Phytochemicals in Garlic Extract Inhibit Therapeutic Enzyme DPP-4 and Induce Skeletal Muscle Cell Proliferation: A Possible Mechanism of Action to Benefit the Treatment of Diabetes Mellitus

Abstract

Diabetes mellitus is a severe health problem in Mexico, and its prevalence is increasing exponentially every year. Recently, DPP-4 (dipeptidyl peptidase-4) inhibitors have become attractive oral anti-hyperglycemic agents to reduce the pathology of diabetes. Gliptin’s family, such as sitagliptin, vildagliptin, and alogliptin, are in clinical use to treat diabetes mellitus but possess side effects. Therefore, there is a specific need to look for new therapeutic scaffolds (biomolecules). Garlic bulb is widely used as a traditional remedy for the treatment of diabetes. The garlic extracts are scientifically proven to control glucose levels in patients with diabetes, despite the unknown mechanism of action. The aim of the study is to investigate the antidiabetic effects of ultrasonication assisted garlic bulb extract. To achieve this, in-vitro assays such as DPP-4 inhibitory and antioxidant activities were investigated. Further, functional group analysis using FTIR and identification of phytochemicals using mass spectrometry analysis was performed. The results showed that 70.9 µg/mL of garlic bulb extract inhibited 50% DPP-4 activity. On top of that, the garlic extract exhibited a 20% scavenging activity, equivalent to 10 µg/mL of ascorbic acid. Molecular docking simulations on identified phytochemicals using mass spectrometry revealed their potential binding at the DPP-4 druggable region, and therefore the possible DPP-4 inhibition mechanism. These results suggest that prepared garlic extract contains phytochemicals that inhibit DPP-4 and have antioxidant activity. Also, the prepared extract induces skeletal muscle cell proliferation that demonstrates the antidiabetic effect and its possible mechanism of action.

Improvements in HOMA indices and pancreatic endocrinal tissues in type 2-diabetic rats by DPP-4 inhibition and antioxidant potential of an ethanol fruit extract of Withania coagulans 

“…Whereas, the treatments of the test extract (W. coagulans fruit ethanol extract) and standard drug caused signi cant reductions in glucose, insulin and HOMA indices resulted in improvements in glucose homeostasis and increased pancreatic β-cell mass. These kinds of results may follow the interaction with DPP-4 by possesses active metabolites (phytochemicals) of extract through prolonging the GLP-1 postprandial stimulation to pancreatic tissues as reported by several studies [54,55]. Accordingly, the results of LCMS analysis shown that occurrence of potent bioactive phytocompounds in ethanol fruit extract of Withania coagulans known as withanoids, including withanolide D, sitoindoside IX, withanoside IV, withanone, withanolide B, withaferin A, withasomnine, withangulatin A, withacoagulin H, and withanolide E. Subsequently, the invitro assay of the test extract against DPP-4 performed the 63.2% inhibition which validate the interaction with target enzyme (DPP-4) and phytocompounds.…”

“…In same context, it is illustrated that the phytocompounds have the ability to inhibit speci c enzymes by binding to the active site within the enzyme molecule or a related mode of action [56,57]. Ideal inhibitors have a low molecular weight that can reduce or completely inhibit enzyme activity at low concentrations [55]. Several human enzyme inhibitors, such as antithrombin and antitrypsin, control enzyme activity in the body, and can function under normal physiological conditions.…”

Improvements in HOMA indices and pancreatic endocrinal tissues in type 2-diabetic rats by DPP-4 inhibition and antioxidant potential of an ethanol fruit extract of Withania coagulans

“…Whereas, the treatments of the test extract ( W. coagulans fruit ethanol extract) and standard drug caused significant reductions in glucose, insulin and HOMA indices resulted in improvements in glucose homeostasis and increased pancreatic β-cell mass. These kinds of results may follow the interaction with DPP-4 by possesses active metabolites (phytochemicals) of extract through prolonging the GLP-1 postprandial stimulation to pancreatic tissues as reported by several studies [ 54 , 55 ]. Accordingly, the results of LCMS analysis shown that occurrence of potent bioactive phytocompounds in ethanol fruit extract of W coagulans known as withanoids, including withanolide D, sitoindoside IX, withanoside IV, withanone, withanolide B, withaferin A, withasomnine, withangulatin A, withacoagulin H, and withanolide E. Subsequently, the in-vitro assay of the test extract against DPP-4 performed the 63.2% inhibition which validate the interaction with target enzyme (DPP-4) and phytocompounds.…”

Improvements in HOMA Indices and Pancreatic Endocrinal Tissues in Type -2 Diabetic Rats by DPP-4 Inhibition and Antioxidant Potential of an Ethanol Fruit Extract of Withania Coagulans

“…Whereas, the treatments of the test extract (W. coagulans fruit ethanol extract) and standard drug caused signi cant reductions in glucose, insulin and HOMA indices resulted in improvements in glucose homeostasis and increased pancreatic β-cell mass. These kinds of results may follow the interaction with DPP-4 by possesses active metabolites (phytochemicals) of extract through prolonging the GLP-1 postprandial stimulation to pancreatic tissues as reported by several studies[52,53]. Accordingly, the results of LCMS analysis shown that occurrence of potent bioactive phytocompounds in ethanol fruit extract of Withania coagulans known as withanoids, including withanolide D, sitoindoside IX, withanoside IV, withanone, withanolide B, withaferin A, withasomnine, withangulatin A, withacoagulin H, and withanolide E. Subsequently, the invitro assay of the test extract against DPP-4 performed the 63.2% inhibition which validate the interaction with target enzyme (DPP-4) and phytocompounds.In same context, it is illustrated that the phytocompounds have the ability to inhibit speci c enzymes by binding to the active site within the enzyme molecule or a related mode of action(Akhtar et al 2018; Lankatillake et al 2019).…”

“…Accordingly, the results of LCMS analysis shown that occurrence of potent bioactive phytocompounds in ethanol fruit extract of Withania coagulans known as withanoids, including withanolide D, sitoindoside IX, withanoside IV, withanone, withanolide B, withaferin A, withasomnine, withangulatin A, withacoagulin H, and withanolide E. Subsequently, the invitro assay of the test extract against DPP-4 performed the 63.2% inhibition which validate the interaction with target enzyme (DPP-4) and phytocompounds.In same context, it is illustrated that the phytocompounds have the ability to inhibit speci c enzymes by binding to the active site within the enzyme molecule or a related mode of action(Akhtar et al 2018; Lankatillake et al 2019). Ideal inhibitors have a low molecular weight that can reduce or completely inhibit enzyme activity at low concentrations(Kalhotra et al 2020). Several human enzyme inhibitors, such as antithrombin and antitrypsin, control enzyme activity in the body, and can function under normal physiological conditions.…”