Goji Bery: Important Bioactive Ingredients. A Mini-Review

Introduction

General

Goji berry (Lycium sp) well known as wolfberry, boxthorn andkuko (in Japanese) orgou qi and keitze in Chinese is the common name of the fruits given by the expert in Tibetan traditional medicine and ethnobotanist Dr. Bradley Dobos. The genus Lycium (Solanaceae) contains about 80 representatives sprouting in distinct regions and distributed from the temperate to the subtropical regions of Eurasia, North America, South America South Africa and Australia [1]. Nowadays, the largest quantities of commercially produced goji berry fruits come from the Ningxia Hui in north-central China. Goji berry has been used as a medicine and functional food in Asia since ancient times and historical use of these fruits is important in traditional medicinal cultures such as China and Japan. According to traditional Chinese medicine the beneficial action of Goji berries, was related to their ability to contribute to the regeneration and stimulation of the liver and kidneys, improve the vision and act as a tonic to human body [2]. Thus, since the decade of 1980’s numerous of research studies have been published with the aim to relate human health with the beneficial effects of goji berries fruit consumption. These studies have mainly focused on the antioxidant, anti-aging protection, neuro-protection, protection against glaucoma and diabetes, antimicrobial protection and antitumor properties as well as the immune-modulating effects of goji berry consumption [3-10]. Additional positive effects related to goji berry consumption are that it significantly reduces fatigue and stress and improves regularity of gastrointestinal function [11].

Important Bioactive Ingredients

According to Zhong, et al. [12] the proximate composition of dry goji berry fruits is 46% carbohydrates, 13% protein, 1.5% fat and 16% dietary fiber. Concerning vitamin and mineral content, Montesano, et al. [13], reported that 00 g of fresh goji berries contains 35 mg of vitamin C, 150.8 mg of potassium (K) and 61.4 mg of sodium (Na).

Polysaccharides: Among the biofunctional compounds described in goji berry fruit, polysaccharides are considered as one of the most important and their concentration varies from 1.02%- 2.48% and 5%-8% for fresh and dried fruits, respectively [14]. Goji berry polysaccharides are well explored for their bioactivity and considered among the most important bioactive ingredients of the fruit. They are glycosylated proteins, and most of them are water soluble. Pectic polysaccharides are major components, but glucan, xylan and arabino-galactan-proteins (AGPs) are also included. In the literature, they are designated as L. barbarum polysaccharides (LBP), and the range of their molecular weights is 10-2300 kDa [15,16]. LBP consist of nine monosaccharides, arabinose (Ara), galactose (Gal), glucose (Glc), fucose (Fuc), mannose (Man), rhamnose (Rha), xylose (Xyl), fructose (ribose), galacturonic acid (GalA) and glucuronic acid (GlcA), and 22 amino acids, aspartic acid, glutamic acid, hydroxyproline, serine, alanine, glycine, histidine, arginine, threonine, proline, tyrosine, valine, methionine, cystine, isoleucine, leucine, phenylalanine, tryptophan, ornithine and lysine. LBP qualitative and quantitative profile in monosaccharides as well as the position of their glycosidic linkages and their molecular weight collectively determine their pharmacological function. So far, about 30 polysaccharides in L. barbarum and 10 polysaccharides in L. chinense have been identified and characterized.

Polyphenols: Polyphenols are a complex group of more than 8000 known compounds found in many plant species and plant residuals that have become very popular in recent years due to the biological properties attributed to them [17-25]. The polyphenolic profile of L. barbarum consists of flavonoids and phenolic acids. According to Wang, et al. [26], the L. barbarum polyphenolic profile consists of phenolic acids (caffeic, coumaric, chlorogenic and caffeoylquinate) and flavonoids (quercetin diglucoside, -quercetin-3-O-rutinoside and nicotinflorin). Donno, et al. [27] carried out high pressure liquid chromatography (HPLC) analysis of polyphenolic profile of three samples of goji berry fruits originating from northern Italy plants of a variety developed after crossing L. barbarum and L.chinense species. The analytical results indicated that the three samples contained on average sinaminic acids, benzoic acids, flavonols, catechins, organic acids and vitamin C at levels of 461.14, 15.31, 116.27, 347.94, 4461.02 and 48.94 mg per 100 g-1fresh fruit. In addition, Zhang, et al. [28], by testing eight samples of Chinese goji berry genotypes, came to the conclusion that fresh fruits derived from the four genotypes of the Ningxia region had the highest phenolic content and that quercetin-rhamno-dihexoside (435-1065 μg g-1) and quercetin-3-O-rutinoside (159-629 μg g-1) appeared at higher concentrations than the flavonoid group, whereas chlorogenic acid was the predominant phenolic acid (526 μg g-1).

Carotenoids: Carotenoids possess remarkable bioactive properties. The high percentage of carotenoids of goji berry fruits as well as their carotenoid profile make then an ideal source of these nutrients. According to Ma, et al. [29] goji berry carotenoid content depends on the season and territory of cultivation, and it is found to be higher in summer fruits than in fruit harvested in later seasons. Peng, et al. [30] observed that the total carotenoid content of different varieties of goji berry fruits ranges between 0.03% and 0.5% w/w. Among carotenoids, zeaxanthin and its esters are the most important carotenoids of L. barbarum [31,32]. The content of zeaxanthinates in goji berry fruit at the maturation stage can reach 77.5% of total carotenoids [33]. In particular, zeaxanthin dipalmitate is the predominant carotenoid in goji berries and along with zeaxanthin has been the focus of many researchers concerning their protective role against macular atrophic degeneration (AMD) [30,34,35]. Furthermore, zeaxanthin and its esters have been reported to exhibit anti-hepatotoxic activity comparable to that of silybin [36]. Zeaxanthin and other carotenoids such as β-carotene are also powerful antioxidants with proven positive health effects against oxidative stress-induced diseases. Concerning the carotenoid qualitative and quantitative profile in goji berries, Li, et al. [31], by using HPLC-DAD analysis, isolated and identified 10 carotenoids in total, including zeaxanthin, β-cryptoxanthin and their esters. In addition, Inbaraj, et al. [37], using HPLC-MS/GC flame ionization detector (GC-FID), isolated, identified and quantified 11 free carotenoids and 7 carotenoid esters, in particular zeaxanthin dipalmitate (1143.7 μg/g), monopalmitate β-cryptoxanthin isomers (32.9–68.5 μg/g), isoxanthinmonopalmitate isomers (11.3–62,8 μg/g), trans-β-carotene (23.7 μg/g) and all-trans-zeaxanthin (1.4 μg/g).

Fatty Acids: The beneficial properties of fatty acids, which are constituents of phospholipids- glycolipids in biological membranes in the human body, are related to the fact that they are involved in important metabolic processes. Fatty acids are also precursor molecules for the biosynthesis of essential steroid hormones and carry intracellular messages [38-41]. A number of studies, represented in provide data about the qualitative and quantitative fatty acid profile of Goji berries [8,42-47]. The results of these studies suggest that linoleic, oleic, palmitic, α-linolenic, stearic and arachidic acids are the primary fatty acids found in higher concentrations in goji berry fruits. On the contrary, Li, et al. [46] found that the concentration of the previously mentioned fatty acids was very low in oil derived from L. barbarum seeds.

Other Bioactive Ingredients: In addition to the major components mentioned previously, goji berry fruit also contains alkaloids, terpenes, cyclic peptides, cerebrosides, betaine, phytosterols and a number of important volatile compounds [48] presenting biological activity. Cerebrosides have been identified in L. chinense and, according to a study completed by Kim, et al. [49] they demonstrated hepato-protective activity against galactosamine-induced hepatotoxicity in a rat model. Other goji berry compounds with hepato-protective effects are the pyrrole derivatives and betaine [50]. On a dry basis, the betaine content of goji berry L. chinense leaves was reported to be 1.5% and 0.9%- 1.4% throughout the L. barbarum plant [51,52]. Lyciumin, a cyclic octapeptide (phenylpropanoids) found also in the roots of L. chinense, and it has been reported as a potential antihypertensive agent due to its inhibitory effects on the angiotensin-converting enzyme [53]. In addition, the 2-O-(β-D-glucopyranosyl) ascorbic acid (AA-2βG), which is a precursor of vitamin C, was isolated from Goji berries. The content of this pro-vitamin C compound was reported to be about 0.5% w/w on a dry basis for L. barbarum fruit, and relevant studies have shown that it increases the level of ascorbic acid in rat blood and additionally contributes to the antioxidant and anti-aging properties of goji berries [54].

Conclusion

The beneficial effects of goji berry fruits on human health include antioxidant and anti-aging activity; immunomodulatory and anti-cancer activities; antidiabetic, anti-hypertensive and hepatoprotective activity; protective effects on vision and finally prebiotic activity. Thus, the use of goji berries and their extracts in the production of high added value food and nutraceuticals that promote human health seems to be a quite promising research topic, involving innovative cutting-edge technologies that allowing full preservation of fruit bioactivity in the finished products.

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Review and Case Report: Active Surveillance Therapy with Citrus-Peel Extracts’ Efficacy Against Prostate Cancer

Introduction

Prostate cancer is the most common cancer for men in Japan. It usually grows very slowly. Most men who develop prostate cancer are older than 65 years and do not die from the disease since prostate cancer usually grows very slowly [1]. The withdrawal rate from active surveillance therapy to a second (traditional) therapy is said to be 14 – 41% [2]. During active surveillance therapy, patients feel uneasiness for not taking any traditional medications. Some of them thus turn to noninvasive therapy such as complementary and alternative medicine (CAM) [3].

Case Report

This is a case of a 76-year-old male. Because his PSA value rose to 6.4 ng/mL at the age of 61, he was recommended a prostatic biopsy by other doctors. According to the pathological examination, two out of six specimens indicated G3+4. CT and bone scintigraphy revealed his stage was T2aNoMo. This patient chose active surveillance therapy. Obvious changes were not observed for about nine years; however, in 2014 his PSA value gradually increased to over 10 ng/mL. Then he started drinking citrus-peel extract known as GL among researchers (Gold Lotion produced by Miyauchi Citrus Research Center, Ltd., Takasaki, Japan) as a CAM therapy. We recommended another biopsy to him to be assured of no prostate cancer progression. The patient under active surveillance was a little anxious about receiving no traditional medical treatment, so that careful follow-up of PSA levels was required. Although the PSA level was rising, MRI examination did not indicate obvious abnormal lesions. The patient heard about GL by word of mouth and was willing to try it out on him. One-year drinking of GL showed no abnormal results in MRI, except for prostatic adenoma (Figure 1). His PSA increased to 11.2 ng/mL. He decided to have another biopsy. Collected specimens showed no sign of progression in Gleason score but a small number of cancer cells (one out of six specimens with G3+4) in September 2015. He decided to continue active surveillance therapy with GL. As of November 2017, his PSA value remained less than 11 ng/mL for about 4 years despite small interruption periods of GL drinking (Figures 2A & 2B).

Figure 1: MRI showed large prostate adenoma; however, the margin is smooth with no lymph node swelling.

Figure 2: Clinical course of this patient
A. From the initinal diagnosis from 2006 to 2014,
B. Afer GL drinking period from 2014 to 2019.

Discussion and Conclusion

Complementary and alternative medicine (CAM) is a form of treatment used in addition to or instead of standard therapy. Standard treatments go through a long and careful research process to prove they are safe and effective, but less is known about most types of CAM. In the treatment of advanced-stage cancer, CAM is carried out as palliative therapy, about which the National Institute of Health (NIH) provides precise information on their website: calcium, green tea [4], lycopene, pomegranate, selenium and vitamin E, soy, and modified citrus pectin. Selenium and vitamin E are probably two of the most popular dietary supplements being considered for their use in the reduction of prostate cancer risk. Thirty-six percent of cancer patients in Hawaii used CAM [5]. GL, containing citrus pectin, also contains a high amount of nobiletin which is effective against prostate cancer cells, according to an in vivo nude mouse study [6]. Furthermore, GL contains other polymethoxyflavones (PMFs), exerting beneficial effects through antigrowth, antiangiogenesis, and cell cycle arrest commands or mediate signals to live or die by apoptosis.

Treatment with GL by both intraperitoneal (i.p.) injection and oral administration dramatically reduced both weights (57%-100% inhibition) and volumes (78%-94% inhibition) of the tumors without any observed toxicity. These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of inflammatory enzymes (inducible nitric oxide synthase, iNOS and cyclooxygenase-2, COX-2), metastasis (matrix metallopeptidase-2, MMP-2 and MMP-9), angiogenesis (vascular endothelial growth factor, VEGF), and proliferative molecules, as well as by the induction of apoptosis in prostate tumors [7]. Recent research showed flavonoid has a useful compound to prevent proliferation and migration of prostate cancer cells through PI3K/ Akt/NFkB signaling [8]. Among other GL cases, some patients showed favorable clinical results (Figure 3).

Figure 3: List of patients who used GL and clinical and results (supported by Miyauchi citrus laboratories).

During active surveillance therapy, particularly for the patient who often tends to develop anxiety [9], CAM was a useful method to get rid of his anxiety. Although it is unknown whether the rise in PSA when starting to drink GL was due to cancer progression, there was no deterioration in his urination condition nor an increase in the amount of residual urine that indicates the progression of cancer [10]. The rise in PSA may be assumed to be an indication of progression. However, after the start of GL oral administration, his serum free testosterone level stayed normal; therefore, the effect on the endocrine system seems low. Hence, it is my opinion that subsequent treatments shall not be negatively influenced by the use of GL. In conclusion, in some limited cases, the addition of GL to Active Surveillance therapy can be considered as an effective method to eliminate patients’ anxiety, and some anticancer effects can be expected.

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