INTRODUCTION:

Obesity, hypercholesterolemia, and associated cardiovascular diseases contribute to a high percentage of morbidity and mortality in humans, making them major areas of public health interest¹. While the synthesis of lipid-lowering drugs has been made possible in the last few decades through a plethora of scientific endeavors, in many cases, their adverse effects outweigh their benefits.

For this reason, in the last few decades, research interest has diverted towards the study of natural compounds such as medicinal plants, for the potential discovery of phytochemicals with the efficacy to lower lipid and glucose levels^2,3.

In recent years, plant-based products have been considered to be major sources for developing new drugs and functional products due to the negative effects of synthetics. Currently, many studies related to natural products have had substantial impacts in the pharmaceutical and food fields⁴. Ipomoea batatas L., which is commonly known as sweet potato, is a dicotyledonous plant belonging to the Convolvulaceae family, of which the edible part is its tuberous root^5–7. The variants of Ipomoea batatas include white, yellow, and orange, mainly used at the root. Ipomoea batatas purple variants contain many anthocyanins that can trigger treatment effects^8–10. Previous studies have revealed anthocyanins of this plant, include peonidin and cyanidin compounds^11,12. Until now, there have been no studies on the potential content of other parts of plants, such as leaves. Besides, the use of leaves of purple Ipomoea batatas for medicinal purposes is also infrequent.

The production of reactive oxygen compounds that exceed the antioxidant ability will trigger oxidative stress^13,14. Superoxide dismutase becomes the first line of reactive oxygen compounds through scavenging and the catalysis of superoxide dismutation of hydrogen peroxide¹⁵. Until now, mammals have found three superoxide dismutase (SOD) isoforms, namely in the cytoplasm and mitochondrial membrane, mitochondrial matrix, and on the cell surface, extracellular, or body fluids¹⁶. Previous studies have suggested that purple sweet potato anthocyanins can modulate antioxidant enzymes, including SOD, as well as suppress malondialdehyde (MDA)¹⁷.

Superoxide dismutase 2 (SOD2) plays a role in the degradation of superoxide radicals produced by the mitochondrial transport chain¹⁸. Characterization of the genomic structure of SOD2 indicates that human and rat SOD2 contain little TATA and CAAT, but are rich in GC sequence replications. Also, there are binding sites of supportive and suppressive transcription factors¹⁹. SOD2 is highly expressed in atherosclerotic plaques, precisely in lipid-rich regions of foam cells. SOD2 from macrophage cells can be induced by oxidized LDL (ox-LDL). Overexpression of SOD2 inhibits endothelial dysfunction. Previous studies have suggested that the purple Ipomoea batatas anthocyanins can upregulate the SOD2 protein mass in an aging fruit fly model^17,18.

Nuclear factor-erythroid 2 related factor 2 (Nrf-2) is involved in redox homeostasis in the mitochondria through activation of the antioxidant enzyme mitochondria, namely SOD2^18,19 Oxidative stress due to the upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the master regulator of the early and advanced stages of the inflammatory pathway signaling in atherosclerosis²⁰. Previous findings suggest that anthocyanins can also modulate Nrf-2²¹.

In this study, we report the active compound by liquid chromatography high resolution mass spectrometry (LC-HRMS) from Ipomoea batatas purple variant leaf extract, including their oxidative stress, antioxidant, anti-inflammatory activity. Thus, the present study may offer new and innovative perspectives on leaves of purple Ipomoea batatas for the antioxidant and anti-inflammatory in rats fed a high-fat diet.

MATERIAL AND METHODS:

Plant Material and Extract Preparation:

The Ipomoea batatas originate from the Gunung Kawi region, Blitar, East Java, Indonesia. The harvested leaves were processed into powder at UPT Material Medica, Batu City, East Java, Indonesia. The powder was then macerated for 14 hours in ethanol-HCl 0.01% v/v. The solvent in the extract was evaporated at 45°C and low pressure with a rotary evaporator. The crude extract was centrifuged at 4500RPM for 30 minutes, then extraction of the solvent using ethyl acetate. Freeze dry treatment of crude extracts yields 2.74g/100g of wet sample.

LC-HRMS Determination of Active Compounds:

LC-HRMS analysis of the leaf extracts was performed as described previously²². The extracted sample was diluted according to the solvent (polar) and consistency to make the final volume of 1300μl. The sample was vortexed for 1 min and then spun for 2 min. The supernatant was filtered using a 0.22μm syringe filter and placed in vials. The samples in the vials we replaced in an autosampler and injected into the LC-HRMS system. The analysis was carried out by high-performance liquid chromatography (Thermo Scientific Dionex Ultimate 3000 RSLC Nano with a micro flow meter). The mobile phase of the assay was 0.1% formic acid in water (A) or acetonitrile (B). The analysis used Hypersil GOLD AQ 50 x 1.0mm x 1.9 u particle size. The flow rate was 40 μL/min flow. The elution time was 30 min and the column oven temperature was set at 30°C.

Analysis of Antiradical Activity:

Antioxidant activity was assessed through the DPPH radical scavenging capacity, as a procedure in a previous study²³. Measurements were taken of leaf extracts of various ages, including young leaves, medium leaves, and old leaves.

Animals and Experimental Design:

A total of 30 male Wistar rats (age, 8 weeks; weight, 320–350g) were purchased from the Laboratory of Pharmacology, Universitas Brawijaya, Indonesia. All experimental procedures were carried out according to Ethical Standards and approved by the Ethical Committee, Faculty of Medicine, Universitas Brawijaya, Indonesia (Number 109/EC/KPEK/04/2020). Before treatment, rats were acclimated for seven days under laboratory conditions. Ad libitum feeding and drinking. Following an acclimatization period, rats were randomly divided into five experimental groups of six animals in each group. The group included a control group (fed a standard diet/SD), a high - fat diet group (HFD), a high-fat diet group accompanied by Ipomoea batatas leaf extract (IBLE) at the dose of 625mg/kg body weight (HFD + Ib1), a high-fat diet group accompanied by IBLE at the dose of 1250mg/kg body weight (HFD + Ib2), a high diet group fat accompanied by IBLE dose 2500mg/kg body weight (HFD + Ib3). The rats were housed in plastic cages in a room with a 12:12 light-dark cycle and an ambient temperature of 22 ± 2°C. The rats were fed with diets and water at libitum. Intake of diets was recorded daily and body weight gains weekly, through the whole experimental period.

After 12 weeks of experimental period fasted rats were anesthetized with ketamine 90mg/kg²⁴. Aortic tissue was immediately excised, rinsed in phosphate buffer solution (PBS) for the immunohistochemical analysis.

Standard and High-fat Diet:

The standard rodent chow was Comfeed PARS with a composition of calcium (1.1%), phosphorus (0.50%), crude protein (22.5%), fat (5%), crude fiber (5%), ash (7%). Meanwhile, for high-fat diets in the form of standard diet mixed with 2% cholesterol, 0.2% cholic acid, and 5% pork oil.

Immunohistochemistry:

Immunohistochemical analysis was carried out on aortic tissue slices from formalin fixation, paraffin-embedded to assess MDA, SOD2, Nrf-2, and TNF-α expressions. The antibodies used include anti-MDA purchased from Abcam, Cambridge, MA, USA (ab6463). SOD2 antibody (sc-133134), Nrf-2 antibody (sc-722), and TNF-α antibody (sc-52746) from Santa Cruz Biotechnology, Inc. Dallas, Texas, USA. Immunohistochemical staining was carried out according to protocol guidelines. The color density will be analyzed with ImageJ 1.53e software.

Statistical Analysis:

Data were expressed as mean ± standard deviation. The results were analyzed by one-way analysis of variance (ANOVA) followed by post hoc test analysis using the SPSS software (SPSS, Version 21.0, IBM Inc. USA). Differences were considered statistically significant when P < 0,05.

RESULTS:

The scavenging ability of DPPH free radicals is widely used to analyze the antioxidant potential of naturally derived food and plants. The DPPH radical scavenging activity analysis on various leaves of Ipomoea batatas, all the extracts showed an inhibitory potential against DPPH free radical. Sequentially the DPPH scavenging activity of young leaves is 10.50 ± 1.29 ppm; medium leaf 340.82 ± 48.28 ppm; and old leaves of 274.04 ± 13.45 ppm. The characteristic identification of active compounds of young leaves using LC-HRMS can be seen in Table 1.

Table 1. Active Compound by LC-HRMS From Ipomoea batatas Purple Variant Leaf Extract

Peak	Compounds	Molecular Formula	Molecular Weight (g/mol)
1	Betaine	C₅H₁₁NO₂	117.0788
2	Trigonelline	C₇H₇NO₂	137.0473
3	Caffeic acid	C₉H₈O₄	180.0419
4	Jasmonic acid	C₁₂H₁₈O₃	210.1252
5	Chlorogenic acid	C₁₆H₁₈O₉	354.0942
6	4-methoxycinnamic acid	C₁₀H₁₀O₃	178.0626

Oxidative stress is assessed by measuring MDA expression in the aortic (Figure 1a). Lipid peroxidation (MDA expression) in different groups is shown in Figure 1b. Rats that consumed the HFD exhibited significantly increased lipid peroxidation (p > 0.05) compared to the control rats. Oral supplementation with Ipomoea batatas leaf extract (IBLE) prevented the lipid peroxidation in HFD rats, was significantly (p < 0.05), in the dose IBLE of 1250 and 2500 mg/kg body weight compared to HFD (Figure 1b).

a.		b.

Control	HDF

HDF+Ib1	HDF+Ib2

HDF+Ib3
*Figure 2. Ipomoea batatas* Leaf Extract Promotes Expression of Cellular Antioxidants in Rats High-Fat Diet.** (a). Representative photomicrographs of SOD2 immunostaining in aortic sections (400X). Brown staining indicates positive cells. Control group: fed a standard diet/SD; HFD: high-fat diet; HFD + Ib1: high-fat diet and leaf extract at a dose of 625mg/kg body weight; HFD + Ib2: high-fat diet and leaf extract at a dose of 1250mg/kg body weight; HFD + Ib3: high-fat diet and leaf extract with a dose of 2500mg/kg body weight. (b). The quantitative analysis of SOD2 expression. Quantitative analysis of expression intensity was performed by ImageJ 1.53e software. Data are presented as mean ± SD (n=6/group). Statistical analysis was done by one-way ANOVA followed by post hoc test analysis using the SPSS software. Data with different notations in the same chart implied a significant difference (p < 0.05).

a				b.

Control		HDF

HDF+Ib1		HDF+Ib2

HDF+Ib3
Figure 3. Ipomoea batatas Leaf Extract Activates Expression of Oxidative Stress Response in Rats High-Fat Diet. (a). Representative photomicrographs of Nrf-2 immunostaining in aortic sections (400X). Brown staining indicates positive cells. Control group: fed a standard diet/SD; HFD: high-fat diet; HFD + Ib1: high-fat diet and leaf extract at a dose of 625 mg/kg body weight; HFD + Ib2: high-fat diet and leaf extract at a dose of 1250 mg/kg body weight; HFD + Ib3: high-fat diet and leaf extract with a dose of 2500 mg/kg body weight. (b). The quantitative analysis of Nrf-2 expression. Quantitative analysis of expression intensity was performed by ImageJ 1.53e software. Data are presented as mean ± SD (n=6/group). Statistical analysis was done by one-way ANOVA followed by post hoc test analysis using the SPSS software. Data with different notations in the same chart implied a significant difference (p < 0.05).
a.			b.

Control	HDF

HDF+Ib1	HDF+Ib2

HDF+Ib3
*Figure 4. Ipomoea batatas* Leaf Extract Reduces Expression of Pro-Inflammatory Cytokines in Rats High-Fat Diet.** (a). Representative photomicrographs of TNF-α immunostaining in aortic sections (400X). Brown staining indicates positive cells. Control group: fed a standard diet/SD; HFD: high-fat diet; HFD + Ib1: high-fat diet and leaf extract at a dose of 625 mg/kg body weight; HFD + Ib2: high-fat diet and leaf extract at a dose of 1250 mg/kg body weight; HFD + Ib3: high-fat diet and leaf extract with a dose of 2500 mg/kg body weight. (b). The quantitative analysis of TNF-α expression. Quantitative analysis of expression intensity was performed by ImageJ 1.53e software. Data are presented as mean ± SD (n=6/group). Statistical analysis was done by one-way ANOVA followed by post hoc test analysis using the SPSS software. Data with different notations in the same chart implied a significant difference (p < 0.05).

To investigate the underlying mechanisms of anti-inflammation expression in the aortic was tested by immunohistochemical staining analysis, the expression of TNF-α in the aortic presented in Figure 4.a. Rats that consumed the HFD exhibited significantly increased TNF-α expression (p < 0.05) compared to the control rats. Oral supplementation with Ipomoea batatas leaf extract (IBLE) prevented the TNF-α expression in HFD rats, was significantly (p < 0.05), in the all group (Figure 4b) compared to HFD.

DISCUSSION:

In this study, it was proven that IBLE has antioxidant activity, through the mechanism of radical scavenging. Of the various leaf ages, the highest radical scavenging activity was shown in young leaves with IC50 values of 10.50 ±1.29 ppm, and then young leaves are used for in vivo study. Previous studies have investigated anthocyanin differences in various leaf ages²⁵. In addition to testing the antioxidant activity, LC-HRMS analysis was also carried out. We have found six compounds that have antioxidant potential, including betaine, trigonelline, caffeic acid, jasmonic acid, chlorogenic acid, and 4-methoxy cinnamic acid^26–31. The presence of chlorogenic in Ipomoea batatas extract has been revealed in previous studies³². Caffeic acid compounds have been detected in methanol extracts^33,34.

Our study proves that a high-fat diet triggers vascular lipid peroxidation. The mechanism of increased reactive oxygen compounds through enzymatic, non-enzymatic, and mitochondrial transport chains¹⁶. The molecules most sensitive to lipid peroxidation are phospholipid membranes containing polyunsaturated fatty acids (PUFAs), including arachidonic, linoleic, linolenic, eicosapentaenoic, and docosahexaenoic acid³⁵. The increase in MDA in this study is consistent with previous studies^36–38. This increase in oxidative damage can be restored by administering extracts at the two highest doses of IBLE. This normalization mechanism is played by the content of active compounds that are antioxidants^39–42.

Superoxide radicals are produced by enzymatic reactions, NADPH oxidase, and xanthine oxidase, or involve mitochondrial activity^43,44 In this study, SOD2 expression decreased significantly in the HFD group compared to an SD. These findings indicate that there is an increase in SOD2 activity to catalyze superoxide radicals into hydrogen peroxide in the mitochondria of the cell. All dosages of IBLE can restore SOD2 expression to reach the value in the standard diet. This indicates that leaves extract can work intracellularly to help scavenge superoxide radicals. This finding also indicates that the extract can modulate SOD2 formation or inhibit the activity of several superoxide enzyme producers. For SOD2 upregulation, we hypothesized that the active compound of IBLE support binding the transcription factor to the SOD2 promoter. This activity is crucial for the upregulation of SOD2⁴⁵. Previous studies have suggested that trigonelline, chlorogenic acid, and 4-methoxy cinnamic acid can suppress MDA and improve SOD^27,33,46 Jasmonic acid can increase endogenous enzymatic antioxidant activity⁴⁷. This study extends previous findings that purple sweet potato can upregulate SOD2 protein masses in fruit fly aging models¹⁷.

This study is the first study evaluating the effect of Ipomoea batatas on vascular Nrf-2 on high-fat diets. Our results show that a high-fat diet does not trigger changes in Nrf-2 expression. This indicates that the high-fat diet given does not yet trigger the oxidation of key cysteine residues that trigger conformational changes for the release of Nrf-2 into the nucleus⁴⁸. The administration of IBLE increases the expression of Nrf-2, which indicates that the active compound can trigger conformational changes. Polyphenol compounds can trigger this process⁴⁹. This study extends previous findings that purple sweet potatoes can suppress lipid peroxidation⁵⁰. Nrf-2 plays a role in the inhibition of lipid peroxidation ⁵¹.

Ipomoea batatas leaf extract reduces the expression of pro-inflammatory cytokines in rats fed a high-fat diet. A high-fat diet (HFD) causes metabolic inflammation throughout the organism. Levels of endotoxin, circulating free fatty acids, and inflammatory mediators increase in response to HFD, resulting in low-grade systemic inflammation and changes in homeostasis in many organs⁵².

CONCLUSION:

This investigation provides evidence that Ipomoea batatas L purple variant leaf extract supplementation is a potent antioxidant and anti-inflammatory in rats fed a high-fat diet. Therefore, the present study may offer new and innovative perspectives on this plant can be an alternative herbal to prevent vascular oxidative stress in the development of atherosclerosis. Further research is warranted to confirm the beneficial effect on human subjects in a clinical trial.

ACKNOWLEDGEMENT:

The authors were grateful to the Wijaya Kusuma University and Universitas Brawijaya that provided technical support for the development and implementation of this study.

CONFLICT OF INTEREST:

None of the authors declared.

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Received on 02.03.2021 Modified on 16.08.2021

Research J. Pharm. and Tech. 2022; 15(6):2395-2401.

DOI: 10.52711/0974-360X.2022.00398