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1.
Heliyon ; 10(13): e32524, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39027562

RESUMO

Objective: This study aims to explore the impact of Nesfatin-1 on type 2 diabetic erectile dysfunction (T2DMED) and its underlying mechanism in regulating the phenotypic switching of corpus cavernosum smooth muscle cells (CCSMCs). Methods: Twenty-four 4-week-old male C57 wild-type mice were randomly assigned to the control group, model group, and Nesfatin-1 treatment group. Monitoring included body weight, blood glucose levels, and penile cavernous pressure (ICP). Histochemistry and Western blot analyses were conducted to assess the expressions of α-SMA, OPN, and factors related to the PI3K/AKT/mTOR signaling pathway. CCSMCs were categorized into the control group, high glucose and high oleic acid group (GO group), Nesfatin-1 treatment group (GO + N group), sildenafil positive control group (GO + S group), and PI3K inhibitor group (GO + N + E group). Changes in phenotypic markers, cell morphology, and the PI3K/AKT/mTOR signaling pathway were observed in each group. Results: (1) Nesfatin-1 significantly ameliorated the body size, body weight, blood glucose, glucose tolerance, and insulin resistance in T2DMED mice. (2) Following Nesfatin-1 treatment, the ICP/MSBP ratio and the peak of the ICP curve demonstrated a significant increase. (3) Nesfatin-1 significantly enhanced smooth muscle and reduced collagen fibers in the corpus cavernosum. (4) Nesfatin-1 notably increased α-SMA expression and decreased OPN expression in CCSMCs. (5) Nesfatin-1 elevated PI3K, p-AKT/AKT, and p-mTOR/mTOR levels in penile cavernous tissue. Conclusions: Nesfatin-1 not only effectively improves body weight and blood glucose levels in diabetic mice but also enhances erectile function and regulates the phenotypic switching of corpus cavernosum smooth muscle. The potential mechanism involves Nesfatin-1 activating the PI3K/AKT/mTOR signaling pathway to induce the conversion of CCSMCs to a contractile phenotype.

2.
Sci Total Environ ; 946: 174029, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-38944297

RESUMO

Trichloroethylene (TCE) is a common environmental pollutant and industrial chemical that has been associated with adverse health effects, especially on organ systems. The purpose of this review is to summarize the current findings on organ system damage caused by TCE exposure and the underlying mechanisms involved. Numerous studies have shown that TCE exposure may cause damage to multiple organ systems, mainly the skin, liver, kidney, and circulatory system. The mechanisms leading to TCE-induced organ system damage are complex and diverse. TCE is metabolized in vivo to reactive intermediates, through which TCE can induce oxidative stress, interfere with cell signaling pathways, and promote inflammatory responses. In addition, studies have shown that TCE interferes with DNA repair mechanisms, leading to genotoxicity and potentially carcinogenic effects. This review highlights the importance of understanding the deleterious effects of TCE exposure on organ systems and provides insights into the underlying mechanisms involved. Further research is needed to elucidate the full range of organ system damage caused by TCE and to develop effective prevention and treatment strategies.


Assuntos
Exposição Ambiental , Poluentes Ambientais , Tricloroetileno , Tricloroetileno/toxicidade , Humanos , Poluentes Ambientais/toxicidade , Exposição Ambiental/efeitos adversos , Estresse Oxidativo
3.
J Infect Public Health ; 17(7): 102456, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38820896

RESUMO

BACKGROUND: A. baumannii is an important and common clinical pathogen, especially in the intensive care unit (ICU). This study aimed to characterize one hypervirulent A. baumannii strain in a patient with community-acquired pneumonia and herpes simplex type 1 virus infection. METHODS: Minimum inhibitory concentrations (MICs) were determined using the Kirby-Bauer (K-B) and broth microdilution methods. Galleria mellonella infection model experiment was conducted. Whole-genome sequencing (WGS) was performed using the Illumina and Nanopore platforms. The resistance and virulence determinants were identified using the ABRicate program with ResFinder and the VFDB database. The capsular polysaccharide locus (K locus) and lipooligosaccharide outer core locus (OC locus) were identified using Kleborate with Kaptive. Phylogenetic analyses were conducted using the BacWGSTdb server. RESULTS: A. baumannii XH2146 strain belongs to ST10Pas and ST447Oxf. The strain was resistant to cefazolin, ciprofloxacin, and trimethoprim/sulfamethoxazole (TMP-SMX). Bautype and Kaptive analyses showed that XH2146 contains OCL2 and KL49. WGS analysis revealed that the strain harbored blaADC-76, blaOXA-68, ant(3'')-IIa, tet(B), and sul2. Notably, tet(B) and sul2, both were located within a 114,700-bp plasmid (designated pXH2146-1). Virulence assay revealed A. baumannii XH2146 possessed higher virulence than A. baumannii AB5075 at 12 h. Comparative genomic analysis showed that A. baumannii ST447 strains were mainly isolated from the USA and exhibited a relatively close genetic relationship. Importantly, 11 strains were observed to carry blaOXA-58; blaOXA-23 was identified in 11 isolates and three ST447 A. baumannii strains harbored blaNDM-1. CONCLUSIONS: Early detection of community-acquired hypervirulent Acinetobacter baumannii strains is recommended to prevent their extensive spread in hospitals.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Infecções Comunitárias Adquiridas , Herpesvirus Humano 1 , Testes de Sensibilidade Microbiana , Filogenia , Sequenciamento Completo do Genoma , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/epidemiologia , Humanos , Acinetobacter baumannii/genética , Acinetobacter baumannii/patogenicidade , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/isolamento & purificação , China/epidemiologia , Infecções por Acinetobacter/microbiologia , Infecções por Acinetobacter/epidemiologia , Animais , Virulência/genética , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 1/isolamento & purificação , Antibacterianos/farmacologia , Fatores de Virulência/genética , Herpes Simples/virologia , Pneumonia Bacteriana/microbiologia , Masculino , Genoma Bacteriano , Mariposas/microbiologia , Mariposas/virologia
4.
Ecotoxicol Environ Saf ; 278: 116433, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38714087

RESUMO

Trichloroethylene (TCE), a widely distributed environmental chemical contaminant, is extensively dispersed throughout the environment. Individuals who are exposed to TCE may manifest occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Renal impairment typically manifests in the initial phase of OMDT and is intricately linked to the disease progression and patient outcomes. Although recombinant human tumor necrosis factor-α receptor II fusion protein (rh TNFR:Fc) has been employed in the clinical management of OMDT, there was no substantial improvement in renal function observed in patients following one week of treatment. This study primarily examined the mechanism of TNFα- and IFNγ-induced endothelial cells (ECs) PANoptosis in TCE-induced kidney injury and hypothesized that the synergistic effect of TNFα and IFNγ could be the key factor affecting the efficacy of rh TNFR:Fc therapy in OMDT patients. A TCE-sensitized mouse model was utilized in this study to investigate the effects of TNFα and IFNγ neutralizing antibodies on renal vascular endothelial cell PANoptosis. The gene of interferon regulatory factor 1 (IRF1) in human umbilical vein endothelial cells (HUVEC) was silenced by using small interfering RNA (siRNA), and the cells were then treated with TNFα and IFNγ recombinant protein to investigate the mechanism of TNFα combined with IFNγ-induced PANoptosis in HUVEC. The findings indicated that mice sensitized to TCE exhibited increased levels of PANoptosis-related markers in renal endothelial cells, and treatment with TNFα and IFNγ neutralizing antibodies resulted in a significant reduction in PANoptosis and improvement in renal function. In vitro experiments demonstrated that silencing IRF1 could reverse TNFα and IFNγ-induced PANoptosis in endothelial cells. These results suggest that the efficacy of rh TNFR:Fc may be influenced by TNFα and IFNγ-mediated PANoptosis in kidney vascular endothelial cells. The joint application of TNFα and IFNγ neutralizing antibody represented a solid alternative to existing therapeutics.


Assuntos
Células Endoteliais da Veia Umbilical Humana , Fator Regulador 1 de Interferon , Interferon gama , Tricloroetileno , Fator de Necrose Tumoral alfa , Animais , Humanos , Camundongos , Injúria Renal Aguda/induzido quimicamente , Células Endoteliais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Fator Regulador 1 de Interferon/metabolismo , Rim/efeitos dos fármacos , Tricloroetileno/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Feminino , Camundongos Endogâmicos BALB C
5.
Int J Biol Macromol ; 271(Pt 1): 132718, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38821786

RESUMO

The CO2-based reversible ionic liquid solution of 1,1,3,3-tetramethylguanidine (TMG) and ethylene glycol (EG) in dimethyl sulfoxide (DMSO) after capturing CO2, (2[TMGH]+[O2COCH2CH2OCO2]2-/DMSO (χRILs = 0.1), provides a sustainable and effective platform for cellulose dissolution and homogeneous utilization. Highly porous cellulose aerogel beads and monoliths were successfully prepared via a sol-gel process by extruding cellulose solution into different coagulation baths (NaOH aqueous solution or alcohols) and exposing the cellulose solution in open environment, respectively, and followed by different drying techniques, including supercritical CO2-drying, freeze-drying and air-drying. The effect of the coagulation baths and drying protocols on the multi-scale structure of the as-prepared cellulose aerogel beads and monoliths were studied in detail, and the sol-gel transition mechanism was also studied by the solvatochromic parameters determination. High specific surface area of 252 and 207 m2/g for aerogel beads and monoliths were achieved, respectively. The potential of cellulose aerogels in dye adsorption was demonstrated.


Assuntos
Dióxido de Carbono , Celulose , Géis , Líquidos Iônicos , Celulose/química , Líquidos Iônicos/química , Dióxido de Carbono/química , Géis/química , Porosidade , Adsorção , Guanidinas/química , Soluções , Etilenoglicol/química , Dimetil Sulfóxido/química
6.
Nanomaterials (Basel) ; 14(10)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38786791

RESUMO

Electrochemical oxygen reduction reaction (ORR) via the 2e- pathway in an acidic media shows great techno-economic potential for the production of hydrogen peroxide. Currently, carbon-based single-atom catalysts (C-SACs) have attracted extensive attention due to their tunable electronic structures, low cost, and sufficient stability in acidic media. This review summarizes recent advances in metal centers and their coordination environment in C-SACs for 2e--ORR. Firstly, the reaction mechanism of 2e--ORR on the active sites of C-SACs is systematically presented. Secondly, the structural regulation strategies for the active sites of 2e--ORR are further summarized, including the metal active center, its species and configurations of nitrogen coordination or heteroatom coordination, and their near functional groups or substitute groups, which would provide available and proper ideas for developing superior acidic 2e--ORR electrocatalysts of C-SACs. Finally, we propose the current challenges and future opportunities regarding the acidic 2e--ORR pathway on C-SACs, which will eventually accelerate the development of the distributed H2O2 electrosynthesis process.

7.
Sci Total Environ ; 923: 171378, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38447712

RESUMO

Trichloroethylene (TCE) is a common environmental contaminant that can cause a severe allergic reaction called TCE hypersensitivity syndrome, which often implicates the patient's kidneys. Our previous study revealed that C5b-9-induced tubular ferroptosis is involved in TCE-caused kidney damage. However, the study did not explain how tubule-specific C5b-9 causes free iron overload, a key event in ferroptosis. Here, we aimed to explore the role of NCOA4-mediated ferritinophagy in C5b-9-induced iron overload and ferroptosis in TCE-sensitized mice. Our results showed that TCE sensitization does not affect iron import or export, but does affect iron storage, causing ferritin degradation and free iron overload. In addition, mitochondrial ROS was upregulated, and these changes were blocked by C5b-9 inhibition. Interestingly, TCE-induced ferritin degradation and ferroptosis were significantly antagonized by the application of the mitochondrial ROS inhibitor, Mito-TEMPO. Moreover, all of these modes of action were further verified in C5b-9-attack signalling HK-2 cells. Further investigation demonstrated that C5b-9-upregulated mitochondrial ROS induced a marked increase in nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy. In addition, the application of NCOA4 small interfering RNA not only significantly reversed ferritinophagy caused by C5b-9 but also reduced C5b-9-induced ferroptosis in HK-2 cells. Taken together, these results suggest that tubule-specific C5b-9 deposition activates NCOA4 through the upregulation of mitochondrial ROS, causing ferritin degradation and elevated free iron, which ultimately leads to tubular epithelial cell ferroptosis and kidney injury in TCE-sensitized mice.


Assuntos
Ferroptose , Sobrecarga de Ferro , Tricloroetileno , Animais , Camundongos , Humanos , Tricloroetileno/toxicidade , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ferro/toxicidade , Ferro/metabolismo , Ferritinas/metabolismo , Células Epiteliais
8.
Angew Chem Int Ed Engl ; 63(14): e202319051, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38305690

RESUMO

The design of aqueous zinc (Zn) chemistry energy storage with high rate-capability and long serving life is a great challenge due to its inhospitable coordination environment and dismal interfacial chemistry. To bridge this big gap, herein, we build a highly reversible aqueous Zn battery by taking advantages of the biomass-derived cellulose nanocrystals (CNCs) electrolyte additive with unique physical and chemical characteristics simultaneously. The CNCs additive not only serves as fast ion carriers for enhancing Zn2+ transport kinetics but regulates the coordination environment and interface chemistry to form dynamic and self-repairing protective interphase, resulting in building ultra-stable Zn anodes under extreme conditions. As a result, the engineered electrolyte system achieves a superior average coulombic efficiency of 97.27 % under 140 mA cm-2, and steady charge-discharge for 982 h under 50 mA cm-2, 50 mAh cm-2, which proposes a universal pathway to challenge aqueous Zn chemistry in green, sustainable, and large-scale applications.

9.
Nat Commun ; 15(1): 1125, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321032

RESUMO

Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord at early developmental stages and myoblast/myocytes at late stages, highlighting their critical roles in the developing spine. Our work provides insights into the developmental biology of the human spine and the pathogenesis of spine malformation.


Assuntos
Anormalidades Musculoesqueléticas , Coluna Vertebral , Humanos , Coluna Vertebral/anormalidades , Anormalidades Musculoesqueléticas/genética , Alelos , Exoma , Proteínas com Domínio T/genética
10.
J Ethnopharmacol ; 324: 117756, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38218503

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Wenzhong Bushen Formula (WZBSF) is a traditional Chinese medicine empirical formula known for its effects in tonifying qi, strengthening the spleen, warming the kidneys, promoting yang, regulating blood circulation, and balancing menstruation. Clinical evidence has demonstrated its significant efficacy in treating Diminished Ovarian Reserve (DOR) by improving ovarian reserves. However, the specific pharmacological mechanisms of WZBSF remain unclear. AIM OF THE STUDY: This study aims to investigate the mechanisms by which WZBSF improves ovarian reserve decline through network pharmacology and animal experiments. METHODS AND MATERIALS: WZBSF was analyzed using a dual UPLC-MS/MS and GC-MS platform. Effective components and targets of WZBSF were obtained from the TCMSP database and standardized using UniProt. Disease targets were collected from GeneCard, OMIM, PHARMGKB, and DisGeNET databases, with cross-referencing between the two sets of targets. A PPI protein interaction network was constructed using Cytoscape3.9.1 and STRING database, followed by KEGG and GO enrichment analysis using the Metascape database. Finally, an ovarian reserve decline model was established in mice, different doses of WZBSF were administered, and experimental validation was conducted through serum hormone detection, H&E staining, immunofluorescence (IF), immunohistochemistry (IHC), and Western blot analysis (WB). RESULTS: WZBSF shares 145 common targets with ovarian reserve decline. GO enrichment analysis revealed involvement in biological processes such as response to hormone stimulation and phosphatase binding, while KEGG analysis implicated pathways including the PI3K-AKT signaling pathway and FoxO signaling pathway. In mice with ovarian reserve decline, WZBSF restored weight gain rate, increased ovarian index, normalized estrous cycles, reversed serum hormone imbalances, restored various follicle counts, and improved ovarian morphology. Additionally, WZBSF reduced p-AKT and p-FOXO3a levels, preventing excessive activation of primordial follicles and maintaining ovarian reserve. CONCLUSION: WZBSF can ameliorate cyclophosphamide and busulfan-induced ovarian reserve decline, and its mechanism may be associated with the inhibition of the PI3K/AKT/FOXO3a signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas , Reserva Ovariana , Feminino , Animais , Camundongos , Farmacologia em Rede , Cromatografia Líquida , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Espectrometria de Massas em Tandem , Medicamentos de Ervas Chinesas/farmacologia , Hormônios , Simulação de Acoplamento Molecular
11.
World Neurosurg ; 181: e655-e677, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37898266

RESUMO

OBJECTIVE: A meta-analysis of randomized controlled trials was conducted to assess efficacy and safety of bilateral ultrasound-guided erector spinae plane block (ESPB) for postoperative analgesia in patients receiving spine surgery. METHODS: PubMed, Embase, and CENTRAL databases were searched by 2 reviewers independently to identify randomized controlled trials evaluating the efficacy of ultrasound-guided ESPB for pain management in patients undergoing spine surgery. For meta-analysis, mean difference (MD) and 95% confidence interval (CI) were selected for continuous data, and risk ratio (RR) and 95% CI were selected for dichotomous variables. RESULTS: A total of 25 randomized controlled trials including 1917 patients (873 in ESPB group and 874 in control group) were eligible for inclusion. At rest, ESPB was associated with significantly lower pain intensity at 0, 2, 4, 6, 8, 12, 24, and 48 hours compared with the control group. During movement, ESPB was associated with significantly lower pain intensity at 0, 4, 6, 8, 12, 24, and 48 hours compared with the control group. Significantly reduced opioid consumption (MD = -6.29, 95% CI [-8.16, 4.41], P < 0.001), prolonged time for first rescue analgesia (MD = 7.51, 95% CI [3.47, 11.54], P < 0.001), fewer patients needing rescue analgesia (RR = 0.34, 95% CI [0.28, 0.43], P < 0.0001), improved patient satisfaction (MD = 1.34, 95% CI [0.88, 1.80], P < 0.001), and shorter length of hospital stay (MD = -0.38, [95% CI -0.50, -0.26], P < 0.001) were demonstrated after use of ESPB. Additionally, ESPB was associated with decreased risks of any adverse event (RR = 0.51, 95% CI [0.43, 0.60], P < 0.001) and postoperative nausea and vomiting events (RR = 0.39, 95% CI [0.31, 0.49], P < 0.001). CONCLUSIONS: Ultrasound-guided ESPB is an effective adjunctive technique with good tolerability for multimodal analgesia in management of pain in patients undergoing spine surgery.


Assuntos
Analgesia , Bloqueio Nervoso , Humanos , Dor , Dor Pós-Operatória/tratamento farmacológico , Náusea e Vômito Pós-Operatórios , Ensaios Clínicos Controlados Aleatórios como Assunto , Ultrassonografia de Intervenção
12.
ACS Macro Lett ; 13(1): 14-20, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38091470

RESUMO

Nonisocyanate polyurethanes (NIPUs) are considered greener alternatives to traditional polyurethanes, and the preparation of NIPUs considerably depends on the design and synthesis of suitable monomers. Herein, we propose a toolbox for in situ capturing and conversion of CO2 into α,ω-diene-functionalized carbamate monomers by taking advantage of the facile reversible reaction of CO2 with diamines in the presence of organic superbases. The activation of CO2 into carbamate intermedia was demonstrated by NMR and in situ FTIR, and the optimal conditions to prepare α,ω-diene-functionalized carbamate monomers were established. Thiol-ene and acyclic diene metathesis (ADMET) polymerization of these monomers under mild conditions yielded a series of poly(thioether urethane)s and unsaturated aromatic-aliphatic polyurethanes with high yield and glass transition temperatures ranging from -26.8 to -1.1 °C. These obtained NIPUs could be further modified via postpolymerization oxidation or hydrogenation to yield poly(sulfone urethane) and saturated polyurethane with tunable properties.

13.
Chembiochem ; 25(4): e202300685, 2024 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-38116854

RESUMO

Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable CRBN ligands, which exert high selectivity over the well-known CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized CRBN recruiters that circumvent the promiscuity from traditional IMiDs, and this study is informative to the development of selective CRBN-recruiting PROTACs for many other therapeutic targets.


Assuntos
Proteínas Nucleares , Peptídeo Hidrolases , Ftalimidas , Proteólise , Peptídeo Hidrolases/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Agentes de Imunomodulação , Benzimidazóis , Ligantes
14.
Open Biol ; 13(12): 230228, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38086423

RESUMO

Cilia are hair-like organelles that protrude from the surface of eukaryotic cells and are present on the surface of nearly all human cells. Cilia play a crucial role in signal transduction, organ development and tissue homeostasis. Abnormalities in the structure and function of cilia can lead to a group of human diseases known as ciliopathies. Currently, zebrafish serves as an ideal model for studying ciliary function and ciliopathies due to its relatively conserved structure and function of cilia compared to humans. In this review, we will summarize the different types of cilia that present in embryonic and adult zebrafish, and provide an overview of the advantages of using zebrafish as a vertebrate model for cilia research. We will specifically focus on the roles of cilia during zebrafish organogenesis based on recent studies. Additionally, we will highlight future prospects for ciliary research in zebrafish.


Assuntos
Ciliopatias , Peixe-Zebra , Animais , Humanos , Cílios/fisiologia , Homeostase , Organogênese
15.
J Med Chem ; 66(18): 13028-13042, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37703322

RESUMO

CARM1 is amplified or overexpressed in many cancer types, and its overexpression correlates with poor prognosis. Potent small-molecule inhibitors for CARM1 have been developed, but the cellular efficacy of the CARM1 inhibitors is limited. We herein report the development of the proteolysis targeting chimera (PROTAC) for CARM1, which contains a CARM1 ligand TP-064, a linker, and a VHL E3 ligase ligand. Compound 3b elicited potent cellular degradation activity (DC50 = 8 nM and Dmax > 95%) in a few hours. Compound 3b degraded CARM1 in VHL- and proteasome-dependent manner and was highly selective for CARM1 over other protein arginine methyltransferases. CARM1 degradation by 3b resulted in potent downregulation of CARM1 substrate methylation and inhibition of cancer cell migration in cell-based assays. Thus, CARM1 PROTACs can be used to interrogate CARM1's cellular functions and potentially be developed as therapeutic agents for targeting CARM1-driven cancers.


Assuntos
Complexo de Endopeptidases do Proteassoma , Proteína-Arginina N-Metiltransferases , Ligantes , Regulação para Baixo , Complexo de Endopeptidases do Proteassoma/metabolismo , Arginina
16.
ACS Appl Mater Interfaces ; 15(35): 41483-41493, 2023 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-37608581

RESUMO

The facile fabrication of gel polymer electrolytes is crucial to the development of flexible electronics, and the use of natural polymers as sources has obtained great attention due to their abundant, low-cost, biodegradable, easy modification, and biocompatible features. In this article, a facile fabrication protocol to engineer gelatin into gel electrolytes was developed by taking the advantages of both deep eutectic solvent (DES) (including its good solubility to gelatin and satisfactory electrochemical properties) and rich active functional groups of gelatin, through in situ derivatization and crosslinking strategy. A double-crosslinked DES gel electrolyte was prepared with the dissolution of gelatin in choline chloride and alcohol-based DES and a further crosslinking with Fe3+ ions. The obtained DES gel presented outstanding mechanical properties, excellent ionic conductivity (up to 101-102 mS/cm), a wide operating temperature range (-40 to 80 °C), satisfactory self-healing property, and good degradability. Moreover, the obtained DES gel electrolyte was successfully applied to supercapacitors and flexible sensors, showing excellent electrochemical performance and strain-response properties. In a word, our study provides a facile protocol to engineer gelatin into gel electrolytes by using deep eutectic solvent, showing significant insights into the design and preparation of sustainable gel polymer electrolytes and having great application potential in next-generation high-performance flexible electronics.

17.
Int J Biol Macromol ; 252: 126584, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37648137

RESUMO

Cellulose graft copolymers having well-defined structures could incorporate the characteristics of both the cellulose skeleton and side chains, providing a new method for the preparation functionalised cellulose derivatives. Herein, a series of multifunctional cellulose grafted, alternating 3,4-dihydrocoumarin (DHC) and epoxide (EPO) copolymers (cell-g-P(DHC-alt-EPO)) were prepared in a metal-free DBU/DMSO/CO2 solvent system without adding additional catalyst. Four examples of cell-g-P(DHC-alt-EPO) with tunable thermal and optical properties were synthesized by copolymerization of DHC with styrene oxide (SO), propylene oxide (PO), cyclohexene oxide (CHO) or furfuryl glycidyl ether (FGE) onto cellulose. The nonconjugated cell-g-P(DHC-alt-EPO) showed UV absorption properties with the maximum absorption peak at 282 nm and 295 nm and photoluminescence performance. A clustering-triggered emission mechanism was confirmed and consistent with DFT theoretical calculations. In DMSO solution, the copolymer (DHCSO5) with DP of 11.64 showed ACQ behaviour as the concentration increased. In addition, DHCSO5 had good antioxidant capacity with an instantaneous radical scavenging activity of 2,2-diphenyl-1-picrylhydrazine (DPPH) up to 65 % at a concentration of 40 mg/ ml and increased to 100 % after 30 min. Thus, the multifunctional cell-g-P(DHC-alt-EPO) materials had a variety of potential applications in the fields of fluorescent printing, bio-imaging, UV- shielding and antioxidants.


Assuntos
Dióxido de Carbono , Celulose , Celulose/química , Dióxido de Carbono/química , Dimetil Sulfóxido , Solventes , Polímeros/química , Compostos de Epóxi/química
18.
Luminescence ; 38(10): 1720-1728, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37462124

RESUMO

Multistimuli-responsive fluorescent materials have garnered great research interest benefited from their practical applications. Two twisted-structure compounds containing tetraphenylethylene (TPE) as the aggregation-induced emission (AIE) group and a pyridine unit as the acid reaction site to obtain new multistimuli-responsive fluorescent compounds (namely, TPECNPy: TPECNPy-2 and TPECNPy-3) were successfully synthesized through a one-step Knoevenagel condensation reaction. The multiple-stimuli response process of TPECNPy was investigated by means of photoluminescence (PL) spectra and emission colour. The results showed that both TPECNPy compounds with excellent AIE abilities displayed reversible emission wavelength and colour changes in response to multiple external stimuli, including grinding-fuming by CH2 Cl2 or annealing and HCl-NH3 vapour fuming. More importantly, fluorescent nanofibre films were prepared by electrospinning a solution of TPECNPy mixed with cellulose acetate (CA), and these exhibited reversible acid-induced discolouration, even with only 1 wt% TPECNPy. The results of this study may inspire strategies for designing multistimuli-responsive materials and preparing fluorescent sensing nanofibre films.


Assuntos
Nanofibras , Fluorescência , Corantes Fluorescentes/química
19.
ACS Macro Lett ; 12(8): 1151-1158, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37505463

RESUMO

One-component epoxy resins based on latent curing agents have garnered research attention owing to their outstanding storage stability and excellent processability, while their development considerably depends on the design and preparation of sustainable latent curing agents. Herein, taking structural advantage of lignin-derived vanillin, a biobased polymerizable aromatic imidazole monomer with α,ω-diene functionality was designed and prepared, which was applicable in subsequent thiol-ene polymerization, yielding a series of robust poly(thioether imidazoles) with excellent tunability of the structure and properties. The findings indicated that the precursors comprising poly(thioether imidazole) and commercially available epoxy resins could keep their fluidity at 25 °C for over 90 days and rapidly cured into resins under elevated temperature, demonstrating that the poly(thioether imidazole) can serve as both a latent curing and toughening agent for one-component epoxy resins because of homopolymerization initiated by imidazole groups and the introduction of an aliphatic chain in the as-prepared poly(thioether imidazole) matrix.

20.
Toxicol Ind Health ; 39(9): 515-527, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37449946

RESUMO

Trichloroethylene (TCE) is a metal detergent commonly used in industry that can enter the human body through the respiratory tract and skin, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and multiple organ damage, including liver failure. However, the pathogenesis of liver injury remains unclear. Kupffer cells (KCs) are important tissue macrophages in the body because the polarization of KCs plays a crucial role in immune-mediated liver injury. However, the mechanism of KCs polarization in TCE-induced immune liver injury has not been thoroughly elucidated. In this study, we investigated the effect of TCE-induced KCs polarization on liver function and signal transduction pathways using the TCE sensitization model developed by our group. BALB/c mouse skin was exposed to TCE for sensitization, and an increase in the expression of M1 macrophage-specific markers (CD16/CD32, iNOS), M1 macrophage-specific cytokines IL-1ß, and IFN-γ, P-JAK-1 and P-STAT1 levels were also found to be dramatically increased. When using low doses of gadolinium trichloride (GdCl3), the expression of these proteins and mRNA was significantly reduced. This phenomenon indicates that GdCl3 blocks TCE-induced polarization of KCs and suggests that the IFN-γ/STAT1 signaling pathway may be involved in the polarization process of KCs. These findings clarify the relationship between the polarization of KCs and immune liver injury and highlight the importance of further study of immune-mediated liver injury in TCE-sensitized mice.


Assuntos
Tricloroetileno , Humanos , Animais , Camundongos , Tricloroetileno/toxicidade , Células de Kupffer/metabolismo , Fígado , Transdução de Sinais , Citocinas/metabolismo , Camundongos Endogâmicos BALB C , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/farmacologia
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