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1.
J Alzheimers Dis ; 101(s1): S141-S154, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39422951

RESUMO

One pathological feature of Alzheimer's disease (AD) is the dysregulated metal ions, e.g., zinc, copper, and iron in the affected brain regions. The dysregulation of metal homeostasis may cause neurotoxicity and directly addressing these dysregulated metals through metal chelation or mitigating the downstream neurotoxicity stands as a pivotal strategy for AD therapy. This review aims to provide an up-to-date comprehensive overview of the application of metal chelators and drugs targeting metal-related neurotoxicity, such as antioxidants (ferroptotic inhibitors), in the context of AD treatment. It encompasses an exploration of their pharmacological effects, clinical research progress, and potential underlying mechanisms.


Assuntos
Doença de Alzheimer , Quelantes , Metais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Quelantes/uso terapêutico , Metais/metabolismo , Animais , Zinco/uso terapêutico , Zinco/metabolismo , Antioxidantes/uso terapêutico , Antioxidantes/farmacologia , Ferro/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cobre/metabolismo
2.
Zool Res ; 45(6): 1235-1248, 2024 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-39397243

RESUMO

Stroke is a major cause of death and disability worldwide, with the majority of cases resulting from ischemic events due to arterial occlusion. Current therapeutic approaches focus on rapid reperfusion through intravenous thrombolysis and intravascular thrombectomy. Although these interventions can mitigate long-term disability, reperfusion itself may induce neuronal injury. The exact mechanisms underlying neuronal damage following cerebral ischemia have yet to be reported. Recent research suggests that ferroptosis may play a significant role in post-ischemic neuronal death, which can be targeted to prevent neuronal loss. This review explores the three essential hallmarks of ferroptosis: the presence of redox-active iron, the peroxidation of polyunsaturated fatty acid-containing phospholipids, and the loss of lipid peroxide repair capacity. The involvement of ferroptosis in neuronal injury following ischemic stroke is also explored, along with an overview of ferroptosis-associated changes in different ischemic stroke animal models. Furthermore, recent therapeutic interventions targeting the ferroptosis pathway, as well as the opportunities, difficulties, and future directions of ferroptosis-targeted therapies in ischemic stroke, are discussed.


Assuntos
Modelos Animais de Doenças , Ferroptose , AVC Isquêmico , Ferroptose/fisiologia , Animais , Humanos , Isquemia Encefálica , Acidente Vascular Cerebral
3.
Mol Nutr Food Res ; : e2400535, 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39361249

RESUMO

SCOPE: This study aims to investigate the effect of sulforaphane (SFN) on hepatic metabolism and gut microbiota in a shifted circadian rhythm (CR) mouse model fed with a high-fat diet (HFD). METHODS AND RESULTS: A shifted CR mouse model with HFD is constructed. Biochemical analyses are used to evaluate the effects of SFN on lipid accumulation and liver function. Targeted metabolomics is used for liver metabolites. Results from hematoxylin and eosin staining and Oil Red O staining show that SFN improves liver lipid accumulation and intestinal inflammatory damage in shifted CR treatment with HFD. The concentrations of amino acid metabolites are increased, and the levels of bile acid metabolites are significantly decreased by SFN treatment. Results from 16S rRNA gene sequencing indicate that SFN modulates gut microbiota, particularly by enhancing beneficial bacteria such as Lachnospiraceae, Lactobacillus, Alistipes, Akkermansia, and Eubacteriaum coprostanoligenes. Correlation analysis confirms a close relationship between intestinal microbiota and hepatic metabolites. SFN significantly regulates CR protein expression in the hypothalamus and liver tissues. CONCLUSION: SFN alleviates hepatic metabolic disorder and gut microbiota dysbiosis induced by CR disruption under a high-fat diet in a mouse model, indicating the potential of SFN in regulating CR disruption.

4.
Mikrochim Acta ; 191(11): 701, 2024 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-39461925

RESUMO

A dual-responsive ratio electrochemical-colorimetric method for nitrite (NO2-) is established based on the combination of nanoenzyme (Mn3O4) catalysis with diazotization reactions. The Mn3O4 can oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue TMBox. The NO2- induces the diazotization reaction of TMBox, leading to a decrease of  the signal at 652 nm and the generation of a new signal from diazotized TMBox at 445 nm. Furthermore, the presence of NO2- reduces the electrochemical oxidation signal of TMB and simultaneously provides its electrochemical signal. Compared with traditional single-mode detection, dual-mode detection offers higher sensitivity, lower detection limits, and better interference resistance. The inherent advantages of this method make it feasible to detect NO2- in real samples, offering broad prospects for applications in food safety and environmental monitoring.


Assuntos
Benzidinas , Colorimetria , Técnicas Eletroquímicas , Limite de Detecção , Nitritos , Nitritos/análise , Colorimetria/métodos , Técnicas Eletroquímicas/métodos , Benzidinas/química , Contaminação de Alimentos/análise , Oxirredução , Monitoramento Ambiental/métodos , Análise de Alimentos/métodos , Catálise
5.
Microorganisms ; 12(10)2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39458325

RESUMO

The exopolysaccharide (EPS) produced by Pantoea alhagi NX-11, referred to as alhagan, enhances plant stress resistance, improves soil properties, and exhibits notable rheological properties. Despite these benefits, the exact bio-synthetic process of alhagan by P. alhagi NX-11 remains unclear. This study focused on sequencing the complete genome of P. alhagi NX-11 and identifying an alhagan synthesis gene cluster (LQ939_RS12550 to LQ939_RS12700). Gene annotation revealed that alhagan biosynthesis in P. alhagi NX-11 follows the Wzx/Wzy-dependent pathway. Furthermore, transcriptome analysis of P. alhagi NX-11 highlighted significant upregulation of four glycosyltransferase genes (alhH, wcaJ, alhK, and alhM) within the alhagan synthesis gene cluster. These glycosyltransferases are crucial for alhagan synthesis. To delve deeper into this process, two upregulated and uncharacterized glycosyltransferase genes, alhH and alhK, were knocked out. The resulting mutants, ΔalhH and ΔalhK, showed a notable decrease in EPS yield, reduced molecular weight, and altered monosaccharide compositions. These findings contribute to a better understanding of the alhagan biosynthesis mechanism in P. alhagi NX-11.

6.
Phytochem Anal ; 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39313958

RESUMO

INTRODUCTION: Traditionally, Callicarpa species have been utilized their anti-inflammatory and hemostatic properties. Prominently featured species in the 2020 Edition of the Chinese Pharmacopoeia were Callicarpa nudiflora (CN), Callicarpa macrophylla (CM), Callicarpa formosana (CF), and Callicarpa kwangtungensis (CK), which were formulated into several medicinal preparations. Extensive applications led to the significant depletion of CN's wild resources. The management of germplasm resources was significantly disordered. Adulteration issues were also prevalent. OBJECTIVE: It is imperative that the study aims to identify alternative sources for CN and other pharmacopeial varieties and develop methods to distinguish different Callicarpa species. RESULTS: Data were acquired using three mass spectrometry modes: Data Dependent Analysis (DDA), Data-Independent Analysis (DIA), and full mass spectrometry (MS). The DDA mode identified or inferred information on 54 compounds. The Full MS mode identified or inferred 74 compounds, including 20 that were previously unreported in Callicarpa. These compounds were confirmed using standards. The DIA mode did not facilitate identification due to missing precursor ion data. With metabolomics, 19 differential compounds were identified or inferred. Luteolin, chrysoeriol, and quercetin were selected as potential markers, integrating the 10 active compounds from network pharmacology. CONCLUSION: Based on the relative abundance of these markers, it was proposed that Callicarpa giraldii Hesse ex Rehd. var. (CGHRV) and CM could serve as alternative resource species to CN, while CGHRV and Callicarpa giraldii Hesse ex Rehd. (CGHR) could substitute the pharmacopeial CM. Callicarpa longissimi (CLG) was suggested as an alternative to CK, while Callicarpa cathayana (CC) and Callicarpa rubella (CRL) could replace CF. Furthermore, the absence of certain compounds in CK presented a novel opportunity for the differentiation of various Callicarpa species.

7.
J Agric Food Chem ; 72(40): 22054-22062, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39320050

RESUMO

As part of continuous work to explore novel and efficient fungicides originating from natural products, a series of cyclobutyl oxime ester derivatives containing an α,ß-unsaturated carbonyl moiety were designed and synthesized. In line with the primary evaluation of the inhibitory effect on common pathogenic fungi causing crop failure, a systematic study on the antifungal activity of target compounds against Rhizoctonia solani was carried out. Most target compounds exhibited satisfactory antifungal activity, and 10 of them were superior to the positive control trifloxystrobin. The most notable median effective concentration (EC50) of compound 6b was 1.70 µg/mL, which was considerable for an intensive study. The control efficacy of compound 6b on potted rice against R. solani was superior to trifloxystrobin at identical concentration. The mycelial morphology and cell membrane permeability of the treated fungi were disrupted, and the meaningful enzyme activities of SDH and POD were also restrained. The reactive oxygen species, nuclear morphology, and mitochondrial membrane potential of the treated hypha reflected an apparent difference compared with the normal morphology, which represented mitochondrial function damage. In addition, chemical features essential for the activity and docking mode within the compound and cytochrome bc1 complex were accessed by computer-aided technology. This study provided insights into the development of new green and efficient fungicides targeting the mitochondria.


Assuntos
Fungicidas Industriais , Mitocôndrias , Oximas , Rhizoctonia , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/síntese química , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/crescimento & desenvolvimento , Oximas/química , Oximas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Relação Estrutura-Atividade , Ésteres/química , Ésteres/farmacologia , Doenças das Plantas/microbiologia , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Estrutura Molecular , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Testes de Sensibilidade Microbiana
8.
Chem Biodivers ; : e202401955, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39230658

RESUMO

In order to develop novel, efficient and green fungicides, a series of novel isoaurone derivatives were designed and synthesized, which were characterized by 1H and 13C NMR, high-resolution mass spectra and melting points. The target compounds showed different inhibitory activities against seven plant pathogenic fungi. Compounds 1, 12, 17, 20, 22, 24 and intermediate A showed more than 90% inhibition rates against S. s at 50 mg/L. Interestingly, compound 22 and intermediate A showed the great inhibitory effect against S. s with EC50 values of 4.65 and 4.24 mg/L, which were better than the lead compound isoaurone (EC50 = 15.62 mg/L). The EC50 values of compounds 17 and 24 against B. c were 13.94 and 22.13 mg/L. Moreover, compound 19 displayed significant antifungal activity against G. g with the EC50 value of 11.88 mg/L. Theoretical calculations by DFT revealed that the α, ß-unsaturated carbonyl bond and the benzyl ring are very importantly linked to the strength of the fungicidal activity. Therefore, this study identified a valuable antifungal lead compound for further development of green fungicides.

9.
Angew Chem Int Ed Engl ; : e202415726, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39240581

RESUMO

The electrochemical CO2 reduction reaction (ECR) is a promising pathway to producing valuable chemicals and fuels. Despite extensive studies reported, improving CO2 adsorption for local CO2 enrichment or water dissociation to generate sufficient H* is still not enough to achieve industrial-relevant current densities. Herein, we report a "two-in-one" catalyst, defective Bi nanosheets modified by CrOx (Bi-CrOx), to simultaneously promote CO2 adsorption and water dissociation, thereby enhancing the activity and selectivity of ECR to formate. The Bi-CrOx exhibits an excellent Faradic efficiency (≈ 100 %) in a wide potential range from ‒0.4 to ‒0.9 V. In addition, it achieves a remarkable formate partial current density of 687 mA cm‒2 at a moderate potential of ‒0.9 V without iR compensation, the highest value at ‒0.9 V reported so far. Control experiments and theoretical simulations revealed that the defective Bi facilitates CO2 adsorption/activation while the CrOx accounts for enhancing the protonation process via accelerating H2O dissociation. This work presents a pathway to boosting formate production through tuning CO2 and H2O species at the same time.

10.
Genes Dis ; 11(6): 101262, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39286656

RESUMO

Programmed cell death contributes to neurological damage in ischemic stroke, especially during the reperfusion stage. Several cell death pathways have been tested preclinically and clinically, including ferroptosis, necroptosis, and apoptosis. However, the sequence and complex interplay between cell death pathways during ischemia/reperfusion remains under investigation. Here, we unbiasedly investigated cell death pathways during ischemia/reperfusion by utilizing RNA sequencing analysis and immunoblot assays and revealed that ferroptosis and necroptosis occurred early post-reperfusion, followed by apoptosis. Ferroptosis inhibitor Liproxstatin-1 effectively inhibited necroptosis during reperfusion, while the necroptosis inhibitor Necrostatin-1 suppressed protein expression consistent with ferroptosis activation. Protein-protein interaction analysis and iron chelation therapy by deferoxamine mesylate indicate that iron is capable of promoting both ferroptosis and necroptosis in middle cerebral artery occlusion/repression modeled mice. Treatment of cells with iron led to a disruption in redox balance with activated necroptosis and increased susceptibility to ferroptosis. Collectively, these data uncovered a complex interplay between ferroptosis and necroptosis during ischemic stroke and indicated that multiple programmed cell death pathways may be targeted co-currently.

11.
Langmuir ; 40(36): 18999-19007, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39208070

RESUMO

In this research, the self-assembly behaviors of two different symmetry carboxylic acid derivatives (H3BTE and H4BTE) regulated by solvent and guest molecule (coronene, COR) were explored at the liquid/solid interface by scanning tunneling microscopy, and the formation mechanism was investigated by density functional theory. In 1-phenyloctane, only H3BTE molecules dissolved with extremely low concentration and self-assembled into a honeycomb structure and a new strip structure, while H4BTE could not. In 1-heptanoic acid, H3BTE and H4BTE were easily dissolved, in which H3BTE formed a regular row structure and H4BTE formed a tetragonal structure, respectively. The host-guest interaction was investigated by introducing the COR molecules into their self-assembly structures, and due to the different symmetry, H3BTE and H4BTE displayed different accommodation behavior.

12.
Talanta ; 280: 126787, 2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39213887

RESUMO

Utilizing non-invasive, real-time dynamic imaging and high-resolution detection tools to track polarity changes in Sjögren's syndrome (SS) contributes to a better understanding of the disease progression. Herein, a ratiometric polarity-sensitive fluorescent probe (DIM) was designed and synthesized, DIM consisted of dicyanoisophorone as the fluorophore and morpholine moiety as lysosome targeting. DIM showed a ratiometric response to polarity and high selectivity (unaffected by viscosity, pH, ROS, RNS, etc.), offering a more accurate analysis of intracellular polarity through a built-in internal reference calibration. The polarity abnormality of submandibular glands in non-obese diabetic (NOD) mice was revealed and verified by in vivo ratiometric fluorescence imaging of DIM, suggesting that fluorescent probe have great potential in the diagnosis of salivary gland abnormalities.


Assuntos
Corantes Fluorescentes , Lisossomos , Camundongos Endogâmicos NOD , Síndrome de Sjogren , Animais , Síndrome de Sjogren/diagnóstico por imagem , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Lisossomos/metabolismo , Lisossomos/química , Camundongos , Imagem Óptica , Glândula Submandibular/diagnóstico por imagem , Glândula Submandibular/patologia , Feminino , Morfolinas/química , Morfolinas/síntese química
13.
Talanta ; 280: 126707, 2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39146870

RESUMO

Monitoring lysosomal dynamics in real-time, especially in vivo, poses significant challenges due to the complex and dynamic nature of cellular environments. It is extremely important to construct fluorescent probes with high stability for imaging lysosomes to minimize interference from other cellular components, in order to ensure prolonged imaging. A fluorescent probe (PDB) has been proposed for targeting lysosomes, which was less affected to changes in the cellular microenvironment (such as pH, viscosity and polarity). PDB can be easily prepared by 4'-piperazinoacetophenone and 2-(4-diethylamino)-2-hydroxybenzoyl) benzoicacid, containing a piperazine group for labeling and imaging lysosomes and the high pKa value (∼9.35) allowed PDB to efficiently track lysosomes. The emission wavelength of PDB in aqueous solution was 634 nm (λex = 572 nm, Фf = 0.11). The dynamic process of lysosome induced by starvation and rapamycin was successfully explored by fluorescence imaging. Compared with the commercially available Lyso-Tracker green, the high photostability fluorescent probe can ensure 3D high-fidelity tracking and resist photobleaching. Therefore, PDB, unaffected by the cell microenvironment, successfully achieved long-term tracking of lysosomal movement, even enabling imaging in tumor-bearing mice over 11 days. The strong fluorescence signal, high stability, and long-term tracking capability indicate that PDB has tremendous potential in monitoring biological processes.


Assuntos
Corantes Fluorescentes , Lisossomos , Lisossomos/metabolismo , Lisossomos/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Animais , Humanos , Camundongos , Imagem Óptica/métodos , Camundongos Nus , Células HeLa
14.
Opt Lett ; 49(16): 4541-4544, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39146098

RESUMO

Stimulated Brillouin scattering (SBS) is a nonlinear optical phenomenon mediated from the coupling of photons and phonons. It has found applications in various realms, yet the acousto-optic interaction strength remains relatively weak. Enhancing the SBS with resonant structures could be a promising solution, but this method faces strict constraints in operational bandwidth. Here, we present the first demonstration to our knowledge of the broadband enhancement of Brillouin nonlinearities by a suspended coupled resonator optical waveguide (CROW) on an SOI platform. By comprehensively balancing the Brillouin gain and operational bandwidth, a 3-fold enhancement for the Brillouin gain coefficient (GB) and a broad operational bandwidth of over 80 GHz have been achieved. Furthermore, this 1.1 mm device shows a forward Brillouin gain coefficient of 2422 m-1W-1 and a high mechanical quality factor (Qm) of 1060. This approach marks a pivotal advancement toward wide bandwidth, low energy consumption, and compact integrated nonlinear photonic devices, with potential applications in tunable microwave photonic filters and phonon-based non-reciprocal devices.

15.
Opt Lett ; 49(17): 4918-4921, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39207997

RESUMO

Optically pumped metastable rare gas lasers have been extensively investigated as promising high-energy lasers. These systems employ discharge-excited metastable inert gases as the lasing medium. Following optical pumping, a buffer gas, typically helium, is introduced to facilitate a collisional population transfer to the p2[1/2]1 level, thereby establishing population inversion. To date, laser outputs in the watt level have been demonstrated. However, further power scaling crucially depends on the ability to stably generate high metastable densities at elevated pressures approaching atmospheric conditions. In this Letter, we report a pulsed discharge technique based on a peaking capacitor rapid discharge circuit, which is capable of producing metastable particle densities exceeding 1014 cm-3 at pressures up to 900 mbar. By employing this discharge approach in conjunction with transverse optical pumping, we have realized a maximum output power of 12.5 W from a semiconductor-pumped metastable argon laser system.

16.
Artigo em Inglês | MEDLINE | ID: mdl-39052867

RESUMO

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p up-regulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.


Assuntos
Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Magnésio , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Magnésio/metabolismo , Transição Epitelial-Mesenquimal/genética , Actinina/genética , Actinina/metabolismo , Mutação , Proteômica/métodos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Fosforilação , Linhagem Celular Tumoral , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Genômica , Regulação Neoplásica da Expressão Gênica/genética , Multiômica , Proteínas de Ligação a DNA
17.
J Med Chem ; 67(16): 14277-14291, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39072617

RESUMO

Proteolysis-targeting chimeras (PROTACs) have emerged as potentially effective therapeutic medicines, but their high molecular weight and poor solubility directly impact their oral bioavailability. This work synthesized 14C-labeled bavdegalutamide (ARV-110) as a model compound of PROTACs to evaluate its ADME features. Compared with targeted antitumor drugs, the use of food increased oral bioavailability of ARV-110 in rats from 10.75% to 20.97%, which is still undesirable. However, the therapeutic effect of ARV-110 at a low dose was much better than that of enzalutamide, demonstrating the specific catalytic medicinal properties of PROTACs. Moreover, the specific distribution of ARV-110 in subcutaneous prostate tumors was determined by quantitative whole-body autoradiography (QWBA). Notably, the specificity and activity of PROTACs take precedence over their oral absorption, and high oral bioavailability is not necessary to produce excellent therapeutic effects. This work presents a roadmap for developing future PROTAC medications from a radioactive drug metabolism and pharmacokinetics (DMPK) perspective.


Assuntos
Disponibilidade Biológica , Animais , Masculino , Administração Oral , Ratos , Humanos , Ratos Sprague-Dawley , Antineoplásicos/farmacocinética , Antineoplásicos/química , Neoplasias da Próstata/tratamento farmacológico , Proteólise/efeitos dos fármacos , Radioisótopos de Carbono , Distribuição Tecidual , Linhagem Celular Tumoral , Camundongos
18.
Food Funct ; 15(17): 8644-8660, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39045769

RESUMO

Background: Insulin resistance (IR) is closely associated with non-alcoholic fatty liver disease (NAFLD), and the gut microbiome contributes to the development of NAFLD. Sulforaphane (SFN) is a phytochemical in cruciferous vegetables that could improve lipid metabolism disorder. However, whether SFN can alleviate IR in NAFLD by regulating the intestinal flora remains unclear. Methods: SFN was administered to high fat diet (HFD)-fed Wistar rats for 10 weeks. Gut microbiota was analysed by 16S rRNA sequencing and the short chain fatty acids (SCFAs) by gas chromatography. The expression of tight junction protein and the numbers of Lactobacillus, Bacteroides and Bifidobacterium were determined by qPCR. The expression of G-protein-coupled receptor 41/43 (GPR41/43) was determined by western blot. A randomized controlled trial (RCT) was conducted in NAFLD patients with broccoli seed tablets (rich in SFN, 42 mg d-1) as intervention for 12 weeks. Thirty-six volunteers with abnormal glucose before the broccoli seed tablet treatment were selected in the intervention group to analyze their blood glucose, insulin, homeostasis model assessment-insulin resistance index (HOMA-IRI), homeostasis model assessment-insulin sensitivity index (HOMA-ISI) and glucagon-like peptide (GLP-1). Results: SFN reduced blood glucose and HOMA-IRI while increasing insulin sensitivity in HFD rats. SFN reduced glycogen synthase kinase 3 (GSK-3), phosphoenolpyruvate carboxykinase (PEPCK) activity, and phosphorylation of serine residues of IRS-2 induced by HFD. SFN reshaped the gut microbiota composition of HFD-induced rats and, especially, increased the content of Bacteroidaceae, Lactobacillaceae and Bifidobacteriaceae, which are related to the improvement from SFN of the blood glucose and HOMA-IRI. The increased numbers of Bacteroides and Lactobacillus were the targets of SFN to enhance the expression of tight junction proteins ZO-1 and occludin, thereby lowering lipopolysaccharide content to reduce inflammation, ultimately alleviating IR. Bacteroides and Lactobacillus produced SCFAs, which activated GPR41/43 to secrete GLP1. Moreover, it was also confirmed in RCT that SFN intervention increased the level of GLP1 in NAFLD patients, which was positively correlated with the reduction of blood glucose and HOMA-IR. Conclusions: SFN alleviated IR in NAFLD via the Bacteroides and Lactobacillus SCFAs-GPR41/43-GLP1 axis and protected the intestinal mucosal barrier to decrease inflammation.


Assuntos
Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Peptídeo 1 Semelhante ao Glucagon , Resistência à Insulina , Isotiocianatos , Hepatopatia Gordurosa não Alcoólica , Ratos Wistar , Receptores Acoplados a Proteínas G , Sulfóxidos , Isotiocianatos/farmacologia , Animais , Ratos , Humanos , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ácidos Graxos Voláteis/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lactobacillus/efeitos dos fármacos , Pessoa de Meia-Idade , Dieta Hiperlipídica , Feminino , Adulto
19.
J Med Chem ; 67(12): 10275-10292, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38842846

RESUMO

Due to the wide application of reporter gene-related visible/NIR-I bioluminescent imaging, multiplexed fluorescence imaging across visible/NIR-I/NIR-II has excellent potential in biomedical research. However, in vivo multiplexed imaging applications across those regions have rarely been reported due to the lack of proper fluorophores. Herein, nine squaraine dyes, which exhibit diverse adsorption and emission wavelengths, were synthesized. Among them, water-soluble SQ 710-5k and SQ 905 were found to have significant absorption differences, which allowed the tumor and lymph nodes to be identified. Then, for the first time, six-channel multiplexed fluorescence imaging across visible/NIR-I/II was achieved by coordination with reporter gene-related bioluminescent phosphors. Additional research revealed that SQ 710-5k exhibited higher-quality blood vessels and tumor imaging in NIR-II. H-aggregates SQ 905 demonstrated a high photothermal conversion efficiency for photothermal therapy. This study proposed an approach to creating small molecular dyes that coordinate with reporter gene-related bioluminescent phosphors for six-color fluorescence imaging.


Assuntos
Ciclobutanos , Corantes Fluorescentes , Imagem Óptica , Fenóis , Terapia Fototérmica , Ciclobutanos/química , Ciclobutanos/síntese química , Animais , Corantes Fluorescentes/química , Humanos , Camundongos , Fenóis/química , Terapia Fototérmica/métodos , Raios Infravermelhos , Camundongos Nus , Linhagem Celular Tumoral , Feminino , Estrutura Molecular , Camundongos Endogâmicos BALB C
20.
Front Oncol ; 14: 1297405, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38868533

RESUMO

Objectives: The aims of this study were to explore the incidence characteristics and trend prediction of lymphoma from 2005 to 2035, and to provide data basis for the prevention and control of lymphoma in China. Method: The data on lymphoma incidence in China from 2005 to 2017 were obtained from the Chinese Cancer Registry Annual Report. The Joinpoint regression model was used to calculate annual percentage change (APC) and average annual percentage change (AAPC) to reflect time trends. Age-period-cohort models were conducted to estimate age, period, and cohort effects on the lymphoma incidence. A Bayesian age-period-cohort model was used to predict lymphoma incidence trends from 2018 to 2035. Results: From 2005 to 2017, the incidence of lymphoma was 6.26/100,000, and the age-standardized incidence rate (ASIR) was 4.11/100,000, with an AAPC of 1.4% [95% confidence interval (CI): 0.3%, 2.5%]. The ASIR was higher in men and urban areas than in women and rural areas, respectively. The age effect showed that the incidence risk of lymphoma increased with age. In the period effect, the incidence risk of lymphoma in rural areas decreased first and then increased with 2010 as the cutoff point. The overall risk of lymphoma incidence was higher in the cohort before the 1970-1974 birth cohort than in the cohort after. From 2018 to 2035, the lymphoma incidence in men, women, and urban areas will show an upward trend. Conclusion: From 2005 to 2017, the incidence of lymphoma showed an increasing trend, and was different in regions, genders, and age groups in China. It will show an upward trend from 2018 to 2035. These results are helpful for the formulation and adjustment of lymphoma prevention, control, and management strategies, and have important reference significance for the treatment of lymphoma in China.

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