Yellow Himalayan Raspberry (Rubus ellipticus Sm.): Ethnomedicinal, Nutraceutical, and Pharmacological Aspects

Yellow Himalayan raspberry (Rubus ellipticus Sm., Rosaceae) is a native species of the Indian subcontinent, Southern China, and the Philippines, which has been historically used as a traditional medicine and food. All of the parts of this plant have been used in traditional medicine to treat respiratory ailments, diabetes, and gastrointestinal disorder, and as an anti-infective agent. The scientific evaluation revealed a richness of macronutrients, micronutrients, and minerals in the fruits, indicating its potential use as a nutraceutical. Furthermore, this plant has been found to be rich in various secondary metabolites, including polyphenols, flavonoids, anthocyanins, tannins, and terpenoids. Ascorbic acid, kaempferol, gallic acid, and catechin are some of the compounds found in this plant, which have been widely discussed for their health benefits. Furthermore, various extracts and compounds obtained from R. ellipticus have shown antioxidant, antidiabetic, anticancer, anti-inflammatory, nephroprotective, antipyretic, anticonvulsant, and anti-infective activities investigated through different study models. These findings in the literature have validated some of the widespread uses of the fruits in folk medicinal systems and the consumption of this nutritious wild fruit by local communities. In conclusion, R. ellipticus holds strong potential for its development as a nutraceutical. It can also improve the nutritional status of villagers and uplift the economy if properly utilized and marketed.


Introduction
Medicinal plants serve as an integral component of healthcare in large populations throughout the world. The incorporation of medicinal plants in traditional medicine, spices, nutraceuticals, and as a source of lead compounds has helped humanity fight against many health ailments. Only a fraction of plants have been scientifically documented and studied, and there are many higher plants that are yet to be discovered [1,2]. This diversity of plants and secondary metabolites present in these plants indicates tremendous possibilities for drug discovery and development [3,4]. Currently, scientists are more inclined toward investigating and gathering scientific evidence of ethnomedicinal plants to discover new lead compounds [5][6][7]. This approach, on one hand, would help validate the use of these plants as traditional medicine and nutraceuticals, and on the other hand, increases the likelihood of the discovery of lead compounds compared to random screening [8,9]. Furthermore, polyherbal formulation synergistic therapeutic effects and reduced adverse effects due to

Methods
More than 100 research publications were used as the primary source of data for this review paper. Original research articles, review papers, books, book chapters, reports, and short communications were used as the data source from different database sites like Google Scholar, Scopus, and Web of Science. Various keywords such as ethnomedicinal uses of Rubus ellipticus, in vitro and in vivo studies of R. ellipticus, chemical constituents of R. ellipticus, nutritional importance of R. ellipticus, and different pharmacological properties of R. ellipticus were used to search the required information for the database. Ethnomedicinal uses, bioactive chemical constituents, and nutritional composition were especially taken into consideration and the reported pharmaceutical activities of such contained bioactive chemicals were extracted from the database to prepare this manuscript.

Botanical Description and Distribution
Rubus ellipticus is a shrub about 1-3 m tall with purplish brown or brownish branches, covered in sparse, curved prickles and dense, purplish brown bristles or glandular hairs. The leaves are composed of three leaflets, with the terminal leaflet having a longer petiole than the lateral leaflets, and the petiole is 2-6 cm long. The leaves have stipules that are linear and 7-11 mm long, and the blade of the leaflets is elliptic or obovate, with the terminal leaflet being larger than the lateral leaflets. The inflorescences are terminal, with

Methods
More than 100 research publications were used as the primary source of data for this review paper. Original research articles, review papers, books, book chapters, reports, and short communications were used as the data source from different database sites like Google Scholar, Scopus, and Web of Science. Various keywords such as ethnomedicinal uses of Rubus ellipticus, in vitro and in vivo studies of R. ellipticus, chemical constituents of R. ellipticus, nutritional importance of R. ellipticus, and different pharmacological properties of R. ellipticus were used to search the required information for the database. Ethnomedicinal uses, bioactive chemical constituents, and nutritional composition were especially taken into consideration and the reported pharmaceutical activities of such contained bioactive chemicals were extracted from the database to prepare this manuscript.

Botanical Description and Distribution
Rubus ellipticus is a shrub about 1-3 m tall with purplish brown or brownish branches, covered in sparse, curved prickles and dense, purplish brown bristles or glandular hairs. The leaves are composed of three leaflets, with the terminal leaflet having a longer petiole than the lateral leaflets, and the petiole is 2-6 cm long. The leaves have stipules that are linear and 7-11 mm long, and the blade of the leaflets is elliptic or obovate, with the terminal leaflet being larger than the lateral leaflets. The inflorescences are terminal, with dense glomerate racemes that have several (10 or more) flowers. The flowers are 1-1.5 cm in diameter, bisexual, and have white or pink petals that are longer than the sepals. The aggregate fruit is golden yellow and subglobose, with a diameter of approximately 1 cm. It blooms from March to April and bears fruit from April to May [43][44][45].
It grows quickly in both open, sunny areas and dense rainforests and thrives in moist forests in the high-altitude forests of the Himalaya region [46]. It grows along highways, hillsides, thickets, slopes, mountain valleys, and sparsely populated woodlands between 300 and 2600 meters above sea level in an area with annual rainfall between 2000 and 6500 mm [47]. The plant is commonly found in Southern Asia, Southwestern China, Myanmar, Bhutan, Laos, Pakistan, Sri-Lanka, Nepal, Philippines, Vietnam, Thailand, and India. The plant is also found in a certain area of Australia's Central Coastal New South Wales, Southern Queensland [47] and some countries of Africa [48]. Within India, it is found in Assam, Sikkim, Tamil Nadu, Kerala, and Maharashtra states [32].

Ethnomedicinal Uses
The Rubus genus offers opportunities for the farmers not only economically but also medicinally. Its fruits provide extra income to farmers in rural areas without investment, thereby helping to uplift their economic status [49]. According to Tibetan traditional medicine, the leaves and fruits of R. ellipticus can be used treat a variety of conditions such as bronchitis, nausea, ulcers, and diabetes, as well as for its antimicrobial, carminative, and tonic properties [37,50,51]. The root bark is used to treat diarrhea, dysentery, fractured bones, and as an abortifacient and emmenagogue [52]. The shoot of the plant is sometimes chewed to soothe stomach discomfort, and a root decoction can be consumed to warm the stomach [53][54][55][56]. This plant comes under the top ten wild edible medicinal plants of the Tanahun District of Nepal, owing to the widespread use of its fruits and root in folk medicine. Additionally, the juice of R. ellipticus is used for making squash and jams because of its flavor and color [50]. Details of ethnomedicinal uses of R. ellipticus are mentioned in Table 1.

Bark
Bark juice is consumed Common cold and blood disorders [57] Paste mixed with water and consumed As an antidiuretic and renal tonic [32,55] - Juice is consumed Mouth ulcer and gastrointestinal disorders [69,70] Leaves and fruits Consumed as juice, powder, or in raw form Gastrointestinal problems and mouth disorders [71]  Juice is taken Gastrointestinal and respiratory problems [77] Decoction is prepared together with other plants and consumed Typhoid and stomach pain, Respiratory tract infection, Gastrointestinal tract infection [77] Decoction is consumed Used to kill stomach worms and cure other gastric problems [74] Powder Rhinitis and sinusitis [77] 10-20 mL of juice taken Diarrhea, cholera, gastritis, sore throat [78] Decoction is consumed Typhoid fever [79] Juice is consumed Urinary tract infection [57] Root and fruit Eaten raw Excessive thirst and weakness [73] Root and shoot -Colic pains, antiprotozoal activity against Entamoeba histolytica, hypoglycemic activity [64] Root and young shoots Paste is taken orally Throat pain [80] Whole part

Nutritional Composition
Many studies have reported macronutrients such as carbohydrates, protein, fat, fiber, and several minerals such as calcium, phosphorus, and copper on fruits of the Rubus species. Tables 2 and 3 below show a comparative representation of the profile of macronutrients and micronutrients of R. ellipticus, respectively. Values for R. fruticosus, another species of Rubus, are also provided, but some of these values are for residues after extracting juice. However, it should be noted that the nutritional composition, total phytochemical content, and compounds isolated vary based on various factors such as environmental factors, ripening stage, processing after collection such as drying, extraction solvents and methods, and analysis methods [84][85][86][87][88][89].  DW: dry weight

Phytochemical Constituents
Rubus species possess diverse secondary metabolites including phenolics, flavonoids, anthocyanins, and tannins. Table 4 shows the values of total phenolic, flavonoid, anthocyanin, and tannin contents observed in R. ellipticus and R. fruticosus. The main compounds isolated/identified from R. ellipticus are listed in Table 5 and structures of main compounds are provided in Figure 2. With respect to another species of Rubus, the main compounds reported from R. fruticosus were campesterol, rubinic acid, rubitic acid, kaempferol, stigmasterol, matairesinol, tocopherol, morin, etc. [90,96]. 6.50 ± 3.1% of dry matter [99] µg GAE/mg: Microgram gallic acid equivalent per milligram of extract; mg CE/100 g: milligram catechin.

Antioxidant Activity
Rubus species are enriched with various bioactive phytochemicals, especially anthocyanin, phenolic, and flavonoid compounds. All these components play an important role in combating various diseases by scavenging reactive oxygen species (ROS) [35,112]. There are various mechanisms through which R. ellipticus exhibits its antioxidant potential depending upon the bioactive chemical constituents present on the plant. These include scavenging free radicals and ROS, thereby reducing oxidative stress and cellular damage, neutralizing the free radicals by donating electrons, quenching singlet oxygen, and chelation of the metal ions [113]. According to Badhani et al., a high level of various types of chemical constituents including 19.80 mg/100 g fresh weight (fw) of ascorbic acid and 0.99 mg/100 g fw of β-carotene contributes to the antioxidant properties of R. ellipticus [33]. For instance, half maximum inhibitory concentration (IC 50, ) values of R. ellipticus fruit extract from the α, α-diphenyl-β-picrylhydrazyl (DPPH) assay, ferric ion reducing antioxidant power (FRAP) assay, and 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABST) assay were found to be 32.8 ± 0.5 µg/mL, 73.1 ± 0.5 µM Fe 2+ equivalent, and 39.2 ± 1.1 µg/mL, respectively, revealing the strong antioxidant property of R. ellipticus [114]. Likewise, George et al. reported the significant potential of methanolic leaf extract to scavenge DPPH free radicals with an IC 50 value of 6.96 ± 2.32 µg/mL, which was comparable to standard BHA, BHT, and quercetin with IC 50 values of 4.88 ± 1.45 µg/mL, 13.18 ± 1.43 µg/mL, and 4.12 ± 1.67 µg/mL, respectively [115].

Antimalarial Activity
Sachdeva et al. reported the potent anti-malarial activity of R. ellipticus leaf extract in both in vitro and in vivo models. From an in vitro study, they found the antimalarial efficacy of R. ellipticus with an IC 50 value of 14.26 µg/mL against the Plasmodium falciparum INDO strain (PfINDO). They observed 64% of inhibition against Plasmodium berghei at a dose of 500 mg/kg [80]. Another study using silver nanoparticles of the leaf extract of R. ellipticus also showed an antimalarial effect against the malarial vector Anophelese stephensi [116]. They found that the aqueous-extract-loaded silver nanoparticles showed greater larvicidal, ovicidal, oviposition deterrent, and adulticidal activities against Culex quinquefasciatus, Anophelese stephensi, and Aedes aegypti as compared to the leaf extract alone [116].

Antidiabetic Activity
α-Amylase and α-glucosidase are the carbohydrate-hydrolyzing enzymes that catalyze the breakdown of starch and disaccharides into glucose and are thus important in regulating blood glucose level [117,118]. Subba et al. reported a moderate α-amylase inhibitory activity of the methanolic leaf extract with an IC 50 value of 269.94 ± 0.11 µg/mL [37]. Li et al. isolated 31 triterpenoids present in R. ellipticus and performed their α-glucosidase inhibition assay. They found that, among all the extracted compounds, euscaphic acid was found to be the most potent with an IC 50 value of 0.65 ± 0.09 mM, which was comparable with the positive control, acarbose (0.82 ± 0.11 mM) [42]. Sharma et al. performed an antidiabetic activity assay of R. ellipticus fruit extract using the glucose tolerance test and alloxaninduced diabetes assay using two different experimental diabetic models (Swiss albino mice and Wistar albino rats). It was reported that the ethanolic extract of the fruit was more effective in reducing the blood glucose level in alloxan-induced diabetic Wistar albino rats and Swiss albino mice as compared with its ether and aqueous extract [119]. Since the ethanolic extract was found to contain triterpenoids, flavonoids, as well as saponins, these compounds might contribute to the higher antidiabetic activity of the ethanolic extract compared to others [42,118,120,121].

Antiproliferative and Anticancer Activity
Uncontrolled proliferation or production of the cells results in cancer. Recently, most researchers have been focused on either synthesizing new compounds or searching potent natural compounds that can be used for the treatment of cancer. A study conducted by George et al. showed an increased survival in tumor-enriched Swiss albino rats with the administration of 250 mg/kg of methanolic leaf extract from R. ellipticus. A similar finding was observed in another study showing a reduced solid tumor volume of Dalton's Lymphoma Ascites-induced Swiss albino mice when treated with 100 mg/kg of R. ellipticus methanolic leaf extract [115]. An in vitro study by Saini et al., against two human cervical cancer cell lines (C33A and HeLa), showed reduced cell proliferation upon treatment with fruit extract. They found a 60% inhibition in proliferation of the C33A cell line by methanol and acetone extract and the complete inhibition of proliferation in the HeLa cell, with no toxicity to the normal cells [41,122]. The antiproliferative activity of R. ellipticus extract might be due to the presence of the higher concentration of gallic acid and ellagic acid in its extract [122,123]. Different extracts of R. ellipticus, R. niveus, and R. fairholmianus also showed a potent antiproliferative activity of human colon cancer cells (Caco-2) in the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay [38]. This might be due to the presence of diverse phytochemicals in the fruit extract such as kaempferol [38,124].

Anti-Inflammatory Activity
Parimelazhagan et al. reported the anti-inflammatory activity of R. ellipticus methanolic leaf extract using carrageenan-induced inflammation and croton-oil-induced ear inflammation models in rats. The supplementation of methanolic leaf extract at doses of 400 mg/kg and 200 mg/kg to carrageenan-induced inflamed rats showed a reduction in inflammation. The extract showed a reduction in rat paw with edema by about 66.47% and 45.78%, respectively, at those doses, which were comparable to the standard drug, indomethacin [46]. Hydroalcoholic (90% ethanol) extract of the root of R. ellipticus significantly inhibited the inflammation induced by the carrageenan in rats. The extract was able to reduce the vascular permeability induced by carrageenan, resulting from reduced accumulation of the fluid in the vascular tissues, lowering inflammation [50].

Antifertility Activity
Prakash et al. performed a series of screening in order to identify the ability of the ethanolic extract of the R. ellipticus plant for its anti-fertility properties. They observed that the extract of R. ellipticus possessed a potent antifertility effect with estrogenic action, as evidenced from screening using rats, mice, and hamsters [125]. Likewise, Dhanabal et al. reported 91.43% of anti-fertility activity, 37.10% of early abortifacient activity, and 54.33% of anti-implantation activity, when 200 mg/mL of R. ellipticus leaf extract was administered to female Wistar albino rats. Additionally, an anti-implantation effect was also observed in female albino rats due to the significantly increased reabsorption site and decreased implantation sites upon treatment with the extract [126]. Similarly, the anti-implantation activities of R. ellipticus root extract and the whole plant without the root extract were reported as 60% and almost 100%, respectively, in albino rats during 7 days of pregnancy [127].

Nephroprotective Activity
Sharma et al. studied the nephroprotective activity of various extracts of R. ellipticus (petroleum ether, ethanolic, aqueous). These extracts were able to normalize increased blood urea nitrogen, serum uric acid, creatinine, and serum urea levels induced by cisplatin and gentamicin [128]. Such a potent nephroprotective activity might be due to the presence of certain phytochemicals like phenols, tannins, flavonoids, and triterpenoids, which act as an antioxidant, reducing the risk of renal dysfunction [129][130][131]. Likewise, the ethanolic extract of R. ellipticus was found to be an effective nephroprotective agent compared to its petroleum ether and aqueous extract. The extract also improved histological disturbance in acetaminophen-induced nephrotoxicity in animal models [110].

Antiviral Activity
According to Panda et al., both aqueous as well as ethanol extracts of R. ellipticus showed potent antiviral as well as cytotoxic activities against enterovirus 71 strains revealed by various parameters like the selectivity index, selectivity surface, as well as therapeutic index [132].

Antipyretic Activity
The antipyretic activity of the leaf methanolic extract of R. ellipticus was studied using yeast-induced hyperpyrexia in rats. Rectal temperature was continuously monitored after the treatment of 200 and 400 mg/kg doses of the extract. A reduction in elevated rectal temperature was observed in the 3rd to 7th hour after treatment, which was comparable to that of the standard drug, paracetamol. This suggested the ability of R. ellipticus extracts to inhibit various inflammatory cytokines produced during hyperpyrexia [46].

Effect on Central Nervous System (CNS)
The anticonvulsant property of R. ellipticus ethanolic leaf extract was reported using maximum electroshock-induced convulsion in an experimental animal model [133]. In such studies, the severity of convulsion is assessed based on the duration of the flexion, extension, clonus, stupor, and recovery phase [134]. Administration of the ethanolic extract (100 mg/kg per oral) was found to inhibit the extensor phase of convulsion [32,133].

Antimicrobial Activity
Panda et al. studied the antimicrobial effect of acetone, water, and ethanolic extracts of the leaf of R. ellipticus against Escherichia coli, Staphylococcus aureus, and Candida albicans. More than 50% of growth inhibition of all these microorganisms (bacteria and fungi) was shown by most of the extracts (acetone, water, ethanol) [132]. Likewise, Khanal et al. used disc diffusion and the Resazurin microtiter assay technique to test the methanolic extract of R. ellipticus root bark for antibacterial activity against Gram-positive S. aureus, Gramnegative Klebsiella pneumoniae, and Salmonella typhi. They found that the methanolic extract of R. ellipticus root bark has significant antibacterial activity against S. aureus with a zone of inhibition of 17 mm, but no impact was observed on Gram-negative organisms [135]. Singh et al. reported that the ethanolic leaf extract was capable of inhibiting Pseudomonas aeruginosa and Enterococcus faecalis at an extract concentration of 62.5 µg/mL, whereas S. aureus and S. typhi were sensitive at 125 µg/mL of crude extract [136]. R. ellipticus ethanolic fruit extract was also reported to have significant inhibition against E. coli and Streptococcus pyogenes [39]. Dhatwalia et al. studied the antimicrobial effect of cuprous-oxide-mediated nanoparticles of the fruit extract of R. ellipticus. They found that the synthesized nanoparticle can significantly inhibit Gram-positive bacteria (Bacillus subtilis and S. aureus) with minimum inhibitory concentrations (MICs) of 7.81 µg/mL and 15.62 µg/mL, respectively. Those nanoparticles also inhibited the growth of Gram-negative P. aeruginosa and E. coli with MICs of 31.25 µg/ mL and 31.25, µg/mL, respectively [114].

Wound Healing Activity
George et al. studied the percentage of contraction of the wound via an excision and infection model with 1% and 2% w/w ointments of R. ellipticus methanolic leaf extract. In the excision model, a 2% acetone-extract-treated Wistar male rat demonstrated 94.23% of contraction on the 12th day of excision, which was comparable with the percentage contraction of betadine, a standard drug. Meanwhile, in the case of an S. aureus-infected wound, complete epithelization was observed in the 2% acetone-extract-treated group on the 12th day with a percentage wound contraction of 79.25% [46].

Photocatalytic Activity
Methylene blue is a toxic cationic dye used to color paper, leather, and textiles. The dye in industrial effluent is mixed with river as well as other water sources, preventing solar radiation from penetrating and eventually affecting water-based photosynthesis, causing harm to the water ecology, environmental pollution, and poisoning the food chain [137]. Zinc-oxide nanoparticles obtained by green synthesis using fruit aqueous extract of R. ellipticus were found to degrade 17.5% of methylene blue within 1 h, with 72.7% of methylene dye degradation at the end of the experiment [138]. Likewise, Khalil et al. reported 98% of degradation of methylene blue dye after 150 minutes of exposure of R. ellipticus-leaf-mediated silver particles [139]. Thus, R. ellipticus is not only useful for its pharmacological properties but also showed a significant role (photocatalytic) in eliminating water pollution via dye degradation.

Conclusions and Future Prospective
Rubus ellipticus is a highly nutritious wild fruit with many health benefits including antioxidant, antidiabetic, anticancer, anti-inflammatory, nephroprotective, antipyretic, anticonvulsant, and anti-infective activities. Its fruits, leaves, and roots are rich in secondary metabolites like polyphenols, flavonoids, anthocyanins, tannins, and terpenoids. These findings in the literature validated the widespread use of this fruit in the folk medicinal system and the consumption of this wild fruit by local communities. Based on this evidence, this wild fruit and extract from different part of this medicinal plant hold strong potential for developing as a nutraceutical. Indeed, as this fruit is readily available in rural villages, it can also help to improve the nutritional status of people living in those areas and also uplift their economy, if properly utilized and marketed. Moreover, detailed research including focused bioactivity studies, standardizations of fruits from different climatic conditions, and advanced toxicological, pharmacological, and pharmacokinetic evaluations is necessary to determine additional uses and the impact of this fruit on the molecular level.
As the drug discovery research using herbal medicine and the demand of nutraceuticals continue growing, the future of wild nutritious fruits like R. ellipticus seems promising. This can play an important role as a source of lead compounds, herbal therapeutic agents, and functional foods. Moreover, this wildly growing medicinal plant can become a good source of nutrition and a means of economic upliftment for the people living in villages. So, future research should focus on confirming the scientific relevance of ethnomedicinal values, the mechanism of action on animal and human subjects, and the commercialization of this wild fruit. Such studies will help highlight this wild fruit and also establish good market value. Furthermore, as this fruit is merely collected from the wild, research on the cultivation and optimization of cultivation to obtain higher yield is also necessary to conserve this plant. This will ensure the sustainable use of this wild fruit and protect against overexploitation.  Acknowledgments: Authors would like to thank Dipa Paneru and Sujata Lamichhane for providing permission to use their photographs in this manuscript.

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Not applicable.