Cistanches Anti-aging Second Part

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3.1.2 Memory and learning enhancement effects of echinacoside

The gradual loss of cognition is one of the main characteristics of aging [69, 70]. It is recorded that PhGs containing echinacoside of Herb Cistanche could enhance the ability of learning and memorization [66]. P-tau is implicated in vascular dementia (VD) and AD because both share a common correlation with regard to vascular risk factors [71]. The glycosides of cistanche, which mainly contains echinacoside, play a critical role in protecting hippocampal neurons in VD by decreasing Ptau phosphorylation and increasing collapsin response mediator protein-2 (CRMP-2) expression level [72]. Cistanche tubulosa glycoside capsules (CTG capsule, Memoregain®) containing mainly echinacoside had the potential to be a possible treatment option for mild to moderate AD. Memoregain® capsules are effective and safe for the treatment of moderate AD, which is in accordance with the ability of Cistanche tubulosa glycosides to inhibit excessive apoptosis of nerve cells. However, the mechanisms underlying the treatment of AD with Cistanche tubulosa glycosides are not only different from that of acetylcholinesterase inhibitors but also different from that of other types of traditional Chinese medicines. Antagonism of nerve cell apoptosis is a specific neuroprotective effect of Cistanche tubulosa glycosides [73].

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3.1.3 Antioxidant effect of echinacoside

Echinacoside isolated from Herba Cistanches possesses free radical scavenging properties and protects oxidativestress-induced toxic injuries via different mechanisms. Recent studies proved the anti-oxidant activity of echinacoside, particularly in the clearing of all types of free radicals in vivo and in vitro [39, 74]. Echinacoside improved the activity of antioxidant enzymes and inhibited the formation of lipid peroxide, MDA, and NO [66, 74-76]. It possessed free radical scavenging properties [77] and was capable of protecting against oxidative stress-induced organ injuries, by entering cells through the injured membrane, affecting the signaling pathway between ROS and the opening of the Ca2+channel [66].

3.1.4 Neuroprotective effects of echinacoside

Herba Cistanches containing echinacoside could improve cognitive and independent living abilities of moderate AD patients, reducing the levels of T-tau, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) [78]. Transient treatment with echinacoside inhibited cytochrome c release and caspase-3 activation caused by ensuing rotenone exposure via activation of Trkextracellular signal-regulated kinase (ERK) pathway in neuronal cells [79]. The inhibitory effect of echinacoside on evoked glutamate release was associated with reduced voltage-dependent Ca2+ entry and subsequent suppression of protein kinase C activity [80].

Cistanche can improve immunity 

3.1.5 Anti-inflammatory effects of echinacoside

Aging in humans is associated with chronic low-grade inflammation (systemic) state characterized by an increase in pro-inflammatory markers including but not restricted to TNF-α, IL-6, IL-1β, and C-reactive protein [81]. Echinacoside possesses anti-inflammatory effects through scavenging the NO radical [74, 82]. Cistanche tubulosa extract markedly attenuated inflammatory signs by blocking the TNF-α-NO and cyclooxygenase--IIprostaglandin E2 (COX-II-PGE2) pathways in carrageenan-induced air pouch inflammation [37]. Echinacoside protected the intestinal epithelium from inflammatory injury in DSS-induced colitis in mice by upregulating transforming growth factor (TGF)-β1 as well as increasing the number of Ki67(+) proliferating cells in diseased colons [83]. In addition, echinacoside significantly alleviated the inflammatory responses induced by 6-hydroxydopamine (6-OHDA) [63].

3.1.6 Anti-neurodegenerative effect of echinacoside

As echinacoside could cross the blood-brain barrier freely, it may have a promising potential in treating neurodegenerative diseases [79]; it acts as an anti-inflammatory and neuroprotective agent [65]. PhGs might exert potential inhibitory effects on microglia-involved neuroinflammation, resulting in neuroprotection in inflammation-related neuronal degenerative diseases including AD and PD [65, 75, 84]. Additionally, echinacoside could increase expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) mRNA and protein, induce neurotrophic factors (NTFs) and inhibit apoptosis [85]. Echinacoside was demonstrated to increase the viability of rat pheochromocytoma PC12 cells injured by Aβ and suppress the increase in intracellular ROS triggered by Aβ. The interactions between echinacoside and amyloid-forming proteins shed light on the protection of echinacoside against amyloid fibril-induced neuronal cell death [77]. The Cistanche tubulosa extract, which contains enough echinacoside, ameliorated the cognitive dysfunction caused by Aβ 1-42 via blocking amyloid deposition, especially in hippocampal areas [41]

3.1.7 Immunomodulatory and anti-neoplastic effects of echinacoside

Extensive evidence exists indicating that aging in an organism is characterized by immune deficiency [86]. Echinacoside could be used as a specific immunostimulatory adjuvant against colorectal cancer [58]. Echinacoside caused a significant increase of intracellular oxidized guanine, 8-oxoG [87], a dramatic upregulation of the double-strand DNA break (DSB)-binding protein 53BP, induced cell cycle arrest, and apoptosis, and significantly increased active caspase 3 and cleaved poly ADP-ribose polymerase (PARP). It upregulated the G1/S-CDK blocker CDKN1B (p21) in SW480 cancer cells via induction of oxidative DNA damage [58].

3.1.8 Hepatoprotection effects of echinacoside

Echinacoside exhibited significant inhibition on both ascorbic acid/Fe2+ and ADP/NADPH/Fe3+ induced lipid peroxidation in rat liver microsomes, which were more potent than α-tocopherol of caffeic acid [39]. It also inhibited D-GalN-induced death of hepatocytes and reduced TNF-α-induced cytotoxicity in L929 cells [49]. It was reported that PhGs have significant anti-hepatic fibrosis effects by reducing NF-κB RNA levels [88, 89]. Echinacoside possesses an anti-hepatic fibrosis effect by inhibiting hepatic stellate cell (HSC) activation and the TGF-β1/smad pathway (increasing the mRNA level and protein expression of smad7, and decreasing the mRNA levels of smad2, smad3 and the protein expression of smad2, phospho-smad2, smad3, phospho-smad3) [89]. Echinacoside could also provide a definite protective effect against acute hepatic injury by ameliorating histopathological damage of the liver and the number of apoptotic hepatocytes, which was accompanied by the reduction of serum alanine aminotransferase (ALT), aspertate aminotransferase (AST) levels, and hepatic MDA content as well as ROS production, and the restoration of hepatic SOD activity and glutathione (GSH)content [77]. Echinacoside also has a strong effect against hepatitis B virus (HBV) replication and antigen expression [90].

3.1.9 Anti-osteoporosis effects of echinacoside

Osteoporosis has already become one of the leading threats for the health of the aging population [91, 92]. Echinacoside, like estrogen, has a stimulatory effect on osteoblastic bone formation whereby it promotes bone regeneration in cultured osteoblastic MC3T3-E1 cells. It was effective and safe in treating ovariectomy (OVX)-induced osteoporosis by increasing cell proliferation, alkaline phosphatase (ALP) activity, collagen type I (COL I) contents, osteocalcin (OCN) levels and mineralization in osteoblasts, decreasing receptor activator of nuclear factor-𝜅B ligand (RANKL) level and elevating the osteoprotegerin (OPG)/RANKL ratio in serum [93-95]. In addition, echinacoside could promote the differentiation of bone marrow mesenchymal stem cells in vitro, and the mechanism may be correlated with the increase in the zinc fingers and homeoboxes 3 (ZHX₃) expression [96].

3.1.10 Aphrodisiac effects of echinacoside

There are different opinions about the safety of Herba Cistanch's treatment for diseases involving the male reproductive system. Some studies showed that Herba Cistanches displayed cytotoxic effects on the male reproductive system, thus it may not be appropriate for therapies seeking to improve the function of the male reproductive system [97]. Other studies demonstrated that Echinacoside could increase sperm count and sperm motility, and attenuate poor sperm quality and testicular toxicity in rats through the up-regulation of steroidogenesis enzymes including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD,CYP17A1 [98] and CYP3A4 [31].

3.1.11 Anti-diabetic and anti-fatigue effects of echinacoside

Cistanche tubulosa could significantly suppress elevated fasting blood glucose and postprandial blood glucose levels, improve insulin resistance and dyslipidemia, and suppress bodyweight loss in db/db mice [99]. One study showed that echinacoside had potent aldose reductase inhibitory activity [100]. The phenylethanoid-rich extract of Cistanche deserticola Y.C. Ma containing echinacoside as its major constituent played an important role in antifatigue activity through enhancing the swimming capacity of mice by decreasing muscle damage, delaying the accumulation of lactic acid, and by improving energy storage [36].

3.2 Acteoside (Verbascoside)

Acteoside, also known as verbascoside or orobanchin, is another major active phenylethanoid glycoside present in Herba Cistanches. Its functions and mechanisms are summarized in Table 4.

3.2.1 Lifespan extension by acteoside

There are no direct reports about lifespan extension by acteoside. Previous studies have indicated that acteosidesignificantly improved cell viability via anti-apoptotic effects. Acteoside exhibits a significant inhibitory effect on hepatic apoptosis [49, 101, 102]. In addition, acteoside could improve learning and memory in a mouse model of senescence induced by a combination of D-galactose and AlCl3 [103]. It also improved the behavior in senescenceaccelerated OXYS rats [67].

3.2.2 Memory and learning enhancement effects of acteoside

Acteoside has been shown to have significant protective effects on learning and memory impairment in a mouse scopolamine-induced amnesia model through the increase in the activities of GSH-Px, T-SOD, total cholinesterase (TChE), and decreasing MDA content [103]. mechanisms of memory enhancement of acteoside were partly due to inhibition of acetylcholine esterase and elevation of antioxidant enzymes [33]. Acteoside could decrease the activity of NO synthase and the expression of caspase-3 protein [104]. It also could promote the release of nerve growth factor (NGF) and neuronal actions, including neurite outgrowth and synapse formation, and increase tropomyosin receptor kinase A (TrkA) expression [105]. One clinical trial showed that Herba Cistanches containing acteoside could improve cognitive and independent living abilities of moderate AD patients [77].

3.2.3 Antioxidant effect of acteoside

Acteoside protects the cell from oxidative stress and the scavenging of free radicals. As an antioxidant, acteoside could not only scavenge radical oxygen, such as NO radical and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical [65, 106], but also decrease the activity of NO synthase [103]. Acteoside showed stronger free radical scavenging activities than α-tocopherol on DPPH radical and xanthine/xanthine oxidase generated superoxide anion radical O2-, and exhibited significant inhibition on both ascorbic acid/Fe2+ and ADP/NADPH/Fe3+ induced lipid peroxidation in rat liver microsomes [38]. The numbers of phenolic hydroxyl groups of phenylpropanoid glycosides are directly related to their scavenging activities. The scavenging activities are likely related to the odihydroxy group of phenylpropanoid glycosides as well [107].

3.2.4 Neuroprotective effect of acteoside

Recent studies indicated that acteoside could exhibit neuroprotective capabilities [104, 105]. Acteoside could increase the number of neurons and nissl bodies in the hippocampus [104]. Acteoside significantly attenuated Parkinsonism symptoms by inhibiting rotenone-induced α-synuclein and caspase-3 upregulation, and microtubuleassociated protein 2 downregulation in PD rats [108]. Acteoside ameliorated the cognitive dysfunction caused by Aβ 1-42 via blocking amyloid deposition, reversing cholinergic and dopaminergic neuronal function [41]. In addition, acteoside has a significant protective effect on a cellular model of AD induced by okadaic acid through improving SK-N-SH cell morphology, enhancing cell survival rate, decreasing cell lactate dehydrogenase release rate, and the expression of phosphorylated tau proteins at the p-Ser 199/202 and p-Ser 404 sites, and upregulating the expression of non-phosphorylated tau proteins at the Ser 202 site and Ser 404 sites [109].

3.2.5 Anti-inflammatory effect of acteoside

Acteoside had an anti-inflammatory effect against Degalactosamine/ lipopolysaccharide-induced hepatitis in mice [109], which was possibly related to its NO radical-scavenging activity [74].

3.2.6 Immunomodulatory and anti-neoplastic effects of acteoside

Acteoside is a potent immunostimulant with extensive effects on immune organs, immune cells, and immune factors. It could inhibit basophilic cell-derived immediate-type and delayed-type allergic reactions. It was reported that acteoside inhibited the release of β-hexosaminidase and Ca2+ influx from immunoglobulin Emediated RBL-2H3 cells. It inhibited histamine release, production of TNF-α and IL-4 in human basophilic (KU812) cells [110]. The anti-allergy effects of acteoside were due to downregulation of the expressions of the chemokine ligand (CCL) 1, CCL2, CCL3, CCL4, Fc fragment of IgE, high affinity I, the receptor for alpha polypeptide (FCER1A), nuclear factor of activated T cell, cytoplasmic, and calcineurin-dependent 1 (NFATC1)genes and inhibition of the mitogen-activated protein kinase (MAPK) pathway through decreased C-jun N terminal kinase (JNK) phosphorylation [111]. Acteosidealso exhibited inhibitory effects on the proliferation of the prostate cancer PC-3 cell line, which was roughly double the potency afforded by echinacoside [86].

3.2.7 Hepatoprotective effect of acteoside

The mode of action of acteoside in hepatic protection is at least in part related to its antioxidative, immunoregulatory properties, and its ability to regulate hepatic apoptosis [96, 102]. Acteoside could effectively inhibit TNF-α-mediated hepatic apoptosis and the subsequent necrosis in DGalN/LPS-induced liver failure. The protective effect of acteoside on immunological liver injury may be due to its ability to scavenge free radicals, inhibit lipid peroxidation, protect hepatic membranes, and restore the balance of Th1/Th2 and Bax/Bcl-2 [102]. The protective effects against carbon tetrachloride were possibly related to the acteoside’s ability to block the P450-mediated bioactivation and scavenge free radicals during liver injury [50]. Acteoside also inhibited DGalN-induced death of hepatocytes and reduced TNF-α-induced cytotoxicity in L929 cells [49]. Acteoside may be a potential herbal medicine for the treatment of liver fibrosis because of its ability to block the TGF-β1/smad signaling pathway and inhibit the activation of hepatic stellate cells [90].

3.2.8 Anti-hypercholesterolemia and anti-diabetic effects of acteoside

Acteoside, acquired from the aqueous ethanol extract of the roots of Cistanche tubulosa, was involved in regulating the hypocholesterolemic activity through enhancing the mRNA expressions of apolipoprotein B, very-low-density lipoprotein (VLDL) receptor, and cytochrome P450 SCC in HepG2 hepatocytes of hypercholesterolemia mice [25]. Acteoside was also found to significantly improve glucose tolerance in starch-loaded mice [36].