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1.
ACS Biomater Sci Eng ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38991039

RESUMO

Within the context of seeking eco-friendly and readily available materials for energy storage, there is a pressing demand for energy storage solutions that employ environmentally sustainable, high-performance, and adaptable constituents. Specifically, such materials are essential for use in wearable technology, smart sensors, and implantable medical devices, whereas, more broadly, their use plays a pivotal role in shaping their efficiency and ecological footprint. Here, we demonstrate an entirely biopolymer-based supercapacitor with a remarkable performance, achieving a capacitance greater than 0.2 F cm-2 at a charge-discharge current of 10 mA cm-2 with 94% capacitance retention after 20,000 cycles. The supercapacitor is composed of three distinct silk fibroin (SF) composite materials, namely, photo-cross-linkable SF (Sil-MA) hydrogel, SF-polydopamine (SF-PDA), and SF bioplastic, to create a gel electrolyte, electrode binder, and encapsulation, respectively. Together, these elements form a mechanically and electrochemically robust skeleton for biofriendly energy storage devices. Moreover, these biomaterial-based supercapacitor devices show stretchability, flexibility, and compressibility while maintaining their electrochemical performance. The biomaterials and fabrication techniques presented can serve as a foundation for investigating various aqueous electrochemical energy storage systems, especially for emerging applications in wearable electronics and environmentally friendly material systems.

2.
J Vis Exp ; (208)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38912770

RESUMO

Transgenesis in Drosophila is an essential approach to studying gene function at the organism level. Embryo microinjection is a crucial step for the construction of transgenic flies. Microinjection requires some types of equipment, including a microinjector, a micromanipulator, an inverted microscope, and a stereo microscope. Plasmids isolated with a plasmid miniprep kit are qualified for microinjection. Embryos at the pre-blastoderm or syncytial blastoderm stage, where nuclei share a common cytoplasm, are subjected to microinjection. A cell strainer eases the process of dechorionating embryos. The optimal time for dechorionation and desiccation of embryos needs to be determined experimentally. To increase the efficiency of embryo microinjection, needles prepared by a puller need to be beveled by a needle grinder. In the process of grinding needles, we utilize a foot air pump with a pressure gauge to avoid the capillary effect of the needle tip. We routinely inject 120-140 embryos for each plasmid and obtain at least one transgenic line for around 85% of plasmids. This article takes the phiC31 integrase-mediated transgenesis in Drosophila as an example and presents a detailed protocol for embryo microinjection for transgenesis in Drosophila.


Assuntos
Drosophila , Técnicas de Transferência de Genes , Microinjeções , Animais , Microinjeções/métodos , Técnicas de Transferência de Genes/instrumentação , Drosophila/genética , Drosophila/embriologia , Plasmídeos/genética , Plasmídeos/administração & dosagem , Embrião não Mamífero , Animais Geneticamente Modificados , Integrases/genética
3.
J Cell Mol Med ; 28(11): e18362, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38837666

RESUMO

Chimeric antigen receptor- (CAR-)modified T cells have been successfully used to treat blood cancer. With the improved research on anti-tumour adoptive cell therapy, researchers have focused on immune cells other than T lymphocytes. Natural killer (NK) cells have received widespread attention as barriers to natural immunity. Compared to T lymphocyte-related adoptive cell therapy, the use of NK cells to treat tumours does not cause graft-versus-host disease, significantly improving immunity. Moreover, NK cells have more sources than T cells, and the related modified cells are less expensive. NK cells function through several pathways in anti-tumour mechanisms. Currently, many anti-tumour clinical trials have used NK cell-related adoptive cell therapies. In this review, we have summarized the recent progress in NK cell-related adoptive cellular immunotherapy for tumour treatment and propose the current challenges faced by CAR-NK cell therapy.


Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais
4.
Eur J Med Chem ; 275: 116572, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38861809

RESUMO

The development of effective drugs for cervical cancer is urgently required because of its high mortality rate and the limited treatment options. Herein, we report the design, synthesis, and evaluation of a series of novel and effective Hsp90-targeting PROTACs. These compounds exhibited potent anti-proliferative activity against cervical cancer cells with low IC50 values. Compound lw13 effectively degraded Hsp90 at a concentration of only 0.05 µM. In addition, it can inhibit the metastasis of cancer cells and induce significant cell cycle arrest and apoptosis. Furthermore, lw13 demonstrated remarkable antitumor activity both in vitro and in vivo, and has a synergistic effect in combination with cisplatin. Moreover, lw13 can prevent the activation of the HER2/AKT/mTOR signaling pathway by indirectly reducing the levels of HER2 and AKT. This study paves the way for cancer treatment and provides valuable insights into the combination therapy of cervical cancer.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Cisplatino , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90 , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Cisplatino/farmacologia , Feminino , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Sinergismo Farmacológico , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Animais , Linhagem Celular Tumoral , Camundongos , Quimera de Direcionamento de Proteólise
5.
J Vis Exp ; (207)2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38829124

RESUMO

Functional genomics screening offers a powerful approach to probe gene function and relies on the construction of genome-wide plasmid libraries. Conventional approaches for plasmid library construction are time-consuming and laborious. Therefore, we recently developed a simple and efficient method, CRISPR-based modular assembly (CRISPRmass), for high-throughput construction of a genome-wide upstream activating sequence-complementary DNA/open reading frame (UAS-cDNA/ORF) plasmid library. Here, we present a protocol for CRISPRmass, taking as an example the construction of a GAL4/UAS-based UAS-cDNA/ORF plasmid library. The protocol includes massively parallel two-step test tube reactions followed by bacterial transformation. The first step is to linearize the existing complementary DNA (cDNA) or open reading frame (ORF) cDNA or ORF library plasmids by cutting the shared upstream vector sequences adjacent to the 5' end of cDNAs or ORFs using CRISPR/Cas9 together with single guide RNA (sgRNA), and the second step is to insert a UAS module into the linearized cDNA or ORF plasmids using a single step reaction. CRISPRmass allows the simple, fast, efficient, and cost-effective construction of various plasmid libraries. The UAS-cDNA/ORF plasmid library can be utilized for gain-of-function screening in cultured cells and for constructing a genome-wide transgenic UAS-cDNA/ORF library in Drosophila.


Assuntos
Sistemas CRISPR-Cas , Biblioteca Gênica , Fases de Leitura Aberta , Plasmídeos , Plasmídeos/genética , Animais , Sistemas CRISPR-Cas/genética , Fases de Leitura Aberta/genética , DNA Complementar/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Drosophila melanogaster/genética
6.
Cancer Med ; 13(9): e7221, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38733179

RESUMO

BACKGROUND: Cervical cancer is one of the most common gynecological cancers. Accumulated evidence shows that long non-coding RNAs (lncRNAs) play essential roles in cervical cancer occurrence and progression, but their specific functions and mechanisms remain to be further explored. METHODS: The RT-qPCR assay was used to detect the expression of NEAT1 in cervical cancer tissues and cell lines. CCK-8, colony formation, flow cytometry, western blotting, and Transwell assays were used to evaluate the impact of NEAT1 on the malignant behavior of cervical cancer cells. Glucose consumption, lactate production, ATP levels, ROS levels, MMP levels, and the mRNA expressions of glycolysis-related genes and tricarboxylic acid cycle-related genes were detected to analyze the effect of NEAT1 on metabolism reprograming in cervical cancer cells. The expressions of PDK1, ß-catenin and downstream molecules of the WNT/ß-catenin signaling pathway in cervical cancer cells and tissues were detected by western blotting, RT-qPCR, immunofluorescence and immunohistochemistry assays. RESULTS: This study investigated the role and possible molecular mechanism of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in cervical cancer. Our results showed that NEAT1 was highly expressed in cervical cancer tissues and cell lines. Downregulation of NEAT1 inhibited the proliferation, migration, invasion and glycolysis of cervical cancer cells, while overexpression of NEAT1 led to the opposite effects. Mechanistically, NEAT1 upregulated pyruvate dehydrogenase kinase (PDK1) through the WNT/ß-catenin signaling pathway, which enhanced glycolysis and then facilitated cervical cancer metastasis. Furthermore, NEAT1 maintained the protein stability of ß-catenin but did not affect its mRNA level. We also excluded the direct binding of NEAT1 to the ß-catenin protein via RNA pull-down assay. The suppressive impact of NEAT1 knockdown on cell proliferation, invasion, and migration was rescued by ß-catenin overexpression. The WNT inhibitor iCRT3 attenuated the carcinogenic effect induced by NEAT1 overexpression. CONCLUSION: In summary, these findings indicated that NEAT1 may contribute to the progression of cervical cancer by activating the WNT/ß-catenin/PDK1 signaling axis.


Assuntos
Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Piruvato Desidrogenase Quinase de Transferência de Acetil , RNA Longo não Codificante , Neoplasias do Colo do Útero , Via de Sinalização Wnt , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Feminino , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Linhagem Celular Tumoral , beta Catenina/metabolismo , beta Catenina/genética , Glicólise , Movimento Celular
7.
Appl Opt ; 63(10): 2570-2577, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38568538

RESUMO

The limited excitation efficiency of quantum dots in the detection of subsurface defects in optical elements by quantum dot fluorescence gives rise to insufficient accuracy. To enhance the excitation efficiency of quantum dots, we studied the modulation of the polarization direction of linearly polarized incident light on quantum dot fluorescence. We first apply density matrix evolution theory to study the quantum dots interacting with linearly polarized incident light and emitting fluorescence. The fluorescence intensity exhibits cosine oscillations versus modulated laser polarization. It reaches a maximum value at the polarization angle zero, and then decreases as the angle becomes larger until π/2. The experimental results for the quantum dot in both solutions and subsurface defect of optical elements confirmed these results. For optical elements tagged with CdSe/ZnS quantum dots, the fluorescence intensity increases by 61.7%, and the area for the detected subsurface defects increases by 142.9%. Similarly, for C and InP/ZnS quantum dots, there are also increases in both the fluorescence intensity and the area of subsurface defects. Our study suggests that the subsurface defect detection in optical elements by the linearly polarized incident light could enhance the detection accuracy of subsurface defects in optical elements, and potentially achieve super-resolution imaging of subsurface defects.

8.
Front Public Health ; 12: 1365479, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38572001

RESUMO

Introduction: An easily accessible and cost-free machine learning model based on prior probabilities of vascular aging enables an application to pinpoint high-risk populations before physical checks and optimize healthcare investment. Methods: A dataset containing questionnaire responses and physical measurement parameters from 77,134 adults was extracted from the electronic records of the Health Management Center at the Third Xiangya Hospital. The least absolute shrinkage and selection operator and recursive feature elimination-Lightweight Gradient Elevator were employed to select features from a pool of potential covariates. The participants were randomly divided into training (70%) and test cohorts (30%). Four machine learning algorithms were applied to build the screening models for elevated arterial stiffness (EAS), and the performance of models was evaluated by calculating the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results: Fourteen easily accessible features were selected to construct the model, including "systolic blood pressure" (SBP), "age," "waist circumference," "history of hypertension," "sex," "exercise," "awareness of normal blood pressure," "eat fruit," "work intensity," "drink milk," "eat bean products," "smoking," "alcohol consumption," and "Irritableness." The extreme gradient boosting (XGBoost) model outperformed the other three models, achieving AUC values of 0.8722 and 0.8710 in the training and test sets, respectively. The most important five features are SBP, age, waist, history of hypertension, and sex. Conclusion: The XGBoost model ideally assesses the prior probability of the current EAS in the general population. The integration of the model into primary care facilities has the potential to lower medical expenses and enhance the management of arterial aging.


Assuntos
Envelhecimento , Hipertensão , Adulto , Humanos , China , Análise Custo-Benefício , Hipertensão/diagnóstico , População do Leste Asiático
9.
Inorg Chem ; 63(10): 4738-4746, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38426406

RESUMO

Low-dimensional (LD) organic metal halides (OMHs) have a bright future due to their excellent photoelectric characteristics and unique structure. However, the synthesis and emission control of LD-OMHs are still unclear. Herein, the different dimensional (zero-dimensional (0D), one-dimensional (1D), and three-dimensional (3D)) of OMHs were obtained by the reaction of 1,4-diazabicyclo (2.2.2) octane with PbBr2 in different stoichiometric ratios. This discovery shows that the structure and properties of OMHs can be regulated while maintaining the functional organic cations of OMHs, which broadens the path for the development of functional LD-OMHs. Among them, 0D-OMH 1 and 1D-OMH 3 have narrow-band (full width at half-maximum (fwhm) = 74 nm) and broad-band (fwhm = 201 nm) emission, respectively. We found that when organic cations have no contribution to the formation of conduction band minimum and valence band maximum, and the distances between polyhedrons are larger than the van der Waals diameter of the halogen atom, the effect of phonons on exciton transitions can be reduced to achieve a narrow-band emission. Further, Cu(I)- and Mn (II)-based 0D-OMHs were synthesized, which have high photoluminescence quantum yield (PLQY) (33.97 and 47.33%, respectively). When the emitting of 0D-OMHs produced by the interaction of the metal-center and halogens, the asymmetric planar metal-halogen structure will result in a higher PLQY.

10.
Genes Dev ; 38(3-4): 168-188, 2024 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-38479840

RESUMO

CTCF is crucial for chromatin structure and transcription regulation in early embryonic development. However, the kinetics of CTCF chromatin occupation in preimplantation embryos have remained unclear. In this study, we used CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for CTCF-anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we identified a specific set of binding sites enriched in the mouse-specific short interspersed element (SINE) family B2 that are restricted to the cleavage stages. Notably, we discovered that the neuroprotective protein ADNP counteracts the stable association of CTCF at SINE B2-derived CTCF-binding sites. Knockout of Adnp in the zygote led to impaired CTCF binding signal recovery, failed deposition of H3K9me3, and transcriptional derepression of SINE B2 during the morula-to-blastocyst transition, which further led to unfaithful cell differentiation in embryos around implantation. Our analysis highlights an ADNP-dependent restriction of CTCF binding during cell differentiation in preimplantation embryos. Furthermore, our findings shed light on the functional importance of transposable elements (TEs) in promoting genetic innovation and actively shaping the early embryo developmental process specific to mammals.


Assuntos
Cromatina , Desenvolvimento Embrionário , Animais , Camundongos , Sítios de Ligação , Blastocisto/metabolismo , Cromatina/metabolismo , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Mamíferos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Zigoto/metabolismo
11.
Biometals ; 37(4): 1023-1035, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38548904

RESUMO

Iron deficiency anemia (IDA) is one of the most serious forms of malnutrition. Wild type strains of Saccharomyces cerevisiae have higher tolerance to inorganic iron and higher iron conversion and accumulation capacity. The aim of this study was to investigate the effect of S. cerevisiae enriched iron as a potential organic iron supplement on mice with iron deficiency anemia. 60 male Kunming mice (KM mice, with strong adaptability and high reproduction rate, it can be widely used in pharmacology, toxicology, microbiology and other research) were randomly divided into normal control group and iron deficiency diet model group to establish IDA model. After the model was established, IDA mice were randomly divided into 5 groups: normal control group, IDA group, organic iron group (ferrous glycinate), inorganic iron group (ferrous sulfate) and S. cerevisiae enriched iron group. Mice in the experimental group were given different kinds of iron by intragastric administration once a day for 4w. The results showed that S. cerevisiae enriched iron had an effective recovery function, and the body weight and hematological parameters of IDA mice returned to normal levels. The activities of superoxide dismutase, glutathione peroxidase and total antioxidant capacity in serum were increased. In addition, the strain no. F8, able to grow in an iron-rich environment, was more effective in alleviating IDA and improving organ indices with fewer side effects compared to ferrous glycinate and ferrous sulfate groups. This study suggests that the iron-rich strain no. F8 may play an important role in improving IDA mice and may be developed as a new iron supplement.


Assuntos
Anemia Ferropriva , Ferro , Saccharomyces cerevisiae , Animais , Anemia Ferropriva/tratamento farmacológico , Masculino , Camundongos , Saccharomyces cerevisiae/metabolismo , Ferro/metabolismo , Modelos Animais de Doenças , Animais não Endogâmicos
12.
Aging (Albany NY) ; 16(1): 207-225, 2024 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-38175687

RESUMO

Ovarian cancer (OC) ranks as the second leading cause of death among gynecological cancers. Numerous studies have indicated a correlation between the tumor microenvironment (TME) and the clinical response to treatment in OC patients. Tumor-associated macrophages (TAMs), a crucial component of the TME, exert influence on invasion, metastasis, and recurrence in OC patients. To delve deeper into the role of TAMs in OC, this study conducted an extensive analysis of single-cell data from OC patients. The aim is to develop a new risk score (RS) to characterize the response to treatment in OC patients to inform clinical treatment. We first identified TAM-associated genes (TAMGs) in OC patients and examined the protein and mRNA expression levels of TAMGs by Western blot and PCR experiments. Additionally, a scoring system for TAMGs was constructed, successfully categorizing patients into high and low RS subgroups. Remarkably, significant disparities were observed in immune cell infiltration and immunotherapy response between the high and low RS subgroups. The findings revealed that patients in the high RS group had a poorer prognosis but displayed greater sensitivity to immunotherapy. Another important finding was that patients in the high RS subgroup had a higher IC50 for chemotherapeutic agents. Furthermore, further experimental investigations led to the discovery that THEMIS2 could serve as a potential target in OC patients and is associated with EMT (epithelial-mesenchymal transition). Overall, the TAMGs-based scoring system holds promise for screening patients who would benefit from therapy and provides valuable information for the clinical treatment of OC.


Assuntos
Neoplasias Ovarianas , Macrófagos Associados a Tumor , Humanos , Feminino , Macrófagos Associados a Tumor/metabolismo , Macrófagos/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Transição Epitelial-Mesenquimal/genética , Microambiente Tumoral/genética
13.
Front Nutr ; 10: 1104859, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37794971

RESUMO

Background: Non-alcoholic fatty liver disease (NAFLD), especially lean NAFLD is associated with an increased risk of atherosclerotic cardiovascular disease (CVD). It is not currently known which clinical phenotypes of NAFLD contribute most to individual subclinical atherosclerosis risk. We examined the relationship between body mass index (BMI), the metabolically healthy status, and subclinical atherosclerosis in the NAFLD population. Methods: Data from asymptomatic NAFLD subjects who participated in a routine health check-up examination were collected. Participants were stratified by BMI (cutoff values: 24.0-27.9 kg/m2 for overweight and ≥28.0 kg/m2 for obesity) and metabolic status, which was defined by Adult Treatment Panel III criteria. Subclinical atherosclerosis was evaluated by brachial-ankle pulse wave velocity (baPWV) in 27,738 participants and by carotid plaque in 14,323 participants. Results: Within each BMI strata, metabolically unhealthy subjects had a significantly higher prevalence of subclinical atherosclerosis than metabolically healthy subjects, whereas fewer differences were observed across subjects within the same metabolic category. When BMI and metabolic status were assessed together, a metabolically unhealthy status was the main contributor to the association of clinical phenotypes with the subclinical atherosclerosis burden (all p < 0.001). When BMI and metabolic abnormalities were assessed separately, the incidence of subclinical disease did not increase across BMI categories; however, it increased with an increase in the number of metabolic abnormalities (0, 1, 2 and ≥3). Conclusion: A metabolically healthy status in NAFLD patients was closely correlated with subclinical atherosclerosis, beyond that of the BMI-based obesity phenotype. The application of metabolic phenotyping strategies could enable more precise classification in evaluating cardiovascular risk in NAFLD.

14.
Appl Opt ; 62(27): 7263-7269, 2023 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-37855583

RESUMO

The use of the fast steering mirror in an optical path requires strict volume control, and traditional structures have low space-utilization efficiency, resulting in traditional actuators having limited output in narrow spaces. The design in this paper adopts a combination of flexible universal supports and piezoelectric ceramic actuators, greatly reducing the layout space of the rotating-shaft system. We accurately model the design structure and develop closed-loop control methods to further improve the closed-loop control accuracy of the system. The experimental results indicate that the developed control method effectively improves the response speed and bandwidth and thus has good potential for use in engineering applications.

15.
Mitochondrial DNA B Resour ; 8(6): 658-662, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37303611

RESUMO

The perennial herbal medicine species Aconitum tschangbaischanense, is endemic to Changhai Mountain, Jilin province. In this study, we attempted to uncover the complete chloroplast (cp) genome of A. tschangbaischanense based on sequencing data using the Illumina sequencing technology. As per the results: (1) the length of its complete cp genome is 155,881 bp with a typical tetrad structure; (2) the structure of its cp genome contains large single-copy and small single-copy (LSC and SSC) regions of 86,351 and 16,9444 bp, respectively, isolated by two inverted repeat regions (IRs) of 26,293 bp; (3) we annotated a total 131 genes, consisting of 86 protein-coding genes, eight rRNA genes, and 37 tRNA genes. According to the maximum-likelihood phylogenetic tree based on complete cp genomes, A. tschangbaischanense, showed close association with A. carmichaelii, which belongs to clade I. Finally, this study provides the characteristics of the cp genome of A. tschangbaischanense, and its phylogenetic position.

16.
J Fungi (Basel) ; 9(6)2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-37367621

RESUMO

Although 1-hydroxy-4-quinolone derivatives, such as 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), aurachin C, and floxacrine, have been reported as effective cytochrome bc1 complex inhibitors, the bioactivity of these products is not ideal, presumably due to their low bioavailability in tissues, particularly their poor solubility and low mitochondrial accumulation. In order to overcome the drawbacks of these compounds and develop their use as agricultural fungicides acting by cytochrome bc1 inhibition, in this study, three novel mitochondria-targeting quinolone analogs (mitoQNOs) were designed and synthesized by conjugating triphenylphosphonium (TPP) with quinolone. They exhibited greatly enhanced fungicidal activity compared to the parent molecule, especially mitoQNO11, which showed high antifungal activity against Phytophthora capsici and Sclerotinia sclerotiorum with EC50 values of 7.42 and 4.43 µmol/L, respectively. In addition, mitoQNO11 could inhibit the activity of the cytochrome bc1 complex of P. capsici in a dose-dependent manner and effectively depress its respiration and ATP production. The greatly decreased mitochondrial membrane potential and massively generated reactive oxygen species (ROS) strongly suggested that the inhibition of complex III led to the leakage of free electrons, which resulted in the damage of the pathogen cell structure. The results of this study indicated that TPP-conjugated QNOs might be used as agricultural fungicides by conjugating them with TPP.

17.
Front Immunol ; 14: 1193222, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37325638

RESUMO

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target immune checkpoints that suppress immune cell activity. Low efficiency and high resistance are currently the main barriers to their clinical application. As a representative technology of targeted protein degradation, proteolysis-targeting chimeras (PROTACs) are considered to have potential for addressing these limitations. Methods: We synthesized a stapled peptide-based PROTAC (SP-PROTAC) that specifically targeted palmitoyltransferase ZDHHC3 and resulted in the decrease of PD-L1 in human cervical cancer cell lines. Flow cytometry, confocal microscopy, protein immunoblotting, Cellular Thermal Shift Assay (CETSA), and MTT assay analyses were conducted to evaluate the effects of the designed peptide and verify its safety in human cells. Results: In cervical cancer celllines C33A and HeLa, the stapled peptide strongly downregulated PD-L1 to < 50% of baseline level at 0.1 µM. DHHC3 expression decreased in both dosedependentand time-dependent manners. MG132, the proteasome inhibitor, can alleviate the SP-PROTAC mediated degradation of PD-L1 in human cancer cells. In a co-culture model of C33A and T cells, treatment with the peptide induced IFN-γ and TNF-α release in a dose-dependent manner by degrading PD-L1. These effects were more significant than that of the PD-L1 inhibitor, BMS-8. Conclusions: Cells treated with 0.1 µM of SP-PROTAC or BMS-8 for 4 h revealed that the stapled peptide decreased PD-L1 more effectively than BMS-8. DHHC3-targeting SP-PROTAC decreased PD-L1 in human cervical cancer more effectively than the inhibitor BMS-8.


Assuntos
Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Células HeLa , Peptídeos/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos T
18.
Front Endocrinol (Lausanne) ; 14: 1137098, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37223043

RESUMO

Background: Insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD) are closely related. The triglyceride-glucose index (TyG index) has been proposed as a new indicator of IR. It remains unclear whether the triglyceride-glucose (TyG) index is prospectively associated with incident nonalcoholic fatty liver disease (NAFLD). Methods: This large-scale study comprised 1 prospective cohort totaling 22,758 subjects without NAFLD at baseline who underwent repeated health examinations and 1 subcohort totaling 7,722 subjects with more than three visits. The TyG index was ascertained mathematically by ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). NAFLD was diagnosed by ultrasound without other concomitant liver diseases. A combinatorial Cox proportional hazard model and latent class growth mixture modeling method were used to identify the association of the TyG index and its transition trajectories with NAFLD risk. Results: During 53,481 person-years of follow-up, there were 5319 incident cases with NAFLD. Compared with those in the lowest quartile of the baseline TyG index, participants in the highest quartile had 2.52-fold (95% confidence interval, 2.21-2.86) higher odds of incident NAFLD. Similarly, restricted cubic spline analysis showed a dose-response relationship (p nonlinearity<0.001). Subgroup analyses showed a more significant association in the female and normal body size populations (p for interaction<0.001). Three distinct trajectories of changes in the TyG index were identified. Compared with the continued low group, the moderately increasing and highly increasing groups conferred 1.91-fold (1.65-2.21) and 2.19-fold (1.73-2.77) higher NAFLD risk, respectively. Conclusions: Participants with a higher baseline TyG index or a higher excessive TyG exposure were associated with an increased NAFLD risk. The findings imply that lifestyle interventions and modulation of IR might be considered to both reduce TyG index levels and prevent NAFLD development.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Humanos , Feminino , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos de Coortes , Estudos Prospectivos , Glucose , Triglicerídeos
19.
Sci Adv ; 9(17): eadg6079, 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37115926

RESUMO

In the rising advent of organic Li-ion positive electrode materials with increased energy content, chemistries with high redox potential and intrinsic oxidation stability remain a challenge. Here, we report the solid-phase reversible electrochemistry of the oximate organic redox functionality. The disclosed oximate chemistries, including cyclic, acyclic, aliphatic, and tetra-functional stereotypes, uncover the complex interplay between the molecular structure and the electroactivity. Among the exotic features, the most appealing one is the reversible electrochemical polymerization accompanying the charge storage process in solid phase, through intermolecular azodioxy bond coupling. The best-performing oximate delivers a high reversible capacity of 350 mAh g-1 at an average potential of 3.0 versus Li+/Li0, attaining 1 kWh kg-1 specific energy content at the material level metric. This work ascertains a strong link between electrochemistry, organic chemistry, and battery science by emphasizing on how different phases, mechanisms, and performances can be accessed using a single chemical functionality.

20.
Plant Physiol Biochem ; 198: 107675, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37043997

RESUMO

Bicolor flower lotus is rare with high ornamental value. During the long history of breeding and artificial selection, a very famous lotus cultivar 'Da Sajin' with red and white picotee bicolor petals were obtained. In order to reveal the mechanism underlying the formation of its picotee bicolor pattern in the petal, an integrative metabolomics and proteomics analyses were conducted between red and white parts of its petals. The results showed that the defect of anthocyanidin 3-O-glucosyltransferases (UFGTs) accumulation resulted in the failure of the glycosylation of anthocyanidin, the last step of anthocyanin biosynthesis in white part of the petals. And proteomic data and biochemical analysis showed that the defect of UFGTs accumulation is not related to their transcription, but because of their degradation. Function of one differentially accumulated NnUFGT were proven being involved in anthocyanin biosynthesis through both in-vitro enzyme assay and in-vivo transgenic analyses. This regulation on the protein accumulation of structural genes in anthocyanin biosynthesis was not explored in any other plants, and hence supposed to be a novel mechanism for the formation of picotee bicolor pattern flower. The results not only provide some new insights into the understanding of lotus flower coloration, but also might assist the breeding of flower lotus.


Assuntos
Lotus , Nelumbo , Antocianinas/metabolismo , Nelumbo/genética , Nelumbo/metabolismo , Lotus/genética , Lotus/metabolismo , Proteômica , Melhoramento Vegetal , Pigmentação/genética , Flores/metabolismo
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