1. Introduction
Aging, from the beginning of life, is a complex, irreversible, multifactorial and inevitable physiological activity that everyone must experience. From a biological point of view, aging is the progressive degradation of physical compositions and tissue structures accompanied by a gradually loss of physiological functions. From a pathological viewpoint, aging is the accumulation of stress, injury, strain, immune decline, metabolic disorders and so on. It is continuous, causing a slowdown in metabolic rate, a decrease in body and organ function, and an increase in the prevalence of related diseases, including cardiovascular and cerebrovascular diseases, tumors and neurodegenerative diseases, making it considerably challenging to stay healthy [1]. Delaying aging has always been an appealing study topic. A variety of drugs have been confirmed to have a certain anti-aging effect, including metformin, rapamycin and procaine, etc. [2,3,4]. However, their long-term use may be restricted by side effects. Medicinal herbs and functional edible herbs have gradually attracted more attention in the field of anti-aging due to their multiple compounds and targets [5].
Momordica charantia L., commonly known as bitter melon, balsam pear and bitter gourd, is annual herbaceous climbing plant belonging to the family Cucurbitaceae. It originated in Asia but is more common in India and the south of China. It is widely planted in tropical and subtropical regions because of its high nutritional value and various pharmacological effects [6]. It can be cooked directly as daily food or processed into tea or wine for drinking. In addition, it is also used as a medicine in many areas [7]. Bioactive compounds, including terpenoids, saponins, flavonoids, sterols, glycosides, phenols, etc., have been isolated from the seeds, fruits and leaves of Momordica charantia L. [8], and these contribute to the various antidiabetic, anticancer, antiviral, antioxidant, antimalarial, anti-inflammatory, neuroprotective and immunomodulatory activities [9,10,11,12,13,14,15].
Many discoveries and applications of medicinal herbs in the anti-aging field were based on aging theories such as the free radical theory, the cross-linking theory, the mitochondrial DNA damage theory and immunosenescence theory, etc. [16,17,18,19]. At present, studies have shown that saponins of Momordica charantia L. could significantly prolong the lifespan of Caenorhabditis elegans and yeast by alleviating the state of oxidative stress [20,21]. However, excessive free radicals cause not only oxidative stress and redox imbalance but also apoptosis [22,23]. Numerous reports have suggested that aging is closely related to apoptosis and autophagy [24,25]. Based on this consideration, the PI3K/AKT signaling pathway, which has a regulatory effect on survival, apoptosis and autophagy, was selected for our experiment.
In this study, firstly, ultra-high-performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometry (UHPLC-Q-Exative Orbitrap MS) was used for a qualitative analysis of the chemical components in Momordica charantia L. ethanol extract (MCE). The effect of MCE on subacute aging mice was then studied from the following aspects: behavioral assessments, antioxidant status and a histopathological observation of the hippocampus and the anti-aging mechanism, in a bid to verify the anti-aging effect and provide the potential mechanisms of Momordica charantia L.
2. Results
2.1. UHPLC-MS Analysis
The chemical components of MCE were analyzed using UHPLC-MS and MS/MS. The molecular mass was determined using full scanning mass spectrometry in positive and negative ion modes. The mass error was obtained by calculating the difference between the measured molecular mass and the theoretical value of the compound. The mass error was less than 10 ppm in this identification experiment. In the positive ion mode, the [M + H]+ and sodium adduct [M + Na]+ ions were mainly generated, while in the negative ion mode, the compounds showed deprotonated [M − H]− ions and [M + HCOO]− ions. A preliminary analysis of the results showed that the chromatographic peaks generated in the negative mode were more abundant and the MS/MS compound fragment information was much clearer, which was beneficial to identifying the compounds. Therefore, the negative mode was chosen for the following process of analysis. The total ion chromatogram (TIC) of MCE (Figure 1) showed that the chromatographic peaks were well separated, and all compounds were preliminarily characterized by analyzing the UHPLC-MS and MS/MS data and comparing them with the relevant literature.
Finally, a total of 14 major compounds, triterpenoids, were identified in MCE. The m/z values of the ions are expressed as integers to facilitate the statement in discussion. The glycosides of these triterpenoids are normally composed of β-
2.2. Behavioral Assessments
2.2.1. Effects of MCE on Morris Water Maze (MWM) Test
Cognitive impairment along with a decline in learning and memory are symptoms of brain dysfunction that are closely related to aging. In a spatial navigation test, it was clear that long-term
2.2.2. Effects of MCE on Step-Down Test
After training, the escape latency and error times of the step-down test in each group were calculated, and the results are shown in Table 3. The
2.3. Effects of MCE on Oxidant Status In Vivo
The determination results of antioxidant enzyme activity in vivo are shown in Figure 5. It can be seen that the activities of SOD, GSH-Px and CAT in the
2.4. Effects of MCE on Body Weight and Organ Index
As shown in Table 4, the body weight of mice in the
2.5. Effects of MCE on Histopathological Alterations
The hippocampus (HP), located in the temporal lobe of the brain, is part of the limbic system and plays a crucial role in learning, memory and spatial positioning. Cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus (DG) are important regions of the HP with complex structures and are influenced by a variety of factors. Therefore, these regions were selected for comparison and analysis in this experiment. H&E staining of the CA1, CA3 and DG regions have been highlighted in Figure 6. It can be seen that the cells in the CA1 and CA3 regions of the mice in the control group are plump with intact morphology and are arranged in an orderly fashion. There are approximately three or four layers of cells in the DG region with distinct layers, an exact structure, a uniform size and a tight arrangement. Moreover, the nuclei are round or oval and the chromatin is evenly distributed. In stark contrast, the cells in the CA1 region of the mice in the
2.6. Effects of MCE on PI3K/AKT Signaling Pathway
In order to reveal the anti-aging mechanism of MCE, the expression of aging-related proteins in the hippocampus of subacute aging mice after MCE intervention were detected in this study. As shown in Figure 7A,D,E,
3. Discussion
Momordica charantia L. is a common edible medicinal plant that contains various bioactive chemical components. Its chemical composition can be analyzed by nuclear magnetic resonance spectroscopy, but this requires high purity of the sample [26]. In this study, the UHPLC-Q-Exactive Orbitrap MS method was used for a qualitative analysis of its chemical components. UHPLC-MS has the advantages of being rapid with high resolution, high selectivity and sensitivity, making it easier to analyze the components of complex herbal mixtures by comparing their relative molecular mass, retention times, mass error and fragment ions [27]. By using the UHPLC-MS method, the compounds of MCE could be analyzed without separation or purification, which greatly shortened the experimental time and provided more data for the screening of monomeric compounds in the future.
Finally, 14 triterpenoids were detected and identified in MCE. The saponins were proven to have the ability to prolong the lifespan of elegans and yeast, as previously described in the introduction. As a result, it is reasonable to consider that triterpenoids are the main anti-aging substances in MCE. Of course, it cannot be denied that other unidentified substances may also have anti-aging activities, and this requires further research.
The free radical theory and the oxidative stress theory are widely accepted in research on the aging process, and previous studies have shown that an excessive accumulation of free radicals is the cause of many diseases, including aging [28]. Our results are consistent with these studies; a repeated injection of
Further, it has been demonstrated that mice with an intraperitoneal administration of
In order to examine the effects of MCE on aging mice from different perspectives, pathological observations of the hippocampus were also carried out. Previous studies have shown that the number and density of neurons in the hippocampus are inversely correlated with age [34]. In the process of aging, neurons undergo varying degrees of apoptosis, leading to a decrease in memory capacity, which is consistent with our observations for the
Previous studies have shown that apoptosis contributes to the aging process induced by
mTOR belongs to the PIKK family and is closely related to protein synthesis and autophagy in the body. mTOR promotes protein synthesis when it is highly expressed in an appropriate range but inhibits autophagy when over-regulated [42,43]. Apoptosis and autophagy, two important physiological processes with distinct differences and mutual influences, play an important role in the aging process. Autophagy is a natural regulatory mechanism that breaks down defective or old proteins into amino acids and reapplies them to build new proteins and tissues. This is a regenerative process that affects longevity and anti-aging, making cells healthier and more active. In recent years, many studies have focused on prolonging the lifespan of organisms by inhibiting the high expression of mTOR to activate autophagy [44,45]. Our data indicate that MCE could relieve the autophagy inhibition caused by long-term
4. Materials and Methods
4.1. Chemicals and Reagents
Fresh Momordica charantia L. was obtained from Shouguang country (Shandong, China), identified by Dr. Bo Li (Changchun University of Chinese Medicine, Changchun, China) and stored in the Jilin Ginseng Academy with voucher specimen No. 20200016. Both the HPLC-grade acetonitrile (ACN) and formic acid were purchased from Fisher Scientific (Waltham, MA, USA). The Milli-Q® IQ 7000 system (Darmstadt, Germany) was used to purify 18 MΩ water.
4.2. Preparation of MCE
In this experiment, the fruit part of the plant was selected. The pulp and seeds were removed after washing, then the fruit was cut into 1 cm thick slices and placed in an oven at 105 °C for 20 min first, then transferred to an oven at 45 °C for drying to obtain dried samples. Soon afterwards, the samples were ground into powder, then immersed in 70% aqueous ethanol (ethanol: water, 70:30, v/v) and extracted in an ultrasonic bath at 45 °C for 30 min. After repeating the extraction 3 times, the 3 aliquots were combined and centrifuged at 10,000 rpm for 10 min, then the MCE was prepared. Part of the MCE was filtered through a 0.45 μm filter for analysis of UHPLC-MS, while the other was evaporated under nitrogen and redissolved with water for intragastric administration in mice.
4.3. UHPLC-MS Analysis
UHPLC analysis was performed on an Ultimate 3000 high-performance liquid chromatography system equipped with a PDA detector and a hybrid quadrupole high-resolution accurate mass (HRAM) Orbitrap (Thermo Fisher Scientific, Sunnyvale, CA, USA) system. The instrument was calibrated to reduce errors by using a calibration solution. A reversed-phase BEH RP-18 column (2.1 mm × 100 mm, particle size 1.7 μm, Waters, Milford, MA, USA) balanced at 45 °C was used for chromatographic separation. Mobile phase A (0.1%, v/v, aqueous formic acid) and mobile phase B (100%, ACN) were used with the flow rate of 0.3 mL/min. The liner gradient elution was carried out as follows: 0–2 min (5–20% B), 2–8 min (20–40% B), 8–15 min (40–45% B), 15–25 min (45–60% B), 25–28 min (60–95% B) and 28–30 min (95–5% B). The injection volume was 3.0 µL, and samples were kept at the temperature of 4 °C.
MS spectrometric detection was performed on a Q-Exactive Orbitrap MS (Thermo Fisher Scientific, Sunnyvale, CA, USA) equipped with an electrospray ionization (ESI) source. The ESI source was configured as follows: the full scan and ddMS2 mode in both positive and negative ion modes were selected in this experiment over an m/z range of 200–2000. The sheath gasflow was 6.125 Mpa, the aux gasflow was 2.625 Mpa and the sweep gasflow was 0.175 Mpa. The capacity temperature was 300 °C and the capillary voltage was 3.5 kv. All data were exported by SIEVE (Version 2.1, Agilent Technologies, Santa Clara, CA, USA) and analyzed by Xcalibur 4.1 software (Thermo Fisher Scientific, Sunnyvale, CA, USA).
4.4. Animal Experiments
Eight-week-old male Kunming mice (weight: 20 ± 2 g) were obtained from Changsheng Laboratory Animal Technology Co., Ltd., Liaoning, China (permit number: SCXK2020-0001). The animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Changchun University of Chinese Medicine (permit number: CPCCUCM IACUC 2021-062). After a 1-week acclimation to the laboratory environment (constant temperature of 23 ± 2 °C, 50–60% humidity, 12 h light/dark cycle and adequate food and water), the mice were divided into four groups randomly (n = 20): the control group (healthy mice with administration of water by gavage), the
4.5. Behavioral Assessments
4.5.1. MWM Test
In this study, the MWM test was used to evaluate the spatial learning and memory ability of
4.5.2. Step-Down Test
The step-down test was a passive avoidance experiment, also used to assess learning and memory ability, in which the mice were trained to jump onto an insulated platform to avoid the electric copper grid [48]. The apparatus consisted of a plurality of rectangular reflection boxes separated by plastic plates, with an electric copper grid at the bottom. Each individual box was equipped with an insulated platform 5 cm in diameter. The mice were trained before the test, they were placed in the box to familiarize themselves with the environment, then 36 V alternating current was applied for 5 min. The mice were placed on the platform 24 h after the training, and an image recorder connected to a computer was used to record the latency and error times.
4.6. Biological Sample Collection and Preparation
After the behavioral assessments, the mice in all groups were fasted for 24 h. Blood samples were obtained from the retrobulbar vein and preserved in sterile tubes, centrifuged at 3000 rpm for 10 min at 4 °C. Then, the supernatant serum was separated and snap-frozen with liquid nitrogen and finally stored separately at −80 °C. The determination of biochemical parameters (SOD, GSH-Px, CAT activities as well as the accumulation content of MDA and LPO) in the serum samples was carried out according to the manufacturer’s protocol. The spleens and thymuses were obtained for the calculation of organ index (organ weight/body weight (mg/g)) [49]. Simultaneously, the hippocampi were excised from the brains, part of which were fixed with paraformaldehyde for over 24 h before histological examination, and the rest were used for Western blot analysis.
4.7. Histopathological Examination
The fixed hippocampi were observed by H&E staining [50]. Briefly, tissues were dehydrated using different dilutions of ethanol, remaining briefly in xylene before the addition of paraffin. The paraffin blocks were precooled for more than 30 min, sliced into 4 μm sections and stained with hemotoxylin and eosin (H&E) for microscopic observation.
4.8. Western Blot Analysis
The appropriate hippocampi were weighed and immersed in a complete RIPA (RIPA:Cocktail:PMSF:Phosphorylase inhibitor = 100:2:1:1) buffer, then homogenized with a low-temperature grinding instrument, followed by an ice bath for 30 min to lyse completely. Later, centrifuged at 10,000 rpm for 10 min, the supernatant was collected for protein content determination using a BCA protein assay kit. Finally, a protein loading buffer was added, and the samples were boiled for 10 min. An amount of 10 μL of the sample (20 μg protein) was separated on 6–10% sodium dodecyl sulfate (SDS)-polyacrylamide gels (Servicebio, Wuhan, China), electrophoresed and transferred to PVDF membranes. The membranes were incubated with PI3K, P-PI3K, AKT, P-AKT, caspase-3, Bax, mTOR, P-mTOR and β-actin antibodies at 4 °C for 24 h after quick blocking. Then, a horseradish peroxidase-conjugated secondary antibody was added to incubate for 1 h at an ambient temperature with shaking. Finally, the membranes were developed with an ECL kit, visualized and captured by an imaging system (Tanon, Shanghai, China). Image J software was used to analyze the gray value of the target proteins.
4.9. Statistical Analysis
All data were presented as mean ± S.D. and analyzed using GraphPad PRISM version 8.0.2 software (GraphPad Software, San Diego, CA, USA). The differences between the two groups were determined using Student’s t-test, while a one-way analysis of variance (ANOVA), followed by Tukey’s post hoc test, was used to compare multiple groups. It was considered statistically significant when p < 0.05.
5. Conclusions
This experiment was the first to demonstrate the anti-aging effect of Momordica charantia L. on subacute aging mice. The study of the chemical components of Momordica charantia L. indicated that the anti-aging effect may be closely related to triterpenoids. The biochemical and pharmacological parameters indicated that Momordica charantia L. could maintain redox balance and reduce oxidative stress in aging mice. It has the potential to promote cell survival and to reverse the decline in learning and memory ability caused by
Conceptualization, D.W. and W.W.; methodology, D.W. and W.W.; software, D.W., E.W. and Y.L.; validation, W.W.; investigation, Y.T., H.L. and L.J.; data curation, D.W.; writing—original draft preparation, D.W.; writing—review and editing, W.W.; supervision, W.W.; funding acquisition, W.W. All authors have read and agreed to the published version of the manuscript.
The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Animal Care and Use Committee (IACUC) of the Changchun University of Chinese Medicine (protocol code CPCCUCM IACUC 2021-062 on 3 March 2021).
Not applicable.
All the data used in this study are available within this article. Further inquiries can be directed to the authors.
The authors declare no conflict of interest.
Samples of the compounds are not available from the authors.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compounds identified in MCE using UHPLC-MS and MS/MS.
| Peak | tR |
Measured |
Mass Error |
Molecular |
Adduct | MS/MS | Compound |
|---|---|---|---|---|---|---|---|
| 1 | 7.43 | 857.4567 | 3.1 | C42H68O15 | [M + HCOO]− | 179.0548, 631.3800 |
Momordicoside O |
| 2 | 8.17 | 843.4779 | 3.7 | C42H70O14 | [M + HCOO]− | 797.4688, 635.4132 |
Kugualycoside E |
| 3 | 8.18 | 977.5341 | 1.4 | C48H82O20 | [M − H]− | 815.4693, 797.4680 |
Momordicoside S |
| 4 | 9.20 | 815.4794 | −0.5 | C42H72O15 | [M − H]− | 653.4269, 491.3715 |
Momordicoside A |
| 5 | 9.65 | 859.4731 | 4.0 | C42H70O15 | [M + HCOO]− | 813.4646, 651.4112 |
Goyaglycoside h |
| 6 | 11.26 | 699.4344 | 2.7 | C36H62O10 | [M + HCOO]− | 653.4269, 491.3735 |
Momorcharaside B |
| 7 | 11.40 | 697.4191 | 3.2 | C36H60O10 | [M + HCOO]− | 651.4116, 633.3973 |
Momordicoside Q/ |
| 8 | 12.00 | 841.4617 | 3.1 | C42H68O14 | [M + HCOO]− | 795.4536, 633,4033 |
Momorcharaside M/N |
| 9 | 12.58 | 1377.6312 | −1.5 | C65H102O31 | [M − H]− | 1377.6312, 807.4169 |
Goyasaponin I |
| 10 | 12.90 | 1509.6751 | −0.3 | C70H110O35 | [M − H]− | 1509.6751, 627.3533 |
Goyasaponin II |
| 11 | 13.02 | 825.4681 | 4.7 | C42H68O13 | [M + HCOO]− | 779.4583, 617.4055 |
Goyalycoside e/f |
| 12 | 15.38 | 679.4094 | 4.6 | C36H58O9 | [M + HCOO]− | 633.4007, 471.3479 |
Momordicoside L |
| 13 | 17.28 | 679.4091 | 4.1 | C36H58O9 | [M + HCOO]− | 633.4006, 471.3443 |
Momord icoside P |
| 14 | 17.87 | 679.4088 | 3.7 | C36H58O9 | [M + HCOO]− | 633.4030, 455.3177 |
Momordicin II |
Effects of MCE on escape latency, target quadrant crossing times and dwell time in MWM test.
| Groups | Escape Latency (s) | Target Quadrant Crossing Times | Dwell Time (s) |
|---|---|---|---|
| Control | 10.39 ± 1.91 | 12.00 ± 0.82 | 49.05 ± 6.86 |
| 45.17 ± 5.13 ### | 5.00 ± 0.82 ### | 19.50 ± 3.31 ### | |
| 12.5 ± 1.65 *** | 10.50± 1.29 ** | 40.4 ± 4.32 ** | |
| 13.07 ± 2.57 *** | 11.75 ± 0.96 *** | 39.13 ± 5.47 ** |
Data were reported as the mean ± S.D. of 20 mice in each group. ### p < 0.001 vs. control group; *** p < 0.001, ** p < 0.01 vs.
Effects of MCE on escape latency and error times of step-down test.
| Groups | Escape Latency (s) | Error Times | Dwell Time (s) |
|---|---|---|---|
| Control | 277.89 ± 19.77 | 1.17 ± 0.75 | 49.05 ± 6.86 |
| 84.56 ± 20.24 ### | 3.33 ± 1.03 ## | 19.50 ± 3.31 ### | |
| 262.63 ± 32.58 *** | 1.00 ± 063 ** | 40.4 ± 4.32 ** | |
| 262.15 ± 26.41 *** | 1.17 ± 0.75 ** | 39.13 ± 5.47 ** |
Data were reported as the mean ± S.D. of 20 mice in each group. ### p < 0.001, ## p < 0.01 vs. control group; *** p < 0.001, ** p < 0.01 vs.
Effects of MCE on body weight and organ index.
| Groups | Body Weight (g) | Organ Index | |
|---|---|---|---|
| Spleen (mg/g) | Thymus (mg/g) | ||
| Control | 47.86 ± 3.15 | 3.65 ± 0.04 | 1.50 ± 0.07 |
| 41.25 ± 2.46 ## | 2.00 ± 0.08 ### | 0.84 ± 0.17 ## | |
| 45.68 ± 2.32 ** | 3.43 ± 0.15 ** | 1.42 ± 0.10 ** | |
| 45.88 ± 2.65 ** | 3.49 ± 0.11 *** | 1.45 ± 0.04 ** | |
Data were reported as mean ± S.D. of 20 mice in each group. ### p < 0.001, ## p < 0.01 vs. control group; *** p < 0.001, ** p < 0.01 vs.
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Abstract
Anti-aging is a challenging and necessary research topic. Momordica charantia L. is a common edible medicinal plant that has various pharmacological activities and is often employed in daily health care. However, its anti-aging effect on mice and the underlying mechanism thereof remain unclear. Our current study mainly focused on the effect of Momordica charantia L. on
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