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1.
Phytomedicine ; : 153498, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33640247

RESUMO

BACKGROUND: The incidence of nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), has significantly increased in recent years and has become an important public health issue. However, no U.S. Food and Drug Administration (FDA)-approved first-line drug is currently available for the treatment of NAFLD and NASH; therefore, research on new drugs is currently a hot topic. Oroxylum indicum (Linn.) Kurz is extensively distributed in South China and South Asia and has many biological activities. However, its effects on NAFLD or even NASH and the corresponding mechanisms are still not clear. PURPOSE: To investigate the effect and mechanism of O. indicum seed extract (OISE) on preventing anti-inflammatory action in the progression from simple nonalcoholic fatty liver (NAFL) to NASH. METHODS: A network pharmacology method to construct ingredient-target networks and the protein-protein interaction (PPI) network of OISE in NASH were constructed for topological analyses and hub-target screening. Enrichment analyses were performed to identify the critical biological processes and signaling pathways. Simultaneously, in vitro and in vivo experiments investigated the effect and mechanism of OISE, baicalein, and chrysin on inflammation by biochemical indicator detection, luciferase reporters, pathological staining, and immunoblotting in oleic acid-stimulated HepG2 cells or in high-fat diet-fed rats. RESULTS: The network pharmacology showed that OISE prevented the development and progression of NAFL into NASH through various pathways and targets and that the nuclear factor NF-κB (NF-κB) pathway regulated by baicalein and chrysin played an important role in the treatment of NASH. In in vitro experiments, we further showed that OISE and its ingredients, namely, baicalein and chrysin, all improved the inflammatory status in oleic acid-stimulated HepG2 cells, inhibited the nuclear transcriptional activities of NF-κB, increased the IκB level, and decreased the phosphorylation level of NF-κB. Furthermore, in a high-fat diet-induced NASH model in rats, we also showed that OISE prevented the development and progression of NASH by inhibiting the nuclear transcriptional activity of NF-κB. CONCLUSION: OISE suppressed inflammatory responses and prevented the development and progression of NAFL into NASH through inhibition of the nuclear transcriptional activity of NF-κB. OISE may be used to treat NAFLD through many functions, including an increase in insulin sensitivity, a decrease in lipid accumulation in the liver, suppression of inflammation, and clearance of free radicals.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33625823

RESUMO

The activation and transformation of inert alkyl C(sp3)-H bonds to obtain high-value fine chemicals by sustainable solar energy are of great significance. Herein, by incorporating IrIII-porphyrin into metal-organic frameworks (MOFs) to stabilize the highly active carbene, we reported a new approach to combining metallo- and photocatalysis to efficiently accelerate carbene migratory insertion and C-H bond activation via the radical coupling pathway for inert alkane functionalization. The in situ-formed carbene was restricted into the pores of MOFs to produce IrIII-carbene, allowing the first-time isolation and structural characterization of the IrIII-carbene intermediate which are not stabilized by a heteroatom. The product of the reaction, especially the cyclic ethers as substrates, suggested that the functionalization of the α position of the alkoxy group was favored. Additionally, the new approach could be extended to stabilize the metal carbene intermediates to realize C(sp3)-H bond alkylation and arylation.

3.
Sci Total Environ ; 761: 144192, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33352340

RESUMO

The catalytic boron­hydrogen bond break is usually regarded as an important reaction both in the area of environment treatment and hydrogen energy, attracting increasing attention in the past decades. Due to the limitation of conventional noble metal-based catalyst, cost-effective transition metal-based catalysts with high activity have been recently developed to become the promising candidates. Herein, the coffee ground waste was utilized as the biochar substrate loaded with ultrafine NiCoO2 nanoparticles. The abundant function groups on the biochar substrate efficiently adsorbed the metal ions and confined the crystal growth spatially, making the NiCoO2 nanoparticles highly dispersed on the surface. Moreover, the oxygen vacancies were further created in the catalysts by a vacuum-calcination strategy to boost their catalytic activity towards boron­hydrogen bond break both in the systems of 4-nitrophenol reduction by NaBH4 and hydrogen release from NH3BH3. The results indicated that the moderate presence of oxygen vacancies could effectively accelerate the boron­hydrogen bond break and the catalytic activity performed a satisfied stability during several recycles. The theoretical calculation method was adopted to analysis and discuss the mechanism within this process. This design strategy on active catalysts not only offered a novel solution of biowaste resource reuse but also demonstrated the significant role of oxygen vacancies in energy and environmental catalysis.


Assuntos
Boro , Nanopartículas , Carvão Vegetal , Café , Ligação de Hidrogênio
4.
Biomed Pharmacother ; 133: 110954, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378992

RESUMO

Anemarrhena asphodeloides is an herb widely used to treat symptoms associated with diabetes in traditional Chinese medicine. However, its key components and metabolites have low bioavailability and poor host absorption. To clarify the anti-diabetic mechanism of A. asphodeloides extract (AAE), we examined the anti-diabetic effects of AAE in rats with diabetes induced by a high-fat diet and streptozotocin. Faeces levels of the main components and metabolites of AAE were significantly higher than levels in plasma, which indicated that gut microbiota might play important roles in its anti-diabetic effect. Microbiological studies showed that unabsorbed components increased the diversity of the gut microbiota, enriched potentially beneficial bacteria, and suppressed potentially harmful bacteria. In vitro studies showed that AAE promoted the proliferation of Blautia coccoides, a bacterium with positive implication for diabetes, in a dose-dependent manner. AAE also promoted pancreatic cell regeneration and restored the function of pancreatic islet cells via peroxiredoxin 4 overexpression. Overall, these results suggest that AAE alleviates diabetes via modulating gut microbiota and protein expression.


Assuntos
Anemarrhena , Bactérias/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Intestinos/microbiologia , Ilhotas Pancreáticas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Anemarrhena/química , Animais , Bactérias/crescimento & desenvolvimento , Biomarcadores/sangue , Glicemia/metabolismo , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Disbiose , Hipoglicemiantes/isolamento & purificação , Mediadores da Inflamação/sangue , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Lipídeos/sangue , Masculino , Peroxirredoxinas/metabolismo , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Estreptozocina
5.
Gastroenterol Res Pract ; 2020: 7641761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32802046

RESUMO

Aims: Tripartite motif protein 36 (TRIM36) plays a tumor-suppressive role in prostate cancer. However, there is little information on the clinical relevance of TRIM36 expression in esophageal cancer (ESCA). Methods: TRIM36 expression was analyzed by using The Cancer Genome Atlas (TCGA) ESCA dataset as well as by quantitative real-time polymerase chain reaction (PCR) and immunohistochemical (IHC) staining on samples from our hospital. Results: In the current study, the analysis of TCGA ESCA dataset suggested the decreased expression of TRIM36 in ESCA tissues. Further analyses on samples from our hospital demonstrated that TRIM36 was significantly downregulated in ESCA tissues than in the noncancerous controls at both the mRNA and protein levels. Moreover, gene set enrichment analysis on TCGA ESCA dataset suggested that TRIM36 expression was inversely correlated with the ß-catenin pathway. IHC staining data showed that 66.25% (53/80) and 51.25% (41/80) of ESCA cases had a low expression of TRIM36 and a high expression of ß-catenin, respectively. By Fisher's exact test, we found that TRIM36 protein expression was significantly correlated with tumor size (P = 0.0104), tumor stage (P = 0.0169), lymph node metastasis (P = 0.0021), vital status (P = 0.0443), and ß-catenin expression (P = 0.0329). These findings suggest the potential clinical significance of TRIM36 in ESCA. Kaplan-Meier and log-rank test demonstrated that a low expression of TRIM6 and a high expression of ß-catenin were associated with poor overall survival of ESCA patients. Conclusions: Our study provides evidence for the prognostic value of TRIM36 in ESCA.

6.
PLoS One ; 15(8): e0235502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790666

RESUMO

Traditionally, machine learning algorithms relied on reliable labels from experts to build predictions. More recently however, algorithms have been receiving data from the general population in the form of labeling, annotations, etc. The result is that algorithms are subject to bias that is born from ingesting unchecked information, such as biased samples and biased labels. Furthermore, people and algorithms are increasingly engaged in interactive processes wherein neither the human nor the algorithms receive unbiased data. Algorithms can also make biased predictions, leading to what is now known as algorithmic bias. On the other hand, human's reaction to the output of machine learning methods with algorithmic bias worsen the situations by making decision based on biased information, which will probably be consumed by algorithms later. Some recent research has focused on the ethical and moral implication of machine learning algorithmic bias on society. However, most research has so far treated algorithmic bias as a static factor, which fails to capture the dynamic and iterative properties of bias. We argue that algorithmic bias interacts with humans in an iterative manner, which has a long-term effect on algorithms' performance. For this purpose, we present an iterated-learning framework that is inspired from human language evolution to study the interaction between machine learning algorithms and humans. Our goal is to study two sources of bias that interact: the process by which people select information to label (human action); and the process by which an algorithm selects the subset of information to present to people (iterated algorithmic bias mode). We investigate three forms of iterated algorithmic bias (personalization filter, active learning, and random) and how they affect the performance of machine learning algorithms by formulating research questions about the impact of each type of bias. Based on statistical analyses of the results of several controlled experiments, we found that the three different iterated bias modes, as well as initial training data class imbalance and human action, do affect the models learned by machine learning algorithms. We also found that iterated filter bias, which is prominent in personalized user interfaces, can lead to more inequality in estimated relevance and to a limited human ability to discover relevant data. Our findings indicate that the relevance blind spot (items from the testing set whose predicted relevance probability is less than 0.5 and who thus risk being hidden from humans) amounted to 4% of all relevant items when using a content-based filter that predicts relevant items. A similar simulation using a real-life rating data set found that the same filter resulted in a blind spot size of 75% of the relevant testing set.


Assuntos
Aprendizagem , Aprendizado de Máquina/normas , Viés , Humanos
7.
Molecules ; 25(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019168

RESUMO

Baicalein, a widely-distributed natural flavonoid, exhibits antioxidative activity in mice with type-2 diabetes. However, the underlying mechanisms remain partially elucidated. In this study, we investigated the effect of baicalein on protein kinase R-like ER kinase (PERK)/nuclear factor erythroid-2-related factor 2 (Nrf2) pathway for the alleviation of oxidative stress and apoptosis. Human liver HL-7702 cells were stimulated with 60.5 mM of glucose to induce oxidative stress and treated with baicalein. The apoptosis was determined by fluorescence microscopy and flow cytometry. The regulation of the PERK/Nrf2 pathway by baicalein was determined by immunoblotting in both HL-7702 cells and liver tissues from diabetic mice. We found that baicalein significantly alleviated the oxidative stress and apoptosis in HL-7702 cells stimulated with glucose. Mechanistic studies showed that baicalein downregulated PERK and upregulated Nrf2, two key proteins involved in endoplasmic reticulum stress, in both HL-7702 cells and liver tissues from diabetic mice receiving baicalein treatment. Furthermore, the subcellular localization of Nrf2 and the regulation of downstream proteins including heme oxygenase-1 and CCAAT-enhancer-binding protein homologous protein (CHOP) by baicalein were also investigated. Our results suggest that the regulation of the PERK/Nrf2 pathway is one of the mechanisms contributing to the bioactivities of baicalein to improve diabetes-associated complications.


Assuntos
Apoptose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavanonas/farmacologia , Glucose/efeitos adversos , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , eIF-2 Quinase/metabolismo , Animais , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Edulcorantes/efeitos adversos , eIF-2 Quinase/genética
8.
Food Funct ; 11(1): 711-721, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31909773

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide; thus, a dietary supplement that can restrict hepatic fat accumulation is needed. Baicalein, a major component of Scutellaria baicalensis, is used as a dietary supplement in Eastern and Western cultures and can reduce hepatic fat accumulation. However, the detailed mechanism by which baicalein exerts this effect has yet to be elucidated in vivo and in vitro. In this study, we characterized the hepatic fat-lowering activity of baicalein and found that baicalein reduced hepatic fat accumulation by activating AMPK and suppressing SREBP1 cleavage, thus consequently inhibiting the transcriptional activity of SREBP1 and the synthesis of hepatic fat in oleic acid-induced HepG2 cells and high-fat diet-induced non-insulin-resistant mice. Moreover, baicalein improved NAFLD by decreasing TC, increasing HDLC, decreasing LDLC, affecting antioxidant activity, and exerting other effects. Therefore, the mechanism of baicalein with regard to NAFLD prevention and treatment might involve effects on multiple targets and pathways. Our study supports the use of baicalein as a dietary supplement due to its ability to reduce hepatic fat accumulation and to ameliorate NAFLD-related biochemical abnormalities.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antioxidantes/farmacologia , Flavanonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Dieta Hiperlipídica , Flavanonas/administração & dosagem , Células Hep G2/metabolismo , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Oleico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
9.
Chem Commun (Camb) ; 55(26): 3805-3808, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30869088

RESUMO

Synergistic effects of bimetallic Ni and Cu supported on metal-organic polymer composites based on Wells-Dawson P2W18O626- clusters as photosensitizer units were identified, and we report a novel approach for addressing these issues for dehydrogenation and hydrogen production reactions.

10.
ACS Appl Mater Interfaces ; 10(16): 13462-13469, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29608262

RESUMO

Dehydrogenation of the tetrahydroisoquinoline derivatives coupled with hydrogen production is important for hydrogen storage applications. Herein, we formulated a new system that embedded Dawson-type polyoxometalates as efficient photosensitizers into the pores of redox-active coordination polymers for the light-driven photocatalytic oxidative Mannich reaction and hydrogen evolution. In the designed Co-POM polymer, UV light excitation gives the excited state of the Dawson-type polyoxometalate first to oxidize electron donors or substrates; the reduced form (i.e., heteropolyblue) adsorbs visible light to achieve a new excited state, which reduced the cobalt redox sites and facilitates hydrogen evolution reaction. The photosensitizer recovered to the ground state, completing the catalytic cycle. Under the optimized conditions, Co-POM enabled the hydrogen evolution and dehydrogenation of tetrahydroisoquinoline without the presence of any other additives. The high catalytic efficiency and robustness indicated the advantages of the combining functional polyoxometalate-based catalysts and porous characters of the coordination polymers for the development of highly active heterogeneous catalysts.

11.
Phytomedicine ; 38: 24-34, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29425652

RESUMO

BACKGROUND: Oroxylum indicum (L.) Kurz (Bignoniaceae) has been widely used for the treatment of respiratory infections and gastrointestinal disorders. Our previous study showed that an ethanol-water O. indicum seed extract (OISE), when combined with acarbose, reduced the risk of diabetes by 75% and effectively prevented the associated complications. Oroxin A, a major component of OISE, can activate PPARγ and inhibit α-glucosidase and it represents a promising candidate for diabetes intervention. PURPOSE: The aim of this study is to investigate the effect of oroxin A from O. indicum on the progression of prediabetes to diabetes and the underlying mechanisms in streptozotocin and high-fat-diet induced prediabetic mice. METHODS: Oroxin A was purified from OISE and its PPARγ transcriptional activation was determined in vitro and in vivo. The prediabetic mice were established by high-fat diet and streptozotocin, which was followed by treatment with oroxin A. The effect of oroxin A was determined by analysis of the lipid profiles, oxidative stress, hepatic function and histology. The mechanism of oroxin A was also investigated. RESULTS: Oroxin A is a compound with low toxicity that has reduced the relative risk of progression from prediabetes to diabetes by 66.7% without inducing weight gain or hepatotoxicity. Oroxin A also improved the complications of prediabetes, such as lipid metabolism dysfunction and liver injury. Results of mechanism studies suggested that oroxin A is a partial PPARγ agonist that can activate PPARγ transcriptional activation in vitro and in vivo. Oroxin A also exhibited an inhibitory activity against α-glucosidase and an antioxidant capacity. CONCLUSION: Oroxin A prevents the progression from prediabetes to diabetes through a multi-pathway intervention mechanism.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Flavonas/farmacologia , Glucosídeos/farmacologia , Estado Pré-Diabético/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Bignoniaceae/química , Diabetes Mellitus Experimental/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Estado Pré-Diabético/complicações , Estado Pré-Diabético/metabolismo , Sementes/química , Estreptozocina/toxicidade , alfa-Glucosidases
12.
Eng Life Sci ; 18(4): 227-235, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32624901

RESUMO

While the methylotrophic yeast Pichia pastoris enables the industrial-scale biosynthesis of many recombinant products, large amount of nutrient-rich biomass emerged along this process. Polysaccharides, especially glucans that are abundant in the cell wall of P. pastoris, are yet to be better utilized owing to their various biological activities. However, the isolation and purification of cell wall glucan from P. pastoris has not been reported. In this study, we established an environment-friendly approach, including induced autolysis, hot-water treatment, ultrasonication, isopropanol extraction, and protease treatment, to isolate and purify glucan from the cell wall of P. pastoris. We achieved a purity of 85.3% and a yield of 11.7% for the purified glucan. Proteins, nucleic acids, lipids, and ash were efficiently removed during the purification. The activities of the purified glucan were investigated in mice fed with a high-fat diet. The purified glucan decreased the level of total cholesterol and triglycerides by 30.3 and 29.7%, respectively. This result suggested that the cell wall glucan of P. pastoris could be developed to a therapeutic agent for dyslipidemia. Our study proposed an environment-friendly and effective method to isolate and purify the glucan from P. pastoris, providing solid foundation for the high-value utilization of this yeast.

13.
Bioorg Med Chem Lett ; 27(22): 5065-5070, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28964635

RESUMO

In this paper, the inhibition of α-amylase and α-glucosidase by nine pentacyclic triterpenes was determined. For α-amylase inhibitory activity, the IC50 values of ursolic acid, corosolic acid, and oleanolic acid were 22.6±2.4µM, 31.2±3.4µM, and 94.1±6.7µM, respectively. For α-glucosidase inhibition, the IC50 values of ursolic acid, corosolic acid, betulinic acid, and oleanolic acid were 12.1±1.0µM, 17.2±0.9µM, 14.9±1.9µM, and 35.6±2.6µM, respectively. The combination of corosolic acid and oleanolic acid with acarbose showed synergistic inhibition against α-amylase. The combination of the tested triterpenes with acarbose mainly exhibited additive inhibition against α-glucosidase. Kinetic studies revealed that corosolic acid and oleanolic acid showed non-competitive inhibition and acarbose showed mixed-type inhibition against α-amylase. The results provide valuable implications for the triterpenes (ursolic acid, corosolic acid, and oleanolic acid) alone or in combination with acarbose as a therapeutic agent for the treatment of diabetes mellitus.


Assuntos
Acarbose/química , Triterpenos Pentacíclicos/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/química , Acarbose/metabolismo , Sinergismo Farmacológico , Concentração Inibidora 50 , Cinética , Ácido Oleanólico/química , Ácido Oleanólico/metabolismo , Triterpenos Pentacíclicos/metabolismo , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/metabolismo , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
14.
J Agric Food Chem ; 65(38): 8319-8330, 2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28875706

RESUMO

The inhibition of porcine pancreatic α-amylase and mammalian α-glucosidase by 16 individual flavonoids was determined. The IC50 values for baicalein, (+)-catechin, quercetin, and luteolin were 74.1 ± 5.6, 175.1 ± 9.1, 281.2 ± 19.2, and 339.4 ± 16.3 µM, respectively, against α-glucosidase. The IC50 values for apigenin and baicalein were 146.8 ± 7.1 and 446.4 ± 23.9 µM, respectively, against α-amylase. The combination of baicalein, quercetin, or luteolin with acarbose showed synergistic inhibition, and the combination of (+)-catechin with acarbose showed antagonistic inhibition of α-glucosidase. The combination of baicalein or apigenin with acarbose showed additive inhibition of α-amylase at lower concentrations and antagonistic inhibition at a higher concentration. Kinetic studies of α-glucosidase activity revealed that baicalein alone, acarbose alone, and the combination showed noncompetitive, competitive, and mixed-type inhibition, respectively. Molecular modeling revealed that baicalein had higher affinity to the noncompetitive binding site of maltase, glucoamylase, and isomaltase subunits of α-glucosidase, with glide scores of -7.64, -6.98, and -6.88, respectively. (+)-Catechin had higher affinity to the active sites of maltase and glucoamylase and to the noncompetitive site of isomaltase. After sucrose loading, baicalein dose-dependently reduced the postprandial blood glucose (PBG) level in mice. The combination of 80 mg/kg baicalein and 1 mg/kg acarbose synergistically lowered the level of PBG, and the hypoglycemic effect was comparable to 8 mg/kg acarbose. The results indicated that baicalein could be used as a supplemental drug or dietary supplement in dietary therapy for diabetes mellitus.


Assuntos
Acarbose/química , Glicemia/metabolismo , Diabetes Mellitus/enzimologia , Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , alfa-Glucosidases/química , Acarbose/administração & dosagem , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Sinergismo Farmacológico , Flavonoides/administração & dosagem , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Cinética , Camundongos , Simulação de Acoplamento Molecular , Período Pós-Prandial/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Suínos
15.
Bioorg Med Chem Lett ; 27(15): 3382-3385, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28642102

RESUMO

Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential therapies for diabetes and obesity have attracted much attention in recent years. Six varic acid analogues were isolated from two strains of fungi and evaluated for PTP1B inhibition activities. The structure-activity relationships were also characterized and predicted by molecular modeling. Further kinetic studies indicated the reversible and competitive inhibition manner of varic acid analogues. Trivaric acid showed insulin-sensitizing effect not only in vitro but also in vivo, representing a promising lead compound for further optimization.


Assuntos
Depsídeos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Fungos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Glicemia/efeitos dos fármacos , Depsídeos/química , Depsídeos/isolamento & purificação , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Camundongos , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade
16.
Biomed Pharmacother ; 91: 890-898, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28511342

RESUMO

The combined effect of Oroxylum indicum seed extracts (OISE) or major flavonoids from OISE and acarbose on reducing postprandial blood glucose (PBG) levels was investigated in vitro and in vivo. In vitro, the IC50 values of OISE and baicalein against α-glucosidase were 43.4±0.731µgmL-1 and 25.9±0.412µgmL-1 respectively. A combination of acarbose with OISE or baicalein synergistically inhibited rat intestinal α-glucosidase. The combination index (CI) values for acarbose with OISE ranged from 0.33 to 0.75, suggesting a synergistic but not additive effect. OISE was determined to be a non-competitive inhibitor of maltose-hydrolyzing activity. In vivo, OISE were administered to normoglycemic and diabetic mice, either alone or in combination with acarbose. At doses between 50 and 200mgkg-1, OISE enhanced the efficacy of acarbose by up to 5-fold. These results demonstrated that OISE enhances the efficacy of acarbose in vivo, and that the combination of OISE and acarbose displayed a synergistic effect in vitro. Therefore, OISE can be used to design dietary supplements to treat diabetes.


Assuntos
Bignoniaceae/química , Glicemia/metabolismo , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Sementes/química , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/farmacologia , Acarbose/farmacologia , Animais , Sinergismo Farmacológico , Flavanonas/farmacologia , Hipoglicemiantes/farmacologia , Intestinos/enzimologia , Masculino , Camundongos , Pâncreas/enzimologia , Período Pós-Prandial/efeitos dos fármacos , Ratos Sprague-Dawley , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
17.
Biomed Pharmacother ; 87: 160-170, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28056420

RESUMO

Prediabetes is defined as blood glucose levels above normal but below diabetes thresholds, and up to 70% of individuals with prediabetes will eventually develop diabetes if left untreated. Acarbose, the first FDA approved anti-prediabetes agent, has some disadvantages, such as reducing the risk of diabetes by only 36%, side effects and limited effects on complications. The aim of this study is to develop a new agent to treat prediabetes and to investigate the anti-prediabetes effects and mechanisms of acarbose and an Oroxylum indicum seed extract (OISE) in prediabetic mice. The combined drugs can reduce the dose of acarbose by 80% and reduce the risk of diabetes by 75%, which is one fold higher than acarbose monotherapy. The combined drugs showed synergistic anti-prediabetes effects and could be effective in preventing the complications of prediabetes. The combined drugs could improve glucose tolerance, improve lipid metabolism and reduce oxidative stress and tissue damage. For the mechanisms, the combined drugs can reduce synergistically postprandial hyperglycaemia by inhibiting α-glucosidase. Furthermore, baicalein in OISE was demonstrated to be a major component in reducing oxidative stress and chrysin was the primary compound that activated PPARγ.


Assuntos
Acarbose/administração & dosagem , Bignoniaceae , Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Extratos Vegetais/administração & dosagem , Estado Pré-Diabético/tratamento farmacológico , Animais , Diabetes Mellitus Experimental/metabolismo , Sinergismo Farmacológico , Células HEK293 , Células Hep G2 , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Camundongos , Casca de Planta , Extratos Vegetais/isolamento & purificação , Estado Pré-Diabético/etiologia , Estado Pré-Diabético/metabolismo , Sementes , Estreptozocina
18.
Life Sci ; 169: 52-64, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27871946

RESUMO

AIM: To screen a potential PTP1b inhibitor from the microbial origin-based compound library and to investigate the potential anti-diabetic effects of the inhibitor in vivo and determine its primary anti-diabetic mechanism in vitro and in silico. METHODS: PTP1b inhibitory activity was measured using recombination protein as the enzyme and p-NPP as the substrate. The binding of the inhibitor to PTP1b was analysed by docking in silico and confirmed by ITC experiments. The intracellular signalling pathway was detected by Western blot analysis in HepG2 cells. The anti-diabetic effects were evaluated using a diabetic mice model in vivo. RESULTS: Among 545 microbial origin-based pure compounds tested, trivaric acid, a tridepside, was selected as a PTP1B inhibitor exhibiting strong inhibitory activity with an IC50 of 173nM. Docking and ITC studies showed that trivaric acid was able to spontaneously bind to PTP1b and may inhibit PTP1b by blocking the catalytic domain of the phosphatase. Trivaric acid also enhanced the ability of insulin to stimulate the IR/IRS/Akt/GLUT2 pathway and increase the glucose consumption in HepG2 cells. In diabetic mice, trivaric acid that had been encapsulated into Eudrgit L100-5.5 showed significant anti-diabetic effects, improving insulin resistance, leptin resistance and lipid profile and weight control at doses of 5mg/kg and 50mg/kg. SIGNIFICANCE: Trivaric acid is a potential lead compound in the search for anti-diabetic agents targeting PTP1b.


Assuntos
Depsídeos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Resinas Acrílicas/química , Animais , Glicemia/metabolismo , Depsídeos/administração & dosagem , Depsídeos/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Portadores de Fármacos/química , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Chem Commun (Camb) ; 52(25): 4714-7, 2016 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-26954389

RESUMO

The efficient photosensitizing of decatungstate-based MOF with 1D channels was achieved via in situ synthesis under solvothermal conditions for light driven acceleration of ß- or γ-site C-H alkylation of aliphatic nitriles. The high catalytic efficiency, excellent size selectivity, high stability and good recyclability of the photocatalyst offer an environmentally-friendly route for widening the scope of accessible nitriles in both laboratory and industry.

20.
Dalton Trans ; 43(43): 16322-7, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25215602

RESUMO

By choosing V-shaped ligands, Cu2+ cations and isopolymolybdates as starting materials, a novel double helical compound [Cu(H2O)(bimb)]2[ß-Mo8O26] (1) (bimb = 1,3-bis(1-imidazoly)benzene) was hydrothermally synthesized and characterized by elemental analyses, single-crystal X-ray diffraction, powder X-ray diffraction and IR spectroscopy. A structural feature is that compound 1 represents the first example of a helical compound based on polyoxometalates, which possesses an unprecedented helical disposition, namely the coexistence of both interconnected and interweaved double helices in one structure. The photocatalytic properties of compound 1 were also investigated in detail and the result of photocatalytic experiments shows that compound 1 can be used as a stable photocatalyst toward the decomposition of the organic pollutant methylene blue.


Assuntos
Complexos de Coordenação/síntese química , Molibdênio/química , Catálise , Complexos de Coordenação/química , Cristalografia por Raios X , Radicais Livres/química , Azul de Metileno/química , Conformação Molecular , Fotólise , Raios Ultravioleta
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