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1.
Sci Total Environ ; 858(Pt 2): 159938, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36336057

RESUMO

In this study, we combined the measured bulk particle number concentration (NCN), particle number size distribution (PNSD) and bulk cloud condensation nuclei concentration (NCCN) at various supersaturation (SS) levels to investigate competitive activation of aerosols in the marine atmospheres over the marginal seas of China during two winter campaigns Campaign A (December 9-19, 2019) and Campaign B (December 28, 2019-January 16, 2020). During the two campaigns, we observed various categories of aerosols, i.e., long-range transport continental aerosols, clean marine aerosols, grown new particles ranging from nucleation mode to larger sizes, and grown pre-existing particles ranging from Aitken mode to accumulation mode size, etc. We found that the measured NCCN increased by only approximately 30 % with increases in SS levels from 0.2 % to 1.0 %, e.g., (1.8 ± 1.4) × 103 cm-3 at SS = 0.2 % and (2.4 ± 1.4) × 103 cm-3 at SS = 1.0 % during Campaign A. We further calculated the hygroscopicity parameter kappa (κ) by combining simultaneously measured PNSD and bulk NCCN to explore the causes. The calculated κ values were below 0.1 at SS = 0.4 % during the 72 % (or 88 %) period of Campaign A (or Campaign B). When κ values below 0.1 (or 0.2) were excluded, the remaining κ values were apparently reasonable, with an average of 0.22 (or 0.36) and a standard deviation of 0.10 (or 0.21) at SS = 0.4 % during Campaign A (or Campaign B). The unexpectedly lower κ values were discussed in terms of competitive activation of aerosols in marine atmospheres together with its net contribution to lowering the measured bulk NCCN below the expected value.


Assuntos
Poluentes Atmosféricos , Atmosfera , Tamanho da Partícula , Aerossóis/análise , Atmosfera/análise , Oceanos e Mares , China , Poluentes Atmosféricos/análise , Material Particulado/análise
2.
Int J Oncol ; 62(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36382642

RESUMO

Oral cancer is one of the highly malignant tumors with poor prognosis. The pathogenic mechanisms of oral cancer have remained to be fully elucidated and this brings significant challenges to the treatment. RNA modification is a common intracellular chemical modification that has been related to various pathological processes, such as blood diseases, immune system diseases and cancer. As the most common and abundant RNA modification in eukaryotic mRNA, N6­methyladenosine (m6A) modification has a crucial role in several cancers, including oral cancer. m6A modification directly affects gene expression levels and regulates various physiological and pathological processes. It has been demonstrated that m6A modification may affect the proliferation, migration and invasion of oral cancer cells by regulating the level of m6A modification. In the present review, the effects of m6A modification on the proliferation and death of oral cancer cells, as well as the occurrence and development of oral cancer, were analyzed in order to provide a new target for treatment. Furthermore, the roles of m6A modification in chemotherapy resistance and potential immunotherapy were analyzed and new treatment ideas were provided.


Assuntos
Adenosina , Neoplasias Bucais , Humanos , Metilação , RNA Mensageiro/genética , Neoplasias Bucais/genética
3.
Chemosphere ; 312(Pt 1): 137239, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36379431

RESUMO

Harmful algae blooms (HABs), caused by severe eutrophication and extreme weather, have spread all over the world, posing adverse effects on eco-environment and human health. Microcystis aeruginosa is the dominant harmful cyanobacterial species when HABs occur, and the toxic metabolites produced by it, microcystins, are even fatal to humans. Photocatalytic technology has received wide attention from researchers for its clean and energy-efficient features, while the basic mechanisms and modification methods of photocatalysts have also been widely reported. In recent years, photocatalytic technology has shown great promise in the inhibition of HABs. In this article, we systematically reviewed the progress in photocatalytic performance and algae removal efficiency, discuss the damage mechanisms of photocatalysts for algae removal, including physical damage and various oxidative stresses, and also explore the degradation rates and possible pathways of microcystins. It can be concluded that during the photocatalytic process, the cytoarchitectural integrity of algae cells was damaged, a variety of important protein and enzyme systems were disrupted, and the antioxidant systems collapsed due to the continuous attack of ROS, which adversely affected the normal physiological activities and growth, resulting in the inactivation of algae cells. Moreover, photocatalysts have a degrading effect on microcystins, thus reducing the adverse effects of HAB. Finally, a brief summary of future research priorities regarding the photocatalytic degradation of algae cells is presented. This study helps to enhance the understanding of the destruction mechanism of Microcystis aeruginosa during the photocatalytic process, and provides a reference for the photodegradation of HAB in water bodies.

4.
J Control Release ; 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36462640

RESUMO

Nanocarrier-aided drug delivery techniques have improved the absorption and permeability of drugs in nose-to-brain delivery. However, the molecular properties of nanocarriers during the delivery process are of great interest; in particular, the characteristics when penetrating barriers in vivo are crucial for the screening and optimization of materials for nasal inhalation. In this study, we have focused on two types of delivery systems: mucoadhesive nanoparticles (MAPs) and mucopenetrating nanoparticles (MPPs); both have been widely used for mucosal delivery, although a method for selecting the more effective type of drug carriers for mucosal delivery has not been established. Molecular dynamics (MD) simulations were used to reveal the all-atom dynamic characteristics of the interaction between different delivery systems and the nasal mucus protein MUC5AC. Among the systems tested, hydroxypropyltrimethyl ammonium chloride chitosan (HTCC) had the strongest interaction with mucin, suggesting it had better mucoadhesive performance, and that it interacted with MUC5AC more strongly than unmodified chitosan. In contrast, the mucus-penetrating material polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA), had almost no interaction with MUC5AC. The results of the MD simulations were verified by in vitro experiments on nanoparticles (NPs) and mucin binding. The drug delivery performance of the four types of NPs, analyzed by in vitro and ex vivo mucosal penetration, were all generally consistent with the properties of the material predicted from the MD simulation. These clues to the molecular mechanism of MAPs and MPPs may provide useful insight into the screening and optimization of nanomaterials suitable for nasal inhalation.

5.
Front Microbiol ; 13: 1056392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452919

RESUMO

3-Decalinoyltetramic acids (DTAs) are a class of natural products with chemical diversity and potent bioactivities. In fungal species there is a general biosynthetic route to synthesize this type of compounds, which usually features a polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) and a lipocalin-like Diels-Alderase (LLDAse). Using a synthetic biology approach, combining the bioinformatics analysis prediction and heterologous expression, we mined a PKS-NRPS and LLDAse encoding gene cluster from the plant pathogenic fungus Macrophomina phaseolina and characterized the cluster to be responsible for the biosynthesis of novel DTAs, macrophasetins. In addition, we investigated the biosynthesis of these compounds and validated the accuracy of the phylogeny-guided bioinformatics analysis prediction. Our results provided a proof of concept example to this approach, which may facilitate the discovery of novel DTAs from the fungal kingdom.

6.
Soft Matter ; 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36458862

RESUMO

This paper proposes a strategy for fabricating new artificial light-harvesting systems (ALHSs) based on supramolecular multi-component metallogels. Al3+ was introduced into a solution of an acylhydrazone compound (L) in DMSO or DMF to form the L-Al3+ assembly. After adding Al3+ to the L solution, a noticeable blue shift appeared in the fluorescence spectra of L. Moreover, L could form a gel (L-B-gel) with 1,3:2,4-dibenzylidene sorbitol (B) in a DMSO-H2O binary solution. Finally, we obtained a multi-component metallogel (L-Al3+-B-gel) and successfully fabricated two ALHSs (L-Al3+/rhodamine 6G (Rh6G) and L-Al3+/rhodamine B (RhB)). In these systems, the L-Al3+ supramolecular assembly acts as the donor, while Rh6G and RhB act as acceptors. Additionally, we confirmed an energy-transfer process from the L-Al3+ component to Rh6G and RhB separately. The proposed fabrication strategy will facilitate the development of ALHSs.

7.
Chem Commun (Camb) ; 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36448575

RESUMO

The exploration of green C-H oxidation for the rapid construction of functional molecules, remains a permanent goal in synthetic chemistry. Herein, a traceless N-nitroso enabled oxidative Heck and amidation cascade was realized, leading to quinolinones that feature green oxidation and great functional group tolerance. The expedient construction of quinolinone containing pharmaceuticals including Flucarbril, Clostamide and Aripiprazole was achieved in a concise and environmentally friendly manner.

8.
EBioMedicine ; 86: 104352, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36371988

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). METHODS: The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. FINDINGS: We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. INTERPRETATION: Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. FUNDING: This study was supported by The National Natural Science Foundation of China.

9.
Artigo em Inglês | MEDLINE | ID: mdl-36448973

RESUMO

Automated detection and validation of fine-grained human activities from egocentric vision has gained increased attention in recent years due to the rich information afforded by RGB images. However, it is not easy to discern how much rich information is necessary to detect the activity of interest reliably. Localization of hands and objects in the image has proven helpful to distinguishing between hand-related fine-grained activities. This paper describes the design of a hand-object-based mask obfuscation method (HOBM) and assesses its effect on automated recognition of fine-grained human activities. HOBM masks all pixels other than the hand and object in-hand, improving the protection of personal user information (PUI). We test a deep learning model trained with and without obfuscation using a public egocentric activity dataset with 86 class labels and achieve almost similar classification accuracies (2% decrease with obfuscation). Our findings show that it is possible to protect PUI at smaller image utility costs (loss of accuracy).

10.
Artigo em Inglês | MEDLINE | ID: mdl-36448975

RESUMO

Screen time is associated with several health risk behaviors including mindless eating, sedentary behavior, and decreased academic performance. Screen time behavior is traditionally assessed with self-report measures, which are known to be burdensome, inaccurate, and imprecise. Recent methods to automatically detect screen time are geared more towards detecting television screens from wearable cameras that record high-resolution video. Activity-oriented wearable cameras (i.e., cameras oriented towards the wearer with a fisheye lens) have recently been designed and shown to reduce privacy concerns, yet pose a greater challenge in capturing screens due to their orientation and fewer pixels on target. Methods that detect screens from low-power, low-resolution wearable camera video are needed given the increased adoption of such devices in longitudinal studies. We propose a method that leverages deep learning algorithms and lower-resolution images from an activity-oriented camera to detect screen presence from multiple types of screens with high variability of pixel on target (e.g., near and far TV, smartphones, laptops, and tablets). We test our system in a real-world study comprising 10 individuals, 80 hours of data, and 1.2 million low-resolution RGB frames. Our results outperform existing state-of-the-art video screen detection methods yielding an F1-score of 81%. This paper demonstrates the potential for detecting screen-watching behavior in longitudinal studies using activity-oriented cameras, paving the way for a nuanced understanding of screen time's relationship with health risk behaviors.

11.
Hypertension ; 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36330811

RESUMO

BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular disorder with high mortality and lacking underlying mechanisms or effective treatments. REGγ, the 11S proteasome activator known to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner, emerges as a new regulator in the cardiovascular system. METHODS: Using ß-aminopropionitrile (BAPN)-subjected REGγ knockout AD mice and Ang II (angiotensin II)-treated REGγ deficiency vascular smooth muscle cells (VSMCs) to explore the effect of REGγ in AD progression. RESULTS: REGγ was upregulated in mouse aorta of ß-aminopropionitrile-induced AD model in vivo and Ang II-treated VSMCs in vitro. REGγ deficiency ameliorated AD progression in ß-aminopropionitrile-induced mice by protecting against the switch in VSMCs from contractile to synthetic phenotype through suppressing RBM3 (RNA-binding motif protein 3) decay. Mechanically, REGγ interacted with and degraded the RNA-binding protein RBM3 directly, leading to decreased mRNA stability, lowered expression and transcriptional activity of transcription factor SRF (serum response factor), subsequently reduced transcription of VSMCs-specific contractile genes, α-SMA (alpha-smooth muscle actin) and SM22α (smooth muscle 22 alpha), caused the switch in VSMCs from contractile to synthetic phenotype and associated AD progression. Ablation of endogenous SRF or RBM3, or overexpressing exogenous RBM3 in VSMCs significantly blocked or reestablished the REGγ-dependent action on VSMCs phenotypic switch of Ang II stimulation in vitro. Furthermore, exogenously introducing RBM3 improved the switch in VSMCs from contractile to synthetic phenotype and associated AD features caused by REGγ in vivo. CONCLUSIONS: Our results demonstrated that REGγ promoted the switch in VSMCs from contractile to synthetic phenotype and AD progression by inhibiting RBM3-SRF pathway, indicated that modulating REGγ-proteasome activity may be a potential therapeutic approach for AD-associated cardiovascular dysfunction.

12.
Front Public Health ; 10: 952858, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339140

RESUMO

The use of the Internet has a promoting effect on the physical health of the older people. However, previous studies are mostly focused on the perspective of the overall population, or limited to the direct effects, ignoring the exploration of the mechanism of action and the perspective of the older people. Based on the data of the China Family Panel Survey (CFPS) in 2014, 2016, 2018, and 2020, this study found that the use of the Internet has a significant effect on the physical health of the older people, especially among the population groups of females, rural residents, and those living in central and western regions of China. In addition, this study also found that the use of the Internet by the older people can increase their exercise frequency, thereby improving their physical health. Therefore, to promote active aging, this study proposes to further increase the popularity of the Internet among the older people, encourage the introduction of age-appropriate Internet systems and sports facilities, create an online fitness platform for the older people, and promote scientific fitness programs for them.


Assuntos
Exercício Físico , Uso da Internet , Feminino , Humanos , Idoso , China , Inquéritos e Questionários , População Rural
13.
Cancers (Basel) ; 14(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36358653

RESUMO

Background: Aerobic glycolysis plays a key role in tumor metabolic reprogramming to reshape the immune microenvironment. The phosphoglycerate kinase 1 (PGK1) gene codes a glycolytic enzyme that converts 1,3-diphosphoglycerate to 3-phosphoglycerate. However, in lung adenocarcinoma (LUAD), the role of PGK1 in altering the tumor microenvironment (TME) has not yet been determined. Methods: Raw data, including bulk DNA and mRNA-seq data, methylation modification data, single-cell RNA-seq data, proteomics data, clinical case characteristics survival, immunotherapy data, and so on, were obtained from multiple independent public data sets. These data were reanalyzed to uncover the prognosis and immunological characteristics of PGK1 in LUAD. Results: We found that PGK1 mRNA and protein were considerably over-expressed in LUAD compared to normal tissue and that high PGK1 expression is associated with poorer prognostic outcomes in LUAD. The enrichment analysis of PGK1 co-expressed genes in lung adenocarcinoma revealed that PGK1 may be involved in hypoxia, metabolism, DNA synthesis, cell cycle, PI3K/AKT, and various immune and inflammatory signaling pathways. Furthermore, PGK1 is also linked to the recruitment of numerous immune cells, including aDC (dendritic cells), macrophages, and neutrophils. More importantly, PGK1 was highly expressed in immunosuppressive cells, including M2 macrophages, Tregs, and exhausted T cells, among others. Finally, higher PGK1 expression indicated significant correlations to immune checkpoints, TMB (tumor mutation burden), and high response to immunotherapy. Conclusions: The presented findings imply that PGK1, as a glycolysis core gene, may be important for the modification of the immune microenvironment by interacting with the tumor metabolism. The results of this study provide clues for a potential immunometabolic combination therapy strategy in LUAD, for which more experimental and clinical translational research is needed.

14.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430183

RESUMO

Myostatin (Mstn) is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes. The deletion of the Mstn gene in mice leads to reduced mitochondrial functions. However, the underlying regulatory mechanisms remain unclear. In this study, we used CRISPR/Cas9 to generate myostatin-knockout (Mstn-KO) mice via pronuclear microinjection. Mstn-KO mice exhibited significantly larger skeletal muscles. Meanwhile, Mstn knockout regulated the organ weights of mice. Moreover, we found that Mstn knockout reduced the basal metabolic rate, muscle adenosine triphosphate (ATP) synthesis, activities of mitochondrial respiration chain complexes, tricarboxylic acid cycle (TCA) cycle, and thermogenesis. Mechanistically, expressions of silent information regulator 1 (SIRT1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) were down-regulated, while peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) acetylation modification increased in the Mstn-KO mice. Skeletal muscle cells from Mstn-KO and WT were treated with AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR), and the AMPK inhibitor Compound C, respectively. Compared with the wild-type (WT) group, Compound C treatment further down-regulated the expression or activity of pAMPK, SIRT1, citrate synthase (CS), isocitrate dehydrogenase (ICDHm), and α-ketoglutarate acid dehydrogenase (α-KGDH) in Mstn-KO mice, while Mstn knockout inhibited the AICAR activation effect. Therefore, Mstn knockout affects mitochondrial function by inhibiting the AMPK/SIRT1/PGC1α signaling pathway. The present study reveals a new mechanism for Mstn knockout in regulating energy homeostasis.


Assuntos
Proteínas Quinases Ativadas por AMP , Miostatina , Camundongos , Animais , Miostatina/genética , Miostatina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Camundongos Knockout , Músculo Esquelético/metabolismo , Aminoimidazol Carboxamida/farmacologia , Mitocôndrias/genética , Mitocôndrias/metabolismo
15.
Technol Health Care ; 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36442220

RESUMO

BACKGROUND: Aspheric intraocular lens (IOLs) implantation has been widely applied in cataract surgery. However, there is no consensus on the optimal guidance for the operations in IOLs implantation. OBJECTIVE: This study evaluated the visual function of Chinese cataract patients six months after cataract surgery with two different guiding ideologies. METHODS: We evaluated 50 patients (61 eyes) with implantation of different aspheric IOLs (SN60WF IOLs, ZCB00 IOLs, PY-60AD IOLs, AO IOLs) 6 months after cataract surgery. Twenty-four patients (30 eyes) under individual implantation were ascribed to group 1 and 26 patients (31 eyes) with randomized implantation were ascribed to the control group (group 2). Postoperatively parameters included monocular best-corrected visual acuity (BCVA), contrast sensitivity (CS), total spherical aberration Z (4, 0) at 5 mm pupil size, and patient satisfaction. The quality of life after operation was assessed through the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). RESULTS: Six months after cataract operation, the contrast sensitivity with glare of group 1 at 2.5∘ was 0.697 ± 0.027, and 0.532 ± 0.049 in group 2. Besides, there was no significant difference at any other special frequency. The mean spherical aberration Z (4, 0) at 5 mm pupil size in group 1 was 0.015 ± 0.028 um, and in group 2 was 0.043 ± 0.109 um, with a significant difference (p< 0.01). The mean scores obtained from NEI VFQ-25 were not significantly different. CONCLUSION: It is effective to implant aspheric IOLs individually according to preoperative corneal spherical aberration. Patients obtained better contrast sensitivity with glare at 2.5∘, but there was no significant difference in BCVA, contrast sensitivity at other special frequency, and subjective visual function.

16.
Genes Genomics ; 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36445573

RESUMO

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) show a low survival rate, owing to the lack of early diagnostic method and high invasiveness. Long non-coding RNA MAPKAPK5-AS1 that regulates tumor genesis and progression through multiple signals, is upregulated and involved in the growth and apoptosis in lung adenocarcinoma (LUAD). OBJECTIVE: To investigate whether MAPKAPK5-AS1 affected the malignant progression of NSCLC. METHODS: The levels of MAPKAPK5-AS1, miR-490-3p and HMGB2 in lung cancer were first analyzed through StarBase website, and confirmed by a quantitative reverse transcriptase-PCR (qRT-PCR) assay. The biological functions of NSCLC cells were examined by CCK-8, 5-ethynyl-2'-deoxyuridine (EdU) and flow cytometry assays. The potential binding sequences lncRNA-miRNA and miRNA-mRNA were predicted by StarBase software and verified via dual luciferase reporter experiment. The effects of MAPKAPK5-AS1 on tumor growth were evaluated in a xenografted mice model. RESULTS: The expression of MAPKAPK5-AS1 was upregulated in tumor tissues from NSCLC patients. Patients with high expression of MAPKAPK5-AS1 had higher tumor size, advanced TNM stage, higher incidence of lymph node and distant metastasis, and shorter overall survival. Knockdown of MAPKAPK5-AS1 inhibited the proliferation, induced apoptosis and blocked epithelial mesenchymal transformation (EMT) of NSCLC cells. Mechanically, MAPKAPK5-AS1 could upregulate the HMGB2 level in NSCLC cells through competitively binding to miR-490-3p. MiR-490-3p inhibitor reversed the roles of MAPKAPK5-AS1 knockdown on tumor cell proliferation, apoptosis and EMT. Also, HMGB2 knockdown suppressed tumor cell malignant phenotypes. Furthermore, interference of MAPKAPK5-AS1 slowed NSCLC tumor growth in vivo. CONCLUSION: Knockdown of MAPKAPK5-AS1 inhibited the aggressive tumor phenotypes through miR-490-3p/HMGB2 axis in NSCLC. MAPKAPK5-AS1/miR-490-3p/HMGB2 might be potential biomarkers or therapeutic targets for NSCLC.

17.
Nucleic Acids Res ; 50(20): 11965-11978, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36400570

RESUMO

Twinkle is a mitochondrial replicative helicase which can self-load onto and unwind mitochondrial DNA. Nearly 60 mutations on Twinkle have been linked to human mitochondrial diseases. Using cryo-electron microscopy (cryo-EM) and high-speed atomic force microscopy (HS-AFM), we obtained the atomic-resolution structure of a vertebrate Twinkle homolog with DNA and captured in real-time how Twinkle is self-loaded onto DNA. Our data highlight the important role of the non-catalytic N-terminal domain of Twinkle. The N-terminal domain directly contacts the C-terminal helicase domain, and the contact interface is a hotspot for disease-related mutations. Mutations at the interface destabilize Twinkle hexamer and reduce helicase activity. With HS-AFM, we observed that a highly dynamic Twinkle domain, which is likely to be the N-terminal domain, can protrude ∼5 nm to transiently capture nearby DNA and initialize Twinkle loading onto DNA. Moreover, structural analysis and subunit doping experiments suggest that Twinkle hydrolyzes ATP stochastically, which is distinct from related helicases from bacteriophages.

18.
Int Immunopharmacol ; 113(Pt B): 109451, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36423429

RESUMO

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms and non-motor symptoms, and affects millions of people worldwide. Growing evidence implies ß-Hydroxybutyrate (BHB), one of the ketone bodies generated by ketogenesis, plays a neuroprotective role in neurodegenerative diseases. We aimed to verify the anti-inflammatory effect of BHB on PD and further explore potential molecular mechanisms. METHODS: We performed the experiments on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model in vivo and 1-methyl-4-phenylpyridinium (MPP+)-simulated BV2 cell model in vitro, with or without BHB pretreatment. Motor function was assessed by pole test, forced swimming test, traction test and open field test. Immunofluorescence was used to evaluate the loss of dopaminergic neurons and glial cell activation in MPTP-induced PD model mice. The expression of the STAT3/NLRP3/GSDMD signal pathway was measured by western blots. Proinflammatory cytokines was assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: BHB treatment reversed motor deficits, loss of dopaminergic neurons and glial cell activation in PD mice induced by MPTP. Moreover, BHB inhibited microglia pyroptosis by negatively regulating STAT3/NLRP3/GSDMD signal pathway, resulting in downregulation of proinflammatory cytokines (IL-1ß and IL-18) in vivo and vitro. CONCLUSION: These data suggested BHB supplement inhibited pyroptosis by down-regulating STAT3-mediated NLRP3 inflammasome activation for PD models in vivo and in vitro. Our findings provided novel insights and available interventions for the prevention and treatment of PD, and highlighted pyroptosis as a potential therapeutic target for PD.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Animais , Camundongos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , 1-Metil-4-fenilpiridínio , Ácido 3-Hidroxibutírico/uso terapêutico , Citocinas , Corpos Cetônicos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Doença de Parkinson/tratamento farmacológico , Piroptose
19.
ACS Appl Mater Interfaces ; 14(45): 51420-51428, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36318451

RESUMO

Conductive, stretchable, and flexible hydrogel wearable sensors have attracted extensive attention in the fields of artificial intelligence and electronic equipment. However, it is an enormous challenge to fabricate conductive hydrogel sensors with biocompatibility, antibacterial properties, and toughness. Here, a highly conductive hydrogel with excellent toughness, good biocompatibility, and strong antibacterial properties was prepared by incorporating acetylated distarch phosphate (ADSP) into poly(vinyl alcohol) (PVA)/polyhexamethylene biguanide hydrochloride (PHMG). The addition of ADSP not only ionized sodium ions to make the hydrogel conductive but also provided abundant hydroxyl groups to form hydrogen bonds with PVA to improve the toughness of the hydrogel. Furthermore, PHMG endowed the hydrogel with antibacterial properties toward E. coli (Escherichia coli, Gram-negative bacteria) and S. aureus (Staphylococcus aureus, Gram-positive bacteria). Meanwhile, the hydrogel was implanted in mice for 14 days, and the surrounding tissue remained in good condition. More importantly, the hydrogel could detect ECG signals and electrical signals under different actions. This study affords a novel approach for exploiting wearable sensors with antibacterial properties and biocompatibility.


Assuntos
Hidrogéis , Dispositivos Eletrônicos Vestíveis , Camundongos , Animais , Hidrogéis/farmacologia , Hidrogéis/química , Staphylococcus aureus , Escherichia coli , Fosfatos , Inteligência Artificial , Condutividade Elétrica , Antibacterianos/farmacologia
20.
Int J Biol Macromol ; 223(Pt A): 391-403, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36356865

RESUMO

Recently, hydrogel dressings have been rapidly developed for wound healing. However, it is still a huge challenge to endow hydrogel wound dressings with excellent hemostatic performance. Here, a new wound treatment material, foam gel wound dressing, is reported, which possesses rapid hemostasis and antibacterial properties. The foam gel dressing is composed of chitooligosaccharide modified graphene oxide (CG) nanocomposites and calcium alginate foam substrate. In this system, CG has a strong interaction with platelets, which is helpful for rapid hemostasis. So the wound dressing could stop bleeding quickly within 10 s. Meanwhile, CG also provides excellent antibacterial properties to dressings, which is conducive to wound healing. Full-thickness wound healing experiments showed that compared with blank control and CG-free foam gel dressings, CG-loaded foam gel dressings shows better healing properties, and the wounds covered with them are almost completely healed within 12 days. In addition, histological morphology analysis displays CG-loaded wound dressing could significantly accelerate wound healing by reducing the inflammatory response and promoting vascular remodeling. This unique strategy provides a simple and practical method for the clinical application of the next generation of wound dressings.

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