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1.
Am J Hypertens ; 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39023012

RESUMO

BACKGROUND: Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3) / AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. METHODS: The study involved 7-week-old male Dahl salt-sensitive that were fed either high-salt diet (8% NaCl; DSH group) or normal diet (0.3% NaCl; DSN group). Then DSH group were administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of SBP, the expression levels of lipid metabolism-related biomarker, pathological examination of atrial fibrosis and lipid accumulation, as well as AF inducibility and AF duration. RESULTS: DSH decrease SIRT3, phosphorylation-AMPK and VLCAD expression, increased FASN and FABP4 expression and concentrations of FFA and TG, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. CONCLUSIONS: We have confirmed that high-salt diet can result in hypertension, associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.

2.
Front Public Health ; 12: 1397260, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38832222

RESUMO

Objective: This study focuses on enhancing the precision of epidemic time series data prediction by integrating Gated Recurrent Unit (GRU) into a Graph Neural Network (GNN), forming the GRGNN. The accuracy of the GNN (Graph Neural Network) network with introduced GRU (Gated Recurrent Units) is validated by comparing it with seven commonly used prediction methods. Method: The GRGNN methodology involves multivariate time series prediction using a GNN (Graph Neural Network) network improved by the integration of GRU (Gated Recurrent Units). Additionally, Graphical Fourier Transform (GFT) and Discrete Fourier Transform (DFT) are introduced. GFT captures inter-sequence correlations in the spectral domain, while DFT transforms data from the time domain to the frequency domain, revealing temporal node correlations. Following GFT and DFT, outbreak data are predicted through one-dimensional convolution and gated linear regression in the frequency domain, graph convolution in the spectral domain, and GRU (Gated Recurrent Units) in the time domain. The inverse transformation of GFT and DFT is employed, and final predictions are obtained after passing through a fully connected layer. Evaluation is conducted on three datasets: the COVID-19 datasets of 38 African countries and 42 European countries from worldometers, and the chickenpox dataset of 20 Hungarian regions from Kaggle. Metrics include Average Root Mean Square Error (ARMSE) and Average Mean Absolute Error (AMAE). Result: For African COVID-19 dataset and Hungarian Chickenpox dataset, GRGNN consistently outperforms other methods in ARMSE and AMAE across various prediction step lengths. Optimal results are achieved even at extended prediction steps, highlighting the model's robustness. Conclusion: GRGNN proves effective in predicting epidemic time series data with high accuracy, demonstrating its potential in epidemic surveillance and early warning applications. However, further discussions and studies are warranted to refine its application and judgment methods, emphasizing the ongoing need for exploration and research in this domain.


Assuntos
Redes Neurais de Computação , Humanos , COVID-19/epidemiologia , Doenças Transmissíveis/epidemiologia , Análise de Fourier , Surtos de Doenças
3.
J Environ Manage ; 360: 121139, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38744212

RESUMO

For the simultaneous energetic utilization of corn stalk and azo-dye contaminated wastewater, an ECMO-like integrated reactor was come up to achieve the biogas production and azo-dye degradation during anaerobic digestion (AD). Methyl orange (MO) was selected as the model compound for azo-dye. The ECMO-like reactor included AD main reactor with a spray device and solid-liquid separation components, integrated with an aeration reactor for biogas slurry. Methane yields of corn stalks (100.82 mL/g VS) were highest in the ECMO-like reactor, compared with reactors without aeration. As a stable metabolite, 4-aminobenzenesulfonic acid (4-ABA) was detected in AD, while it was assumed that the metabolites can be further transformed in the ECMO-like reactor (R3), due to the 4-ABA removal efficiency as 92.87 % after 35 days' digestion. Class Alphaproteobacteria and Clostridia were assumed as functional microbes responding to aeration. Overall, this ECMO-like integrated reactor provided a novel biotechnology strategy for agricultural and azo dye waste treatment.


Assuntos
Compostos Azo , Reatores Biológicos , Zea mays , Anaerobiose , Biocombustíveis , Biodegradação Ambiental , Eliminação de Resíduos Líquidos/métodos , Metano/metabolismo , Águas Residuárias/química
4.
bioRxiv ; 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38712260

RESUMO

Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Although considerable attention has been paid to the mechanisms underlying synaptic strengthening and new learning, little scrutiny has been given to those involved in the attenuation of synaptic strength that attends suppression of a previously learned association. Our studies revealed a novel, non-Hebbian, long-term, postsynaptic depression of glutamatergic SPN synapses induced by interneuronal nitric oxide (NO) signaling (NO-LTD) that was preferentially engaged at quiescent synapses. This form of plasticity was gated by local Ca 2+ influx through CaV1.3 Ca 2+ channels and stimulation of phosphodiesterase 1 (PDE1), which degraded cyclic guanosine monophosphate (cGMP) and blunted NO signaling. Consistent with this model, mice harboring a gain-of-function mutation in the gene coding for the pore-forming subunit of CaV1.3 channels had elevated depolarization-induced dendritic Ca 2+ entry and impaired NO-LTD. Extracellular uncaging of glutamate and intracellular uncaging of cGMP suggested that this Ca 2+ -dependent regulation of PDE1 activity allowed for local regulation of dendritic NO signaling. This inference was supported by simulation of SPN dendritic integration, which revealed that dendritic spikes engaged PDE1 in a branch-specific manner. In a mouse model of Parkinson's disease (PD), NO-LTD was absent not because of a postsynaptic deficit in NO signaling machinery, but rather due to impaired interneuronal NO release. Re-balancing intrastriatal neuromodulatory signaling in the PD model restored NO release and NO-LTD. Taken together, these studies provide novel insights into the mechanisms governing NO-LTD in SPN and its role in psychomotor disorders, like PD.

5.
Materials (Basel) ; 17(3)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38591377

RESUMO

The determination of the electrochemically active surface area (ECSA) of a catalyst layer (CL) of a non-precious metal catalyst is of fundamental importance in optimizing the design of a durable CL for anion exchange membrane (AEM) water electrolysis, but has yet to be developed. Traditional double layer capacitance (Cdl), measured by cyclic voltammetry (CV), is not suitable for the estimation of the ECSA due to the nonconductive nature of Ni-based oxides and hydroxides in the non-Faradaic region. This paper analyses the applicability of electrochemical impedance spectroscopy (EIS) compared to CV in determining capacitances for the estimation of the ECSA of AEM-based CLs in an aqueous KOH electrolyte solution. A porous electrode transmission line (TML) model was employed to obtain the capacitance-voltage dependence from 1.0 V to 1.5 V at 20 mV intervals, covering both non-Faradic and Faradic regions. This allows for the identification of the contribution of a NiFe-layered double hydroxide (LDH) catalyst and supports in a CL, to capacitances in both non-Faradic and Faradic regions. A nearly constant double layer capacitance (Qdl) observed in the non-Faradic region represents the interfaces between catalyst supports and electrolytes. The capacitance determined in the Faradic region by EIS experiences a peak capacitance (QF), which represents the maximum achievable ECSA in an AEMCL during reactions. The EIS method was additionally validated in durability testing. An approximate 30% loss of QF was noted while Qdl remained unchanged following an eight-week test at 1 A/cm2 constant current density, implying that QF, determined by EIS, is sensitive to and therefore suitable for assessing the loss of ECSA. This universal method can provide a reasonable estimate of catalyst utilization and enable the monitoring of catalyst degradation in CLs, in particular in liquid alkaline electrolyte water electrolysis systems.

6.
J Control Release ; 370: 339-353, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38685383

RESUMO

Chronic skin wounds are a serious complication of diabetes with a high incidence rate, which can lead to disability or even death. Previous studies have shown that mesenchymal stem cells derived extracellular vesicles (EVs) have beneficial effects on wound healing. However, the human foreskin mesenchymal stem cell (FSMSCs)-derived extracellular vesicle (FM-EV) has not yet been isolated and characterized. Furthermore, the limited supply and short lifespan of EVs also hinder their practical use. In this study, we developed an injectable dual-physical cross-linking hydrogel (PSiW) with self-healing, adhesive, and antibacterial properties, using polyvinylpyrrolidone and silicotungstic acid to load FM-EV. The EVs were evenly distributed in the hydrogel and continuously released. In vivo and vitro tests demonstrated that the synergistic effect of EVs and hydrogel could significantly promote the repair of diabetic wounds by regulating macrophage polarization, promoting angiogenesis, and improving the microenvironment. Overall, the obtained EVs-loaded hydrogels developed in this work exhibited promising applicability for the repair of chronic skin wounds in diabetes patients.


Assuntos
Vesículas Extracelulares , Prepúcio do Pênis , Hidrogéis , Células-Tronco Mesenquimais , Cicatrização , Hidrogéis/administração & dosagem , Hidrogéis/química , Humanos , Cicatrização/efeitos dos fármacos , Animais , Masculino , Prepúcio do Pênis/citologia , Pele/lesões , Pele/metabolismo , Diabetes Mellitus Experimental/complicações , Camundongos , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Injeções
7.
Int J Biol Macromol ; 266(Pt 2): 131255, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38556221

RESUMO

An imbalanced gut microflora may contribute to immune disorders in neonates due to an immature gut barrier. Bacterial toxins, particularly, can trigger the immune system, potentially resulting in uncontrolled gut and systemic inflammation. Previous research has revealed that Bifidobacterium animalis subsp. lactis (B. lactis) could protect against early-life pathogen infections by enhancing the gut barrier. However, the effects of B. lactis on a compromised immune system remain uncertain. Hence, this study concentrated on the immunomodulatory effects and mechanisms of B. lactis in neonatal rats intraperitoneally injected with lipopolysaccharide (LPS), a bacterial toxin and inflammatory mediator. First, B. lactis significantly alleviated the adverse effects induced by LPS on the growth, development, and body temperature of neonatal rats. Second, B. lactis significantly reduced the immune responses and damage induced by LPS, affecting both systemic and local immune responses in the peripheral blood, gut, and brain. Notably, B. lactis exhibited extra potent neuroprotective and neurorepair effects. Our research found that pre-treatment with B. lactis shaped the diverse gut microecology by altering both microbial populations and metabolic biomolecules, closely linked to immunomodulation. Overall, this study elucidated the multifaceted roles of B. lactis in neonatal hosts against pathogenic infection and immune disorder, revealing the existence of the microbiota-gut-brain axis.


Assuntos
Animais Recém-Nascidos , Bifidobacterium animalis , Eixo Encéfalo-Intestino , Microbioma Gastrointestinal , Lipopolissacarídeos , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Ratos , Eixo Encéfalo-Intestino/efeitos dos fármacos , Probióticos/farmacologia , Imunomodulação/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/imunologia
8.
Food Res Int ; 181: 114094, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38448096

RESUMO

The detailed dynamics of small molecular nonvolatile chemical and bacterial diversities, as well as their relationship are still unclear in the manufacturing process of Keemun black tea (KMBT). Herein, mass spectrometry-based untargeted metabolomics, Feature-based Molecular Networking (FBMN) and bacterial DNA amplicon sequencing were used to investigate the dense temporal samples of the manufacturing process. For the first time, we reveal that the pyrogallol-type catechins are oxidized asynchronously before catechol-type catechins during the black tea processing. Rolling is the key procedure for forming the small molecular nonvolatile metabolite profile (SMNMetProf), increasing the metabolite richness, and then shaping the bacterial community structure in the KMBT manufacturing process, which decreases both molecular weight and molecular polarity of the small molecular nonvolatile metabolites. The SMNMetProf of black tea is formed by the endogenous enzymatic oxidation of tea leaves, rather than bacterial fermentation.


Assuntos
Camellia sinensis , Catequina , Chá , Comércio , DNA Bacteriano/genética
9.
Gut Liver ; 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38384181

RESUMO

Background/Aims: : Colorectal cancer (CRC) is a common malignant tumor, and circular RNAs (circRNAs) are abnormally expressed in CRC. However, the function and underlying mechanism of circRNA pinin (circ-PNN; hsa_circ_0101802) in CRC remain unclear. Methods: : Exosomes were isolated from the plasma of CRC patients and identified by transmission electron microscopy and Western blotting. The RNA expression levels of circ-PNN, miR-1225-5p, and fibroblast growth factor 13 (FGF13) were measured by quantitative real-time polymerase chain reaction. Cell proliferation was detected by Cell Counting K-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays. Cell apoptosis was assessed by flow cytometry. The expression of apoptosis and metastasis-related proteins was evaluated by Western blotting. The associations among circ-PNN, miR-1225-5p, and FGF13 were confirmed by dual-luciferase report assay and RNA immunoprecipitation assay. A xenograft model was used to verify the function of circ-PNN in tumor formation in vivo. Results: : circ-PNN expression was upregulated in plasmic exosomes derived from CRC patients. The expression of circ-PNN and FGF13 was upregulated, while miR-1225-5p expression was downregulated in CRC cells incubated with plasmic exosomes derived from CRC patients. Tumor-derived exosomes promoted the proliferation, migration, and invasion but inhibited apoptosis of CRC cells. Moreover, the addition of tumor-derived exosomes partly reversed the inhibitory effect of circ-PNN knockdown on CRC tumor progression in vitro and in vivo. Thus, circ-PNN acts as a sponge for miR-1225-5p to regulate FGF13 expression. Conclusions: : Tumor-derived exosomal circ-PNN promoted CRC progression through the regulation of the miR-1225-5p/FGF13 pathway, providing a potential therapeutic target for CRC.

10.
Int J Environ Health Res ; 34(2): 708-718, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36628496

RESUMO

Previous studies have linked exposure to light at night (LAN) with various health outcomes, but evidence is limited for the LAN-obesity association. Thestudy analysed data from 24,845 participants of the 33 Communities Chinese Health Study and obesity (BMI ≥28 kg/m2) was defined according to the Working Group on Obesity in China. The Global Radiance Calibrated Nighttime Lights data were used to estimate participants' LAN exposure. The mixed-effect regression models examined the LAN-BMI and LAN-obesity association. We found that higher LAN exposure was significantly associated with greater BMI and higher risk of obesity. Changes of BMI and the odds ratios (ORs) of obesity and 95% confidence intervals (CIs) for 2nd, 3rd, and 4th against the 1st quartile of LAN exposure were 0.363 (0.208, 0.519), 0.364 (0.211, 0.516) and 0.217 (0.051, 0.383); 1.228 (1.099, 1.371), 1.356 (1.196, 1.538) and 1.269 (1.124, 1.433), respectively. Age and regular exercise showed significant modification effects on the LAN-obesity association.


Assuntos
Luz , Obesidade , Adulto , Humanos , Obesidade/epidemiologia , Saúde Pública , China/epidemiologia
11.
Prostate ; 84(3): 254-268, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37905842

RESUMO

BACKGROUND: Even though prostate cancer (PCa) patients initially respond to androgen deprivation therapy, some will eventually develop castration resistant prostate cancer (CRPC). Androgen receptor (AR) mediated cell signaling is a major driver in the progression of CRPC while only a fraction of PCa becomes AR negative. This study aimed to understand the regulation of AR levels by N-myristoyltransferase in PCa cells. METHODS: Two enantiomers, (1S,2S)- d-NMAPPD and (1R,2R)- d-NMAPPD (LCL4), were characterized by various methods (1 H and 13 C NMR, UHPLC, high-resolution mass spectra, circular dichroism) and evaluated for the ability to bind to N-myristoyltransferase 1 (NMT1) using computational docking analysis. structure-activity relationship analysis of these compounds led to the synthesis of (1R,2R)-LCL204 and evaluation as a potential NMT1 inhibitor utilizing the purified full length NMT1 enzyme. The NMT inhibitory activity wase determined by Click chemistry and immunoblotting. Regulation of NMT1 on tumor growth was evaluated in a xenograft tumor model. RESULTS: (1R,2R)- d-NMAPPD, but not its enantiomer (1S,2S)- d-NMAPPD, inhibited NMT1 activity and reduced AR protein levels. (1R,2R)-LCL204, a derivative of (1R,2R)- d-NMAPPD, inhibited global protein myristoylation. It also suppressed protein levels, nuclear translocation, and transcriptional activity of AR full-length or variants in PCa cells. This was due to enhanced ubiquitin and proteasome-mediated degradation of AR. Knockdown of NMT1 levels inhibited tumor growth and proliferation of cancer cells. CONCLUSION: Inhibitory efficacy on N-myristoyltransferase activity by d-NMAPPD is stereospecific. (1R,2R)-LCL204 reduced global N-myristoylation and androgen receptor protein levels at low micromolar concentrations in prostate cancer cells. pharmacological inhibition of NMT1 enhances ubiquitin-mediated proteasome degradation of AR. This study illustrates a novel function of N-myristoyltransferase and provides a potential strategy for treatment of CRPC.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Masculino , Humanos , Receptores Androgênicos/metabolismo , Androgênios , Neoplasias de Próstata Resistentes à Castração/patologia , Antagonistas de Androgênios , Complexo de Endopeptidases do Proteassoma , Ubiquitinas , Linhagem Celular Tumoral
13.
Sci Adv ; 9(51): eadk1704, 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-38117883

RESUMO

Here, an Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition of 1,6-diynes and ynamines was developed, forging various functionalized C─N axially chiral indoles and pyrroles in generally good to excellent yields (up to 99%), excellent chemoselectivities, and high enantioselectivities (up to 98% enantiomeric excess) with wide substrate scope. This cocatalyzed strategy not only provided an alternative promising and reliable way for asymmetric alkyne [2+2+2] cyclotrimerization in an easy handle but also settled the issues of previous [Rh(COD)2]BF4-catalyzed system on the construction of C─N axial chirality such as complex operations, limited substrate scope, and low efficiency. In addition, control experiments and theoretical calculations disclosed that Zn(OTf)2 markedly reduced the barrier of migration insertion to significantly increase reaction efficiency, which was distinctly different from previous work on the Lewis acid for improving reaction yield through accelerating oxidative addition and reductive elimination.

14.
Dalton Trans ; 52(46): 17524-17537, 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-37961750

RESUMO

Highly active Keggin-type silicotungstic acid (SiW12) with oxygen vacancy (Ov) defects was encapsulated into the magnetic floral N-doped carbon microspheres (γ-Fe2O3@NC-300) through the facile one-step air pyrolysis of the precursor comprising core-shell Fe3O4@polydopamine (Fe3O4@PDA) and SiW12 to prepare γ-Fe2O3@NC@SiW12-300. The fabricated catalysts were systematically characterized and subsequently employed for the oxidation desulfurization (ODS) of the model fuel. The magnetic floral γ-Fe2O3@NC@SiW12-300 catalyst exhibited nearly perfect catalytic activity, which under mild conditions could remove 100% amount of 4000 ppm DBT in model fuel within 20 min (0.03 g catalysts and n(H2O2)/n(S) of 2). The catalyst activity is mainly attributed to the high activity SiW12 with the Ov defect and its outstanding dispersibility in γ-Fe2O3@NC, along with the high number of exposed active sites. A selected catalyst, γ-Fe2O3@NC@SiW12-300, showed a noticeable turnover frequency (TOF) (110.07 h-1) and lower activation energy (38.79 kJ mol-1) in oxidative desulfurization (ODS) with good recyclability. HO˙ radical was found to be the active species involved in ODS as confirmed by the EPR and scavenger experiments. Additionally, the fabricated catalyst can be conveniently separated and recycled within an externally applied magnetic field.

15.
Neuron ; 111(23): 3775-3788.e7, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-37716354

RESUMO

Parkin-mediated mitophagy has been studied extensively, but whether mutations in parkin contribute to Parkinson's disease pathogenesis through alternative mechanisms remains unexplored. Using patient-derived dopaminergic neurons, we found that phosphorylation of parkin by Ca2+/calmodulin-dependent protein kinase 2 (CaMK2) at Ser9 leads to activation of parkin in a neuronal-activity-dependent manner. Activated parkin ubiquitinates synaptojanin-1, facilitating its interaction with endophilin A1 and synaptic vesicle recycling. Neurons from PD patients with mutant parkin displayed defective recycling of synaptic vesicles, leading to accumulation of toxic oxidized dopamine that was attenuated by boosting endophilin A1 expression. Notably, combined heterozygous parkin and homozygous PTEN-induced kinase 1 (PINK1) mutations led to earlier disease onset compared with homozygous mutant PINK1 alone, further underscoring a PINK1-independent role for parkin in contributing to disease. Thus, this study identifies a pathway for selective activation of parkin at human dopaminergic synapses and highlights the importance of this mechanism in the pathogenesis of Parkinson's disease.


Assuntos
Neurônios Dopaminérgicos , Doença de Parkinson , Humanos , Neurônios Dopaminérgicos/metabolismo , Mutação , Doença de Parkinson/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Vesículas Sinápticas/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
16.
Phys Chem Chem Phys ; 25(28): 19082-19090, 2023 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-37427572

RESUMO

By using density functional theory calculations combined with the nonequilibrium Green's function method and machine learning, we systematically studied the thermoelectric properties of four kinds of porous graphene nanosheets (PGNS) before and after nitrogen doping. The results show that the thermoelectric performance of porous graphene nanosheets along the armchair or zigzag chiral direction is improved due to the dramatically enhanced power factor caused by nitrogen doping. The calculated ZT values of nitrogen-doped porous graphene nanosheets are boosted by about one order of magnitude compared with those of undoped porous graphene nanosheets at room temperature. More importantly, an anisotropic thermoelectric transport is found in the nitrogen-doped porous graphene nanosheets. The results show that the ZT values of nitrogen-doped porous graphene nanosheets along the zigzag transport direction are nearly 11 times larger than those of them along the armchair transport direction. These results reveal that the thermoelectric properties of porous graphene nanosheets can be well regulated by nitrogen doping, and provide a good theoretical guidance for their application in thermoelectric devices.

17.
Br J Cancer ; 129(5): 884-894, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37474721

RESUMO

BACKGROUND: It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers. METHODS: A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa. RESULTS: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts. CONCLUSION: Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.


Assuntos
Nicardipino , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Apoptose , Linhagem Celular Tumoral , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Nicardipino/farmacologia , Nicardipino/uso terapêutico , Complexo Repressor Polycomb 2 , Neoplasias da Próstata/tratamento farmacológico
18.
J Biol Chem ; 299(8): 105049, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37451485

RESUMO

Rufomycins constitute a class of cyclic heptapeptides isolated from actinomycetes. They are secondary metabolites that show promising treatment against Mycobacterium tuberculosis infections by inhibiting a novel drug target. Several nonproteinogenic amino acids are integrated into rufomycins, including a conserved 3-nitro-tyrosine. RufO, a cytochrome P450 (CYP)-like enzyme, was proposed to catalyze the formation of 3-nitro-tyrosine in the presence of O2 and NO. To define its biological function, the interaction between RufO and the proposed substrate tyrosine is investigated using various spectroscopic methods that are sensitive to the structural change of a heme center. However, a low- to high-spin state transition and a dramatic increase in the redox potential that are commonly found in CYPs upon ligand binding have not been observed. Furthermore, a 1.89-Å crystal structure of RufO shows that the enzyme has flexible surface regions, a wide-open substrate access tunnel, and the heme center is largely exposed to solvent. Comparison with a closely related nitrating CYP reveals a spacious and hydrophobic distal pocket in RufO, which is incapable of stabilizing a free amino acid. Molecular docking validates the experimental data and proposes a possible substrate. Collectively, our results disfavor tyrosine as the substrate of RufO and point to the possibility that the nitration occurs during or after the assembly of the peptides. This study indicates a new function of the unique nitrating enzyme and provides insights into the biosynthesis of nonribosomal peptides.


Assuntos
Aminoácidos , Sistema Enzimático do Citocromo P-450 , Oligopeptídeos , Sistema Enzimático do Citocromo P-450/metabolismo , Heme/metabolismo , Simulação de Acoplamento Molecular , Nitratos , Tirosina/metabolismo , Actinobacteria , Oligopeptídeos/biossíntese
19.
Front Oncol ; 13: 1174306, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37441417

RESUMO

Multiple primary malignant neoplasms (MPMNs) are defined as the presence of two or more malignancies with different histologies in the same patient. MPMNs are rare, accounting for fewer than 4% of all tumor cases. Depending on the time interval between the diagnosis of the different malignancies, they are classified as either simultaneous or metachronous MPMNs, with simultaneous being rarer in MPMNs. Here, we present a 63-year-old female patient presenting with multiple primary renal and thyroid carcinomas and discuss the risk factors, treatment options, and prognosis of rare dual carcinomas. We focus on managing multidisciplinary teams and selecting individualized treatment options to deliver valuable treatment strategies to patients.

20.
J Environ Manage ; 344: 118358, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37329578

RESUMO

Agriculture wastes have been proved to be the potential adsorbents to remove azo dye from textile wastewater, but the post-treatment of azo dye loaded agriculture waste is generally ignored. A three-step strategy including sequential adsorption-biomethanation-composting was developed to realize the co-processing of azo dye and corn straw (CS). Results showed that CS represented a potential adsorbent to remove methyl orange (MO) from textile wastewater, with the maximum MO adsorption capacity of 10.00 ± 0.46 mg/g, deriving from the Langmuir model. During the biomethanation, CS could serve as electron donor for MO decolorization and substrate for biogas production simultaneously. Though the cumulative methane yield of CS loaded with MO was 11.7 ± 2.28% lower than that of blank CS, almost complete de-colorization of MO could be achieved within 72 h. Composting could achieve the further degradation of aromatic amines (intermediates during the degradation of MO) and decomposition of digestate. After 5 days' composting, 4-aminobenzenesulfonic acid (4-ABA) was not detectable. The germination index (GI) also indicated that the toxicity of aromatic amine was eliminated. The overall utilization strategy gives novel light on the management of agriculture waste and textile wastewater.


Assuntos
Compostagem , Poluentes Químicos da Água , Águas Residuárias , Zea mays/metabolismo , Adsorção , Poluentes Químicos da Água/química , Compostos Azo/química , Corantes/química , Cinética
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