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Ligand and protein (a) root mean square deviation (RMSD), (b) Gyrate, and (c) solvent accessible surface (SAS).
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Adenosine monophosphate-activated protein kinase (AMPK) acts as a master mediator of metabolic homeostasis. It is considered as a significant millstone to treat metabolic syndromes including obesity, diabetes, and fatty liver. It can sense cellular energy or nutrient status by switching on the catabolic pathways. Investigation of AMPK has new findi...
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In recent years, metabolic syndromes (MetSs), including diabetes mellitus, dyslipidemia, and cardiovascular diseases, have become a common health problem in both developed and developing countries. Accumulating data have suggested that traditional herbs might be able to provide a wide range of remedies in prevention and treatment of MetSs. Ginger (...
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and its pathogenesis is complex and has not yet been fully elucidated. Abnormal glucose and lipid metabolism is key to understanding the pathogenesis of diabetic nephropathy, which can develop in both type 1 and type 2 diabetes. A hallmark of this disease is the accumulation...
Citations
... package was utilized [64]. CHARMM36, which is an all-atom-drive lipid force field, was used to write the PPARα and AMPK [65][66][67] atomic drive field parameters. The topology of SSB, SSC, or the control atomic drive field parameters were obtained from the Gromos54a7 force field using the Automated Topology Builder (ATB, https://atb.uq.edu.au/index.py, ...
(1) Background: Soyasapogenol C (SSC), a derivative of soyasapogenol B (SSB), is specifically found high in many fermented soybean (Glycine max) products, including Cheonggukjang (in Korean). However, the biological activities for preventing and treating hepatic steatosis, and the precise underlying mechanisms of SSC, remain to be explored. (2) Methods: A novel SANDA (structural screening, ADMET prediction, network pharmacology, docking validation, and activity evaluation) methodology was used to examine whether SSC exerts hepatoprotective effects in silico and in vitro. (3) Results: SSC had better ADMET characteristics and a higher binding affinity with predicted targets chosen from network pathway analysis than SSB. SSC induced the phosphorylation of AMP-activated protein kinase (AMPK) and stimulated the nuclear translocation of peroxisome proliferator-activated receptor alpha (PPARα), further enhancing PPAR response element (PPRE) binding activity in HepG2 cells. Concurrently, SSC significantly inhibited triglyceride accumulation, which was associated with the suppression of lipogenesis genes and the enhancement of fatty acid oxidation gene expression in HepG2 cells. (4) Conclusions: Soyasapogenol C, discovered using a novel SANDA methodology from fermented soybean, is a novel AMPK/PPARα dual activator that is effective against hepatic steatosis. Dietary supplementation with soyasapogenol C may prevent the development of hepatic steatosis and other diseases associated with fat accumulation in the liver.
... 27 A molecular docking study reveals that L and OXL shows higher binding affinity with AMPK as comparable with drug metformin. As like bis-chalcone derivative that is, (2E, 5E)-2, 5-bis (4-hydroxy-3-methoxybenzylidene cyclopentanone) exhibits binding toward AMPK, 28 OXL exhibits highest binding energy of ΔG = −15.9 kcal/mol. ...
The stimulation of adenosine monophosphate‐activated protein kinase (AMPK) is a prime target to decrease the hyperglycemic condition, hence it is a lutein (L) and oxidised lutein (OXL) is a target molecule for the treatment of type II diabetes. In the current study, a plausible interaction of L and OXL with AMPK was investigated by molecular docking. In addition, the effect of L and OXL for the activation of AMPK that triggers the downstream regulator peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α), TFAM expression, mitochondrial DNA (mtDNA), mitochondrial biogenesis and superoxide dismutase 2 (SOD2) in high glucose treated HepG2 cells were investigated by quantitative polymerase chain reaction and Western blot analysis. Molecular docking reveals higher binding affinity of L (ΔG = −6.3 kcal/mol) and OXL (ΔG = −15.5 kcal/mol) with AMPK, compared with metformin (ΔG = −5.0 kcal/mol). The phosphorylation of AMPK increased by 1.3‐ and 1.5‐fold with L and OXL treatment, respectively, in high glucose induced HepG2 cells. The activation of PGC‐1α is significant (P < 0.05) in OXL group than L. Similarly, TFAM expression is increased with L and OXL compared with the high glucose group. Further increase in SOD2 and mtDNA, confirms the efficacy of L and OXL in restoring the mitochondrial biogenesis in high glucose induced cells through AMPK, PGC‐1α, and TFAM.
... It is believed that salidroside inhibits Complex I of the electron transport chain, and thereby increases the AMP/ATP ratio, which is an activating factor for AMPK [60]. An unusual approach for the search of AMPK activators among the drugs of traditional Chinese medicine was applied in the paper [61]. The scientists used the most comprehensive database of traditional Chinese medicine compounds (TCM Database@Taiwan, http://tcm.cmu.edu.tw) for virtual screening of AMPK activators, which interact with the AMPbinding sites. ...
Adenosine monophosphate-activated protein kinase (AMP-activated protein kinase, AMPK) has become an attractive target for the treatment of diseases, associated with metabolic disorders over the last decade. The
therapeutic significance of the AMPK activation is evident in diabetes, obesity, metabolic syndrome, cardiovascular diseases, and even in cancer. AMPK activators of plant origin and their synthetic modifications are considered; presumed mechanisms of their action and therapeutic effects are noted in this chapter.
... In virtue of this, researchers worldwide emphasize the need for studies with new natural products which employ rigorous methodological designs -the aim thus being to assess their efficacy, safety and mechanism of action [11][12][13]. In Brazil, one of the current proposals from the Ministry of Health is to encourage studies on decision-making in health which involve the development, validation, efficacy and consequent incorporation of technologies in the Unified Health System (SUS) [14]. ...
... (Brazil's National Health Promotion Policy). In spite of this, outside Brazil, there continues to be a great need to list new evidence and/or information in order to definitively officialize the use of natural products in the traditional clinical care of the person with DM [11,12,43]. ...
Background
The single or combined use of herbal and dietary products with medications has shown benefits in the metabolic modulation of carbohydrates, in the restoring of the function of pancreatic beta cells, and in insulin resistance. To analyze the effect of the use of flour made from the rind of the yellow passion fruit on the glycemic control of people with diabetes mellitus type 2. Methods
An open, prospective, randomized clinical trial was undertaken with 54 participants over an eight-week period. The participants from the case group were advised to ingest 12 g of the flour, three times daily; before breakfast, lunch and dinner. ResultsAfter eight weeks of use of the flour made from the rind of the yellow passion fruit, we did not identify significant statistical differences in the values for capillary blood glucose (p = 0.562), fasting blood glucose (p = 0.268) or glycated hemoglobin (p = 0.229) between the study groups. In the case group, we identified an increase (29.6%–37%) of the people with normal HbA1c; however, this did not have statistical relevance (p = 0.274). DiscussionBased in our findings, we believe it is important to extend the time of exposure to the intervention and increase the rigor in the monitoring of adherence in future studies on this topic. Only in this way will we be able to make confident inferences in relation to the use of flour made from the rind of theyellow passion fruit as a therapeutic tool for glycemic and/or metabolic control in persons with DM 2. Conclusions
In the sample in question, the use of the flour made from the rind of the yellow passion fruit, over an eight-week period, did not improve the glycemic control of people with type 2 diabetes. Trial registration: U1111.1187.3616. Registered 6 September, retrospectively registered, in the Brazilian Clinical Trials Registry.
... Indirect activation of AMPK by the existing antidiabetic drug (metformin) [1.1] has been proposed and its new application for the treatment of cancer is being clinically investigated [13]. Pharmacology of a number of drugs and natural products, including resveratrol [1.2], berberine [1.3], rosiglitazone [1.4], α-lipoic acid [1.5], bortezomib [1.6], cilostazol [1.7], estrogen [1.8], 3,3′-diindolylmethane (DIM) [1.9], genistein [1.10], lycopene [1.11], ketamine [1.12], pitavastatin [1.13], olanzapine [1.14], and atorvastatin [1.15] are also postulated to act by indirect AMPK activation (Fig. 2) [7,10,[13][14][15][16][17][18][19][20][21][22][23][24][25][26]. ...
... Recently, rat AMPK was also employed to build a homology model for AMPK (Uniprot Knowledgebase: Q13131, human) (PDB: 2Y94) [25]. The identity between these two structures was found to be 89.4 % and similarity was found to be (89.6 %). ...
... Further, the homology model was employed to conduct molecular dynamics and virtual screening studies. The study was conducted to identify the AMPK activators [25]. ...
Adenosine monophosphate-activated protein kinase (AMPK) is viewed as a privileged therapeutic target for several diseases such as cancer, diabetes, inflammation, obesity, etc. In addition, AMPK has entered the limelight of current drug discovery with its evolution as a key metabolic regulator. AMPK also plays a key role in the maintenance of cellular energy homeostasis. Structurally, AMPK is a heterotrimeric protein, which consists of three protein subunits (α, β, and γ). The crystal structure of AMPK was solved, and several computational studies including homology modeling, molecular docking, molecular dynamics, and QSAR have been reported in order to explore the structure and function of this diverse therapeutic target. In this review, we present a comprehensive up-to-date overview on the computational and molecular modeling approaches that have been carried out on AMPK in order to understand its structure, function, dynamics, and its drug binding landscape. Information provided in this review would be of great interest to a wide pool of researchers involved in the design of new molecules against various diseases where AMPK plays a predominant role.
Graphical Abstract
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... Based on the target prediction of TCM compounds, Liang et al. tried to construct the network about one case of TCM, which represents the newest progress of network approach in pharmacology [7]. Some researches tried to construct the relationship between TCM and disease in silico [8,9]. Fang et al. collected the target genes of TCM into a database TCMGeneDIT and analyzed those genes [10]. ...
Liuwei-dihuang (LWDH) is widely used in traditional Chinese medicine (TCM), but its molecular mechanism about gene interactions is unclear. LWDH genes were extracted from the existing literatures based on text mining technology. To simulate the complex molecular interactions that occur in the whole body, protein-protein interaction networks (PPINs) were constructed and the topological properties of LWDH genes were analyzed. LWDH genes have higher centrality properties and may play important roles in the complex biological network environment. It was also found that the distances within LWDH genes are smaller than expected, which means that the communication of LWDH genes during the biological process is rapid and effectual. At last, a comprehensive network of LWDH genes, including the related drugs and regulatory pathways at both the transcriptional and posttranscriptional levels, was constructed and analyzed. The biological network analysis strategy used in this study may be helpful for the understanding of molecular mechanism of TCM.
Background:
Naringin and its aglycone naringenin are citrus-derived flavonoids with several pharmacological effects. On the other hand, the mechanism for the anti-diabetic effects of naringenin and naringin are controversial and remain to be clarified further.
Objective:
This study examined the relationship between glucose uptake and AMP-activated protein kinase (AMPK) phosphorylation by naringenin and naringin in high glucose-treated HepG2 cells.
Methods:
Glucose uptake was measured using the 2-NBDG fluorescent D-glucose analog. The phosphorylation levels of AMPK and GSK3β (Glycogen synthase kinase 3 beta) were observed by Western blotting. Molecular docking analysis was performed to evaluate the binding affinity of naringenin and naringin to the γ-subunit of AMPK.
Results:
The treatment with naringenin and naringin stimulated glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Both flavonoids increased glucose uptake by promoting the phosphorylation of AMPK at Thr172 and increased the phosphorylation of GSK3β. Molecular docking analysis showed that both naringenin and naringin bind to the γ-subunit of AMPK with high binding affinities. In particular, naringin showed higher binding affinity than the true modulator, AMP with all three CBS domains (CBS1, 3, and 4) in the γ-subunit of AMPK. Therefore, both naringenin and naringin could be positive modulators of AMPK activation, which enhance glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells.
Conclusions:
The increased phosphorylation of AMPK at Thr172 by naringenin and naringin might enhance glucose uptake regardless of insulin stimulation in high glucose treated HepG2 cells.
AMP-activated protein kinase (AMPK) is a key regulator of energy balance at both the cellular and whole-body levels. The activation of AMPK has a considerable potential in the therapy of a number of metabolic disorders as well as cancer. The achievements in the development of small-molecule activators of AMPK are reviewed.
Recent study about physiological regulators of oncogenic growth has been published in the literature. When H-ras gene mutates, the mutant H-ras(G12V) protein causes uncontrolled cell growth. We tried to observe is there any difference of the wild type and mutant H-ras protein in the molecular character and structural variation in silico. Our hypothesis is H-ras(G12V) protein accompanied with altered structure might be responsible for excess signal transduction and even tumor formation. In this study, we wanted to find the potent compound that could bind to H-ras(G12V) protein and interfere the phosphorylation of substrate protein. By the methods of homology modeling, structure-based docking, candidate screening, and molecular dynamics (MD) simulation, we demonstrated that structural and molecular character of H-ras(G12V) protein was different from the wild type H-ras protein. GTP-bound H-ras(G12V) might provide a more convenient condition to phosphorylate the substrate protein. Abrine could bind to H-ras(G12V) and might interfere the phosphorylation process. These results provided a novel insight for the management of tumor or cancer which harbored H-ras(G12V) mutation.
