ANALYST
·
2015
·Vol. 140
·期 23
·8017-8022
·
IF 4.107
Jun Lv,Xiaonan Wang,Yuanyuan Zhang,Defeng Li,Juan Zhang,Lizhou Sun
Based on the adsorption between tetracycline (TC) and phosphate groups, a general colorimetric method is explored in this work by using TC-stabilized gold nanoparticles (TC/AuNPs) and 4-aminophenyl phosphate-functionalized Fe3O4 magnetic nanoparticles (APP/MNPs). Taking protein tyrosine phosphatase 1B (PTP1B) as an example, 4-aminophenyl phosphate (APP) can be hydrolyzed into 4-aminophenol (AP) by PTP1B, resulting in the disappearance of the phosphate group on the outer layer of MNPs and the loss of corresponding adsorptive ability. Upon addition of TC/AuNP solution, TC/AuNPs will remain in the supernatant solution after magnetic separation and a high absorbance value can be observed. So PTP1B activity is related to the concentrations of TC/AuNPs in the supernatant solution. In this work, the enzyme activity can be determined at levels as low as 0.0885 U mL−1 and over a linear detection range as wide as 0.1 U mL−1 to 0.9 U mL−1. Moreover, using the proposed method, the inhibition effect of betulinic acid (BA) and sodium orthovanadate (Na3VO4) on PTP1B activity can be tested with IC50 values of 30 μM and 4 μM, respectively. Therefore, a universal platform for the accurate colorimetric analysis of kinase and phosphatase activities can be established through the adsorption between TC and phosphate groups.
研究领域:
生物化学
·
分析化学
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纳米生物学
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产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2021
·
IF 3.512
Fanzhen Yu,Yingxin Wang,Yilong Teng,Shutong Yang,Yanming He,Zeng Zhang,Hongjie Yang,Chuan-Fan Ding,Ping Zhou
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and an effective target for the treatment of type 2 diabetes (T2D). A natural hyperbranched proteoglycan extracted from Ganoderma lucidum, namely, Fudan-Yueyang G. Lucidum (FYGL), was demonstrated capable of inhibiting the activity of PTP1B. Here, to identify the effective active components of FYGL, three different components, the polysaccharide FYGL-1, proteoglycans FYGL-2, and FYGL-3, were isolated from FYGL, and then, the protein moiety of FYGL-3 was further separated, namely, FYGL-3-P. Their abilities to enhance the glucose uptake in cells and inhibit the activity of PTP1B were compared. The inhibitory mechanisms were systematically explored by spectroscopic methods and MD simulations. The results showed that FYGL-3 and FYGL-3-P significantly enhanced the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, detected by the glucose oxidase method. Also, the FYGL-3-P protein moiety in FYGL played an essential role in inhibiting the activity of PTP1B. A strong, enthalpy-driven, and multitargeted interaction by electrostatic forces between PTP1B and FYGL-3-P dramatically inhibited the catalytic activity of PTP1B. These results provided deep insights into the molecular mechanisms of FYGL inhibiting the activity of PTP1B and structurally helped researchers seek natural PTP1B inhibitors.
研究领域:
生物化学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
Nutrients
·
2022
·Vol. 14
·期 15
·3031
·
IF 6.706
Jie Hao,Zhiming Qian,Zijian Liu,Guirong Zhang,Di Wang,Weiwei Han
The aim of this study was to provide a practical experimental basis for the development of Neocryptotanshinone (NCTS) as an effective hypoglycemic drug and a theoretical method for the rapid screening of natural compounds with hypoglycemic effects. Molecular docking was used to screen the most suitable ligand. Hematoxylin and eosin, immunohistochemical staining, enzyme-linked immunosorbent assay and Western Blotting approved the hypoglycemic effect of NCTS. According to the free energy of binding, among 180 active compounds from the Traditional Chinese Medicine Integrated Database, NCTS was finally chose for investigation its hypoglycemic effects. In db/db mice, NCTS significantly reduced body weight and plasma glucose, improved glucose tolerance and levels of fasting plasma glucose and glycated hemoglobin A1c, and decreased insulin resistance after six-week administration. NCTS restored the pathological state in the liver of db/db mice and significantly decreased protein tyrosine phosphatase 1B (PTP1B) expression in the liver and muscle of db/db mice, which is related to the regulatory effect of NCTS on insulin receptor substrate 1. In conclusion, we successfully explored the hypoglycemic effect of NCTS in db/db mice via regulating the expression of PTP1B.Keywords:virtual screening;molecular docking;NCTS;Diabetes mellitus;PTP1B
研究领域:
药理学
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分子生物学
·
糖尿病研究
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2022
·Vol. 60
·期 2
·524-544
·
IF 5.682
Wu Mengyu,Liao Wenli,Zhang Ruyi,Gao Yuting,Chen Tao,Hua Liangliang,Cai Fei
Accumulating clinical and epidemiological studies indicate that learning and memory impairment is more prevalent among people with diabetes mellitus (DM). PTP1B is a member of protein tyrosine phosphatase family and participates in a variety of pathophysiological effects including inflammatory, insulin signaling pathway, and learning and memory. This study was aimed to investigate the effects of CA, a specific inhibitor of PTP1B, on spatial learning and memory impairment in diabetic mice caused by high-fat diet and injection of streptozotocin. We found that the protein expressions of PTP1B increased in hippocampal CA1, CA3, and PFC regions of diabetic mice. Network pharmacology results showed that PTP1B might be one of the key targets between diabetes and cognitive dysfunction, and CA might alleviate DM-induced cognitive dysfunction. Animal experiments showed that CA ameliorated DM-induced spatial learning and memory impairment, and improved glucose and lipid metabolic disorders. Moreover, administration of CA alleviated hippocampal structure damage and enhanced the expressions of synaptic proteins, including PSD-95, SYN-1, and SYP in diabetic mice. Furthermore, CA treatment not only significantly down-regulated the expressions of PTP1B and NLRP3 inflammatory related proteins (NLRP3, ASC, Caspase-1, COX-2, IL-1β, and TNF-α), but also significantly up-regulated the expressions of insulin signaling pathway–related proteins (p-IRS1, p-PI3K, p-AKT, and p-GSK-3β) in diabetic mice. Taken together, these results suggested that PTP1B might be a targeted strategy to rescue learning and memory deficits in DM, possibly through inhibition of NLRP3 inflammasome and regulation of insulin signaling pathway.
研究领域:
药理学
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神经科学
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内分泌学
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糖尿病研究
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认知科学
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-11
·
IF 7
Liu Cong,Xiang Jinjin,Chen Yueqin,He Chang,Tong Jun,Liao Yinglin,Lei Huangyi,Sun Lingyun,Yao Genhong,Xie Zhenggao
Diabetic retinopathy (DR) ranks among the primary causes of adult blindness globally. Oxidative stress and mitochondrial dysfunction play a critical role in the progression of DR. Mounting data indicated that small extracellular vesicles (sEVs) of mesenchymal stem cell (MSC) have the ability to transport bioactive chemicals to target cells, leading to changes in their phenotype. Nevertheless, it remains elusive how MSC-derived sEVs regulate oxidative stress and mitochondrial function in DR. MSC-sEVs was intravitreally injected to streptozotocin (STZ)-treated Sprague-Dawley rats to assess the therapeutic effects on DR. The underlying regulatory mechanism was investigated by coculturing advanced glycation end-products (AGEs)-induced rat Müller cells with/without PTP1B overexpression with MSC-sEVs in vitro, with or without miR-125a-5p suppression. Intravitreal injection of MSC-sEVs improved histological morphology and blood-retinal barrier function, alleviated Müller gliosis, decreased PTP1B expression, redox stress and apoptosis in retina of diabetic rat. MSC-sEVs decreased the accumulation of ROS and improved the structure and function of mitochondria of Müller cells with AGEs treatment. Mechanically, MSC-sEVs activated the mitophagy of AGEs-treated Müller cells, represented by an increased expression of the LC3II/LC3I ratio, TOM20, PINK1 and Parkin along with a decreased expression of P62. Importantly, miR-125a-5p inhibitor abolished the protective effects of MSC-sEVs. Furthermore, the overexpression of PTP1B in Müller cells reduced the effects of MSC-sEVs. These findings suggested that miR-125a-5p of MSC-sEVs alleviates Müller cells injury in DR by modulating PINK1/Parkin-mediated mitophagy via PTP1B pathway.
研究领域:
医学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Wencheng Zhao,Hengzheng Yang,Huizi Cui,Wannan Li,Shu Xing,Weiwei Han
Vitamin B 12 is a group of biologically active cobalamin compounds. In this study, we investigated the inhibitory effects of methylcobalamin (MeCbl) and hydroxocobalamin acetate (OHCbl Acetate) on protein tyrosine phosphatase 1B (PTP1B). MeCbl and OHCbl Acetate exhibited an IC 50 of approximately 58.390 ± 2.811 μM and 8.998 ± 0.587 μM, respectively. The K i values of MeCbl and OHCbl Acetate were 25.01 μM and 4.04 μM respectively. To elucidate the inhibition mechanism, we conducted a 500 ns Gaussian accelerated molecular dynamics (GaMD) simulation. Utilizing PCA and tICA, we constructed Markov state models (MSM) to examine secondary structure changes during motion. Our findings revealed that the α-helix at residues 37–42 remained the most stable in the PTP1B-OHCbl Acetate system. Furthermore, upon binding of OHCbl Acetate or MeCbl, the WPD loop of PTP1B moved inward to the active pocket, forming a closed conformation and potentially obstructs substrate entry. Protein-ligand interaction analysis and MM-PBSA showed that OHCbl Acetate exhibited lower binding free energy and engaged in more residue interactions with PTP1B. In summary, our study confirmed the substantial inhibitory activity of OHCbl Acetate against PTP1B, with its inhibitory potency notably surpassing that of MeCbl. We demonstrated potential molecular mechanisms of OHCbl Acetate inhibiting PTP1B.
研究领域:
生物化学
·
药物化学
·
计算生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2017
·Vol. 9
·期 1
·397-406
·
IF 3.247
Zhou Yang,Fan Wu,Yanming He,Qiang Zhang,Yuan Zhang,Guangrong Zhou,Hongjie Yang,Ping Zhou
Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extracted from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels. We found that FYGL can decrease blood glucose, reduce body weight and ameliorate insulin resistance in ob/ob mice. Decrease of PTP1B expression and increase of the phosphorylation of PTP1B targets in the insulin signaling pathway of skeletal muscles were observed. In order to clearly reveal the underlying mechanism of the hypoglycemic effect caused by FYGL, we further investigated the effects of FYGL on the PTP1B-involved insulin signaling pathway in rat myoblast L6 cells. We demonstrated that FYGL had excellent cell permeability by using a confocal laser scanning microscope and a flow cytometer. We found that FYGL had a positive effect on insulin-stimulated glucose uptake by using the 2-deoxyglucose (2-DG) method. FYGL could inhibit PTP1B expression at the mRNA level, phosphorylating insulin receptor substrate-1 (IRS1), as well as activating phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt). Finally, FYGL increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and consequently up-regulated the expression of glucose transporter type 4 (GLUT4), promoting GLUT4 transportation to the plasma membrane in PTP1B-transfected L6 cells. Our study provides theoretical evidence for FYGL to be potentially used in T2D management.
研究领域:
药理学
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内分泌学
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分子生物学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY
·
2024
·
IF 1.8
Xin Yu,Xinyi Yang,Junqing Qian,Hui Guo
Mangiferin is one of the main bioactive ingredients in leaves of Mangifera indica . But the poor liposolubility and low bioavailability restrict its application. This study aimed to esterify mangiferin with lipase to improve its lipophilicity, and evaluate its antioxidant activity and hypoglycemic properties. Four fatty acids (palmitic acid, lauric acid, stearic acid, oleic acid) were selected for enzymatic esterification with mangiferin by single-factor experiments. Under the following optimum reaction conditions of tetrahydrofuran (THF): tert -amyl alcohol (2:1) was used as solvent, water activity was 0.31, TLIM lipase was 45 mg mL –1 , The ratio of mangiferin to fatty acid was 1:50, and the substrates were pretreated by ultrasonic for 0.5 h, then reacted at 55°C for 21 h, the resulting conversion rates of mangiferin-esterified derivatives exceeded 70.0%. Lipophilicity, antioxidant, and PTP1B inhibitory activity of mangiferin-esterified derivatives were determined. The results demonstrated that compared with mangiferin, the ability to scavenge DPPH radicals decreased by about 9%, but the lipophilicity was increased by 10–30 times, and the lipid antioxidant capacity was also improved significantly. Moreover, the inhibitory activity of protein tyrosine phosphatase 1B (PTP1B) exhibited minimal alteration. This indicates that esterification can not only improve the lipophilicity of mangiferin, but also improve its lipid antioxidant capacity. Practical Applications : In the study, a series of mangiferin-esterified derivatives were synthesized and their lipophilicity, antioxidant properties, and PTP1B inhibitory activity were determined. The results indicated that, compared with the untreated mangiferin, the mangiferin-esterified derivatives exhibited superior lipid antioxidant and hypoglycemic activities. Furthermore, the enzymatic esterification method employed in this study offered greater economic and environmental advantages when compared to chemical catalysis. Therefore, the preparation of mangiferin derivatives through enzymatic esterification were deemed feasible with potential application value for enhancing lipid antioxidant capacity in high-fat foods.
研究领域:
食品科学
·
生物化学
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DOI
高影响因子
Marine Drugs
·
2020
·Vol. 18
·期 11
·526
·
IF 4.073
Bihong Hong,Jianlin He,Chaochun Fan,Chao Tang,Qingqing Le,Kaikai Bai,Siwen Niu,Meitian Xiao
In recent years, a large number of pharmacologically active compounds containing a butenolide functional group have been isolated from secondary metabolites of marine microorganisms. Butyrolactone I was found to be produced byAspergillus terreusisolated from several marine-derived samples. The hypoglycemic activity of butyrolactone I has aroused our great interest. In this study, we synthesized six racemic butenolide derivatives (namely BL-1–BL-6) by modifying the C-4 side chain of butyrolactone I. Among them, BL-3 and BL-5 improved the insulin resistance of HepG2 cells and did not affect the proliferation of RIN-m5f cell line, which indicated the efficacy and safety of BL-3 and BL-5. Furthermore, BL-3, BL-4, BL-5, and BL-6 displayed a significant protein tyrosine phosphatase 1B (PTP1B) inhibitory effect, while the enantiomers of BL-3 displayed different 50% percentage inhibition concentration (IC50) values against PTP1B. The results of molecular docking simulation of the BLs and PTP1B explained the differences of biological consequences observed between the enantiomers of BL-3, which supported BLs as PTP1B inhibitors, and also indicated that the chirality of C-4 might influence the inhibitory effect of the BLs. Our findings provide a novel strategy for the development of butyrolactone derivatives as potential PTP1B inhibitors for the treatment of type 2 diabetes mellitus.Keywords:butenolide;insulin resistance;secondary metabolites;chirality
研究领域:
药理学
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生物化学
·
药物化学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Daiyu Xu,Ruidi Liu,Zhenqiang Zhang,Xiaowei Zhang,Gai Gao,Zhishen Xie
Ethnopharmacological relevance Rehmanniae Radix Praeparata, the processed root of Rehmannia glutinosa Steud. (Orobanchaceae), a traditional Chinese medicine, has traditionally been used for metabolic disorders related deficiency patterns in traditional Chinese medicine. As a pharmacopoeial quality control marker of Rehmanniae Radix Praeparata, rehmannioside D (RD) possesses hepatoprotective and metabolic regulatory potential; however, its therapeutic role in MAFLD remains unclear. Aim of the study This study aimed to evaluate the therapeutic effects of RD against MAFLD and to elucidate its underlying molecular mechanisms. Materials and methods db/db mice and free fatty acid (FFA)-induced HepG2 cells were used to assess the effects of RD in vivo and in vitro . Lipid accumulation, liver injury, insulin signaling, and endoplasmic reticulum (ER) stress were evaluated. Limited proteolysis-mass spectrometry (LiP-MS) was used to identify potential targets of RD. Molecular docking, cellular thermal shift assay (CETSA), and molecular dynamics (MD) simulations were performed to validate the interaction between RD and the target protein. Results Marked amelioration of lipid metabolic disorders was observed in both db/db mice and FFA-induced HepG2 cells following RD treatment. This intervention effectively attenuated ALT and AST elevations while mitigating histopathological hepatic injury. LiP-MS identified PTP1B as a potential target of RD; molecular docking, CETSA, and MD simulation further corroborated stable binding between RD and PTP1B, identifying Asp181 as an important residue contributing to the RD–PTP1B interaction. Mechanistically, RD inhibited PTP1B activity, suppressed SREBP-1c transcription and expression, and downregulated lipogenesis-related genes. RD also inhibited the PERK/eIF2α pathway, alleviated ER stress, and restored the PI3K/AKT insulin signaling. Conclusion RD ameliorates MAFLD by inhibiting PTP1B, orchestrating a concerted improvement in lipid metabolism, ER stress resolution, and insulin signaling, supporting its potential as a therapeutic agent for MAFLD management.
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Wanxian Wang,Yanfang Liu,Dian Liu,Han Zhou,Yan Li,Wenjie Yuan,Suowen Xu,Jixia Wang,Xinmiao Liang,Jianping Weng
Pueraria lobata (Willd.) Ohwi, known as kudzu and used as a “longevity powder” in China, is an edible plant which is rich in flavonoids and believed to be useful for regulating blood sugar and treating diabetes, although the modes of action are unknown. Here, a total of 53 flavonoids including 6 novel compounds were isolated from kudzu using multidimensional preparative liquid chromatography. The flavonoid components were found to lower blood sugar levels, promote urine sugar levels in mice, and reduce the urine volume. Molecular docking and in vitro assays suggested that the antidiabetic effect of kudzu was attributed to at least three targets: sodium-dependent glucose transporter 2 (SGLT2), protein tyrosine phosphatase-1B (PTP1B), and alpha-glucosidase (AG). This study suggests a possible mechanism for the antidiabetic effect that may involve the synergistic action of multiple active compounds from kudzu.
研究领域:
药理学
·
生物化学
·
植物科学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2023
·
IF 3.4
Jinqiang Wang,Dandan Feng,Yimin Xiang,Ji Guo,Nianyu Huang,Na Yu,Huishu Yang,Chengxiong Liu,Kun Zou
Diabetes mellitus is a serious threat to human life and health. The α-glucosidase and protein tyrosine phosphatase 1B (PTP1B) were important targets for the treatment of type 2 diabetes mellitus . In this paper, euparin, a natural product from Eupatorium chinense possessed extensive pharmacological activities , was selected as the lead compound. It was derived into chalcone compounds with high efficiency, and the inhibitory activities of these 30 products on α-glucosidase and PTP1B were tested. The results showed that compounds 12 and 15 had good inhibitory activities against both enzymes. The IC 50 value of 12 to inhibit α-glucosidase and PTP1B was 39.77 and 39.31 μM, and the IC 50 value of 15 to inhibit α-glucosidase and PTP1B was 9.02 and 3.47 μ M , respectively. In addition, molecular docking results showed that compounds 12 and 15 exhibited good binding affinities toward both α -glucosidase and PTP1B with negative binding energies. The results of the present study demonstrate that compounds 12 and 15 might be beneficial in the treatment of type 2 diabetes.
研究领域:
药理学
·
药物化学
·
糖尿病研究
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DOI
PubMed
高影响因子
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