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1.
Autophagy ; 16(2): 347-370, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30983487

RESUMO

Parkinson disease (PD) is an age-related neurodegenerative disorder associated with misfolded SNCA/α-synuclein accumulation in brain. Impaired catabolism of SNCA potentiates formation of its toxic oligomers. LRRK2 (leucine-rich repeat kinase-2) mutations predispose to familial and sporadic PD. Mutant LRRK2 perturbs chaperone-mediated-autophagy (CMA) to degrade SNCA. We showed greater age-dependent accumulation of oligomeric SNCA in striatum and cortex of aged LRRK2R1441G knockin (KI) mice, compared to age-matched wildtype (WT) by 53% and 31%, respectively. Lysosomal clustering and accumulation of CMA-specific LAMP2A and HSPA8/HSC70 proteins were observed in aged mutant striatum along with increased GAPDH (CMA substrate) by immunohistochemistry of dorsal striatum and flow cytometry of ventral midbrain cells. Using our new reporter protein clearance assay, mutant mouse embryonic fibroblasts (MEFs) expressing either SNCA or CMA recognition 'KFERQ'-like motif conjugated with photoactivated-PAmCherry showed slower cellular clearance compared to WT by 28% and 34%, respectively. However, such difference was not observed after the 'KFERQ'-motif was mutated. LRRK2 mutant MEFs exhibited lower lysosomal degradation than WT indicating lysosomal dysfunction. LAMP2A-knockdown reduced total lysosomal activity and clearance of 'KFERQ'-substrate in WT but not in mutant MEFs, indicating impaired CMA in the latter. A CMA-specific activator, AR7, induced neuronal LAMP2A transcription and lysosomal activity in MEFs. AR7 also attenuated the progressive accumulation of both intracellular and extracellular SNCA oligomers in prolonged cultures of mutant cortical neurons (DIV21), indicating that oligomer accumulation can be suppressed by CMA activation. Activation of autophagic pathways to reduce aged-related accumulation of pathogenic SNCA oligomers is a viable disease-modifying therapeutic strategy for PD.Abbreviations: 3-MA: 3-methyladenine; AR7: 7-chloro-3-(4-methylphenyl)-2H-1,4-benzoxazine; CMA: chaperone-mediated autophagy; CQ: chloroquine; CSF: cerebrospinal fluid; DDM: n-dodecyl ß-D-maltoside; DIV: days in vitro; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GWAS: genome-wide association studies; HSPA8/HSC70: heat shock protein 8; KFERQ: CMA recognition pentapeptide; KI: knockin; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LDH: lactate dehydrogenase; LRRK2: leucine-rich repeat kinase 2; MEF: mouse embryonic fibroblast; NDUFS4: NADH:ubiquinone oxidoreductase core subunit S4; NE: novel epitope; PD: Parkinson disease; RARA/RARα: retinoic acid receptor, alpha; SNCA: synuclein, alpha; TUBB3/TUJ1: tubulin, beta 3 class III; WT: wild-type.

2.
ACS Nano ; 14(1): 434-441, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31877250

RESUMO

Maintaining the rapid development of information technology by scaling down a metal-oxide semiconductor field-effect transistor faces two serious challenges. First, the gate field loses control of the channel as it continuously decreases. Second, the fundamental thermionic limit restricts the reduction in supply voltage. Thus, further scaling down necessitates alternative device structures and different switching mechanisms. Here, we report impact-ionization transistors (IITs) based on nanoscale (∼30 nm) vertical graphene/black phosphorus (BP)/indium selenide (InSe) heterostructures. By facilitating the carrier multiplication of the ballistic impact-ionization process as the internal gain mechanism in sub-mean-free-path (sub-MFP) channels, the IITs exhibit a low average subthreshold swing (SS < 1 mV/dec) over five current levels. High stability (>10 000 cycles) and small hysteresis (<1%) switching properties are also obtained. The experimental demonstration of such transistor combining steep SS, high ON-state current density, reliable robustness, miniature footprint, and low bias voltage approaches fulfillments of targets for next-generation devices in the International Technology Roadmap for Semiconductors.

3.
Small ; 16(4): e1905902, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31867892

RESUMO

Semiconducting nanowires offer many opportunities for electronic and optoelectronic device applications due to their unique geometries and physical properties. However, it is challenging to synthesize semiconducting nanowires directly on a SiO2 /Si substrate due to lattice mismatch. Here, a catalysis-free approach is developed to achieve direct synthesis of long and straight InSe nanowires on SiO2 /Si substrates through edge-homoepitaxial growth. Parallel InSe nanowires are achieved further on SiO2 /Si substrates through controlling growth conditions. The underlying growth mechanism is attributed to a selenium self-driven vapor-liquid-solid process, which is distinct from the conventional metal-catalytic vapor-liquid-solid method widely used for growing Si and III-V nanowires. Furthermore, it is demonstrated that the as-grown InSe nanowire-based visible light photodetector simultaneously possesses an extraordinary photoresponsivity of 271 A W-1 , ultrahigh detectivity of 1.57 × 1014 Jones, and a fast response speed of microsecond scale. The excellent performance of the photodetector indicates that as-grown InSe nanowires are promising in future optoelectronic applications. More importantly, the proposed edge-homoepitaxial approach may open up a novel avenue for direct synthesis of semiconducting nanowire arrays on SiO2 /Si substrates.

4.
Nanotechnology ; 31(14): 145602, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-31860876

RESUMO

Germanium quantum dots (GeQDs), addressed by self-aligned and epitaxial silicon nanowires (SiNWs) as electrodes, represent the most fundamental and the smallest units that can be integrated into Si optoelectronics for 1550 nm wavelength detection. In this work, individual GeQD photodetectors have been fabricated based on a low temperature self-condensation of uniform amorphous Si (a-Si)/a-Ge bilayers at 300 °C, led by rolling indium (In) droplets. Remarkably, the diameter of the GeQD nodes can be independently controlled to achieve wider GeQDs for maximizing infrared absorption with narrower SiNW electrodes to ensure a high quality Ge/Si hetero-epitaxial connection. Importantly, these hetero GeQD/SiNW photodetectors can be deployed into predesigned locations for scalable device fabrication. The photodetectors demonstrate a responsivity of 1.5 mA W-1 and a photoconductive gain exceeding 102 to the communication wavelength signals, which are related to the beneficial type-II Ge/Si alignment, gradient Ge/Si epitaxial transition and a larger QD/NW diameter ratio. These results indicate a new approach to batch-fabricate and integrate GeQDs for ultra-compact Si-compatible photodetection and imaging applications.

5.
Int J Genomics ; 2019: 4393905, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781588

RESUMO

Michelia maudiae Dunn is one of the important ornamental plants in the Magnoliaceae family, and the color of its flowers usually appears naturally pure white. The discovery of a rubellis flower named M. maudiae Dunn var. rubicunda provides an opportunity to reveal the metabolism of the flavonoids and anthocyanins of this "early angiosperm" plant. Combined metabolome and transcriptome analyses were applied using white and rubellis mutant tepals. Seven stages have been divided for flower development, and forty-eight differentially altered metabolites were identified between white and rubellis tepals at a later stage. The major anthocyanins including peonidin O-hexoside, cyanidin O-syringic acid, cyanidin 3,5-O-diglucoside, cyanidin 3-O-glucoside, and pelargonidin 3-O-glucoside were upregulated over 157-fold in the mutant. Conversely, the highly significant accumulation of the colorless procyanidin or the slightly yellow epicatechin and catechin was found in white flowers. Putative homologues of color-related genes involved in the phenylpropanoid and flavonoid biosynthesis pathway were identified in the transcriptome. The increasing expression of dihydroflavonol 4-reductase (DFR) might play an important role in the occurrence of rubellis pigments, while the overexpression of anthocyanidin reductase (ANR) in white flowers may promote the biosynthesis of proanthocyanidins. Additionally, several coloration-related repressor R2R3-MYB transcription factors showed different expression levels in the tepals of the rubellis mutant. This study provides a comprehensive analysis relating color compounds to gene expression profiles of the Magnoliids plant M. maudiae. The newly generated information will provide a profound effect on horticultural applications of Magnoliaceae.

6.
ACS Nano ; 13(12): 14191-14197, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31755701

RESUMO

Hot electron transistors (HETs) containing two-dimensional (2D) materials promise great potential in high-frequency analog and digital applications. Here, we experimentally demonstrate all-2D van der Waals (vdW) HETs formed by graphene, hBN, and WSe2, in which the polarity of carriers could be tuned by changing bias conditions. We proposed a theoretical model to distinguish hot hole and hot electron components in the ambipolar vdW HET. Importantly, both hot hole and hot electron modes are achieved with pronounced saturation behavior as well as record-high collection efficiency approaching theoretical limits (99.9%) at room temperature. The vdW HETs show a maximum output current density of 400 A/cm2. The observed ambipolar hot carrier transport with high collection efficiency is promising for high-speed nanoelectronics and 2D hot electron spectroscopy.

7.
Food Funct ; 10(12): 7714-7723, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31750473

RESUMO

Cranberries (Vaccinium macrocarpon) are full of polyphenols, which display various health benefits. Most studies have focused on extractable polyphenols (EPs) rather than non-extractable polyphenols (NEPs) but NEPs may possess important biological functions. The objective of this work was to characterize EP and NEP fractions from whole cranberries and determine their potential as anti-inflammation and anti-colon-cancer agents. Our results showed that of the identified polyphenols, anthocyanins were the major ones in the cranberry EP fraction, while phenolic acids were most abundant in the NEP fraction. The oxygen radical absorbance capacity (ORAC) of the NEPs was significantly higher than that of the EPs. Both the EPs and NEPs showed anti-inflammatory effects in inhibiting LPS-induced production of nitric oxide in macrophages. At the concentrations tested, the NEPs showed significantly higher inhibition of the production of nitric oxide in macrophages than the EPs, which was accompanied by decreased expression of inducible nitric oxide synthase (iNOS) and increased expression of HO-1. EP and NEP samples showed anti-cancer capacities in HCT116 cells. And the NEPs showed stronger inhibitory effects on the viability and colony formation capacity of human colon cancer HCT116 cells than the EPs. In a flow cytometry analysis, the NEPs caused cell cycle arrest at the G0/G1 phase and induced significant cellular apoptosis in colon cancer cells. Overall, our results suggested that both the EP and NEP fractions from cranberries were bioactive, and importantly, the NEP fraction showed promising anti-inflammation and anti-colon-cancer potential.

8.
Int J Biol Sci ; 15(9): 1962-1976, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523197

RESUMO

Both cell migration and proliferation are indispensable parts of reepithelialization during skin wound healing, which is a complex process for which the underlying molecular mechanisms are largely unknown. Here, we identify a novel role for microtubule-associated protein 4 (MAP4), a cytosolic microtubule-binding protein that regulates microtubule dynamics through phosphorylation modification, as a critical regulator of epidermal wound repair. We showed that MAP4 phosphorylation was induced in skin wounds. In an aberrant phosphorylated MAP4 mouse model, hyperphosphorylation of MAP4 (S737 and S760) accelerated keratinocyte migration and proliferation and skin wound healing. Data from both primary cultured keratinocytes and HaCaT cells in vitro revealed the same results. The promigration and proproliferation effects of MAP4 phosphorylation depended on microtubule rearrangement and could be abolished by MAP4 dephosphorylation. We also identified p38/MAPK as an upstream regulator of MAP4 phosphorylation in keratinocytes. Our findings provide new insights into the molecular mechanisms underlying wound-associated keratinocyte migration and proliferation and identify potential targets for the remediation of defective wound healing.

9.
Transl Neurodegener ; 8: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428316

RESUMO

Background: Parkinson's disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies (LB). During the course of disease, misfolded α-synuclein, the major constituent of LB, spreads to different regions of the brain in a prion-like fashion, giving rise to successive non-motor and motor symptoms. Etiology is likely multifactorial, and involves interplay among aging, genetic susceptibility and environmental factors. Main body: The prevalence of PD rises exponentially with age, and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death. However, the majority of those over the age of 80 do not have PD, thus other factors in addition to aging are needed to cause disease. Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk. Nevertheless, the causality of most environmental factors is not conclusively established, and alternative explanations such as reverse causality and recall bias cannot be excluded. The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD. Rare mutations as well as common variants in genes such as SNCA, LRRK2 and GBA are associated with risk of PD, but Mendelian causes collectively only account for 5% of PD and common polymorphisms are associated with small increase in PD risk. Heritability of PD has been estimated to be around 30%. Thus, aging, genetics and environmental factors each alone is rarely sufficient to cause PD for most patients. Conclusion: PD is a multifactorial disorder involving interplay of aging, genetics and environmental factors. This has implications on the development of appropriate animal models of PD which take all these factors into account. Common converging pathways likely include mitochondrial dysfunction, impaired autophagy, oxidative stress and neuroinflammation, which are associated with the accumulation and spread of misfolded α-synuclein and neurodegeneration. Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

10.
EBioMedicine ; 45: 615-623, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31208948

RESUMO

Intracranial haemorrhage (ICH) is a life-threatening type of stroke with high mortality, morbidity, and recurrence rates. However, no effective treatment has been established to improve functional outcomes in patients with ICH to date. Strategies targeting secondary brain injury are of great interest in both experimental and translational studies. The immune system is increasingly considered to be a crucial contributor to ICH-induced brain injury because it participates in multiple phases of ICH, from the early vascular rupture events to brain recovery. Various pathobiological processes that contribute to secondary brain injury closely interact with the immune system, such as brain oedema, neuroinflammation, and neuronal damage. Hence, we summarize the immune response to ICH and recent progress in treatments targeting the immune system in this review. The emerging therapeutic strategies that target the immune system after ICH are a particular focus and have been summarized.


Assuntos
Edema Encefálico/imunologia , Lesões Encefálicas/imunologia , Hemorragia Cerebral/imunologia , Inflamação/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Edema Encefálico/patologia , Edema Encefálico/terapia , Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/terapia , Humanos , Sistema Imunitário/patologia , Inflamação/patologia , Inflamação/terapia , Neurônios/imunologia , Neurônios/patologia , Pesquisa Médica Translacional
11.
Oxid Med Cell Longev ; 2019: 6428924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223422

RESUMO

Maladaptive cardiac metabolism is a common trigger of cardiac lipid accumulation and cardiac injury under serious burn challenge. Adipose triglyceride lipase (ATGL) is the key enzyme that catalyzes triglyceride hydrolysis; however, its alteration and impact on cardiac function following serious burn injury are still unknown. Here, we found that the cardiac fatty acid (FA) metabolism increased, accompanied by augmented FA accumulation and ATGL expression, after serious burn injury. We generated heterozygous ATGL knockout and heterozygous cardiac-specific ATGL overexpression thermal burn mice. The results demonstrated that partial loss of ATGL could not relieve burn-induced cardiac lipid accumulation and cardiac injury, possibly due to the suppression of cardiac FA metabolism plus insufficient compensatory glucose utilization. In contrast, cardiac-specific overexpression of ATGL alleviated cardiac lipid accumulation and cardiac injury following burn challenge by switching the substrate preference from FA towards increased glucose utilization. The underlying mechanism was possibly related to increased glucose transporter-1 expression and reduced cardiac lipid accumulation induced by ATGL overexpression. Our data first demonstrated that elevated cardiac ATGL expression after serious burn injury is an adaptive, albeit insufficient, response to compensate for the increase in energy consumption and that further overexpression of ATGL is beneficial for ameliorating cardiac injury, indicating its therapeutic potential.


Assuntos
Lipase/metabolismo , Metabolismo dos Lipídeos/fisiologia , Miocárdio/metabolismo , Triglicerídeos/metabolismo , Animais , Camundongos
12.
Front Pharmacol ; 10: 368, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040780

RESUMO

Endothelial cells play a critical role in the process of angiogenesis during skin wound healing. The migration and proliferation of endothelial cells are processes that are initiated by the hypoxic microenvironment in a wound, but the underlying mechanisms remain largely unknown. Here, we identified a novel role for microtubule-associated protein 4 (MAP4) in angiogenesis. We firstly demonstrated that MAP4 phosphorylation was induced in hypoxic endothelial cells; the increase in MAP4 phosphorylation enhanced the migration and proliferation of endothelial cells. We also found that hypoxia (2% O2) activated p38/mitogen-activated protein kinase (MAPK) signaling, and we identified p38/MAPK as an upstream regulator of MAP4 phosphorylation in endothelial cells. Moreover, we showed that the promigration and proproliferation effects of MAP4 phosphorylation were attributed to its role in microtubule dynamics. These results indicated that MAP4 phosphorylation induced by p38/MAPK signaling promotes angiogenesis by inducing the proliferation and migration of endothelial cells cultured under hypoxic conditions via microtubule dynamics regulation. These findings provide new insights into the potential mechanisms underlying the initiation of the migration and proliferation of endothelial cells.

13.
Insects ; 10(5)2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31109148

RESUMO

To obtain a better understanding of feeding adaptations, the fine structure of the mouthparts in adults of Cheilocapsus nigrescens Liu and Wang, including the sculpture and interlocking mechanisms of the stylets and distribution and abundance of sensilla located on the labium, were studied using scanning electron microscopy. The mouthparts are similar to those of previously studied mirid species in most aspects and composed of a cone-shaped labrum, a tube-like, four-segmented labium with a deep groove on the anterior side, and a stylet fascicle consisting of two mandibular and two maxillary stylets. Each mandibular stylet tip has about 6-8 indistinctive notches, which help in penetrating the leaf surface. A series of transverse squamous textures are present on the adaxial surface of the mandibular stylets. The maxillary stylets interlock to form a food canal and a salivary canal, equipped with an external longitudinal process that engages grooves in the mandibular stylets. Three kinds of sensilla, including four types of sensilla basiconica (I, II, III, and IV), four types of sensilla trichodea (I, II, III, and IV), and one type of sensillum campaniformium, occur at different locations on the labium. Among them, sensilla trichodea I and II are the most abundant; sensilla basiconica II occurs between the first segment and second segment, and between the third and fourth segment. The tripartite apex of the labium consists of two lateral lobes and an apical plate. Each lateral lobe possesses a field of 11 sensilla basiconica IV and 1 sensillum trichodeum IV. The morphology of the mouthparts and the distribution of sensilla located on the labium in C. nigrescens are discussed with respect to their possible taxonomic and functional significance. In particular, the indistinct notches of the mandibular stylet and smooth inner surface of the right maxillary stylets are suited primarily for phytophagy.

14.
Nano Lett ; 19(5): 3295-3304, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31025869

RESUMO

Photogenerated nonequilibrium hot carriers play a key role in graphene's intriguing optoelectronic properties. Compared to conventional photoexcitation, plasmon excitation can be engineered to enhance and control the generation and dynamics of hot carriers. Here, we report an unusual negative differential photoresponse of plasmon-induced "ultrahot" electrons in a graphene-boron nitride-graphene tunneling junction. We demonstrate nanocrescent gold plasmonic nanostructures that substantially enhance the absorption of long-wavelength photons whose energy is greatly below the tunneling barrier and significantly boost the electron thermalization in graphene. We further analyze the generation and transfer of ultrahot electrons under different bias and power conditions. We find that the competition among thermionic emission, the carrier-cooling effect, and the field effect results in a hitherto unusual negative differential photoresponse in the photocurrent-bias plot. Our results not only exemplify a promising platform for detecting low-energy photons, enhancing the photoresponse, and reducing the dark current but also reveal the critically coupled pathways for harvesting ultrahot carriers.

15.
Cell Death Dis ; 10(4): 295, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931925

RESUMO

Following publication of the original article, it has come to our attention that the Materials and Methods section of the paper was missing. This is because this section was accidentally omitted from the final version of the manuscript when it was submitted to production. Both the PDF and HTML versions of the article have been updated with the missing section and references. As a result, the references at the end of article have been renumbered as well. We apologize for this inconvenience.

16.
Burns Trauma ; 7: 8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906793

RESUMO

Background: Our previous work suggested that microtubule associated protein 4 (MAP4) phosphorylation led to mitochondrial dysfunction in MAP4 phosphorylation mutant mice with cardiomyopathy, but the detailed mechanism was still unknown. Thus, the aim of this study was to investigate the potential mechanism involved in mitochondrial dysfunction responsible for cardiomyopathy. Methods: The present study was conducted to explore the potential mechanism underlying the mitochondrial dysfunction driven by MAP4 phosphorylation. Strain of mouse that mimicked constant MAP4 phosphorylation (S737 and S760) was generated. The isobaric tag for relative and absolute quantitation (iTRAQ) analysis was applied to the heart tissue. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) were all analyzed on the basis of differential expressed proteins (DEPs). Results: Among the 72 cardiac DEPs detected between the two genotypes of mice, 12 were upregulated and 60 were downregulated. GO analysis showed the biological process, molecular function, and cellular component of DEPs, and KEGG enrichment analysis linked DEPs to 96 different biochemical pathways. In addition, the PPI network was also extended on the basis of DEPs as the seed proteins. Three proteins, including mitochondrial ubiquitin ligase activator of NF-κB 1, reduced form of nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial and growth arrest, and DNA-damage-inducible proteins-interacting protein 1, which play an important role in the regulation of mitochondrial function, may correlate with MAP4 phosphorylation-induced mitochondrial dysfunction. Western blot was used to validate the expression of the three proteins, which was consistent with iTRAQ experiments. Conclusions: These findings revealed that the DEPs caused by MAP4 phosphorylation in heart tissue using iTRAQ technique and may provide clues to uncover the potential mechanism of MAP4 phosphorylation-induced mitochondrial dysfunction.

17.
Cell Death Dis ; 10(3): 234, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850584

RESUMO

BNIP3 is an atypical BH3-only member of the Bcl-2 family with pro-death, pro-autophagic, and cytoprotective functions, depending on the type of stress and cellular context. Recently, we demonstrated that BNIP3 stimulates the migration of epidermal keratinocytes under hypoxia. In the present study found that autophagy and BNIP3 expression were concomitantly elevated in the migrating epidermis during wound healing in a hypoxia-dependent manner. Inhibition of autophagy through lysosome-specific chemicals (CQ and BafA1) or Atg5-targeted small-interfering RNAs greatly attenuated the hypoxia-induced cell migration, and knockdown of BNIP3 in keratinocytes significantly suppressed hypoxia-induced autophagy activation and cell migration, suggesting a positive role of BNIP3-induced autophagy in keratinocyte migration. Furthermore, these results indicated that the accumulation of reactive oxygen species (ROS) by hypoxia triggered the activation of p38 and JNK mitogen-activated protein kinase (MAPK) in human immortalized keratinocyte HaCaT cells. In turn, activated p38 and JNK MAPK mediated the activation of BNIP3-induced autophagy and the enhancement of keratinocyte migration. These data revealed a previously unknown mechanism that BNIP3-induced autophagy occurs through hypoxia-induced ROS-mediated p38 and JNK MAPK activation and supports the migration of epidermal keratinocytes during wound healing.

18.
Front Physiol ; 10: 24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745880

RESUMO

Wound healing is delayed frequently in patients with diabetes. Proper keratinocyte migration is an essential step during re-epithelialization. Impaired keratinocyte migration is a critical underlying factor responsible for the deficiency of diabetic wound healing, which is mainly attributed to the hyperglycemic state. However, the underlying mechanisms remain largely unknown. Previously, we demonstrated a marked activation of p38/mitogen-activated protein kinase (MAPK) pathway in the regenerated migrating epidermis, which in turn promoted keratinocyte migration. In the present study, we find that p38/MAPK pathway is downregulated and accompanied by inactivation of autophagy under high glucose (HG) environment. In addition, we demonstrate that inactivation of p38/MAPK and autophagy result in the inhibition of keratinocyte migration under HG environment, and the activating p38/MAPK by MKK6(Glu) overexpression rescues cell migration through an autophagy-dependent way. Moreover, diabetic wound epidermis shows a significant inhibition of p38/MAPK and autophagy. Targeting these dysfunctions may provide novel therapeutic approaches.

19.
EBioMedicine ; 37: 221-235, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30327268

RESUMO

BACKGROUND: Cardiac remodeling is a pathophysiological process that involves various changes in heart, including cardiac hypertrophy and fibrosis. Cardiac remodeling following pathological stimuli is common trigger leading to cardiac maladaptation and onset of heart failure, and their pathogenesis remains unclear. METHODS: Heart specimens of tetralogy of Fallot (TOF) patients, myocardial infarction (MI) and transverse aortic constriction (TAC) mouse models were collected to determine changes of microtubule associated protein 4 (MAP4) phosphorylation. MAP4 (S667A, S737E and S760E) knock in (MAP4 KI) mouse and cultured neonatal mouse cardiomyocytes or fibroblasts were used to investigate changes of cardiac phenotypes and possible mechanisms with a variety of approaches, including functional, histocytological and pathological observations. FINDINGS: Elevated cardiac phosphorylation of MAP4 (S737 and S760) was observed in TOF patients, MI and TAC mouse models. In MAP4 KI mice, age-dependent cardiac phenotypes, including cardiac hypertrophy, fibrosis, diastolic and systolic dysfunction were observed. In addition, increased cardiomyocyte apoptosis together with microtubule disassembly and mitochondrial translocation of phosphorylated MAP4 was detected prior to the onset of cardiac remodeling, and p38/MAPK was demonstrated to be the possible signaling pathway that mediated MAP4 (S737 and S760) phosphorylation. INTERPRETATION: Our data reveal for the first time that MAP4 drives pathological cardiac remodeling through its phosphorylation. These findings bear the therapeutic potential to ameliorate pathological cardiac remodeling by attenuating MAP4 phosphorylation. FUND: This work was supported by the Key Program of National Natural Science Foundation of China (No.81430042) and National Natural Science Foundation of China (No.81671913).


Assuntos
Doenças da Aorta/metabolismo , Fibroblastos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Miócitos Cardíacos/metabolismo , Tetralogia de Fallot/metabolismo , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Modelos Animais de Doenças , Feminino , Fibroblastos/patologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Miócitos Cardíacos/patologia , Fosforilação , Tetralogia de Fallot/genética , Tetralogia de Fallot/patologia
20.
Sci Rep ; 8(1): 15431, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30337574

RESUMO

Previous studies have used several models to investigate the mechanisms for growing and evolving real social networks. These models have been widely used to simulate large networks in many applications. In this paper, based on the evolutionary mechanisms of homophily and popularity, we propose a new generation model for growing and evolving social networks, namely, the Homophily-Popularity model. In this new model, new links are added, and old links are deleted based on the link probabilities between every node pair. The results of our simulation-based experimental studies provide evidence that the proposed model is capable of modelling a variety of real social networks.


Assuntos
Comportamento Competitivo , Modelos Teóricos , Comportamento Social , Rede Social , Fenômenos Biológicos , Humanos , Relações Interpessoais , Apoio Social
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