INTRODUCTION:

Diabetes is a common metabolic disorder associated with high morbidity and death, as well as the onset of other diseases. The pancreas is the major direct or indirect target of diabetics. Patients with type 1 or type 2 diabetes are more likely than those without diabetes to develop hepatobiliary diseases^1,2,3,4. Even while using insulin, diabetic people display significant tissue growth anomalies. The liver size of juvenile and adult diabetes patients has altered clinically, which may be attributable to alterations in cell number, cell growth, or cell death^5,6.

In both type 1 and type 2 diabetes, the other research found inadequacies in antioxidant defense enzymes, vitamins, and supplements, as well as an increase in oxidative damage. Oxygen, antioxidant defenses, and the redox state of cells are considered to play crucial roles in diabetes. Using the the malondialdehyde (MDA) test, elevated levels of lipid peroxidation (LPO) were observed in the plasma of young boys with type 1 diabetes, indicating increased oxidative stress in these patients.MDA is produced when hydroxyl radicals attack polyunsaturated fatty acyl chains, a process that can also damage DNA-generating molecules such as 8-hydroxy-2 deoxyguanosine. Growing data suggests that hyperglycemia accelerates the production of hydroxyl radicals in diabetic animal models, such as streptozotocin-induced diabetic (SID) rats and mice. This acceleration has been linked to the concentration of thiobarbituric acid (TBA) - reactive chemicals, which is utilized to measure LPO. The chemical agent streptozotocin (STZ) is widely used to generate experimental DM models by destroying the pancreatic beta cells of animals and resulting in hyperglycemia. Along with a high-fat diet, type 2 diabetes can be modeled in animals⁷^-11.

Apoptosis has a significant role in the pathogenesis of type 2 diabetes. The several causes of T2DM include insulin resistance caused by obesity, inadequate insulin synthesis, and loss of -cell mass owing to -cell death. In T2DM, -cell apoptosis is mediated by a huge quantity of caspase family cascade machinery. The primary pathophysiology of diabetes is glucose-induced insulin secretion, and persistent hyperglycemia or diabetes is caused by inadequate insulin secretion^12-15. Recent research on the balance of pro- and anti-apoptotic Bcl-2 proteins (Bad, Bid, Bik, and Bax) toward apoptosis in vitro isolated islets and insulinoma cell culture has concentrated largely on hyperglycemia-induced -cell death. Apoptosis occurs only when the level of pro-apoptotic Bcl-2 at the mitochondrial membrane of the intrinsic pathway is larger than the amount of anti-apoptotic proteins^16,17. On beta cells, hyperglycemia-induced apoptosis has been the subject of a substantial amount of recent research focusing on the complexities of glucose toxicity at the molecular level as well as cell membrane potential by adenosine triphosphate generation through K+ channel closure, opening of the Ca2+ channel, and plasma membrane depolarization^18-20.

Chayote is the common name for the fruit of Sechium edule (Jacq.) Swartz, which is utilized in traditional medicine and cuisine. Numerous health benefits have been related to its high phenol content. Sechium edule has been extensively studied for its pharmacological properties, which include antihypercholesterol, antihypertension, anticancer, and immunomodulator^21-25. The purpose of this study was to assess the impact of Sechium edule extract on apoptotic parameters in rats with type II diabetes.

MATERIAL AND METHODS:

Chemicals:

STZ, Nicotinamide, carboxymethyl cellulose (CMC), 2% fat, 57% carbohydrates, 17.5% protein, 4.9% vitamin and mineral combination, 6.6% fiber, water, ethanol, caspase-3 elisa kit, caspase-8 elisa kit, caspase-3 elisa kit.

Plant:

The extract from the fruit of the Siamese Gourd (Sechium edule (Jacq.) Swartz) taken from the yard of the residents of Pagar Batu village, Sipoholon District, North Tapanuli Regency, North Sumatra with coordinates 2°06'15.7"N 98°57'07.7"E. Plant determination was carried out by the Indonesian Institute of science research center for biology number 1137/IPH.1.01/If.07/V/2019.

Preparation of extract:

The shade-dried Sechium edule was powdered using a Wiley mill at room temperature. A Soxhlet apparatus containing 100grams of powdered leaves was loaded with ethanol for the extraction procedure. The extracts were subjected to a qualitative test in accordance with recognized techniques in order to identify various phytochemical elements. Concentrating the ethanol extracts in a rotary evaporator. Concentrated ethanol extracts were utilized for antidiabetic studies^21-25.

Animal handling:

Wistar adult male rats weighing 180–200g were housed with full access to food and water under standard conditions. The animals were confined to cages with a 12hour light/dark cycle and an average air temperature of 23.2 degrees Celsius. All methods involving animals were authorized by the university's ethical commission (160/KEPK-FKUMI/EC/2022).

Induction of Type II Diabetic Rats:

The high fat diet composition were consisting of 4L of coconut oil, 7kg of beef liver, 7kg of beef fat, 8kg of butter, and 30 quail eggs. The high fat diet were administered 2ml along with 1 ml of quill egg for one rat of each day for 1 months, followed by a single injection of STZ at a dosage of 55mg/kgbw and oral administration of nicotinamide (NICO) at a rate of 120 mg/kgbw. The next day, blood glucose levels were measured

Experimental Design:

The animals were divided into four groups (n = 6) as following:

Group I (Control): normal rats

Group II (Negative control/Diabetic Rats): Rats were given HFD for 1 months + 55mg/kgbw of STZ + 120 mg/kgbw of NICO

Group III (Positive control): Rats were given HFD for 1 months + 55mg/kgbw of STZ + 120 mg/kgbw of NICO + metformin 500mg/kgbw for 21 days.

Group IV (treatment I): Rats were given HFD for 1 months + 55mg/kgbw of STZ + 120mg/kgbw of NICO + 50mg/kgbw of extract for 21 days.

Group V (treatment II): Rats were given HFD for 1 months + 55mg/kgbw of STZ + 120mg/kgbw of NICO + 100mg/kgbw of extract for 21 days.

Group VI (treatment III): Rats were given HFD for 1 months + 55mg/kgbw of STZ + 120mg/kgbw of NICO + 150mg/kgbw of extract for 21 days.

At the end of the study, all groups were anaesthetized using ketamine/xylazine, and blood samples were collected for serum preparation.

The research design can bee seen in the figure below:

Figure 1. Experimental Design

Determination of caspase-3:

Caspase-3 rat cardiac measurement, Elisa kit (Bioassay, China). The preparation according to the manufacturer's instructions. The caspase-3 concentration was measured using 450nm microplates. The concentration in nanograms per milliliter.

Determination of caspase-8:

Caspase-8 rat cardiac measurement, Elisa kit (Bioassay, China). The preparation according to the manufacturer's instructions. The caspase-8 concentration was measured using 450nm microplates. The concentration in nanograms per milliliter.

Determination of Bcl-xl:

Bclx rat cardiac assessment, Elisa kit (Bioassay, China). The preparation according to the manufacturer's instructions. The Bclx concentration was measured using 450nm microplates. The concentration in nanograms per milliliter.

Determination of Bcl-2:

Bcl rat cardiac measurement, Elisa kit (Bioassay, China). The preparation according to the manufacturer's instructions. The Bcl concentration was measured using 450nm microplates. The concentration in nanograms per milliliter.

Pancreas Histopathology:

pancreas were fixed with 10% formalin solution for 3–4 h, followed by three applications of acetone, according to the method described in³¹. (two hours in each). After that, three cleanings with toluene were performed (1–2 h in each). Three repetitions of embedding the sample in paraffin liquid 60–70C (two hours in each). The procedure of molding paraffin blocks is carried out. The phases of cutting the paraffin block were performed using a microtome with a 5m sheet thickness. The layer is placed in a 30C water bath, adhered to a glass slide, and then cooked in the oven for two to three minutes. Under a microscope with 1040 magnification, the outcome was noticed; the quantity of necrotic and healthy cells was detected.

Statistical Analysis:

Program 21 of the Statistical Package for Social Science (SPSS) was used to analyze the data. The data are shown as Mean SEM. One-way ANOVA followed by post-hoc Tukey for comparisons involving more than 2 groups. Statistical significance was established as p 0.05

RESULTS AND DISCUSSION:

This study demonstrates the levels of caspase-3, caspase-8, bclx, and bcl in diabetic rats treated with extract dosages of 50, 100, and 150mg/kgbw in addition to metformin. The outcome is shown in the table below:

Determination caspase-3

Tabel 1. The level of caspase-3 on rats with or without treatment

No.	Group	Caspase-3 level (ng/mL) ± SEM
1.	Group I (Control)	2,347 ± 0,021
2.	Group II (Negative control/Diabetic Rats)	5,392 ± 0,033*
3.	Group III (Positive control)	2,559 ± 0,022#
4.	Group IV (treatment I)	4,253 ± 0,031
5.	Group V (treatment II)	3,364 ± 0,028
6.	Group VI (treatment III)	2,159 ± 0,021#
p value		0,0415

Data are presented Mean ± SEM. *(p < 0,05) significant different from normal group. #(p < 0,05) significant different from control group.

Table 1 demonstrates that rats in the control group that were orally administered CMC had a caspase 3 level of 2,347 0,021ng/mL, but rats in the diabetes group had a caspase 3 level of 5,392 0,033ng/mL, which was statistically greater (p0,05) than the control group. In contrast, the 150mg/kgbw group treatment showed a substantial reduction (p 0.05) compared to the negative group. Analyzing the amount of caspase-3 as a marker of apoptosis is crucial for elucidating the pharmacological mechanism of T2DM prevention by extract.

Determination caspase-8:

Tabel 2. The level of caspase-8 on rats with or without treatment

No.	Group	Caspase-8 level (ng/mL) ± SEM
1.	Group I (Control)	10,498 ± 2,811
2.	Group II (Negative control/Diabetic Rats)	15,338 ± 4,192*
3.	Group III (Positive control)	9,249 ± 1,937#
4.	Group IV (treatment I)	8,833 ± 1,837
5.	Group V (treatment II)	7,566 ± 1,562
6.	Group VI (treatment III)	5,719 ± 1,611#
p value		0,234

Data are presented Mean ± SEM. *(p < 0,05) significant different from normal group. #(p < 0,05) significant different from control group.

Table 2 shows that the level of caspase 8 in the control group, which was administered CMC orally, is 2,347± 0.021ng/mL, but the level of caspase 8 in the diabetes group is 15,338±4,192ng/mL, which is statistically greater (p<0.05) than in the control group. In contrast, the 150mg/kgbw group treatment showed a substantial reduction (p <0.05) compared to the negative group.

Determination Bcl-xl:

Tabel 3. The level of Bcl-xl on rats with or without treatment

No.	Group	Bcl-xl (ng/mL) ± SEM
1.	Group I (Control)	4,722 ± 0,711
2.	Group II (Negative control/Diabetic Rats)	8,485 ± 1,563
3.	Group III (Positive control)	5,257 ± 0,892
4.	Group IV (treatment I)	6,822 ± 1,433
5.	Group V (treatment II)	5,569 ± 0,813
6.	Group VI (treatment III)	5,216 ± 0,562
p value		0,001

Data are presented Mean ± SEM. *(p < 0,05) significant different from normal group. #(p < 0,05) significant different from control group.

Table 3 The level of bcl-xl in the control group, which was administered CMC orally, was 4,722 ± 0,711 ng/mL, whereas the level of bcl-xl in the diabetes group was 8,485 ± 1,563 ng/mL, which was statistically greater (p<0,05) than in the control group. On the other hand, the dose of 150 mg/kgbw in the treatment group is considerably lower (p< 0.05) than in the negative group. As a pro-apoptotic parameter, Bcl-xl plays a crucial function in regulating the activation of the apoptosis pathway.

Determination Bcl-2

Tabel 4. The level of Bcl-2 on rats with or without treatment

No.	Group	Bcl-2 (ng/mL) ± SEM
1.	Group I (Control)	9,502 ± 1,76
2.	Group II (Negative control/Diabetic Rats)	5,06 ± 0,87*
3.	Group III (Positive control)	10,04 ± 1,98#
4.	Group IV (treatment I)	7,954 ± 1,71
5.	Group V (treatment II)	8,459 ± 1,92
6.	Group VI (treatment III)	9,216 ± 2,01#
p value		0,1546

Data are presented Mean ± SEM. *(p < 0,05) significant different from normal group. #(p < 0,05) significant different from control group.

Table 4 demonstrates that the level of bcl-2 in the control group of rats that were orally administered CMC is 9,502±1,76ng/mL, but the level of bcl-2 in the diabetic rats' group is 5,06±0,87ng/mL, which is statistically lower (p<0,05) than in the control group. In contrast, the 150mg/kgbw group treatment showed a substantial increase (p<0.05) compared to the negative grou. Bcl-2 plays a crucial function as an antiapoptotic gene, hence it was discovered in this study that the antiapoptotic bcl-2 was up in the group that received treatment extract and metformin.

Pancreas Histopathology:

Histopathology of pancreas with H&E (10x40), (A) normal group, (B) diabetic group, (C) positive control group, (D) treatment I, (E) treatment II, and (F) treatment III can be seen in the figure 2.

Figure 2. Histopathology of Pancreas

The histopathology of pancreas shows that group negative diabetic group/B show the inflammation of cell while in the group normal/A show that the cells are healthy without injury, in the group C with metformin treatment show a bit necrosis, while in the given treatment I, II, and III show the cell oedema.

DISCUSSION:

The current investigation validated the construction of the type II diabetic rat model, which exhibited lower body weight and higher blood glucose levels compared to normal rats. The expression levels of Bax and caspase-3 rose in diabetic rats, while the expression of Bcl-2 decreased. Streptozotocin may increase or decrease the oxidative stress index and pro-inflammatory cytokines in order to further enhance apoptosis^26,27. Numerous in vitro studies have demonstrated that caspase-dependent apoptotic pathways are essential for cell apoptosis. Fas, a receptor that begins the extrinsic apoptotic pathway, was upregulated in human islet cells cultivated under high glucose conditions, indicating that these cells undergo apoptosis in response. In addition, c-Flip, a protein known to block caspase-8-mediated apoptosis, prevented Fas-induced apoptosis and improved -cell proliferation²⁸. In vivo studies using nonobese diabetic (NOD) mice and diabetes-prone BB/S rats utilizing terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed the occurrence of islet apoptosis (TUNEL). Caspases-8 and caspase-9 are the upstream caspases involved in the extrinsic and intrinsic pathways, respectively²⁹. Caspases-3, -6, and -7 serve as effector caspases downstream of both pathways. The physiologic role of individual caspases in vivo has been investigated using gene targeting methods, which have proven their involvement in apoptosis as well as other key cellular processes^30,31. It has been established that caspase-3 and caspase-9 are necessary for neuronal apoptosis to develop. This study demonstrates that the levels of caspase-3 and caspase-8 were elevated in the diabetic control group, which was associated with the advancement of beta cell death in the pancreas. Streptozotocin is a natural glucosamine nitrosourea compound that was initially discovered as an antibiotic; it may cause DNA damage in mammalian pancreatic islet cells. When pancreatic islet cells were damaged by streptozotocin, blood glucose levels were controlled by insulin production. In this study, the blood glucose levels of rats in the diabetes model group rose quickly, but the blood glucose levels of rats in the therapy group decreased. Apoptosis is the process through which multicellular organisms execute programmed cell death. In addition to the importance of apoptosis as a biological event, defective apoptotic processes have been connected to several diseases. Fas receptors and caspases are apoptosis-promoting agents, while Bcl-2 family members inhibit apoptosis. Bax is a pro-apoptotic regulator, whereas Bcl-2 is an important anti-apoptotic protein^32-34. Caspase-3 is required for the endoplasmic reticulum to transmit apoptotic signals. After demonstrating that apoptosis contributes to the development of T2DM, the apoptosis proteins Bcl-2, Bax, and caspase-3 were investigated in further detail. Bax and caspase-3 expression increased with prolonged streptozotocin induction, but Bcl-2 expression decreased, suggesting that apoptosis contributed to the development of DN in rats. In T2DM, only a few therapies that suppress cell apoptosis are being researched due to a lack of resources and available pharmacological treatments. Sechium edule contains several secondary metabolites, including flavonoid. Flavonoid has a crucial function in preventing the elevation of pro-apoptotic parameters such as caspase-3 and caspase-8. Our earlier research also demonstrated that Sechium edule had antioxidant properties that counteract the oxidative generation caused by STZ in diabetic rats. In addition, the Sechium edule prevents damage to the lipid membrane of the beta cell, hence decreasing the MDA parameter in diabetic rats. By reducing the activity of caspase-3, caspase-8, and Bcl-xl, the ethanolic extract of Chayote (Sechium edule (Jacq.) Swartz) protects pancreatic cells, but the rise in Bcl-2 shows that the Siamese pumpkin (Sechium edule) extract has antiapoptotic pancreatic cell potential. The function of flavonoid active components as apoptosis inhibitors by lowering caspase-3 activity in pancreatic cells and human islet cells subjected to chronic hyperglycemia. This protective impact is also connected with enhanced cAMP signaling, Akt protein production, and antiapoptotic Bcl-2 as well as insulin secretion and cell synthesis^35-39. This work is consistent with Zang's findings that Kaempferol flavonol at a concentration of 10 M inhibits caspase-3 activity in pancreatic cells subjected to sustained hyperglycemia. In addition, Ola discovered that flavonoids had antiapoptotic potential with caspase-3 levels and boost Bcl-2 levels in diabetic rats with retinopathy. By lowering the activity of caspase-3, the active components of alkaloids also play an antiapoptotic impact⁴⁰. As a result of harmine's enhanced glycemic control, alkaloids alter the apoptosis of several organs, including the kidney. Harmine is a tricyclic alkaloid molecule in the -carbolin family that was obtained from the herbal plant P. harmala L. Saponins produced from alfalfa (Medicago sativa) extract at concentrations of 25 and 40 g/mL lowered the expression of caspase-3, caspase-9, and Bax in cells while increasing the expression of the Bcl-2 gene^41-42. The exact mechanism of Sechium edule as an anti-diabetic drug must be elucidated in future research. In the future study it’s important to elucidate the exact mechanism of Sechium edule as antidiabetic agent.

CONCLUSION:

We demonstrated that injections of STZ and Sechium edule extract ethanol impact apoptotic parameters. The ethanol extract of Sechium edule reduces pro-apoptosis characteristics. This plant has the potential to become a diabetic medication candidate.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

ACKNOWLEDGMENT:

The Directorate of Research, Technology, and Community Service (DRTPM) of the Ministry of Research, Technology, and Higher Education supported the 2022 research with contract numbers 057/LL1/lt/k/2022, 453/N/LPPM-UMI /2022 until the publication of this study.

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Received on 16.01.2024 Revised on 12.11.2024

Accepted on 14.05.2025 Published on 13.01.2026

Available online from January 17, 2026

Research J. Pharmacy and Technology. 2026;19(1):404-410.

DOI: 10.52711/0974-360X.2026.00059

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