Nutraceutical, functional, and therapeutic properties of Garcinia cambogia: a review

ABSTRACT

Garcinia gummigutta, also known as Garcinia cambogia, has been shown to have excellent properties beneficial against many health conditions. The use of Garcinia cambogia in traditional medicine has involved treating gastrointestinal ailments, intestinal parasites, rheumatism, digestive disturbances, among other ethnobotanical applications. The fruit, which resembles a pumpkin in appearance, is presently most often used and heavily promoted as a supplement for weight loss. According to studies, hydroxycitric acid (HCA), the main organic acid present in the fruit rind, has antiobesity properties that include lowering appetite and reducing body fat gain by regulating serotonin levels linked to satiety, increasing fat oxidation, and reducing de novo lipogenesis. HCA is a strong inhibitor of the enzyme adenosine triphosphate citrate lyase, which converts citrate to acetyl-coenzyme A, a catalyst for the synthesis of fatty acids, cholesterol, and triglycerides. In in vitro and in vivo models, the plant’s crude extract or components also have hepatoprotective, anti-cholinesterase, anti-inflammatory, anticancer, and anti-inflammatory effects. Studies on the phytochemistry of several plant components found that organic acids and xanthones, such as carbogiol and benzophenones, were also present. There are already several G. cambogia/HCA dietary supplements available for weight loss, however there are some safety concerns about the potential toxicity of continuous usage of these supplements. The majority of complaints have been in connection with multi-component formulations. G. cambogia has not been positively identified as a possibly harmful aggressor. In this paper, the scientific properties of G. cambogia are discussed in relation to pertinent botanical features, ethnobotanical applications, phytochemistry, biological activity, and toxicity. The study could be very helpful in emphasizing the therapeutic properties and mechanism of this plant and its applications.

KEYWORDS:

• Garcinia cambogia
• hydroxycitric acid
• garcinol
• anti-cancer
• anti-obesity

Introduction

Garcinia cambogia is a native fruit of the South-East Asian region, with a diameter of approx. 1.5 inches and a green-to-yellow color change in the maturation process. However, the fruits are too acidic to eat. Different parts are used as food preservatives, spices, and bulking agents for foodstuffs. It is most often used for culinary purposes, especially for fish curries and ‘Asam laksa. The G. cambogia fruit extract for constipation, hemorrhoids, and intestinal parasites has been used. Edemas, rheumatism and irregular menstruation are other medicinal uses. Whilst many chemicals from cambogia have been isolated, hydroxycitric acid (HCA) is considered the weight-loss ingredient.^[1] Between 20 to 60% of hydroxycitric acid (HCA) is found in garcinia supplements, and many of these products contain many active components in addition to Garcinia cambogia. When evaluating the quality, effectiveness, and safety of these items, this should also be taken into account, as have been reported for other natural products in several studies.^[2,3] Additionally, it has been stated that the claimed concentration of HCA in many products is lower than the amount stated. Many clinical studies have been performed on the effectiveness of cambogia for obesity.^[4] Cambogia is planted and manufactured in mass quantities and is an important economic product in India, thanks to its outstanding therapeutic value. Figure 1 shows the image of Garcinia cambogia. This study concisely reviewed the health, medicinal, and therapeutic roles of Garcinia cambogia and its bioactive constituents.^[5 Citric acid can also be used as the starting point for the manufacture of hydroxycitric acid. Dehydration of the acid first forms aconitic acid, which then undergoes oxidation to create hydroxycitric acid. According to research, HCA inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which catalyses the additional mitochondrial breakdown of citrate into oxaloacetate and acetyl-coenzyme A (acetyl-CoA), a precursor to the production of fatty acids. According to several research, HCA helps people lose weight without activating their central nervous system. It is obvious that there are numerous opposing opinions on the effectiveness and safety of G. cambogia. This study provides a concise summary of the scientific data on the biological activity and toxicity of Garcinia cambogia and HCA as well as phytochemical.^[6]

Figure 1. Garcinia cambogia.

Botanical description

In the Clusiaceae family Garcinia is the largest of 390 species. The plant is distributed primarily in tropical Asia. It has a circular crown and tilted branches up to 12 meters high and is small or medium sized. The young twigs are subtle, glabrous, reddish-brown and lenticellate. The hooks are dark-green and are brilliant on the face, with pétioles 5–16 centimeters long and 5–13 for linen 2–6 centimeters. The leaves are elliptic, oblanceolate, with the apex usually shaped acutely and rarely.^[7,8] The rose polygamous flora is axilla or terminal with a sepal and petal cream. Flowers occur in summer and fruiting occurs during rainy season (June-September). The eggs have a width of about 5 cm and diameters of 6 to 8 rags. When ripe, the fruit can be yellow, orange or red. It contains 6 to 8 succulent aril seeds. Tree growth is slow. In four healthy adult volunteers, the bioavailability of HCA-SX was evaluated. These authors administered HCA-SX 2 g under quick conditions and each 30 minutes they measured HCA-SX plasma concentrations for four hours in total. HCA-SX plasma levels after administration were 0.8 μg/mL 30 minutes and 8.4 μg/mL 2 hours after intake. The peak after administration was between 4.7 and 8.4 μg/mL. Although HCA-SX plasma levels started to decline after 2.5 hours, they remained much higher than pre-administration values. The study showed that the HCA-SX absorption intake is relatively rapid after acute consumption and that the product remains in plasma for several hours.^[6]

Proximate and phytochemical properties

The rind contains protein (1%), tannins (1.7%), total sugar (4.1%), pectins (0.9%) and fat (1.4%), moisture (80.0 g/100 g), all of which have been shown to have important therapeutic properties.^[9,10] It was reported that Garcinia leaves contained 75% moisture, 2.3% protein, 0.5% fat, 1.24% fire, 17.2% carbohydrate, 14% iron, 25% calcium and 10% ascorbic acid, and 10% oxalic acid. The seeds are very rich in triglycerides stearic, oleic and stearic. The plant also has lactone and citric hydroxycitric acid but in small amounts.^[11] The phytochemistry of Garcinia cambogia has not been well studied and published. Alkaloids, flavonoids, phenolic chemicals, saponins, tannins, polysaccharides, and proteins were discovered in preliminary phytochemical research. A few xanthones, benzophenones, organic acids, and amino acids have so far been isolated from diverse plant components.^[12,13] The presence of alkaloids, flavonoids, phenolic compounds, saponins, tannins, carbohydrates and protéins has been demonstrated by preliminary phytochemical studies. These phytochemicals exert several important functions, including antioxidant, antimicrobial, antidiabetic, immunomodulatory, and anti-inflammatory properties.^[14–16] To date, some xanthones, benzophenones, organic acids and amino acids have been found in different parts of the plant (Table 1), all of which also have important nutraceutical properties as shown in the table. However, emergent studies suggest that garcinol may be a useful anti-cancer agent and a pleiotropic agent that modulates key regulatory pathways for cell signals with garcinol pharmacological activities.^[22]

Table 1. Functional and nutraceutical properties of common phytochemicals in Cambogia.

Compound	Part of plant	Activity	References
Garbogiol	Roots	Inhibition of α-glucosid	Nguyen et al., 2019^[Citation17]
]Oxy-guttiferone i	Fruits	Hepatoprotective	Espirito et al., 2020^[Citation8]
Rheedia xanthone A	Peel	Anticancer activity	Kurniawan et al., 2021^[Citation23]
Oxy-guttiferone k2	Fruits	Antitumor activity	Wu et al., 2017^[Citation24]
Oxy-guttiferone k	Fruits	Anticancer and antitumor	Wu, M et al., 2015^[Citation25]
Oxy-guttiferone m	Fruits	Antiproliferative activity	Semwal et al., 2015^[Citation6]
garcinol	Peel	Anticancer, antiparasitic, Antiinflammatory, action on nervous system	Schobert et al., 2019^[Citation18]
Isogarcinol	Peel	Anticancer, action on nervous system, antiparasitic,	Schobert et al., 2019^[Citation18]
Guttiferone i	Fruits	Hepatoprotective	Jamila et al., 2017^[Citation19]
Guttiferone m	Fruits	Topoisomerase II inhibitor	Di micco et al., 2019^[Citation26]
Guttiferone k		Topoisomerase II inhibitor	Di micco et al., 2019^[Citation26]
Guttiferone j	Fruits	Semisynthesis and antimicrobial activity	Conceição et al., 2022^[Citation20]
Guttiferone n	Fruits	Antiplasmodial, antioxidant	Espirito et al., 2020^[Citation8]
Tartaric acid	Fruits	Antiemetic, expectorant	Sambavathas et al., 2022^[Citation21]
Heterocyclic amines	Fruits	Antiobesity	Murthy et al., 2019^[Citation27]
Citric acid	Fruits	Skin diseases, metabolic acidosis, renal infection	Nguyen et al., 2019^[Citation17]
Malic acid	Fruits	Antimicrobial	Abdallah et al., 2017^[Citation7]
Garcinialactone	Fruits	Nephroprotective, cardioprotective	Espirito Santo et al., 2020^[Citation8]
Amino acids	All parts	Amino acids are Arginine, asparagine, glutamine, threonin, glycine, proline, leucine, isoleucine, ornithine, and lysine. Amino acids are the most common amino acids	Espirito Santo et al., 2020^[Citation8]

Ethnobotanical uses of Garcinia cambogia

Garcinia cambogia is an expensive spice used for dried sun rind, in particular for fish curries, often used for flavors. For the treatment of fish with salt in India and Sri Lanka, a dried rind bacteriotic agent is used. It also substitutes for cocoa butter and is a common food additive for the treatment of rheumatism and darkness with a purging, hidragogue, anthelmintic and emethyl. Garcinia cambogiais a high-priced spice used for sun-dried smoked rind.^[28] According to ethnobotanical surveys, the plant is widely used by tribal people as a meal or dietary supplement, as well as in the treatment of different diseases such as stomach issues, skin diseases, and weight reduction treatments. The peel of the fruit contains high amounts of hydroxycitric acid (HCA), which is the active ingredient believed to be responsible for most of its weight loss benefits. The fruit is high in carbohydrate and starch, according to nutritional analysis. The fruits are high in nutraceutical bioactive components such as saponin, tannins, alkaloids, terpenoid, and phenolic compounds, according to a qualitative phytochemical study.^[22,29]

Biological activities of Garcinia cambogia

Organic activities in vivo as well as in vitro models were demonstrated to exist mainly from Garcinia cambogia fruits in different extracts and pure compounds. Clinical trials mainly report on anti-obesity activities in Cambodia/HCA supplements. Although the common use of weight loss supplements is cambogia and cambogia, many more studies have found positive antimicrobial, anti-ulcer and liver-protective effects.

Anti-obesity activity of hydroxycitric acid (HCA)

There is increasing demand for natural substances that will help fight obesity worldwide.^[30,31] The genus Clusiaceae Garcinia has a population of over 300 species from Asia and Africa including Garcinia cambogia, garcinia mangostana and garcinia atroviridis. The potential therapeutic effects of this genus include anti-obesity, anti-ulcerogenic, anti-oxidant, anti-diabetes, antifungal, anti-inflammatory, and anti-neoplastic. This has led to several investigations by pharmaceutical companies. Some of the bioactive compounds isolated from Garcinia include garcinol, isogarcin, (−) hydroxycitric (HCA), mangostin and xanthoquimol. Garcinia cambogia is the most commonly used supplement for weight loss or maintenance of the above-mentioned species. Anti-obesity characteristics were attributed to HCA, which is present in rind or fruit epicarps with 20–30% of dry weight. Many supplements containing HCA are currently available on the market to reduce weight.^[8,28] The HCA effects include the reduction of intake, including an increase in fat oxidation, the novo lipogenesis and hepatic glycogenesis stimuli, by means of serotonin levels regulation and metabolic changes. This increases the energy costs. HCA is a competitive adenosine-triphosphate (ATP), an enzyme that catalyses extramitochondrial lyasium oxaloacetate/acetyl-CoA collapses, limiting the availability of the ingredient acetyl-CoA, a key component of the dietary fatty acid synthesis as shown in the Figure 2.

Figure 2. Garcinia cambogia oil is highly beneficial for weight loss.

Appetite-suppressant activity

Over the eight-week period, HCA and HCAL were administered to Wistar albino rats at 1,1 and 3,7 mmol and 5,5 kg 1-Day 1 concentrations in many studies, which measured average feed intake and gain in weight.^[5,32,33] Food intake in both HCA and HCAL was deleted and HCAL in all dosage groups was less consumed. Dose-dependent weight gain is considerably reduced. HCAL is superior compared with HCA because the rats showed a minimum weight increase and a maximum weight loss at the end of this study period. HCAL also found activity of antibestone in rats.The fluoxetine (100 mμM) plus clomipramine (10 mμM) was similar to that of serotonin-specific inhibitors. In isolated rats brain inhibitor slicing, HCA was inhibited by radioserotonin (10 μM to 1 mM) Serotonin deficiency conditions, such as depression and migraine, can help control the appetite, therefore cambogia extract as the ascophyl nodosum were found to be appetite modulatory (L). The formulation was provided to 28 individuals with a random crossover design over a week period without any differences in energy consumption between the groups.^[32,33] The various factors that contribute to the effect of HCA for Garcinia/anti-obesity are shown in Figure 3.

Figure 3. Multiple factors that contribute to the effect of HCA for Garcinia/anti-obesity: (a) Summary of regulation of the serotonin and the removal of food intakes; (b) Summary of reduction in de novo lipogenesis; (c) Summary of fat oxidation stimulation; and (d) Glucose reduction Summary; (a) and (b) contribute to Garcinia/HCA weight management effect, while (b) and [c) are responsible for the Garcinia/HCA anti-obesity effect.

Anticancer properties of garcinol

Cancers are uncontrolled cell growth and spread, caused by multiple factors including carcinogenic exposure, repeated damage to genes, oxidative stress, chronic inflammation, or hormonal imbalances. Most chemotherapy therapy has adverse toxic reactions that can be as effective against cancer cell growth as they can be relatively nontoxic without side effects. Recent evidence supports the therapeutic effects of non-nutrients in the diet, including the control of survival signaling and simultaneous activation of multiple death pathways in cancer cell growth. For its anti-cancer activity, garcinol, isolated from G, cambogia has recently been extensively investigated. Indication and Several studies recently explored the potential of non-nutritive dietary garcinol for various types of cancer. Cambogia has received great scientific attention. Several possibilities were also developed to explain the underlying mechanism for the chemical prevention and/or treatment of garcinol. Studies in Garcinia have shown the development and proliferation of four human leukemia cell lines to be affected by phytochemicals garcinol, isogarcinol and xanthochymol. The growth inhibitories were more powerful than garcinol infections in isogarcinol and xanthochymol.^[11,21]

Hypolipidaemic and antioxidant activity

Flavonoids can inhibit different stages in which atherosclerosis, damage to endothelia, activation of leucocytes, adhesion platelets and aggregation and secretion occur.^[10,34] The plasma total cholesterol and atherogenic index have decreased by 1 to 2% by supplementing tea catechins with a rat diet. Tannic acid and Morin can cause beneficial plasma lipid changes in the heart disease-related type. Flavonoids’ hypolipidemic and antioxidant activity from various sources have been extensively described.^[35–37] A study evaluated the hypolipidemic activity of the Garcinia cambogia fruit, which in Indian medicine has a high therapeutical value and is even now used in medicines for different diseases.^[22] A study investigated the antihyperlipidemic and antioxidant activities of the ethanolic extract of Garcinia cambogia on high fat diet-fed rats. Male Wistar rats were fed with either standard rodent diet or 30% high-fat diet and administered with GE at a dose of 400 mg/kg body weight/day for 10 weeks. At the end, lipid profile and oxidative stress parameters were estimated. Results of the study showed that administration of GE decreased food intake, plasma TC, TAG, non HDL-C, MDA, increased HDL-C and blood antioxidants GSH, GPx, catalase. GE also reduced TOS, OSI and elevated TAS in plasma and liver of fat-fed rats. Renal OSI was significantly reduced upon GE treatment. Garcinia was effective in ameliorating high-fat-diet-induced hyperlipidemia and oxidative stress.^[38] An in vitro antioxidant activity in fruit rin, hydroxyl radical scavenging, thiocyanate ferrous, total peroxide radical trapping and lipid peroxidation testing were reported in aqueous extract. In vitro protective effects against lipid and protein oxidation have been shown in garcinol and guttiferone K isolated from the fruit. The growth of plasma, platelet and thiobarbituric acid-reactive species induced by peroxynitrite in both cases has reduced significantly the growth of carbonyl groups. These compounds, however, did not inhibit the plasma and platelet nitrate induced by peroxynitrite [N. H.^[39]]

Anti-inflammatory activity

The extract of the plant could contribute to the treatment inflammatory bowel conditions resulting from a dysregulated immune response. Various anti-inflammatory cambogia compounds have been shown. Inhibited NF-μB activation by Garcinol and/or JAK/STAT-1 activation. The expression of iNOS and carbon dioxide was inhibited in LPS activated macrophages and the growth in intracellular ROS was decreased by LPS.^[40] The emission of 40%–50% of arachidon metabolite Garcinol of human colon lines of adenocarcinoma (HT-29 and HCT-116) and immortal intestinal line of rats; (IEC-6). Mechanisms used were used to modifies the metabolism of arachidonic acid by blocking CPLA2 and reducing iNOS proteins by inhibiting activation of STAT-1. Cytocin signaling for cultivated human breast cancer (MDA-MB-231) and Rato Insulinoma Cell (INS-1E) has been found to inhibit the nuclear transfer of STAT-1 and the binding of DNA to Garcinol, guttiferone K and guttiferone M. Cytokine IFNμ induced activation of STAT-1 in MDA-MB-231 cells had obstructed all compounds. Garcinol (25 microns) followed by welltiferone M (50 microns) and guttiferone K were the most effective treatments (50 microns). Inhibited the cytokine-induced STAT-1 activation of Garcinol (25 μ M) and Guttiferone K (25 μ M), while guttiferone M was only slightly inhibited at similar concentration. In addition, in cells MDA-MB-231, garcinol inhibited 50 micro-activation of the NF-α-induced, whilst the intestinal K and intestinal M had low activity at the same level. In INS-1E cells, activation of garcinol and guttiferone K has been decreased by 25 μM significantly while guttiferone M has been detected as inactive. Hydroxycitrate of potassium magnesium (KMgHCA) given with 28 and 84 mg/day daily intakes. The systematic blood stress and carageenic paw edema of Sprague–Dawley rats have improved without any toxic effect, with decreases of the CRP and TNF-α. The activity was considered moderate compared to the control group.^[20,41]

Hepatoprotective activity

The antioxidant properties of the extract are associated with the ethanol-causing lipid and peroxidant damage. Following treatment, the levels of serum AST, ALT and alkaline phosphatase (ALP) have demonstrated their normality. In-vitro reports show that 1% of cambogia extracts (50% HCA), while cambogia/HCA were suspected of causing hepatotoxicity in people, have reduced molecule damage and palmitate-induced aldehydes to attenuate lipotoxicity in HepG2 cells. In addition, Antichol containing active ingredients Cambogia avoided cholesterol-induced degeneration of liver fatty and changes in the antioxidant enzymes of the liver, including dismutases of superoxide, glutathione and catalase in rats.^[19] Another research examined at how Garcinia cambogia fruit extract affected ethanol-induced peroxidative damage in albino rats weighing 125 to 150 kg. The rats were given ethanol (7.11 grammes per kilogram of body weight per day) for 45 days. Garcinia cambogia fruit extract (1 g/kg body weight/day) was given orally to ethanol-treated rats for 45 days. The antioxidant enzymes, LPO, conjugated diene in the liver tissue, serum AST, ALT, and alkaline phosphatase, and lipid levels in both serum and liver tissue were measured at the end of the experiment. The results of this study revealed that co-treating rats with Garcinia cambogia dramatically reduced lipid levels as well as the peroxidative damage induced by ethanol, as evidenced by the enhanced antioxidant status. In Garcinia cambogia-treated rats, serum AST, ALT, and alkaline phosphatase levels were kept around normal. The increase in lipid peroxidation might be due to an imbalance in lipid metabolism. Both serum and liver lipids were reduced to near-normal levels after treatment with Garcinia cambogia fruit extract. Garcinia cambogia’s hypolipidemic characteristic decreases peroxidative damage, which is enhanced by ethanol (Mahendran and Shyamala, 2001).^[42]

Anticholinesterase activity

In acetyl-cholinesterase enzymes, neuromuscular joints and cholinergic brain synapses play a crucial role for acetylcholine, a major neurotransmitter. This enzyme is responsible for the loss of cognitive capacity, the first stage of the disease of Alzheimer’s.^[6] Cambogia fruit rind extract produced significant activity with cholinesterase inhibition of 30% and 30% and 67%, respectively, of 500 and 1000 μg/ml. The activity is comparable to the positive neostigmine control with inhibited 5 and 10 μg/mL of 78 and 92% cholinesterase.

Antimicrobial and anthelmintic activity

There has been increase in search of plants with antimicrobial substances, including antifungal, antibacterial, antiviral, and antiparasitic substances (Palai et al., 2021).^[43,14] The antimicrobial activity of Etherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa with inhibition zone diameters ranging from 15 to 34 mm, was demonstrated by ethyl acetate, ethanole and hydroalcohol extracts from the fruit rind tested at a concentration of 25 mg/ml. In addition to ethanol and hydroalcoholic extracts, ethyl acetate extracts were found to be most active, while all test pathogens had hexane extracts not been found inactive. The inhibiting activities against the main HIV-enzymes, HIV-1 protease and HI V-1 were demonstrated through ethanolic and water minerals from cambogy leaves [N. H.^[39]] Differently, there was activity against earthworms at various concentrations (i.e. 20, 40 and 60 mg/ml petroleum ether, chloroform and ethanol extracts obtained from cambogia sheets). The time required for earthworm paralysis was between 1.1 and 2.5 minutes, whereas the time needed to cause death was between 3.1 and 7.4 minutes. Positive control (Albendazole) caused 1.2 minutes of paralysis, and death at 60 mg/mL at 3.2 minutes. Anthelmine extract was shown to be strongest and chloroform and petroleum ether extracts were followed [D. C.^[17]]

Effects on fertility

An ethanol extract from the cambogia seeds was administered to male rats 6 days a week to examine its impact on testis histology as well as the sperm count for 6 weeks. The extract increased the sperm count and interstitial spaces considerably at doses of 100 and 200 mg/kg BW/day, causing degenerating and distorting the cells of the sperm series in all experimental rats.^[18] The level of testis meiosis-aktivating sterol, which may be responsible for the transmission of the spermatogenesis signal, was reduced by oral administration at 102 mmol/kg of BW to male rats, which is intermediate in cholesterol biosynthesis. The serum hormone levels – follicle-stimulating hormones, luteinizing hormone, estradiol and progesterone – have not changed in female rats, shows a subsequent study by the same group that (−) HCA administered at a dose of 154 mmol kg−1 day−1 for 4 weeks. The concentrations of follicle and corpus luteum, the follicular fluid ovarienic meiosis-activating sterol and the sterol testis have not changed over the course of the treatment. After treatment, body weight and abdominal fat decreased (Shaik et al., 2017).^[44]

Toxicity of Garcinia cambogia

The majority of research agrees that taking Garcinia cambogia in the recommended quantities, which is up to 2,800 mg of HCA per day, is safe for healthy persons. Garcinia cambogia has also been linked to certain negative side effects. Digestive problems, headaches, and skin rashes are the most prevalent. However, more significant adverse effects have been reported in other trials. Garcinia cambogia consumption well beyond the maximum suggested dosage has been shown in animal tests to induce testicular atrophy, or shrinkage of the testicles. It has been shown in rats that it can influence sperm production. One lady suffered serotonin poisoning as a result of taking Garcinia cambogia with her antidepressant medicines, according to one study. Furthermore, numerous case studies show that Garcinia cambogia pills may cause liver damage or even death in certain people^[45]

Conclusion

HCA as an active ingredient is typically high in organic acid. Several other components of different plants with different therapeutic functionalities have been isolated such as appetite suppressant, anti-obesity, fertility, anti-cancer, anti-microbial and anti-hyperlipidaemic activity. The current research may be very helpful which suggests that this therapeutic mechanism needs to be carefully programmed and applied. However, the potential benefits that this fruit rind has in human health and illness are required for detailed mechanical studies. Garcinia cambogia’s recommended dosage should be kept in mind while using for better result.

Author contributions

MKN collected the data. SN and CGA analyzed the data: MKN, CGA, FH and AA wrote the original draft. All authors interpreted the data and critically revised the manuscript for important intellectual contents and approved the final version.

Acknowledgments

The authors acknowledge the University of Lahore, Pakistan, and Kampala International University, Kampala, Uganda, for providing the facilities used in preparing this work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Additional data will be made available on request