Terapeutisk potentiale af phenylethanoidglycosider: en systematisk gennemgang

Abstrakt:

Phenylethanoid glycosides (PhGs) are generally water-soluble phenolic compounds that occur in many medicinal plants. Until June 2020, more than 572 PhGs have been isolated and identified. PhGs possessantioxidant, neuroprotective, anti-inflammatory, antibakteriel, antiviral, antidiabetic, mod kræft, and antiobesity properties. Despite of these promising benefits, PhGs have failed to fulfill its their therapeutic applications due to their poor bioavailability. The attempts to understand their metabolic pathways to improve their bioavailability are investigated. In this review article, we will first summarize the number of PhGs compounds which is not accurate in the literature. The latest information on the biological activities, structure-activity relationships, mechanisms and especially the clinical applications of PhGs will be reviewed. The bioavailability of PhGs will be summarized and factors leading to the low bioavailability will be analyzed. Recent advances in methods such as bioenhancers and nanotechnology to improve the bioavailability of PhGs are also summarized. The existing scientific gaps of PhGs in knowledge are also discussed, highlighting research directions in the future. Keywords: Phenylethanoid glycosides; Bioavailability; Acteoside; Salidroside; Echinacoside

Phenylethanoid glycosider Specifikation i Cistanche Herba

Introduktion

Phenylethanoid glycosides (PhGs) are generally water-soluble phenolic compounds that occur in many medicinal plants. PhGs have been isolated from the roots, stems, bark, leaves, flowers, fruits and seeds of medical plants, as well as from suspension cell cultures, callus tissues and hairy roots cultures. They are also found in various plant-based foods such as edible flowers and tea. However, their accumulations in each plant organ may vary considerably1-3 . The main PhGs are reported from the families Acanthaceae, Berberidaceae, Asteraceae, Gesneriaceae, Lamiaceae, Loganiaceae, Magnoliaceae, Oleaceae, Orobanchaceae, Plantaginaceae, Portulacaceae, Rosaceae, Scrophulariaceae, and Verbenaceae4 . For example, a total of 69, 51, 21 and 16 PhGs have been isolated from Cistanche herba5 , Forsythiae fructus6 , Magnoliae officinalis7 and Houttuynia cordata8 , respectively. Acteoside (also known as acteoside), one of the representative PhGs, is widely distributed in the family Lamiaceae,Plantaginaceae, Scrophulariaceae, and Orobanchaceae9 . In1994, Jiménez and Riguera summarized the structures and biological activities of 155 PhGs reported before 19922 . In 2008, Fu et al. provided an overview in the advances on 190 new PhGs isolated from 1997 to 200710 . The detailed information of 116 new PhGs identified during 2009-2016 was given in 20163 . In the present review, we summarized the 111 PhGs11-56 that have not been reviewed previously (1993-1997, 2007-2009 and 2016-present) in Table 1 and Table 2. The latest new PhGs (Ginkgoside C and D) was published on 16 June 2020. Up to 572 PhGs were identified from nature until June 2020. These 572 PhGs are distributed in 21 orders and 35 families of the plant kingdom (Figure 1). It should be noted that some PhGs identified were not published in English. Thus, the actual number identified must be over 572. In general, the basic structure of PhGs consists of a hydroxyphenylethyl unit as an aglycone which is attached to a sugar moiety mostly a -D-glucopyranose through a glycosidic bond at the C-1 site. In most cases, the glucose moiety is esterified with a hydroxycinnamic acid derivative such as caffeic acid, coumaric acid, cinnamic acid, and ferulic acid. Rhamnose, xylose, arabinose, allose, galactose, and apiose, among others, may also be attached to the glucose residue (Figure 2, Table 1 and 2). The diversity of sugar and hydroxyphenylethyl moieties make the plentiful variation of PhGs. Generally, the number of sugars ranges from one to three. However, four-sugar and five-sugar residues are also found occasionally. According to the number of the sugars bonded to hydroxyphenylethyl moieties, PhGs can be classified into monosaccharidic PhGs, dissaccharidic PhGs, trisaccharidic PhGs, tetrasaccharidic PhGs, and pentasaccharidic PhGs4 . To date, there are 10 tetrasaccharidic PhGs reported, namely, magnolosides C57 , ballotetroside58, trichosanthoside B59, marruboside60, velutinosides I61, velutinosides II61 , lunariifolioside62 ,raduloside63, barlerinoside64, and poliumoside B65. Only one pentasaccharidic PhGs named yulanoside A from M.salicifolia was reported in 201566

Most purified PhGs are white, buff or yellow amorphous powders with high polarity. They are soluble in polar solvents but insoluble in non-polar organic solvents67 . As the characteristics of the strong ultraviolet (UV) absorption in PhGs, it is easy to monitor these compounds by UV spectrophotometer. The specific UV spectra of each PhGs can also serve as an index to deduce the structure. For example, the UV absorption peaks of Acteoside and isoActeoside are 232, 246, 289, 332 nm, and 232, 246, 286, 328 nm, respectively68 . And that of echinacoside are 236, 288, 330 nm69 . PhGs and the extracts rich in PhGs exhibited various benefits, such as antioxidant activity, neuroprotective effect, anti-inflammatory activity, antibacterial activity, antivirus activity, anti-diabetic activity, anti-cancer activity, and anti-obesity activity3, 9. Figure 3 shows the number of papers and times cited of papers indexed in the Web of Science related to "PhGs", illustrating a significant increase in publication in this area. Although over 572 PhGs have been isolated and identified, only a few of them are extensively studied. For example, the number of papers on salidroside, Acteoside, echinacoside, forsythoside and isoActeoside are 1746, 1258, 538, 370 and 230, respectively. And the numbers of citations of the papers about Acteoside, salidroside, echinacoside, forsythoside and isoActeoside are 19356, 14352, 6468, 3234 and 4098, respectively. Other PhGs have fewer than 100 papers published. The number of papers published and number of citation of the papers of specific PhGs are also shown in Figure 3. Despite of the many promising biological activities, PhGs have failed to fulfill the therapeutic applications due to poor oral bioavailability3 . The bioavailability of Acteoside was found to be 0.12 percent in rats after Acteoside was given at the dosages of 100 mg/kg oral administration (p.o.) and 3 mg/kg intravenous injection (i.v.) 70 , but the bioavailability of vActeosidein dogs was around 4 percent after vActeosidewas given at 40 mg/kg intragastric administration (i.g.) and 5 mg/kg i.v.71 . The bioavailability of echinacoside, and angoroside C in rats at the dose of 100 mg/kg i.g. and 5 mg/kg i.v., was reported to be 0.83%72 and 2.1%73 , respectively. The bioavailability of forsythiaside (100 mg/kg p.o. and 5 mg/kg i.v.) and poliumoside (200 mg/kg p.o. and 10 mg/kg i.v.) in rats was 0.5%74 and 0.69%75 , respectively. Feng et al. compared the pharmacokinetic and bioavailability characteristics of savaside A, vActeoside and isovActeosidein rats after the compounds were given at the dosages of 1000 mg/kg p.o. and 5 mg/kg i.v.. The bioavailability order of the three PhGs appears to be vActeoside> isovActeoside> savaside A76 . Zhang et al investigated the pharmacokinetic of four PhGs (vActeoside isovActeoside martynoside, and crenatoside) after orally administrated 10.0 g crude Acanthus ilicifolius herb /kg to rats. Although the four PhGs share similar molecular structures, they displayed different elimination half-lives (T1/2), and different areas under the curves (AUC0–t), ranging from 3.4 to 9.0 h, and 1826.3 to 23.6 ug/L×h, respectively77 . Different dosages and administrative patterns might affect the bioavailability of PhGs. However, there is one exception. The bioavailability of salidroside was reported to be 51.97 percent 78 . As for the reasons why the bioavailability of salidroside was significantly higher than other PhGs, this may be ascribed to its relatively simple structure (Figure. 2). Salidroside belongs to monosaccharidic PhGs consisting of phenylethanol and sucrose, and the relatively large polarity allowed it to be easily excreted from the urine without complicated metabolic processes. The higher absorption of salidroside may also lead to its obviously higher bioavailability than other PhGs (section 5.1). Numerous approaches such as bioenhancers, -cyclodextrin encapsulation, liposomal PhGs, nanoparticles and phospholipid complex have been applied to improve the bioavailability of PhGs. There have been a number of reviews on PhGs since the 90's. As early as 1994, Jiménez and Riguera reviewed the isolation, purification, as well as structure and biological activity of PhGs2 . Pan et al. highlighted the pharmacological activities of natural PhGs in 200379 . Fu et al. summarized the phytochemistry and bioactivity of PhGs in 200810. Radev et al. published a mini review on pharmacological effects of PhGs in 201080 . Xue and Yang summarized advances in the phytochemistry, pharmacology and pharmacokinetics of PhGs in 20163 . Alipieva et al. reviewed the biosynthesis and pharmacological significance of vActeoside the most popular phenylethanoid glycoside in 20149 . Liu et al. generalized the distribution, extraction methods, poor pharmacokinetics and therapeutic uses of echinacosidei 201881. Tao et al. gav et detaljeret resumé af kemiske, farmakologiske, toksikologiske og kliniske undersøgelser af forskellige Rhodiola-arter med salidrosid som de karakteristiske kemiske bestanddele i 201982. Der er dog ingen omfattende anmeldelser vedrørende stabilitet, biotransformation, klinisk anvendelse og biotilgængelighed af phG'er. Denne gennemgang vil opsummere de seneste oplysninger om kemi, farmakologi, stabilitet, klinisk anvendelse, farmakokinetik, metabolitter og biotransformation af PhG'er. Nylige fremskridt inden for metoder såsom bioenhancers og nanoteknologi til at forbedre biotilgængeligheden af ​​phG'er vil også blive opsummeret. PhG'ernes eksisterende videnskabelige huller i viden diskuteres også, hvilket fremhæver forskningsretninger i fremtiden

2. Pharmacology of PhGs

PhGs have been reported to have various bioactivities in cell and animal models. Herein, the potential health benefits of PhGs are summarized, and the structure-activity relationship and mechanisms of PhGs' pharmacology are highlighted. 

2.1 Antioxidant og frie radikaler fjernende aktivitet afPhenylethanoid glycosides

Many PhGs and extracts rich in PhGs have shown powerful antioxidant activity. Two new PhGs named macrophylloside E and macrophylloside F, together with eight known PhGs (jionoside C, forsythoside B, alyssonoside, Acteoside, isoActeoside, martinoside, isomartinoside and leucosceptoside) were isolated from Callicarpa macrophylla. All the ten PhGs showed high to moderate antioxidant effect with the IC50 from 2.72 to 38.65 μM in the DPPH assay43 . Acteoside isolated from Plantago major can significantly scavenge both DPPH radical (IC50, 11.27 μM) and superoxide radicals (IC50, 1.51 μM). Acteoside can also inhibit lipopolysaccharide induced production of nitric oxide in RAW264.7 macrophages (IC50, 75.0 μM) 83. Seven PhGs (plantalide A, vActeoside plantamajoside, martynoside, himaloside B, desrhamnosyl isovActeosideand plantainoside D) discovered from P. asiatica showed DPPH radical scavenging activity with the IC50 values ranging from 22.9–88.5 μM. While other 22 compounds from P. asiatica showed weak antioxidant activity85. In addition, VActeosidevActeosideand salidroside were demonstrated to be two major PhGs contributing to the great antioxidant capacities of Osmanthus fragrans flowers85 . All nine PhGs (magnolosides Ia, Ib, Ic, IIa, IIb, IIIa, Iva, and Va and crassifolioside) from M. officinalis were found to possess strong free radical scavenging potential with the IC50 ranging from 11.79 to 20.99 μM, and magnoloside Ia (IC50, 11.79 μM) was the strongest one86 . The DPPH radical scavenging capacity of crassifolioside (IC50, 21.38 μM), magnoloside IIa (22.94 μM), and magnoloside IIb (24.62 μM) was weaker than that of magnoloside Ia (11.79 μM), magnoloside Ic (12.99 μM), magnoloside Ib (16.23 μM), and magnoloside Va (20.99 μM). As we can see from the structures of these compounds, crassifolioside, magnoloside IIa and magnoloside IIb contained three sugars while magnoloside Ia, magnoloside Ic, magnoloside Ib, and magnoloside Va contained two sugars. More sugars mean larger steric hindrance in compounds and prevent them from easily approaching the free radicals, finally causing the weaker DPPH radical scavenging capacity. In addition, compared with the other seven PhGs, magnoloside IIIa (32.18 μM) and magnoloside IV (35.17 μM) with two adjacent phenolic groups only in one side exhibited poor activity86 . Furthermore, benzene ring plane conjugation in PhGs can be increased by the , -conjugated unsaturated ester structures and allow electron delocalization to inhibit free radicals86.

2.2 Neuroprotective effect of Phenylethanoid glycosides 

Acteoside, salidroside ogechinacosideudviste antioxidant- og neurobeskyttende aktiviteter i hydrogenperoxid-induceret apoptose i PC12-celler via den nuklear faktor erythroid 2-relaterede pathway87. CaleolariosideB, parabosid B og parabosid II isoleret fra Paraboea martinii beskyttede effektivt PC12-celler mod H2O2-induceret skade ved at opregulere HO-1 88. Det antages, at amyloidpeptid (A) er en væsentlig årsag til Alzheimers sygdom89. Totale PhG'er ekstraheret fra C. Herba i koncentrationer på 5, 25 og 50 ug/mL øgede levedygtigheden og reducerede LDH- og MDA-frigivelse af PC12-celler skadet med A 1-4290. Torenosid B og Savatiside savatisid A blev påvist at forbedre enzymaktiviteten af ​​GSH-Px og SOD, reducere indholdet af MDA og ROS og nedregulere intracellulære Ca2 plus-koncentrationer og Calnexin-ekspression i A 25-35-inducerede SH-SY5Y-celler91. VActeosid salidroside og PhG'er fra C. Herba har et betydeligt beskyttelsespotentiale mod oxidativt stress induceret af A 92, 93. Den karakteristiske patologi ved Parkinsons sygdom er degenerationen af ​​dopaminneuroner i substantia nigra pars compacta94. Campneoid og tubulosid B kan beskytte neuroner mod 1-methyl-4-phenylpyridinium-induceret apoptose in vivo 95, 96. VActeoside har potentiel terapeutisk værdi mod PD ved at dæmpe det oxidative stress og aktivere Nrf2/ARE-signalvejen97. SAMP8-mus, en model for AD, blev administreret af PhG'er ekstraheret fra C. Herba dagligt intraperitonealt ved 25, 50 eller 100 mg/kg/dag i 30 dage. PhG'er viste sig at forbedre kognitive underskud hos SAMP8-mus ved at forbedre synaptogenese og synaptisk plasticitet98. Det er blevet rapporteret, at den gennemsnitlige levetid for caenorhabditis elegans blev forlænget med 13,64 procent og 15,82 procent efter behandling med henholdsvis 200 μM og 300 μM ECH. Den beskyttende effekt af ECH på A-induceret toksicitet i C. elegans var næsten lig med den for ginkgolide A, et velkendt middel med positive effekter for AD99. Liu et al. syntetiserede otte PhGs-derivater baseret på calceolariosid A og undersøgte deres neurobeskyttende virkninger i PC12-celler. Resultaterne viste, at syv forbindelser kunne beskytte celleskaden eller døden mod skader fra frie radikaler undtagen den chlor-substituerede analog. Struktur-aktivitets-forholdet indikerede, at catechol-delen måske ikke monopoliserede bioaktiviteten, men sandsynligvis kunne spille en vigtig rolle i neurobeskyttelse, og glucose-delen syntes ikke at være vigtig for neurobeskyttelsen100. Resultaterne var i overensstemmelse med den nylige struktur-aktivitet af koffeinsyre-phenethylester-analoger101, 102

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2.3 Hepatoprotective effect of Phenylethanoid glycosides 

Acteoside, echinacoside, tubuloside B, cistanoside A and 2-acetylacteosid possess offer hepatoprotective effects via multiple mechanisms including strengthening antioxidant defense system, free radicals scavenging, and blocking cytochrome P450 biotransformation103 . Leucoseceptoside A, crenatoside, martynoside, and 3-O-methylcrenatoside extracted from Incarvillea compacta alleviated CCl4-induced hepatotoxicity by enhancing the activity of superoxide dismutase, decreasing the intracellular ROS and malondialdehyde content as well as activating NF-κB pathway104 . 14 Fourteen PhGs isolated from Forsythia suspensa were evaluated for their hepatoprotective effects on HepG2 cells damage induced by APAP. It was found that forsythoside N, forsythoside O, forsythenside A and forsythenside B exerted significant hepatoprotective activities28 with the cell survival rates from 52.48 percent to 67.15 percent , 67.61 percent , and 64.88 percent at the concentration of 10 μM, respectively. Cistanoside A (125, 250, and 500 mg/kg/day) could alleviate ethanol-induced hepatotoxicity in mice by improving the activities of the activities of energy metabolism enzymes (Ca2 plus -Mg2 plus -ATPase, ATPase, and Na plus -K plus -ATPase), mitochondrial antioxidant enzymes (SOD, GST and CAT), and antioxidant defense system105 . Besides, cistanoside A (100, 75, 50, and 25 ug/mL) suppressed the apoptosis of hepatocytes by increasing the expression of Bcl-2 and supressing cfos105 . Echinacoside (60 mg/kg, i.p.) could significantly protect LPS and D-galactosamine induced acute liver injury in mice due to its anti-apoptotic and anti-inflammatory activities106 . PhGs from C. deserticola was assessed for their hepatoprotective activity in vitro and in vivo. Concentrations of 0.33, 1.00, 3.00 mg/mL PhGs can could improve the HepG2 cells viability to almost 10 percent , 22 percent and 35 percent , respectively. After orally administered with PhGs at 200, 600 or 1800 mg/kg for 31 consecutive days, ICR mice with liver injury induced by alcohol showed improved hepatic indicators (superoxide dismutase, glutathione Stransferase, glutathione, glutathione peroxidase, malondialdehyde and triglyceride) levels107 . Structure–activity relationship indicated that the catechol moiety on PhGs was important for the hepatoprotective activity108 . Acteoside (IC50, 4.6 μM), 2ʹ-acetylActeoside (4.8 μM), isoActeoside (5.3 μM), tubuloside A (8.6 μM) and echinacoside (10.2 μM) inhibited D-GalN-induced death of hepatocytes109 . Acteoside (IC50, 4.6 μM) showed significantly stronger activity than kankanose (>100 μM), and echinacoside (10.2 μM) showed significantly stronger activity than cistanoside F (>100 μM), hvilket indikerede, at aglycon var en vigtig gruppe for aktiviteten109. Da aktiviteten af ​​isovActeosid(5,3 μM) var højere end kankanosid G (14,8 μM), kan det konkluderes, at aglycon med 4-hydroxygruppen viste svagere aktivitet end den, der havde 3,4-dihydroxygruppe109. 8-O- -D-glucopyranosyldelen med 6ʹ-O-caffeolgruppe (Tubulosid B, 14,6 μM) viste svagere aktivitet end den med 4ʹ-O-caffeoylgruppen (2ʹ-acetylvActeosid 4,8 μM)10 . Introduktionen af ​​6-O- -D-glucopyranosyl (echinacoside ＜ vActeosid og 2ʹ-O-acetyldel (2ʹ-acetylvActeosidevActeosid kunne reducere den beskyttende

2.4 Anti-cancer aktivitet af Phenylethanoid glycosider

I en nylig undersøgelse,echinacosideblev rapporteret at have antiproliferative aktiviteter (20 ug/ml, 9,57 procent; 50 ug/ml, 26,67 procent; 100 ug/ml, 37,20 procent) på HepG2-celler ved at inaktivere AKT-vejen og reducere TREM2-ekspression110. Acteosid,echinacoside, cistantubulosid A, cistanosid A og 2´-acetylActeosid hæmmede spredningen af ​​musehudsmelanomcancercellelinje KML med inhiberingsraten fra 33 procent til 93 procent 111 . Forbehandling med 5, 10, 20, 40 og 50 μM salidrosid i 48 timer kan hæmme proliferationen af ​​humane brystkræft MCF-7-celler til næsten 70 procent, 60 procent, 55 procent, 45 procent og 30 procent hhv. Mekanismen kan muligvis relateres til øget caspaseaktivitet, nedregulering af Bcl-2-udtrykket og opregulering af Bax-udtrykket. Desuden hæmmede salidrosidbehandling tumorvækst i en xenograft-tumormodel. Sammenlignet med kontrolgruppen, efter behandling med salidrosid (50 mg/kg kropsvægt) på skiftende dage i 3 uger, blev vægten og volumenet af tumoren reduceret med henholdsvis 0,7 g og 300 mm3112. Salidroside blev rapporteret at have anti-tumor aktivitet mod Wilms' tumor113, brystcancer114, ovariecancer115, gastrisk cancer116, hudcancer117, nyrecellecarcinom118 og kolorektal cancer119. Li et al. undersøgte virkningerne af PhGs-ekstrakt fra C. tubulosa (CTPG) på inhiberingen af ​​melanomcelle (B16-F10) vækst. In vitro hæmmede 100 ug/mL CTPG i 48 timer eller 200 ug/mL CTPG i 72 timers behandling vækstraterne for B16-F10-celler til henholdsvis højere end 60 procent og 90 procent. CTPG kan opregulere udtryk for BAX, nedregulere udtryk for BCL-2, øge dannelsen af ​​ROS og reducere mitokondriemembranpotentialet in vitro. Endvidere varede subkutant administration af 400 mg/kg CTPG i mus hver 2. dag i op til 15 dage, musenes overlevelse fra 8,3 procent til 41,7 procent 120 . Acteosid fra Pedicularis striata kan hæmme cancercellevækst og cellecyklus i G2/M-fasen, inducere apoptose og hæmning af telomeraseaktivitet og reduceret telomerlængde121. Det skal bemærkes, at ikke alle PhG'er udviser anticancer egenskaber. For eksempel beskriver Kirmizibekmez et al. testede den cytotoksiske aktivitet af fire PhG'er (plantainosid D, calceolariosid D, neocalceolariosid D og lugrandosid) mod en række cancercellelinjer, nemlig SH-SY5Y, T98G, A375, HT29, MCF-7, PC3. Alle de fire forbindelser viste ingen toksicitet mod de seks cancercellelinjer ved koncentrationen på 1-50 μM122. En række struktur-aktivitetsforhold viste, at koffeinsyredelen og katekolgruppen er essentielle for cytotoksiciteten af ​​PhG'er. Antallet af acetyldele og deres position i de alifatiske ringe spiller også en vigtig rolle i de anti-proliferative aktiviteter af PhG'er123-125. Den antiproliferative aktivitet af Acteoside var næsten dobbelt så stor somechinacosideog calceolariosid. Den lignende cytotoksiske aktivitet af calceoriosid A og vActeosides tyder på, at rhamnosesubstitution ikke påvirker den cytotoksiske aktivitet af PhGs126. VActeosid hæmmede omkring 23 procent –30 procent af kræftcellernes spredningsaktivitet, hvilket er næsten dobbelt så mange somechinacoside(10 procent –18 procent), calceolariosid A (13 procent –18 procent) og calceolariosid B (5 procent –15 procent). Den højere antiproliferative aktivitet kan være relateret til -Rha-(1→3)-Glc-disaccharidenheden og 4-caffeoylfunktionen i vActeoside27. Struktur-cytotoksicitetsforholdet mellem 14 PhGs-forbindelser indikerede, at jo færre sukkerenheder de har, jo stærkere aktiviteter kan de have. Desuden påvirker placeringen af ​​phenolsyre ikke aktiviteten. Desuden har methylering af de phenoliske hydroxylgrupper en negativ indvirkning på aktiviteten128.

2.5 Anti-inflammatorisk aktivitet af phenylethanoid glycosider

Den antiinflammatoriske aktivitet af PhG'er er ofte forbundet med undertrykkelse af MAPK, NF-KB og JAKSTAT's veje og aktivering af Nrf2 pathway129. Wu et al. bekræftede, at phG'er (Acteosid, parviflorosid A, syringalid A, 3'- -L-rhanmnopyranosid, forsythoside B, poliumosid og alyssonosid) fra C. kwangtungensis gav beskyttelse mod LPS-induceret inflammatorisk respons i RAW 264.7-makrofager ved at aktivere Keap164.7 Nrf2/HO-1 signalvej130 .Echinacoside attenuated LPS-induced inflammation in rat intestine epithelial cells by suppressing the mTOR/STAT3 pathway131 . Acteoside can inhibit the release of β-hexosaminidase, arachidonic acid and histamine in RBL-2H3 cells through inhibiting MAPK and JNK pathways and Ca2+ independent phospholipase132-134 . Acteoside (30, or 60 mg/kg) was shown to decrease inflammatory response against LPS-induced acute lung injury in mice by inhibiting NF-κB signaling pathway135. Gao et al. investigated the anti-inflammatory effects of vActeoside isovActeoside torenoside B and savaside A and found that isovActeoside(80 μM), possessed the strongest activity on inhibiting the expression of iNOS and COX-2 136. IsovActeosideexerts anti-inflammatory via modifying NF-κB and MAPK pathways136 . Forsythiaside A was reported to have protective potential on LPS-induced inflammation in BV2 microglia cells and primary microglia cells via increasing Nrf2 and HO-1 levels and suppressing NF-κB pathway137 . Forsythiaside A could attenuate inflammation in acute liver injury animals by activating Nrf2 and inhibiting NF-κB pathway138 . PhGs from Phlomis younghusbandii exerted anti-inflammatory properties on acute hypobaric hypoxia-stimulated HACE in rats by rehabilitating the oxidative stress levels and inhibiting the expression of pro-inflammatory cytokines regulated by the NF-κB signaling pathways139 . The anti-inflammatory activity of seven PhGs on inhibiting NO production showed that leucosceptoside A (IC50, 9.0 μM ), lipedoside A-I (11.6 μM ), vActeoside(12.8 μM ), isovActeoside(13.7 μM ), and campneoside II (22.1 μM ) possessed stronger activity than martynoside (>100.0 μM) and angoroside C (>100,0 μM). Dette indikerede, at de to tilstødende hydroxidgrupper i PhG'er kan være relateret til deres antiinflammatoriske aktivitet140. Yang et al. påvist, at phG'er med to sukkergrupper havde svagere aktiviteter end andre141.

2.6 Antiviral, den antibakterielle og antiprotozoale aktivitet af PhG'er

To nye PhG'er, Llippiarubelloside A og lippiarubelloside B, sammen med fire kendte PhG'er, Acteosid forsythoside A og podiumside, isoleret fra Lippia rubella kunne kraftigt hæmme væksten af ​​Cryptococcus neoformans ved koncentrationerne af {{0}} ug /ml32. Total PhG-ekstrakt fra Monochasma savatieri viste signifikante antibakterielle virkninger ved en koncentration fra 0.0625 til 16 mg/mL142. VeActeosident forsythoside B viste høje antibakterielle aktiviteter mod fem stammer af Staphylococcus aureus fra 64 g/l til 256 g/l, som var sammenlignelige med norfloxacin143. Når det anvendes alene i en dosis på 200 ug/ml, veActeosidead hæmmende aktivitet mod klinisk isolat af Escherichia. coli og stafylokokker. aureus. Imidlertid viste samtidig administration af veActeoside gentamicin en synergistisk effekt mod E. coli og S. aureus. Dette indikerede, at veActeoside skulle anvendes til at overvinde bakteriel resistens forårsaget af traditionel medicin144. Isoforsythiaside og forsythiaside er de vigtigste antibakterielle bestanddele i Forsythia-suspense, som ofte anvendes til at behandle infektionen i de øvre luftveje. Isoforsythiaside og forsythiaside hæmmede godt væksten af ​​E. coli, P. aeruginosa og S. aureus145, 146. Derudover udviste forsythoside H stærke hæmmende virkninger mod B. vulgare, B. dysenteriae, M. pneumonia og A. bacillus147. VeActeosideas antiviral aktivitet in vitro og antiinfluenzaaktivitet in vivo. Og den antivirale mekanisme af veActeosideas relateret til aktiveringen af ​​ERK og forbedring af IFN-produktion148. Forsythiasid og calceolariosid B viste signifikant antiviralt potentiale på respiratorisk syncytialvirus in vitro149. Forsythiaside hæmmede smitsomheden af ​​aviær infektiøs bronkitisvirus 150. Taraffinisosid A, en ny PhG'er isoleret fra Tarphochlamys affinis, viste antihepatitis B-aktivitet med IC50-værdier på 0,50 og 0,93 mM mod henholdsvis hepatitis B-overfladeantigen og hepatitis B-eantigen67. Forsythoside A fra F. suspensa reducerede virustitrene for forskellige influenzavirus-subtyper i cellekulturer ved en dosis på 160 μM. Forsythoside A øgede også overlevelsesraten for musene i en influenzavirusinfektionsmodel ved 5 eller 10 ug/g kropsvægt 151. Hu et al. evaluerede anti-influenzavirus virkningerne af PhG'er in vitro og in vivo. PhG'er ved 0,5 mg/ml kunne hæmme infektionen af ​​influenza A-virus H1N1 type af Madin Darby hundenyrecelle in vitro. PhG'er ved 300 og 900 mg/kg reducerede markant muselungeindekset (p＜0,05), lindrede influenza-induceret dødelighed og kliniske symptomer og forlængede museoverlevelsestid (p＜0,05). Mekanismen kan muligvis relateres til opregulering af IFN- 152. Det er blevet rapporteret, at veActeoside besad antiprotozoal aktivitet mod Trypanosoma brucei rhodesiense, Leishmania infantum, L. donovani og L. amazonensis153, 154. VeActeoside viste en EC50 på 19 μM mod L. promastigotes og er en konkurrerende arginasehæmmer med Ki på 0,7 μM155. Blandt syv PhG'er ekstraheret fra Tecoma mollis viste luteosid B og luteosid A den stærkeste antileishmaniale aktivitet med IC50-værdierne på henholdsvis 6,7 og 15,1 ug/ml156. Der er kun få oplysninger om struktur-aktivitetsforholdet mellem PhG'er i dets antivirale og antibakterielle aktiviteter. Kyriakpoulou et al. opdagede, at samiosid er mere aktivt end veActeoside mod fire bakteriestammer, hvilket indikerer, at en ekstra sukkerdel (apiose) ved C-4 af rhamnose kunne bidrage til den antibakterielle aktivitet157. Selvom phlinosid C og forsythosid B har en lignende struktur, hæmmer phlinosid C næppe multi-lægemiddel-resistente stammer af S. aureus. Dette indikerede, at introduktion af det tredje glycosid (rhamnose) til forsythosid B kunne forårsage dets inaktivitet143.

2.7 Antidiabetisk aktivitet af PhG'er

En ny PhG'er ved navn flavaiosid fra Scrophularia flava viste -glucosidase-hæmmende aktiviteter med IC50-værdi på 6,50 ug/ml. Derudover havde flavaiosid en signifikant hæmmende aktivitet på glucosidase-enzymet, og den hæmmende aktivitet (91,85 procent) var sammenlignelig med det kendte anti-type 2-diabetiske lægemiddel, acarbose (92,87 procent)158. In vitro-forsøgene viste, at veActeosidechinacoside, isoveActeosid2'-acetylveActeosidetubulosider A, tubulosider B, syringalid A' 3-O- rhamnose, campneosid I og kankanosid J1 fra C. tubulosa kunne tilbyde stærk hæmning mod linsealdosereduktase med deres IC56 på 3. , 1,2, 4,6, 0.0henholdsvis 71, 8,8, 4,0, 11,1, 0,53 og 9,3 μM. Især viste 2'-acetylveActeoside den lignende aktivitet med epalrestat, en klinisk aldosereduktaseinhibitor159. VeActeosidentechinacosideblev vist at forbedre glukosetolerancen og sænke glukoseniveauet hos mus ved doser på 250-500 mg/kg159. VeActeosidentechinacosidekunne undertrykke det øgede postprandiale blodsukkerniveau ved at hæmme glucosetransportør 1-medieret glucoseoptagelse160. Isocampneosid II isoleret fra P. coreana kunne signifikant hæmme rekombinant human aldosereduktase med IC50 på 9,72 μM. Ydermere hæmmede veActeosideisoveActeosideisocampneosid II og cistanoside F effektivt sorbitolakkumulering i en rottelinse inkuberet med en høj koncentration af glucose med henholdsvis næsten 70,6, 47,9, 71,3 og 31,7 procent ved 50 μM161. Sammenlignet med kontrolgruppen forårsagede tre ugers oral administration af veActeoside10, 20 og 40 mg/kg) en signifikant reduktion af blodglukose til henholdsvis 111,30, 74,88 og 75,15 mg/dL hos diabetiske rotter. Med hensyn til seruminsulinniveauer hævede oral behandling med veActeoside10, 20 og 40 mg/kg) seruminsulinniveauet til henholdsvis 3,23, 5,38 og 6,80 μIU/mL hos diabetiske rotter162.

2.8 PhG'ers andre aktiviteter

Wu et al. undersøgte anti-fedme egenskaberne af PhG'er fra Ligustrum purpurascens. Resultaterne viste, at PhG'er hæmmede -chymotrypsin, trypsin og pepsin med IC50-værdierne på henholdsvis 0.42, 0.38 og 0,68 mg/mL. VeActeoside øvede anti-fedme-effekterne ved at hæmme pancreas-lipase. VeActeosidelydende til lipase ved Ka=1.88×104/l mol163. Anti-fedme-effekten af ​​PhG'er fra L. purpurascens over for mus, der fik fedtet diæt, var forbundet med opreguleringen af ​​mRNA- og proteinniveauer af fedtleptin164.Echinacoside(0.01-10 nmol/L) blev rapporteret at booste knogleregenerering i MC3T3-E1-celler ved at forstærke receptoraktivator af NF-KB-ligand (RANKL)165. Tilsvarende 12 ugers daglig ig administration afechinacoside(30, 90 og 270 mg/kg/dag) til ovariektomerede (OVX) rotter øgede signifikant osteoprotegerin (OPG) niveauet og nedsatte RANKL-niveauet166. Sammenlignet med OVX-gruppen, 270 mg/kg/dagechinacosidebehandling forårsagede de højeste niveauer af OPG og OPG/RANKL-forhold (150,14 procent og 197,64 procent)166. Efter 12 ugers daglig oral administration af echinacosid (30, 90, 270 mg/kg/dag) hos OVX-rotter var urinkoncentrationen af ​​calcium, uorganisk fosfor og hydroxyprolin øget med henholdsvis 92,23 procent, 66,67 procent og 36,41 procent. i 270 mg/kg/dag gruppe167. Cistanoside A (po, 20, 40 og 80 mg/kg/dag i 12 uger) viste sig at fremme knogledannelse og forhindre knogleresorption hos OVX-rotter ved at nedregulere TRAF6, koordinere hæmningen af ​​NF-kB-vejen og stimulere PI3K/Akt-vejen168 .

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