Next Article in Journal
Embedding Group VIII Elements into a 2D Rigid pc-C3N2 Monolayer to Achieve Single-Atom Catalysts with Excellent OER Activity: A DFT Theoretical Study
Previous Article in Journal
Tuning Size and Properties of Zinc Ascorbate Metal-Organic Framework via Acid Modulation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 1
10.3390/molecules28010255
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Bioactive Chemical Constituents and Pharmacological Activities of Ponciri Fructus

by
Gopal Lamichhane
1,†,
Jitendra Pandey
2,† and
Hari Prasad Devkota
3,4,5,*
1
Department of Oriental Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan 570-749, Republic of Korea
2
Department of Pharmacy, Crimson College of Technology, Pokhara University, Devinagar-11, Butwal 32900, Nepal
3
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
4
Headquarters for Admissions and Education, Kumamoto University, Kurokami, 2-39-1, Chuo-ku, Kumamoto 860-8555, Japan
5
Pharmacy Program, Gandaki University, Pokhara 33700, Nepal
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(1), 255; https://doi.org/10.3390/molecules28010255
Submission received: 11 November 2022 / Revised: 15 December 2022 / Accepted: 22 December 2022 / Published: 28 December 2022
(This article belongs to the Special Issue Theme Issue Honoring Professor Pamela Weathers’ 75th Birthday: Plant Metabolites–Chemistry, Biology and Applications)
Browse Figures
Versions Notes

Abstract

:
Ponciri Fructus is a crude drug obtained from the dried immature fruits of Poncirus trifoliata (L). Raf. (Syn. Citrus trifoliata L.). This study aims to compile and analyze the ethnomedicinal uses, bioactive constituents, and pharmacological activities of Ponciri Fructus. Various online bibliographic databases namely, SciFinder, PubMed, Google Scholar, and Web of Science were used for collecting information on traditional uses, biological activities, and bioactive constituents. Concerning ethnomedicinal uses, Ponciri Fructus is extensively used in traditional Korean, Chinese, and Kampo medicines to mitigate allergic reactions, inflammation, edema, digestive complications, respiratory problems, spleen-related problems, liver complications, neuronal pain, hyperlipidemia, rheumatoid arthritis, cardiovascular problems, hernia, sinusitis, and insomnia. Several studies have shown that Ponciri Fructus is a major source of diverse classes of bioactive compounds namely flavonoids, terpenoids, coumarins, phytosterols, and alkaloids. Several in vivo and in vitro pharmacological activity evaluations such as antidiabetic, anti-obesity, anti-inflammatory, antiallergic, antimelanogenic, gastroprotective, anticancer, and neuroprotective effects have been conducted from Ponciri Fructus. However, scientific investigations focusing on bioassay-guided isolation and identification of specific bioactive constituents are limited. Therefore, an in-depth scientific investigation of Ponciri Fructus focusing on bioassay-guided isolation, mechanism based pharmacological studies, pharmacokinetic studies, and evaluation of possible toxicities is necessary in the future.

1. Introduction

Plants possessing medicinal properties have been playing a crucial role in maintaining human health via their multiple utilizations as conventional medicines, spices, and food, and as a paramount source of the lead molecule during novel drug discovery and development [1,2]. In current years, interest in plant-derived functional foods and nutraceuticals has been increasing tremendously in order to protect human beings from numerous lifestyle-associated diseases and several other health issues such as atherosclerosis [3], inflammation [4,5], endothelial dysfunction [6], cancer progression [7,8,9], hypercholesterolemia [10], and asthma [11]. Diverse types of plant-derived nutritional constituents such as vitamins, minerals, and amino acids, as well as bioactive phytoconstituents such as polyphenols (flavonoids and phenolic acids), are gaining increased interest [12,13,14]. In addition, various plant-based products are being manufactured as edible formulations. This is despite the fact that in order to identify the exact chemical structure of bioactive molecules present in these plants, an in-depth investigation of the pharmacological actions and an outline of worthwhile drug delivery system and formulations are crucial and challenging scientific tasks that have to be performed [7].
Ponciri Fructus (Figure 1) is a dried immature fruit of P. trifoliata (L). Raf. (Syn. Citrus trifoliata L.) is commonly known as Trifoliate Orange, Japanese Bitter Orange, or Chinese Bitter Orange. It is a deciduous or semi-deciduous prickly shrub belonging to the family Rutaceae and is widely distributed in temperate regions of East Asian countries such as South Korea, North Korea, China, and Japan with a height of 3.5 m. Although recent plant databases include this plant in the genus Citrus, some other classify it into the genus Poncirus as this plant possesses some distinguishable features such as deciduous distribution, pubescent fruits, and compound leaves [15,16]. Only two species i.e., P. trifoliata and P. polyandra have been recognized from this genus [17]. In South Korea, P. trifoliata is native to Gaduk and Jeju Island [18]. Nowadays, it is being cultivated commercially in the central and southern regions of Korea [18,19]. This species is an extremely cold-resistant plant and is cross-compatible with other subtropical citrus plants. For this reason, in the temperate regions of many countries such as Japan, China, New Zealand, and Australia, it has been utilized as a rootstock to graft other citrus fruits. In addition, citrus plants in this rootstock can produce high-yield and quality fruits [17,20]. The most applicable part of this plant is pubescent fruit (3–4 cm in diameter) with greenish pulp, which looks like a small orange and gives a pleasing fragrance. The fruit changes from green to yellow or golden color, upon maturity [15,21,22]. This fruit is called ‘Jisil’ (in Korean) and Zhishi (in Chinese), is a well-known oriental medicine for management of allergic diseases [23,24]. Another characteristic feature of this plant is the presence of distinctive leaves which are formed by the fusion of oval-shaped three-lobed leaflets where the central leaflet is slightly larger. These leaves are scarce, glossy, and leathery in appearance. The most aromatic parts of this plant are the white-colored five-flowered petals. In the middle of the spring season, the plant starts to bloom before the appearance of leaves, and fruits ripen completely in the late fall. The harvesting time of mature fruits is from May to June [19]. The fresh fruits of this plant are not suitable for oral consumption due to the presence of numerous seeds, the low quantity of pulp, and its unpleasant taste. Therefore, fruits are dried and comminuted into fine powder for consumption as a condiment. Nowadays, the fermentation of fresh fruit is very popular, as it can reduce the bitter taste and improve the nutritional value of fruit [16].

2. Cultivation of P. trifoliata

Most often, P. trifoliata is cultivated either by directly sowing the seeds in the spring season or through cutting propogation in the summer season. The seeds are greatly resistant to extremely cold environments up to −30 °C but intolerant to drought conditions. Normally, seeds are stratified in a cold environment for four weeks, before sowing in a greenhouse in the early spring. After two weeks, seedlings are plucked and transferred into individual pots and filled with acid soil (pH 4) inside the greenhouse. The relative humidity of the greenhouse should be in the range of 40–80%. It is necessary to let them grow in the pot for no less than their first winter. After that, plants are transferred to permanent places near to the summer season. These plants prefer a sunny area with well-drained sandy, acidic soil for their proper growth. In addition, the supply of water should be comparatively high during the fruiting season of this plant [25,26]. Moreover, other sophisticated techniques such as tissue sub-culturing [27], rootstock grafting [28], seed inoculation with arbuscular mycorrhizal fungi [29,30], etc., are gaining popularity in the commercial production of this plant.

3. Traditional Uses of Ponciri Fructus

In the traditional Chinese and Korean systems of medicine, the dried immature fruit has been used to mitigate allergic reactions [23,31], indigestion, inflammation [23], edema [32], duodenal ulcers, gastric ulcers [33], gastritis, constipation, dysentery, and other digestion related complications [34,35]. In eastern Asian countries, its dried immature fruits are considered an effective remedy to treat hepatotoxicity and inflammation [36]. In traditional Korean and Chinese formulations such as Samchulgeonbi-tang (combination of 14 different crude drugs) [37], Mahwangyounpae-tang (combination of 22 different crude drugs) [38], CGX (combination of 13 different crude drugs) [39,40], Sayuk-san (combination of 4 different crude drugs) [41], and Jeechool-Whan (combination of Ponciri Fructus and Atractylodis Rhizoma Alba) [42], Ponciri Fructus is incorporated as a significant constituent and these formulations are widely used for various complications such as gastric ulcers, indigestion, chronic gastritis, gastroptosis, emesis, and diarrhea [37,41,42], along with several respiratory problems [38], spleen related problems [42], and liver complications (liver cirrhosis, viral hepatitis, jaundice, and alcoholic liver damage) [39,40]. Moreover, another Korean traditional formulation Ojeok-san (a combination of 17 different crude drugs including Ponciri Fructus) has been used as a folk remedy for the mitigation of numerous pathological conditions such as neuronal pain, hyperlipidemia, fever, and rheumatoid arthritis [43,44,45]. Ethnomedicinally, Ponciri Fructus is extensively being used as a prokinetic agent, to improve the abnormal contraction of the uterus, to ameliorate the flow of the blood [18,46,47], and to cure gastroesophageal reflux disease [48]. According to the philosophy of traditional Chinese medicine, Ponciri Fructus can modulate the proper flow of stagnant qi energy, remove the unwanted accumulation of food, eliminate excess mucus, and get rid of unwanted mass formations in the body [49]. Therefore, it is widely used in traditional Chinese medicine to treat chest pain, fullness of the chest, sputum, asthma, and bronchitis [49,50,51,52,53]. As a folk remedy for diverse digestive complications such as abnormality of gastric motility and abnormal GI secretion [54], a usual dose of Ponciri Fructus varies from 2–75 mg [55]. In Korea, Ponciri Fructus extract is incorporated into several allopathic over-the-counter drugs to treat several pathological conditions of the gastrointestinal tract [55,56]. Moreover, dried immature fruits are also widely accepted folk remedies for the complications of hernia, sinusitis, insomnia, and sputum formation [25].

4. Bioactive Chemical Constituents

4.1. Phytochemical Constituents of Ponciri Fructus

Although the ethnomedicinal use of P. trifoliata has a very long history in Korea, Japan, and China, scientific investigations focused on the in-depth phytochemistry are limited. Even though various parts of the plant such as root, stem bark, leaves, flower, fruits, and seeds are being examined for their bioactive compounds, the majority of the investigations have been focused on immature fruits of this plant. Several studies have shown that the dried immature fruits are a major source of diverse classes of bioactive compounds namely flavonoids, terpenoids, coumarins, phytosterols, and alkaloids [49]. Structure of representative compounds isolated from Ponciri Fructus are presented in Figure 2.

4.1.1. Flavonoids

Flavonoids are the most abundant bioactive constituents present in Ponciri Fructus, and poncirin is the most widely distributed flavonoid compound, which constitutes 6% of the dried fruit extract. Several flavonoid derivatives namely poncirin, neoponcirn, naringin [32,33], hesperidin, neohesperidin, sinensetin, nobiletin, hesperetin [18,47,57], narirutin, naringin 4′-glucoside [16,58], poncirenin, (2R)-5-hydroxy-4′-methoxyflavanone-7-O-{β-glucopyranosyl-(1→2)- β-glucopyranoside} [59], and hesperidin methyl chalone [60] have also been discovered from the Ponciri Fructus.

4.1.2. Terpenoids

Terpenoids are largest groups of secondary metabolites widely distributed in plants [61]. From the methanolic extract of Ponciri Fructus, four different bioactive terpenoids 21β-methylmelianodiol, ispidol β 25-methyl ether, hispidol A 25-methyl ether, and 21α-methylmelianodiol have been identified [31]. Similarly, novel terpenoid derivatives (Pancastatin A and B) [62], 25-methoxyhispidol A and B, [51,63] were also reported from the Ponciri Fructus.

4.1.3. Coumarins

Citrus species are among the richest sources of coumarin and its derivatives [64]. Ponciri Fructus methanolic extract was reported to contain diverse coumarin compounds such as isoschininallylol [31], methoxsalen [21], imperatorin [32], isoimperatorin [36,65], phellopterin [65], auraptene [52], umbelliferone [32], phellopterin, oxypeucedanin [66], triphasiol, and ponciol [67]. According to a previous study conducted in South Korea, three potent chemopreventive coumarins: poncimarin, oxypeucedanin methanolate, and heraclenol 30′-methyl ester were isolated from the methylene chloride extract of Ponciri Fructus [68].

4.1.4. Miscellaneous Compounds

Several other subclasses of bioactive compounds such as β-sitosterol (phytosterol) [66], bis(2-methylheptyl) phthalate, avenalumic acid methyl ester (styrene derivative) [69], limonin (furanolactone) [53], synephrine (alkaloid) [70], 2-hydroxyl-1,2,3-propanetricarboxylic acid 2-methyl ester [71] have also been reported from Ponciri Fructus.

4.2. Volatile Constituents from the Peel of P. trifoliata Fresh Fruits

In a previous study, essential oils were isolated from the fresh peel of fruits by using hydro-distillation, and volatile chemical constituents present in the oil were identified by GC-MS total ion chromatogram. All the identified essential oils and their relative amounts are depicted in Table 1 [72]. Similarly, another study conducted in China reported two other different volatile components: ocimene and cis-caryophyllene [73] along with 19 other previously identified volatile compounds [72].

4.3. Chemical Constituents from the Fresh Fruit Juice and Seed Extract of P. trifoliata

Tundis et al. investigated phytochemicals from the juice of fresh fruits and methanolic extract of the seeds extracts by using HPLC connected with a photodiode array detector. By comparing chromatogram with standard compounds, they found several flavonoid derivatives and phenolic acids in tested samples [69]. The name of the bioactive compounds detected in fruit juice and seed extract are given in Table 2

5. Pharmacological Activities

5.1. Anti-Obesity Effects

Ban et al. reported the anti-obesity effects of Ponciri Fructus in rats that were fed a high-fat diet (HFD). They found that fruit extract, when fed with a high-fat diet, significantly reduced serum levels of low-density lipoprotein (LDL), fatty acids, and glyceride in rats [74]. Another study on C57BL/6 mice treated with fruit extract also reduced mice weight, fasting blood glucose, liver and adipose tissue weight, serum triglyceride, and LDL significantly [75]. They found that the extract effectively increased expression of carnitine palmitoyltransferase 1α and insulin receptor substrate, modulated serum insulin, adiponectin and leptin expression, while reducing transcription levels of fatty acid synthase and stearoyl-CoA desaturase 1 [75]. Kim et al. found that Ponciri Fructus ameliorated macrophage-mediated inflammation and improved insulin resistance in HFD-fed mice [46]. Shim et al. proposed that the anti-obesity of fruit might be due to its prokinetic effect through the inhibition of nutrient absorption into the blood stream [55]. The absorption might have been hindered due to the inhibition of α-amylase and glucosidase enzymes by this fruit [69]. The observed anti-obesity activity might also be due to the anti-adipogenic effect of fruits as ethanol extract, and hexane and ethyl acetate fraction of this fruit extract significantly reduced adipogenesis in 3T3-L1 preadipocytes [66]. The extract was found to contain poncirin, phellopterin, oxypeucedanin as potent anti-adipogenic agents in it. All of these compounds are effective in reducing lipid deposition in differentiated 3T3-L1 preadipocytes. Moreover, oxypeucedanin, a potent anti-adipogenic coumarin, was found to regulate major players of adipogenesis, namely, PPAR-γ, SREBP-1, C/EBP-α, FABP-4, aP2, LPL and leptin expression in cells [66]. Water extract also showed similar inhibition of adipogenesis by inhibition of LPL secretion and induction of sortilin-related receptors mediated by C/EBPβ [76].

5.2. Activity in Prostatic Hyperplasia

Hydroalcoholic (70% Ethanol) extract of Ponciri Fructus significantly inhibited testosterone propionate induced prostatic hyperplasia in male Sprague Dawley rats. The extract reduced the weight of the prostate, the level of testosterone and dihydrotestosterone in the prostate tissue and serum of rats. This finding was attributed to diminished expression of proliferating cell nuclear antigen and increased endogenous antioxidant enzyme levels on subcutaneous administration of extract [32].

5.3. Anti-Inflammatory Activity/Anti-Allergic Effect/Immunoprotective Effects

The widespread exploitation of Ponciri fruits in traditional medicine as an anti-allergic agent in China, Korea, and Japan has also been supported by scientific studies. Lee et al., 2018, identified the anti-inflammatory activity of Ponciri Fructus on an in vitro model of Raw 264.7 cells [77]. The fruit extract reduced nitrous oxide production, matrix metallopeptidase, and proinflammatory cytokines (tumor necrosis factor alpha and interleukin-6) significantly in studied cells. The extract was also found to inhibit phosphorylation of ERK1/2, JNK, P38, MAPK, and nuclear translocation of P65 and NF-κB in LPS-stimulated cells [77]. The anti-allergic potential of this fruit was also demonstrated on an in vivo mouse model [78]. It was found that the administration of ponciri fruits together with Jiyutang decreased reactive oxygen intermediates (O2− and H2O2) in neutrophil and macrophase, and reduced contact hypersensitivity without affecting spleen capacity to form rosette [78]. The dermal anti-allergic effect of fruit extract was also demonstrated in mice models showing decreased dermal thickness, epidermal skin, mast cell count, and IgE in serum. Furthermore, scratching frequency, nerve growth factor, and cytokine (IL-4, IL-6, IFN-γ and TNF-α) levels were also reduced significantly [79]. A recent study by Hwang et al. have shown that ethanol extract effectively inhibited septic shock and increased survival in LPS- and CLP-induced mice by inhibiting STAT1 signaling, supporting the anti-inflammatory activity of fruits [35]. Fruit extract consumption also controlled type-1 hypersensitivity reaction induced by anti-dinitrophenyl (DNP)-IgE and dinitrophenyl-human serum albumin in rats by inhibition of histamine secretion [80,81].
Isolation of active pharmacological constituents yielded a triterpenoid, hispidol A 25-methyl ether, with strong anti-inflammatory effects [82]. This compound inhibited bacterial infection-induced neuroinflammation in mice by inhibiting expression of proinflammatory cytokines [82]. These isolated compounds also showed significant anti-inflammatory activities in a carrageenan-induced paw edema model of mice and in vitro RAW 264.7 cells [83]. Rho et al. also isolated coumarin derivatives, imperatorin and phellopterin with strong anti-inflammatory effects [65].

5.4. Inhibition of Melanogenesis

Ethanol extract from immature fruits was found to significantly inhibit melanogenesis in B16F10 cells revealing its potential application as a cosmeceutical agent [84]. Extract hindered melanin biosynthesis by significantly reducing tyrosinase enzymatic activity and TRP-1 protein [84]. The potential was further extended to the anti-wrinkle activity of fruits in human dermal fibroblasts exposed to UVA radiation. They found that fruit extract fermented with Ganoderma lucidum inhibited matrix metalloproteinase 1 and also increased collagen biosynthesis in a dose dependent manner [85]. Interestingly, Son et al. isolated bis(2-methylheptyl) phthalate, a potent melanogenesis inhibitor from fruits. The isolated compound was highly effective with an IC50 value of 36.8 µM compared to standard kojic acid (IC50; 150 µM) in the B-16 melanoma cell line of mice [71].

5.5. Hypolipidemic Acactivity

Administration of Ponciri Fructus extract reduced total cholesterol, LDL cholesterol and triglyceride in the plasma and liver of hyperlipidemic rats while increasing indigenous antioxidant enzymes (catalase and glutathione peroxidase) activity [86]. A similar hypolipidemic activity was replicated by Ham et al. on triton WR-1339 induced hyperlipidemic rats showing with significant reduction of triglyceride, total cholesterol and LDL cholesterol on treatment with extract [87].

5.6. Anti-Cancer Activity

Methanolic extract of Ponciri Fructus was found to selectively induce apoptosis in glucose-deprived pancreatic cancer (PANC-1) cells [88]. The extract inhibited the expression of glucose-regulated protein 78 (GRP78; a marker that increases cell survival and decreases apoptotic potential during stress response) dose-dependently in pancreatic cells under hypoglycemic conditions [88]. Interestingly, triterpenoids pancastatin A and B were isolated from this fruit which showed similar selective cytotoxicity and reduction of GRP78 protein in PANC-1 cells [62]. The result was further supported by Kang et al. finding that aqueous decoction of Ponciri Fructus significantly increased natural killer cell activity responsible for antitumor immunity in vitro [89] and in vivo [90]. Sim et al. found that the extract treatment increased the survival of mice inoculated with sarcoma-180 cells by increasing natural killer cell activity [90]. Another imperative study on colorectal cancer cell line CT-26 showed that 70% methanolic extract from fruit significantly increased apoptosis by increasing mitochondrial autophagy [91]. The antiproliferative activity of fruit extract was also extended to the pituitary tumor cell line (GH3) [92]. The extract of fruit was also found to alleviate triple-negative breast cancer by increasing apoptosis through c-Jun(2)-terminal kinase and extracellular regulated kinase [93]. Furthermore, a triterpenoid, 25-Methoxyhispidol A, was isolated from this fruit showing anticancer activity in human hepatocarcinoma cells (SK-HEP-1) by cell cycle arrest in the G1 phase and by induction of apoptosis [51]. The extract also demonstrated dose-dependent cytotoxicity in HL-60 leukemia cells mainly increasing apoptosis by activation of caspase-3 and DNA fragmentation [50]. Interestingly, imperatorin and limonin isolated from seeds of Ponciri Fructus showed growth inhibition in liver cancer (SNU 449), and colon cancer (HCT-15) cells line. They caused cell cycle arrest and promoted apoptosis by regulating proapoptotic Bax and Bcl-2 expression dose dependently [53].

5.7. Cosmeceutical Uses

Ethyl acetate fraction of Ponciri Fructus inhibited the growth of nine different strains of methicillin resistant Staphylococcus aureus, a pathogen known to cause serious skin infections, with the minimum inhibitory concentration of 256 to 1024 µg/mL indicating its potential use as a cosmeceutical [94].
A case study on an 85 year old liver cirrhosis patient with an itching sensation on whole body showed topical administration of decoction obtained from Ponciri Fructus and Radix Lithospermi for 37 days improved erythema and pruritis [95].

5.8. Anti-Helicobactor pylori Effect (Gastroprotective)

Gastroesophageal reflux disease is one of the major health complications for many people around the world. Extract of Ponciri Fructus hastens gastric emptying and improves mucus secretion, ameliorating the effects. The activity of the fruit is due to the presence of bioactive compounds such as poncirin (by reducing gastric lesion induced by HCl), naringin (by preventing gastric ulcers), hesperidin (by improving delayed gastric emptying), neohesperidin (by stimulating mucus secretion) [48]. Administration of poncirin, a major flavonoid of Ponciri Fructus, after metabolism gets converted into ponciretin and inhibits the growth of Helicobactor pylori in the intestine with a MIC of 10–20 μg/mL [33].

5.9. Prokinetic Effect

The serotonin receptor (5-HT receptor) of the gastrointestinal tract is known to play a key role in intestinal motility. Intestinal cells of Cajal in the murine model have three of those serotonin receptor subtypes making it a key target for studying the influence on gastric movements [54]. The methanolic extract of Ponciri Fructus modulated pacemaker potential interstitial Cajal cells of the small intestine by 5-HT3, 5-HT4 receptor mediated channels. The extract increases the influx of Na+ and Ca2+ externally, and Ca2+ from the internal store proportional to mitogen-activated protein kinase levels increasing gastric peristalsis [54]. The hexane extract of Ponciri Fructus was found to stimulate longitudinal muscles of the distal colon in rats mediated by acetylcholinergic M2 and M3 receptors, supporting its prokinetic activity [96]. In vivo and in vitro study by Choi et al. showed that hexane extract from the fruit significantly and dose-dependently increased longitudinal muscle contraction in the distal part of colon [96]. The prokinetic activity of the aqueous extract was also identified by Lee et al. in mice showing an acceleration of gastric contents throughout the gastrointestinal tract [56].
A clinical trial on 25 patients with neurogenic bowel due to spinal cord injury, fed with 800 mg of water decoction of Ponciri Fructus twice a day for 2-week periods, showing improved constipation resulting from short colon transit and improved stool morphology [97]. None of the subjects showed serious side effects except soft stool (2 people) and diarrhea (5 people) [97].

5.10. Hepatoprotective Activity

Ponciri Fructus contains hepatoprotective moieties isoimperatorin, which significantly inhibited aflatoxin B1-induced cytotoxicity in H4IIE cells by increasing endogenous glutathione and cytochrome p450 enzymes [36].

5.11. Tick Repellent Effect

Decoction of Ponciri Fructus showed tick-repellent properties towards Boophilus microplus and Haemaphysalis bispinosum species [98].

5.12. Effect on Acute Pancreatis

Pretreatment with Ponciri Fructus at the doses of 200 and 400 mg/kg ameliorated cerulein-induced acute pancreatitis in mice. The extract reduced pancreatic damage, myloperoxide level, and serum amylase in studied mice [99].

5.13. Neuroprotective Effects

25-Methoxy hispidol A isolated from fruits showed a significant neuroprotective effect in the anxiety and depression model of mice induced by bacterial infection. The compound demonstrated significant improvement in different behavioral tests, endogenous antioxidant enzyme levels, neurodegeneration of the hippocampus, and degree of inflammation [82].

5.14. Antiviral Activity

Ethanol extract of Ponciri Fructus inhibited the oseltamivir-resistant strain of influenza virus grown in Madin-Darby canine kidney cells. The extract was reported to work by altering the cellular penetration pathway of the virus into the cells [100].
Table 3 below shows list of bioactive compounds and their bioactivities observed in literature.

6. Polyherbal Formulations Containing Ponciri Fructus

6.1. Sam-Chul-Kun-Bi-Tang

Sam-chul-kun-bi-tang constitutes fourteen different herbal agents among which Ponciri Fructus covers 1/15th part by weight. This is widely used in Korean traditional medicine for the treatment of gastroptosis, chronic gastritis, and gastric ulcer. Several pharmacological activities have been identified in this formula including immunoregulatory activities, anti-inflammatory activity, and gastroprotective activity [171]. The formulation was found to modulate the pacemaker activity of interstitial cells of Cajal to control intestinal motility [172]. Yoo et al. also identified in vitro anti-adipogenic activity in 3T3-L1 preadipocytes and antioxidant activity in DPPH and ABTS free radical scavenging assays [37].

6.2. Jeechool-Whan

Jeechool-Whan is a traditional Korean medicine for the treatment of allergic diseases by strengthening spleen and stomach functions. This is due to the belief in Eastern Medical Theory that all diseases are the result of altered spleen and stomach functions. This formulation is made by mixing Ponciri Fructus and Atractylodis Rhizoma in a ratio of 1:2. A study on female BALB/c mice model of allergic rhinitis induced by ovalbumin showed that this formulation inhibited itching, levels of IgE, histamine, and inflammatory cytokines inhibiting the allergic response [42].

6.3. Mahwangyounpae-Tang

This herbal formula contains 22 different herbal extracts and has been used for ages to treat asthma and other respiratory diseases. Ponciri Fructus constitutes 1/25th part by weight in this formula. Park et al. found that an aqueous extract of this polyherbal formula is safe up to a 400 mg/kg dose in mice [38]. However, the extract was found to be effective at the low dose of 30 mg/kg in ovalbumin-induced asthmatic mice. The extract preserved trachea architecture by reducing inflammation [173]. The anti-asthmatic activity of this formulation was also supported by antibacterial effects and synergism with standard antibiotics [174].

6.4. Cheonggan (CGX)

Traditional Korean herbal medicine, CGX, is made by mixing 13 different herbs, in which Ponciri Fructus constitutes 1/19th part by weight. It is a famous formula for the treatment of patients with chronic hepatic diseases including hepatitis-B, fatty liver and alcoholic hepatitis [39]. Traditional use of this formula was also demonstrated in different clinical and experimental models of liver toxicity. This formula was also found to work by its antioxidant and immune regulatory potential [39].

6.5. Ojeok-San

This is one of the long used traditional Korean medicines prepared by mixing 17 different herbal agents including Ponciri Fructus (almost 1/18th part by weight). This formulation is prescribed for fever, rheumatism, inflammation, and hyperlipidemia [42].

7. Safety Issues

This fruit has been used for ages in traditional medicine safely; however, recent scientific studies also support those findings. A clinical trial on 25 patients with neurogenic bowel dysfunction were fed with 800 mg of water decoction obtained from Ponciri Fructus twice a day for 2-week periods. Which was found to be safe with minor side effects in a very low population (7 Patients: soft stool (2 people) and diarrhea (5 people)) [97]. Ojeok-San was also found safe in ICR mice up to a dose of 5000 mg/kg without noticeable toxicity [175]. Research showed no toxicity associated with Samchulgeonbi-tang consumption at the dose of 2000 mg/kg in ICR mice [176].
Figure 3 below shows summery of biological activities shown by Ponciri Fructus extract on different studies model.

8. Conclusion and Future Recommendation

In summary, this review article abridged the ethnomedicinal uses, bioactive constituents, and biological activities of Ponciri Fructus, a popular nutritional and medicinal plant used extensively in East Asian countries. Different books, traditional monographs, and scientific articles have mentioned Ponciri Fructus as a valuable nutritional component and effective folk remedy. Despite this, comprehensive information about collection time and techniques, processing methods, formulation technique, adequate dose, duration of medication, and possible toxicity have not been explained in detail yet. Therefore, there should be future clinical practice and investigation of Ponciri Fructus. Meticulous investigation of bioassay-guided isolation is mandatory because it is a very difficult task to optimize the biological activity of a multi-component complex herbal mixture to a targeted single bioactive molecule, because it possesses several classes of bioactive constituents. Moreover, the quantitative determination of major bioactive compounds present in Ponciri Fructus will be a key step to standardize the pharmacopeial standards for the crude drug, its extract, and possible formulations. In addition, great emphasis on the examination of possible toxicity in the human model and the study of pharmacokinetic parameters is recommended strongly. Moreover, sophisticated scientific investigations involving animal models and the discovery of the mechanism of action of bioactive molecules at the molecular level are very much crucial in future works.

Author Contributions

Conceptualization, G.L., J.P. and H.P.D.; writing—original draft preparation, G.L. and J.P.; writing—review and editing, G.L., J.P. and H.P.D.; supervision, H.P.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank Masato Watanabe, Kumamoto University, Japan for providing photographs.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

References

  1. Kunwar, R.M.; Bussmann, R.W. Ethnobotany in the Nepal Himalaya. J. Ethnobiol. Ethnomed. 2008, 4, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Atanasov, A.G.; Waltenberger, B.; Pferschy-Wenzig, E.M.; Linder, T.; Wawrosch, C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E.H.; et al. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol. Adv. 2015, 33, 1582–1614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Paudel, K.R.; Lee, U.W.; Kim, D.W. Chungtaejeon, A Korean fermented tea, prevents the risk of atherosclerosis in rats fed a high-fat atherogenic diet. J. Integr. Med. 2016, 14, 134–142. [Google Scholar] [CrossRef] [PubMed]
  4. Wadhwa, R.; Paudel, K.R.; Chin, L.H.; Hon, C.M.; Madheswaran, T.; Gupta, G.; Panneerselvam, J.; Lakshmi, T.; Singh, S.K.; Gulati, M.; et al. Anti-inflammatory and anticancer activities of naringenin-loaded liquid crystalline nanoparticles in vitro. J. Food Biochem. 2021, 45, e13572. [Google Scholar] [CrossRef] [PubMed]
  5. Paudel, K.R.; Karki, R.; Kim, D.W. Cepharanthine inhibits in vitro VSMC proliferation and migration and vascular inflammatory responses mediated by RAW264.7. Toxicol. Vitr. 2016, 34, 16–25. [Google Scholar] [CrossRef]
  6. Panth, N.; Paudel, K.R.; Gong, D.S.; Oak, M.H. Vascular protection by ethanol extract of Morus alba root bark: Endothelium dependent relaxation of rat aorta and decrease of smooth muscle cell migration and proliferation. Evid. Based Complement. Altern. Med. 2018, 2018, 7905763. [Google Scholar] [CrossRef] [Green Version]
  7. Devkota, H.P.; Paudel, K.R.; Khanal, S.; Baral, A.; Panth, N.; Adhikari-Devkota, A.; Jha, N.K.; Das, N.; Singh, S.K.; Chellappan, D.K.; et al. Stinging nettle (Urtica dioica L.): Nutritional composition, bioactive compounds, and food functional properties. Molecules 2022, 27, 5219. [Google Scholar] [CrossRef]
  8. Maiuolo, J.; Gliozzi, M.; Carresi, C.; Musolino, V.; Oppedisano, F.; Scarano, F.; Nucera, S.; Scicchitano, M.; Bosco, F.; Macri, R.; et al. Nutraceuticals and cancer: Potential for natural polyphenols. Nutrients 2021, 13, 3834. [Google Scholar] [CrossRef]
  9. Devkota, H.P.; Adhikari-Devkota, A.; Paudel, K.R.; Panth, N.; Chellappan, D.K.; Hansbro, P.M.; Dua, K. Tea (Catechins Including (−)-Epigallocatechin-3-Gallate) and Cancer. In Nutraceuticals and Cancer Signaling. Food Bioactive Ingredients; Jafari, S.M., Nabavi, S.M., Silva, A.S., Eds.; Springer: Cham, Switzerland, 2021; pp. 451–466. [Google Scholar]
  10. Lee, H.H.; Paudel, K.R.; Jeong, J.; Wi, A.J.; Park, W.S.; Kim, D.W.; Oak, M.H. Antiatherogenic effect of Camellia japonica fruit extract in high fat diet-fed rats. Evid. Based Complement. Altern. Med. 2016, 2016, 9679867. [Google Scholar] [CrossRef] [Green Version]
  11. Rehman, A.; Mehmood, M.H.; Haneef, M.; Gilani, A.H.; Ilyas, M.; Siddiqui, B.S.; Ahmed, M. Potential of black pepper as a functional food for treatment of airways disorders. J. Funct. Foods 2015, 19, 126–140. [Google Scholar] [CrossRef]
  12. De Vico, G.; Guida, V.; Carella, F. Urtica dioica (Stinging Nettle): A neglected plant with emerging growth promoter/immunostimulant properties for farmed fish. Front. Physiol. 2018, 9, 285. [Google Scholar] [CrossRef] [PubMed]
  13. Arya, S.S.; Salve, A.R.; Chauhan, S. Peanuts as Functional Food: A Review. J. Food Sci. Technol. 2016, 53, 31–41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Sidor, A.; Gramza-Michałowska, A. Advanced research on the antioxidant and health benefit of elderberry (Sambucus nigra) in food—A review. J. Funct. Foods 2015, 18, 941–958. [Google Scholar] [CrossRef]
  15. Jang, Y.; Kim, E.K.; Shim, W.S. Phytotherapeutic effects of the fruits of Poncirus trifoliata (L.) Raf. on cancer, inflammation, and digestive dysfunction. Phytother. Res. 2018, 32, 616–624. [Google Scholar] [CrossRef] [PubMed]
  16. Gao, D.; Cho, C.W.; Vinh, L.B.; Kim, J.H.; Kim, Y.H.; Kang, J.S. Phytochemical analysis of trifoliate orange during fermentation by HPLC–DAD–ESI–MS/MS coupled with multivariate statistical analysis. Acta Chromatogr. 2021, 33, 371–377. [Google Scholar] [CrossRef]
  17. Pang, X.M.; Wen, X.P.; Hu, C.G.; Deng, X.X. Genetic diversity of Poncirus accessions as revealed by amplified fragment length polymorphism (AFLP). J. Hortic. Sci. Biotechnol. 2006, 81, 269–275. [Google Scholar] [CrossRef]
  18. Yu, D.J.; Jun, J.H.; Kim, T.J.; Suh, D.K.; Youn, D.H.; Kim, T.W. The relaxing effect of Poncirus fructus and its flavonoid content on porcine coronary artery. Lab. Anim. Res. 2015, 31, 33–39. [Google Scholar] [CrossRef] [Green Version]
  19. Park, S.H.; Kwak, I.S. Effect of Photoprotective activities of Poncirus trifoliata immature Fruit extract and Naringin compound. J. Korea Converg. Soc. 2019, 10, 267–279. [Google Scholar]
  20. Wang, M.; Dai, W.; Du, J.; Ming, R.; Dahro, B.; Liu, J.H. ERF 109 of trifoliate orange (Poncirus trifoliata (L.) Raf.) contributes to cold tolerance by directly regulating expression of Prx1 involved in antioxidative process. Plant. Biotechnol. J. 2019, 17, 1316–1332. [Google Scholar] [CrossRef] [Green Version]
  21. Kim, J.K.; Choi, S.J.; Bae, H.; Kim, C.R.; Cho, H.Y.; Kim, Y.J.; Lim, S.T.; Kim, C.J.; Kim, H.K.; Peterson, S.; et al. Effects of methoxsalen from Poncirus trifoliata on acetylcholinesterase and trimethyltin-induced learning and memory impairment. Biosci. Biotechnol. Biochem. 2011, 75, 1984–1989. [Google Scholar] [CrossRef] [Green Version]
  22. World Flora Online (WFO). Poncirus trifoliata L. 2022. Available online: https://wfoplantlist.org/plant-list/taxon/wfo-0000608305-2022-06?matched_id=wfo-0001132893 (accessed on 25 October 2022).
  23. Hong, S.H.; Kim, H.M. Anti-Allergic Effect of Ponciri fructus. In Proceedings of the Korean Society of Food Science and Nutrition Conference; The Korean Society of Food Science and Nutrition: Jeju, Korea, 2004; pp. 110–115. [Google Scholar]
  24. Tong, R.; Peng, M.; Tong, C.; Guo, K.; Shi, S. Online extraction–high performance liquid chromatography–diode array detector–quadrupole time-of-flight tandem mass spectrometry for rapid flavonoid profiling of Fructus aurantii immaturus. J. Chromatogr. B 2018, 1077, 1–6. [Google Scholar] [CrossRef] [PubMed]
  25. Lim, T.K. Poncirus trifoliata. In Edible Medicinal and Non-Medicinal Plants; Springer: Dordrecht, The Netherlands, 2012; pp. 893–899. [Google Scholar]
  26. Changxun, G.; Zhiyong, P.; Shu’ang, P. Effect of biochar on the growth of Poncirus trifoliata (L.) Raf. seedlings in Gannan acidic red soil. Soil. Scie. Plant. Nutr. 2016, 62, 194–200. [Google Scholar] [CrossRef] [Green Version]
  27. Chatzissavvidis, C.; Antonopoulou, C.; Therios, I.; Dimassi, K. Responses of trifoliate orange (Poncirus trifoliata (L.) Raf.) to continuously and gradually increasing NaCl concentration. Acta. Bot. Croat. 2014, 73, 275–280. [Google Scholar] [CrossRef]
  28. Martínez-Alcántara, B.; Rodriguez-Gamir, J.; Martínez-Cuenca, M.R.; Iglesias, D.J.; Primo-Millo, E.; Forner-Giner, M.A. Relationship between hydraulic conductance and citrus dwarfing by the Flying Dragon rootstock (Poncirus trifoliata L. Raft var. monstruosa). Trees 2013, 27, 629–638. [Google Scholar] [CrossRef]
  29. Kroeff Schmitz, J.A.; Dutra de Souza, P.V.; Koller, O.C. Vegetative growth of Poncirus trifoliata L. Raf. inoculated with mycorrhizal fungi in three growing media. Commun. Soil. Sci. Plant Anal. 2001, 32, 3031–3043. [Google Scholar] [CrossRef]
  30. Wu, Q.S.; Xia, R.X.; Zou, Y.N.; Wang, G.Y. Osmotic solute responses of mycorrhizal citrus (Poncirus trifoliata) seedlings to drought stress. Acta Physiol. Plant. 2007, 29, 543–549. [Google Scholar] [CrossRef]
  31. Xu, G.H.; Kim, J.A.; Kim, S.Y.; Ryu, J.C.; Kim, Y.S.; Jung, S.H.; Kim, M.K.; Lee, S.H. Terpenoids and coumarins isolated from the fruits of Poncirus trifoliata. Chem. Pharm. Bull. 2008, 56, 839–842. [Google Scholar] [CrossRef] [Green Version]
  32. Jeon, W.Y.; Kim, O.S.; Seo, C.S.; Jin, S.E.; Kim, J.; Shin, H.K.; Kim, Y.U.; Lee, M.Y. Inhibitory effects of Ponciri Fructus on testosterone-induced benign prostatic hyperplasia in rats. BMC Complement. Altern. Med. 2017, 17, 384. [Google Scholar] [CrossRef] [Green Version]
  33. Kim, D.H.; Bae, E.A.; Han, M.J. Anti-Helicobacter pylori activity of the metabolites of poncirin from Poncirus trifoliata by human intestinal bacteria. Biol. Pharm. Bull. 1999, 22, 422–424. [Google Scholar] [CrossRef] [Green Version]
  34. Cho, H.E.; Ahn, S.Y.; Kim, S.C.; Woo, M.H.; Hong, J.T.; Moon, D.C. Determination of flavonoid glycosides, polymethoxyflavones, and coumarins in herbal drugs of citrus and poncirus fruits by high performance liquid chromatography–electrospray ionization/tandem mass spectrometry. Anal. Lett. 2014, 47, 1299–1323. [Google Scholar] [CrossRef]
  35. Hwang, Y.S.; Jang, J.P.; Park, S.H.; Kim, A.; Jang, J.H.; Yoon, H.R.; Yoon, S.R.; Park, J.H.; Cho, H.J.; Lee, H.G. Ponciri Fructus Immaturus ethanol extract attenuates septic shock through inhibition of the STAT1 signaling pathway. Front. Nutr. 2022, 9, 988309. [Google Scholar] [CrossRef] [PubMed]
  36. Pokharel, Y.R.; Han, E.H.; Kim, J.Y.; Oh, S.J.; Kim, S.K.; Woo, E.R.; Jeong, H.G.; Kang, K.W. Potent protective effect of isoimperatorin against aflatoxin B 1-inducible cytotoxicity in H4IIE cells: Bifunctional effects on glutathione S-transferase and CYP1A. Carcinogenesis 2006, 27, 2483–2490. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Yoo, S.R.; Seo, C.S.; Kim, O.S.; Shin, H.K.; Jeong, S.J. Anti-adipogenic and antioxidant effects of the traditional Korean herbal formula Samchulgeonbi-tang: An in vitro study. Int. J. Clin. Exp. Med. 2015, 8, 8698–8708. [Google Scholar] [PubMed]
  38. Park, M.Y.; Choi, H.Y.; Kim, J.D.; Lee, H.S.; Ku, S.K. 28 Days repeated oral dose toxicity test of aqueous extracts of mahwangyounpae-tang, a polyherbal formula. Food Chem. Toxicol. 2010, 48, 2477–2482. [Google Scholar] [CrossRef] [PubMed]
  39. Shin, J.W.; Park, H.J.; Kwon, M.; Son, C.G. Scientific evaluation of the chronic toxicity of the herbal medicine CGX in beagle dogs. Food. Chem. Toxicol. 2010, 48, 743–749. [Google Scholar] [CrossRef] [PubMed]
  40. Shin, J.W.; Kim, H.G.; Park, H.J.; Sung, N.W.; Son, C.G. Safety of the traditional Korean herbal medicine CGX: A 6-month repeated-dose study in rats. J. Ethnopharmacol. 2010, 128, 221–229. [Google Scholar] [CrossRef]
  41. Lee, M.K.; Lee, K.Y.; Kim, S.H.; Jeon, M.J.; Cho, J.H.; Oh, M.H.; Baek, J.H.; Kim, H.J.; Sung, S.H. Simultaneous determination of paeoniflorin and glycyrrhizin in sayuk-san by HPLC/DAD. J. Pharm. Investig. 2009, 39, 23–27. [Google Scholar] [CrossRef] [Green Version]
  42. Oh, H.A.; Ryu, J.G.; Cha, W.S.; Kim, H.M.; Jeong, H.J. Therapeutic effects of traditional Korean medicine, Jeechool-Whan in allergic rhinitis model. Cellmed 2012, 2, 1–9. [Google Scholar] [CrossRef] [Green Version]
  43. Weon, J.B.; Park, H.; Yang, H.J.; Ma, J.Y.; Ma, C.J. Simultaneous quantification of marker components in Ojeok-san by HPLC–DAD. J Nat. Med. 2011, 65, 375–380. [Google Scholar] [CrossRef]
  44. Han, S.H.; Jeong, B.J.; Woo, S.H.; Kim, B.C.; Kim, Y.H.; Seo, H.S.; Hwang, G.D.; Cho, C.J.; Nam, H.I.; Kim, J.W. A case report of diabetic hyperlipidemia in a patient with cerebral infarction treated with Ojeok-san. J. Int. Korean Med. 2005, 26, 275–280. [Google Scholar]
  45. Moon, Y.H.; Park, Y.J. Studies on the anti-inflammatory and analgesic activities of Ohjuksan. Korean J. Pharmacogn. 1994, 25, 258–263. [Google Scholar]
  46. Kim, M.; Seol, M.H.; Lee, B.C. The Effects of Poncirus fructus on insulin resistance and the macrophage-mediated inflammatory response in high fat diet-induced obese mice. Int. J. Mol. Sci. 2019, 20, 2858. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Lee, J.H.; Lee, S.H.; Kim, Y.S.; Jeong, C.S. Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease. Phytother. Res. 2009, 23, 1748–1753. [Google Scholar] [CrossRef] [PubMed]
  48. Park, J.; Jang, D.; Phung, H.M.; Choi, T.J.; Kim, C.E.; Lee, S.; Kang, K.S.; Choi, S.H. The potential of pharmacological activities of the multi-compound treatment for GERD: Literature review and a network pharmacology-based analysis. Appl. Biol. Chem. 2021, 64, 48. [Google Scholar] [CrossRef]
  49. Han, H.Y.; Park, B.S.; Lee, G.S.; Jeong, S.H.; Kim, H.; Ryu, M.H. Autophagic cell death by Poncirus trifoliata Rafin., a traditional oriental medicine, in human oral cancer HSC-4 cells. Evid. Based Complement. Altern. Med. 2015, 2015, 394263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Yi, J.M.; Kim, M.S.; Koo, H.N.; Song, B.K.; Yoo, Y.H.; Kim, H.M. Poncirus trifoliata fruit induces apoptosis in human promyelocytic leukemia cells. Clin. Chim. Acta. 2004, 340, 179–185. [Google Scholar] [CrossRef]
  51. Hong, J.Y.; Min, H.Y.; Xu, G.H.; Lee, J.G.; Lee, S.H.; Kim, Y.S.; Kang, S.S.; Lee, S.K. Growth inhibition and G1 cell cycle arrest mediated by 25-methoxyhispidol A, a novel triterpenoid, isolated from the fruit of Poncirus trifoliata in human hepatocellular carcinoma cells. Planta Med. 2008, 74, 151–155. [Google Scholar] [CrossRef]
  52. Yan, H.; Ma, Z.; Peng, S.A.; Deng, X. Anti-inflammatory effect of auraptene extracted from trifoliate orange (Poncirus trifoliate) on LPS-stimulated RAW 264.7 cells. Inflammation 2013, 36, 1525–1532. [Google Scholar] [CrossRef]
  53. Rahman, A.; Alam Siddiqui, S.; Jakhar, R.; Chul Kang, S. Growth inhibition of various human cancer cell lines by imperatorin and limonin from Poncirus trifoliata Rafin. seeds. Anti Cancer Agents Med. Chem. 2015, 15, 236–241. [Google Scholar] [CrossRef]
  54. Kim, B.J.; San Lee, G.; Kim, H.W. Involvement of transient receptor potential melastatin type 7 channels on Poncirus fructus-induced depolarizations of pacemaking activity in interstitial cells of cajal from murine small intestine. Integr. Med. Res. 2013, 2, 62–69. [Google Scholar] [CrossRef] [Green Version]
  55. Shim, W.S.; Back, H.; Seo, E.K.; Lee, H.T.; Shim, C.K. Long-term administration of an aqueous extract of dried, immature fruit of Poncirus trifoliata (L.) Raf. Suppresses body weight gain in rats. J. Ethnopharmacol. 2009, 126, 294–299. [Google Scholar] [CrossRef] [PubMed]
  56. Lee, H.T.; Seo, E.K.; Chung, S.J.; Shim, C.K. Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf. J. Ethnopharmacol. 2005, 102, 131–136. [Google Scholar] [CrossRef] [PubMed]
  57. Lu, Y.; Zhang, C.; Bucheli, P.; Wei, D. Citrus flavonoids in fruit and traditional Chinese medicinal food ingredients in China. Plant Foods Hum. Nutr. 2006, 61, 55–63. [Google Scholar] [CrossRef] [PubMed]
  58. Zhao, B.T.; Kim, E.J.; Son, K.H.; Son, J.K.; Min, B.S.; Woo, M.H. Quality evaluation and pattern recognition analyses of marker compounds from five medicinal drugs of Rutaceae family by HPLC/PDA. Arch. Pharm. Res. 2015, 38, 1512–1520. [Google Scholar] [CrossRef] [PubMed]
  59. Han, A.R.; Kim, J.B.; Lee, J.; Nam, J.W.; Lee, I.S.; Shim, C.K.; Lee, K.T.; Seo, E.K. A new flavanone glycoside from the dried immature fruits of Poncirus trifoliata. Chem. Pharm. Bull. 2007, 55, 1270–1273. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Nizamutdinova, I.T.; Jeong, J.J.; Xu, G.H.; Lee, S.H.; Kang, S.S.; Kim, Y.S.; Chang, K.C.; Kim, H.J. Hesperidin, hesperidin methyl chalone and phellopterin from Poncirus trifoliata (Rutaceae) differentially regulate the expression of adhesion molecules in tumor necrosis factor-α-stimulated human umbilical vein endothelial cells. Int. Immunopharmacol. 2008, 8, 670–678. [Google Scholar] [CrossRef]
  61. Martin-Smith, M.; Khatoon, T. Biological activity of the terpenoids and their derivatives. Prog. Drug Res./Fortschr. Der Arzneim./Progrès Des Rech. Pharm. 1963, 279–346. [Google Scholar]
  62. Park, H.R. Pancastatin A and B have selective cytotoxicity on glucose-deprived PANC-1human pancreatic cancer cells. J. Microbiol. Biotechnol. 2020, 30, 733–738. [Google Scholar] [CrossRef]
  63. Chung, H.J.; Park, E.J.; Pyee, Y.; Xu, G.H.; Lee, S.H.; Kim, Y.S.; Lee, S.K. 25-Methoxyhispidol A, a novel triterpenoid of Poncirus trifoliata, inhibits cell growth via the modulation of EGFR/c-Src signaling pathway in MDA-MB-231 human breast cancer cells. Food. Chem. Toxicol. 2011, 49, 2942–2946. [Google Scholar] [CrossRef]
  64. Genovese, S.; Taddeo, V.A.; Epifano, F.; Fiorito, S. Prenylated coumarins of the genus citrus: An overview of the 2006–2016 literature data. Curr. Med. Chem. 2018, 25, 1186–1193. [Google Scholar] [CrossRef]
  65. Rho, T.C.; Choi, H.C.; Kim, B.Y.; Kim, Y.H.; Ahn, J.S.; Kim, Y.K.; Lee, H.S. Inhibitory Effect of Coumarins on Nitric Oxide Production in LPS-Activated Murine Macrophages. Korean J. Pharmacogn. 1999, 30, 413–416. [Google Scholar]
  66. Lamichhane, G.; Pandeya, P.R.; Lamichhane, R.; Rhee, S.J.; Devkota, H.P.; Jung, H.J. Anti-obesity potential of Ponciri Fructus: Effects of extracts, fractions and compounds on adipogenesis in 3T3-L1 preadipocytes. Molecules 2022, 27, 676. [Google Scholar] [CrossRef] [PubMed]
  67. Lee, H.W. Isolation and Structure Determination of Bioactive Constituents from Poncirus trifoliata Raf. Master’s Thesis, Seoul National University, Seoul, South Korea, 2018. [Google Scholar]
  68. Pokharel, Y.R.; Jeong, J.E.; Oh, S.J.; Kim, S.K.; Woo, E.R.; Kang, K.W. Screening of potential chemopreventive compounds from Poncirus trifoliata Raf. Int. J. Pharm. Sci. 2006, 61, 796–798. [Google Scholar]
  69. Tundis, R.; Bonesi, M.; Sicari, V.; Pellicanò, T.M.; Tenuta, M.C.; Leporini, M.; Menichini, F.; Loizzo, M.R. Poncirus trifoliata (L.) Raf.: Chemical composition, antioxidant properties and hypoglycaemic activity via the inhibition of α-amylase and α-glucosidase enzymes. J. Funct. Foods. 2016, 25, 477–485. [Google Scholar] [CrossRef]
  70. Pan, X.; Liang, M. Analysis of essential Oil from fructus Ponciri trifoliatae immaturi by GC-MS. Tradit. Chin. Drug Res. Clin. Pharmacol. 2000, 6. [Google Scholar]
  71. Son, A.R.; Choi, J.Y.; Kim, J.A.; Cho, S.H.; Xu, G.H.; Park, S.H.; Chung, S.R.; Chung, T.C.; Jahng, Y.D.; Son, J.K.; et al. Isolation of melanogenesis inhibitors from Ponciri fructus. Korean J. Pharmacogn. 2005, 36, 1–8. [Google Scholar]
  72. Lee, H.T.; Seo, E.K.; Chung, S.J.; Shim, C.K. Effect of an aqueous extract of dried immature fruit of Poncirus trifoliata (L.) Raf. on intestinal transit in rodents with experimental gastrointestinal motility dysfunctions. J. Ethnopharmacol. 2005, 102, 302–306. [Google Scholar] [CrossRef] [PubMed]
  73. Jayaprakasha, G.K.; Mandadi, K.K.; Poulose, S.M.; Jadegoud, Y.; Gowda, G.N.; Patil, B.S. Inhibition of colon cancer cell growth and antioxidant activity of bioactive compounds from Poncirus trifoliata (L.) Raf. Bioorg. Med. Chem. 2007, 15, 4923–4932. [Google Scholar] [CrossRef]
  74. Ban, S.S.; Yoon, H.D.; Shin, O.C.; Shin, Y.J.; Park, C.S.; Park, J.H.; Seo, B.I. The effects of Artemisiae Capillaris, Ponciri Fructus and Cartaegi Fructus in obese rats induced by high fat diet. Korea J. Herbol. 2006, 21, 55–67. [Google Scholar]
  75. Jia, S.; Gao, Z.; Yan, S.; Chen, Y.; Sun, C.; Li, X.; Chen, K. Anti-obesity and hypoglycemic effects of Poncirus trifoliata L. extracts in high-fat diet C57BL/6 mice. Molecules 2016, 21, 453. [Google Scholar] [CrossRef] [Green Version]
  76. Lee, S.M.; Kang, Y.H.; Kim, K.K.; Kim, T.W.; Choe, M. A study of the lipoprotein lipase inhibitory mechanism of Poncirus trifoliata water extracts. J. Nutr. Health 2015, 48, 9–18. [Google Scholar] [CrossRef]
  77. Lee, J.W.; Jung, H.S.; Sohn, Y.; Kang, Y.J. Anti-inflammatory Effects of Ponciri Fructus Extracts on Raw 264.7 Cells. In Proceedings of the Plant Resources Society of Korea Conference; The Plant Resources Society of Korea: Chungbuk, Korea, 2018; p. 91. [Google Scholar]
  78. Song, C.S.; Park, E.J.; Jeong, G.M. Effects of Jiyutang with Fructus Immaturus Ponciri on the immune response in the Mouse. J. Pediatr. Korean Med. 1992, 6, 15–32. [Google Scholar]
  79. Jung, S.A.; Choi, Y.Y.; Yang, W.M. Anti-atopic dermatitis effects of poncirus trifoliata rafinesque via regulation of immune response and nerve growth factor. J. Korean Med. 2016, 37, 10–20. [Google Scholar] [CrossRef]
  80. Aeom, Y.D.; Kim, D.H.; Jeong, J.G.; Shin, M.K.; Song, H.J. The comparative study of Fructus Immaturus Ponciri and Fructus Ponciri effect on allergic reaction. J. Korean Orient. Med. 2001, 22, 10–21. [Google Scholar]
  81. Lee, Y.M.; Kim, C.Y.; Kim, Y.C.; Kim, H.M. Effects of Poncirus trifoliata on type I hypersensitivity reaction. Am. J. Chin. Med. 1997, 25, 51–56. [Google Scholar] [CrossRef] [PubMed]
  82. Shal, B.; Khan, A.; Naveed, M.; Khan, N.U.; AlSharari, S.D.; Kim, Y.S.; Khan, S. Effect of 25-methoxy hispidol A isolated from Poncirus trifoliate against bacteria-induced anxiety and depression by targeting neuroinflammation, oxidative stress and apoptosis in mice. Biomed. Pharmacother. 2019, 111, 209–223. [Google Scholar] [CrossRef]
  83. Shin, E.M.; Zhou, H.Y.; Xu, G.H.; Lee, S.H.; Merfort, I.; Kim, Y.S. Anti-inflammatory activity of hispidol A 25-methyl ether, a triterpenoid isolated from Ponciri Immaturus Fructus. Eur. J. Pharmacol. 2010, 627, 318–324. [Google Scholar] [CrossRef]
  84. Ko, J.S.; Lee, J.C.; Jang, Y.M.; Mun, Y.J.; Woo, W.H.; Lim, K.S.; Lee, Y.C. Inhibitory effect on melanogenesis of Ponciri fructus ethanol extract. J. Physiol. Pathol. Korean Med. 2008, 22, 829–834. [Google Scholar]
  85. Lee, G.W.; Park, S.M.; Yoo, Y.C.; Cho, Y.H. Effect of ponciri fructus extracts fermented with ganoderma lucidum on the collagen synthesis and expression of matrix metalloproteinase-1. KSBB J. 2013, 28, 106–114. [Google Scholar] [CrossRef] [Green Version]
  86. Lee, E. Antihyperlipidemic and antioxidant effects of Poncirus trifoliata. Korean J. Plant Resour. 2006, 19, 273–276. [Google Scholar]
  87. Ham, I.H.; Lee, U.C.; Lee, B.H.; Choi, H.Y. Lipid lowering activity of Ponciri Fructus and Aurantii Fructus Immaturus on hyperlipemia rats induced by Triton WR-1339. Korea J. Herbol. 2007, 22, 109–116. [Google Scholar]
  88. Cha, M.R.; Yoon, M.Y.; Son, E.S.; Park, H.R. Selective cytotoxicity of Ponciri Fructus against glucose-deprived PANC-1 human pancreatic cancer cells via blocking activation of GRP78. Biosci. Biotechnol. Biochem. 2009, 73, 2167–2171. [Google Scholar] [CrossRef] [PubMed]
  89. Kang, Y.H.; Kim, B.W.; Ha, Y.M.; Park, J.K.; Nam, S.Y.; Choi, K.C.; Choi, Y.M. Experimental Studies on Antitumor Activity of Herb Drugs (I)-Effectiveness on Rat Natural Killer Cell Activity. Korean J. Pharmacogn. 1987, 18, 118–126. [Google Scholar]
  90. Sim, J.R.; Jea, Y.; Kim, B.W. Study on Anticancer Effects of Putative Ponciri Fruit, Houttuyniae Herb, Manitis Squama and Polyporus in Rats. Kyung Hee Univ. Orient. Med. Diss. 1998, 11, 99–112. [Google Scholar]
  91. Kim, S.Y.; Yi, H.K.; Yun, B.S.; Lee, D.Y.; Hwang, P.H.; Park, H.R.; Kim, M.S. The extract of the immature fruit of Poncirus trifoliata induces apoptosis in colorectal cancer cells via mitochondrial autophagy. Food Sci. Hum. Wellness 2020, 9, 237–244. [Google Scholar] [CrossRef]
  92. Choi, Y.M.; Gu, J.B.; Kim, M.H.; Lee, J.S. Antioxidant and antiproliferative activities of methanolic extracts from thirty Korean medicinal plants. Food Sci. Biotechnol. 2008, 17, 1235–1239. [Google Scholar]
  93. Han, H.Y.; Ryu, M.H.; Son, Y.; Lee, G.; Jeong, S.H.; Kim, H. Poncirus trifoliata Rafin. induces the apoptosis of triple-negative breast cancer cells via activation of the c-Jun NH (2)-terminal kinase and extracellular signal-regulated kinase pathways. Pharmacogn. Mag. 2015, 11 (Suppl. S2), S237. [Google Scholar]
  94. Kim, Y.M. An Anti-MRSA (Methicillin Resistant Staphylococcus aureus) Activity and Antioxidant Activity of Poncirus trifoliata Extract. Ph.D. Thesis, Pukyung National University, Busan, Republic of Korea, 2008. [Google Scholar]
  95. Park, I.H.; Moon, G.; Kim, H.R.; Kim, J.H.; Hong, S.H. A Case of Liver Cirrhosis Patients Senile Pruritus Treated by External Preparation Containing Ponciri fructus and Radix lithospermi. J. Korean Med. Ophthalmol. Otolaryngol. Dermatol. 2016, 29, 231–239. [Google Scholar] [CrossRef]
  96. Choi, K.H.; Jeong, S.I.; Hwang, B.S.; Lee, J.H.; Ryoo, H.K.; Lee, S.; Choi, B.K.; Jung, K.Y. Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon. J. Ethnopharmacol. 2010, 127, 718–724. [Google Scholar] [CrossRef]
  97. Kim, J.H.; Lee, S.K.; Joo, M.C. Effects and safety of aqueous extract of Poncirus fructus in spinal cord injury with neurogenic bowel. Evid. Based Complement. Altern. Med. 2016, 2016, 7154616. [Google Scholar] [CrossRef] [Green Version]
  98. Lee, J.N. Studies on the Tick Killing and Repellent Effects of Two Korean Indigenous Crude Drugs, Radix Jingyu and Fructus Ponciri. Korean J. Vet. Res. 1962, 2, 15–26. [Google Scholar]
  99. Park, K.C.; Bae, G.S.; Choi, S.B.; Jo, I.J.; Gwak, T.S.; Lee, G.S.; Park, S.J.; Song, H.J. Protective effect of Poncirus trifoliata and Citrus aurantium extract on acute pancreatitis in mice model. Korea J. Herbol. 2012, 27, 9–14. [Google Scholar] [CrossRef] [Green Version]
  100. Heo, Y.; Cho, Y.; Cho, H.; Park, K.H.; Choi, H.; Yoon, J.K.; Moon, C.; Kim, Y.B. Antiviral activity of Poncirus trifoliata seed extract against oseltamivir-resistant influenza virus. J. Microbiol. 2018, 56, 586–592. [Google Scholar] [CrossRef] [PubMed]
  101. Venkatarame Gowda Saralamma, V.; Nagappan, A.; Hong, G.E.; Lee, H.J.; Yumnam, S.; Raha, S.; Heo, J.D.; Lee, S.J.; Lee, W.S.; Kim, E.H.; et al. Poncirin induces apoptosis in AGS human gastric cancer cells through extrinsic apoptotic pathway by up-regulation of fas ligand. Int. J. Mol. Sci. 2015, 16, 22676–22691. [Google Scholar] [CrossRef] [Green Version]
  102. Zhu, X.; Luo, F.; Zheng, Y.; Zhang, J.; Huang, J.; Sun, C.; Li, X.; Chen, K. Characterization, purification of poncirin from edible citrus ougan (Citrus reticulate cv. suavissima) and its growth inhibitory effect on human gastric cancer cells SGC-7901. Int. J. Mol. Sci. 2013, 14, 8684–8697. [Google Scholar] [CrossRef] [Green Version]
  103. Ali, M.Y.; Zaib, S.; Rahman, M.M.; Jannat, S.; Iqbal, J.; Park, S.K.; Chang, M.S. Poncirin, an orally active flavonoid exerts antidiabetic complications and improves glucose uptake activating PI3K/Akt signaling pathway in insulin resistant C2C12 cells with anti-glycation capacities. Bioorg. Chem. 2020, 102, 104061. [Google Scholar]
  104. Ullah, H.; Khan, A.; Baig, M.W.; Ullah, N.; Ahmed, N.; Tipu, M.K.; Ali, H.; Khan, S. Poncirin attenuates CCL4-induced liver injury through inhibition of oxidative stress and inflammatory cytokines in mice. BMC Complement. Med. Ther. 2020, 20, 115. [Google Scholar] [CrossRef] [Green Version]
  105. Ullah, H.; Khan, A.; Bibi, T.; Ahmad, S.; Shehzad, O.; Ali, H.; Seo, E.K.; Khan, S. Comprehensive in vivo and in silico approaches to explore the hepatoprotective activity of poncirin against paracetamol toxicity. Naunyn Schmiedeberg’s Arch. Pharmacol. 2022, 395, 195–215. [Google Scholar] [CrossRef]
  106. Afridi, R.; Khan, A.U.; Khalid, S.; Shal, B.; Rasheed, H.; Ullah, M.Z.; Shehzad, O.; Kim, Y.S.; Khan, S. Anti-hyperalgesic properties of a flavanone derivative Poncirin in acute and chronic inflammatory pain models in mice. BMC Pharmacol. Toxicol. 2019, 20, 57. [Google Scholar] [CrossRef] [Green Version]
  107. Yang, L.X.; Chen, F.Y.; Yu, H.L.; Liu, P.Y.; Bao, X.Y.; Xia, S.N.; Gu, Y.; Xu, Y.; Cao, X. Poncirin suppresses lipopolysaccharide (LPS)-induced microglial inflammation and ameliorates brain ischemic injury in experimental stroke in mice. Ann. Transl. Med. 2020, 8, 1344. [Google Scholar] [CrossRef]
  108. Kang, G.D.; Kim, D.H. Poncirin and its metabolite ponciretin attenuate colitis in mice by inhibiting LPS binding on TLR4 of macrophages and correcting Th17/Treg imbalance. J. Ethnopharmacol. 2016, 189, 175–185. [Google Scholar] [CrossRef] [PubMed]
  109. Lin, J.; Zhu, J.; Wang, Y.; Zhang, N.; Gober, H.J.; Qiu, X.; Li, D.; Wang, L. Chinese single herbs and active ingredients for postmenopausal osteoporosis: From preclinical evidence to action mechanism. Biosci. Trends 2017, 11, 496–506. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Wang, R.; Li, L.; Wang, B. Poncirin ameliorates oxygen glucose deprivation/reperfusion injury in cortical neurons via inhibiting NOX4-mediated NLRP3 inflammasome activation. Int. Immunopharmacol. 2022, 102, 107210. [Google Scholar] [CrossRef] [PubMed]
  111. Chun, K.H.; Jin, H.C.; Kang, K.S.; Chang, T.S.; Hwang, G.S. Poncirin inhibits osteoclast differentiation and bone loss through down-regulation of NFATc1 in vitro and in vivo. Biomol. Ther. 2020, 28, 337. [Google Scholar] [CrossRef]
  112. Yao, Q.; Lin, M.T.; Zhu, Y.D.; Xu, H.L.; Zhao, Y.Z. Recent trends in potential therapeutic applications of the dietary flavonoid didymin. Molecules 2018, 23, 2547. [Google Scholar] [CrossRef] [Green Version]
  113. Ali, M.Y.; Zaib, S.; Rahman, M.M.; Jannat, S.; Iqbal, J.; Park, S.K.; Chang, M.S. Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Chem. Biol. Interact. 2019, 305, 180–194. [Google Scholar] [CrossRef]
  114. Chen, R.; Qi, Q.L.; Wang, M.T.; Li, Q.Y. Therapeutic potential of naringin: An overview. Pharm. Biol. 2016, 54, 3203–3210. [Google Scholar] [CrossRef] [Green Version]
  115. Kiran, S.D.; Rohini, P.; Bhagyasree, P. Flavonoid: A review on Naringenin. J. Pharmacogn. Phytochem. 2017, 6, 2778–2783. [Google Scholar]
  116. Da Silva, R.R.; De Oliveira, T.T.; Nagem, T.J.; Pinto, A.S.; Albino, L.F.; De Almeida, M.R.; De Moraes, G.H.; Pinto, J.G. Hypocholesterolemic effect of naringin and rutin flavonoids. Arch. Latinoam. Nutr. 2001, 51, 258–264. [Google Scholar]
  117. Sehrawat, N.; Upadhyay, S.K.; Sharma, A.K.; Kumar, S.; Yadav, M. Emerging renoprotective role of citrus flavonoid naringin: Current pharmaceutical status and future perspectives. Curr. Pharmacol. Rep. 2021, 7, 96–101. [Google Scholar] [CrossRef]
  118. Pereira, R.M.; Andrades, N.E.; Paulino, N.; Sawaya, A.C.; Eberlin, M.N.; Marcucci, M.C.; Favero, G.M.; Novak, E.M.; Bydlowski, S.P. Synthesis and characterization of a metal complex containing naringin and Cu, and its antioxidant, antimicrobial, antiinflammatory and tumor cell cytotoxicity. Molecules 2007, 12, 1352–1366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Pyrzynska, K. Hesperidin: A Review on Extraction Methods, Stability and Biological Activities. Nutrients 2022, 14, 2387. [Google Scholar] [CrossRef] [PubMed]
  120. Dhanya, R.; Jayamurthy, P. In vitro evaluation of antidiabetic potential of hesperidin and its aglycone hesperetin under oxidative stress in skeletal muscle cell line. Cell Biochem. Funct. 2020, 38, 419–427. [Google Scholar] [CrossRef] [PubMed]
  121. Akhter, S.; Arman, M.S.; Tayab, M.A.; Islam, M.N.; Xiao, J. Recent advances in the biosynthesis, bioavailability, toxicology, pharmacology, and controlled release of citrus neohesperidin. Crit. Rev. Food Sci. Nutr. 2022, 1–20. [Google Scholar] [CrossRef] [PubMed]
  122. Shishir, M.R.; Karim, N.; Gowd, V.; Xie, J.; Zheng, X.; Chen, W. Pectin-chitosan conjugated nanoliposome as a promising delivery system for neohesperidin: Characterization, release behavior, cellular uptake, and antioxidant property. Food Hydrocoll. 2019, 95, 432–444. [Google Scholar] [CrossRef]
  123. Zhang, J.; Sun, C.; Yan, Y.; Chen, Q.; Luo, F.; Zhu, X.; Li, X.; Chen, K. Purification of naringin and neohesperidin from Huyou (Citrus changshanensis) fruit and their effects on glucose consumption in human HepG2 cells. Food Chem. 2012, 135, 1471–1478. [Google Scholar] [CrossRef]
  124. Han Jie, L.; Jantan, I.; Yusoff, S.D.; Jalil, J.; Husain, K. Sinensetin: An insight on its pharmacological activities, mechanisms of action and toxicity. Front. Pharmacol. 2021, 11, 553404. [Google Scholar] [CrossRef]
  125. Yang, D.; Yang, R.; Shen, J.; Huang, L.; Men, S.; Wang, T. Sinensetin attenuates oxygen–glucose deprivation/reperfusion-induced neurotoxicity by MAPK pathway in human cerebral microvascular endothelial cells. J. Appl. Toxicol. 2022, 42, 683–693. [Google Scholar] [CrossRef]
  126. Kim, J.A.; Kim, S.M.; Ha, S.E.; Vetrivel, P.; Saralamma, V.V.; Kim, E.H.; Kim, G.S. Sinensetin regulates age-related sarcopenia in cultured primary thigh and calf muscle cells. BMC Complement. Altern. Med. 2019, 19, 287. [Google Scholar] [CrossRef] [Green Version]
  127. Xiong, Y.J.; Deng, Z.B.; Liu, J.N.; Qiu, J.J.; Guo, L.; Feng, P.P.; Sui, J.R.; Chen, D.P.; Guo, H.S. Enhancement of epithelial cell autophagy induced by sinensetin alleviates epithelial barrier dysfunction in colitis. Pharmacol. Res. 2019, 148, 104461. [Google Scholar] [CrossRef]
  128. Singh, A.P.; Kandpal, J.B.; Sharma, R.K.; Chitme, H. Nobiletin a biologically active phytoconstituent: Systematic review. J. Biol. Act. Prod. Nat. 2021, 11, 204–211. [Google Scholar] [CrossRef]
  129. Li, S.; Wang, H.; Guo, L.; Zhao, H.; Ho, C.T. Chemistry and bioactivity of nobiletin and its metabolites. J. Funct. Foods 2014, 6, 2–10. [Google Scholar] [CrossRef]
  130. Mileykovskaya, E.; Yoo, S.H.; Dowhan, W.; Chen, Z. Nobiletin: Targeting the circadian network to promote bioenergetics and healthy aging. Biochemistry 2020, 85, 1554–1559. [Google Scholar] [CrossRef]
  131. Salehi, B.; Cruz-Martins, N.; Butnariu, M.; Sarac, I.; Bagiu, I.C.; Ezzat, S.M.; Wang, J.; Koay, A.; Sheridan, H.; Adetunji, C.O.; et al. Hesperetin’s health potential: Moving from preclinical to clinical evidence and bioavailability issues, to upcoming strategies to overcome current limitations. Crit. Rev. Food Sci. Nutr. 2022, 62, 4449–4464. [Google Scholar] [CrossRef] [PubMed]
  132. Yang, H.; Wang, Y.; Xu, S.; Ren, J.; Tang, L.; Gong, J.; Lin, Y.; Fang, H.; Su, D. Hesperetin, a promising treatment option for diabetes and related complications: A literature review. J. Agric. Food Chem. 2022, 70, 8582–8592. [Google Scholar] [CrossRef] [PubMed]
  133. Famurewa, A.C.; Renu, K.; Eladl, M.A.; Chakraborty, R.; Myakala, H.; El-Sherbiny, M.; Elsherbini, D.M.; Vellingiri, B.; Madhyastha, H.; Wanjari, U.R.; et al. Hesperidin and hesperetin against heavy metal toxicity: Insight on the molecular mechanism of mitigation. Biomed. Pharmacother. 2022, 149, 112914. [Google Scholar] [CrossRef] [PubMed]
  134. Scoditti, E. Neuroinflammation and neurodegeneration: The promising protective role of the citrus flavanone hesperetin. Nutrients 2020, 12, 2336. [Google Scholar] [CrossRef]
  135. Mitra, S.; Lami, M.S.; Uddin, T.M.; Das, R.; Islam, F.; Anjum, J.; Hossain, M.J.; Emran, T.B. Prospective multifunctional roles and pharmacological potential of dietary flavonoid narirutin. Biomed. Pharmacother. 2022, 150, 112932. [Google Scholar] [CrossRef]
  136. Yang, H.; Shan, Z.; Guo, W.; Wang, Y.; Cai, S.; Li, F.; Huang, Q.; Liu, J.A.; Cheung, C.W.; Cai, S. Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1. 7 Voltage-Gated Sodium Channel. Int. J. Mol. Sci. 2022, 23, 14842. [Google Scholar] [CrossRef]
  137. Qurtam, A.A.; Mechchate, H.; Es-Safi, I.; Al-Zharani, M.; Nasr, F.A.; Noman, O.M.; Aleissa, M.; Imtara, H.; Aleissa, A.M.; Bouhrim, M.; et al. Citrus flavanone narirutin, in vitro and in silico mechanistic antidiabetic potential. Pharmaceutics 2021, 13, 1818. [Google Scholar] [CrossRef]
  138. Zhou, H.Y.; Shin, E.M.; Guo, L.Y.; Zou, L.B.; Xu, G.H.; Lee, S.H.; Ze, K.R.; Kim, E.K.; Kang, S.S.; Kim, Y.S. Anti-inflammatory activity of 21 (α, β)-methylmelianodiols, novel compounds from Poncirus trifoliata Rafinesque. Eur. J. Pharmacol. 2007, 572, 239–248. [Google Scholar] [CrossRef] [PubMed]
  139. Shal, B.; Khan, A.; Naveed, M.; Ali, H.; Seo, E.K.; Choi, H.; Khan, S. Neuroprotective effect of 25-Methoxyhispidol A against CCl4-induced behavioral alterations by targeting VEGF/BDNF and caspase-3 in mice. Life Sci. 2020, 253, 117684. [Google Scholar] [CrossRef] [PubMed]
  140. Aldonza, M.B.; Hong, J.Y.; Bae, S.Y.; Song, J.; Kim, W.K.; Oh, J.; Shin, Y.; Lee, S.H.; Lee, S.K. Suppression of MAPK signaling and reversal of mTOR-dependent MDR1-associated multidrug resistance by 21α-methylmelianodiol in lung cancer cells. PLoS ONE 2015, 10, e0127841. [Google Scholar]
  141. Garg, B.J.; Garg, N.K.; Beg, S.; Singh, B.; Katare, O.P. Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: Formulation optimization, in vitro evaluation and preclinical assessment. J. Drug Target. 2016, 24, 233–246. [Google Scholar] [CrossRef]
  142. Deng, M.; Xie, L.; Zhong, L.; Liao, Y.; Liu, L.; Li, X. Imperatorin: A review of its pharmacology, toxicity and pharmacokinetics. Eur. J. Pharmacol. 2020, 879, 173124. [Google Scholar] [CrossRef]
  143. Nasser, M.I.; Zhu, S.; Hu, H.; Huang, H.; Guo, M.; Zhu, P. Effects of imperatorin in the cardiovascular system and cancer. Biomed. Pharmacother. 2019, 120, 109401. [Google Scholar] [CrossRef]
  144. Wang, N.; Wang, J.; Zhang, Y.; Zeng, Y.; Hu, S.; Bai, H.; Hou, Y.; Wang, C.; He, H.; He, L. Imperatorin ameliorates mast cell-mediated allergic airway inflammation by inhibiting MRGPRX2 and CamKII/ERK signaling pathway. Biochem. Pharmacol. 2021, 184, 114401. [Google Scholar] [CrossRef]
  145. Tsai, Y.F.; Chen, C.Y.; Lin, I.W.; Leu, Y.L.; Yang, S.C.; Syu, Y.T.; Chen, P.J.; Hwang, T.L. Imperatorin alleviates psoriasiform dermatitis by blocking neutrophil respiratory burst, adhesion, and chemotaxis through selective phosphodiesterase 4 inhibition. Antioxid. Redox Signal. 2021, 35, 885–903. [Google Scholar] [CrossRef]
  146. Kim, T.; Hyun, C.G. Imperatorin Positively Regulates Melanogenesis through Signaling Pathways Involving PKA/CREB, ERK, AKT, and GSK3β/β-Catenin. Molecules 2022, 27, 6512. [Google Scholar] [CrossRef]
  147. Kowalczyk, J.; Nakos-Bimpos, M.; Polissidis, A.; Dalla, C.; Kokras, N.; Skalicka-Woźniak, K.; Budzyńska, B. Imperatorin Influences Depressive-like Behaviors: A Preclinical Study on Behavioral and Neurochemical Sex Differences. Molecules 2022, 27, 1179. [Google Scholar] [CrossRef]
  148. Kim, N.Y.; Jung, Y.Y.; Yang, M.H.; Um, J.Y.; Sethi, G.; Ahn, K.S. Isoimperatorin down-regulates epithelial mesenchymal transition through modulating NF-κB signaling and CXCR4 expression in colorectal and hepatocellular carcinoma cells. Cell. Signal. 2022, 99, 110433. [Google Scholar] [CrossRef] [PubMed]
  149. Tong, K.; Xin, C.; Chen, W. Isoimperatorin induces apoptosis of the SGC-7901 human gastric cancer cell line via the mitochondria-mediated pathway. Oncol. Lett. 2017, 13, 518–524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. Lai, Y.; Han, T.; Zhan, S.; Jiang, Y.; Liu, X.; Li, G. Antiviral Activity of Isoimperatorin against Influenza a Virus in vitro and its Inhibition of Neuraminidase. Front. Pharmacol. 2021, 12, 657826. [Google Scholar] [CrossRef]
  151. Wijerathne, C.U.; Seo, C.S.; Song, J.W.; Park, H.S.; Moon, O.S.; Won, Y.S.; Kwon, H.J.; Son, H.Y. Isoimperatorin attenuates airway inflammation and mucus hypersecretion in an ovalbumin-induced murine model of asthma. Int. Immunopharmacol. 2017, 49, 67–76. [Google Scholar] [CrossRef] [PubMed]
  152. Guo, N.; Wu, J.; Fan, J.; Yuan, P.; Shi, Q.; Jin, K.; Cheng, W.; Zhao, X.; Zhang, Y.; Li, W.; et al. In vitro activity of isoimperatorin, alone and in combination, against M ycobacterium tuberculosis. Lett. Appl. Microbiol. 2014, 58, 344–349. [Google Scholar] [CrossRef]
  153. Jiang, T.; Shi, X.; Yan, Z.; Wang, X.; Gun, S. Isoimperatorin enhances 3T3 L1 preadipocyte differentiation by regulating PPARγ and C/EBPα through the Akt signaling pathway. Exp. Ther. Med. 2019, 18, 2160–2166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Chen, G.; Liu, Y.; Xu, Y.; Zhang, M.; Guo, S.; Zhang, G. Isoimperatorin exerts anti-inflammatory activity by targeting the LPS-TLR4/MD-2-NF-κB pathway. Eur. J. Inflamm. 2021, 19, 1–10. [Google Scholar] [CrossRef]
  155. Ouyang, J.; Jiang, H.; Fang, H.; Cui, W.; Cai, D. Isoimperatorin ameliorates osteoarthritis by downregulating the mammalian target of rapamycin C1 signaling pathway. Mol. Med. Rep. 2017, 16, 9636–9644. [Google Scholar] [CrossRef] [Green Version]
  156. Zou, J.; Duan, Y.; Wang, Y.; Liu, A.; Chen, Y.; Guo, D.; Guo, W.; Li, S.; Su, Z.; Wu, Y.; et al. Phellopterin cream exerts an anti-inflammatory effect that facilitates diabetes-associated cutaneous wound healing via SIRT1. Phytomedicine 2022, 107, 154447. [Google Scholar] [CrossRef]
  157. Bao, R.; Wang, S.; Yang, X.; Chen, G.; Meng, X. Phellopterin-induced caspase-dependent apoptosis through PI3K/AKT pathway inhibition in SMMC-7721 human hepatoma cells. Lat. Am. J. Pharm. 2018, 37, 2498–2501. [Google Scholar]
  158. Fiorito, S.; Preziuso, F.; Sharifi-Rad, M.; Marchetti, L.; Epifano, F.; Genovese, S. Auraptene and umbelliprenin: A review on their latest literature acquisitions. Phytochem. Rev. 2022, 21, 317–326. [Google Scholar] [CrossRef]
  159. Sunagawa, Y.; Kawaguchi, S.; Miyazaki, Y.; Katanasaka, Y.; Funamoto, M.; Shimizu, K.; Shimizu, S.; Hamabe-Horiike, T.; Kawase, Y.; Komiyama, M.; et al. Auraptene, a citrus peel-derived natural product, prevents myocardial infarction-induced heart failure by activating PPARα in rats. Phytomedicine 2022, 107, 154457. [Google Scholar] [CrossRef] [PubMed]
  160. Hsia, C.H.; Jayakumar, T.; Lu, W.J.; Sheu, J.R.; Hsia, C.W.; Saravana Bhavan, P.; Manubolu, M.; Huang, W.C.; Chang, Y. Auraptene, a Monoterpene Coumarin, Inhibits LTA-Induced Inflammatory Mediators via Modulating NF-κB/MAPKs Signaling Pathways. Evid. Based Complement. Altern. Med. 2021, 2021, 5319584. [Google Scholar] [CrossRef] [PubMed]
  161. Charmforoshan, E.; Karimi, E.; Oskoueian, E.; Iranshahi, M. Antibacterial, Antioxidant and Melanogenesis Inhibitory Activity of Auraptene, a Coumarin from Ferula szowitsiana Root. Nutr. Cancer 2022, 74, 1829–1836. [Google Scholar] [CrossRef]
  162. Mazimba, O. Umbelliferone: Sources, chemistry and bioactivities review. Bull. Fac. Pharm. Cairo Univ. 2017, 55, 223–232. [Google Scholar] [CrossRef]
  163. Zhao, L.; Jin, X.; Xiong, Z.; Tang, H.; Guo, H.; Ye, G.; Chen, D.; Yang, S.; Yin, Z.; Fu, H.; et al. The Antivirulence Activity of Umbelliferone and Its Protective Effect against A. hydrophila-Infected Grass Carp. Int. J. Mol. Sci. 2022, 23, 11119. [Google Scholar] [CrossRef] [PubMed]
  164. Cruz, L.F.; de Figueiredo, G.F.; Pedro, L.P.; Amorin, Y.M.; Andrade, J.T.; Passos, T.F.; Rodrigues, F.F.; Souza, I.L.; Gonçalves, T.P.; dos Santos Lima, L.A.; et al. Umbelliferone (7-hydroxycoumarin): A non-toxic antidiarrheal and antiulcerogenic coumarin. Biomed. Pharmacother. 2020, 129, 110432. [Google Scholar] [CrossRef]
  165. Khan, A.; Shehzad, O.; Seo, E.K.; Onder, A.; Khan, S. Anti-allergic activities of Umbelliferone against histamine-and Picryl chloride-induced ear edema by targeting Nrf2/iNOS signaling in mice. BMC Complement. Med. Ther. 2021, 21, 215. [Google Scholar]
  166. Hindam, M.O.; Sayed, R.H.; Skalicka-Woźniak, K.; Budzyńska, B.; El Sayed, N.S. Xanthotoxin and umbelliferone attenuate cognitive dysfunction in a streptozotocin-induced rat model of sporadic Alzheimer’s disease: The role of JAK2/STAT3 and Nrf2/HO-1 signalling pathway modulation. Phytother. Res. 2020, 34, 2351–2365. [Google Scholar] [CrossRef]
  167. Mottaghipisheh, J. Oxypeucedanin: Chemotaxonomy, isolation, and bioactivities. Plants 2021, 10, 1577. [Google Scholar] [CrossRef]
  168. Tavakoli, S.; Delnavazi, M.R.; Hadjiaghaee, R.; Jafari-Nodooshan, S.; Khalighi-Sigaroodi, F.; Akhbari, M.; Hadjiakhoondi, A.; Yassa, N. Bioactive coumarins from the roots and fruits of Ferulago trifida Boiss., an endemic species to Iran. Nat. Prod. Res. 2018, 32, 2724–2728. [Google Scholar] [CrossRef] [PubMed]
  169. Wangchuk, P.; Pyne, S.G.; Keller, P.A.; Taweechotipatr, M.; Kamchonwongpaisan, S. Phenylpropanoids and furanocoumarins as antibacterial and antimalarial constituents of the Bhutanese medicinal plant Pleurospermum amabile. Nat. Prod. Commun. 2014, 9, 957–960. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Okada, R.; Abe, H.; Okuyama, T.; Nishidono, Y.; Ishii, T.; Sato, T.; Shirako, S.; Tanaka, K.; Ikeya, Y.; Nishizawa, M. Comparison of the anti-inflammatory activities of furanocoumarins from the roots of Angelica dahurica. Bioact. Compd. Health Dis. 2021, 4, 287–300. [Google Scholar] [CrossRef]
  171. Lee, J.A.; Ha, H.K.; Jung, D.Y.; Lee, H.Y.; Lee, N.H.; Lee, J.K.; Huang, D.S.; Shin, H.K. Anti-inflammatory Effects of Sam-chul-kun-bi-tang. J. Korean Med. 2010, 31, 47–54. [Google Scholar] [CrossRef] [PubMed]
  172. Kim, J.N.; Kwon, Y.K.; Kim, B.J. Effects of Samchulkunbi-tang in Cultured Interstitial Cells of Cajal of Murine Small Intestine. J. Physiol. Pathol. Korean Med. 2013, 27, 112–117. [Google Scholar]
  173. Kim, J.Y.; Kim, J.D.; Kam, C.W. Effects of mahwangyoonpye-tang on asthma induced by ovalbumin in mouse. J. Physiol. Pathol. Korean Med. 2003, 17, 1453–1462. [Google Scholar]
  174. Liu, H.H.; Park, M.Y.; Choi, H.Y.; Gu, D.M.; Kim, J.D.; Song, K.K. Synergic effect of Mahwangyounpae-tang and ciprofloxacin on 5 strains of aerobic Gram-negative bacteria. J. Physiol. Pathol. Korean Med. 2005, 19, 684–689. [Google Scholar]
  175. Um, Y.R.; Lee, J.H.; Moon, H.J.; Park, H.Y.; Ma, J.Y. Acute toxicity study on Ojeok-san (Wuji-san) in mice. J. Korean Obstet. Gynecol. 2009, 22, 135–142. [Google Scholar]
  176. Jung, Y.P.; Yim, N.H.; Kim, A.; Hwang, Y.H.; Park, H.; Ma, J.Y. Single Oral Dose Toxicity Test of Fermented Samchulgeonbi-tang Extract in ICR mice. Korea J. Herbol. 2013, 28, 61–65. [Google Scholar] [CrossRef]
Molecules 28 00255 g001 550
Figure 1. Photographs of different plant parts of Poncirus trifoliata. (a) Tree bearing mature fruits, (b) flower (c) immature fruits and (d) dried immature fruits used as crude drug Ponciri Fructus. [Photo credits: Masato Watanabe (a–c), Gopal Lamichhane (d)].
Figure 1. Photographs of different plant parts of Poncirus trifoliata. (a) Tree bearing mature fruits, (b) flower (c) immature fruits and (d) dried immature fruits used as crude drug Ponciri Fructus. [Photo credits: Masato Watanabe (a–c), Gopal Lamichhane (d)].
Molecules 28 00255 g001
Molecules 28 00255 g002 550
Figure 2. Structure of representative bioactive compounds isolated from Ponciri Fructus.
Figure 2. Structure of representative bioactive compounds isolated from Ponciri Fructus.
Molecules 28 00255 g002
Molecules 28 00255 g003 550
Figure 3. Summary of pharmacological activities of Ponciri Fructus.
Figure 3. Summary of pharmacological activities of Ponciri Fructus.
Molecules 28 00255 g003
Table
Table 1. Chemical composition of essential oils isolated from the fresh peel of P. trifoliata fruits [69].
Table 1. Chemical composition of essential oils isolated from the fresh peel of P. trifoliata fruits [69].
CompoundsRelative Amount (%)
Limonene41.73
Myrcene15.68
(E)-β-Ocimene5.05
α-Phellandrene4.11
β-Pinene3.95
trans-Caryophyllene3.59
Ethyl hexanoate2.22
Ethyl octanoate2.12
p-Cimene1.5
α-Pinene1.19
Sabinene1.17
β-Farnesene1.16
(E,Z)-Farnesol1.02
Hexyl butanoate0.98
δ-Cadinene0.73
α-Humulene0.72
Ethyl decanoate0.72
γ-Terpinene0.70
Linalool0.69
Nerol0.65
β-Elemene0.59
Geranyl acetate0.56
Terpinolene0.54
Geraniol0.52
Germacrene B0.51
p-Mentha-1,3,8-triene0.46
Ethyl laurate0.46
Spathulenol0.44
(E)-Nerolidol0.42
Decanal0.42
Pentacosane0.42
Ethyl stearate0.35
Eicosane0.35
Neryl acetate0.34
Heptacosane0.32
Ethyl myristate0.31
α-Terpineol0.30
α-Cubebene0.28
Myristic acid0.26
Ethyl linoleate0.23
Dodecanal0.22
γ-Cadinene0.20
Octadecane0.14
Nonadecane0.12
Nonacosane<0.1
Nonanal<0.1
Terpinen-4-ol<0.1
α-Terpinene<0.1
Table
Table 2. Quantitative analysis of the chemical constituents from the fresh fruit juice and seed extract of P. trifoliata by using HPLC [69].
Table 2. Quantitative analysis of the chemical constituents from the fresh fruit juice and seed extract of P. trifoliata by using HPLC [69].
Identified CompoundsFresh Fruit Juice
(µg/mL)		Seed Extract
(µg/g of Dry Extract)
Flavanone aglycones
Hesperetin55.13Not detected
Naringenin28.65Not detected
Flavanone-O-glycosides
Didymin78.83156.42
Hesperidin129.33Not detected
Naringin115.79Not detected
Narirutin75.7337.62
Neohesperedin32.7580.12
Poncirin49.37Not detected
Flavone aglycones
Rhamnetin0.37Not detected
Quercetin0.76Not detected
Flavone-O-glycoside
Rutin1.85Not detected
Phenolic acids
Caffeic acid18.4632.85
Chlorogenic acid112.54Not Detected
Table
Table 3. Bioactive chemical constituents isolated from Ponciri Fructus and their pharmacological activities.
Table 3. Bioactive chemical constituents isolated from Ponciri Fructus and their pharmacological activities.
Bioactive CompoundPharmacological Activities
PoncirinAnticancer [101,102], antidiabetic [103], hepatoprotective [104,105], analgesics [106], anti-inflammatory [106,107], attenuation of colitis [108], anti-bacterial, anti-adipogenic [109], neuroprotective [110], suppression of osteoclast differentiation [111]
Neoponcirin (didymin)Anticancer, neuroprotective, anxiolytic, antinociceptive hepatoprotective, and cardioprotective, anti-inflammatory activities [112], antidiabetic [113]
NaringinAnticancer, antioxidant, anti-inflammatory, neuroprotective, increased bone regeneration, genoprotective, amelioration of metabolic syndrome [114], hepatoprotective, cardioprotective, gastroprotective, immuno-promotive [115], hypocholesterolemic [116], renoprotective [117], antibacterial [118]
HespiridinAntioxident, anti-inflammatory, anticancer, antiviral, cardioprotective, neuroprotective, antibacterial, radioprotective, wound healing [119], antidiabetic [120]
NeohesperidinNeuroprotective, anti-inflammatory, antidiabetic, antimicrobial, anticancer, gastroprotective, cardioprotective, hepatoprotective, anti-obesity [121], antioxidant [122], increased glucose uptake [123]
SinensetinAntiangiogenetic, anticancer, anti-dementia, anti-inflammatory, antimicrobial, anti-obesity, antidiabetic, antioxidant, anti-trypanosomal, diuretic, hypolipidemic, vasorelaxant [124], neuroprotective [125], alleviation of age-related muscle loss [126], gastroprotective [127]
NobiletinAnticancer, anti-obesity, antioxidant, memory enhancing, chondroprotective, anti-tuberculosis, hepatoprotective, cardioprotective, anti-hypertensive, immunoenhancing, gastroprotective, antiviral [128], amelioration of metabolic disorders [129], anti-aging [130]
HesperetinAnticancer, cardioprotective, regulation of carbohydrate and lipids metabolism, osteoprotective, anti-asthmatic, radioprotective, regulation of melanogenesis, anti-inflammatory [131], antidiabetic [132], mitigation of heavy metals toxicity [133], neuroprotective [134]
NarirutinAnticancer, neuroprotective, anti-inflammatory, antidepressant, hepatoprotective, antioxidant, anti-adipogenic, immunomodulatory, antiallergic [135], analgesics [136], antidiabetic [137]
21β-MethylmelianodiolAnti-inflammatory [138]
Hispidol β 25-methyl etherAnti-inflammatory [83], neuroprotective [82]
Hispidol A 25-methyl etherNeuroprotective [139]
21α-MethylmelianodiolAnti-inflammatory [138], anticancer [140]
Pancastatin A and BAnticancer [62]
25-Methoxyhispidol A and BNeuroprotective [139], anticancer [51], anti-inflammatory [83]
MethoxsalenVitiligo management [141]
ImperatorinNeuroprotective, anticancer, anti-inflammatory, antihypertensive, antibacterial, antiviral, anticoagulant [142], antioxidant [143], antiallergic [144], anti-psoriatic [145], regulation of melanogenesis [146], antidepressant [147]
IsoimperatorinAnticancer [148,149], antiviral [150], anti-asthmatic [151], antibacterial [152], anti-adipogenic [153], anti-inflammatory [154], alleviation of osteoarthritis [155]
PhellopterinWound healing, anti-inflammatory [156], anticancer [157], anti-adipogenic [66]
AurapteneNeuroprotective, antioxidant, anticancer, inhibition of platelet aggregation, hepatoprotective, antibacterial [158], cardioprotection [159], anti-inflammatory [160], melanogenesis inhibition [161]
UmbelliferoneAntibacterial, antifungal, antioxidant, antidiabetic, anticancer, molluscicidal [162], antiviral [163], antidiarrheal [164], antiallergic [165], anti- Alzheimer [166]
OxypeucedaninAntiallergic, antiarrhythmic, anticonvulsant, antifeedant, antigenotoxic, ant inflammatory, antimalarial, antimicrobial, antioxidant, antiproliferative, antiviral, calcium antagonistic, cytotoxic, insecticidal, phytotoxic [167], anti-adipogenic [66]
Oxypeucedanin methanolateAntioxidant, antibacterial [168], antimalarial [169], anti-inflammatory [170]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lamichhane, G.; Pandey, J.; Devkota, H.P. Bioactive Chemical Constituents and Pharmacological Activities of Ponciri Fructus. Molecules 2023, 28, 255. https://doi.org/10.3390/molecules28010255

AMA Style

Lamichhane G, Pandey J, Devkota HP. Bioactive Chemical Constituents and Pharmacological Activities of Ponciri Fructus. Molecules. 2023; 28(1):255. https://doi.org/10.3390/molecules28010255

Chicago/Turabian Style

Lamichhane, Gopal, Jitendra Pandey, and Hari Prasad Devkota. 2023. "Bioactive Chemical Constituents and Pharmacological Activities of Ponciri Fructus" Molecules 28, no. 1: 255. https://doi.org/10.3390/molecules28010255

Article Metrics

Back to TopTop