INTRODUCTION:

The skin, the body's largest organ, serves various functions such as physical protection, excretion, sensation, immunological defense, temperature regulation, and vitamin D synthesis. It comprises three layers: the epidermis, dermis, and subcutaneous tissue, which work together to fulfill these functions and respond to skin damage.

Wounds are events where many body tissues are torn or torn, including muscle tissue, skin, nerves, lymph vessels, and blood. The classification of wounds consists of the mechanism of injury¹. They are classified based on the mechanism of injury, such as open wounds caused by trauma or clean wounds from surgical incisions²^,³.

The wound healing process involves several components, including cells and chemicals needed for inflammation, angiogenesis, and collagen deposition. The wound healing process has several stages: hemostasis, inflammation, proliferation, and remodeling⁴^,⁵. The wound healing process involves several stages: hemostasis, inflammation, proliferation, and remodeling. Hemostasis, occurring immediately after injury, involves platelet aggregation to stop bleeding. Inflammation, 1-4 days post-injury, involves leukocytes, particularly neutrophils. Proliferation, from 4 to 21 days post-injury, includes angiogenesis, collagen deposition, tissue formation, wound contraction, and epithelialization. Remodeling marks the final stage, characterized by the formation of a new, intact network of tissues²^,⁶.

Anti-inflammatory drugs are commonly used in wound treatment, inhibiting inflammatory mediator formation or leukocyte migration to reduce inflammation⁷^,⁸. The mechanism of action of this drug is related to the prostaglandin biosynthesis system, namely by inhibiting the formation of inflammatory mediators or inhibiting the migration of leukocyte cells to areas of inflammation⁹^,¹⁰.

Traditional plants like parijoto (Medinilla speciosa) are alternative wound healing agents, traditionally known for their anti-inflammatory, anti-cholesterol, and anti-bacterial properties. Despite their widespread use, scientific studies on Parijoto fruit extract's efficacy in wound healing are lacking. Parijoto (Medinilla speciosa) is a plant that thrives in the highlands, including in the village area of Bandungan, Semarang Regency, Central Java¹¹.

In this study, a gel formulation containing parijoto fruit extract was used as a test material due to its advantages in drug release, water solubility, and good skin spreadability¹². The gel had been optimized for formulation based on previous study¹³^,¹⁴^,¹⁵. The research method used in this study was in vivo, using white male Wistar rats.

The study aims to further investigate the effectiveness of parijoto fruit extract gel in healing incision wounds and its impact on leukocyte count in Wistar rats. This research endeavors to provide insights into utilizing parijoto fruit as a gel formulation for wound healing.

MATERIALS AND METHODS:

Materials:

The materials used in this study include Parijoto fruit obtained from Bandungan District, Semarang Regency. The technical-grade HPMC (Hydroxypropyl Methylcellulose). Other materials include pharmaceutical-grade glycerin, propylene glycol, and methyl parabens, as well as Whatman filter paper. Additionally Octenilin gel, technical-grade 96% ethanol, and quercetin and rutin (both from Sigma) were utilized in the study.

Methods:

Making of parijoto fruit extract:

Parijoto fruit extract is prepared using the maceration method based on previous research¹¹. Four hundred grams of Parijoto fruit powder is soaked in 96% ethanol solvent at a ratio of 1:7.5 (3L total, with 1.75L for maceration and 1.25L for re-maceration). The maceration process is conducted for 24hours over three days. After three days, the mixture is filtered, separating the residue from the filtrate, which becomes the first filtrate. Re-maceration is then performed. After two days, the first filtrate is homogenized with the second filtrate from re-maceration. The mixture is evaporated using a rotary evaporator (Ika) at 50°C. The resulting extract is further concentrated using a waterbath (IWAKI), and the yield is calculated (Ohaus)¹⁴.

Determination of water content and ash content:

Water content analysis was conducted to ascertain the moisture content in simplicia powder and ethanol extract of parijoto fruits. Approximately 2-3 grams of simplicia powder or ethanol extract of parijoto fruits were weighed and placed in a shallow aluminum cup preheated to 105°C. The samples were then dried in a moisture balance (Ohaus) dring chamber until the desired temperature was reached, as indicated by the automatic reading. Ideally, the water content should be <10%.

For the determination of ash content, 2 grams of simplicia powder or ethanol extract of karika seeds were weighed and placed into a tarred porcelain crucible. The samples were then slowly incinerated in a muffle furnace (Thermolyne), with the temperature gradually increased to approximately 600°C over a period of about 6 hours, or until carbon-free (charcoal is completely burnt). After cooling, the ash residue was weighed using standard procedures outlined by the Ministry of Health of the Republic of Indonesia¹⁶.

Phytochemical screening of parijoto fruit extract:

The parijoto fruit extract was spotted onto a silica gel TLC plate (Merck) under 254nm UV light and then placed in a chamber saturated with a mobile phase of n-hexane:ethyl acetate (8:2 ratio). Upon reaching the elution distance, the plate was removed, aerated, and observed under UV light at 254nm and 366nm to assess stain color and elution distance. Additionally, the TLC plates were sprayed with Sitroborate spotter and re-evaluated under 254nm UV light. Observations and recordings of Rf values under 254nm UV light revealed green, yellow, and blue colors, confirming the presence of flavonoid-type secondary metabolites.

The selection of n-hexane and ethyl acetate with an 8:2 ratio as the mobile phase demonstrated optimal separation capability compared to other eluents. This experiment highlights the efficacy of n-hexane:ethyl acetate (8:2) in effectively separating flavonoid compounds, suggesting a close polarity between the compounds and the eluent, facilitating their efficient movement with the mobile phase¹⁷.

Formula of parijoto fruit gel:

The formula for parijoto fruit extract gel can be found in Table 1 based on previous research¹⁴. HPMC is weighed according to each formula, then dissolved in hot water in a glass beaker, stirred thoroughly, and left to stand for 24hours. In a separate beaker, methylparaben is dissolved in 2mL of pharmaceutical-grade ethanol, along with glycerin and propylene glycol. This mixture is combined with the dissolved methylparaben and homogenized. Parijoto fruit extract is then weighed and slowly dissolved with 3 drops of ethanol and hot water (approximately 20mL). The resulting extract solution is added to the beaker containing the mixture of methylparaben, glycerin, and propylene glycol, and stirred until homogeneous. Subsequently, the contents of beaker 2 are gradually added to beaker 1, which contains expanded and melted HPMC, achieved by using a water bath at a temperature of 70°C. The mixture is then filled with distilled water up to 100g, stirred, and homogenized.

Table 1. Gel formulations parijoto fruits extract

Substance	Amount (gram)
Substance	Base	FI	FII	FIII
Parijoto fruits extract	-	0.5	1	1.5
HPMC	2	2	2	2
Glycerin	5	5	5	5
Propylene glycol	2,5	2,5	2,5	2,5
Methyl paraben	0.2	0.2	0.2	0.2
Total amount	Ad 100	Ad 100	Ad 100	Ad 100
Information : Base : base control group FI : 0,5% extract treatment group FII: 1 % extract treatment group FIII: 1,5% extract treatment group

Testing the wound healing activity:

Twenty-four white male Wistar rats were utilized for this study. The testing for this activity was approved by the Research Ethics Committee (KEP) of Ngudi Waluyo University under Number: 28/KEP/EC/UNW/2022. Before the experiment, the rats underwent a seven-day adaptation period. Subsequently, they were divided into six groups using Federer's formula, with each group comprising four randomly selected rats. The grouping of test animals is outlined as follows:

1. Positive control group: rats treated with Octenillin gel

2. Negative control group: rats receiving no treatment after incision

3. Base control group: rats treated with extract base gel

4. 0.5% extract treatment group: rats treated with Parijoto fruit extract gel at a concentration of 0.5%

5. 1% extract treatment group: rats treated with Parijoto fruit extract gel at a concentration of 1%

6. 1.5% extract treatment group: rats treated with Parijoto fruit extract gel at a concentration of 1.5%

The backs of the test animals were shaved adequately, followed by rubbing with alcohol at the incision site. The incision, 2cm in length with a depth of approximately 2mm was then made using a scalpel. After the wound was made, the surrounding area was cleansed until bleeding ceased, and then dried using sterile gauze. Each group was administered approximately 0.5grams of the respective gel, except for the negative control group. Treatments were applied twice daily, in the morning and evening, until complete healing or for a duration of seven days, with continued observation for up to 14 days if full healing had not occurred. The length of the wound is measured using a caliper (Mitutoyo).

Testing the number of leukocytes:

Blood samples were collected both after incision and upon wound healing. Approximately ±1ml of blood was drawn from the tail vein of white rats. The blood samples were then placed in microtubes (Monotes) containing ethylenediaminetetraacetic acid (EDTA). The leukocyte count was determined using a hematology analyzer (Rayto RT-7600 for Vet).

Data analysis:

The primary data source for this study was obtained through observations. The AUC observations were statistically processed using the one-way analysis of variance (ANOVA) method with a significance level (α) of 95%. Leukocyte data were analyzed using the Paired Sample T-Test, conducted with the assistance of the SPSS computer program at a confidence level of 95% (α = 0.05).

RESULT:

Determination of parijoto plant:

The test sample used was Parijoto fruit obtained from Bandungan, Central Java. Prior to the extraction process, the material underwent determination process to identify that the plant used was Parijoto (Figure 1).

Mass spectroscopy

Figure 1. Parijoto plant and fruits

Determination of water content and ash content:

The obtained Parijoto fruit extract underwent specific and non-specific standardization tests, including: organoleptic assessment, water content analysis, ash content analysis, and phytochemical screening. The results can be seen in Table 2.

Table 2. Results of the organoleptic, ash, water content tests, and yield of parijoto fruit extract

Parameter	Results
Extract color	Dark brown
Smell	Aromatic
Yield content	15.78% w/w
Water content	1.40% w/v
Ash content	22.5% w/w

Phytochemical screening of parijoto fruit extract:

The specific characterization results, namely the phytochemical testing of ethanol extract of Parijoto fruit using TLC, can be seen in Table 3. The chromatogram profile obtained indicates that the ethanol extract of Parijoto fruit contains flavonoids (Figure 2).

Figure 2. TLC results of parijoto fruits extract. Description : (A) parijoto extract, (B) standard rutin, (C) quercetin standard, (1) Observation of flavonoids under UV light 366 nm, (2) Observation of flavonoids under UV light 254 nm, (3) Observation of flavonoids under UV light 366 nm after citroborate spraying

Table 3. The results of the thin layer chromatography test of the ethanol extract of parijoto fruit

Spot	Rf value	Observation of flavonoids under		Compound
Spot	Rf value	UV 245nm	UV 366 nm (after citroborat spraying)	Compound
1	0.25	Purple	Red	Flavonoids
2	0.34	Purple	Red	Flavonoids
3	0.45	Purple	Red	Flavonoids
4	0.97	Purple	Red	Flavonoids
5	0.94	Green	Green	Chlorophyll

Healing efficacy assessed based on AUC and percentage of anti-inflammatory power:

The results of the testing of Parijoto fruit extract gel on incision wound healing indicate that the concentration variations administered to the test animals can accelerate wound closure (Figure 3). The higher the concentration of Parijoto fruit extract gel administered, the lower the AUC value, and the higher the percentage of anti-inflammatory activity in the test animals (Table 4). In the statistical analysis using One-Way ANOVA, the administration of 1.5% Parijoto fruit extract gel showed no significant difference compared to the positive control Octenilin gel (Table 5).

Table 4. AUC values and percentage of anti-inflammatory efficacy (PAIE) in the test groups

The test group	AUC Total Value ± SD	PAIE (%)
Positive control	35,97 ± 1,4	35,63
Negative control	55,88 ± 0,72	0
Base control	52,46 ± 0,89	6,124
0,5% extract treatment group	48,18 ± 0,77	13,79
1% extract treatment group	48,01 ± 0,78	14,09
1,5% extract treatment group	42,08 ± 0,4	24,71

Table 5. Statistical results of AUC data using one-way ANOVA

The test group	Positive control	Negative control	Base control	0,5% extract treatment group	1% extract treatment group	1,5% extract treatment group
Positive control	-	SD	SD	SD	SD	NSD
Negative control	SD	-	NSD	NSD	NSD	SD
Base control	SD	NSD	-	NSD	NSD	SD
0,5% extract treatment group	SD	NSD	NSD	-	NSD	NSD
1% extract treatment group	SD	NSD	NSD	NSD	-	NSD
1,5% extract treatment group	NSD	SD	SD	NSD	NSD	-
Information :
SD: Significantly different (p<0.05)
NSD: Not significantly different (p>0.05)

Figure 3. Graph showing reduction in incision size in the test group until 14 day treatment

The assestment of healing effectiveness based on leukocyte count:

The administration of Parijoto fruit extract gel affects the change in leukocyte count in the blood. There is a decrease in the leukocyte count after the administration of Parijoto fruit extract for 14 days (Figure 4).

Figure 4. Diagram of leukocyte count in the test group

DISCUSSION:

Characterization of parijoto fruit extract:

Parijoto fruit samples (Medinilla speciosa) used were sourced from the Bandungan area, Semarang Regency, Central Java (Figure 1). The obtained Parijoto fruit is then authenticated. The determination results indicate that the sample used is indeed the genuine Parijoto plant (Family: 95 Melastomaceae, Genus: Medinilla, Species: Medinilla speciosa).

The obtained samples are processed into simplicia. Maceration with 96% ethanol is used for extracting secondary metabolites from parijoto fruit, chosen for its preservation of compound integrity. The maceration method was chosen based on previous research¹¹, because it is suspected that the metabolites of the compounds contained in parijoto are easily damaged at high temperatures. The research study found that 96% ethanol yielded 18.50% compared to 70% ethanol of 15.33%¹⁸. Extracts undergo characterization, including organoleptic, moisture, ash, and phytochemical tests, with results detailed in Table 2.

The viscous parijoto extract, dark brown with a typical aroma, yields 15.78%, the requirement for yield is to have a value of more than 10%. Water content analysis in Table 2 reveals values below 10%, crucial for preventing bacterial and fungal growth that can compromise the simplicia compounds¹⁹^,²⁰. The high ash content suggests elevated mineral levels in parijoto fruit.

Phytochemical identification using Thin Layer Chromatography (TLC) aims to determine secondary metabolites, utilizing a mobile phase of n-hexane and ethyl acetate (8:2) known for effective separation of flavonoids²¹. TLC stains under UV 254nm and UV 366nm (Figure 2) reveal yellow, light blue, and brown spots indicating flavonoids, while red or purple spots denote anthocyanins presence²². In Table 3, the parijoto fruit extract produces four stain spots. The Rf values obtained for three spots range from 0.2 to 0.8. Citroborate is used to detect flavonoid compounds, with more polar compounds strongly bound to the stationary phase, hence exhibiting lower Rf values²³.

Testing the efficacy of wound healing:

a. Healing efficacy assessed based on AAUC and percentage of anti-inflammatory power:

This study evaluated wound healing activity by measuring the reduction in incision size. The incision was made using a scalpel rubbed on the epidermal skin of the rat's back to form an incision with a length of 2 cm and a depth of 2mm. Making cuts on the back, resulting in bleeding. Bleeding occurs due to damage to blood vessels, potentially in the papillary pars (protruding dermis from the epidermis), which contains nerve fibers and blood vessels. When tissue is injured, bleeding from cut blood vessels initiates. The body's initial response is to stop bleeding, leading to a hemostatic reaction where blood contacts collagen and the extracellular matrix²⁴^,²⁵. The effect of applying Parijoto fruit ethanol extract gel on wound healing is observed through the dry and closed wounds depicted in Figure 3.

On the first day post-treatment, all six groups experienced bleeding at the incision sites on the backs of the test animals. By the second day, wound closure was observed in the positive control group, treated with Octenilin gel containing Octenidine Hydrochloride 0.15% and Allantoin 0.20%, known to accelerate wound healing²⁶. The group treated with parijoto fruit ethanol extract gel exhibited wound closure starting on day two and complete closure by day 13, suggesting its potential as being a wound-healing agent²⁷. Animals receiving basic treatment and those with illnesses showed the longest healing process, lasting until the 14th day.

The AUC parameter (area under the curve) was used to assess the percentage of anti-inflammatory activity across various treatments. The percentage of anti-inflammatory activity reflects a drug's ability to reduce inflammation, with the AUC value inversely proportional to percentage of anti-inflammatory activity. Lower AUC values indicate greater anti-inflammatory²⁸.

Table 4 reveals that the positive control group, 1.5% concentration, 1% concentration, base group, and 0.5% concentration had the smallest total AUC values. The negative control group exhibited the lowest anti-inflammatory activity value. Topical application of parijoto fruit (Medinilla speciosa) ethanol extract gel was conducted twice daily until the 14th day, resulting in incision closure and hair regrowth in the wounded area, indicating wound healing.

The One-Way ANOVA statistical test conducted on the group treated with the gel base exhibited a significantly different effect (p<0.05) compared to the positive control and the 1.5% concentration gel groups of parijoto fruit ethanol extract based on Table 5. These findings indicate that the gel base functions solely as a gelling agent without any pharmacological activity.

Furthermore, the parijoto fruit extract gel at a concentration of 1.5% demonstrated an effect comparable to the positive control, suggesting equivalent anti-inflammatory activity between the 1.5% concentration gel and the positive control (Octenillin gel). In previous research, the total phenolic content of ethanol extract from Parijoto fruit was tested to be 21.67 μgGAE/g, and the total flavonoid content was 9.21 μgQE/g. These secondary metabolite contents significantly influence its anti-inflammatory activity²⁹. Flavonoids have various effects on inflammation, angiogenesis, wound healing, and oxidative stress. They can influence macrophages, fibroblasts, and endothelial cells by regulating the release and expression of certain factors such as TGF-β1, VEGF, Ang, Tie, Smad 2 and 3, and IL-10. Additionally, flavonoids reduce the release of inflammatory cytokines, NFκB, ROS, and the M1 phenotype. They also positively regulate MMPs 2, 8, 9, and 13, as well as the Ras/Raf/MEK/ERK, PI3K/Akt, and NO pathways³⁰. These interpretations highlight the wound-healing potential of parijoto fruit ethanol extract gel.

b. The assesment of healing effectiveness based on leukocyte count:

Leukocytes, integral components of the blood cell system, play a vital role in the immune system by combating invading antigens. In instances of injury and potential infection, leukocyte levels typically surge³¹^,³². The leukocyte count was evaluated on both the first day of incision treatment and the 14th day upon wound observation completion presented on Figure 4. Initial assessments on the first day post-treatment revealed elevated leukocyte levels across all test groups, exceeding normal ranges (2.9-15.3), indicative of leukocyte migration to the wound site. By day 14, a decline in leukocyte counts was observed in all test groups, with the most significant reductions noted in the 1% concentration group, followed by the 1.5% concentration, 0.5% concentration, base control, positive control, and negative control groups.

The paired T-Test analysis conducted on white rat leukocyte counts before (day 0) and after (day 14) administration of the test drug yielded significant results (p < 0.000, α = 0.05), indicating the impact of extract gel intervention on leukocyte reduction in test animals. Parijoto fruit extract, rich in flavonoids, possesses anti-inflammatory properties attributed to various mechanisms, including the inhibition of key enzymes and transcription factors crucial in modulating inflammation mediators³³^,³⁴. Flavonoids effectively curtail leukocyte migration and suppress the eicosanoid pathway. These mechanisms contribute to reduced leukocyte counts and inhibition of eicosanoid synthesis by diminishing arachidonic acid levels³⁵, underscoring the extract's potential in wound healing applications.

CONCLUSION:

Based on the research findings, it can be concluded that topically applying the ethanol extract gel of parijoto fruit (Medinilla speciosa) has a significant impact on wound healing and alters the number of leukocyte cells in test animals

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

Acknowledgments are extended to the Parijoto research team, Universitas Tidar, and the Laboratory of the Pharmacy Department at Universitas Ngudi Waluyo for their valuable contributions to this research, enabling its successful completion.

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Received on 10.02.2024 Revised on 05.10.2024

Accepted on 04.02.2025 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):2010-2016.

DOI: 10.52711/0974-360X.2025.00287

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