Abstract Lycibarbarspermidines are unusual phenolamide glycosides characterized by a dicaffeoylspermidine core with multiple glycosyl substitutions, and serve as a major class of bioactive ingredients in the wolfberry. So far, little is known about the enzymatic basis of the glycosylation of phenolamides including dicaffeoylspermidine. Here, we identify five lycibarbarspermidine glycosyltransferases, LbUGT1-5, which are the first phenolamide-type glycosyltransferases and catalyze regioselective glycosylation of dicaffeoylspermidines to form structurally diverse lycibarbarspermidines in wolfberry. Notably, LbUGT3 acts as a distinctive enzyme that catalyzes a tandem sugar transfer to the ortho-dihydroxy group on the caffeoyl moiety to form the unusual ortho-diglucosylated product, while LbUGT1 accurately discriminates caffeoyl and dihydrocaffeoyl groups to catalyze a site-selective sugar transfer. Crystal structure analysis of the complexes of LbUGT1 and LbUGT3 with UDP, combined with molecular dynamics simulations, revealed the structural basis of the difference in glycosylation selectivity between LbUGT1 and LbUGT3. Site-directed mutagenesis illuminates a conserved tyrosine residue (Y389 in LbUGT1 and Y390 in LbUGT3) in PSPG box that plays a crucial role in regulating the regioselectivity of LbUGT1 and LbUGT3. Our study thus sheds light on the enzymatic underpinnings of the chemical diversity of lycibarbarspermidines in wolfberry, and expands the repertoire of glycosyltransferases in nature.
Goji berry is a famous edible and medicinal substance around the world. In this research, 15 phenylpropionyl phenylethylamine derivatives (1−15), including one new compound (1), were separated and identified from goji berry. All isolates were elucidated via extensive NMR spectral analyses and chemical techniques. Six known isolates were first obtained from Lycium genus. Six isolates were effectively split into double chromatographic peaks accompanied by the basically identical areas, indicating they belong to racemates. The ORAC experiment indicated that all isolates displayed a capacity of scavenging free radicals, and most of them exhibited higher ORAC values than EGCG. In ethanol/palmitic acid (PA)-established in vitro hepatocyte injury model, four phenylpropionyl phenylethylamine derivatives (1, 2, 9, and 15) significantly alleviated hepatocyte injury, among which compound 1 exerted the strongest protective activity. Notably, the hepatoprotective effect of compound 1 was further confirmed in ethanol-established liver damage mouse model, reflected by the reduction of lipid accumulation and the attenuation of pathological alteration. Combined with the in vitro results, the in vivo observations suggested that compound 1 suppressed cell apoptosis and the outburst of inflammation. Our findings provided first-hand evidence proving that goji berry-derived phenylpropionyl phenylethylamine derivatives hold a potential in treating alcoholic liver disease.
Zeaxanthin dipalmitate (3) and two zeaxanthin dipalmitate derivatives, including one new compound (1), were obtained from wolfberry [the fruit of Lycium barbarum L. (Solanaceae)]. Their structures were unambiguously elucidated by spectroscopic analyses. Compound 2 is isolated from the genus Lycium for the first time, and its 1D/2D NMR data are firstly reported. All the compounds belong to carotenoids which are a kind of major bioactive constituents in wolfberry and are also responsible for wolfberry's red color.
Wolfberry is a traditional “affinal drug and diet” in Chinese and Eastern cultures, which is thought to nourish the liver, kidneys, and eyes for over one thousand years. Modern scientific studies have proved that wolfberry and its derivatives could prevent and treat a variety of diseases of the liver, gut, retina, neuron, and kidneys. However, due to its nature of mixture of a large number of constituents, it is quite difficult to delineate the major effective constituent and therapeutic mechanism responsible for those beneficial effects. This review will briefly introduce the recent progress of the botanical characteristic, metabolism, structural classification and disease therapy of the major constituent—zeaxanthin dipalmitate (ZD)—and its derivatives from wolfberry carotenoids. In most published literatures, the health-promoting properties of wolfberry were investigated from Lycium barbarum polysaccharides, which were mixtures of mostly carbohydrates and a small part of pigments/proteins. Recently, we isolated wolfberry into 5 parts, including polysaccharides, lycibarbars- permidines, polyphenols, phenylpropionoyl phenylethylamine, and carotenoids. By using several disease screening models, we found that the carotenoid extract of wolfberry could, at least partly, represent its disease prevention and therapy functions. Since ZD was shown to be the major constituent (~81.5%–87.5%) in total carotenoids of wolfberry, we considered that ZD could be a representative constituent of wolfberry. Thus, we firstly investigated the molecular mechanisms for the storage, synthesis, and degradation of ZD and other carotenoids during Lycium barbarum growth. Then we isolated and characterized all 15 carotenoid constituents from wolfberry. It was found that free carotenoids were the main pigments of immature wolfberry while esterified carotenoids (e.g. ZD) consisted most of the pigment materials in mature fruit. Thirdly, we reviewed the protective effects and possible mechanisms of ZD and its derivatives on liver diseases (e.g. acute liver failure, alcoholic liver injury, non-alcoholic fatty liver disease and viral hepatitis), stem cell injury and transplantation, cardiovascular disorders, eye diseases, and other digestive system syndromes, including tumors. In addition, possible future research directions and contents of ZD will also be discussed, such as (i) can ZD represent most of the beneficial functions of wolfberry, or synergistic promoting effects are existed between ZD and other distinct constituents from wolfberry (e.g. lycibarbarspermidines or polyphenols)? (ii) what is the optimal consumption dosage of ZD in daily life and is there any adverse effect of this kind of carotenoids? (iii) what is the exact metabolic pathways and tissue distribution after ZD consumption? We strongly believe that delineation of those questions will definitive promote basic study, clinical application, and industrial development of wolfberry in the world.
Four new dicaffeoylspermidine derivatives, lycibarbarspermidines P-S (1-4), were isolated from the fruit of Lycium barbarum (wolfberry). The structures were determined by extensive spectroscopic (HRESIMS, 1D NMR, and 2D NMR) analyses and chemical methods. Dicaffeoylspermidine derivatives are a kind of major bioactive and characteristic constituents in wolfberry, and the discovery of 1 -4 added new members of this family.
Scope Besides abstinence and nutritional support, there is no proven clinical treatment for patients with alcoholic fatty liver disease (AFLD). Here, the therapeutic effects and mechanisms of action of wolfberry‐derived zeaxanthin dipalmitate (ZD) on AFLD models are demonstrated. Methods and results The hepatoprotective effects of ZD are evaluated in vitro and in vivo. Direct interacting receptors of ZD on cell membranes are identified by liver‐specific knockdown and biophysical measurements. Downstream signaling pathways are delineated using molecular and cellular biological methods. It is demonstrated that ZD attenuates hepatocyte and whole‐liver injury in ethanol‐treated cells (dose: 1 µ m ) and a chronic binge AFLD rat model (dose: 10 mg kg –1 ), respectively. The direct targets of ZD on the cell membrane include receptor P2X7 and adiponectin receptor 1 (adipoR1). Signals from P2X7 and adipoR1 modulate the phosphatidylinositide 3‐kinase‐Akt and/or AMP‐activated protein kinase‐FoxO3a pathways, to restore mitochondrial autophagy (mitophagy) functions suppressed by ethanol intoxication. In addition, ZD alleviates hepatic inflammation partially via the inhibition of Nod‐like receptor 3 inflammasome, whose activation is a direct consequence of suppressed mitophagy. Liver‐specific inhibition of receptors or mitophagy significantly impairs the beneficial effects of ZD. Conclusions ZD is an effective and promising agent for the potential treatment of AFLD.
Eight new (1a/1b, 2a, 3a, 4a/4b, and 5a/5b) and seven known (2b, 3b, and 6-10) asarone-derived phenylpropanoids, a known asarone-derived lignan (12), and four known lignan analogues (11 and 13-15) were isolated from the rhizome of Acorus tatarinowii Schott. The structures were elucidated via comprehensive spectroscopic analyses, modified Mosher's method, and quantum chemical calculations. Compounds 1-8 were present as enantiomers, and 1-5 were successfully resolved via chiral-phase HPLC. Compounds 1a/1b were the first cases of asarone-derived phenylpropanoids with an isopropyl C-3 side-chain tethered to a benzene core from nature. Hypoglycemic, antioxidant, and AChE inhibitory activities of 1-15 were assessed by the α-glucosidase inhibitory, ORAC, DPPH radical scavenging, and AChE inhibitory assays, respectively. All compounds except 3a showed α-glucosidase inhibitory activity. Compound 3b has the highest α-glucosidase inhibitory effect with an IC50 of 80.6 μM (positive drug acarbose IC50 of 442.4 μM). In the antioxidant assays, compounds 13-15 exhibited ORAC and DPPH radical scavenging activities. The results of the AChE inhibitory assay indicated that all compounds exhibited weak AChE inhibitory activities.
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