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Goji berry fruits demonstrated anti-oxidative properties that are associated with age-related diseases such as diabetes, atherosclerosis and antitumor and immunoregulatory activities. Bioactive secondary metabolites contained in fruit lead to positive effects for human vision, while other biochemicals contained in the root bark have shown hepatoprotective and inhibitory actions on the rennin/angiotensin system.
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1. Introduction
Modern life-styles and dietary habits are the main cause of several human modern diseases such as diabetes, hepatitis and cardiovascular issues [1,2,3][1][2][3]. About 1/5 of the known plant species [4] that have participated in pharmaceutical studies cover a wide range of beneficial effects on human health, animal welfare and crop protection by enhancing human health against free radical damage [5,6,7,8,9,10,11,12,13][5][6][7][8][9][10][11][12][13]. The high concentrations of phytochemicals found in plants are accumulated mainly in their fruits and vegetables. Among beneficial phytochemicals, antioxidant compounds including phenolics, anthocyanins, carotenoids, and tocopherols may be used as a supplement for the human body by acting as natural antioxidants [14]. Thus, the consumption of fruit and vegetables has been linked with several health benefits, as a result of medicinal properties and high nutritional value [15] and is recommended by many scientists throughout the world [16]. In more detail, many studies mention the antioxidant and pharmacological activities of different plant extracts [17,18,19,20][17][18][19][20].
Among important plant species with significant biomedical issues is the Goji berry where fruit juice, roots and leaves contain ingredients that have a variety of bioactive properties [21,22,23,24][21][22][23][24].
2. Bioactivities
2.1. Antioxidant Activity
The most studied molecular mechanism of the oxidation of cellular components is that of lipid peroxidation. This is a circular feedback chain process, which, if started and not suspended in time, can oxidize all the biological material. DNA can tolerate a large number of different oxidative lesions, depending on the factors that cause them. Unlike oxidized proteins, which are usually fragmented and their amino acids reused, the oxidized DNA can be repaired in situ. Insufficient DNA repair can result in mutation and, ultimately, cell death by either necrosis or apoptosis.
The amino acids cysteine, methionine, tyrosine, phenylalanine, tryptophan and histidine are more susceptible to oxidative modifications. Relatively recent research results in this field commented on the fact that oxidative modifications of amino acid residues in proteins, besides the negative effects, may also play a positive role by participating in the redox signaling process.
Goji berries have been shown to possess antioxidant properties, neutralizing the oxidative action of free radicals and activating antioxidant mechanisms (Figure 1), such as an increase in superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), and erythroid-derived 2-like 2 (Nrf2) expression of several antioxidant and cytoprotective enzymes [25]. Thus, L. barbarum extracts exhibited the binding of peroxide anion radicals and the subsequent reduction of their activity [26].
Figure 1. Health-promoting properties of goji berry fruits and extracts.
The protective effect on the inhibition of lipid peroxidation by goji berry extracts is probably due to the polyphenols of goji berry fruit (Figure 2) [27]. Caffeic acid, which is the main hydroxycinnamic acid in goji berries, not only has potent antioxidant effects but also has anti-inflammatory and anti-cancer effects, while recent studies have shown that caffeic acid in its free form or conjugated to other groups, such as quinic acid and sugars, has a protective effect against Alzheimer’s disease [28].
Figure 2. The chemical structure of the polyphenols contained in “Goji berries”.
Moreover, ethanol extract (70% w/v) of L. chinense protects hepatic cells against oxidative stress-induced cell damage by removing intracellular ROS, SOD recovery, CAT and glutathione action, reducing lipid oxidation, DNA destruction and protein carbonyl values [29]. Further, Changbo et al. [30] have shown that the administration of LBP in mice can reduce the oxidative stress caused after exercise in swimming, increasing the antioxidant enzymes SOD, CAT and GPx.
2.2. Antiaging Activity
Aging is defined as the accumulation of various deleterious changes in cells and tissues [34][31], especially for elderly people [35][32]. Several studies have shown that genetic and environmental factors regulate specific pathways involved in hormone signaling, nutritional signaling and the detection of mitochondrial and ROS signaling and genomic survival. It is a common belief that the accumulation of the effects of oxidative stress contributes to the aging process [36,37,38][33][34][35]. For this reason, many of the experimental aging models use the pouring of D-galactose into mouse or rat tissues for a period of 6–8 weeks as a toxin in order to produce free radicals [39][36]. According to Deng et al. [40][37], the addition on a daily basis of 100 mg LBP/kg to the diet of mice reduced serum advanced glycation end products (AGE), retrieving the memory pointer back to experimental animals, increasing superoxide dismutase levels in erythrocytes and finally helping them to restore kinetic activity. The life cycle of Drosophila melanogaster (fruit-fly) has been used as an alternative model for aging studies. Based on this model, the addition of 16 mg LBP/kg shows a statistically significant increase of the average life span of male insects [41][38]. Furthermore, studies conducted on elderly mice have shown that the consumption of 200–500 mg/kg of LBP promotes oxidative stress reduction, as it reduces the oxidative stress markers associated with the aging process [42][39]. It has also been reported that LBP activates the antioxidative pathways Nrf2/ARE and Nrf2/HO-1 by activating antioxidants and detoxifying enzymes. One of these enzymes is heme oxygenase-1 (HO-1), which is regulated by the factor associated with the nuclear factor erythroid 2–related factor 2 (Nrf2) [43][40]. In vivo studies on Factor Nrf2 have shown that it plays an important role in the endogenous antioxidant system by regulating the expression of important antioxidant enzymes, such as oxygenase-1 (HO-1), SOD and CAT. In particular, in oxidative stress or exogenous (pharmacological) activation, Nrf2 moves into the cell nucleus and induces the expression of antioxidant enzymes by blocking the antioxidant response (ARE) [44][41]. It has also been commented that activation of PI3K/AKT/Nrf2 not only prevents the development of oxidative stress but also prevents metabolic glucose abnormalities such as the occurrence of insulin resistance. Activation of Nrf2 by LBP offers a new alternative therapeutic approach to the prevention of insulin resistance caused by a long-term high-fat diet [45][42]. The effect of ultraviolet radiation (UVB) causes skin damage by inducing oxidative and inflammatory lesions and thus causes aging and carcinogenicity of the skin. The protective effect of LBPs through the induction of Nrf2 is likely to exert a protective effect against the negative effect of ultraviolet radiation on the skin by binding to the active radicals and reducing DNA damage, resulting in the suppression of the ultraviolet-induced P38 MAP pathway. Based on the previous beneficial effects, LBP could potentially be used as an ingredient in products intended to protect the skin against oxidative damage from environmental conditions [32][43].2.3. Antitumor and Immunoregulatory Activity
The defensive mechanisms of vertebrates are also known as the immune system. The immune system recognizes and destroys foreign invaders and toxic substances by a process known as an immune response. The molecule that causes the immune response is called an antigen. In addition, these mechanisms are involved in the body’s effort to remove aged or damaged cells, as well as destroying cancer cells, while sometimes they cause damage against the tissues of the organism itself. The two main groups of cells in the immune system are the cells of the medullary line and the lymphocytes. Lymphocytes include B-lymphocytes and T-lymphocytes as well as a large granular cell, NK (or natural killer cells). The medullary cells consist of monocytes/macrophages, dendritic cells, neutrophils, eosinophils and basophils. B lymphocytes have an antibody molecule in their membrane, whereas T lymphocytes have an antigen-binding receptor in their membrane. When a B cell encounters an antigen, it quickly divides and differentiates into a B-cell memory and a B-cell effector or plasmid cell. Plasmocytes produce a large number of antibodies (antibody, Ab) or immunoglobulin (immunoglobulin, Ig) that act on the antigen and destroy it. T-lymphocytes, when they meet an antigen or tumor, secrete cytokines (growth factors), directly killing the infected target cell (CD8 killer T cells) and also activating B-cells to make antibody responses and macrophages to destroy microorganisms that either invaded the macrophage or were ingested by it (CD4 helper T cell). There are two types of immunity—humoral and cellular. Humoral immunity is mediated by antibodies produced by B cells and is the main defensive mechanism against extracellular microbes and their toxins, with secreted antibodies binding to them by inducing their elimination. Cellular immunity is mediated by T cells, with dendritic cells playing an important role against antigens.2.4. Antidiabetic Activity
The number of patients with diabetes worldwide has quadrupled over the last 30 years, and it is the ninth leading cause of death. One in 11 adults today has type II diabetes, accounting for 90% of diabetes cases, and the prediction is that by 2050, one in three will suffer from diabetes. The majority of people suffering from diabetes are aged between 45 and 64. Sugar, a common constituent of diet, is also a major factor often responsible for elevating the glucose level in diabetic patients [59][44]. Diabetes mellitus is a metabolic disease characterized by an increase in blood sugar (hyperglycemia) and a metabolic disorder of glucose (C6H12O6), either as a result of decreased insulin secretion or due to a decrease in the sensitivity of cells to insulin. Insulin is a hormone produced in the pancreas that forces the liver and muscle cells to absorb blood glucose and store it as glycogen for future body energy needs. In case the insulin concentration in the body is low or zero and glucose absorption cannot take place, the body begins to use fat as a source of energy by transporting lipids from adipose tissue to the liver [60][45]. Nowadays, there are known various types of diabetes. The main diabetes types are type I and type II. In general, diabetes is associated with the risk of serious health complications, including myocardial infarction, stroke, kidney failure, vision loss and premature death. So required care for diabetics is likely to be needed for many years [61][46]. The effect of the antidiabetic action of goji berry extracts has been investigated in various studies. Goji berries may have a positive effect on blood glucose control, as documented in relevant studies described in a study published by Silva et al. [62][47]. Furthermore, in a study completed by Wu et al. [63][48] feeding of type 2 diabetic mice with goji berry extract for 4 weeks showed a decrease in blood glucose levels by 35%. Moreover, Zhang et al. [64][49] suggested that the fraction LBPF4-OL of the LBP promotes lymphocyte proliferation secreting TNF-α and IL-1β. Luo et al. [48][50] also showed that L. barbarum extracts have hypoglycemic and hypolipidemic effects as well as strong antioxidant activity in rabbits with diabetes and hyperlipidemia from aloxane.2.5. Hypertension and Heart Protective Effects
Hypertension is today one of the major public health problems due to its high incidence, its importance in cardiovascular disease and its correlation with a large number of health problems leading to death. Nearly one in two adults (about 103 million people) suffer from hypertension in the United States only [72][51]. Hypertension is influenced by factors such as genetics, lack of exercise and dietary intake of sodium, which is one of the most common causes of hypertension. It has been reported that the dietary sodium intake has been correlated with blood pressure, confirming the sensitivity of blood pressure to salt [73][52].
Regarding LBP’s protective positive effects on myocardial I/R damage Shao Ping and Pin-Ting [74][53] used in their study of Wistar adult male rats. In their study, it was presented that LBPs protected rat hearts from I/R injury via upregulation of heart Na+/K+-ATPase and inhibition of cardiomyocyte apoptosis concluding the cardioprotective effect of LBP stems caused by their antioxidant, anti-inflammatory and anti-apoptotic activities.
Prophylactic activity of LBP against cardiotoxic side effects of doxorubicin (DOX), which is a potent antitumor agent, has been also demonstrated in acute DOX-induced cardiotoxicity in rats [75,76][54][55] and beagle dogs [77][56]. Data of previous studies indicated that L. barbarum fruits and extracts may exert a potent protective effect on DOX-induced cardiomyocyte damage, mainly via antioxidative and free radical-scavenging pathways. Zhang et al. [78][57] in their study, related the anti-hypertensive effect of L. barbarum to down regulated expression of renal endothelial lncRNAs ONE in a rat model of salt-sensitive hypertension. In conclusion, their study commented that L. barbarum treatment can restore blood pressure to normal levels. At the same time, the expression of long noncoding RNA (lncRNA) was found to be reduced by the suppression of the antisense mRNA (sONE). Moreover, the improvement of endothelial nitric oxide synthase (eNOS) levels in the hypertensive model rats treated with L. barbarum compared with that receiving a high-salt diet was also observed. In addition, Guo et al. [79][58], using a meta-analysis of randomized controlled trials, presented that L. barbarum treatment significantly reduced fasting glucose concentrations while marginally reducing concentrations of total cholesterol and yielded no benefit in terms of bodyweight and blood pressure.
2.6. Hepatoprotective Activity
Alcohol use is the third leading risk factor contributing to the global burden of disease, after high blood pressure and tobacco smoking. According to a WHO report published in September 2018, alcohol causes 3 million annual deaths globally and accounts for 5.3% of all deaths. Despite the three above mentioned factors affecting liver Demori and Voci [80][59] commented that modern eating habits involving high-calorie diets that lead to obesity also can cause liver diseases such as hepatic steatosis. Chronic alcohol overdrinking (CAO) typically progresses through the stages of fatty liver or simple steatosis, alcoholic hepatitis and chronic hepatitis with hepatic fibrosis or cirrhosis [81][60].
The use of L. barbarum was originally proposed in traditional Chinese medicine for the treatment of liver diseases. Nowadays, studies done by Xiao et al. [82][61] have proved that feeding alcohol-induced liver injury rats with 300 mg/kg LBP for 30 days showed positive reverse effects, reducing liver injury, preventing the progression of alcohol-induced fatty liver and improving antioxidant function, in contrast with the ethanol group.
Pretreatment with 50 µg/mL LBP of rat normal hepatocyte line BRL-3A cells has shown a significant reduction of 24-hour ethanol-induced over expression of thioredoxin-interacting protein (TXNIP) increasing cellular apoptosis. Xiao et al. [83][62] also observed an activation of NOD-like receptor 3 (NLRP3) inflammasome and reduction of the antioxidant enzyme expression and ROS. Non-alcoholic fatty liver disease is an important factor in causing hepatocarcinoma and is associated with obesity, insulin resistance and metabolic syndrome. As mentioned previously, obesity leads to a decrease in insulin sensitivity (IR), a decrease in the antioxidant enzymes SOD, CAT and GSH-Px but also an increase in ROS, leading to liver dysfunction, hepatic steatosis and depletion of the hepatocyte population [80,84,85][59][63][64].
