{"id":63297,"date":"2024-12-30T10:06:01","date_gmt":"2024-12-30T10:06:01","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=63297"},"modified":"2025-01-07T04:24:31","modified_gmt":"2025-01-07T04:24:31","slug":"exploration-of-the-glut-4-modulation-potential-of-gynura-procumbens-as-a-mechanism-behind-its-antidiabetic-activity","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no4\/exploration-of-the-glut-4-modulation-potential-of-gynura-procumbens-as-a-mechanism-behind-its-antidiabetic-activity\/","title":{"rendered":"Exploration of the GLUT-4 Modulation Potential of Gynura procumbens as a Mechanism Behind its Antidiabetic Activity"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n

Type 2 diabetes mellitus, one of the most common non-communicable chronic diseases, has become a glaring concern for healthcare practitioners worldwide, especially due to the digitalization and a general shift towards a sedentary, less labour-intensive lifestyle1<\/sup>. In fact, it is often afflicted with other chronic diseases, resulting in co-morbid conditions and increasing the overall impact on health. According to a report by the American Diabetes Association, in patients with diabetes mellitus, hypertension is not only the greatest cause of morbidity and mortality, but it also exerts the largest toll financially2<\/sup>. Diabetes-associated dyslipidemia only adds to the risk and furthers the possibility of cardiovascular complications3<\/sup>. Moreover, these conditions require lifelong pharmacological interventions, which can result in hepatorenal complications associated with chronic pharmacotherapy. Therefore, concurrent administration of herbal medicinal supplements that allow a less strenuous pharmacologic regimen or provide hepatoprotective effects can be therapeutically relevant.<\/p>\n

Gynura procumbens<\/em> is a plant with tremendous potential in the field of herbal medication development. The ethnomedical uses of the plant are versatile, and many of these claims have been ascertained scientifically4<\/sup>. Previously, we and other groups had reported this plant to possess significant anti-diabetic, anti-hypertensive, anti-hyperlipidemic, hepatoprotective, anti-inflammatory, antioxidant, and anticancer activities both in vitro<\/em> and in vivo<\/em> in preclinical trials5-8<\/sup>. In the alloxan-induced diabetic murine model, the ethanolic extract of the plant not only exerted a significant antihyperglycemic effect but also reversed several alloxan-mediated adverse biochemical changes5<\/sup>. In the streptozotocin-induced diabetic murine model, the ethanolic plant extract was observed to exert hypoglycemic activity and inactivate Glycogen synthase kinase-3 beta (GSK3\u03b2) in hepatic tissue9<\/sup>. The association between the expression of GLUT-4 and the amount of insulin utilized by the cells has been established long ago10<\/sup>. While exploring the mechanism of action behind the antidiabetic activity of G. procumbens<\/em>, the chance of its ability to increase GLUT-4 expression can be hypothesized. In this communication, we aim to report the results of the animal experiment where the level of GLUT-4 expression among diabetes-induced rats treated with different doses of G. procumbens<\/em> extract have been compared with healthy control, disease control, and metformin-controlled rats using enzyme-linked immunosorbent assay (ELISA) technique.<\/p>\n

Materials and Methods<\/strong><\/p>\n

Drugs, Chemicals, and Instruments<\/strong><\/p>\n

Ethanol for extraction, chloroform for euthanasia and alloxan for diabetes induction were purchased from Sigma Aldrich (Germany). Metformin (Standard antidiabetic drug) as control, syringe, gloves, lancets and strips were purchased from nearby pharmacy of Dhaka Medical College. Rat GLUT-4 ELISA kit for 96 well plate was purchased from MyBioSource (Cat. No.: MBS765109).<\/p>\n

Plant Collection and Extract Preparation<\/strong><\/p>\n

G. procumbens<\/em> leaves were gathered from the medicinal plant garden of the University of Dhaka, Bangladesh. Then, taxonomic identification and authentication were completed. The National Herbarium of Bangladesh maintained plant specimens in accordance with their regulations. The herbarium administrators assigned accession number 47380, dated 11-2-2019, for future reference. After a 7-10 day period of shade drying, the leaves were coarsely crushed. Powdered leaves soaked in ethanol (70%) were forcefully agitated for 96 hours. Following the extraction’s soaking period, the filtered liquid was collected. The extracted solution was then concentrated using a rotary evaporator. The dried extract was then meticulously gathered and diluted with water. Tween 20 was used to solubilize the extract in water. The concentration of the extract was determined and then stored at -20\u00b0C.<\/p>\n

Experimental Animal Handling <\/strong><\/p>\n

Adult and healthy Albino rats of either sex weighing between 100 and 200 g, were collected from the Jahangirnagar University in Savar, Dhaka, Bangladesh. They were kept with sufficient facilities at the Institute of Nutrition and Food Science, University of Dhaka, Bangladesh. These rats were kept at a steady temperature of 25 \u00b0C in a 12-hour cycle of light and dark. A standard pellet diet and sufficient pure water were provided regularly. They were left there to become accustomed to the new environment before the investigation began. Rats were used in all of the experiments, and they were all conducted in accordance with the rules established by the Institutional Animal Ethics Committee (IAEC). The Swiss Academy of Medical Sciences (SAMS) and the Swiss Academy of Sciences (SCNAT) guidelines were followed in the care and handling of the animals.<\/p>\n

Experimental Guidelines <\/strong><\/p>\n

The 2013 Declaration of Helsinki’s ethical guidelines were followed in the execution of all tests. The \u201c3R\u201d principles, a cornerstone of Swiss and international guidelines governing the exploitation of animals for experimental purposes, were strictly maintained during the whole length of this study.<\/p>\n

Sample Size Estimation for the Animal Model <\/strong><\/p>\n

The sample size was kept at six rats per group as it is sufficient to obtain statistical significance according to previous literature.<\/p>\n

Dose Selection <\/strong><\/p>\n

At a dose of 250 mg\/kg, the plant extract (G. procumbens<\/em>) started to exert its pharmacological effect, according to a previous study, indicating that its MEC (minimum effective concentration) value was higher than 250 mg\/kg. A steady increase in this effect was observed as the dosage was increased. Eventually, there was no discernible change in the pharmacological effects when the dosage was increased from 750 mg\/kg to 1000 mg\/kg5<\/sup>. The three doses were therefore chosen accordingly. The standard dose of Metformin which is 500 mg\/kg was chosen based on a previous literature review.<\/p>\n

Experimental Design<\/strong><\/p>\n

Rats were separated into six groups, each consisting of six rats, based on their body weight. The oral glucose tolerance test (OGTT) and the enzyme-linked immunosorbent assay were used to measure the peak plasma glucose concentration (Table 1).<\/p>\n

Table 1: Group distribution of rats for the experiment.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n
\n

Group number<\/strong><\/p>\n<\/td>\n

\n

Group status<\/strong><\/p>\n<\/td>\n

\n

Treatment specimen<\/strong><\/p>\n<\/td>\n

\n

Dose of the treatment specimen<\/strong><\/p>\n<\/td>\n

\n

Group abbreviation<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n<\/td>\n

\n

G. procumbens<\/em><\/p>\n<\/td>\n

\n

G. procumbens <\/em>ethanolic extract<\/p>\n<\/td>\n

\n

250 mg\/kg<\/p>\n<\/td>\n

\n

GP 250<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

G. procumbens<\/em><\/p>\n<\/td>\n

\n

G. procumbens <\/em>ethanolic extract<\/p>\n<\/td>\n

\n

500 mg.kg<\/p>\n<\/td>\n

\n

GP 500<\/p>\n<\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

G. procumbens<\/em><\/p>\n<\/td>\n

\n

G. procumbens<\/em> ethanolic extract<\/p>\n<\/td>\n

\n

750 mg\/kg<\/p>\n<\/td>\n

\n

GP 750<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

Metformin control<\/p>\n<\/td>\n

\n

Metformin<\/p>\n<\/td>\n

\n

500 mg\/kg<\/p>\n<\/td>\n

\n

MET 500<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

Normal Control<\/p>\n<\/td>\n

\n

Physiological saline<\/p>\n<\/td>\n

\n

10 mL\/kg<\/p>\n<\/td>\n

\n

NORM<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

Diabetic Control<\/p>\n<\/td>\n

\n

Physiological saline<\/p>\n<\/td>\n

\n

10 mL\/kg<\/p>\n<\/td>\n

\n

DIA<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Alloxan administration and treatment<\/strong><\/p>\n

To induce diabetes in the rat model alloxan was applied at 150 mg\/kg dose. The desired amount was calculated for each rat and was measured carefully. Immediately it was dissolved in normal saline and then administered into the rat by intraperitoneal route.<\/p>\n

Following the administration of alloxan, blood glucose levels were measured to check for hyperglycaemia. The majority of the rats treated with alloxan had blood glucose levels ranging from 7 to 11 mmol\/L on average after 3\u20134 days, which was a clear sign of hyperglycaemia or diabetes. Then, for a total of 28 days, oral treatment was initiated with Metformin and three doses of G. procumbens<\/em> extract administered by oral gavage.<\/p>\n

Biological Sample Collection<\/strong><\/p>\n

Blood samples were taken by puncturing the tip of rats’ tails to evaluate blood glucose levels. After 4 weeks of treatment, each rat was euthanized using chloroform, and immediately after, the abdomen was dissected and the liver was collected in a glass vial. The samples were flash frozen using dry ice and then stored at a -20\u00b0 C freezer for future use.<\/p>\n

Preparing tissue samples for ELISA<\/strong><\/p>\n

The frozen liver samples were thawed to room temperature and then 120 \u00b1 30 mg of liver tissue was taken into a 2 mm Eppendorf tube after measurement and 300 \u00b5L of RIPA buffer was added into the tube. Each of the tissue samples was homogenized using an ultrasonic homogenizer for 1 minute and then centrifuged at 4\u00b0C, for 10 minutes at 10000 rpm. The supernatant was taken into another Eppendorf tube and stored at -20\u00b0C for further use.<\/p>\n

Running ELISA and Collecting absorbance data <\/strong><\/p>\n

96 well-plate Rat GLUT-4 ELISA kit purchased from MyBioSource was used for performing the assay. A manual with detailed directions was supplied with the kit which was followed to the point for conducting the experiment. To determine the dilution factor for samples, a trial batch was run using different concentrations of the standard kit against 2-200 times diluted homogenized tissue samples. It was shown that the 2X dilution gave the absorbance value within the accepted range of the test kit. So, the final assay was performed by using 2X dilution of the samples. ELISA plate reader was used to measure the absorbance value.<\/p>\n

Data processing and statistical analysis <\/strong><\/p>\n

The blood glucose measurement data obtained from the oral glucose tolerance test (OGTT) were analyzed by independent sample t-test using SPSS software. The absorbance data obtained from the ELISA plate reader were adjusted for the dilution factor and weight of the tissue sample taken. Then amount of GLUT-4 per unit of tissue was determined using the standard curve. Finally, these data were analyzed by one-way ANOVA test to interpret intergroup heterogeneity using Prism software. The \u201cp\u201d value margin was set to less than 0.05 (p<0.05) for statistical significance.<\/p>\n

Results and Discussion<\/strong><\/p>\n

G. procumbens<\/em><\/strong> extract restores the weight of diabetic animals<\/strong><\/p>\n

In the current experiment, it was observed that the weight of the experimental animals took a downward turn in all experimental groups after the administration of alloxan and consequent induction of diabetes. This is to be expected, as not only is alloxan a toxic substance that stresses out the physiological system in the course of diabetes induction, but also diabetes itself is a condition that has been reported to cause muscular damage11,12<\/sup>. The latter statement is also reflected heavily in the case of the diabetic control rats, where body weights took a further drop after 28 days of observation. The diabetes-mediated reduction in body weight was prevented in all three test groups, i.e., GP 250, GP 500, and GP 750, as well as the metformin control group. In all four groups, the reduction in body weight due to alloxan administration was recovered, and body weights continued to rise gradually under treatment. In a previously reported study, the aqueous extract of the plant was reported to retard diabetes-induced body weight loss13<\/sup>. The change in body weights is depicted in Graph 1.<\/p>\n\n\n\n
\"\"<\/td>\n\n

Graph 1: Weight of experimental animals over the course of the experiment. GP 250= Diabetic rats treated with 250 mg\/kg G. procumbens<\/em> extract, GP 500= Diabetic rats treated with 500 mg\/kg G. procumbens<\/em> extract, GP 750= Diabetic rats treated with 750mg\/kg<\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Graph<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

G. procumbens<\/em><\/strong> extract reduces fasting blood glucose of diabetic animals<\/strong><\/p>\n

Fasting blood glucose (FBG) and postprandial blood glucose (PBG; blood glucose 2 hours after eating) are two important measures for monitoring diabetic status. In the current study, we observed that the initial fasting blood glucose of all experimental animals had a mean 4.84 \u00b1 0.37 mmol\/L, which has been reported to be within the normal range for rats14<\/sup>. After the administration of alloxan, the mean fasting blood glucose value increased to 9.18 \u00b1 1.99 mmol\/L, indicating the attainment of diabetic status of the experimental animals. After the 28-day treatment period, reductions in blood glucose were recorded in all three GP treatment groups along with the metformin control group. The differences in data between the diabetic control group and the other groups; including the GP test groups, the metformin control group, and normal control group; were found to be statistically significant using the independent variables T-test. No statistical significance was obtained between the metformin control group, the normal control group, and the GP 500 and GP 750 groups, although GP 250 was deemed to have a statistically significant difference. Algariri and others have also communicated the fasting blood glucose-lowering activity of the ethanolic extract of the plant leaf, although a higher dose of the extract (1 gm\/kg) was employed in the mentioned study, and a different concentration of ethanol (50%, 25% and 0%) was utilized for the extract preparation15<\/sup>. Lee and others reported the ethanolic extract to exert a similar effect on the fasting blood glucose levels of the streptozotocin-induced diabetic murine models; where 50, 100, and 150 mg\/kg doses of the ethanolic extract reached statistical significance compared to the control16<\/sup>.<\/p>\n

The fasting blood glucose data over the course of the experiment is depicted in Graph 2.<\/p>\n\n\n\n
\"\"<\/td>\n\n

Graph 2: Fasting blood glucose of experimental animals over the course of the experiment. GP 250= Diabetic rats treated with 250 mg\/kg G. procumbens<\/em> extract, GP 500= Diabetic rats treated with 500 mg\/kg G.<\/em><\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Graph<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

G. procumbens<\/em><\/strong> extract reduces postprandial blood glucose of diabetic animals<\/strong><\/p>\n

The postprandial blood glucose data of the experimental animals followed a similar pattern as the fasting blood glucose data. Prior to alloxan administration, the postprandial blood glucose of all experimental animals displayed a mean value of 6.019 \u00b1 0.66 mmol\/L. Administration of alloxan resulted in this increasing to a mean value of 12.166 \u00b1 3.19 mmol\/L. GP treatment brought this data down, and statistical significance was achieved for each GP test group compared to the diabetic control. Only the differences between the GP 250 group and the metformin control group and the normal control group were deemed statistically significant, the other GP treatment groups displayed no significant differences with the two aforementioned groups. The ethanolic extract was previously communicated to lower postprandial blood glucose in streptozotocin-induced diabetic rat models, although the 150 mg\/kg dose, not the higher 300 mg\/kg dose, was considered to yield the most statistically significant effect17<\/sup>. The difference in observations in the mentioned study and the current study may be owed to the different concentrations of the solvents used for extraction (95% vs 70%), as well as other geo-ecological factors that may have contributed to changes in plant matter composition. Further analysis in this regard is warranted. The postprandial blood glucose data of the experimental animals over the course of the experiment is depicted in Graph 3.<\/p>\n\n\n\n
\"\"<\/td>\n\n

Graph 3: Postprandial blood glucose data of the experimental animals over the course of the experiment. GP 250= Diabetic rats treated with 250 mg\/kg G. procumbens<\/em> extract, GP 500= Diabetic rats treated with 500 mg\/kg<\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Graph<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

G. <\/strong>procumbens<\/em><\/strong> extract stimulates GLUT-4 expression in diabetic animals.<\/strong><\/p>\n

We observed that the concentration of the GLUT-4 protein in the liver tissue of the diabetic control group decreased to a level lower than that observed in the other groups, although no statistical significance was reported between the normal control and the diabetic control group data. All three GP test groups and the metformin control group exhibited higher GLUT-4 protein in the liver tissue compared to the diabetic control group (p < 0.05). Metformin has also been previously observed to upregulate GLUT-4 expression in murine metabolic disorder models18<\/sup>. Surprisingly, GP 750 group also showed expression of GLUT-4 higher than the normal control group. The GLUT-4 expression level of the experimental animals is presented in Graph 4.<\/p>\n\n\n\n
\"\"<\/td>\n\n

Graph 4: GLUT-4 expression level in the liver tissue of the experimental animals. GP 250= Diabetic rats treated with 250 mg\/kg G. procumbens<\/em> extract, GP 500= Diabetic rats treated with 500 mg\/kg G. procumbens <\/em>extract, GP 750= Diabetic rats treated with 750mg\/kg<\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Graph<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Previous studies have hypothesized that G. procumbens <\/em>exerts its antidiabetic effects by enhancing glucose uptake13<\/sup>. Sathiyaseelan and others reported that the ethyl acetate fraction of the methanolic extract enhanced glucose uptake in hepatic cell line HepG2, an incidence that can be explained by an increased expression level of the GLUT-4 protein19<\/sup>. Moreover, in murine cell line 3T3-L1, the ethanolic extract increased GLUT-4 expression significantly20<\/sup>. The serum-glucose modulatory antidiabetic activity of ethanolic extract of G. procumbens<\/em> is therefore mediated though the upregulation of GLUT-4 expression, and consequent increased uptake of glucose.<\/p>\n

Conclusion<\/strong><\/p>\n

The study demonstrated that Gynura procumbens<\/em> leaf extract exhibits significant antidiabetic activity, with a dose-dependent effect supporting its therapeutic value. In alloxan-induced diabetic rats, G. procumbens<\/em> effectively restored body weight and reduced fasting and postprandial blood glucose levels, comparable to metformin. The increase in GLUT-4 expression in diabetic rats, as evidenced by ELISA assay, further supports the potential mechanism of action of G. procumbens <\/em>in diabetes management. These findings highlight G. procumbens<\/em> as a promising candidate for antidiabetic drug development. Additional studies are necessary to isolate, characterize, and determine which secondary metabolites are accountable for the antidiabetic effects observed.\u00a0<\/strong><\/p>\n

Acknowledgments (Separate the acknowledgement and funding)<\/strong><\/p>\n

This work was supported by a financial grant from the Grant for Advanced Research in Education (GARE) from Bangladesh Bureau of Educational Information and Statistics (BANBEIS) under the Ministry of Education, Government of the People\u2019s Republic of Bangladesh, Project ID: LS 20191133 (no. 37.20.0000.004.033.020.2016.1053, dated: 13-10-2019).<\/p>\n

Funding Sources<\/strong>\u00a0<\/p>\n

There was supported by a financial grant from the Grant for Advanced Research in Education (GARE) from Bangladesh Bureau of Educational Information and Statistics (BANBEIS) under the Ministry of Education, Government of the People\u2019s Republic of Bangladesh, Project ID: LS 20191133 (no. 37.20.0000.004.033.020.2016.1053, dated: 13-10-2019).<\/p>\n

Conflict of Interest<\/strong><\/p>\n

The author(s) do not have any conflict of interest.<\/p>\n

Data Availability<\/strong><\/p>\n

This statement does not apply to this article<\/p>\n

Ethics Statement<\/strong><\/p>\n

This study has been approved (Ref. no. 146\/Biol. Scs.) by the Ethical Review Committee of the Faculty of Biological Sciences, University of Dhaka.<\/p>\n

Informed Consent Statement<\/strong><\/p>\n

This study did not involve human participants, and therefore, informed consent was not required<\/p>\n

Clinical Trial Registration<\/strong><\/p>\n

This research does not involve any clinical trials<\/p>\n

Author\u2019s contribution<\/strong><\/p>\n

Shah Amran: Originating the concept, Supervision of the overall work.<\/p>\n

Juhaer Anjum: Literature study, Labwork, Manuscript writing<\/p>\n

Maniza Muni: Literature study, Labwork, Manuscript writing<\/p>\n

Nusrat Jahan Shawon: Labwork, Manuscript reviewing and editing<\/p>\n

Mehadi Hasan: Labwork, Manuscript reviewing and editing<\/p>\n

Mohammad Sofi: Labwork, Manuscript reviewing and editing<\/p>\n

Rafat Tahsin: Critically reviewed the whole activities.<\/p>\n

Md Reaz Uddin: Critically reviewed the whole activities.<\/p>\n

Fahima Aktar: Critically reviewed the whole activities.<\/p>\n

Abu Asad Chowdhury: Critically reviewed the whole activities.<\/p>\n

Jakir Ahmed Chowdhury: Critically reviewed the whole activities.<\/p>\n

Shaila Kabir: Critically reviewed the whole activities.<\/p>\n

Al Amin Sikder: Critically reviewed the whole activities.<\/p>\n

References<\/strong><\/p>\n

    \n
  1. Arora C, Sinha B, Malhotra A and Ranjan P. Development and validation of health education tools and evaluation questionnaires for improving patient care in lifestyle related diseases. J. Clin. Diagnostic Res.: JCDR<\/em>, 2017; 11(5): JE06.
    CrossRef<\/a><\/li>\n
  2. De Boer I.H, Bangalore S, Benetos A, Davis A.M, and Michos E.D, Muntner P, Rossing P, Zoungas S and Bakris G. Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care<\/em>, 2017; 40: 1273\u20131284.
    CrossRef<\/a><\/li>\n
  3. O\u2019Brien T, Nguyen T.T and Zimmerman B.R. Hyperlipidemia and Diabetes Mellitus. Mayo Clin. Proc.<\/em>, 1998; 73: 969\u2013976.
    CrossRef<\/a><\/li>\n
  4. Haque E, Kamal M.S, Tahsin M.R, Ahmed R, Choudhury J.A, Chowdhury A.A, Kabir S, Amran M.S and Uddin M.S. Current Knowledge Regarding Pharmacological Profile and Chemical Constituents of Gynura procumbens<\/em>. Curr. Top. Med. Chem<\/em>., 2021; 21: 2671\u20132686.
    CrossRef<\/a><\/li>\n
  5. Tahsin M.R, Tithi T.I, Mim S.R, Haque E, Sultana A, Bahar N.B, Ahmed R, Chowdhury J.A, Chowdhury A.A, Kabir S, Aktar F, Uddin M.S and Amran M.S. In Vivo and in Silico Assessment of Diabetes Ameliorating Potentiality and Safety Profile of Gynura procumbens<\/em> Leaves, Evidence-Based Complement. Altern. Med.,<\/em> 2022; 2022(1): 9095504.
    CrossRef<\/a><\/li>\n
  6. June C.C, Wen L.H, Sani H.A, Latip J, Gansau J.A, Chin L.P, Embi N and Sidek H.M. Hypoglycemic effects of Gynura procumbens<\/em> fractions on streptozotocin- induced diabetic rats involved phosphorylation of GSK3\u03b2 (Ser-9) in liver. Sains Malaysiana, <\/em>2012; 41: 969\u2013975.<\/li>\n
  7. Kim M.G and Lee H.S. Insecticidal toxicities of naphthoquinone and its structural derivatives. Appl. Biol. Chem., <\/em>2016; 59: 3\u20138.
    CrossRef<\/a><\/li>\n
  8. Poh T.F, Ng H.K, Hoe S.-Z and Lam S.K. Gynura procumbens<\/em> causes vasodilation by inhibiting angiotensin II and enhancing bradykinin actions. J. Cardiovasc. Pharmacol., <\/em>2013; 61: 378\u2013384.
    CrossRef<\/a><\/li>\n
  9. Gansau J.A, Chin L, Embi N and Sidek H.M. Hypoglycemic effects of Gynura procumbens<\/em> fractions on streptozotocin-induced diabetic rats involved phosphorylation of GSK3\u03b2 (Ser-9) in liver. Sains Malays,<\/em> 2012; 41: 969\u2013975.<\/li>\n
  10. James D.E and Piper R.C. Insulin resistance, diabetes, and the insulin-regulated trafficking of GLUT-4. J. Cell Biol., <\/em>1994; 126: 1123\u20131126.
    CrossRef<\/a><\/li>\n
  11. Rohilla A and Ali S. Alloxan induced diabetes: mechanisms and effects. Int. J. Res. Pharm. Biomed. Sci.,<\/em> 2012; 3: 819\u2013823.<\/li>\n
  12. OKON U. A, Owo D.U, Udokang N.E, Udobang J.A and Ekpenyong C.E. Oral administration of aqueous leaf extract of Ocimum gratissimum<\/em> ameliorates polyphagia, polydipsia and weight loss in streptozotocin-induced diabetic rats. Am. J. Med. Med. Sci.,<\/em> 2012; 2: 45\u201349.
    CrossRef<\/a><\/li>\n
  13. Hassan Z, Yam M.F, Ahmad M and Yusof A.P.M. Antidiabetic Properties and Mechanism of Action of Gynura procumbens<\/em> Water Extract in Streptozotocin-Induced Diabetic Rats. Molecules, <\/em>2010; 15: 9008\u20139023.
    CrossRef<\/a><\/li>\n
  14. Wang Z, Yang Y, Xiang X, Zhu Y, Men J and He M. Estimation of the normal range of blood glucose in rats. Wei Sheng Yan Jiu, <\/em>2010; 39: 133-7,142.<\/li>\n
  15. Algariri K, Meng K.Y, Atangwho I.J, Asmawi M.Z, Sadikun A, Murugaiyah V and Ismail N. Hypoglycemic and anti\u2013hyperglycemic study of Gynura procumbens<\/em> leaf extracts. Asian Pac. J. Trop. Biomed.,<\/em> 2013; 3: 358\u2013366.
    CrossRef<\/a><\/li>\n
  16. Lee H.W, Hakim P, Rabu A and Sani H.A. Antidiabetic effect of Gynura procumbens<\/em> leaves extracts involve modulation of hepatic carbohydrate metabolism in streptozotocin-induced diabetic rats. J. Med. Plants Res.,<\/em> 2012; 6: 796\u2013812.
    CrossRef<\/a><\/li>\n
  17. Zhang X.F and Tan B.K.H. Effects of an ethanolic extract of Gynura procumbens<\/em> on serum glucose, cholesterol and triglyceride levels in normal and streptozotocin-induced diabetic rats. Singapore Med. J.,<\/em> 2000; 41: 9\u201313.<\/li>\n
  18. Zayed E.A, AinShoka A.A, El Shazly K.A and Abd El Latif H.A. Improvement of insulin resistance via increase of GLUT4 and PPAR\u03b3 in metabolic syndrome\u2010induced rats treated with omega\u20103 fatty acid or l\u2010carnitine. J. Biochem. Mol. Toxicol.,<\/em> 2018; 32: e22218.
    CrossRef<\/a><\/li>\n
  19. Sathiyaseelan A, Park S, Saravanakumar K, Mariadoss A.V.A and Wang M.H. Evaluation of phytochemicals, antioxidants, and antidiabetic efficacy of various solvent fractions of Gynura procumbens<\/em> (Lour.) Merr. Process Biochem.,<\/em> 2021; 111: 51\u201362.
    CrossRef<\/a><\/li>\n
  20. Aung C.L, Kawakami F, Imai M, Lwin T, Kanzaki M, Mar O, Phyu K.P, Thwin M.M and Maruyama H. Blood glucose\u2010lowering effect of water and ethanolic extracts of Gynura procumbens<\/em> (Lour.) Merr. Tradit. Kampo Med.,<\/em> 2021; 8: 138\u2013147.
    CrossRef<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":15,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[119],"tags":[],"class_list":["post-63297","post","type-post","status-publish","format-standard","hentry","category-vol17no4"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/63297","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/15"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=63297"}],"version-history":[{"count":5,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/63297\/revisions"}],"predecessor-version":[{"id":63569,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/63297\/revisions\/63569"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=63297"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=63297"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=63297"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}