Targeting mitochondrial alterations to prevent type 2 diabetes-Evidence from studies of dietary redox-active compounds

Abstract Background: Type 2 Diabetes Mellitus(T2DM) is an endocrine disease that caused mainly by insulin resistance (IR) and β cell dysfunction. The incidence of T2DM is quite high in the worldwide. To explore the molecular mechanism of Jinqi Jiangtang Tablet(JJT) in treating of T2DM based on Network Pharmacology. Methods: The active compounds, targets of three Traditional Chinese medicines in JJT were obtained by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP） database and Uniprot database; The targets of T2DM were screened through the Drugbank database; The compound-target network was constructed via the Cytoscape 3.7.2 software and used the built-in Network analyzer to analyze and select the key active compounds; The overlapping targets of drug and disease targets were gained by the VENNY online tool and the targets were built by STRING website to select the key genes; Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed on the potential targets using DAVID6.8 online tool to study the mechanism of overlapping targets. Via Systems Dock platform to validate the interaction between compound and targets Results: Twenty-five active compounds of JJT were screened, 101 drug targets, 142 disease targets and twenty-one overlapping targets. GO enrichment analysis showed that the biological processes (BP)mainly included the blood circulation ,etc. Cell composition(CC) mainly affected the integral component of plasma membrane, etc. Molecular functions(MF) mainly involved alpha-adrenergic receptor activity, etc. KEGG pathway analysis showed that there were twelve pathways related to T2DM, among which PPAR signaling pathway was related to T2DM mostly. RXRA is one of key targets of JJT and berberine performed well. Conclusions: This study revealed the mechanism of JJT in treatment of T2DM preliminarily and supplied a further foundation for studying its mechanism.

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Quercetin promotes long noncoding RNA lncSHGL expression via estrogen receptor α to suppress type 2 diabetes mellitus in mice

10.21203/rs.2.24284/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hanlu Fan ◽

Haiwen Li ◽

Huijiao Liu ◽

Peng Li ◽

Xiaomeng Jia ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Estrogen Receptor ◽

Noncoding Rna ◽

Estrogen Receptor Alpha ◽

Grape Pomace ◽

Active Compounds ◽

Organ Systems

Abstract Background Type 2 diabetes mellitus (T2DM) is the most common type of metabolic disorder involving multiple organ systems. Grape has been reported to improve the symptoms of T2DM, the precise mechanism of its action is unclear. Our study was aimed to determine the effect and mechanism of grape pomace extract in T2DM mice induced by high fat diet (HFD). Materials and methods Ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry were used to identify the main active compounds in grape pomace extract to improve T2DM. C57BLK/6J mice induced by HFD supplemented with or without quercetin were used to show the effects of quercetin improving T2DM. By online database research, bioinformatics analysis and molecular biology experiments, Estrogen receptor alpha (ERα)-lncSHGL (lncRNA suppressor of hepatic gluconeogenesis and lipogenesis) pathway was identify as the target for quercetin. Results Quercetin was identified as one of the most active compounds in grape pomace extract to improve T2DM. Quercetin could inhibit HFD-induced T2DM in mice by activing ERα. LncSHGL was identified as the downstream of ERα and inhibited HFD-induced T2DM. Conclusions Quercetin could be beneficial for T2DM by promoting lncSHGL transcription and activating the lncSHGL pathway, and may be used as a drug component to treat T2DM.

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In Vitro Investigation and Evaluation of Novel Drug Based on Polyherbal Extract against Type 2 Diabetes

Journal of Diabetes Research ◽

10.1155/2020/7357482 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Zainab Riaz ◽

Murtaza Najabat Ali ◽

Zunaira Qureshi ◽

Muhammad Mohsin

Keyword(s):

Type 2 Diabetes ◽

Digestive Enzyme ◽

Yeast Cells ◽

Antidiabetic Activity ◽

Alcoholic Extract ◽

Dissolution Profile ◽

Active Compounds ◽

Standard Drug ◽

In Vitro Investigation

Background/Aim. Type 2 diabetes is the most common form of diabetes mellitus. The aim of this study was to develop and standardize the polyhedral formulation (granule) and check its efficacy with regard to type 2 diabetes. Methods. The alcoholic extract of each plant (H. antidysentrica, Prunus dulcis and Cicer arietinum) and oleic acid was mixed and then formulated by wet granulation method. FTIR was done to investigate the presence of active compounds. Physicochemical properties of granules were evaluated and antidiabetic potential was substantiated through inhibition of carbohydrate digestive enzyme (α-amylase and α-glucosidase), glucose uptake activity in yeast cells, and antioxidant activity. Results. IR spectra indicated the presence of active compounds by showing the characteristic peaks of phenols and amines. The FTIR results also showed no interaction between drug and excipients. The prepared granules exhibited excellent flow properties according to USP 30. The dissolution profile of active pharmaceutical ingredient (API) from granules showed 72–80% release in 2 hrs. Granules exhibited better inhibition of α-amylase and α-glucosidase as in comparison with the standard drug and found to be dose-dependent. The enhanced uptake of glucose was observed with a decrease in drug concentration. Moreover, the DPPH scavenging activity was high (98%) at 1 mg/ml. Conclusion. The stabilized formulation (granules) was formed and the presence of active compounds is responsible for better antidiabetic activity by inhibiting carbohydrate-digesting enzymes. Hence, it could lower the postprandial hyperglycemia and has the potential to be used for the treatment of type II diabetes after determining the dose regime.

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Mitochondrial Dysfunctions: A Thread Sewing Together Alzheimer’s Disease, Diabetes, and Obesity

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7210892 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 8

Author(s):

Giulia Rigotto ◽

Emy Basso

Keyword(s):

Alzheimer’S Disease ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Environmental Factors ◽

Metabolic Disorders ◽

Mitochondrial Dysfunctions ◽

Mitochondrial Alterations ◽

Multiple Genes ◽

Diabetes And Obesity

Metabolic disorders are severe and chronic impairments of the health of many people and represent a challenge for the society as a whole that has to deal with an ever-increasing number of affected individuals. Among common metabolic disorders are Alzheimer’s disease, obesity, and type 2 diabetes. These disorders do not have a univocal genetic cause but rather can result from the interaction of multiple genes, lifestyle, and environmental factors. Mitochondrial alterations have emerged as a feature common to all these disorders, underlining perhaps an impaired coordination between cellular needs and mitochondrial responses that could contribute to their development and/or progression.

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Isolation and Identification of Potent Antidiabetic Compounds from Antrodia cinnamomea—An Edible Taiwanese Mushroom

Molecules ◽

10.3390/molecules23112864 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2864 ◽

Cited By ~ 11

Author(s):

Hung Huang ◽

San-Lang Wang ◽

Van Nguyen ◽

Yao-Haur Kuo

Keyword(s):

Type 2 Diabetes ◽

Natural Resource ◽

Fruiting Bodies ◽

Inhibitory Effects ◽

Meoh Extract ◽

Isolation And Identification ◽

Active Compounds ◽

Antrodia Cinnamomea ◽

Glucosidase Inhibitors

Antrodia cinnamomea (AC), an edible Taiwanese mushroom, has been recognized as a valuable natural resource with vast biological and medicinal benefits. Recently, the hypoglycemic and anti-diabetic effects of AC were mentioned in several studies. However, no studies have investigated α-glucosidase inhibitors from AC fruiting bodies (ACFB) as they relate to type 2 diabetes (T2D) treatment. The purpose of this study was to gain evidence of potent α-glucosidase inhibitory effects, as well as isolate, identify and characterize the active compounds of ACFB. The MeOH extract of ACFB demonstrated potent α-glucosidase inhibitory activity, and possessed high pH stability (pH 2–11) and thermostable properties at 40–50 °C. Further purification led to the isolation of eight constituents from ACFB, identified as: 25S-antcin K (1), 25R-antcin K (2), dehydrosulphurenic acid (3), 25S-antcin I (4), 25S-antcin B (5), 25R-antcin B (6), dehydroeburicoic acid (7) and eburicoic acid (8). Notably, the ACFB extract and its identified compounds, except 1, 4, and 6 demonstrated a greater effect (EC50 = 0.025–0.21 mg/mL) than acarbose (EC50 = 0.278 mg/mL). As such, these active compounds were determined to be new potent mushroom α-glucosidase inhibitors. These active compounds were also identified on the HPLC fingerprints of ACFB.

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Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

Royal Society Open Science ◽

10.1098/rsos.191171 ◽

2020 ◽

Vol 7 (1) ◽

pp. 191171 ◽

Cited By ~ 3

Author(s):

Vladimir Grubelnik ◽

Rene Markovič ◽

Saška Lipovšek ◽

Gerd Leitinger ◽

Marko Gosak ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Metabolism ◽

Glucagon Secretion ◽

Pancreatic Tissue ◽

Β Cells ◽

High Blood Glucose ◽

Atp Production ◽

Mitochondrial Alterations ◽

Blood Glucose Concentrations

Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.

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Mechanisms of Rhizoma Coptidis against type 2 diabetes mellitus explored by network pharmacology combined with molecular docking and experimental validation

Scientific Reports ◽

10.1038/s41598-021-00293-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wenrong An ◽

Yanqin Huang ◽

Shouqiang Chen ◽

Tao Teng ◽

Yingning Shi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Molecular Docking ◽

Experimental Validation ◽

Network Pharmacology ◽

Therapeutic Effects ◽

Active Compounds ◽

Rhizoma Coptidis

AbstractThis study systematically explored the underlying mechanism of Rhizoma Coptidis against type 2 diabetes mellitus (T2DM) by using network pharmacology and molecular docking and experimental validation. We retrieved and screened active compounds of Rhizoma Coptidis and corresponding T2DM-related targets across multiple databases. PPI networks of the genes were constructed using STRING, and the core targets were screened via topological analysis. GO and KEGG enrichment analyses were performed by using DAVID. Finally, molecular docking and experimental studies were performed after bioinformatic analysis for verification. There were 14 active compounds and 19 core targets of Rhizoma Coptidis-T2DM, of which quercetin was identified as the main compound and IL6, VEGFA and TNF were the most significant core targets. GO and KEGG enrichment analyses showed that Rhizoma Coptidis ameliorated T2DM by regulating multiple biological processes and pathways. Docking studies indicated that IL6, VEGFA and TNF could stably bind with all active compounds of Rhizoma Coptidis. The results of our experiments revealed that Rhizoma Coptidis could inhibit the expression of IL6 and TNFα and enhance islet cell viability. This study suggests anti-inflammatory therapeutic effects of Rhizoma Coptidis on T2DM, thereby providing a scientific basis and new insight for further research on the antidiabetic effect of Rhizoma Coptidis.

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