Teaghrelin protected dopaminergic neurons in MPTP-induced Parkinson's disease animal model by promoting PINK1/Parkin-mediated mitophagy and AMPK/SIRT1/PGC1-α-mediated mitochondrial biogenesis.

Mitochondrial dysfunction, a common cellular hallmark in both familial and sporadic forms of Parkinson's disease (PD), is assumed to play a significant role in pathologic development and progression of the disease. Teaghrelin, a unique bioactive compound in some oolong tea varieties, has been demonstrated to protect SH-SY5Y cells against 1-methyl-4-phenylpyridinium induced neurotoxicity by binding to the ghrelin receptor to activate the AMPK/SIRT1/PGC-1α pathway. In this study, an animal model was established using a neurotoxin, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), a byproduct of a prohibited drug, to evaluate the oral efficacy of teaghrelin on PD by monitoring motor dysfunction of mice in open field, pole, and bean walking tests. The results showed that MPTP-induced motor dysfunction of mice was significantly attenuated by teaghrelin supplementation. Tyrosine hydroxylase and dopamine transporter protein were found reduced in the striatum and midbrain of MPTP-treated mice, and significantly mitigated by teaghrelin supplementation. Furthermore, teaghrelin administration enhanced mitophagy and mitochondria biogenesis, which maintained cell homeostasis and prevented the accumulation of αSyn and apoptosis-related proteins. It seemed that teaghrelin protected dopaminergic neurons in MPTP-treated mice by increasing PINK1/Parkin-mediated mitophagy and AMPK/SIRT1/PGC-1α-mediated mitochondria biogenesis, highlighting its potential therapeutic role in maintaining dopaminergic neurons function in PD. Mitochondrial dysfunction, a common cellular hallmark in both familial and sporadic forms of Parkinson's disease (PD), is assumed to play a significant role in pathologic development and progression of the disease. Teaghrelin, a unique bioactive compound in some oolong tea varieties, has been demonstrated to protect SH-SY5Y cells against 1-methyl-4-phenylpyridinium induced neurotoxicity by binding to the ghrelin receptor to activate the AMPK/SIRT1/PGC-1α pathway. In this study, an animal model was established using a neurotoxin, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), a byproduct of a prohibited drug, to evaluate the oral efficacy of teaghrelin on PD by monitoring motor dysfunction of mice in open field, pole, and bean walking tests. The results showed that MPTP-induced motor dysfunction of mice was significantly attenuated by teaghrelin supplementation. Tyrosine hydroxylase and dopamine transporter protein were found reduced in the striatum and midbrain of MPTP-treated mice, and significantly mitigated by teaghrelin supplementation. Furthermore, teaghrelin administration enhanced mitophagy and mitochondria biogenesis, which maintained cell homeostasis and prevented the accumulation of αSyn and apoptosis-related proteins. It seemed that teaghrelin protected dopaminergic neurons in MPTP-treated mice by increasing PINK1/Parkin-mediated mitophagy and AMPK/SIRT1/PGC-1α-mediated mitochondria biogenesis, highlighting its potential therapeutic role in maintaining dopaminergic neurons function in PD.

Wogonin induces apoptosis in macrophages by exhibiting cytotoxic and genotoxic effects.

Macrophages play an important role in defending the body against invading pathogens. In the face of pathogens, macrophages become activated and release toxic materials that disrupt the pathogens. Macrophage overactivation can lead to severe illness and inflammation. Wogonin has several therapeutic effects, including anti-inflammatory, anticancer, antioxidant, and neuroprotective effects. No studies have investigated the cytotoxic effects of wogonin at concentrations of more than 0.1 mM in RAW264.7 cells. In this study, RAW 264.7 cells were treated with wogonin, which, at concentrations of more than 0.1 mM, had cytotoxic and genotoxic effects in the RAW264.7 cells, leading to apoptosis and necrosis. Further, wogonin at concentrations of more than 0.1 mM induced caspase-3, caspase-8, and caspase-9 activation and mitochondrial dysfunction and death receptor expression. These results suggest that wogonin induces apoptosis through upstream intrinsic and extrinsic pathways by exhibiting cytotoxic and genotoxic effects.

Strictinin: A Key Ingredient of Tea.

Strictinin is a relatively tiny ellagitannin, which is found in many plants as a minor constituent. Catechins are known as the major constituents in the young leaves of most tea plants, while strictinin was found as a major constituent in the Pu'er tea plant. In some Pu'er tea varieties, strictinin was identified as the most abundant phenolic compound rather than catechins. In the past decade, strictinin was demonstrated to possess several functional activities, including antiviral, antibacterial, anti-obesity, laxative, anticaries, anti-allergic, antipsoriatic, antihyperuricemia, antidiabetic, and anticancer effects. These functional activities were in accordance with the therapeutic effects empirically perceived for Pu'er tea. Evidently, strictinin is the key ingredient in Pu'er tea that acts as a herbal medicine. In functionally-based applications, an instant powder of Pu'er tea infusion was formulated as an active raw material to be supplemented in food, cosmetics, and beverages; a new type of tea named Bitter Citrus Tzen Tea was developed by combining three teas empirically consumed to expel the cold, and new edible oral care products were designed for caries prevention by supplementation with Pu'er tea extract. More functional activities and practical applications of strictinin are scientifically anticipated in follow-up research.

Strictinin, a Major Ingredient in Yunnan Kucha Tea Possessing Inhibitory Activity on the Infection of Mouse Hepatitis Virus to Mouse L Cells.

Theacrine and strictinin of Yunnan Kucha tea prepared from a mutant variety of wild Pu'er tea plants were two major ingredients responsible for the anti-influenza activity. As the COVID-19 outbreak is still lurking, developing safe and cost-effective therapeutics is an urgent need. This study aimed to evaluate the effects of these tea compounds on the infection of mouse hepatitis virus (MHV), a ß-coronavirus serving as a surrogate for SARS-CoV. Treatment with strictinin (100 µM), but not theacrine, completely eliminated MHV infection, as indicated by a pronounced reduction in plaque formation, nucleocapsid protein expression, and progeny production of MHV. Subsequently, a time-of-drug addition protocol, including pre-, co-, or post-treatment, was exploited to further evaluate the possible mechanism of antiviral activity mediated by strictinin, and remdesivir, a potential drug for the treatment of SARS-CoV-2, was used as a positive control against MHV infection. The results showed that all three treatments of remdesivir (20 µM) completely blocked MHV infection. In contrast, no significant effect on MHV infection was observed when cells were pre-treated with strictinin (100 µM) prior to infection, while significant inhibition of MHV infection was observed when strictinin was introduced upon viral adsorption (co-treatment) and after viral entry (post-treatment). Of note, as compared with the co-treatment group, the inhibitory effect of strictinin was more striking in the post-treatment group. These results indicate that strictinin suppresses MHV infection by multiple mechanisms; it possibly interferes with viral entry and also critical step(s) of viral infection. Evidently, strictinin significantly inhibited MHV infection and might be a suitable ingredient for protection against coronavirus infection.

Alleviation of Hyperuricemia by Strictinin in AML12 Mouse Hepatocytes Treated with Xanthine and in Mice Treated with Potassium Oxonate.

Hyperuricemia, an abnormally high level of blood uric acid, is a major risk factor for gout. Although xanthine oxidase inhibitors were clinically used to lower blood uric acid level, the concerned side effects restricted their utilization. In this study, strictinin, an abundant polyphenol in Pu'er tea, was evaluated for its preventive effects on hyperuricemia. The results showed that the xanthine oxidase activity, uric acid production, and inflammation in AML12 mouse hepatocytes treated with xanthine were significantly reduced by the supplementation of strictinin. Detailed analyses revealed that strictinin inhibited xanthine-induced NLRP3 inflammasome activation. Consistently, the elevated blood uric acid level and the enhanced xanthine oxidase activity in mice treated with potassium oxonate were effectively diminished by strictinin supplementation. Moreover, for the first time, strictinin was found to promote healthy gut microbiota. Overall, strictinin possesses a great potential to be utilized as a functional ingredient for the prevention of hyperuricemia.

Attenuation of Skeletal Muscle Atrophy Induced by Dexamethasone in Rats by Teaghrelin Supplementation.

Muscle atrophy caused by an imbalance between the synthesis and the degradation of proteins is a syndrome commonly found in the elders. Teaghrelin, a natural compound from oolong tea, has been shown to promote cell differentiation and to inhibit dexamethasone-induced muscle atrophy in C2C12 cells. In this study, the therapeutic effects of teaghrelin on muscle atrophy were evaluated in Sprague Dawley rats treated with dexamethasone. The masses of the soleus, gastrocnemius and extensor digitorum longus muscles were reduced in dexamethasone-treated rats, and the reduction of these muscle masses was significantly attenuated when the rats were supplemented with teaghrelin. Accordingly, the level of serum creatine kinase, a marker enzyme of muscle proteolysis, was elevated in dexamethasone-treated rats, and the elevation was substantially reduced by teaghrelin supplementation. A decrease in Akt phosphorylation causing the activation of the ubiquitin-proteasome system and autophagy for protein degradation was detected in the gastrocnemius muscles of the dexamethasone-treated rats, and this signaling pathway for protein degradation was significantly inhibited by teaghrelin supplementation. Protein synthesis via the mTOR/p70S6K pathway was slowed down in the gastrocnemius muscles of the dexamethasone-treated rats and was significantly rescued after teaghrelin supplementation. Teaghrelin seemed to prevent muscle atrophy by reducing protein degradation and enhancing protein synthesis via Akt phosphorylation.

Establishment of a Cell Line Stably Expressing the Growth Hormone Secretagogue Receptor to Identify Crocin as a Ghrelin Agonist.

The growth hormone secretagogue receptor-1a (GHSR1a) is the endogenous receptor for ghrelin. Activation of GHSR1a participates in many physiological processes including energy homeostasis and eating behavior. Due to its transitory half-life, the efficacy of ghrelin treatment in patients is restricted; hence the development of new adjuvant therapy is an urgent need. This study aimed to establish a cell line stably expressing GHSR1a, which could be employed to screen potential ghrelin agonists from natural compounds. First, by means of lentiviral transduction, the genome of a human HEK293T cell was modified, and a cell platform stably overexpressing GHSR1a was successfully established. In this platform, GHSR1a was expressed as a fusion protein tagged with mCherry, which allowed the monitoring of the dynamic cellular distribution of GHSR1a by fluorescent microscopy. Subsequently, the authenticity of the GHSR1a mediated signaling was further characterized by using ghrelin and teaghrelin, two molecules known to stimulate GHSR1a. The results indicated that both ghrelin and teaghrelin readily activated GHSR1a mediated signaling pathways, presumably via increasing phosphorylation levels of ERK. The specific GHSR1a signaling was further validated by using SP-analog, an antagonist of GHSR1a as well as using a cell model with the knockdown expression of GHSR1a. Molecular modeling predicted that crocin might be a potential ghrelin agonist, and this prediction was further confirmed by the established platform.

Exploring The Relative Astringency of Tea Catechins and Distinct Astringent Sensation of Catechins and Flavonol Glycosides via an In Vitro Assay Composed of Artificial Oil Bodies.

Artificial oil bodies covered by a recombinant surface protein, caleosin fused with histatin 3 (a major human salivary peptide), were employed to explore the relative astringency of eight tea catechins. The results showed that gallate-type catechins were more astringent than non-gallate-type catechins, with an astringency order of epicatechin gallate > epigallocatechin gallate > gallocatechin gallate > catechin gallate > epigallocatechin > epicatechin > gallocatechin > catechin. As expected, the extension of brewing time led to an increase in catechin content in the tea infusion, thus elevating tea astringency. Detailed analysis showed that the enhanced proportion of gallate-type catechins was significantly higher than that of non-gallate-type catechins, indicating that tea astringency was elevated exponentially, rather than proportionally, when brewing time was extended. Rough surfaces were observed on artificial oil bodies when they were complexed with epigallocatechin gallate (a catechin), while a smooth surface was observed on those complexed with rutin (a flavonol glycoside) under an atomic force microscope and a scanning electron microscope. The results indicate that catechins and flavonol glycosides induce the sensation of rough (puckering) and smooth (velvety) astringency in tea, respectively.

Molecular characterization of polyphenol oxidase between small and large leaf tea cultivars.

Tea is a widely consumed beverage prepared using the fresh leaves of Camellia sinensis L. Tea plants are classified into small- and large-leaf varieties. Polyphenol oxidase (PPO), a crucial enzyme in tea manufacturing, catalyzes essential phenolic metabolites into different derivatives. To compare the molecular characteristics of CsPPO between cultivars, we cloned the full-length sequence of CsPPO cDNA from four representative tea cultivars in Taiwan. Amino acid sequence alignment analyses indicated that CsPPO is highly conserved. PPO exhibited similar enzymatic activity in different tea cultivars. Quantitative real-time polymerase chain reaction revealed no significant differences in the CsPPO transcript level between the small- and large-leaf varieties. However, tea harvested in summer and from low-altitude areas had a higher CsPPO transcript level than that harvested in winter and from high-altitude areas. Regulation of CsPPO by temperature was more significant in the small-leaf variety than in the large-leaf variety. The content of flavonoids and the expression of chalcone synthase, anthocyanidin synthase, and anthocyanidin reductase genes involved in the tea flavonoid biosynthesis pathway were higher in the large-leaf than in the small-leaf varieties, suggesting that the large-leaf variety had a higher antioxidative capacity than did the small-leaf variety. Our study compared the molecular properties of CsPPO between two tea varieties and clarified the physiological role of PPO in tea.

Investigating Potential GLP-1 Receptor Agonists in Cyclopeptides from Pseudostellaria heterophylla, Linum usitatissimum, and Drymaria diandra, and Peptides Derived from Heterophyllin B for the Treatment of Type 2 Diabetes: An In Silico Study.

GLP-1 receptor agonists stimulate GLP-1R to promote insulin secretion, whereas DPP4 inhibitors slow GLP-1 degradation. Both approaches are incretin-based therapies for T2D. In addition to GLP-1 analogs, small nonpeptide GLP-1RAs such as LY3502970, TT-OAD2, and PF-06882961 have been considered as possible therapeutic alternatives. Pseudostellaria heterophylla, Linum usitatissimum, and Drymaria diandra are plants rich in cyclopeptides with hypoglycemic effects. Our previous study demonstrated the potential of their cyclopeptides for DPP4 inhibition. Reports of cyclic setmelanotide as an MC4R (GPCR) agonist and cyclic α-conotoxin chimeras as GLP-1RAs led to docking studies of these cyclopeptides with GLP-1R. Heterophyllin B, Pseudostellarin B, Cyclolinopeptide B, Cyclolinopeptide C, Drymarin A, and Diandrine C are abundant in these plants, with binding affinities of -9.5, -10.4, -10.3, -10.6, -11.2, and -11.9 kcal/mol, respectively. The configuration they demonstrated established multiple hydrogen bonds with the transmembrane region of GLP-1R. DdC:(cyclo)-GGPYWP showed the most promising docking score. The results suggest that, in addition to DPP4, GLP-1R may be a hypoglycemic target of these cyclopeptides. This may bring about more discussion of plant cyclopeptides as GLP-1RAs. Moreover, peptides derived from the HB precursor (IFGGLPPP), including IFGGWPPP, IFPGWPPP, IFGGYWPPP, and IFGYGWPPPP, exhibited diverse interactions with GLP-1R and displayed backbones available for further research.

The Potential Role of Cyclopeptides from Pseudostellaria heterophylla, Linum usitatissimum and Drymaria diandra, and Peptides Derived from Heterophyllin B as Dipeptidyl Peptidase IV Inhibitors for the Treatment of Type 2 Diabetes: An In Silico Study.

Dipeptidyl peptidase 4 (DPP4) inhibitors can treat type 2 diabetes by slowing GLP-1 degradation to increase insulin secretion. Studies have reported that Pseudostellaria heterophylla, Linum usita-tissimum (flaxseed), and Drymaria diandra, plants rich in Caryophyllaceae-type cyclopeptides and commonly used as herbal or dietary supplements, are effective in controlling blood sugar. The active site of DPP4 is in a cavity large enough to accommodate their cyclopeptides. Molecular modeling by AutoDock Vina reveals that certain cyclopeptides in these plants have the potential for DPP4 inhibition. In particular, "Heterophyllin B" from P. heterophylla, "Cyclolinopeptide C" from flaxseed, and "Diandrine C" from D. diandra, with binding affinities of -10.4, -10.0, and -10.7 kcal/mol, are promising. Docking suggests that DPP4 inhibition may be one of the reasons why these three plants are beneficial for lowering blood sugar. Because many protein hydrolysates have shown the effect of DPP4 inhibition, a series of peptides derived from Heterophyllin B precursor "IFGGLPPP" were included in the study. It was observed that IFWPPP (-10.5 kcal/mol), IFGGWPPP (-11.4 kcal/mol), and IFGWPPP (-12.0 kcal/mol) showed good binding affinity and interaction for DPP4. Various IFGGLPPP derivatives have the potential to serve as scaffolds for the design of novel DPP4 inhibitors.

The Potential Role of Phenolic Acids from Salvia miltiorrhiza and Cynara scolymus and Their Derivatives as JAK Inhibitors: An In Silico Study.

JAK inhibition is a new strategy for treating autoimmune and inflammatory diseases. Previous studies have shown the immunoregulatory and anti-inflammatory effects of Salvia miltiorrhiza and Cynara scolymus and suggest that the bioactivity of their phenolic acids involves the JAK-STAT pathway, but it is unclear whether these effects occur through JAK inhibition. The JAK binding affinities obtained by docking Rosmarinic acid (RosA), Salvianolic acid A (SalA), Salvianolic acid C (SalC), Lithospermic acid, Salvianolic acid B and Cynarin (CY) to JAK (PDB: 6DBN) with AutoDock Vina are -8.8, -9.8, -10.7, -10.0, -10.3 and -9.7 kcal/mol, respectively. Their predicted configurations enable hydrogen bonding with the hinge region and N- and C-terminal lobes of the JAK kinase domain. The benzofuran core of SalC, the compound with the greatest binding affinity, sits near Leu959, such as Tofacitinib's pyrrolopyrimidine. A SalC derivative with a binding affinity of -12.2 kcal/mol was designed while maintaining this relationship. The docking results show follow-up studies of these phenolic acids as JAK inhibitors may be indicated. Furthermore, derivatives of SalC, RosA, CY and SalA can yield better binding affinity or bioavailability scores, indicating that their structures may be suitable as scaffolds for the design of new JAK inhibitors.

Characterisation of teaghrelin-like principles from Assam tea cultivated in Thailand.

Teaghrelins were identified as unique acylated flavonoid tetraglycosides and firstly reported in Chin-shin oolong tea. In the present study, two new teaghrelin-like compounds (1 and 2) were purified and characterised from Assam tea varieties collected in Thailand. Their chemical structures were constructed by the spectroscopic and spectrometric analysis. These two teaghrelin-like compounds were also not supposed to exhibit significant ghrelin receptor affinity according to the structural comparison with those teaghrelin-like compounds previously reported. In addition, compounds 1 and 2 did not display notable anti-inflammatory activity in human neutrophils assay.[Formula: see text].

Attenuation of Tumor Development in Mammary Carcinoma Rats by Theacrine, an Antagonist of Adenosine 2A Receptor.

Caffeine has been reported to induce anti-tumor immunity for attenuating breast cancer by blocking the adenosine 2A receptor. Molecular modeling showed that theacrine, a purine alkaloid structurally similar to caffeine, might be an antagonist of the adenosine 2A receptor equivalent to or more effective than caffeine. Theacrine was further demonstrated to be an effective antagonist of the adenosine 2A receptor as its concurrent supplementation significantly reduced the elevation of AMPK phosphorylation level in MCF-7 human breast cells induced by CGS21680, an agonist of adenosine 2A receptors. In an animal model, the development of mammary carcinoma induced by 7,12-Dimethylbenz[a]anthracene in Sprague-Dawley rats could be attenuated by daily supplement of theacrine of 50 or 100 mg/kg body weight. Both expression levels of cleaved-caspase-3/pro-caspase-3 and granzyme B in tumor tissues were significantly elevated when theacrine was supplemented, indicating the induction of programmed cell death in tumor cells might be involved in the attenuation of mammary carcinoma. Similar to the caffeine, significant elevation of interferon-γ and tumor necrosis factor-α was observed in the serum and tumor tissues of rats after the theacrine supplement of 50 mg/kg body weight. Taken together, theacrine is an effective antagonist of adenosine 2A receptors and possesses great potential to be used to attenuate breast cancer.

Pu'er tea rich in strictinin and catechins prevents biofilm formation of two cariogenic bacteria, Streptococcus mutans and Streptococcus sobrinus.

Cariogenic bacteria, such as Streptococcus mutans and Streptococcus sobrinus, are main pathogens responsible for human dental caries. Pu'er tea is empirically observed to prevent tooth decay. Besides caffeine and catechins commonly found in oolong tea, strictinin is also found as an abundant phenolic compound in Pu'er tea. Infusion of Pu'er tea as well as single compound, strictinin, caffeine or (-)-epigallocatechin gallate (EGCG) was examined for its inhibitory effects on S. mutans and S. sobrinus. Relatively weak inhibition of bacterial growth was observed for these Pu'er tea constituents. However, biofilm formation of S. mutans or S. sobrinus was strongly prevented by the infusion of Pu'er tea as well as by strictinin or EGCG, but not caffeine. Relatively, strictinin showed a higher potency than EGCG to prevent biofilm formation. Anti-caries effect of Pu'er tea seems to be resulted from the prevention of biofilm formation of cariogenic bacteria mainly by strictinin and catechins.

Anti-Inflammatory Principles from the Needles of Pinus taiwanensis Hayata and In Silico Studies of Their Potential Anti-Aging Effects.

Pinus needle tea are very popular in Eastern countries such as Japan, Russia, Korea, and China. Pine needle tea is claimed to have significant anti-aging effects, but no clear evidence has supported this until now. In the present study, five undescribed compounds (1-5) as well as seventy-two known compounds were purified and characterized from the bioactive fraction of methanol extracts of P. taiwanensis needles. Most of the isolates were examined for their anti-inflammatory bioactivity by cellular neutrophil model and six compounds (45, 47, 48, 49, 50, and 51) exhibited a significant inhibition on superoxide anion generation and elastase release with IC50 values ranging from 3.3 ± 0.9 to 8.3 ± 0.8 µM. These anti-inflammatory ingredients were subjected to docking computing to evaluate their binding affinity on the ghrelin receptor, which played an important role in regulating metabolism, with anti-aging effects. Compounds 49, 50, and 51 formed a stable complex with the ghrelin receptor via hydrogen bonds and different types of interactions. These results suggest the flavonoids are responsible for the potential anti-aging effects of pine needle tea.

Characterization of teaghrelin-like compounds from tea cultivars.

Teaghrelins, identified originally in Chin-shin oolong tea, are unique acylated flavonoid tetraglycosides and proposed to be potential oral analogues of ghrelin. In the present study, two new teaghrelin-like compounds were characterized from tea cultivars (TTES No. 12), and their chemical structures were established by the spectroscopic and spectrometric analysis. However, due to the different location of rhamnose, these two teaghrelin-like compounds may not show significant ghrelin receptor affinity.[Figure: see text].

Teaghrelin Protects SH-SY5Y Cells against MPP+-Induced Neurotoxicity through Activation of AMPK/SIRT1/PGC-1α and ERK1/2 Pathways.

The prevalence and incidence of Parkinson's disease (PD), an age-related neurodegenerative disease, are higher among elderly people. Independent of etiology, dysfunction and loss of dopaminergic neurons are common pathophysiological changes in PD patients with impaired motor and non-motor function. Currently, preventive or therapeutic treatment for combating PD is limited. The ghrelin axis and ghrelin receptor have been implicated in the preservation of dopaminergic neurons and have potential implications in PD treatment. Teaghrelin, a compound originating from Chin-Shin Oolong tea, exhibits ghrelin agonist activity. In this study, the neuroprotective potential of teaghrelin against PD was explored in a cell model in which human neuroblastoma SH-SY5Y cells were treated with the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). Upon MPP+ exposure, SH-SY5Y cells exhibited decreased mitochondrial complex I activity and apoptotic cell death. Teaghrelin activated AMP-activated protein kinase (AMPK)/sirtuin 1(SIRT1)/peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways to antagonize MPP+-induced cell death. Herein, we propose that teaghrelin is a potential candidate for the therapeutic treatment of PD.

Quercetin 3-O-malonylglucoside in the leaves of mulberry (Morus alba) is a functional analog of ghrelin.

Mulberry (Morus alba) leaf is traditionally consumed as a functional tea with remedial effects, such as preventing aging-related diseases. Two similar compounds, quercetin 3-O-malonylglucoside, and kaempferol 3-O-malonylglucoside, were detected in mulberry leaves and found to be structural recombinant composites of teaghrelin and emoghrelin, two classes of non-peptidyl compounds functionally identified as analogs of ghrelin. Molecular modeling showed that these two mulberry compounds were able to enter and interact with the ghrelin receptor and theoretical calculation revealed that they were similar to emoghrelin but slightly weaker than teaghrelin in terms of interaction with the receptor. The relatively abundant compound, quercetin 3-O-malonylglucoside was subjected to a bioactivity assay, and the result confirmed that it was able to increase the growth hormone secretion of rat anterior pituitary cells. It seems that quercetin 3-O-malonylglucoside is also a functional analog of ghrelin and presumably a key ingredient for the anti-aging activity of mulberry leaves. PRACTICAL APPLICATIONS: According to this study, quercetin 3-O-malonylglucoside and kaempferol 3-O-malonylglucoside are suggested to serve as active ingredients in tea products prepared from mulberry leaves. Contents of these two compounds might be used as key factors for breeding or screening mulberry varieties for commercial cultivation. Moreover, water extract of mulberry leaves containing these compounds can be used as an adequate supplement for functional food.