These results were reflected in the AUCs. Figure 2 shows incremental changes in glycemia and AUC following the administration of ginseng or placebo either before or together with a g oral glucose challenge in 9 subjects with type 2 diabetes mellitus.

The results from pairwise comparisons shown in the figure indicated that when administered together with the glucose challenge, ginseng significantly lowered incremental glycemia following the oral glucose challenge at 45 minutes 4.

When it was given 40 minutes before the glucose challenge, the same was found at 30 minutes 3. These findings carried over to AUCs.

Whether given together ± min. This study, although small both in size and scope, represents a trial in which a phytomedicine has been challenged by rigorous scientific evaluation. The lack of such trials has been characterized as a major deficiency in the assessment of alternative therapies.

We noticed significant blood glucose—lowering action both in nondiabetic subjects and subjects with type 2 diabetes mellitus when ginseng was given 40 minutes prior to the test meal. When given together with the meal, this effect did not persist in nondiabetic subjects. To avoid an unintended hypoglycemic reaction, these findings suggest that it might be important for persons with type 2 diabetes mellitus to take ginseng with meals.

There are differences between our study and those of others that complicate comparisons to the literature. In our study, we noticed our effect with a high dose 3 g relative to that given by others studying various types of ginseng in humans.

A review of clinical studies shows the quantity administered is typically 1. Our rationale for using a higher dose was based on traditional medical practices.

In Asian medicine, herbs are treated much like diluted drugs, as a result the minimum daily dose for individual nontoxic medicinal herbs is 3 g.

Traditional practices again offer justification. According to Asian medicine, ginseng is usually taken fasting or between meals, 26 not simultaneously. Another contrast is that we investigated American ginseng. Despite these differences, we believe our findings in humans support the hypoglycemic activities of ginseng previously observed in animal models.

These include decreasing glucose tolerance curves in diabetic mice, 19 and decreasing the level of fasting blood glucose both in mice and rats. The latter having been accomplished by several types of ginseng and their isolates: American, 19 , 20 Asian, 6 , 18 Korean red, Shiu-Chi, Eleutherrococcus, Aralia, Canadian white, 19 and fraction DPG The ability of a diet to raise blood glucose levels has been found to be a factor of glycemic control.

We demonstrated previously that the consumption of diets with a low glycemic index GI improve HbA 1c relative to high GI diets in subjects with type 2 diabetes mellitus. The mechanism by which ginseng lowers the blood glucose concentration is unknown. There are several plausible hypotheses that may work independently or in concert.

First, a modulating effect of ginseng on digestion may be involved. An inhibition of neuronal discharge frequency from the gastric compartment of the brainstem in rats by American ginseng has been observed.

Second, an effect on glucose transport may be involved. Asian ginseng has been shown both to increase glucose transporter-2 protein in the livers of normal and hyperglycemic mice 18 and glucose uptake into sheep erthyrocytes in a dose-dependent manner.

It was recently shown that insulin-stimulated glucose uptake in rat skeletal muscles and adipose tissue is NO dependent. Enhanced NO synthesis by ginseng in endothelium of lung, heart, and kidney and in the corpus cavernosum has been noticed.

Last, ginseng may exert its effect through modulation of insulin secretion. Some ginseng fractions have been noticed to increase the blood insulin level and glucose-stimulated insulin secretion in alloxan diabetic mice. It was recently shown that NO stimulates glucose-dependent secretion of insulin in rat islet cells.

These last 2 mechanisms offer a possible explanation why we only saw an effect of ginseng when it was given 40 minutes before the glucose challenge in nondiabetic subjects.

Research done on sildenafil Viagra , which is hypothesized to amplify the NO-signaling cascade, indicates that it should be administered 1 hour before intercourse to allow sufficient time to develop its effect.

Alternatively, its proposed adaptogenic qualities may offer an explanation. Implications of our preliminary findings are promising. Two recent epidemiological cohort studies observed that a reduction in GI of the diet between the highest and lowest quintiles decreased the risk of developing diabetes in women 38 and men.

It is tempting to suggest that in healthy persons, this may indicate a potential use of ginseng in prevention. In people who already have established type 2 diabetes mellitus, an improvement in glycemic control with oral hypoglycemics and insulin was shown to decrease the development and progression of microvascular complications.

In short, either use may offer a new way to use an old medicine. Whether these results will prove clinically relevant, however, is debatable. Before American ginseng's therapeutic benefit in these areas can be realized, studies of the efficacy of long-term administration using HbA 1c as a surrogate end point and dose response are required.

Mechanistic investigations, including those that explore a ginseng-NO link, are also warranted. This research was partially sponsored by the Chai-Na-Ta Corp, Langley, British Columbia; and the Ontario Ministry of Agriculture, Food and Rural Affairs, Agriculture and Agri-Food Canada Ontario Tobacco Diversification Program , Ottawa, Ontario.

Reprints: Vladimir Vuksan, PhD, Clincal Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 6 Queen St E, Toronto, Ontario, Canada M5C 2T2 e-mail: v.

vuksan utoronto. full text icon Full Text. Download PDF Top of Article Abstract Participants and methods Results Comment Article Information References.

Figure 1. View Large Download. Goldbeck-Wood SDorozynski ALie Lg et al. Complementary medicine is booming worldwide. Levin JSGlass TAKushi LHSchuck JRSteele LJonas WB Quantitative methods in research on complementary and alternative medicine: a methodological manifesto: NIH Office of Alternative Medicine.

Med Care. Eisenberg DMDavis RBEttner SL et al. Trends in alternative medicine use in the United States, results of a follow-up national survey.

Tylor VE Basic principles. Herbs of Choice The Therapeutic Use of Phytochemicals Binghamton, NY Haworth Press Inc;1- 15 Google Scholar. Margolin AAvants SKKleber H Investigating alternative medicine therapies in randomized controlled trials. Liu CXXiao PG Recent advances on ginseng research in China.

J Ethnopharmacol. Kim YRLee SYShin BAKim KM Panax ginseng blocks morphine-induced thymic apoptosis by lowering plasma corticosterone level. Gen Pharmacol. Lin JHWu LSTsai KTLeu SPJeang YFHsieh MT Effects of ginseng on the blood chemistry profile of dexamethasone-treated male rats.

Am J Chin Med. Wang LCLee TF Effect of ginseng saponins on exercise performance in non-trained rats. Planta Med.

Murphy LLCadena RSChavez DFerraro JS Effect of American ginseng Panax quinquefolium on male copulatory behavior in the rat. Physiol Behav. Salim KNMcEwen BSChao H Ginsenoside Rb1 regulates ChAT, NGF and trkA mRNA expression in the rat brain. Brain Res Mol Brain Res.

Cui JChen KJ American ginseng compound liquor on retarding-aging process [in Chinese]. Chung Hsi I Chieh Ho Tsa Chih. Yuan CSWu JALowell TGu M Gut and brain effects of American ginseng root on brainstem neuronal activities in rats.

Yoshikawa MMurakami TYashiro K et al. Bioactive saponins and glycosides, XI: structures of new dammarane-type triterpene oligoglycosides, quinquenosides I, II, III, IV, and V, from American ginseng roots of Panax quinquefolium L.

Chem Pharm Bull. Kiesewetter HJung FMrowietz CWenzel E Hemorrheological and circulatory effects of Gincosan. Int J Clin Pharmacol Ther Toxicol.

Allen JDMcLung JNelson AGWelsch M Ginseng supplementation does not enhance healthy young adults' peak aerobic exercise performance.

J Am Coll Nutr. Morris ACJacobs IMcLellan TMKlugerman AWang LCZamecnik J No ergogenic effect of ginseng ingestion. Int J Sport Nutr. Ohnishi YTakagi SMiura T et al. Effect of ginseng radix on GLUT2 protein content in mouse liver in normal and epinephrine-induced hyperglycemic mice.

Biol Pharm Bull. Oshima YSato KHikino H Isolation and hypoglycemic activity of quinquefolans A, B, and C, glycans of Panax quinquefolium roots. J Nat Prod. Martinez BStaba EJ The physiological effects of Aralia , Panax and Eleutherococcus on exercised rats. Jpn J Pharmacol. Sotaniemi EAHaapakoski ERautio A Ginseng therapy in non—insulin-dependent diabetic patients.

Diabetes Care. Wolever TMSJenkins DJAJenkins ALJosse RG The glycemic index: methodology and clinical implications. Am J Clin Nutr. Fontanarosa PBLundberg GD Alternative medicine meets science. Engels HJWirth JC No ergogenic effects of ginseng Panax ginseng CA Meyer during graded maximal aerobic exercise.

J Am Diet Assoc. Bone K Dosage concentrations in herbal medicine. Br J Phytother. Yanchi L The Essential Book of Traditional Chinese Medicine: Clinical Practice Vol 7 New York, NY Columbia University Press;. Wolever TMJenkins DJAVuksan VJenkins ALWong GSJosse RG Beneficial effect of low-glycemic index diet in overweight NIDDM subjects.

Suzuki YIto YKonno CFuruya T Effects of tissue cultured ginseng on gastric secretion and pepsin activity [in Japanese]. Yakugaku Zasshi. Hasegawa HMatsumiya SMurakami C et al. Interactions of ginseng extract, ginseng separated fractions, and some triterpenoid saponins with glucose transporters in sheep erythrocytes.

Roy DPerrault MMarette A Insulin stimulation of glucose uptake in skeletal muscle and adipose tissue in vivo is NO dependent. Am J Physiol. Gillis CN Panax ginseng pharmacology: a nitric oxide link? It indicated that ginsenosides could play a role in regulating BP or signaling pathways. The results of the component-target network, component-target-BP, or signaling pathway network showed that PPT, Rh1, Rh2, Rh4, Rg1, Ro, and PPD had more complex networks compared to other ginsenosides.

We treated the top 9 scoring targets with each of the 28 ginsenosides for molecular docking. The docking protein data were sequentially downloaded from the PDB database IL-1β, EGFR, Caspase 3, VEGFA, STAT3, mTOR, MAPK1, TNF-α and JUN PDB format files.

The screened 28 ginsenosides were downloaded from the PubChem database. The download format was an SDF file. AutoDock software was used to molecularly dock small molecule active ligands to large molecule receptor proteins. We used the AutoDock Vina software to calculate the energy binding of the components to the receptor protein Table 3.

Moreover, When a small molecule ligand binds to a large molecule protein, the lower the binding energy indicates the more stable the two were bound.

In addition, by comparing the docking and MD results, we found that Ginsenoside Rg1, Ginsenoside Rh4 and Protopanaxatriol had lower binding energies and better stability than the standard receptor proteins.

This result further demonstrates the ability of ginsenosides to manage in diabetes. Supplementary Table 9 and Supplementary Fig. Some of the results were visualized with Discovery Studio and PyMol software. Figure 5 A, B shown the interaction modes of ginsenosides with JUN receptor protein: PPD interacts with the residues ANS , and LYS using hydrogen bonding, with the residue GLN , PRO , PHE , THR , GLU , GLU , ASN via van der Waals interactions forces, with the residue HIS via hydrophobicity in the form of a π bond interactions forces, and with the residue HIS through a π Sigma effect.

This process involved two hydrogen bonds and two hydrophobic bonds. The interaction modes of PPT with mTOR receptor protein: PPD interacts with the residues GLN , TYR , SER , ILE , ASP by way of van der Waals interactions forces, with the residues LYS , ARG , HIS , TYR ARG via hydrophobicity and hydrophobicity in the form of a π bond interactions forces, with the residues ARG by means of a conventional hydrogen bond.

One hydrogen bond and twelve hydrophobic bonds were involved in this process Fig. The interaction modes of ginsenoside Rg1 with TNFα receptor protein: ginsenoside Rg1 interacts with the residues CYS 69, LYS 65, ASP by means of hydrogen bonding, with the residues ALA , GLU , GLY 68, PRO 70, THR , PRO , GLN 67, GLY 66 via van der Waals interactions forces, with the residues PRO 70 via a carbon-hydrogen bond, with the residueTYR via hydrophobicity in the form of a π bond interactions forces.

This process involved four hydrogen bonds and two hydrophobic bonds Fig. The interaction modes of ginsenoside Rh1 with VEGFA receptor protein: ginsenoside Rh1 interacts with the residues TYR 95, LYS 42, VAL 93, GLN 38, GLN 39, GLY 42, ALA 40, PRO 41, GLU , PRO , PHR , SER , PHE 83, GLN by van der Waals interactions forces, with the residues GIY 41, THR , THR by means of hydrogen bonding, with the residues PRO , PRO 40 via hydrophobicity.

This process involved three hydrogen bonds and five hydrophobic bonds Fig. The interaction modes of ginsenoside Rh2 with IL-1β receptor protein: ginsenoside Rh2 interacts with the residues LYS 74, GLN 81, TYR 24, LEU 69, THR 79, GLU 25, SER , MET , GLN , ASP through van der Waals interactions forces, with the residues LEU 80 by means of hydrogen bonding, with the residues PRO , PHE , VAL , LEU 26, LEU 82, LEU 80 via hydrophobicity and hydrophobicity in the form of a π bond interactions forces.

This process involved two hydrogen bonds and eight hydrophobic bonds Fig. The interaction modes of ginsenoside Rh4 with STAT3 receptor protein: ginsenoside Rh4 interacts with the residues THR , LYS , ASP , GIUU 24, ILE 22, LEU 98, MET 99, ILE 75, GLN 96 by way of van der Waals interactions forces, with the residues GIU , ASP 97, SER through hydrogen bonding, with the residues MET 99 via a carbon-hydrogen bond, with the residues LEU , ALA 43, VAL 30, LYS 45 by way of hydrophobicity and hydrophobicity in the form of a π bond interactions forces.

This process involved five hydrogen bonds and four hydrophobic bonds Fig. Molecular docking analysis showing bond pattern. Areas of the donor and acceptor of hydrogen bond H-bond A , C , E , G , I , K. We selected ginsenosides with more DM-related targets, and the selected receptor proteins were at the core of the network analysis.

On this basis, we carry out the following molecular dynamics analysis. The ginsenosides—receptor protein was further selected to perform a computer molecular dynamics simulation study in the hope of understanding their stability in the binding pocket.

Of note, the root means square deviation RMSD was an important basis to measure whether the system was stable or not. The mTOR-Protopanaxatriol, STAT3-Ginsenoside Rh4, TNFα-Ginsenoside Rg1, and IL-1β-Ginsenoside Rh2 systems were consistently lower fluctuation throughout the molecular dynamics simulations.

Their average RMSD value were 0. The JUN-Protopanaxadiol and VEGFA-Ginsenoside Rh1 systems fluctuated slightly throughout the molecular dynamics simulations. The protopanaxadiol was unstable against JUN.

But may be suitable drug candidate for JUN. Next, the flexible change in amino acid residues in receptor protein and the root mean square fluctuation RMSF value were evaluated.

We sequentially evaluated the average RMSF of mTOR-Protopanaxatriol, STAT3-Ginsenoside Rh4, TNFα-Ginsenoside Rg1, IL-1β-Ginsenoside Rh2, JUN-Protopanaxadiol, and VEGFA-Ginsenoside Rh1 system. Their average RMSF value were 0.

The fluctuation frequency of the above six systems is low. Among them, the mTOR-Protopanaxatriol system had the least fluctuation Fig. Taken together, all the results confirmed the stability of ginsenosides and core receptor proteins during molecular dynamics simulation.

Profiles of molecular dynamics simulations. RMSD analysis for the protein—ligand complexes A. RMSF analysis for the protein—ligand complexes B. Rg analysis for the protein—ligand complexes C.

SASA analysis for the protein—ligand complexes D. Among the six systems, mTOR-Protopanaxatriol and IL-1β-Ginsenoside Rh2 had the lowest mean Rg values of 1. TNF-α—Ginsenoside Rg1, VEGFA-Ginsenoside Rh1, and STAT3-Ginsenoside Rh4 systems were more stable with Rg values of 1. Jun- Protopanaxadiol was the most fluctuating among the six systems, and its Rg value of 2.

The solvent-accessible surface area SASA was analyzed to distinguish the protein compactness behavior. The results showed that the average values of mTOR-Protopanaxatriol, JUN-Protopanaxadiol,TNF-α-ginsenoside Rg1, VEGFA-ginsenoside Rh1, IL-1β-ginsenoside Rh2, STAT3-ginsenoside Rh4 were The H-bond interaction for each complex was shown in Fig.

The most involved hydrogen bonds during molecular dynamics simulations were IL-1β-Ginsenoside Rh2 11, , followed by VEGFA-Ginsenoside Rh1 10, , TNF-α-Ginsenoside Rg1 10, , STAT3-Ginsenoside Rh4 10, , mTOR-Protopanaxatriol , and JUN-Protopanaxadiol In addition, the IL-1β-Ginsenoside Rh2 and mTOR-Protopanaxatriol systems almost consistently involved hydrogen bonds throughout the molecular dynamics simulations.

The number of hydrogen bonds involved in the binding of proteins with molecules during molecular dynamics simulations. The main contribution of amino acid residues in the binding regions of ginsenoside and receptor proteins to the binding free energy is shown in Fig.

Six amino acids play an active role in STAT3 and ginsenoside Rh4, IL-1β and ginsenoside Rh2, TNF-α and ginsenoside Rg1, JUN and protopanaxadiol, mTOR and protopanaxatriol, VEGFA and ginsenoside Rh1 complex.

In the complex binding over various small molecule ligands plays a greater contribution. Active site information and contribution values of proteins in the process of protein-molecule binding during molecular dynamics simulation.

Among the six systems, the mTOR—Protopanaxatriol and IL-1β -Ginsenoside Rh2 systems had the lowest total binding energy and the most stable binding.

Analysis of the free energy sources involved in the binding of proteins to molecules during molecular dynamics simulations. DM remains an insurmountable problem worldwide Chinese herbal medicine has been handed down in China for thousands of years and has a deep historical heritage.

A large number of ancient texts on Chinese medicine have clearly documented the effects of herbs to manage DM, such as ginseng 30 , There is increasing evidence that ginsenosides have anti-diabetic and insulin-sensitizing properties.

At the same time, ginsenosides not only have the effects of lowering blood sugar, managing insulin sensitivity, and regulating lipid metabolism but also can alleviate the occurrence of DM 32 , Our group conducted some research on ginsenosides to manage DM.

The malonyl ginsenosides significantly reduced the fasting blood glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol levels, etc.

We found that CK could provide beneficial anti-diabetic effects in DM mice, and this protective effect may be mediated by preventing β-cell apoptosis by inhibiting the AMPK-JNK pathway The predicted results of the present work almost coincide with the findings of our group.

The results of KEGG signalling pathway enrichment analysis indicated that the above signalling pathway might be a significant signalling pathway for ginsenosides to manage DM.

However, whether the unreported saponins in ginseng can manage DM mellitus and its mechanism of action are still unclear. Therefore, this study aimed to investigate the managing effects of ginsenosides on DM and their possible mechanisms of action based on network pharmacology and the molecular docking methodology.

As seen above, ginsenosides, as the main active ingredient, can be effective against DM. These previous reports provide sufficient support for our next step to explore the molecular mechanism of components obtained from ginseng to manage DM. In this work, the ginsenosides and their action targets were collected by data mining.

In the Venn diagram of the intersection of components in ginseng and DM, 99 cross targets of protein—protein, and 9 core targets were screened by Cytoscape 3. VEGFA plays a major role in endothelial cell growth and angiogenesis and is an essential factor. There were considerable evidence that when DM occurs it often lead to overexpression of VEGFA, which can have a detrimental effect on the body 39 , TNF is an important pro-inflammatory factor that can manage DM by reducing insulin signaling through phosphorylation of serine Moreover, TNF-α is closely associated with diabetic nephropathy and vascular dysfunction The results of BP results showed that the ginsenosides were related to the process of positive regulation of protein STK activity, positive regulation of MAP kinase activity, regulation of lipid metabolic process, and positive regulation of reactive oxygen species metabolic process, etc.

A lot of evidence has shown that oxidative stress damage leads to lipid peroxidation. Lipid peroxidation causes the rearrangement of peroxyl radicals which can lead to a large of pathological changes in the body. The occurrence of DM often leads to an abnormally high expression of reactive oxygen species ROS.

This can accelerate the onset of cardiovascular disease in DM. Many studies have confirmed that during the development of DM, a shift in glycolytic metabolism occurs, which lead to an overproduction of ROS in monocytes and macrophages.

Furthermore, macrophages were produced in large numbers when DM occurs, releasing excessive amounts of pro-inflammatory factors and proteases that lead to inflammation. Because ROS were important mediators in the activation of pro-inflammatory signaling pathways, obesity- and hyperglycemia-induced ROS overproduction may favor the induction of M1-like pro-inflammatory macrophages during the onset and progression of DM 43 , This will lead to further deterioration of the disease.

These conditions increased the likelihood of cardiovascular disease in people with DM. When a patient suffers from concomitant cardiovascular disease, it was not conducive to the management of DM, forming a vicious circle Fortunately, we found that ginsenosides may have a certain regulatory effect on the regulation of blood vessel diameter and vascular process in the circulatory system.

When DM occurs, the body's skin healing ability is greatly reduced BP results show that ginsenosides have a regulatory effect on epithelial cell proliferation. This BP may manage DM-induced skin healing difficulties. These BP were mainly closely related to the molecular functions of steroid binding, steroid hormone receptor activity, and adrenergic receptor activity.

And that mainly occur in the mitochondrial outer membrane, an integral component of the presynaptic membrane, neuronal cell body, etc. Ginsenosides might be involved in a wide range of BP in managing DM and its complications, and these BP are closely related to a variety of molecular functions and cellular components.

Overall, our GO results clearly indicated that ginseng could be used to manage DM by modulating BP to ultimately manage it. A lot of evidence shown that when DM occurs, it tends to cause a series of symptoms such as obesity, insufficient insulin secretion, inflammation, elevated cholesterol, and hardened blood vessels.

Our KEGG enrichment analysis showed that insulin, AGE-RAGE, TNF, AMPK, VEGF, adipocyte factor, HIF-1, and PI3K-Akt signaling pathway might be the major signaling pathways 12 , The HIF-1 pathway was a well-known regulator of cellular glucose When diabetics were exposed to a hypoxic environment, HIF was activated and this led to the release of large amounts of inflammatory factors from damaged organs 48 , Diabetic patients often had a condition with elevated pro-inflammatory factors, such as TNF-α.

TNF-α mediated inflammation, obesity, and insulin resistance were associated with DM This promoted islet cell proliferation Ultimately it was beneficial for DM to manage.

Overall, our results suggested that ginsenosides could act on multiple targets and in multiple pathways. Our findings showed that ginsenosides might regulate the above signaling pathways by acting on Caspase 3, MTOR, VEGFA, MAPK1, JUN, TNF-α, STAT3, IL-1β, EGFR and other targets, thereby managing DM 52 , This showed that the ginsenosides in ginseng could bind well to the nine core genes.

Ginsenosides bind to core targets in a variety of ways, mainly hydrogen bonds, as we know that the binding energy of molecular docking is determined by both the receptor protein and the small molecule ligand. However, it is not clear which of the two has a greater impact on binding energy.

In this part of the results, we found that receptor proteins had the greatest effect on the binding energy. The conformation and relative molecular mass of small molecules such as S- or R-type receptors had no significant effect on the binding energy.

Although further investigation is needed to obtain more reliable conclusions, these results give us an important hint.

Combined with the results of molecular docking implied that ginsenosides have some targeting to the receptor protein. To some extent, it can explain that ginsenosides can manage DM with certain targeting properties. Furthermore, molecular dynamics simulation, one of the effective tools used to check the stability of the protein ligand complex, was applied to assess the stability of ginsenosides to receptor proteins in the binding pocket in ns.

Interestingly, the molecular dynamics simulation results were in agreement with the molecular docking results and suggest the favorable stability along with proper interaction during the time, for both bioactive ingredients with the receptor proteins.

The MM-PBSA analysis further clarified the major amino acid sites of different targets and their contribution values. The composition of free energy of ginsenosides and targets during the binding process was also defined clearly.

These results further provide that ginsenosides have activity in the management of diabetes mellitus. So far, more than ginsenosides have been identified. Our prediction results indicated that 28 saponins had an anti-diabetic effect The predicted amount of saponins accounted for about one fourth of the total.

The remaining unpredicted ginsenosides may also have anti-diabetic effects. The reason for this could be the low OB and DL of other ginsenosides or their unclear target.

However, compared with the existing reports, our predicted ginsenosides are relatively comprehensive and the mechanism of action is relatively systematic.

Meanwhile, ginseng polysaccharide components have been shown to manage DM, but due to some limitations, these components could not be analyzed by network pharmacology This type of active ingredient still needs further research.

Overall, the application of network pharmacology allowed the mechanisms of action of traditional Chinese medicine in the treatment of disease to be explored at the molecular level. It was more systematic to provide valid evidence and basis for the management of DM by ginseng.

However, there were shortcomings, such as lesser reported herbs not being searchable, less comprehensive targets for some ingredients, and less software available to correspond to them. In conclusion, our findings clearly indicated that the managed results of 28 ginsenosides in ginseng on DM were through a multi-component, multi-target, multi-pathway overall regulation.

The process involved 99 relevant targets, GO terms and signaling pathways. This result was consistent with traditional chinese medicine theory. Among the 28 ginsenosides, PPT, Rh1, Rh2, Rh4, Ro, Rg1, and PPD interacted with more targets, BP, and signaling pathways.

We speculated that these seven saponins might play a significant role in managing DM. A comparison with the literature, molecular docking, and molecular dynamics simulation showed the authenticity and reliability of our results. Bai, Y.

Molecular mechanism of puerarin against diabetes and its complications. Article Google Scholar. Karmazyn, M. Ginseng for the treatment of diabetes and diabetes-related cardiovascular complications: a discussion of the evidence.

Article CAS Google Scholar. Chen, W. Review of ginseng anti-diabetic studies. Warren, R. The stepwise approach to the management of type 2 diabetes.

Diabetes Res. Kim, S. Red ginseng for type 2 diabetes mellitus: A systematic review of randomized controlled trials. Brass, E. The food and drug administration and the future of drug development for the treatment of diabetes. Diabetes Spectr. Zhang, T. et al. The effects of environmental factors on ginsenoside biosynthetic enzyme gene expression and saponin abundance.

Luo, J. Ginseng on Hyperglycemia: Effects and Mechanisms. Evidence-Based Complement Altern. Mohanan, P. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. Ginseng Res. Shi, Y. Yu, H. Ginsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat model.

Cell Mol. Su, W. Liu, X. The potential transformation mechanisms of the marker components of Schizonepetae spica and its charred product. Wang, X. TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches.

Li, S. Traditional Chinese medicine network pharmacology: theory, methodology and application. Article ADS Google Scholar. Zhou, Z. Applications of network pharmacology in traditional chinese medicine research. Huang, Q. Li, Z. Immunoregulatory mechanism studies of ginseng leaves on lung cancer based on network pharmacology and molecular docking.

Article ADS CAS Google Scholar. Du, L. The potential bioactive components of nine TCM prescriptions against COVID in lung cancer were explored based on network pharmacology and molecular docking.

Kang, X. Systematic elucidation of the mechanism of sappan lignum in the treatment of diabetic peripheral neuropathy based on network pharmacology. Evid-Based Complement Altern. Yang, Y.

Network pharmacology and experimental assessment to explore the pharmacological mechanism of qimai feiluoping decoction against pulmonary fibrosis. Kanehisa, M. KEGG: Kyoto encyclopedia of genes and genomes.

Acids Res. Zhang, J. A bioinformatics investigation into molecular mechanism of Yinzhihuang granules for treating hepatitis B by network pharmacology and molecular docking verification. Song, X. Prediction of triptolide targets in rheumatoid arthritis using network pharmacology and molecular docking.

Zhang, X. Network pharmacology based virtual screening of active constituents of Prunella vulgaris L. and the molecular mechanism against breast cancer. Maynard, A. Docking and scoring in discovery studio. Salomon-Ferrer, R. An overview of the Amber biomolecular simulation package.

Wires Comput. Khanal, P. Computational investigation of benzalacetophenone derivatives against SARS-CoV-2 as potential multi-target bioactive compounds. Venables, M. Physical inactivity and obesity: Links with insulin resistance and type 2 diabetes mellitus. Feng, Y. Acupoint therapy on diabetes mellitus and its common chronic complications: A review of its mechanisms.

Sharma, B. A comprehensive review on chemical profiling of nelumbo nucifera: Potential for drug development.

Wong, A. Ginsenoside-Rb1 as an anti-cancer therapeutic: abridged secondary publication. Hong Kong Med. Google Scholar. Zhou, P. Ginsenoside Rb1 as an anti-diabetic agent and its underlying mechanism analysis.

Li, Y. Liu, Z. Antidiabetic effects of malonyl ginsenosides from Panax ginseng on type 2 diabetic rats induced by high-fat diet and streptozotocin. Hypoglycemic and Hypolipidemic Effects of Malonyl Ginsenosides from American Ginseng Panax quinquefolius L.

on Type 2 Diabetic Mice. ACS Omega 6 , — Li, W. Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 diabetes mice induced by high-fat diet combining with Streptozotocin via suppression of hepatic gluconeogenesis.

Fitoterapia 83 , — Guan, F. Life Sci. Kutluay, V. Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L.

in the treatment of type 2 diabetes mellitus. Zhang, A. Role of VEGF-A and LRG1 in abnormal angiogenesis associated with diabetic nephropathy.

Aly, R. Patterns of Toll-like receptor expressions and inflammatory cytokine levels and their implications in the progress of insulin resistance and diabetic nephropathy in type 2 diabetic patients.

Sun, Y. Expression of miRNA in pancreatic beta cells promotes inflammation and diabetes via TRAF3. Cell Rep 34 , de Maranon, A. Good glycaemic control reduces carotid-intima-media thickness, inflammation markers and ros production in type 2 diabetes.

Free Radic. Bio Med. Hasheminasabgorji, E. Dyslipidemia, diabetes and atherosclerosis: role of inflammation and ROS-redox-sensitive factors. Beckman, J. Vascular complications of diabetes. Singh, W. Icariin improves cutaneous wound healing in streptozotocin-induced diabetic rats.

Tissue Viability 31 , — Baryla, I. Tian, Y. Chronic intermittent hypobaric hypoxia ameliorates diabetic nephropathy through enhancing HIF1 signaling in rats. Liu, M. Signalling pathways involved in hypoxia-induced renal fibrosis. Sarkar, P. Gene , Li, L. Saxena, M. Association of TNF-alpha gene expression and release in response to anti-diabetic drugs from human adipocytes in vitro.

Diabetes Metab. S Liadis, N. Caspasedependent beta-cell apoptosis in the initiation of autoimmune diabetes mellitus. Cell Biol. Shin, B. Chemical diversity of ginseng saponins from Panax ginseng.

Sun, C. Anti-hyperglycemic and anti-oxidative activities of ginseng polysaccharides in STZ-induced diabetic mice. Food Funct. Download references. This work was supported by the grants of National Natural Science Foundation of China No. College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, , China.

National and Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun, , China. Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, Dalian Minzu University, Dalian, , Liaoning, China.

Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, China. You can also search for this author in PubMed Google Scholar. Author contributions W.