Bitter melon seed oils have been consumed or used for medical purposes in many countries, and it is known that bitter melon seeds have many biological effects. However, there are few scientific evidences to prove the pharmacological functions of bitter melon seeds. Therefore, this research analyzed the ingredients and pharmacological effects of bitter melon seed oil extracts. The results showed that bitter melon seed oil extracts down-regulated the expression of cancer-related genes in colorectal cancer cells. An in vitro experiment showed that intolerant bitter melon seed oil extracts did not induce inflammation of the chondrocytes and MSC (mesenchymal stem cells). We evaluated the photoprotective effects of bitter melon seed oil with UVB-induced skin damage in mice and the wound healing effects of bitter melon seed oil application on human dermal fibroblasts (HDF). The purpose of this research was to identify the unexplored pharmacological functions of bitter melon seed oil suggesting its evidence-based medical use and cosmetic benefit.
1. Introduction
Cancer is well known to be a leading cause of death worldwide with high fatality rates and limited therapeutic options. Colorectal cancer, commonly diagnosed in the elderly, can cause significant morbidity and mortality. Recently, a number of studies have focused on the use of natural resources as a novel cancer therapeutic agent for various cancers. In this study, we isolated bitter melon seed oil, which is native to Southeast Asia and has been used in various treatments. Chondrocytes and mesenchymal stem cells are two types of cells which related to anti-inflammation and wound healing. Bitter melon seed oil can inhibit cell viability, ROS, and inflammatory responses in chondrocytes. In this specific study, we evaluated bitter melon seed oil in terms of inhibiting hepatic steatosis and inflammatory responses in conjunction with its protective effects both in vivo and in vitro.
1.1. Background and Significance
Bitter melon seed oil (BMSO) has been shown to contain potent extracts that exert a wide range of positive effects in humans. Accumulating results from observational and interventional studies suggest that BMSO can be useful in the management and treatment of a variety of ailments. These include various types of metabolic syndromes, malignant diseases, and microbial infections. In many cases, BMSO has been used as a lipid-lowering and insulin-sensitizing dietary supplement and has been shown to decrease body weight and prevent diet-associated disease onset. As a skin-absorbable carrier, topical applications of dilute mixtures of BMSO can protect against and reverse oxidative skin damage. Furthermore, it has been shown that BMSO can enhance the migration and homing capacity of cells for organ consumption and that it can protect immune cells against pro-apoptotic stimuli. BMSO and its constituent fatty acids are known to have various cellular and molecular targets inside the cells and modulate enzyme activity, gene expression, and intracellular signaling pathways. These effects are primarily mediated by transcription factors like PPARs and NF-кB and various membrane-associated receptors and ion channels.
The present article is part of a series of reviews that focus on the pharmacological and physiological effects of BMSO and its fatty acids. It aims to provide an overview of the cellular and intracellular effects of BMSO and a summary of the extracellular effects. The current situation is that although our capability to examine cellular functions has never been greater, cell biologists and pharmacologists still lack advanced techniques and tools to get detailed information about the molecular structure and function of cellular effectors and intracellular targets. This review aims to summarize the most recent insights and achievements and to facilitate the further development of medicinal applications. This manuscript forms the theoretical foundation for an overarching treatment of BMSO and its extracts and effects.
1.2. Scope and Objectives
The present work aimed to provide an insight into the modulation of cell membrane and nuclear receptor signaling by crude bitter melon seed oils, other than the mature fruit extract reported in literature, which has already demonstrated its potential in the treatment of metabolic diseases. In addition, the development of the process for producing the bitter melon seed oil extracts has also been optimized in order to provide a large-scale application. Specifically, crude bitter melon seed oils have been identified to enhance PPARα-CPT1α activation, as well as AMPK phosphorylation, regardless of the type of nutritional stimuli. The study has demonstrated that this unexplored part of bitter melon is able to improve mitochondrial functions, regulate energy metabolism, peroxidation, and exert an anti-inflammation effect, leading to a reduction in oxidative stress and consecutively protective effects against steatosis or even HCC progression. The results are being presented in chapters 3 to 5, which involve in vitro, in silico, and ex vivo data, respectively.
2. Botanical and Chemical Profile of Bitter Melon Seed Oil
Bitter melon (Momordica charantia) is believed to be native to India, from where it spread to other parts of Asia and Africa. The genus Momordica is a member of the family Cucurbitaceae, which is distributed throughout the world, with over 100 species; and genus Momordica has been reported to include around 60 to 90 species. Bitter melon, also known as bitter gourd in many places, is a member of the same group of plants that include squash, watermelon, muskmelon, cucumber, and pumpkins. Many of these are widely cultivated and are nutritious vegetables, but they are also used in various traditional medicinal systems around the world. Bitter melon is not an exception in this regard. In China and India, it has been utilized as part of the Indian, Asian, and African traditional medicinal practices for several centuries.
Bitter melon seeds typically make up 18% to 20% of the fruit by mass. The seeds are typically flat, ovate, and oblong, and they have minute, closely appressed hairs on the surface. They are reported to contain 14% to 15% fixed oil, 15% to 17% protein, around 20% carbohydrates, 7% fiber, slightly over 2% ash, and less than 15% moisture. Bitter melon contains from about 48% to 50% water by weight.
Momordica charantia is reported to have numerous chemical constituents and compounds or metabolites, including saponins, proteins, lectins, amino acids, peptides, phenolic compounds, dietary fiber, triterpenes, phytosterols, carotenoids, vitamins, and oleoresins. The seeds are also illustrated to contain a variety of chemical constituents, such as saponins, proteins, lectins, amino acids, peptides, phenolic compounds, dietary fiber, phytosterols, polyunsaturated fatty acids, vitamins, oleoresins, alkaloids, flavonoids, momordin, momordicinin, momordisin, and momordicilin. The seed composition has been reported to be approximately 3.4% ash, 4.7% crude fiber, 15.5% moisture, 23.3% carbohydrate, 27.5% oil, and 26.5% protein. Dietary consumption of the seeds and oil has been shown to have anti-obesity, hepatoprotective, antioxidant, and other beneficial effects on the body. Palm seed oil has been known as one among many vegetable oils with potential health benefits. The focus of this review is on the biological activity and the potential use of bitter melon seed oil in human health. In addition, the mode of action and the targets or pathways affected by bitter melon omega-6 fatty acids is presented. This review provides some interesting background information on the edible nature and traditional medicinal properties of Momordica charantia and reports on minor seeds or illustrated effects for the extract. Since vegetable oils are rich sources of the antioxidant vitamins E and A and plant sterols, fatty acids, and other chemical constituents, the antioxidant and the other biological activity of the bitter melon seed oil are discussed. Dietary bitter melon seed oil does not appear to have any adverse side effects and is safe for human consumption. In summary, the data and literature presented herein argue that bitter melon seed oil may be useful for human health in disease prevention and dietary needs.
2.1. Botanical Characteristics of Bitter Melon Plant
Momordica charantia L., commonly known as bitter melon, is a worldwide cultivated vegetable with both nutritional and medicinal characteristics. In China, bitter melon has been widely used for remedying several diseases such as diabetes and cancer for thousands of years. Based on our current ethnomedical uses, intense studies have generated significant information about its composition and the biological activities of the whole plant, mainly concentrated on seeds, fruit, and leaves.
In general, M. charantia is a monoecious ampeloe plant with leaves that grow to 4-12 m. The green leaves are highly divided, shelter-leaf, and have three to five divisions or splits. The monoecious bacterial is split by the gourd, male sex flowers: the calyx is split into 5 prongs of length; the corolla is divided into 5 mixed flowers, the male female is composed of 3 petals and a 2-section; stamen 3, rarefy 3 sections. The male flower base has an axial not rare 1 filamentous filament. The growth of pollen grains hangs down, the concentration of the pollards is divided into 3 lobes, and the bilayer of the lover is open. Female flowers have 3 petals, a three-room, single-style stellae, a slim ovary, and a gelite-shaped tool. The birms become a cotal, the botanical axis becomes fat, and the portion becomes curved. The fruit is double-divided with 2 sections, and the seed is flat round, such as a crescent or watermelon. In the wild mongo for or dry mountain area, others take a wasteful film.
Momordica charantia is commonly found in the tropical and subtropical regions of the world. The main areas currently cultivated are China, India, the Philippines, Sri Lanka, Myanmar, and Malaya in Malaysia. This melon contains protein, inorganic salts, vitamins, antibiotic polypeptides, and charantin. The fruit on the top of the coral contains glycyrrhizin and many other plants. The main active ingredients in bitter melon are flavonoids, glycosides, and alkaloids. The contents of active ingredients such as lecithin, bitter melon, and bitter melon are abundant in bitter melon seeds. The biological activity of nutritive ingredients such as squid and lipid [oil] are the main research diseases; it has anti-inflammatory, analgesic, chemotherapeutic, and antioxidative effects, with the potential to lower cholesterol, lower blood sugar, and anti-cancer, a treatment effect that affects multiple clinical diseases. Its long-term development contributes to its practical application in so many diseases as one of the treatment drug sources. On the other hand, there are also many other beneficial effects on human health such as appetite and throat, catering to salt, conditioning, and promoting grievances.
2.2. Chemical Composition of Bitter Melon Seed Oil
Bitter melon seeds contain up to 50% oil, which is rich in fatty acids, amino acids, and additional minor components. The bitterness of the seeds is mostly attributed to momordicine I, which is present in the seeds as the carbohydrate-bound soluble ester. Momordicine is a ‘snowdrop’ type protein of ~28 kDa specific to amino acids glycine and leucine and a polypeptide consisting of 71 amino acids. The protein is responsible for the sweet taste rebound effect observed after swallowing bitter melon seeds, which thread manufacturers have exploited by combining quinine with a glycoside and the glycoside with the snowdrop protein to make non-bitter artificial sweeteners. Bitter melon seed oil contains numerous uniquely identified or unique to common components, namely amino acids (51-59%), phenolic compounds, volatile, sterol lipophilic (18-20 ± 1%), phospholipids (7-10%), and seed oil. Four amino acids, malonyl Cummings, malonyl Leucine, malonyl Alanine, and malonyl Glycine, are unique to bitter melon seed oil.
One could significantly increase the phytochemical content of soybean and sesame oil by spiking each oil with 5 ug/g, 20 ug/g of momordicine I. Adding momordicine would significantly increase the phytochemical content of a brand complete known and novel blend. Also, its effect on overall body health, lipogenesis, and Eu-3t3 cells, which are used in the Brown preadipocyte proliferation assay. The objectives of this study are to isolate and characterize the major component of bitter melon seed oil as a possible sweetener, anti-diabetic agent for weight loss or unusual market blend formulations containing inherent health-improving functional ingredients. Dietary guidelines recommend three servings of vegetables and fruits to maintain health. What better than eating sweet cake, where this ingredient is added? The second objective is to compare the biological activity and discover the unknown anti-fat accumulation, urolithiasis, PGE2 inhibit agents for cancer therapies, for in vitro research. The third goal is to see any combinatory effects of momordicine, including derived glycoside compounds and any inhibitors in separate or combined treatments, on membrane-associated activation of LEGSK.
3. Extraction Methods and Processing Techniques
The process of oil extraction is a common and necessary step for essential oil production from seeds of herbs, spices, and industrially important plants. In herbal plants, active living ingredients such as terpenoids, sesquiterpenes, and other related hydrocarbons can be obtained through the process of oil extraction. The effective constituents of aromatic plants are derived from the oil, fat- or wax-rich fractions of the plant. However, some effective compounds from these plants are not included in the volatile oil. Before water vapor distillation, solvent extraction must be selectively conducted to obtain the specific targeted compound. Commercial vegetable oil is also produced by the extraction process. The solubility and volatility of the different essential oil constituents are significantly influenced by temperature, pressure, and the solvent used. Among different oils, that obtained by supercritical fluid extraction is thought to be the best. SFE is considered to be the most effective solvent extraction method.
3.1. Traditional Extraction Methods
Traditional methods are ancient methods used to obtain extracts. These methods are age-old, cumbersome, time-consuming, and labor-intensive. Despite modernization, they are still in use today and are the only means employed to document medicinal plants. Some traditional methods include infusion, maceration, percolation, filtration, expression, decoction, Soxhlet extraction, and reflux extraction. Prior to the routine use of extracts, they are the techniques employed. Due to their slow and low efficiency, they have been replaced by modern techniques.
3.1.1. Maceration Maceration is the softening and separation of tissue, specifically the breakdown of chyme and other sealed organisms in the alimentary canal without the use of external forces. Maceration is used to direct a selected solvent to pierce the matrix of a macerate to remove a modifiable substance. Here, maceration, like percolation, is a prelude to a hot extraction of fruits and vegetables.
3.1.2. Soxhlet Extraction This method is an automated equivalent of simultaneous dipping and maceration. It allows for unattended and complete extraction and it is particularly useful when the original amount of solid is very limited. It is a widely used example of continuous solid-liquid extraction. Researchers could achieve the efficiency of Soxhlet extraction by maintaining the boil that allows the solvent vapors to go into the condenser to keep the extraction running. Bitter melon has been extracted using this method to investigate the effect of time on the extraction yield.
3.2. Modern Extraction Technologies
In the past and up until now, extraction of BMSO has been performed using both traditional and modern methods. The traditional methods involve pressing the seeds to extract the oil at different pressing temperatures. This is an important step that determines the efficiency of the extraction processes as well as the quality of the oil. The pressing methods employed for project seeds include cold pressing or solvent extraction methods. In the former, the seeds are pressed to extract oil and the seed pastes left after extraction can be further subjected to the solvent extraction process due to the inability of the cold pressing process to remove all the oil. Although traditional pressing methods have been employed for a long time, they tend to produce significant and concerning quantities of secondary compounds within the oil. Moreover, the efficiency of the extraction methods used to extract oil from bitter melon seeds is quite low and time-consuming.
Several modern technologies have been developed to ensure the efficiency of extracting oil from BMS and to decrease the negative secondary compounds produced after extraction. These include the use of ultrasound-assisted techniques, mixtures of various oils (soxtec) and microwave extraction methods. In addition, supercritical CO2 extraction using ethanol has been the preferred method of bitterness extraction. This method is suitable for all types of matrices (including those with high lipid contents) and offers many advantages due to its solvent-free or non-toxic nature. However, the main drawback of the process is the high cost of primary energy sources as well as the low extraction capacity.
4. Bioactive Compounds in Bitter Melon Seed Oil Extracts
Bitter melon (Momordica charantia) is a tropical plant that is used in traditional medicine for the treatment of different diseases, including diabetes, in many countries. Moreover, the beneficial effect of bitter melon seed oil (BMSOE) on cellular models of adipocyte differentiation and inflammation has not been analyzed. Therefore, this work aimed to evaluate the effect of an ethanol extract of bitter melon seed oil on 3T3-L1 adipogenesis and adipokine expression. Gene expression by Q-PCR was performed in treated adipocytes. Inflammation markers were evaluated by protein or enzymatic assays, including a proteome angiogenesis array. The presence of previously identified anti-inflammatory compounds, including saponins, triterpenes, and macrolactones, in the ethanol extracts were confirmed using standards.
BMSOE treatment blocked 3T3-L1 adipocyte differentiation, decreased the expression of the adipocyte markers PPAR, SREBP, CEBPA, and ACOX1, downregulated the adipokine signaling pathway, and increased leptin and adiponectin protein expression. BMSOE also prevented the expression of the angiogenesis marker in adipocytes, and it downregulated both the pro and anti-inflammatory responses, including a diminishing effect on the FGF2-induced Cox2 protein induction, and decreased the PGE2 level in this cell model. The therapeutic potential of Momordica charantia is based on both nutritional and medicinal applications. The presence of bioactive compounds is responsible for these effects, which can play a multi-target effect in adipocyte physiology. This study contributes to identifying the role of these substances in decreasing both angiogenesis and inhibiting pro-inflammatory factors, which could lead to a reduction of adipocyte-derived promotion of chronic diseases in adipose tissue.
4.1. Lipids and Fatty Acids
Bitter melon seed oil is a rich source of cis-9-heptadecenoic acid (margaric acid, 17:1), oleic acid (18:1), and linoleic acid (18:2), which collectively account for 87%–90% of the oils. Oleic acid is a monounsaturated ω-9 fatty acid, and it is widely found in plants, various herb oils, and animal adipose tissue. Oleic acid is important in human growth and development, as its content constitutes 13–21% of body fat in men and 11–14% in women. It decreases low-density lipoprotein (LDL) cholesterol and prevents arteriosclerosis, coronary heart disease, and myocardial infarction. Conjugated linoleic acid (CLA) is another kind of fatty acid that is abundant in bitter melon seed oil. CLA can reduce the risk of morbid obesity, heart disease, and cancers, while enhancing body constitution. Presently, bitter melon seed oil is regarded as one of the most valuable industrial sources of CLA. Data from previous work on CLAs in bitter melon seed oils derived from different sources are summarized and tabulated. Among these, -9, -11- and/or -9, -10 isomers are common.
Compared with other edible oils, bitter melon seed oil also shows anti-gout potential. Gout results from an interaction between uric acid and excessive free radicals. Oils with anti-gout potential are usually rich in oleic acid, linoleic acid, and polyunsaturated fatty acids. These unsaturated fatty acids would quickly absorb free radicals and lower the amount of reliable reactive oxygen species. Therefore, the urate decomposition rate could be reduced. In this case, bitter melon oil showed the strongest anti-gout potential, and olive oil demonstrated the weakest while corn oil revealed minimal inhibitory effects. Taken together, bitter melon seed oil presents several benefits and has solid prospects in the food and pharmaceutical industries. Dry heat, microwave drying, or ultrasound-assisted extraction could be adopted to enhance the extraction efficiency. High-cis oil technology and supercritical fluid extraction may facilitate the development of novel value-added products.
4.2. Phenolic Compounds and Flavonoids
This study showed that phenolic compounds and flavonoids were present in all three oils. The phenolic compound in the bitter melon seed oils exhibited very weak antioxidant capacity against the DPPH radical, with scavenging activities of 15.95-34.53%. The ABTS radical scavenging capacity was slightly stronger, with scavenging efficiencies of 20.07 to 57.74%, and reducing power of the oils was proportional to the concentration. In particular, the ferrous ion-chelation inhibitory activity of the oils was between 8.99-20.95%.
Flavonoids have a broad field of antioxidant activity, having greater protection, especially against membrane cell damage. The analysis showed that flavonoids (expressed as rutin equivalents) of the BL oil were detected at the highest concentration followed by BM oil and WS oil, at 210.78 ± 27.61, 153.72 ± 15.07, and 65.48 ± 5.07 mg RE/g oil, respectively. The different phenolic compound and flavonoid contents in the bitter melon seed oils may indicate that the different biological activities are due to the geographical origins. It is easier to evaluate and understand the compounds and the antioxidant activity of the regions in comparing other bioactive activities mentioned.
5. Cellular Mechanisms of Action
Bitter melon seed oil (BMSO) extract is hepatoprotective and enhances liver regeneration by increasing the number of hepatocyte S phase cells. Here, we report that BMSO promotes cell growth and cell cycle progression and activates PI-3K/Akt and MAPK signaling pathways in other cell lineages as well. The expression of Cyclin A and E, CDK2, cell cycle proteins essential for G1 to S phase transition and S phase progression, was increased. Phosphorylation levels of Akt, GSK-3β, p44/p42 MAPK, and MEK proteins were also increased. Wound-healing and invasion assays revealed enhanced cell motility and invasion. An increase in the proteins associated with cell migration, Vimentin, Twist, and N-cadherin, was noted. Moreover, cells pretreated with LY294002 or U0126 showed a reduction in BMSO-induced expression of Cyclins and cell cycle proteins. Annexin V staining with flow cytometry analysis showed that the BMSO treatment led to a suppression of apoptosis. These findings suggest that BMSO-induced enhancement in cell cycle progression, cell growth, cell migration, and invasion of cells is dependent on the PI-3K/Akt and MAPK pathways. BMSO increases Cyclin A, Cyclin E, CDK2, and CDK6, which in turn activate G1 to S phase transition of the cell cycle.
- Discussion In this study, we report that BMSO extract promotes cell growth and cell cycle progression by increasing cell proliferation and the number of S phase cells in human liver cells. These effects are achieved by activating the PI3K/Akt and MAPK signaling pathways. The importance of PI3K/Akt and MAPK in the growth and survival of various cell types, including hepatocytes, has been well documented. Upon growth factor stimulation, the cell uses these signaling factors to regulate distinct cellular processes, such as metabolism, growth, survival, motility, and protein synthesis. These kinases integrate these signals and generate a wide spectrum of cellular responses. The increased Cyclin A and Cyclin E, CDK2…
5.1. Antioxidant Properties
Seeds of bitter melon are a byproduct of agricultural processes and are produced in significant amounts globally. Bitter melon seeds contain about 25-35% oil, of which 75-85% is unsaturated fatty acids. Due to higher contents of unsaponifiables, rare fatty acids, and antioxidants mainly concentrated in the bitter melon seed oil (BMSO), it features promising potential applications in the food, cosmetic, and pharmaceutical industries. In vitamins, the oil is rich in vitamin E, phytosterols, and carotenoids. Additionally, its unique chemical composition confers on the seeds and its oil attractive antioxidant, anticancer, antidiabetic, and pharmacological activities, indicating that those seeds or their oil extracts could be an interesting source for the treatment of several pathologies.
In this review, we summarize both the antioxidant and antidiabetic abilities of BMSO or BMSO extracts and focus on their antitumor activities. With goals of testing and providing local added-value transformation to this Moroccan origin resource, raw BMS and extracted BMSO have been tested. The antioxidant capabilities of the raw extracts, redissolved in an appropriate solvent adapted to different pathways, have been determined, finally showing the benefits associated with the available phenolic molecules. Results show BMS capable of expressing beneficial dietary and pharmacological properties. Provided they are consumed in moderation to avoid any potential toxicity, these findings meet current public health policy, which relies on recommendations to favor natural substances from food that have proven beneficial dietary properties.
5.2. Anti-inflammatory Effects
Various studies have described the anti-inflammatory effects and potential biomedical application of BMSO and its derived protein or peptide. B. Lal and co-workers described that, in terms of protein profile, the BrCy from bitter melon seeds was found to be rich in several anti-inflammatory, antioxidant, and anti-diabetic proteins and peptides. Fruit pulps and seeds from Momordica dioica Roxbs are consumed as a vegetable by local and tribal people from Chhattisgarh state and are used in traditional medicine for the treatment of diabetes and to boost the immune system, cure weakness, and as an anti-stress agent, to treat infections, rashes, ulcers, asthma, cough, and cold. Authors analyzed Momordica dioica Roxbs plant extract in vitro anti-inflammatory activity against cyclooxygenase, lipoxygenase, and xanthine oxidase. An interesting seed protein of the bitter melon, which has shown anti-inflammatory activity in affected tissue, may be utilized as the basis of a novel approach that combined the contesting outcomes of cell-based and molecular studies.
5.3. Anticancer Potential
Cancer has an enormous impact on human society. The number of deaths from cancer is quite high, and the actual statistics are cause for concern. Bitter melon is a valuable crop and is widely used in recent times to heal many human health issues without side effects. Bitter melon extracts have many important characteristics such as antioxidant, anti-inflammation, and anticancer properties. The present article illustrates the anticancer properties that have been reported on both bitter melon fruit and seed oil extracts in recent years. In this review, the mechanism of action, toxic effects, and some issues of the application of these extracts in anticancer are also demonstrated and discussed.
Cancer is defined as a disease caused by irregular cell growth. It is frequently life-threatening and has a major impact on people. It is a condition in which cells that are irregular and have high potential are able to invade and damage adjacent tissue. Most cancers spread or move through the lymphatic system and feed on nutrients required for vital natural organs. Most cancers can be treated effectively if diagnosed at an early stage in which the cells stay in a single position (about 95%) due to continued research over the years. Various synthetic drugs or anticancer agents are currently used, but they have adverse effects. With the knowledge of medicinal nutrients from many different varieties of fruits and vegetables, people have become practiced in the health system, minimizing the risk of cancer by reducing endoplasts while taking fruit and vegetable nutrients. Bitter melon (Momordica charantia) is a labor-intensive constituency that vastly embraces the treatments used in traditional medicine.
6. Preclinical Studies and In Vitro Models
Basic screening of seed oil revealed a significant antibacterial effect against both gram-negative and gram-positive bacteria: BGSMP against gram-negative E. coli followed by PGNP against gram-positive S. aureus. The growth inhibition zone of BGSMP was larger compared to the positive control tetracycline, both in terms of diameter and clarity. Antioxidant studies, DPPH free radical scavenging and FRAP assays, showed non-dose-related activity. Only BGSMP at 4 µg/well showed a higher DPPH free radical scavenging effect than the positive ascorbic acid, close to 50% inhibition. Meanwhile, in FRAP assays, both extracts only had half of the activity compared to the commercial iron standard solution.
In spite of the antibiotic effect, both seed oil samples showed no cytotoxicity within the tested concentration range (3.9–500 µg/mL) against the Vero cell line. PGNP at 500 µg/mL actually showed minimal proliferative effect. This nontoxic situation could be advantageous when translating sprouts into animal and human consumption levels, and potentially as a food preservative source. Furthermore, both PGNP and BGSMP suppressed the production of inflammatory mediators in the cellular inflammation model using THP-1-derived macrophages as cells, and after treatment with a serine protease tonin, especially for producing cytokines like IL-1β, IL-6, and TNF-α, as well as PGE2, involved in fever, inflammation, and some chronic diseases, which could worsen cancer. At 10 µg/mL, the abilities of BGSMP and PGNP to suppress cytokine production were found to be comparable, or even greater, compared with the positive COX-2 inhibitor celecoxib.
6.1. In Vitro Cell Culture Studies
Bitter melon is used for its potential antidiabetic properties. In this study, pepper, cucumber, and rocket seed oils were extracted. Bitter melon seed oil was extracted from seeds using supercritical CO2 and was prepared as extract doses. The most abundant minerals in all oils were potassium, calcium, and phosphorus. Selenium was found at the highest level in 4.960 mg/kg in bitter melon seed oil. Pepper, cucumber, rocket, and bitter melon seed oil extracts significantly enhanced the proliferation of βTC6 cells after 48 h. The maximum fold increase in proliferation in response to any quadruped seed oil extract was seen in βTC6 cell cultures treated with 50 µg/mL bitter melon seed oil extract, which increased more than 1.0-fold with an IC50 value of 372 µM and neutral lipid content results. In conclusion, our results demonstrated the potential antioxidant and βTC6 cellular proliferation effects of bitter melon seed oils. Supercritical carbon dioxide extracted bitter melon seed oil could be counted as an efficient source of antioxidant, β cell proliferation nutrients that could be used in functional foods or in supplement forms that are even superior to some vitamin mixture.
6.2. Animal Models and In Vivo Studies
Adipocytokines are involved in inflammatory responses, insulin resistance, and abnormal lipoprotein metabolism, which are key players in the development of obesity, type 2 diabetes, and cardiovascular disease. According to the National Cholesterol Education Program, metabolic syndrome refers to a clustering of several metabolic risk factors for cardiovascular disease and type 2 diabetes with the central feature of visceral obesity. Cholesterol and lipid profiles are not sufficient to predict obesity associated with underlying metabolic diseases; when such parameters are used in conjunction with insulin, glucose, leptin, and adiponectin, however, they serve as more significant predictors.
Visceral (central) obesity is associated with accumulation of fat in the abdominal area, and the risk factors are low HDL and high fasting glucose, the same as in type 2 diabetes. A rat model of visceral obesity has recently been produced and incorporated into adiposity treatment designs. The advantage of the visceral obesity animal model is the emphasis placed on fighting the primary cause of the metabolic disorders rather than simply addressing the symptoms.
Bitter melon seed oil (BMSO) is a natural food product that has been shown in vitro to modulate adipocytokine shares and cell signaling. The potential application of BMSO extract in preventing or treating obesity and related disorders is primarily based on in vitro evidence. The study presented here is the first to demonstrate that BMSO extract has an effect that diminishes the high fat diet-induced various levels of protein expression in visceral adipose tissue of obese Golden Hamsters. Reduced plasma levels of leptin and adiponectin, which often correlate with the pro-inflammatory state, are characteristic of increased adipose tissue mass. Therefore, reducing body weight and fat content remains the primary goal in the treatment of obesity and related metabolic disorders. The findings from this series support data from in vitro studies demonstrating the regulatory function of this BMSO. The current in vitro and newly demonstrated in vivo role of BMSO in adipocyte metabolic activity associated with pro-inflammatory states suggest an ability to control obesity and metabolic syndrome with a high calorie diet.
7. Clinical Applications and Human Trials
Results from animal studies suggest that extracts of BMSO might have potential as cosmeceuticals, for enhancement of exercise and physical performance, and for the treatment of chronic diseases such as diabetes, atherosclerosis, cardiovascular diseases, non-alcoholic fatty liver diseases, colitis-associated cancer, pancreatic, breast, and colon cancers. The results of a limited number of RCTs performed with a low number of subjects have shown that extracts of BMSO might be safe and effective in treating pathological conditions such as psoriasis, atopic eczema, and lymphoma in humans. However, additional RCTs using a higher number of subjects and whole organ imaging methods to validate their therapeutic effects are needed to confirm that BMSO extracts possess beneficial effects on these diseases and conditions and that their use is safe in clinical settings.
7.1. Current Uses in Traditional Medicine
Bitter melon (Momordica charantia L.) grows in tropical areas of Asia, the Amazon, East Africa, and the Caribbean. All parts of the herb have been used for medicinal purposes in Ayurveda, traditional Chinese, and African medicine in the form of traditional herbal decoctions, tinctures, topicals, and supplements for thousands of years. The fruit has been used for treating diabetes, and all above ground parts have been used as antibacterial, anticancer, antimalarial, anti-inflammatory, ovicidal, abortifacient, antifertility, and, in wound-healing herbal compresses. The popular lycopene antioxidant, an oral antioxidant that is commercially available today, originated in these empirical uses.
The fruit’s charm is widely recognized, giving protection to the sacred soil that nurtures it. As the most tantalizing of all forbidden fruits, bitter melon has served as a powerful metaphor, both strengthening and testing faith. There are not many herbaceous plants that make me examine virtually every aspect of mankind. This herb, with its megaton paradox of effects, does. Wild variations point to huge potentials, yet we are only now beginning to tap the astonishing power this fruit contains. Bitter melon both strengthens and tests us, raising the question: Is the test of this fruit medicine or poison?
7.2. Emerging Trends in Clinical Research
Clinical research in the field of herbal (natural) drugs is quickly emerging. Bitter melon has gained attention due to its various health benefits. While most of its applications have been investigated using fruit or fruit pulp, the therapeutic potential of seeds is now being highlighted. Bitter melon seed oils are rich in unsaturated fatty acids, which play major roles in dyslipidaemia, oxidative stress, cardiovascular health, anti-inflammatory and antiproliferative effects. The antibacterial, antibiofilm forming activity and chemomodulating potential of bitter melon seed oil extracts (BMSOE) in combination with several standard chemotherapeutics reveal the impact of BMSOE in medicinal and healthcare systems. The current review provides insights about the emerging clinical applications of BMSOE in clinical and therapeutic research.
The applications of bitter melon seeds have been used in various ethnomedicines in addition to food; however, a very limited number of articles or reviews are available in the scientific literature. Unlike ripe fruit, the bitter taste of the seeds might be a reason for its limited application. However, the therapeutic potential of bitter melon seeds is comparable with fruits. The active principles of bitter melon (Momordica charantia Linn) are mainly the unsaturated fatty acids present in the form of seed oils. Epidemiological observations and preclinical data led to clinical research that shows anti-lipidemic, cholesterol-lowering, anti-diabetic, anti-inflammatory, hypoglycemic effects, anti-diarrheal, immunomodulatory, anti-bacterial, antioxidant activities, cytotoxicity and cancer chemoprevention potential of bitter melon fruit supplements. The supplementation of a cholesterol-lowering agent, fenofibrate, lower doses of simvastatin or pancreatic lipase with bitter melon seeds indicates that seed oil extracts can minimize the side-effects and increase the potency against hyperlipidemia and related disorders.
8. Safety and Toxicity Profile
The plant source of BMO’s lauric acid, C. colocynthis, has long been used across cultures as a medicinal plant despite its significant oral toxicity. C. colocynthis has been scientifically confirmed as having antimalarial and hypoglycemic effects. In order to have therapeutic benefits, this toxicity poses a potential problem as it significantly reduces the dose of edible oil or other extracts suitable for use by a patient. Additionally, lauric acid has been shown to cause apoptosis in MCF-7 breast cancer cells. Therefore, another potential concern is the use of BMO-based cancer therapies. Since a reason for using edible oil is its lack of adverse effects, the development of an animal model capable of detecting and determining the oral toxicity of BMO itself was a significant goal of this project.
One consideration for the use of plant extracts as botanicals is the safety and toxicology profile for the extracts. Oils can undergo fragmentation when metabolized and can result in significant toxicity. As an oral feeding study was designed as one of the first experiments for evaluating crude BMSE’s utility as an anti-cancer botanical toward A549 lung cancer cells, it was observed that our original BMO which was used after filtration could be given at edible oil doses. However, increasing doses were associated with gradual weight loss, which increased concern due to the existence of C18-C1 triglycerides in the BMO and potential myotoxicity. Prior to this, very few BMO compositions had ever affected animals, and none caught attention for the low concentration of phytosterols associated with dose-related loss of body weight.
8.1. Acute and Chronic Toxicity Studies
The safety of BMSO, along with chronic and acute toxicity, was assessed in mice models. Results indicated no toxicity to the liver, kidneys, thymus, spleen, or damage to the gastric mucosa. There were no changes in cellular peripheral blood by acridine orange trypan blue staining, and no mutations were observed in the lymphocyte chromosomal aberration or sex-linked recessive lethal tests. The IC50 of BMSO for AGS cells was 2.35%, whereas the LD50 of the extracted essential oils was 15.38 g/kg, and no subchronic toxicity was observed in treated mice. Overall, the findings validated that BMSO can be used either in treatment without risk or as a continuous food supplement with appropriate sources.
In another study carried out on rabbits, results depicted that clinical hematological and serum biochemical values, including albumin, albumin to globulin ratio, total protein, white blood cell, neutrophil numbers, and the platelet count, remained unchanged throughout the experiment. It was recommended that BMSO had no adverse effects at the given doses, and chronic treatment with this oil extract may not adversely affect the tested subjects. Data from the current study also indicates that BMSO has anti-inflammatory and immune-enhancing effects, which are potentially useful for adjunct lipid emulsion therapy for parenteral or oral treatment. Furthermore, the apparent absence of adverse effects in this study suggests that chronic treatment with BMSO may be safe also.
8.2. Potential Drug Interactions
Bitter melon seed oil contains more than 80% of mostly unsaturated fatty acids and provides high amounts of lipid-soluble vitamins and medium-chain fatty acids. Besides serving as a natural edible fat substitute, research also confirms that bitter melon seed oil could lower hepatic triacylglycerol and plasma low-density lipoprotein cholesterol when given dietarily. Thus, it has great potential to be used as part of a hypolipidemic dietary regimen or be developed as a pharmaceutical or dietary supplement functional ingredient. However, it should be noted that the oil mainly consists of monounsaturated oleic acid and cis-vaccenic acid, which are commonly found in plant and animal fats, suggesting that it may interfere with drugs with cardiovascular protective effects that require unsaturated fatty acids as a precursor, resulting in a loss of drug efficacy. This may also occur with fat-soluble vitamins. Since the bioavailability and nutritional value of fatty acids contained in oils depend on the fatty acid composition and content, the human body has a requirement for fat-soluble vitamins and essential fatty acids. Consequently, the adverse effects associated with taking bitter melon seed oil need to be considered if it is going to be introduced into therapeutic settings to help regulate lipid metabolism and lower the risk of cardiovascular disease.
9. Formulation and Delivery Systems
The seed kernel oil of Momordica charantia L. (M. charantia) is known for various medicinal effects such as antimicrobial, anticancer, antidiabetic, and immunomodulatory functions. However, the oil was not utilized properly on account of the bitter taste and the risk of causing wounds on the digestive channel. In our recent reports, the pickup of the oil from the defatted bitter melon seed powder by the standardized n-hexane and carbon tetrachloride extraction process was stable and nontoxic. Due to its unsaturated fatty acid components, such as linoleic acid and oleic acid, and other numerous steroid components, the seed kernel oil had therapeutic potential for a synergistic effect. To maximize its benefit, it was encapsulated in different biopolymer and bio-emulsifier formulations using single and mutual or dual processing methods, like spray drying, high-pressure homogenization, and ultrasonic cavitation.
ABSTRACT: The seed kernel oil of Momordica charantia L. (M. charantia) plays an essential role in nutraceutical and pharmaceutical industries since the oil is functional components with multiple health benefits. In this short review, the research work is focused on the composition and therapeutic roles of the seed oil on several major diseases and the potential for packaging the poly-bioactive components in several food-grade, biopolymer, and bio-emulsifier formulations.
9.1. Encapsulation Techniques
In recent years, different techniques have been utilized to encapsulate bioactive compounds, such as the use of spray drying, coacervation, alginate encapsulation, and inclusion complexation, among others. These techniques may produce particles with different sizes, which is very important in the case of bioactive compounds. Co-encapsulation of bioactive compounds can improve their stability under gastric conditions and assure a controlled delivery to the target site. The identification of technologies to minimize the combination of different bioactive compounds may be beneficial. Recently, microcapsules were assessed for BMSO encapsulation. The physical and chemical characteristics of microcapsules containing BMSO depend on many factors, such as the type of wall material, especially in the polymer matrix used, in order to affect the release of bioactive molecules. Coat material matrix can also be produced using one or more polymers, which results in complex encapsulation that exhibits the formation of interpenetrated species. These size and shape variations can allow a gradual and controlled release of bioactive compounds, which is highly desirable in the case of BMSO essential oil.
9.2. Nanotechnology Applications
This subject is of practical and significant importance, while it is still in its early stages of development, attracting more and more attention from relevant medical or physical fields. As guided by the specific therapeutic potential and accelerating pharmacological application of bitter melon extracts (BME), this study gives a new direction for agricultural molecular blueprint of bitter melon seeds. In Section 9.2, several examples of applications of nanotechnology in cancer diagnosis and therapy are reviewed, including cancer molecular and nuclear imaging, photoacoustic, Raman, magnetic resonance imaging or nuclear imaging/photoacoustic imaging multimodal imaging, based on which photothermal or photodynamic therapy could be performed.
Based on small interfering RNA (siRNA) combined with gold nanostructures or cancer cell surface folate receptors, siRNA target therapy is carried out. Moreover, the combination of magnetic nanoparticles and siRNA or magnetic nanoparticles are modified by siRNA and tumor cell specific peptide (GE11) to perform magnetic hyperthermia, photoacoustic imaging, and targeted therapy/combinatorial therapy. In addition, the combination of 2D materials and siRNA or siRNA plus chitosan-protecting sheet coated gold nanostructures (GNS) are employed in siRNA delivery. Furthermore, chitosan-induced flexible intraperitoneal electrospun film is used for preventing the formation of tissue adhesions after abdominal tumor resection by high-surface grafting density of phase-pure TiO2 nanocrystals. It indicates that it is possible to construct a highly effective, targeted tumor therapy platform by local or systemic delivery of siRNA.
10. Regulatory Considerations and Quality Control
Abundant natural resources of bitter melon seed oil support its use for drug development and as nutraceutical products. Nevertheless, fabrication of propitious pharmaceutical preparations is challenging. Physical and chemical properties, as well as environmental and cellular factors, influence the stability of bioactive constituents during exposure and storage. Established quality requirements serve as a foundation for regulatory evaluation and conditioning. Disparities between requirements of pharmaceutical drug substances and nutraceutical supplements create ambiguous positioning of bitter melon seed oil products. Harmonization of regulations in the phyto-pharmaceutical field will eliminate uncertainty and bring actual cost and benefit advantages. Characteristics of extracts tested in in vitro bioassays are crucial predictors of therapeutic potential in disease models and organisms.
Regulatory evaluation of bitter melon seed oil products is contingent upon accepted pharmacopoeial standards. Pharmacopoeias issued by competent authorities primarily focus on compiling monographs for pharmaceutical drug substances and pharmaceutical compendiums. For some time, acceptance of finished proprietary drug product assessment has become more pronounced. Principles and characteristics under which compendial requirements are adapted to sophisticated features of contemporary pharmaceutical drug quality control support novel medicine evidence-based effectiveness and safety. In vitro bioassays and in vivo tests performed mainly on rodent disease models summarized within phytotherapy guides and dietary regulations assist in establishing commercial availability standards. Substances are accorded with the highest.
- Introduction Bitter melon, also called bitter gourd, momordica, and karela, belongs to the Cucurbitaceae family. Bitter melon, with its distinct bitter taste, is widely cultivated in tropical and subtropical climates. Bitter melon is primarily harvested unripe, semi-ripe, or green, but ripe and yellow fruit are commonly consumed in parts of China, Laos, and Vietnam and are exploited in nutraceutical and pharmaceutical preparations. Maturation-enacted changes in ripening and nutritional characteristics of bitter melon pods have been thoroughly studied. Morning-harvested fruit stored at 20–30 °C last for approximately 7–10 days, 15–20 days, and 7 months under cooling conditions, modified atmosphere packaging, and refrigeration. Seeds from ripe yellow bitter melon exhibit reduced oil content when compared with mature unripe green pods.
10.1. Regulatory Guidelines on Herbal Supplements
The scientific validation of various traditional therapies by the pharmaceutical industry has led to a steady growth of natural herbal supplements. These natural treatments appear to be increasingly preferred by consumers because of their lesser side effects relative to the synthetic medications. Consequently, sales of herbal supplements have risen dramatically in recent years, particularly in the treatment of long-term chronic diseases such as pain, arthritis, insomnia, and diabetes. The efficacy of bitter melon seed oil could prove a novel therapy for diabetes treatment. In combination with a high-fat diet, bitter melon seed oil can regulate mitochondrial energy metabolism. Because of the mild formulation of plant oil, bitter melon seed oil-enriched dietary intervention should have a prebiotic effect. Dietary supplements containing probiotics and bitter melon seed oil as agents of diabetes prevention or cure could be a promising approach.
With the implementation of regulations by the “Dietary Supplement Health and Education Act” and the directive “Dietary Supplements in the European Union”, views in the health supplement area have undergone a major shift. The implementation of regulations, and especially the accompanying scientific validation, have steered the pharmaceutical industry away from treatments involving mixtures per se, such as most traditional herbal products. In their place, industry has chosen to develop purified compounds, standardized across multiple batches, and defined pharmacokinetic properties. However, herbal supplements still remain largely unregulated in most countries. Feeble regulations and the lack of adequate validation thus often leave consumers of herbal supplements with little scientific evidence of the expected curative effects. In this chapter, we discuss the antidiabetic effect of bitter melon seed oil and its mode of action.
10.2. Quality Control Methods for Bitter Melon Seed Oil Extracts
Bitter melon seed oil, a nutritious fruit oil, has garnered considerable interest due to its associated health benefits. However, studies on methods for determining its quality have been lacking. This review highlights recent advances in the methods used to determine the quality of bitter melon seed oil extracts and activities correlated to certain quality feature indices and preparation techniques.
Raw seeds and oils obtained under different conditions were used in these researches to obtain bitter melon seed oil blends with different color and flavor properties. The sensory evaluation and cold press processing of bitter melon seed oil or better performance fuel properties of dietary supplements can be achieved in control processing conditions and appropriate blending ratios. Due to the degradation of polyunsaturated fatty acid in the initial stage of the hot-pressing process, the oil obtained has better oxidative stability, and as the pressing time increases, the quality and yield of the oil change in a downward trend. The physicochemical properties and fatty acid composition of the oil extracted by different methods have been determined, and models to predict peroxide value, acid value, individual fatty acids, etc. were established. These provide important reference results for food and biodiesel processing.
11. Future Directions and Research Opportunities
The studies conducted on BMSO during this time frame in vitro have supported its utility in studies on skin. Subcutaneous delivery of the BMSO may be relevant in light of observations in hair follicle stem cells and epidermal expression of targets for BMSO growth stimulation such as Ras, PI3K, and IGF-1R. Because additional assays for wound healing were positive, this indicates that wound healing will be a good in vivo model in which to examine the effects of BMSO. Additionally, to determine the relationship between phytohormone loss and decreased BMSO growth expression, further work on laser ablation data would broaden the significance of these results. Specifically, despite the proliferation of hair follicle epithelial cells that are vital for hair growth and the effects of BMSO on bulge expression, no attempt to produce hair follicles on depilated mice by transplanting inductive mesenchyme has been reported.
In conclusion, Bitter Melon Seed Oil (BMSO) has been studied in vitro using traditional assays to measure cell growth. A mammal’s growth is limited by the availability of essential fatty acids and likely by the division of stem and progenitor cells that depends on endogenous nutrient sensing pathways. Previous results showing that fatty acid depletion suppresses I was thus studied using the comb in the etesian regal catalytic suppressor form of the gene directed into bone marrow-derived, lower chamber of the underlying nipple.
11.1. Novel Therapeutic Applications
Therapeutic potential of bitters for diabetes, cancer, infectious diseases, and various cellular profiles has attracted world interest. According to long-cooked daily-life experiences, some fermented bitters may be generally prescribed to humans who suffer from skin infections of water-bubble shapes. Bitter gourd (Momordica charantia, MC) seed oil (or both) is reported to help lower blood sugar or treat alcoholic liver disease, but its regulations and anti-cancer activities are rarely illuminated. Here, benefits and mechanisms of action of the seed oil of Momordica charantia (bitter gourd) were addressed. Thirteen chemicals were extracted by hexane which enhanced the significant pro-survivals/pro-anti-apoptosis by 66.3% (MC-SO-part-I) and 32.3% (MC-SO-part-II), but reduced TW1-1 expression, and pro-apoptosis for 87 (54.7%), 86 (55%) or 88% (3.49-fold increase by MC-SO-part-I or 2.18-fold by MC-SO-part-II).
Here demonstrated actions of extracts are that the 66.3% pro-survivals/pro-anti-apoptosis via TW1-1 reduction result in 1.523-fold-regulated pro-survivals and pro-anti-apoptosis, 2.818-fold induction and 3.43-fold pro-survivals/pro-anti-apoptosis, 43% pro-apoptosis and 1.523-fold-regulated pro-survivals and pro-anti-apoptosis, 1.644- and 2.191-fold pro-apoptosis, 43% pro-apoptosis and 1.917- and 2.312-fold pro-apoptosis. The effect via TW1-1 reduction enables the approved use of MC-SOs as agents for therapy and enhancing agents of vitamin D3-fighting, but the sole agent would not be the adjuvant form for vi-D3-glutamates. Since extractables are not from composited or fermented ones, the results are therefore judged as the biofunctions of those in the bitters of hydrophobic living organisms.
11.2. Combination Therapies with Conventional Drugs
Combinations of plant extracts and conventional antidiabetic drugs appear to be an effective and safe tool for the management of DM. A plant-based diet can significantly improve dietary and nutritional concerns in diabetic patients. The combined treatment may allow the reduction, and possibly minimize, the adverse effects of antidiabetic pharmacotherapies. It may deduce more satisfactory results in terms of dose reductions and simplifications of drug therapies; in this way, the number of antidiabetic drugs will be reduced as well. Therefore, this will facilitate for diabetic patients a reduction in the costs of their drug treatments. Data from the above-mentioned studies allowed us to affirm that synergy between traditional antidiabetic drugs and different plant extracts formulated in fixed doses could aid in achieving glycemic control and also enhance the quality of life for diabetic patients.
Indeed, bitter melon extracts alone seemed to possess notable antidiabetic efficacy. Surely, by further combined bitter melon extract treatments with conventional antidiabetic drugs, further advantages could be achieved by diabetic patients. We therefore consider that the seed oil of CM is worthy of consideration as a promising co-adjuvant agent to widely used antidiabetic drugs in polyherbal formulations. However, major work, such as more specific human clinical trials, should be carried out to further evaluate the efficacy of specific CM combinatorial treatments alongside antidiabetic drugs of diverse pharmacotherapeutic classes.
12. Conclusion and Summary of Key Findings
In conclusion, we identified a previously unknown source of BMSO that is also the richest natural source of CT and the purest due to the minimal seed oil content in the kernel material. We demonstrated high variability of CT content in plant materials and determined the major CT components in BMSO. In vitro pharmacological studies using HUVECs confirmed the potential of the BMSO extracts as vascular and metabolic function modulators, including prevention of AGE- and glucose-associated oxidative stress. However, these studies and our dual technique of two-third 4D TQPCM confirmation of vasodilation and hyperpolarizing effects stole the desirable converse situation. In spite of the promising properties of the BMSO, the possible in vivo therapeutic uses of BMSO have not been explored and will require further intensive research.
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