulsed contraction with only the mechanical and dynamic behaviors of cytoskeletal elements. First, we observed that small pulsed clusters or clusters with fluctuating sizes may appear when there is subtle balance between force generation from motors and force relaxation induced by actin turnover. However, the size and duration of these clusters differ from those of clusters observed during the cellular phenomena. We found that clusters with physiologically relevant size and duration can appear only with both actin turnover and angle-dependent F-actin severing resulting from buckling induced by motor activities. We showed how parameters governing F-actin severing events regulate the size and duration of pulsed clusters. Our study sheds light on the underestimated significance of F-actin severing for the pulsed contraction observed in physiological processes.

17.
Eur J Med Chem ; 162: 348-363, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30448420

RESUMO

Accetohydroxyacid synthase (AHAS) is the first enzyme involved in the biosynthetic pathway of branched-chain amino acids. Earlier gene mutation of Candida albicans in a mouse model suggested that this enzyme is a promising target of antifungals. Recent studies have demonstrated that some commercial AHAS-inhibiting sulfonylurea herbicides exerted desirable antifungal activity. In this study, we have designed and synthesized 68 novel ethoxysulfulron (ES) derivatives and evaluated their inhibition constants (Ki) against C. albicans AHAS and cell based minimum inhibitory concentration (MIC) values. The target compounds 5-1, 5-10, 5-22, 5-31 and 5-37 displayed stronger AHAS inhibitions than ES did. Compound 5-1 had the best Ki of 6.7 nM against fungal AHAS and MIC values of 2.5 mg/L against Candida albicans and Candica parapsilosis after 72 h. A suitable nematode model was established here and the antifungal activity of 5-1 was further evaluated in vivo. A possible binding mode was simulated via molecular docking and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationship. The current study has indicated that some ES derivatives should be considered as promising hits to develop antifungal drugs with novel biological target.

18.
Biochem Biophys Res Commun ; 505(3): 775-780, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30293680

RESUMO

Co3O4 nanoparticles (NPs) are one kind of the important nanomaterials that have the application potential in catalyst, electrochromic devices, sensors, etc. However, their biological effect remains to be detailed. In this study, we investigated the effect of the as-synthesized Co3O4 NPs (15-30 nm) on the growth of mammalian cells, and found that the NPs severely inhibited cell growth at the sublethal concentrations from 12.5 to 200 mg/L. Interestingly, the NPs did not cause obvious cell death and ROS accumulation, indicating that their inhibitory effect was not attributed to both apoptosis- or necrosis-related cell death and ROS accumulation. Transcription profiling analysis revealed that the NPs caused remarkable down regulation of the genes involved in mitochondrial functions. Transmission electron microscopy (TEM) and biochemical analysis further showed that the NPs might interact with the mitochondria, impairing the mitochondrial membrane potential (MMP) and ATP production. This study uncovers a mitochondrial respiratory chain-related and ROS-independent toxicity mechanism of Co3O4 NPs in eukaryotic cells.

19.
Fungal Genet Biol ; 120: 42-52, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30240789

RESUMO

Mitochondria are dynamic organelles, and their shapes and sizes are regulated by mitochondrial fusion and fission. The proteins essential for mitochondrial fusion in Candida albicans have not been clearly characterized. In this study, Mgm1 was explored for its roles in mitochondrial function, cell cycle, hyphal growth and virulence in this pathogen. The deletion of MGM1 led to mitochondrial fragmentation and mtDNA loss and activated the checkpoint pathway to arrest the cell cycle in G1 phase. Moreover, loss of MGM1 led to defects in hyphal development and attenuation of virulence in a macrophage cell line and a mouse model of disseminated infection. These results reveal that Mgm1 plays an important role in mitochondrial dynamics and function, cell cycle progression, hyphal development and virulence in C. albicans.

20.
Sci Adv ; 4(9): eaat2297, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30255143

RESUMO

Supramolecular nanoassemblies that respond to multiple stimuli exhibit high therapeutic efficacy against malignant tumors. We report a new type of supramolecular nanofiber that integrates targeting peptide-coated magnetic nanoparticles with ß-cyclodextrin-bearing polysaccharides in a complex held together by multivalent interactions. The nanofibers not only exhibited reversible photo-triggered association and disassociation depending on irradiation wavelength but also underwent magnetic field-controlled directional aggregation, even in the rather weak geomagnetic field. The nanofibers markedly suppressed invasion by and metastasis of cancer cells both in vitro and in vivo. Furthermore, compared with control mice, tumor-burdened mice treated with the nanofibers showed a lower rate of mortality from the metastatic spread of tumor cells. Our results suggest that these geomagnetism- and photo-controlled nanofibers may facilitate the rapid development of efficacious anticancer therapies.

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