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1.
J Ethnopharmacol ; 334: 118515, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38972530

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In Mongolian medicine, Loulu flower (LLF), the dried inflorescence of Rhaponticum uniflorum (L.) DC. from the Compositae family, has been used to clear heat and relieve toxicity for millennia, particularly in the treatment of pneumonia. AIM OF THIS STUDY: To reveal the effects of LLF on mice with lipopolysaccharide (LPS)-stimulated acute lung injury (ALI) and elucidate the underlying mechanisms. MATERIALS AND METHODS: ALI was established in BALB/c mice via nasal drops administration of LPS (5 mg/kg). The mice were then orally administrated with various doses of LLF extracts and the positive drug dexamethasone (DEX, 5 mg/kg), once daily for seven consecutive days. Last day, after being stimulated with LPS for 6h, the mice were closed dislocation of cervical vertebra, the serum, bronchus alveolar lavage fluid (BALF) and lung tissue were put into the EP tube and stored at -80 °C for further analysis. The changes of histopathology were tested by hematoxylin and eosin stain (H&E), the levels of, IL-1ß, IL-18, TNF-α and IL-4 in BALF and serum were measured by ELISA. The pathways related to the treatment of ALI were predicted by network pharmacology. The expression levels of TLR4/NF-κB and NLRP3 signaling pathway-associated proteins, COX-2 and ERK were tested by western blotting. The levels of P65 and NLRP3 in lung tissues were determined by immunofluorescence analysis. RESULTS: LLF total extract and the extract parts could alleviate the inflammatory cell infiltration, thicken the alveolar walls in lung tissues, reduce the levels of IL-18, IL-1ß in BALF, the TNF-α in both BALF and serum, meantime enhance the level of IL-4 in BALF and serum in mice with LPS-induced ALI. Our network pharmacology and comprehensive gene ontology analyses revealed the active constituents of LLF and the pathways, including TLR4/NF-κB, NLRP3 and MAPK signaling pathways, which play significant roles in ALI. Furthermore, both the total extract and its extraction portions suppressed the expressions of proteins related with the COX-2, p-ERK and TLR4/NF-κB signaling pathway (TLR4, p-IκB, p-p65), as well as the NLRP3 signaling pathway (NLRP3, cleaved caspase-1, caspase-1, IL-1ß). CONCLUSION: LLF could improve the pathological changes and reducing inflammatory reactions in mice induced by LPS. The mechanism may be related to the modulation of the TLR4/NLRP3 signaling pathways.

2.
Front Immunol ; 15: 1412022, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38881898

RESUMO

Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by local abnormal dilation of the aorta accompanied by vascular smooth muscle cell (VSMC) dysfunction and chronic inflammation. VSMC dedifferentiation, transdifferentiation, and increased expression of matrix metalloproteinases (MMPs) are essential causes of AAA formation. Previous studies from us and others have shown that Anemoside B4 (AB4), a saponin from Pulsatilla chinensis, has anti-inflammatory, anti-tumor, and regulatory effects on VSMC dedifferentiation. The current study aimed to investigate whether AB4 inhibits AAA development and its underlying mechanisms. By using an Ang II induced AAA model in vivo and cholesterol loading mediated VSMC to macrophage transdifferentiation model in vitro, our study demonstrated that AB4 could attenuate AAA pathogenesis, prevent VSMC dedifferentiation and transdifferentiation to macrophage-like cells, decrease vascular inflammation, and suppress MMP expression and activity. Furthermore, KLF4 overexpression attenuated the effects of AB4 on VSMC to macrophage-like cell transition and VSMC inflammation in vitro. In conclusion, AB4 protects against AAA formation in mice by inhibiting KLF4 mediated VSMC transdifferentiation and inflammation. Our study provides the first proof of concept of using AB4 for AAA management.


Assuntos
Aneurisma da Aorta Abdominal , Transdiferenciação Celular , Inflamação , Fator 4 Semelhante a Kruppel , Miócitos de Músculo Liso , Saponinas , Animais , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/prevenção & controle , Aneurisma da Aorta Abdominal/induzido quimicamente , Transdiferenciação Celular/efeitos dos fármacos , Fator 4 Semelhante a Kruppel/metabolismo , Camundongos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Inflamação/metabolismo , Saponinas/farmacologia , Modelos Animais de Doenças , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Angiotensina II/farmacologia , Humanos
3.
J Chromatogr A ; 1730: 465094, 2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38889584

RESUMO

In this study, the collision induced dissociation tandem mass spectrometry (CID-MS/MS) fragmentation pathway of chemical components in rhubarb was wholly explored using 34 standards by UHPLC-QTOF-MS/MS in negative ion mode. In consequently, the diagnostic product ions for speedy screening and categorization of chemical components in rhubarb were ascertained based on their MS/MS splitting decomposition patterns and intensity analysis. According to these findings, a fresh two-step data mining strategy had set up. The initial key step involves the use of characteristic product ions and neutral loss to screen for different types of substituents and basic skeletons of compounds. The subsequent key step is to screen and classify different types of compounds based on their characteristic product ions. This method can be utilized for rapid research, classification, and identification of compounds in rhubarb. A total of 356 compounds were rapidly identified or tentatively characterized in three rhubarb species extracts, including 150 acylglucoside, 125 anthraquinone, 65 flavanols and 15 other compounds. This study manifests that the analytical strategy is feasible for the analysis of complex natural products in rhubarb.

4.
Zhongguo Zhong Yao Za Zhi ; 49(10): 2818-2827, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38812181

RESUMO

This study aims to explore the potential metabolic pathways and targets of Puerariae Thomsonii Radix in the clinical treatment of mild dyslipidemia. UPLC-Q-TOF-MS and EASY-nLC-timsTOF-Pro2 were employed to perform metabolomic and proteomic analyses of the plasma samples collected from the patients with mild dyslipidemia at baseline and after 12 weeks of treatment with Puerariae Thomsonii Radix. The multivariate statistical analysis was carried out for comparison between groups, and the correlation analysis was performed for the metabolites and proteins closely related to mild dyslipidemia with the blood lipid indexes. The possible pathways and targets for mitigating mild dyslipidemia were screened out by the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. The results showed that 56 differential metabolites and 78 differential proteins in the plasma of patients were associated with Puerariae Thomsonii Radix treatment. In addition, changes were detected for the proteins or metabolites(ApoB-100, 9,10-DHOME, GAPDH, PGK1, PGAM1, ENO1, etc.) involved in lipoprotein, lipid, and glucose metabolism and the proteins or metabolites(oxidized phospholipid, PLA2G7, LTA4H, etc.) related to inflammation and oxidative stress. Puerariae Thomsonii Radix may down-regulate the overexpression of ApoB-100, activate the peroxisome proliferator-activated receptor α/γ(PPARα/γ), promote the catabolism of fat and glycerol, and alleviate the oxidative stress mediated by oxidized phospholipids and leukotriene B4(LTB4) in the treatment of mild dyslipidemia.


Assuntos
Medicamentos de Ervas Chinesas , Dislipidemias , Metabolômica , Proteômica , Pueraria , Humanos , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Dislipidemias/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Pueraria/química , Masculino , Feminino , Pessoa de Meia-Idade , Adulto
5.
J Med Chem ; 67(9): 7569-7584, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38690687

RESUMO

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.


Assuntos
Hipoglicemiantes , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteólise , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Descoberta de Drogas , Células Hep G2 , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
6.
Fitoterapia ; 176: 106010, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38740341

RESUMO

Flowers of Hosta plantaginea (H. plantaginea), a widely utilized medicinal herb in Mongolian medicine, holds a significant historical background in terms of its medicinal applications. This herb is renowned for its ability to clear heat and detoxify the body, alleviate cough, and provide relief to the throat. However, the active ingredients and the potential mechanism of action remain ambiguity. The objective of this study was to conduct a comprehensive analysis of the efficacy of H. plantaginea in treating pneumonia, identify its active ingredients and unveil the pharmacological mechanism in the treatment of pneumonia. In vivo experiments demonstrate the plant's anti-pneumonia properties, while mass spectrometry analysis identifies 62 chemicals, with 14 absorbed into the bloodstream. Network pharmacology and Venn analysis reveal 195 targets of 52 active ingredients, with 49 gene targets common to H. plantaginea and pneumonia. Protein-protein interaction (PPI) network construction and enrichment analysis highlight the key targets and pathways such as AKT, EGFR, IL-17. Western blotting confirms downregulation of these pathways, indicating the anti-inflammatory effects of H. plantaginea in treating acute lung injury. Our findings showed that the treatment of ALI with the H. plantaginea exerts its anti-inflammatory effects through multiple components, targets, and pathways. This study established a solid experimental foundation for investigating the various components, targets, and pathways involved in the treatment of pneumonia using H. plantaginea. It offers valuable insights from multiple perspectives and can serve as a reference for the clinical application of this plant in pneumonia treatment.


Assuntos
Flores , Farmacologia em Rede , Compostos Fitoquímicos , Pneumonia , Animais , Flores/química , Pneumonia/tratamento farmacológico , Camundongos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Hosta , Anti-Inflamatórios/farmacologia , Mapas de Interação de Proteínas , Masculino , Plantas Medicinais/química , Medicina Tradicional da Mongólia , Lesão Pulmonar Aguda/tratamento farmacológico
7.
RSC Adv ; 14(18): 12556-12560, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38638814

RESUMO

Selenium-containing compounds are important scaffolds owing to their value in medicinal chemistry, biochemistry and material chemistry. Herein, we report an electrochemical approach to access seleno-benzazepines through an oxidative radical cascade cyclization of dienes with diselenides under metal-free, external oxidant-free and base-free conditions. In a simple undivided cell, various dienes and diselenides were suitable for this transformation, generating the desired products in up to 84% yields. This method provides a green and convenient route for the synthesis of valuable selenium-containing seven-membered N-heterocycles from simple starting materials.

8.
Appl Microbiol Biotechnol ; 108(1): 292, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38592514

RESUMO

Pulchinenoside B4, a natural saponin monomer from the Pulsatilla plant, plays an important role as an immunomodulator in the treatment of acute inflammation. Oral ulcer (OU) is a common ulcerative injury disease that occurs in the oral mucosa, including mucosal ulceration and abnormalities of lips and tongue. A close correlation exists between gut microbiota and circulating metabolites in patients with OU. However, the correlation between gut microbiota and serum metabolomics is not clear. Therefore, this study aimed to explore the changes in gut microbiota and metabolites in OU. The 16S ribosomal RNA (16S rRNA) gene sequencing was used to detect the changes in the composition of gut microbiota in OU rat model. Moreover, the endogenous small metabolites were explored by collecting the non-targeted serum metabolomics data. A total of 34 OU-related biomarkers were identified, mainly related to fatty acid metabolism and inflammatory pathways. The administration of B4 effectively reduced the occurrence of OU and restored the levels of multiple endogenous biomarkers and key gut microbial species to the normal level. This study demonstrated that the gut microbiota and metabolites were altered in the OU rat model, which were significantly restored to the normal level by B4, thereby showing good application prospects in the treatment of OU. KEY POINTS: • The first investigating the correlation between OU and gut microbiota. • A close correlation between metabolites and gut microbiota in OU disease was successfully identified. • Pulchinenoside B4 ameliorates oral ulcers in rats by modulating gut microbiota and metabolites.


Assuntos
Microbioma Gastrointestinal , Úlceras Orais , Humanos , Animais , Ratos , RNA Ribossômico 16S/genética , Mucosa Bucal , Biomarcadores
9.
ACS Appl Mater Interfaces ; 16(15): 19205-19213, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38591860

RESUMO

An artificial nociceptor, as a critical and special bionic receptor, plays a key role in a bioelectronic device that detects stimuli and provides warnings. However, fully exploiting bioelectronic applications remains a major challenge due to the lack of the methods of implementing basic nociceptor functions and nociceptive blockade in a single device. In this work, we developed a Pt/LiSiOx/TiN artificial nociceptor. It had excellent stability under the 104 endurance test with pulse stimuli and exhibited a significant threshold current of 1 mA with 1 V pulse stimuli. Other functions such as relaxation, inadaptation, and sensitization were all realized in a single device. Also, the pain blockade function was first achieved in this nociceptor with over a 25% blocking degree, suggesting a self-protection function. More importantly, an obvious depression was activated by a stimulus over 1.6 V due to the cooperative effects of both lithium ions and oxygen ions in LiSiOx and the dramatic accumulation of Joule heat. The conducting channel ruptured partially under sequential potentiation, thus achieving nociceptive blockade, besides basic functions in one single nociceptor, which was rarely reported. These results provided important guidelines for constructing high-performance memristor-based artificial nociceptors and opened up an alternative approach to the realization of bioelectronic systems for artificial intelligence.


Assuntos
Inteligência Artificial , Nociceptores , Humanos , Nociceptores/fisiologia , Dor , Biônica , Íons/farmacologia
10.
Acta Pharm Sin B ; 14(4): 1661-1676, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572101

RESUMO

Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by changes in kidney structure and function. The natural product rosmarinic acid (RA) has demonstrated therapeutic effects, including anti-inflammation and anti-oxidative-stress, in renal damage or dysfunction. In this study, we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels. Our results demonstrated that RA significantly alleviated renal tubular epithelial injury, particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes, while attenuating the inflammatory response of macrophages, oxidative stress, and cytotoxicity of natural killer cells. These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage, oxidative stress, and inflammation, offering valuable guidance for the clinical application of RA in the treatment of DN.

11.
ACS Chem Neurosci ; 15(10): 2042-2057, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38656184

RESUMO

Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 µM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.


Assuntos
Benzofuranos , Indanos , Fármacos Neuroprotetores , Piperidinas , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Piperidinas/farmacologia , Piperidinas/síntese química , Piperidinas/química , Indanos/farmacologia , Indanos/síntese química , Indanos/química , Benzofuranos/farmacologia , Benzofuranos/síntese química , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Masculino , Sobrevivência Celular/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico
12.
J Ethnopharmacol ; 328: 118082, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38522625

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Longdan zhike tablet (LDZK) is a Tibetan medicine formula commonly used in the highland region of Tibet, China, to ameliorate respiratory diseases, such as acute bronchitis and asthma. In Chinese traditional medicine, some herbal formulas with anti-inflammatory properties targeting the respiratory system are clinically adopted as supplementary therapies for chronic obstructive pulmonary disease (COPD). However, the specific anti-COPD effects of LDZK remain to be evaluated. AIM OF THE STUDY: The aim of this study is to identify the principal bioactive compounds in LDZK, and elucidate the effects and mechanisms of the LDZK on COPD. METHODS: High-resolution mass spectrometry was utilized for a comprehensive characterization of the chemical composition of LDZK. The therapeutic effects of LDZK were assessed on the LPS-papain-induced COPD mouse model, and LPS-induced activation model of A549 cells. The safety of LDZK was evaluated by orally administering a single dose of 30 g/kg to rats and monitoring physiological and biochemical indicators after a 14-day period. Network pharmacology and Western blot analysis were employed for mechanism prediction of LDZK. RESULTS: A comprehensive analysis identified a total of 45 compounds as the major constituents of LDZK. Oral administration of LDZK resulted in notable ameliorative effects in respiratory function, accompanied by reduced inflammatory cell counts and cytokine levels in the lungs of COPD mice. Acute toxicity tests demonstrated a favorable safety profile at a dose equivalent to 292 times the clinically prescribed dose. In vitro studies revealed that LDZK exhibited protective effects on A549 cells by mitigating LPS-induced cellular damage, reducing the release of NO, and downregulating the expression of iNOS, COX2, IL-1ß, IL-6, and TNF-α. Network pharmacology and Western blot analysis indicated that LDZK primarily modulated the MAPK signaling pathway and inhibited the phosphorylation of p38/ERK/JNK. CONCLUSIONS: LDZK exerts significant therapeutic effects on COPD through the regulation of the MAPK pathway, suggesting its potential as a promising adjunctive therapy for the treatment of chronic inflammation in COPD.


Assuntos
Medicina Tradicional Tibetana , Doença Pulmonar Obstrutiva Crônica , Ratos , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Pulmão , Transdução de Sinais
13.
Food Chem ; 445: 138648, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38354639

RESUMO

This research investigates the formation of amyloid fibrils using enzymatically hydrolyzed peptides from gluten, including its components glutenin and gliadin. After completing the fibrillation incubation, the gluten group demonstrated the most significant average particle size (908.67 nm) and conversion ratio (57.64 %), with a 19.21 % increase in thioflavin T fluorescence intensity due to self-assembly. The results indicated increased levels of ß-sheet structures after fibrillation. The gliadin group exhibited the highest zeta potential (∼13 mV) and surface hydrophobicity (H0 = 809.70). Around 71.15 % of predicted amyloidogenic regions within gliadin peptides showed heightened hydrophobicity. These findings emphasize the collaborative influence of both glutenin and gliadin in the formation of gluten fibrils, influenced by hydrogen bonding, hydrophobic, and electrostatic interactions. They also highlight the crucial role played by gliadin with amyloidogenic fragments such as ILQQIL and SLVLQTL, aiming to provide a theoretical basis for understanding the utilization of gluten proteins.


Assuntos
Amiloide , Gliadina , Amiloide/metabolismo , Gliadina/química , Peptídeos/química , Glutens/química , Conformação Proteica em Folha beta , Fragmentos de Peptídeos/química
14.
Nat Commun ; 15(1): 1132, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326298

RESUMO

The exponential growth of various complex images is putting tremendous pressure on storage systems. Here, we propose a memristor-based storage system with an integrated near-storage in-memory computing-based convolutional autoencoder compression network to boost the energy efficiency and speed of the image compression/retrieval and improve the storage density. We adopt the 4-bit memristor arrays to experimentally demonstrate the functions of the system. We propose a step-by-step quantization aware training scheme and an equivalent transformation for transpose convolution to improve the system performance. The system exhibits a high (>33 dB) peak signal-to-noise ratio in the compression and decompression of the ImageNet and Kodak24 datasets. Benchmark comparison results show that the 4-bit memristor-based storage system could reduce the latency and energy consumption by over 20×/5.6× and 180×/91×, respectively, compared with the server-grade central processing unit-based/the graphics processing unit-based processing system, and improve the storage density by more than 3 times.

15.
Arch Pharm (Weinheim) ; 357(5): e2300603, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38290060

RESUMO

Alzheimer's disease (AD) is a multifactorial neurological disease, and the multitarget directed ligand (MTDL) strategy may be an effective approach to delay its progression. Based on this strategy, 27 derivatives of l-tryptophan, 3a-1-3d-1, were designed, synthesized, and evaluated for their biological activity. Among them, IC50 (inhibitor concentration resulting in 50% inhibitory activity) values of compounds 3a-18 and 3b-1 were 0.58 and 0.44 µM for human serum butyrylcholinesterase (hBuChE), respectively, and both of them exhibited more than 30-fold selectivity for human serum acetylcholinesterase. Enzyme kinetics studies showed that these two compounds were mixed inhibitors of hBuChE. In addition, these two derivatives possessed extraordinary antioxidant activity in OH radical scavenging and oxygen radical absorption capacity fluorescein assays. Meanwhile, these compounds could also prevent ß-amyloid (Aß) self-aggregation and possessed low toxicity on PC12 and AML12 cells. Molecular modeling studies revealed that these two compounds could interact with the choline binding site, acetyl binding site, and peripheral anionic site to exert submicromolar BuChE inhibitory activity. In the vitro blood-brain barrier permeation assay, compounds 3a-18 and 3b-1 showed enough blood-brain barrier permeability. In drug-likeness prediction, compounds 3a-18 and 3b-1 showed good gastrointestinal absorption and a low risk of human ether-a-go-go-related gene toxicity. Therefore, compounds 3a-18 and 3b-1 are potential multitarget anti-AD lead compounds, which could work as powerful antioxidants with submicromolar selective inhibitory activity for hBuChE as well as prevent Aß self-aggregation.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Peptídeos beta-Amiloides , Antioxidantes , Barreira Hematoencefálica , Butirilcolinesterase , Inibidores da Colinesterase , Desenho de Fármacos , Triptofano , Doença de Alzheimer/tratamento farmacológico , Humanos , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Estrutura-Atividade , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Animais , Triptofano/farmacologia , Triptofano/química , Triptofano/análogos & derivados , Triptofano/síntese química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ratos , Acetilcolinesterase/metabolismo , Estrutura Molecular , Células PC12 , Relação Dose-Resposta a Droga , Modelos Moleculares
16.
Nat Prod Res ; : 1-13, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38189427

RESUMO

Bioactivity-guided purification obtained polysaccharide BP-S1 from seeds of Brucea javanica. The results showed that BP-S1 was a homogenous polysaccharide with molecular weight of 45.7 kDa, mainly composed of arabinose and glucose in the ratio of 1.0:1.0 and the backbone of BP-S1 was deduced to be →3,4)-α-Glup-(1→ with branches of →2)-α-Arap-(1→and α-Arap-(1→, and the possible repetitive units were speculated according to result of methylation and 2D-NMR. Moreover, BP-S1 is a periodic rope-like structure. Functional analysis revealed that BP-S1 inhibited complement activation on the classic and alternative pathways with values of CH50 0.073 ± 0.012 mg/mL and AP50 0.097 ± 0.004 mg/mL, respectively. In mechanism study, using complement component depleted-sera methods indicated that BP-S1 selectively interacted with C3 and C4 components.

17.
Nat Prod Res ; : 1-6, 2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38217490

RESUMO

A novel alkaloid with a hexa-tetra-hexa-cyclic skeleton, Bi-4-methoxycarbonyl-2-quinolone (1), was discovered during the investigation of Brucea javanica. Additionally, six known alkaloids (2-7) were also found. The chemical structures of these compounds were identified using HRESIMS and 1D and 2D NMR spectroscopic analysis. Additionally, the absolute configuration of the new compound 1 was determined through X-ray single crystal diffraction. Compound 1 exhibited significant anti-inflammatory activity in RAW264.7 cells and demonstrated promising anti-cancer effects in Lewis cells.

18.
Phytochem Anal ; 35(2): 288-307, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37814999

RESUMO

BACKGROUND AND OBJECTIVE: The herb Rheum tanguticum (RT), a member of the Polygonaceae family, is listed in the Chinese Pharmacopoeia and has been widely used to treat cardiovascular and gastrointestinal disease. The research aimed to identify the different substances from two kinds of RT extraction methods and the in vivo biotransformation of RT components. METHODS: In this study, by using ultrahigh-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS), we have investigated the metabolomic variation and the in vivo metabolism of RT. A post-acquisition data processing software, PeakView, was applied to an accurate qualitative analysis of the chemical components in RT. RESULTS: Through plant metabolomics analysis, 24 related, differentially expressed metabolites of RT water extract and alcohol extract were obtained. Combined with novel identification strategies and systematic in vivo metabolism analysis, a total of 101 compounds were discovered or tentatively identified in rat serum (including 15 prototype compounds and 86 metabolites). CONCLUSION: In this study, a combination of extraction methods, liquid chromatography-mass spectrometry (LC-MS) technology, and in vivo animal metabolism studies have been established for the screening, identification, and research of chemical active components of natural medicines. LC-MS analysis combined with plant metabolomics was used to study the differential metabolites between different extraction methods of RT. Based on UHPLC-Q-TOF-MS/MS technology, the composition and metabolism of rat plasma before and after RT administration were analysed in vivo, and 15 prototype components and 86 metabolites were detected.


Assuntos
Etanol , Rheum , Animais , Ratos , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Metabolômica
19.
Appl Opt ; 62(30): 7960-7965, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-38038088

RESUMO

We report on a low dark current density P-B-i-N extended short-wavelength infrared photodetector with atomic layer deposited (ALD) A l 2 O 3 passivation based on a InAs/GaSb/AlSb superlattice. The dark current density of the A l 2 O 3 passivated device was reduced by 38% compared to the unpassivated device. The cutoff wavelength of the photodetector is 1.8 µm at 300 K. The photodetector exhibited a room-temperature (300 K) peak responsivity of 0.44 A/W at 1.52 µm, corresponding to a quantum efficiency of 35.8%. The photodetector exhibited a specific detectivity (D ∗) of 1.08×1011 c m⋅H z 1/2/W with a low dark current density of 3.4×10-5 A/c m 2 under -50m v bias at 300 K. The low dark current density A l 2 O 3 passivated device is expected to be used in the fabrication of extended short-wavelength infrared focal plane arrays for imaging.

20.
Antioxidants (Basel) ; 12(8)2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37627572

RESUMO

Proteins have been extensively studied for their outstanding functional properties, while polyphenols have been shown to possess biological activities such as antioxidant properties. There is increasing clarity about the enhanced functional properties as well as the potential application prospects for the polyphenol-protein complexes with antioxidant properties. It is both a means of protein modification to provide enhanced antioxidant capacity and a way to deliver or protect polyphenols from degradation. This review shows that polyphenol-protein complexes could be formed via non-covalent or covalent interactions. The methods to assess the complex's antioxidant capacity, including scavenging free radicals and preventing lipid peroxidation, are summarized. The combination mode, the type of protein or polyphenol, and the external conditions will be the factors affecting the antioxidant properties of the complexes. There are several food systems that can benefit from the enhanced antioxidant properties of polyphenol-protein complexes, including emulsions, gels, packaging films, and bioactive substance delivery systems. Further validation of the cellular and in vivo safety of the complexes and further expansion of the types and sources of proteins and polyphenols for forming complexes are urgently needed to be addressed. The review will provide effective information for expanding applications of proteins and polyphenols in the food industry.

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