|Year : 2021 | Volume
| Issue : 2 | Page : 69-74
The role of Physalis angulata as potential anti-type 2 diabetic agent
Thanh Sang Vo1, Phuong Uyen Le1, Dai Hung Ngo2
1 NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam
2 Faculty of Natural Sciences, Thu Dau Mot University, Binh Duong Province, Vietnam
|Date of Submission||16-May-2019|
|Date of Acceptance||19-Nov-2019|
|Date of Web Publication||29-May-2021|
Dr. Dai Hung Ngo
Faculty of Natural Sciences, Thu Dau Mot University, Binh Duong province
Dr. Thanh Sang Vo
NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Medicinal plants play important roles in the management of several diseases including diabetes. Objective: The aim of this study is to investigate the mechanism of action of Physalis angulata (PA) for its anti-diabetic activity using an in vitro model. Materials and Methods: Alpha-amylase inhibition was investigated through dinitrosalicylic acid assay. Glucose uptake was determined using LO-2 cell model. Radical scavenging activity was performed through 1,1-diphenyl-2-picrylhydrazyl (DPPH), and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS+) assay. Nitric oxide (NO) production was measured using the Griess reaction. Cell viability was examined by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Results: The result showed that PA extract was able to inhibit enzyme alpha-amylase activity up to (56.6% ± 4.7%) at the concentration of 200 μg/ml. Moreover, PA possessed glucose adsorption and glucose uptake capacity up to (2.2 ± 0.18) mM glucose/g extract and (156% ± 10.1%), respectively. In addition, PA extract scavenged (52.6% ± 3.5%) DPPH and (59.7% ± 2.6%) ABTS + radicals and reduced NO production to (34.2% ± 3.8%) from RAW264.7 cells without any cytotoxic effects. Conclusion: PA could be suggested as pharmaceutical ingredient for the development of anti-diabetic products.
Keywords: Alpha-amylase, biological activity, glucose uptake, medicinal plant, Physalis angulata
|How to cite this article:|
Vo TS, Le PU, Ngo DH. The role of Physalis angulata as potential anti-type 2 diabetic agent. Phcog Res 2021;13:69-74
- In this study, Physalis angulata extract has been evidenced as potential antidiabetic agents due to inhibiting the starch digestive enzyme, possessing glucose adsorption and glucose uptake capacity, scavenging free radicals, and inhibiting nitric oxide production. Therefore, it could be applied as a functional ingredient for the prevention of type 2 diabetes.
Abbreviations Used: MTT: -(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide; ABTS: 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid; PA: Physalis angulata, DPPH: 1,1-diphenyl-2-picrylhydrazyl; NO: Nitric oxide; DNA: Deoxyribonucleic acid.
| Introduction|| |
Diabetes is the common endocrine disorder that characterized by chronic hyperglycemia due to dysregulation primarily of carbohydrate metabolism and deficiency of insulin secretion and insulin action. Indeed, diabetes can be managed through proper diet, exercise, and pharmacologic interventions. Various drugs have been applied for the treatment of diabetes through lowering blood glucose with different mechanisms. Notably, the pharmacological drugs for diabetes treatment have some disadvantages, including drug resistance, side effects, and even toxicity. Nowadays, herbal plants have been recommended and preferred as natural source of alternative medicine for the treatment of diabetes. They are considered to be safe, effective, less toxicity, and strong antioxidant activity.
Physalis angulata (PA) belongs to the Solanaceae family, which grows, especially in the Brazilian Amazon Forest and other tropical countries of Africa, America, and Asia. It grows up to 1 m with small stem, cream-colored flowers and light yellowish-orange, edible fruits wrapped by a layer of leaves. Fruits from the PA are used as food in several countries. Especially, PA has important role in remedy of inflammatory symptom such as asthma, hepatitis, dermatitis, rheumatism, and the treatment of several health disorders, such as cold, cough, fever, pain, malaria, and nervous diseases.,, Recently, the phytochemistry of PA has been reported to contain glucocorticoids, flavonoids, withanolides, and physalins. Simultaneously, numerous biological activities of PA such as antinociceptive, immunosuppressive, antiprotozoal, antineoplastic, and anti-inflammatory effects have been determined. According Hu et al., the in vitro and in vivo anti-diabetic activities of Physalis alkekengi have been reported. Moreover, in vivo anti-diabetic activity of PA fruit was also demonstrated. Accordingly, the present study has been decided to investigate the mechanism of action of PA for its anti-diabetic activity using an in vitro model.
| Materials and Methods|| |
Material and chemicals
The aerial parts (leaves and stem) of PA were collected from Tay Ninh province, Vietnam. Alpha-amylase from Bacillus licheniformis (A4582) was purchased from Sigma-Aldrich (USA). Solvent was purchased from Xilong (China). Acarbose and metformin were purchased from the pharmacy store at district 7, Ho Chi Minh City, Vietnam. All other reagents were purchased from Sigma–Aldrich (St. Louis, MO, USA).
Material was air-dried under shade and powdered by a grinder. The extraction was performed following conditions: ethanol 98%, ratio (1/4, w/v), time (4 h), and temperature (60°C). The ethanol extract was kept at 4°C for further investigation.
Alpha-amylase inhibitory assay
The α-amylase inhibitory assay was performed as described by Bhutkar and Bhise. The control (C) was prepared without plant extracts and the blank (B) is without the amylase enzyme. The absorbance was measured at 540 nm using Genova Nano (Jenway, UK). Acarbose was used as a reference. The percentage of inhibition was calculated by the following equations:
Inhibition (%) = ([ODC − ODB] − [ODsample − ODB])/(ODC − ODB) ×100%
Determination of glucose adsorption capacity
The glucose adsorption capacity of extract was determined according to Ou et al. The extract (1%, w/v) was added to 25 ml of glucose solution (10, 50, or 100 mM). The mixture was mixed well, incubated in a shaker water bath at 37°C for 6 h, centrifuged at 4000 g for 20 min and the glucose content in the supernatant was determined. The glucose adsorption was calculated using the following formula (G1 is the glucose concentration of original solution; G2 is the glucose concentration after 6 h):
Glucose adsorption = ([G1 − G2] × Volume of solution)/Weight of sample
Glucose uptake in hepatic LO-2 cells
The glucose uptake in LO-2 cells was determined as described by van de Venter et al. Glucose concentration in the supernatant was measured using Contour™ Plus Meter (Ascensia Diabetes Care, Switzerland). The percentage of glucose uptake was calculated as a percentage compared to control C (The untreated cell group). The amount of glucose uptake was calculated as the following formula (T is glucose concentration in the supernatant of the treated cell group, whereas C is glucose concentration in the supernatant of the untreated cell group):
Glucose uptake (%) = ([8 − T]/[8 − C]) ×100
The antioxidant activity of extract was determined by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay as described by Vo et al. The absorbance of the mixture was then measured at 490 nm using Genova Nano (Jenway, UK). Vitamin C was used as a reference. The ability of the sample to scavenge DPPH radical was determined from:
DPPH scavenging effect (%) = ([ODcontrol − ODsample]/ODcontrol) ×100%.
This assay was performed as described by Vo et al. The antioxidative effect was calculated by determining the decrease in the absorbance at different concentrations by using the following equation:
2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS) scavenging effect (%) = ([ODcontrol − ODsample]/ODcontrol) × 100%
Nitric oxide production assay
Nitric oxide (NO) level in the culture supernatant was measured by the Griess reaction as described by Vo et al. The nitrite oxide level was calculated as a percentage compared to control: Release ratio (%) = (T– B)/(C– B) × 100, where B is the group without stimulation as well as sample treatment, C is the stimulated group without treatment of the tested sample and T is the stimulated group with presence of the tested sample.
Cell viability assay
The viability levels of the cells were determined by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. In brief, the cells (1 × 105 cells/ml) were incubated with the extract (50, 100, or 200 μg/ml) for 24 h. The medium was removed and the cells were incubated with a solution of 1 mg/ml MTT for 4 h. Finally, the supernatant was removed and DMSO was added to solubilize the formed formazan salt. The amount of formazan salt was determined by measuring the absorbance at 540 nm using a microplate reader (Tecan Austria GmbH, Grodig/Salzburg, Austria). The cell viability was calculated as a percentage compared to blank.
Data were analyzed using the analysis of variance test of the Statistical Package for the Social Sciences (SPSS, Chicago, Illinois, USA). The statistical differences among groups were assessed using Duncan's tests. Differences were considered statistically significant at P < 0.05.
| Results|| |
Alpha-amylase inhibitory activity of Physalis angulata extract
In this study, the ethanol extracts of PA were examined for its capability against the alpha-amylase activity. It was found that PA extract possessed significant inhibition on enzyme alpha-amylase activity in a dose-dependent manner [Figure 1]. The inhibitory effect was observed up to (56.6% ± 4.7%) at the concentration of 200 μg/ml. Its activity was comparable with acarbose (59% ± 5.3%) at the concentration of 100 μg/ml.
|Figure 1: The inhibition of Physalis angulata extract on α-amylase activity. Acarbose was used as a reference. Each determination was made in three independent experiments and the data are shown as means ± standard deviation. Different letters a-c indicate significant difference among groups (P < 0.05)|
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The glucose adsorption capacity of Physalis angulata extract
In this assay, the glucose adsorption capacity of PA extract was investigated through measuring the rest glucose after mixing the extract with the indicated concentration of glucose. This assay revealed that 1% (w/v) of PA extract exhibited the capacity on glucose adsorption at different glucose concentration [Figure 2]. The adsorption capacity of the extract was directly proportional to the glucose concentration. The amount of glucose bound increased with increased glucose concentration. In particular, the adsorption capacity of PA was up to (0.3 ± 0.09) mM/g extract, (0.9 ± 0.11) mM/g extract, and (2.2 ± 0.18) mM/g extract at the glucose concentration of 10, 50, or 100 mM, respectively.
|Figure 2: The capacity of Physalis angulata extract on glucose adsorption at the different glucose concentrations. Each determination was made in three independent experiments and the data are shown as means ± standard deviation. Different letters a–c indicate significant difference among groups (P < 0.05)|
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The glucose uptake capacity of Physalis angulata extract
The stimulatory effect of PA extract on glucose uptake in liver LO-2 cells was examined. As shown in [Figure 3], the treatment of PA extract increased glucose uptake in LO-2 cells as compared to the control (without extract treatment). PA extract enhanced glucose uptake up to (156% ± 10.1%) at the concentration of 200 μg/ml. Meanwhile, metformin significantly stimulated glucose uptake up to (197% ± 11.3%).
|Figure 3: The capacity of Physalis angulata extract on glucose uptake in human hepatic LO-2 cells. Metformin was used as a reference. The results were expressed as percentage of control. Each determination was made in three independent experiments and the data are shown as means ± standard deviation. Different letters a–c indicate significant difference among groups (P < 0.05)|
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The free radical scavenging activities of Physalis angulata extract
The antioxidant activity of PA extract was investigated through measuring its scavenging ability on DPPH and ABTS + radicals [Figure 4]. The result showed that PA extract scavenged DPPH and ABTS + radicals up to (52.6% ± 3.5%) and (59.7% ± 2.6%) at the concentration of 200 μg/ml, respectively. Meanwhile, Vitamin C significantly scavenged the free radicals at the concentration of 20 μg/ml, (81.8% for DPPH and 98% for ABTS+).
|Figure 4: The antioxidant activity of Physalis angulata extract via scavenging 1,1-diphenyl-2-picrylhydrazyl (A) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (B) radicals. Vitamin C was used as a reference. Each determination was made in three independent experiments and the data are shown as means ± standard deviation. Different letters a–d indicate significant difference among groups (P < 0.05)|
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The inhibitory effect of Physalis angulata extract on nitric oxide production
To investigate NO production, the RAW 264.7 macrophage cells were pretreated with PA extract before the stimulation of lipopolysaccharide (LPS). The levels of NO production were calculated as a percentage compared to that of control (without extract treatment). In this assay, PA extract-pretreated cells decreased the NO production levels in a dose-dependent manner [Figure 5]. The NO production levels were reduced to (88% ± 5.7%), (49% ± 7.2%), and (34.2% ± 3.8%) at the concentration of 50, 100, and 200 μg/ml, respectively. Ibuprofen was effective in the reduction of NO production to (22% ± 6.3%) at the concentration of 100 μg/ml.
|Figure 5: The inhibitory effect of Physalis angulata extract on nitric oxide production from lipopolysaccharide -stimulated RAW 264.7 cells. Ibuprofen was used as a positive control. The results were expressed as percentage of control. Each determination was made in three independent experiments and the data are shown as means ± standard deviation. Different letters a-e indicate significant difference among groups (P < 0.05)|
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The effect of Physalis angulata extract on cell viability
The MTT assays were performed on hepatic LO-2 cells and RAW 264.7 macrophage cells pretreated with different concentration of PA extract for 24 h. The results showed that cell viability levels were obtained in a range of (93%–103%) for LO-2 cells and (102%–105%) for RAW 264.7 macrophage cells as compared with the blank [Figure 6]. It indicated that PA extract has no significant cytotoxicity effect on hepatic cells and macrophage cells at the concentration of 50, 100, or 200 μg/ml.
|Figure 6: The cell viability of Physalis angulata extract on hepatic LO-2 cells (A) and RAW 264.7 macrophage cells (B). Cell viability was assessed by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide method, and the results were expressed as percentage of surviving cells over blank cells. Each determination was made in three independent experiments and the data are shown as means ± standard deviation|
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| Discussion|| |
The hyperglycemia is described in the development of diabetes and causes various complications in diabetic patients. It is well-known to relate to the excess activity of alpha-amylase, a carbohydrate digestive enzyme in the gastrointestinal system. Therefore, the inhibition of α-amylase has been considered to be an effective strategy to block or slow the carbohydrate absorption after food intake, contributing to the control of hyperglycemia in diabetic patients. Herein, PA extract was determined to be effective in inhibition of α-amylase activity. Notably, the inhibitory capacity of PA extract on alpha-amylase was stronger than that of Momordica charantia (IC50 was 0.267 ± 0.024 mg/ml). Currently, acarbose, miglitol, and voglibose are common anti-diabetic drugs that act mainly by inhibiting enzymes related to carbohydrate digestion such as α-amylase, sucrase, maltase, and α-glucosidase. It has shown that mice treated with acarbose slow the breakdown of sucrose and starch. However, their usage has been limited due to their side-effects such as flatulence and diarrhea. Hence, the inhibitory effect of PA extract on α-amylase may partly attenuate the hyperglycemia in type 2 diabetes.
Beside of carbohydrate digestive enzyme inhibition, the capacity of glucose adsorption of bioactive agents also contributes to the prevention of carbohydrate absorption after food intake. Especially, various herbal plants such as ginseng, bitter melon, fenugreek, banaba, Gymnema sylvestre, and Coptis chinensis have been found as glucose adsorption agents and exhibited hypoglycemic effect in type 2 diabetes. In this sense, PA extract was also found as a potential adsorbent of the glucose. It was reported that the insoluble and soluble constituents and fibers were able to absorb the glucose. According to Bisoi et al., various insoluble fibers from locally available whole grain of millets and cereals such as kodo millet (Paspalum scrobiculatum), Proso millet (Panicum miliaceum), Barnyard millet (Echinochloa frumentaceae), Finger millet (Elusine coracana), wheat (Triticum aestivum), and Great millet (Sorghum vulgare) were determined for their glucose adsorption capacity with adsorption values of (0.49 ± 0.02) − (1.07 ± 0.02) mM/g fiber at 50 mM of glucose. Obviously, the glucose adsorption capacity of PA extract is comparable with that of insoluble fibers from millets and cereals. As the result, the α-amylase inhibitory activity accompanied with the glucose adsorption capacity of PA extract may contribute to the reduction of postprandial hyperglycemia in type 2 diabetic patients.
Glucose uptake into the tissue is an important process for the regulation of glucose homeostasis. In type 2 diabetic patients, insulin resistance or deficiency leads to decrease glucose uptake and increase endogenic hepatic glucose production, thus leading to hyperglycemia. Especially, the bioactive agents which are able to stimulate glucose uptake might play an important role in reducing hyperglycemia in type 2 diabetic patients. Especially, PA extract was observed to be able to stimulate the glucose uptake into the hepatic LO-2 cells. Although this action could not be comparable to metformin, PA extract could be anticipated to contribute to the blood lowering effect when used as alternative medicine in diabetic patients.
The free radical causes the oxidation of several cell components and molecules such as lipids, proteins, and DNA through passing the unpaired electron. Especially, it is evidenced to be associated with many diseases, including diabetes and its complications. Moreover, long-term complications of diabetes is associated with various oxidative reactions, increased free radical generation, and subsequent increase in oxidative stress. Therefore, antioxidants play an important role in the prevention of the pathogenesis as well as complications of diabetes by neutralizing the elevated amount of free radicals. Interestingly, PA extract also exhibited antioxidant activity through scavenging DPPH and ABTS + radicals obviously. It was observed that DPPH scavenging activity of PA extract was similar with that of PA leaves extract as reported by Susanti et al. They showed that PA leaves extract exhibits 50% DPPH scavenging activity at concentration of 180.5 μg/ml. Meanwhile, Akomolafe et al. showed that PA leaves extract scavenges 50% DPPH radical at concentration of 3620 μg/ml. It indicates that the antioxidant activity of PA extract in the present study is significantly higher than that of PA leaves extract as determined by Akomolafe et al. Notably, high total content of phenolics (41.2 mg GAE/g dried extract) and flavonoid (117.7 mg QE/g dried extract) was determined, and various phenolic acids (ellagic acid, caffeic acid, chlorogenic acid, and gallic acid) and flavonoids (kaempferol, isoquercitrin, rutin, quercitrin, and quercetin) were detected in the PA extract., It was evidenced that these antioxidant components possess multiple biological effects and play an important role in the treatment and management of diabetic-related diseases. Thus, the antioxidant activity of PA extract may partly delay the development of the diabetes and its complications.
It has been evidenced that NO has several benefits in physiological and cellular functions. However, the high levels of NO may cause the cell damage due to generating peroxynitrite radical. According to Adela et al., the high NO production was observed in diabetic rats and patients with hyperglycemia as compared to controls. Moreover, it was reported that NO may contribute to the development of diabetes complications, both microvascular and cardiovascular. Thus, NO was also suggested as potential target for the management of diabetes-associated complications. Notably, NO production level from LPS-stimulated RAW 264.7 cells was decreased in the presence of PA extract. The inhibitory activity of PA extract on NO production was observed to be similar with that of oolong tea (Camellia sinensis) and Red Ginger (Zingiber officinale). Numerous studies have evidenced that flavonoids can interact with NO and NO-derived nitrogen species in cell-free systems. Moreover, flavonoids possess inhibitory activity on expression levels of iNOS mRNA and protein and subsequently reduce the production of NO in several cell lines., Especially, the central mechanism down-regulating iNOS expression of flavonoids was suggested due to inactivation of nuclear factor-kB and mitogen-activated protein kinases., As the result, flavonoids in PA extract may be responsible for its inhibitory effect on NO production from RAW 264.7 cells. Accordingly, the free radical scavenging activity and NO production inhibition of PA extract may be useful for the prevention of complications in type 2 diabetes.
A number of herbal plants have been known with therapeutic effects and can be used directly or in combination with other plant for medication purpose. Besides, the knowledge related to the safety of these products is also important. Therefore, the preliminary studies related to cytotoxic effect of herbal plants needs to be evaluated to ensure relatively safe use. For in vitro model, the MTT assay was used to measure cytotoxicity. This assay is based on the metabolic reduction of the soluble MTT salt, which reflects the normal function of mitochondria dehydrogenase activity and cell viability. Importantly, MTT assay has revealed that PA extract did not cause any cytotoxicity on hepatic and macrophage cells at the tested concentrations. However, a further study related to cytotoxicity effect of PA extract on an in vivo model is needed to report due to safe use of this herbal plant.
| Conclusion|| |
Medicinal plant plays vital roles in the development of alternative medicine for healthcare. Especially, it is a huge source of potential bioactive components for the therapy and management of diabetes. In the present study, PA extract has been found as potential anti-diabetic agents due to inhibiting starch digestive enzyme, possessing glucose adsorption and glucose uptake capacity, scavenging free radicals, and inhibiting NO production. Hence, PA could be suggested as a promising material for development of pharmaceutical products that may have the role in lowing hypoglycemia and preventing diabetes-related complication. However, the further studies related to safety and efficacy of PA are necessary.
This research is supported by Nguyen Tat Thanh University, Ho Chi Minh city, Vietnam.
Financial support and sponsorship
This research was funded by NTTU Foundation for Science and Technology Development under Grant number: 2019.01.54.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]