Search

Loganin, one of the two main iridoid glycosides in Cornus officinalis Sieb et Zucc, has been reported to exhibit many biological activities such as immune modulation, as well as anti-inflammatory and anti-shock effects. This study was designed to evaluate the pharmacokinetics of loganin, administered intravenously (5, 10, 20 and 50 mg/kg) and orally (20, 50, 100 and 200 mg/kg), in rats. To evaluate its hepatic and gastrointestinal first-pass effects, loganin was administered intraportally, intragastrically and intraduodenally to rats. Following intravenous administration of 5–50 mg/kg loganin, a linear relationship was observed between the total area under the plasma concentration–time curve from zero to infinity (AUC) and loganin dose, with ~ 19% of the administered dose excreted in the urine. AUCs following oral administration of 20–200 mg/kg loganin were dose-independent, with the extent of absolute oral bioavailability (F) being approximately 4.87%. The AUC of loganin was significantly lower by 90.6% after intraduodenal than intraportal administration, but did not differ between intragastric and intraduodenal administration. The AUC was also significantly lower by 52.7% after intraportal, compared to intravenous, administration, suggesting that the hepatic first-pass effect on loganin after entering the portal vein was approximately 4.95% of the oral dose. Taken together, our data suggest that the low F of loganin in rats was due exclusively to its high intestinal first-pass metabolism.

Three isolates belonging to the ascomycetous genus Zygotorulaspora were obtained from the fruits of Cornus officinalis and Smilax china, and flowers of Dendranthema zawadskii var. latilobum in Gongju-si, Korea. Phylogenetic Analyses of the LSU D1/D2 domain and ITS region sequences supported the recognition of two new species: Zygotorulaspora cornina sp. nov. (type strain NIBRFGC000500475 = KACC93346PPP) and Zygotorulaspora smilacis sp. nov. (type strain NIBRFGC000500476 = KACC93347PPP). The two novel species revealed no growth on D-Galactose, unlike the other six species in the genus Zygotorulaspora. They are distinguished from each other by their phylogenetic differences and phenotypic characteristics such as assimilation of xylitol, 5-keto-D-gluconate, and ethanol. All species in the genus Zygotorulaspora including the two novel species have phenotypic traits of genus Zygotorulaspora: asci are persistent, sucrose and raffinose are assimilated, and m-inositol is not required for growth, and they are mainly associated with plants.

The use of botanical dietary supplements for the alleviation of conditions such as hot flashes, premenstrual syndrome, and fertility is prolific worldwide. Estrogen and progesterone receptors (ER and PR) and their corresponding steroid hormones are critical for the relief of hot flashes and the treatment of patients who develop endometriosis, and these pathways can influence the development of endometrial, ovarian, and breast cancers. However, few studies have investigated or identified the natural product components in herbal supplements that act on the PR. In the current study, a new secoiridoid, demethoxy-cornuside (1), along with six known secoiridoids (2-7) were isolated from the twigs of dogwood (Cornus officinalis) by bioassay-guided isolation with a progesterone response element (PRE)/luciferase (Luc) reporter assay in Ishikawa cells. Four phytoprogestins (1, 2, 6, 7) potentiated the effect of progesterone in the PRE/Luc assay. This study demonstrates that C. officinalis components might potentiate progesterone signaling in the presence of progesterone, which could modify progesterone receptor action in hormone-responsive tissues such as the uterus and mammary gland.

Ruiqi Xu,1,2 Mengnan Zeng,1,2 Yuanyuan Wu,1,2 Shengchao Wang,1,2 Beibei Zhang,1,2 Jingke Zhang,1,2 Yuxuan Kan,1,2 Benke Li,1,2 Bing Cao,1,2 Xiaoke Zheng,1,2 Weisheng Feng1,2 1School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou, People’s Republic of China; 2The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou, People’s Republic of ChinaCorrespondence: Xiaoke Zheng; Weisheng FengSchool of Pharmacy, Henan University of Traditional Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, People’s Republic of ChinaTel +86-371-6019-0296Email zhengxk.2006@163.com; fwsh@hactcm.edu.cnPurpose: This research aims to investigate the intervention and mechanism of 50% acetone extract of C. officinalis leaves (SZYY) on melanoma xenografts.Patients and Methods: Tumor size and cardiac function were measured via ultrasound. The accumulation of 2-deoxy-D-glucose (2-DG) in tumor tissue was examined with near-infrared in vivo imaging. Flow cytometry was performed to assess apoptosis and reactive oxygen species (ROS) levels in tumor and immune cells in spleen. The levels of inflammatory cytokines in serum were detected by cytometric bead array. The expression of proliferation-, apoptosis-, and angiogenesis-related proteins in tumor cells was measured to evaluate the underlying mechanisms. Subsequently, the effects of four compounds separated from SZYY on the proliferation and migration of A375 cells and STAT3 signaling were examined. The peak identification and contents of the four components were performed via high-performance liquid chromatography (HPLC). Finally, we evaluated the inhibitory effects of STAT3 overexpression on the cytotoxic activity of four constituents in A375 cells.Results: SZYY inhibited the growth and glycolysis of melanoma xenograft in mice, improved cardiac function, increased the percentages of macrophages, neutrophils, and lymphocytes in spleen, reduced the levels of IL-6, IL-17A, TNF-α, and IFN-γ in serum, promoted apoptosis and oxidative stress in tumor tissues, and inhibited STAT3 phosphorylation and expression of angiogenic factors. Chemical analysis showed that SZYY is rich in loganin, rutin, triohimas C, and triohimas D, which all could restrain the proliferation and migration of A375 cells and inhibit the phosphorylation and nuclear translocation of STAT3. Moreover, STAT3 overexpression could diminish the cytotoxic activity of four compounds on A375 cells.Conclusion: SZYY could exert anti-melanoma effects via inhibiting STAT3 signaling to induce apoptosis and inhibit tumor angiogenesis. Its active ingredients might be loganin, rutin, triohimas C, and triohimas D.Keywords: Cornus officinalis, melanoma, STAT3, apoptosis, angiogenesis

Information about the physical properties of berries of selected dogwood species is available in the literature, but the basic physical traits of berry seeds have not been investigated to date. In this study, the terminal velocity, thickness, width, length, angle of external friction and mass of seeds of 11 dogwood species were measured. The measured parameters were used to calculate the geometric mean diameter, aspect ratio and sphericity index of each seed. The average values of the evaluated parameters were determined in the following range: terminal velocity - from 9.95 to 13.15 m s-1, thickness - from 3.31 to 5.02 mm, width - from 4.14 to 5.38 mm, length - from 4.33 to 11.55 mm, angle of external friction - from 9.97 to 29.85 ºC, mass - from 33.06 to 175.51 mg. The analyzed dogwood species were arranged in the following ascending order based on the geometric mean diameter of their seeds: Cornus macrophylla, Cornus alba, Cornus amonum, Cornus kousa, Cornus obliqua, Cornus controversa, Cornus walteri, Cornus sanguinea, Cornus florida, Cornus officinalis and Cornus mas. The seeds of Cornus alba, Cornus controversa, Cornus florida, Cornus kousa, Cornus macrophylla, Cornus mas and Cornus officinalis could be sorted with the use of mesh sieves with longitudinal openings, the seeds of Cornus macrophylla, Cornus sanguinea and Cornus walteri - with the use of mesh sieves with round openings, and the seeds of Cornus alba, Cornus macrophylla and Cornus obliqua - with the use of cylindrical graders.

Schisandra chinensis, Lycium chinense, and Cornus officinalis are cultivated in South Korea, China and Japan. Because of their beneficial biological effectiveness, the consumption of these herbs is increasing. The objective of this study was to analyze the pesticide residue levels on these herbal fruits produced in Korea. A short- and long-term risk assessment of the pesticides in herbal fruits was conducted. Pesticides were detected in most samples, and all samples with multiple residues were also noted. The average numbers of pesticides detected in the S. chinensis, L. chinense, and C. officinalis samples were 1.84, 10.28, and 5.87, respectively. The short-term and highest long-term risks, and the cumulative risk (cHI) were 0.633%, 1.14%, and 7.56% (S. chinensis), 1.0 × 10−1%, 1.1 × 10−5%, and 4.0 × 10−5% (L. chinense), and 2.2 × 10−5%, 1.6 × 10−5%, and 8.9 × 10−5% (C. officinalis). No significant health risk for consumers via herbal fruit consumption was detected.

The ultrasonic-assisted extraction process of polysaccharide from Cornus officinalis leaves (COLP) was optimized. After isolation and purification, the antioxidant and antibacterial activities of polysaccharide were studied in vitro. The extraction rate was highest under conditions of ultrasonic power 340 W, solvent to solid ratio 26:1(v/w), extraction temperature 71 °C and extraction time 2.3 h, reaching 7.04%, which was consistent with the model predicted value. The crude polysaccharide was isolated and purified by DEAE-52 cellulose chromatography column, and four components COLP-1, COLP-2, COLP-3 and COLP-4 were obtained. Then, Sephadex G-100 chromatography column was used to purify COLP-1 and COLP-3, and two components COLP-1-1 and COLP-3-2 were obtained. COLP-1-1 had strong scavenging ability against DPPH free radicals, against hydroxyl radical, and superoxide anion radical, with the highest clearance rate reaching 81.48%, 79.48% and 72.87% respectively. COLP-3-2 also had strong scavenging ability against DPPH free radicals, against hydroxyl radical, and superoxide anion radical, with the highest clearance rate reaching 88.57%, 76.64% and 86.08% respectively. The results indicated that COLP-1-1 and COLP-3-2 had higher antioxidant activity, and the antioxidant activity of COLP-3-2 was stronger than COLP-1-1. The results of antibacterial activity showed that COLP-1-1 had the highest antibacterial activity on Bacillus subtilis and weaker antibacterial activity on Escherichia coli, Salmonella typhimurium and Staphylococcus aureus; COLP-3-2 had a certain antibacterial activity on Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium and Bacillus subtilis.

Endophytic fungi are not only ubiquitous in plants, but also play an important role in the balancing of plant microecosystems. Numerous studies have shown that plant species and environment have a significant influence on the richness of endophytic fungi, and endophytic fungi often provide different forms of fitness benefits to their associated host plants. The present work aimed to isolate and identify endophytic fungi harboured in the tissues of the native medicinal plant Cornus officinalis and screen beneficial fungi to inhibit cornel pathogens. A total of 208 strains were recovered from 720 tissue segments. The overall colonisation and isolation rates of endophytic fungi were 33.89% and 28.89%, with triennial twigs (53.33%, 55%) and fruits (6.67%, 3.33%) having the highest and lowest rates, respectively. On the basis of morphological characteristics and internal transcribed spacer sequence analysis, 183 isolates were classified into 13 genera. Amongst them, Alternaria, Botryosphaeria and Talaromyces were dominant communities, and their relative abundances were 31.25%, 26.92% and 10.10%, respectively. A detailed calculation of the Shannon diversity (H′ = 1.65) and Margalef’s richness indices (Dmg = 2.30) revealed that the overall biodiversity of fungal endophytes in C. officinalis was relatively high, with the stems harbouring the highest diversity. The antagonism assay of 75 representative endophytes on the four main fungal pathogens of C. officinalis indicated that nine strains with antibiosis and eight strains with inhibition rate of more than 50% were obtained by the dual culture. To the best of our knowledge, this is the first study that investigated the distribution and antifungal activity of endophytic fungi from the medicinal plant C. officinalis.

Background Shanzhuyu (the dried mature sarcocarp of Cornus officinalis Sieb. et Zucc., DMSCO) is a Chinese herb that can be used for the treatment of Alzheimer’s disease (AD), but its mechanism remains unknown. The present study aimed to investigate the active ingredients and effective mechanisms of DMSCO for the treatment of AD based on a network pharmacology approach. Methods The active components of DMSCO were collected from the TCMSP and ETCM databases and the target proteins of these compounds were predicted using TCMSP, SwissTargetPrediction and the STITCH database. The AD-related target proteins were identified from the OMIM, DisGeNet, GEO and GeneCards databases. The network interaction model of the compound-target-disease was established and was used to obtain the key targets of DMSCO on AD through network topology analysis. Subsequently, gene enrichment in Gene Ontology (GO) and KEGG pathways were conducted using the David 6.8 online tool. Results A total of 30 DMSCO effective compounds and 209 effective drug targets were obtained. A total of 172 AD-related genes and 37 shared targets of DMSCO and AD were identified. A total of 43 key targets for the treatment of AD were obtained from the topological analysis of the DMSCO-AD target network. These key targets were involved in a variety of biological processes, including amyloid deposition, apoptosis, autophagy, inflammatory response and oxidative stress and pathways, such as the PI3K-AKT, MAPK and TNF pathways. Three key compounds, namely ursolic acid, anethole and β-sitosterol were obtained from the analysis of the key targets. Conclusions Ursolic acid, anethole and β-sitosterol may be the main active components of DMSCO in the treatment of AD. DMSCO can treat AD by regulating amyloid deposition, apoptosis, autophagy, inflammatory response and oxidative stress via the PI3K-AKT, MAPK and other signaling pathways.

A high quality vinegar was produced from fresh Cornus officinalis fruits using a two-step fermentative process (ethanol fermentation for 15 days, followed by acetic fermentation for 7 days). The total acid percentage and total polyphenol concentration were 4.86% and 1584 mg/L, respecively. The morroniside and Loganin, as essential components of Cornus officinalis, have been well preserved in the vinegar, the concentration reached 1139.5 g/mL and 779.34 g/mL, respectively. Furthermore, the free radical-scavenging capability of C. officinalis vinegar was higher than that of other commercially available vinegars, such as Cider vinegars, Persimmon vinegar and Red wine vinegar. The results of 2,2-diphenyl-1-picryl-hydrazyl, 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), and hydroxyl free radical assays revealed that the free radical-scavenging rates were 88.46%, 53.96%, and 51.43%, respectively. Compared to the control, the proportions of Clostridia and Firmicutes in the intestinal tracts of mice treated with C. officinalis vinegar decreased significantly, whereas that of Bacteroidetes markedly increased. In summary, our results indicate that C. officinalis vinegar has promising health benefits, and every effort should be made to commercialize this product.

Cornus officinalis is a traditional Chinese herbal medicine rich in active substances, such as iridoid glycosides, esters, polysaccharides, and tannins. C. officinalis replenishes the liver and kidney and retracts and removes phlegm. In this study, the candidate transcription factor bHLH40 from C. officinalis (CobHLH40) was predicted to be involved in iridoid glycoside biosynthesis. CobHLH40 was cloned from C. officinalis. Bioinformatics analysis was performed using the Protparatam, the ProtScale, and the SOPMA. CobHLH40 had a cDNA length of 2100 bp and a relative molecular mass of 63.32 kDa, and encoded 573 amino acids. The subcellular localization analysis indicated that CobHLH40 may be located in the nucleus. The comparison of multiple sequence alignments and phylogenetic relationships showed that the CobHLH40 was similar to the MYC2 of other plants, and that CobHLH40 had high homology with the MYC2 of Sesamum indicum. A prokaryotic expression vector was successfully constructed and transformed into the DE3 cells. The induction and expression of the fusion protein of CobHLH40 need further confirmation. The cloning and bioinformatics analysis results of CobHLH40, which may be related to iridoid glycoside synthesis, were screened and predicted for the first time on the basis of C. officinalis transcriptome sequencing. The temporal and spatial expression patterns of C. officinalis were also established. The CobHLH40 prokaryotic expression system provides a basis to further study its function.

Since silver nanoparticles (AgNPs) synthesized by using plant extracts revealed varied biological activities, the green synthesis of AgNPs has attracted considerable attention. Although the green synthesis of AgNPs have been accomplished by using the extracts of Cornus Officinalis, which is a traditional Chinese medicine and exhibits a wide spectrum of phytochemicals. The effects of biosynthesis parameters on reducing reaction, stability and more broad biological activities of so-prepared AgNPs did not been evaluated. In this paper, we firstly assessed the effects of UV radiation, pH, material proportion and radiation times on the green synthesis of AgNPs under 365 nm UV radiation by UV-visible spectrum and dynamic light scattering (DLS) analysis. The results showed that UV radiation could accelerate the formation of AgNPs and influence the average size below pH 7.0, and the size of so-prepared AgNPs were sensitive to the pH and material proportion, but no obvious changes to UV radiation times, offering a size-controlled synthetic method for AgNPs. The further X-ray diffraction (XRD), transmission electron microscopy (TEM) and DLS studies showed AgNPs synthesized at pH 7.0, extract: AgNO3 = 1 : 1 and after 4 h UV radiation were a face-centered cubic (fcc) structure and both spherical and polygonal in shape with average particle size of 64.5 ± 0.3 nm existed in a monodispersed form. Subsquently, the stability of AgNPs was analyzed by zeta potential (−24.8 mV) and the average size measurement after 30 days storage (63.3 ± 0.4 nm), revealing a high degree of stability. Lastly, the investigation of biological activities showed that the biosynthesized AgNPs had potent antioxidant activity, antimicrobial activity against both S. aureus and E. coli as well as anticancer activity against HCT116 and HepG2 cell lines but negligible cytotoxicity against SW620. And the internalization of biosynthesized AgNPs inside the bacterial cell was evaluated by flow cytometric analysis, where the SSC values have significant increase after treating with nanoparticles. These results confirmed that the biosynthesis parameters on the green synthesis of AgNPs by using Cornus Officinalis extract also played pivotal roles and so-prepared AgNPs would be useful for the development of new alternative antioxidant, antimicrobial and anticancer agents in biomedicine.

The skin is one of the large organs in the human body and the most exposed to outdoor contaminants such as particulate matter < 2.5 µm (PM2.5). Recently, we reported that PM2.5 induced cellular macromolecule disruption of lipids, proteins, and DNA, via reactive oxygen species, eventually causing cellular apoptosis of human keratinocytes. In this study, the ethanol extract of Cornus officinalis fruit (EECF) showed anti-oxidant effect against PM2.5-induced cellular oxidative stress. EECF protected cells against PM2.5-induced DNA damage, lipid peroxidation, and protein carbonylation. PM2.5 up-regulated intracellular and mitochondrial Ca2+ levels excessively, which led to mitochondrial depolarization and cellular apoptosis. However, EECF suppressed the PM2.5-induced excessive Ca2+ accumulation and inhibited apoptosis. The data confirmed that EECF greatly protected human HaCaT keratinocytes from PM2.5-induced oxidative stress.

The present study is a preparation of bioactive peptides from Cornus officinalis proteins by the compound enzymatic hydrolysis method. Response surface methodology (RSM) coupled with Box–Behnken design (BBD) is used to optimize the preparation process of Cornus officinalis peptides. The effects of independent variables, such as the amount of enzyme, pH value, time, extraction times and the ratio of material to liquid on the yield of peptides, are also investigated. The analysis results of the RSM model show that the optimum conditions for the extraction of Cornus officinalis peptides were a pH value of 6.76, temperature of 48.84 °C and the amount of enzyme of 0.19%. Under optimal conditions, the yield of peptides was 36.18 ± 0.26 %, which was close to the predicted yield by the RSM model. Additionally, the prepared Cornus officinalis peptides showed significant antioxidant activity; the scavenging rates of the peptides for DPPH and ·OH were 48.47% and 29.41%, respectively. The results of the cell proliferation assay revealed that the prepared Cornus officinalis peptides could promote embryo fibroblast cells proliferation and repair oxidative damage cells. These results have a practical application value in the design of novel functional food formulations by using Cornus officinalis.

In this study, total phenolic and flavonoid content of methanolic extracts of leaves and fruits from six samples of Cornus mas L. and one sample of Cornus officinalis Siebold & Zucc., Cornaceae, have been investigated. Samples were air-dried, milled and extracted with methanol in an ultrasonic bath. After filtration, organic solvent was removed using a rotary evaporator and the remaining samples were suspended in distilled water, frozen and afterward subjected to lyophilization. Total phenolic content and flavonoid content were evaluated spectrophotometrically in aqueous solutions of obtained lyophilizates using the Folin-Ciocalteu method and the AlCl3 method, respectively. Pearson’s correlation coefficient (r) was used to establish the relationship between leaf and fruit total phenolic and flavonoid content (ɑ = 0.05). Data analysis was performed in Microsoft Excel (2013). Total phenolic content of C. mas leaf and fruit extracts ranged from 195.32 ± 1.59 to 311.21 ± 1.22 mg gallic acid equivalent (GAE)/g dry extract (DE) and from 9.69 ± 0.58 to 16.63 ± 0.26 mg GAE/g DE, respectively. Total phenolic contents of C. officinalis leaf and fruit extracts were 286.70 ± 1.90 mg GAE/g DE and 13.56 ± 0.15 mg GAE/g DE, respectively. Flavonoid content in leaf extracts of C. mas ranged from 1.20 ± 0.06 to 4.51 ± 0.22 mg quercetin equivalent (QE)/g DE, while flavonoid content in fruit extracts ranged from 0.18 ± 0.04 to 1.07 ± 0.02 mg QE/ g DE. Flavonoid contents of C. officinalis leaf and fruit extracts were 3.66 ± 0.03 and 0.42 ± 0.03 mg QE/g DE, respectively. Very strong negative correlation was observed between total phenolic contents in leaves and fruits of C. mas (r = -0.94, P = 0.005), while between leaf and fruit flavonoid contents of C. mas very strong positive correlation was observed (r = 0.90, P = 0.016).

Using various chromatographic methods, four new phenolics, coroffesters A-D (1 − 4) were isolated from the fruit of Cornus officinalis (Cornaceae). Their structures (1 − 4) were elucidated unambiguously by spectroscopic methods such as one- and two-dimensional nuclear magnetic resonance (1 D- and 2 D-NMR) spectroscopy and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The anti-inflammatory activity of the isolated compounds was also evaluated. All compounds (1 − 4) showed moderate inhibitory activity against NO production in a dose-dependent manner in RAW 264.7 cells.

U ovom radu ispitan je sadržaj ukupnih fenola i flavonoida te antioksidativni učinak in vitro metanolnih ekstrakata plodova i listova šest uzoraka vrste Cornus mas L. i jednog uzorka vrste Cornus officinalis Siebold & Zucc., Cornaceae. Uzorci su osušeni na zraku, samljeveni i ekstrahirani metanolom u ultrazvučnoj kupelji. Nakon filtracije, organsko otapalo je uklonjeno pomoću vakuumskog uparivača, a upareni ekstrakti su resuspendirani u destiliranoj vodi, zamrznuti i nakon toga liofilizirani. Sadržaj ukupnih fenola i flavonoida određen je spektrofotometrijski u vodenim otopinama dobivenih liofilizata Folin-Ciocalteu metodom odnosno AlCl3 metodom. Antioksidativni (antiradikalni) učinak određen je pomoću ABTS i DPPH testa. Pearsonov koeficijent korelacije (r) korišten je za utvrđivanje odnosa između izmjerenih parametara (ɑ = 0,05). Sadržaj ukupnih fenola u ekstraktima plodova i listova vrste C. mas kretao se od 9,69 ± 0,58 do 16,63 ± 0,26 mg ekvivalenta galne kiseline (EGK)/g suhog ekstrakta (SE) odnosno od 195,32 ± 1,59 do 311,21 ± 1,22 mg EGK/g SE. Sadržaj ukupnih fenola u ekstraktima plodova i listova vrste C. officinalis iznosio je 13,56 ± 0,15 mg EGK/g SE, odnosno 286,70 ± 1,90 mg EGK/g SE. Sadržaj flavonoida u ekstraktima plodova C. mas kretao se od 0,18 ± 0,04 do 1,07 ± 0,02 mg ekvivalenta kvercetina (EK)/g SE, dok je sadržaj flavonoida u ekstraktima listova bio u rasponu od 1,20 ± 0,06 do 4,51 ± 0,22 0 mg EK/g SE. Sadržaj flavonoida u ekstraktima plodova i listova C. officinalis bio je 0,42 ± 0,03 odnosno 3,66 ± 0,03 mg EK/g SE. Uočena je vrlo dobra negativna povezanost između ukupnog sadržaja fenola u listovima i plodovima vrste C. mas (r = -0,94, P = 0,005), dok je između sadržaja flavonoida u listovima i plodovima vrste C. mas uočena vrlo dobra pozitivna povezanost (r = 0,90, P = 0,016). Antiradikalna aktivnost vrste C. mas procijenjena kao IC50 vrijednost u ABTS testu iznosila je između 52,91 i 179,80 μg/mL za ekstrakte plodova odnosno između 3,32 i 5,51 μg/mL za ekstrakte listova, dok je za ekstrakte plodova i listova vrste C. officinalis iznosila 63,08 μg/mL i 3,97 μg/mL. Antiradikalna aktivnost vrste C. mas procijenjena kao IC50 vrijednost u DPPH testu iznosila je između 68,64 i 259,16 μg/mL za ekstrakte plodova odnosno između 4,53 i 8,25 μg/mL za ekstrakte listova, dok je za ekstrakte plodova i listova vrste C. officinalis iznosila 141,38 μg/mL i 4,35 μg/mL. Uočena je vrlo dobra negativna povezanost između sadržaja ukupnih fenola i antiradikalne aktivnosti listova i plodova istraživanih vrsta procijenjene DPPH testom (r = -0,89, P < 0,001) i ABTS testom (r = -0,80, P < 0,001). Utvrđene vrijednosti za uzorak vrste C. officinalis bile su usporedive s onima uzoraka vrste C. mas. In this study, total phenolic and flavonoid content and antioxidant activity in vitro of methanolic extracts of fruits and leaves from six samples of Cornus mas L. and one sample of Cornus officinalis Siebold & Zucc., Cornaceae, have been investigated. Samples were air-dried, milled and extracted with methanol in an ultrasonic bath. After filtration, organic solvent was removed using a rotary evaporator and the remaining extracts were resuspended in distilled water, frozen and afterward subjected to lyophilization. Total phenolic content and flavonoid content were evaluated spectrophotometrically in aqueous solutions of obtained lyophilizates using the Folin-Ciocalteu method and the AlCl3 method, respectively. The antioxidant (antiradical) activity was determined using the ABTS and DPPH tests. Pearson’s correlation coefficient (r) was used to establish the relationships between the measured parameters (ɑ = 0.05). Total phenolic content of C. mas fruit and leaf extracts ranged from 9.69 ± 0.58 to 16.63 ± 0.26 mg gallic acid equivalent (GAE)/g dry extract (DE) and from 195.32 ± 1.59 to 311.21 ± 1.22 mg GAE/g DE, respectively. Total phenolic contents of C. officinalis fruit and leaf extracts were 13.56 ± 0.15 mg GAE/g DE and 286.70 ± 1.90 mg GAE/g DE, respectively. Flavonoid content in fruit extracts of C. mas ranged from 0.18 ± 0.04 to 1.07 ± 0.02 mg quercetin equivalent (QE)/g DE, while flavonoid content in leaf extracts ranged from 1.20 ± 0.06 to 4.51 ± 0.22 mg QE/g DE. Flavonoid contents of C. officinalis fruit and leaf extracts were 0.42 ± 0.03 and 3.66 ± 0.03 mg QE/g DE, respectively. Very strong negative correlation was observed between total phenolic contents in leaves and fruits of C. mas (r = -0.94, P = 0.005), while very strong positive correlation was observed between leaf and fruit flavonoid contents of C. mas (r = 0.90, P = 0.016). Antiradical activity estimated as IC50 value by the ABTS test of the fruit and leaf extracts of C. mas ranged from 52.91 to 179.80 μg/mL and from 3.32 to 5.51 μg/mL, respectively. The antiradical activity of the fruit and leaf extracts of C. officinalis was 63.08 μg/mL and 3.97 μg/mL, respectively. Antiradical activity estimated as IC50 value by the DPPH test of the fruit and leaf extracts of C. mas ranged from 68.64 to 259.16 μg/mL and from 4.53 to 8.25 μg/mL, respectively. The antiradical activity of the fruit and leaf extracts of C. officinalis was 141.38 μg/mL and 4.35 μg/mL, respectively. Very strong negative correlation was observed between total phenolic content and antiradical activity of leaves and fruits of investigated species evaluated by the DPPH test (r = -0.89, P < 0.001) and the ABTS test (r = -0.80, P < 0.001). The determined values for the C. officinalis sample were comparable to those of the C. mas samples.

The AIM2 inflammasome is an innate immune system component that defends against cytosolic bacteria and DNA viruses, but its aberrant activation can lead to the progression of various inflammatory diseases, including psoriasis. However, there have been few reports of specific inhibitors of AIM2 inflammasome activation. In this study, we aimed to investigate the inhibitory activity of ethanolic extracts of seeds of Cornus officinalis (CO), a herb and food plant used in traditional medicine, on AIM2-inflammasome activation. We found that CO inhibited the release of IL-1β induced by dsDNA in both BMDMs and HaCaT cells, but that it showed no effect on the release of IL-1β induced by NLRP3 inflammasome triggers, such as nigericin and silica, or the NLRC4 inflammasome trigger flagellin. Furthermore, we demonstrated that CO inhibited the cleavage of caspase-1, an inflammasome activation marker, and an upstream event, the translocation and speck formation of ASC. In addition, further experiments and mechanistic investigations revealed that CO can inhibit AIM2 speck formation induced by dsDNA in AIM2-overexpressing HEK293T cells. To verify the correlation in vivo, we investigated the efficacy of CO in an imiquimod (IMQ)-induced psoriasis model, which has reported associations with the AIM2 inflammasome. We found that topical application of CO alleviated psoriasis-like symptoms, such as erythema, scaling, and epidermal thickening, in a dose-dependent manner. Moreover, CO also significantly decreased IMQ-induced expression of AIM2 inflammasome components, including AIM2, ASC, and caspase-1, and led to the elevation of serum IL-17A. In conclusion, our results suggest that CO may be a valuable candidate for the discovery of AIM2 inhibitors and the regulation of AIM2-related diseases.

Medicinal plants are widely used as supplements for the treatment of various diseases because of their few side-effects. Here, we examined the anti-obesity effects of a mixture extract of Cornus officinalis and Ribes fasciculatum (CR) in high-fat diet (HFD)-induced obese male mice. Four week old male C57BL/6J mice were fed a normal diet (ND) or 60% high-fat diet (HFD) with different concentrations of CR extracts (75, 150, and 300 mg/kg/day) by oral administration for 12 weeks. CR extract administration prevented HFD-induced weight gain, hepatic steatosis, and adipocyte enlargement through the downregulation of adipogenesis-associated genes in obese male mice. In addition, CR administration improved the impaired glucose metabolism, insulin action, biochemical obesity parameters, and metabolic profiles in HFD-induced male mice. Consequently, the CR extract exhibited beneficial effects on HFD-induced systemic metabolic challenges. Taken together, our findings suggest that CR extract may be a potent therapeutic supplement for the treatment and prevention of obesity.

Simple Summary Obesity is a general health problem representing a high risk factor for a low-quality lifestyle. Various Food and Drug Administration-approved pharmacological medications have been established for the treatment and prevention of obesity. However, some pharmacotherapies present adverse effects and limited long-term use. Natural herbal medicines as alternative cures have shown low side-effects and suitability for long-term treatment. Cornus officinalis and Ribes fasciculatum (CR) are well-known oriental plants used for health dietary supplements and herbal medicine. This study examined the anti-obesity effect of CR in high-fat diet (HFD)-induced obese male mice. Treatment of CR extract prevented body weight gain through the downregulation of adipogenic inducible genes and recovered the dysregulated energy metabolism in HFD-induced obese male mice. Therefore, CR reduced elevated biochemical obesity parameters in plasma, as well as inhibited hepatic steatosis in the liver and adipocyte size increase in fat tissue. These findings of the study reveal the potential anti-obesity effects of CR as an herbal medicine. Abstract Medicinal plants are widely used as supplements for the treatment of various diseases because of their few side-effects. Here, we examined the anti-obesity effects of a mixture extract of Cornus officinalis and Ribes fasciculatum (CR) in high-fat diet (HFD)-induced obese male mice. Four week old male C57BL/6J mice were fed a normal diet (ND) or 60% high-fat diet (HFD) with different concentrations of CR extracts (75, 150, and 300 mg/kg/day) by oral administration for 12 weeks. CR extract administration prevented HFD-induced weight gain, hepatic steatosis, and adipocyte enlargement through the downregulation of adipogenesis-associated genes in obese male mice. In addition, CR administration improved the impaired glucose metabolism, insulin action, biochemical obesity parameters, and metabolic profiles in HFD-induced male mice. Consequently, the CR extract exhibited beneficial effects on HFD-induced systemic metabolic challenges. Taken together, our findings suggest that CR extract may be a potent therapeutic supplement for the treatment and prevention of obesity.

Obesity, a metabolic disease linked to several other diseases, is emerging as a global problem. We determined the harvest time that maximized the anti-obesity effect by evaluating the inhibition of lipid accumulation in 3T3-L1 cells treated with fruits of Cornus officinalis. FS1 (pericarp + seeds, harvested 15 September) showed excellent anti-obesity activity (Oil Red O; 26.12 ± 1.37% vs. MDI) and inhibited the expression of PPAR-γ (0.05 ± 0.01 ford vs. MDI), C/EBPα (0.03 ± 0.02 ford vs. MDI), and C/EBPβ (0.33 ± 0.07 ford vs. MDI) at 200 μg/mL. The antioxidant activity of FS1 was also the most effective. In addition, FS1 contained higher levels of active ingredients than samples harvested in other periods. Especially, content of loganin, verbenalin, and sweroside was high. In terms of anti-obesity activity and functional components, immature COF (FS1) was the best, and these results indicate that it is necessary to adjust the harvest time, when used as an anti-obesity agent.

The traditional use of plants and their preparations in the treatment of diseases as a first medication in the past centuries indicates the presence of active components for specific targets in the natural material. Many of the tested plants in this study have been traditionally used in the treatment of Diabetes mellitus type 2 and associated symptoms in different cultural areas. Additionally, hypoglycemic effects, such as a decrease in blood glucose concentration, have been demonstrated in vivo for these plants. In order to determine the mode of action, the plants were prepared as methanolic and aqueous extracts and tested for their effects on intestinal glucose and fructose absorption in Caco2 cells. The results of this screening showed significant and reproducible inhibition of glucose uptake between 40 and 80% by methanolic extracts made from the fruits of Aronia melanocarpa, Cornus officinalis, Crataegus pinnatifida, Lycium chinense, and Vaccinium myrtillus; the leaves of Brassica oleracea, Juglans regia, and Peumus boldus; and the roots of Adenophora triphylla. Furthermore, glucose uptake was inhibited between 50 and 70% by aqueous extracts made from the bark of Eucommia ulmoides and the fruit skin of Malus domestica. The methanolic extracts of Juglans regia and Peumus boldus inhibited the fructose transport between 30 and 40% in Caco2 cells as well. These findings can be considered as fundamental work for further research regarding the treatment of obesity-correlated diseases, such as Diabetes mellitus type 2.

Background: Hyperuricemia, abnormally excess accumulation of uric acid, is caused by an imbalance between the production and excretion of uric acid and is a major cause of gout. We compared the effects of extracts from Chrysanthemum indicum L. (Ci) and Cornus officinalis Siebold & Zucc (Co) on hyperuricemia, both individually and in combination (FSU-CC), Methods: We used hypoxanthine-treated human liver cancer (HepG2) cells and primary mouse renal proximal tubule cells for in vitro model, and potassium oxonate-induced hyperuricemic mice for in vivo model.Results: We found that treatment of Ci, Co, and FSU-CC suppressed the activity of xanthine oxidase and mRNA expression of xanthine dehydrogenase, while inducing an increase in the expression levels of the organic anion transporter 1 and organic anion transporter 3 proteins and a decrease in the expression levels of glucose transporter 9 and urate transporter 1 proteins. Particularly, treatment and supplementation with FSU-CC showed stronger effects than those of supplementation with either Ci or Co alone. We observed that the excretion of creatinine and uric acid in the combination of Ci and Co was higher than that observed in their individual supplementations and was similar to that of the normal group.Conclusions: Therefore, our data suggest that a combination of Ci and Co may potentially be used for the development of effective natural anti-hyperuricemic functional foods.

The intestinal microbiota plays an important role in the occurrence and development of alcoholic liver disease (ALD). The aim of this study was to investigate whether the cornel iridoid glycoside (CIG) of Cornus officinalis Sieb. et Zucc. could protect against ALD through the gut-liver axis. The results showed that, compared to an alcohol treated group, CIG could inhibit the activities of AST, ALT and MDA, promote the activities of SOD, CAT and GSH, and reduce oxidative damage to the liver. CIG could significantly alter intestinal microbial diversity, reduce the presence of serum LPS and levels of TNF-α, IL-1β and IL-6 in the liver. In addition, CIG supplementation reduced the imbalance of intestinal microbiota caused by alcohol and improved intestinal barrier function. Therefore, CIG may have a beneficial effect in alcoholic liver disease by maintaining the stability of the intestinal microbiota. We propose CIG as a potential therapeutic and prophylactic compound in clinical treatment of ALD.

Five novel and rare cadinane-type sesquiterpene glycosides, cornucadinoside A-E (1-5) were isolated from water extract of the fruit of Cornus officinalis Sieb. et Zuuc.. The new chemical structures, together with their absolute configurations, were elucidated on the basis of extensive spectroscopic analysis, including a comparison of their experimental and calculated electronic circular dichroism (ECD) spectra. Their structures, which possess a naphthalene skeleton, are the first report on the occurrence of cadinane sesquiterpene glycosides in Cornus. Additionally, all the compounds exhibited marked α-glucosidase inhibitory activity except for 3in vitro.

Objective: To investigate the mechanism of Cornus officinalis Total Glycosides (COTG) on myocardial protection, by studying effects of COTG on cardiomyocyte apoptosis induced by hypoxia/reoxygenation and calcium concentration in rats. Methods: The myocardial cells of born 1-3d SD rats were isolated by enzyme digestion, cultured for 3 days. Cells were divided into five groups: Control group, H/R group, Cornus officinalis Total Glycosides low-dose group (LDG), Cornus officinalis Total Glycosides middle-dose group (MDG) and Cornus officinalis Total Glycosides high-dose group (HDG). Three drug groups were pretreated with different doses of Cornus officinalis Total Glycosides before hypoxia/reoxygenation treatment. The apoptotic rate was determined by flow cytometry assay, the intracellular free calcium concentration was examined by flow cytometry, and the ultrastructure of myocardial cells was observed under transmission electron microscope. Results: The results revealed that Cornus officinalis Total Glycosides pretreatment decreased apoptosis rate, but the effect of lower dosage is not significant. Furthermore, Cornus officinalis Total Glycosides can attenuate mitochondrial calcium overload, improve mitochondrial morphology and inhibit cardiomyocyte apoptosis caused by H/R. Conclusion: Cornus officinalis Total Glycosides pretreatment can inhibit cardiomyocyte apoptosis and calcium overload during H/R injury. However, the underlying mechanisms require us to further study.

Four previously undescribed iridoid glycosides neocornuside A–D (1–4), along with six known ones (5–10), were isolated from Cornus officinalis fruit. Their structures were elucidated by extensive spectroscopic (NMR, UV, IR, and MS) analysis and comparison with data reported in the literature. All isolates were assessed for their antidiabetic activity on the relative glucose consumption in insulin-induced insulin-resistant HepG2 cells. The results showed that compounds 1, 3, and 7 exhibited significant antidiabetic activities with EC50 values of 0.582, 1.275, and 0.742 μM, respectively. Moreover, compounds 1, 3, and 7 could improve the ability of 2-NBDG uptake of insulin-induced HepG2 cells.

Radix Rehmanniae and Cornus Officinalis (RR-CO) have been widely used as “nourishing Yin and tonifying kidney” herb pairs for the treatment of diabetes mellitus (DM) and its complications in traditional Chinese medicine (TCM). Based on the theory of “kidney governing reproduction” in TCM, the aim of this study was to investigate the therapeutic effects of RR-CO on DM-induced reproduction damage through regulating testicular glycolysis. Moreover, the regulation of AGEs/RAGE/HIF-1α axis on the testicular glycolysis process has also been studied. Spontaneous DM model KK-Ay mice were used to investigate the protective effect of RR, CO, RR-CO on DM-induced reproductive disturbances. RR, CO, RR-CO improved DM-induced renal and testicular morphology damages. Moreover, the impaired spermatogenesis, germ cell apoptosis and motility in testis induced upon DM were also attenuated by RR, CO or RR-CO, accompanied by an increased level of glycolysis metabolomics such as l-lactate, d-Fructose 1,6-bisphosphate, etc. Meanwhile, glucose membrane transporters (GLUT1, GLUT3), monocarboxylate transporter 4 (MCT4) expression, lactate dehydrogenase (LDH) activity, HIF-1α were upregulated by RR, CO and RR-CO treatment compared with the model group, whereas AGE level and RAGE expression were decreased with the drug administration. The RR-CO group was associated with superior protective effects in comparison to RR, CO use only. Aminoguanidine (Ami) and FPS-ZM1, the AGEs and RAGE inhibitors, were used as a tool drug to study the mechanism, showing different degrees of protection against DM-induced reproductive damage. This work preliminarily sheds light on the herb pair RR-CO exhibited favorable effects against DM-induced reproductive disturbances through enhancing testicular glycolysis, which might be mediated by AGEs/RAGE/HIF-1α axis.

Ruiqi Xu,1,2 Mengnan Zeng,1,2 Yuanyuan Wu,1,2 Shengchao Wang,1,2 Beibei Zhang,1,2 Jingke Zhang,1,2 Yuxuan Kan,1,2 Benke Li,1,2 Bing Cao,1,2 Xiaoke Zheng,1,2 Weisheng Feng1,2 1School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou, People’s Republic of China; 2The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou, People’s Republic of ChinaCorrespondence: Xiaoke Zheng; Weisheng FengSchool of Pharmacy, Henan University of Traditional Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, People’s Republic of ChinaTel +86-371-6019-0296Email zhengxk.2006@163.com; fwsh@hactcm.edu.cnPurpose: This research aims to investigate the intervention and mechanism of 50% acetone extract of C. officinalis leaves (SZYY) on melanoma xenografts.Patients and Methods: Tumor size and cardiac function were measured via ultrasound. The accumulation of 2-deoxy-D-glucose (2-DG) in tumor tissue was examined with near-infrared in vivo imaging. Flow cytometry was performed to assess apoptosis and reactive oxygen species (ROS) levels in tumor and immune cells in spleen. The levels of inflammatory cytokines in serum were detected by cytometric bead array. The expression of proliferation-, apoptosis-, and angiogenesis-related proteins in tumor cells was measured to evaluate the underlying mechanisms. Subsequently, the effects of four compounds separated from SZYY on the proliferation and migration of A375 cells and STAT3 signaling were examined. The peak identification and contents of the four components were performed via high-performance liquid chromatography (HPLC). Finally, we evaluated the inhibitory effects of STAT3 overexpression on the cytotoxic activity of four constituents in A375 cells.Results: SZYY inhibited the growth and glycolysis of melanoma xenograft in mice, improved cardiac function, increased the percentages of macrophages, neutrophils, and lymphocytes in spleen, reduced the levels of IL-6, IL-17A, TNF-α, and IFN-γ in serum, promoted apoptosis and oxidative stress in tumor tissues, and inhibited STAT3 phosphorylation and expression of angiogenic factors. Chemical analysis showed that SZYY is rich in loganin, rutin, triohimas C, and triohimas D, which all could restrain the proliferation and migration of A375 cells and inhibit the phosphorylation and nuclear translocation of STAT3. Moreover, STAT3 overexpression could diminish the cytotoxic activity of four compounds on A375 cells.Conclusion: SZYY could exert anti-melanoma effects via inhibiting STAT3 signaling to induce apoptosis and inhibit tumor angiogenesis. Its active ingredients might be loganin, rutin, triohimas C, and triohimas D.Keywords: Cornus officinalis, melanoma, STAT3, apoptosis, angiogenesis

The fruits of Cornus mas and Cornus officinalis have been known and appreciated in folk medicine for years and have a high biological value, which is mainly connected with their polyphenols and iridoids content. However, hybrids of C. mas × C. officinalis have not been investigated. The aim of this study was to evaluate the iridoids, anthocyanins, and flavonols content, and antioxidant capacity of Cornus mas, Cornus officinalis, and C. mas × C. officinalis. Iridoids and flavonoids were quantified by the High-Performance Liquid Chromatography (HPLC) method. Antioxidant capacity (AC) was measured using 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2′-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid (ABTS•+), and ferric reducing antioxidant power (FRAP) tests. Total phenolic content (TPC) was evaluated using the Folin–Ciocalteu reagent. Among the C. mas cultivars and C. officinalis genotypes, there was considerable variation in the content of iridoids, flavonoids, and AC. Interspecific hybrids C. mas × C. officinalis contained more iridoids than C. mas and more anthocyanins than C. officinalis and additionally had higher AC and TPC than C. officinalis and most C. mas. AC, TPC, and the presence of iridoids, anthocyanins, and flavonols in hybrids C. mas × C. officinalis are reported for the first time. The Cornus species deserve special attention due to their highly biologically active substances, as well as useful medicinal properties.

Cornus officinalis Sieb. et Zucc. (Shanzhuyu), a herb and food plant in east Asia, has the properties of tonifying the liver and kidney, and nourishing the essence according to the theory of traditional Chinese medicine. C. officinalis has been commonly used to treat asthenia diseases, liver, and kidney diseases, and reproductive system diseases since ancient times. The objectives of this article were to review the pharmacological effects and phytochemistry of C. officinalis. We conducted a literature review of the pharmacological effects of C. officinalis by different systems and compared the effects with the traditional usages, discussed the research status and potential blanks to be filled. The experimental studies showed that C. officinalis extract and its active components had various pharmacological effects such as anti-oxidation, anti-apoptosis, anti-inflammation, anti-diabetes, anti-osteoporosis, immunoregulation, neuroprotection, and cardiovascular protection, but clinical studies are still needed to assess whether the reported pharmacological activities have confirmed efficacy.

Cornus officinalis Sieb et. Zucc and Paeonia lactiflora Pall. have exhibited favorable therapeutic effects against rheumatoid arthritis (RA), but the specific mechanisms of their active compounds remain unclear. The aim of this study was to comprehensively analyze the therapeutic mechanisms of selected active compounds in Cornus officinalis (loganin, ursolic acid, and morroniside) and Paeonia lactiflora (paeoniflorin and albiflorin) via network pharmacology. The pharmacological properties of the five active compounds were evaluated and their potential target genes were identified by database screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analysis were performed to determine the enriched molecular pathways associated with the active compounds. Using network pharmacology tools, eight genes (IL1β, VEGFA, STAT3, TP53, IL6, TNF, FOS, and LGALS3) were identified as common targets between RA and the five active compounds. Molecular docking simulation revealed the compound-target relationship between the five active compounds and three selected targets from the eight common ones (LGALS3, STAT3, and VEGFA). The compound-target relationships were subsequently validated via preliminary in vivo experiments in a rat model of collagen-induced arthritis. Rats subjected to collagen-induced arthritis showed increased protein expression of LGALS3, STAT3, and VEGFA in synovial tissues. However, treatment using Cornus officinalis or/and Paeonia lactiflora, as well as their most drug-like active compounds (ursolic acid or/and paeoniflorin, respectively, identified based on pharmacological properties), attenuated the expression of these three targets, as previously predicted. Collectively, network pharmacology allowed the pharmacological and molecular roles of Cornus officinalis and Paeonia lactiflora to be systematically revealed, further establishing them as important candidate drugs in the treatment and management of RA.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to cartilage destruction and bone erosion. In-depth exploration of the pathogenesis of RA and the development of effective therapeutic drugs are of important clinical and social value. Herein, we explored the medicinal value of Cornus officinalis Sieb. and Paeonia lactiflora Pall. in RA treatment using a rat model of collagen-induced arthritis (CIA). We compared the therapeutic effect of Cornus officinalis and Paeonia lactiflora with that of their main active compounds, ursolic acid and paeoniflorin, respectively. We demonstrated that the combination of Cornus officinalis and Paeonia lactiflora effectively inhibited the release of factors associated with oxidative stress and inflammation during RA, therein ameliorating the symptoms and suppressing the progression of RA. We further showed that the underlying mechanisms may be related to the regulation of apoptosis in synovial tissues, and we investigated the potential involvement of AMPK-mediated mitochondrial dynamics in the therapeutic action of the two drugs and their active components.

Saponins have been extensively used in the food and pharmaceutical industries because of their potent bioactive and pharmacological functions including hypolipidemic, anti-inflammatory, expectorant, antiulcer and androgenic properties. A lot of saponins-containing foods are recommended as nutritional supplements for diabetic patients. As a medicine and food homologous material, Corni Fructus (CF) contains various active ingredients and has the effect of treating diabetes. However, whether and how CF saponins attenuate diabetes is still largely unknown. Here, we isolated total saponins from CF (TSCF) using ultrasonic microwave-assisted extraction combined with response surface methodology. The extract was further purified by a nonpolar copolymer styrene type macroporous resin (HPD-300), with the yield of TSCF elevated to 13.96 mg/g compared to 10.87 mg/g obtained via unassisted extraction. When used to treat high-fat diet and streptozotocin-induced diabetic mice, TSCF significantly improved the glucose and lipid metabolisms of T2DM mice. Additionally, TSCF clearly ameliorated inflammation and oxidative stress as well as pancreas and liver damages in the diabetic mice. Mechanistically, TSCF potently regulated insulin receptor (INSR)-, glucose transporter 4 (GLUT4)-, phosphatidylinositol 3-kinase (PI3K)-, and protein kinase B (PKB/AKT)-associated signaling pathways. Thus, our data collectively demonstrated that TSCF could be a promising functional food ingredient for diabetes improvement.

Four new gallate derivatives—ornusgallate A, ent-cornusgallate A, cornusgallate B and C (1a, 1b, 2, 3)—were isolated from the wine-processed fruit of Cornus officinalis. Among them, 1a and 1b are new natural compounds with novel skeletons. Their chemical structures were elucidated by comprehensive spectroscopy methods including NMR, IR, HRESIMS, UV, ECD spectra and single-crystal X-ray diffraction analysis. The in vitro anti-inflammatory activities of all compounds were assayed in RAW 264.7 cells by assessing LPS-induced NO production. As the result, all compounds exhibited anti-inflammatory activities at attested concentrations. Among the tested compounds, compound 2 exhibited the strongest anti- inflammatory activity.

Fruits of Cornus mas and Cornus officinalis are representative plant materials traditionally used in Europe and Asia, respectively, in the treatment of diabetes and diabetes-related complications, which are often mediated by pathogenic inflammatory agents. Additionally, due to the fact of mutual infiltration of Asian and European medicines, the differentiation as well as standardization of traditional prescriptions seem to be crucial for ensuring the quality of traditional products. The objective of this study was a comparison of biological activity of extracts from fruits of C. mas and C. officinalis by an assessment of their effect on reactive oxygen species (ROS) generation in human neutrophils as well as cytokines secretion both in neutrophils (tumor necrosis factor α, TNF- α, interleukin 8, IL-8, interleukin 1β, IL-1β) and in human colon adenocarcinoma cell line Caco-2 (IL-8). To evaluate the phytochemical differences between the studied extracts as well as to provide a method for standardization procedures, a quantitative analysis of iridoids, such as loganin, sweroside, and loganic acid, found in extracts of Cornus fruits was performed with HPLC-DAD. All standardized extracts significantly inhibited ROS production, whereas the aqueous-alcoholic extracts were particularly active inhibitors of IL-8 secretion by neutrophils. The aqueous-methanolic extract of C. officinalis fruit, decreased IL-8 secretion by neutrophils to 54.64 ± 7.67%, 49.68 ± 6.55%, 50.29 ± 5.87% at concentrations of 5, 50, and 100 µg/mL, respectively, compared to LPS-stimulated control (100%). The aqueous extract of C. officinalis fruit significantly inhibited TNF-α release by neutrophils at concentrations of 50 and 100 µg/mL. On the other hand, the aqueous-ethanolic extract of C. mas fruit showed the propensity to increase TNF-α and IL-1β secretion. The modulatory activity of the Cornus extracts was noted in the case of secretion of IL-8 in Caco-2 cells. The effect was comparable with dexamethasone. The content of loganin in aqueous and aqueous-methanolic extract of C. officinalis fruit was higher than in the aqueous-ethanolic extract of C. mas fruit, which was characterized by a significant quantity of loganic acid. In conclusion, the immunomodulatory effect observed in vitro may partially confirm the traditional use of Cornus fruits through alleviation of the development of diabetes-derived inflammatory complications. Loganin and loganic acid are significant markers for standardization of C. mas and C. officinalis fruit extracts, respectively.

Water extracts of both Morus alba L. root bark (MBW) and Cornus officinalis Siebold and Zucc fruit (CFW) have traditionally been used to promote men&rsquo, s health in the elderly in Asia. We determined that the 12-week consumption of MBW and CFW could alleviate testosterone-deficiency syndrome and osteoarthritis (OA) symptoms in testosterone-deficient rats, and the action mechanisms were explored. Rats with bilateral orchiectomy (ORX) were fed a 45% fat diet containing either 0.5% MBW (ORX-MBW), 0.5% CFW(ORX-CFW), or 0.5% dextrin (ORX-CON). Sham-operated rats also received 0.5% dextrin (Non-ORX-CON). After 8 weeks of treatment, all rats had an injection of monoiodoacetate (MIA) into the left knee, and they continued the same diet for the additional 4 weeks. ORX-CFW and ORX-MBW partially prevented the reduction of serum testosterone concentrations and decreased insulin resistance, compared to the ORX-CON. ORX-CFW and ORX-MBW protected against the reduction of bone mineral density (BMD) and lean body mass (LBM) compared to the ORX-CON. The limping and edema scores were lower in the order of the ORX-CON, ORX-CRF = ORX-MBW, and Non-ORX-CON (p &lt, 0.05). The scores for pain behaviors, measured by weight-distribution on the OA leg and maximum running velocity on a treadmill, significantly decreased in the same order as limping scores. ORX-MBW protected against the increased expression of matrix metalloproteinase (MMP)-3 and MMP-13 and reduced the production of inflammatory markers such as TNF-&alpha, and IL-1&beta, by MIA in the articular cartilage, compared to the ORX-CON (p &lt, 0.05). The cartilage damage near the tidemark of the knee and proteoglycan loss was significantly less in ORX-MBW than ORX-CON. In conclusion, MBW, possibly CFW, could be effective alternative therapeutic agents for preventing osteoarthritis in testosterone-deficient elderly men.

Cornus officinalis Sieb. et Zucc. (Shanzhuyu), a herb and food plant in east Asia, has the properties of tonifying the liver and kidney, and nourishing the essence according to the theory of traditional Chinese medicine. C. officinalis has been commonly used to treat asthenia diseases, liver, and kidney diseases, and reproductive system diseases since ancient times. The objectives of this article were to review the pharmacological effects and phytochemistry of C. officinalis. We conducted a literature review of the pharmacological effects of C. officinalis by different systems and compared the effects with the traditional usages, discussed the research status and potential blanks to be filled. The experimental studies showed that C. officinalis extract and its active components had various pharmacological effects such as anti-oxidation, anti-apoptosis, anti-inflammation, anti-diabetes, anti-osteoporosis, immunoregulation, neuroprotection, and cardiovascular protection, but clinical studies are still needed to assess whether the reported pharmacological activities have confirmed efficacy.

Obesity is a medical condition that presents excessive fat accumulation with high risk of serious chronic diseases. The aim of this clinical trial is to investigate the anti-obesity effects of Cornus officinalis (CO) and Ribes fasciculatum (RF) on body fat reduction in Korean overweight women. A total of 147 overweight female participants enrolled in double-blinded clinical trial for 12 weeks and 76 participants completed the clinical study. Participants were treated with four CO and RF mixture (COEC, 400 mg per tablet) or four placebo tablets once a day. Obesity associated parameters (body weight, body mass index (BMI), waist circumference, waist-to-hip ratio, body fat percentage and body fat mass) and safety assessment were analyzed. After 12 weeks of COEC treatment, primary outcomes such as body fat percentage (0.76% vs. 0.01%, p = 0.022) and mass (1.1 kg vs. 0.5 kg, p = 0.049) were significantly decreased. In addition, the results were statistically significant between the COEC and placebo groups, strongly indicated that COEC had anti-obesity effects on overweight women. Secondary outcomes&mdash, including body weight, waist and hip circumference, waist-to-hip ratio, body mass index and computed tomography measurement of visceral fat area, subcutaneous fat area, total abdominal fat area and visceral-to-subcutaneous fat ratio&mdash, were reduced in COEC-treated group, but no statistical differences were found between the COEC and placebo groups. The safety assessment did not differ between the two groups. These results suggest that treatment of COEC extract reduces body fat percentage and mass in Korean overweight women, indicating it as a protective functional agent for obesity.

Atopic dermatitis (AD) is an allergic and chronic inflammatory skin disease. The present study investigates the anti-allergic, antioxidant, and anti-inflammatory activities of the ethanolic extract of Cornus officinalis (COFE) for possible applications in the treatment of AD. COFE inhibits the release of &beta, hexosaminidase from RBL-2H3 cells sensitized with the dinitrophenyl-immunoglobulin E (IgE-DNP) antibody after stimulation with dinitrophenyl-human serum albumin (DNP-HSA) in a concentration-dependent manner (IC50 = 0.178 mg/mL). Antioxidant activity determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power assay, and 2,2&prime, azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) scavenging activity, result in EC50 values of 1.82, 10.76, and 0.6 mg/mL, respectively. Moreover, the extract significantly inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production and the mRNA expression of iNOS and pro-inflammatory cytokines (IL-1&beta, IL-6, and TNF-&alpha, ) through attenuation of NF-&kappa, B activation in RAW 264.7 cells. COFE significantly inhibits TNF-&alpha, induced apoptosis in HaCaT cells without cytotoxic effects (p &lt, 0.05). Furthermore, 2-furancarboxaldehyde and loganin are identified by gas chromatography/mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, respectively, as the major compounds. Molecular docking analysis shows that loganin, cornuside, and naringenin 7-O-&beta, D-glucoside could potentially disrupt the binding of IgE to human high-affinity IgE receptors (FceRI). Our results suggest that COFE might possess potential inhibitory effects on allergic responses, oxidative stress, and inflammatory responses.

Obesity is a medical condition that presents excessive fat accumulation with high risk of serious chronic diseases. The aim of this clinical trial is to investigate the anti-obesity effects of Cornus officinalis (CO) and Ribes fasciculatum (RF) on body fat reduction in Korean overweight women. A total of 147 overweight female participants enrolled in double-blinded clinical trial for 12 weeks and 76 participants completed the clinical study. Participants were treated with four CO and RF mixture (COEC; 400 mg per tablet) or four placebo tablets once a day. Obesity associated parameters (body weight, body mass index (BMI), waist circumference, waist-to-hip ratio, body fat percentage and body fat mass) and safety assessment were analyzed. After 12 weeks of COEC treatment, primary outcomes such as body fat percentage (0.76% vs. 0.01%; p = 0.022) and mass (1.1 kg vs. 0.5 kg; p = 0.049) were significantly decreased. In addition, the results were statistically significant between the COEC and placebo groups, strongly indicated that COEC had anti-obesity effects on overweight women. Secondary outcomes—including body weight, waist and hip circumference, waist-to-hip ratio, body mass index and computed tomography measurement of visceral fat area, subcutaneous fat area, total abdominal fat area and visceral-to-subcutaneous fat ratio—were reduced in COEC-treated group, but no statistical differences were found between the COEC and placebo groups. The safety assessment did not differ between the two groups. These results suggest that treatment of COEC extract reduces body fat percentage and mass in Korean overweight women, indicating it as a protective functional agent for obesity.

In this study, six phenolic compounds were isolated from the ethyl acetate of Cornus officinalis, including: Gallic acid (1), dimethyl malate (2), 1,4-dimethyl ester 2-(2-formyl-1H-pyrrol-1-yl)butanedioic acid (3), stageobester A (4), coroffester (5), and methyl caffeate (6). The structure of the compounds was determined by such spectroscopic methods as MS, NMR and by comparison with the published NMR data. This is the first time compounds 3-5 have been isolated from this species. Keywords Cornus officinalis, gallic acid, dimethyl malate, 1,4-dimethyl ester 2-(2-formyl-1H-pyrrol-1-yl)butanedioic acid, stageobester A, coroffester, methyl caffeate. References

In the context of global climate change, the current strategy of agroeconomics focuses on the introduction of unique plant species and the selection of new commercially important cultivars adapted to the dramatic weather changes. Cornus officinalis (Cornaceae) has Chinese origin, its reintroduction at the M.M.Gryshko National Botanical Garden, National Academy of Sciences of Ukraine started in 1993. The objectives of this research were: to investigate the biometric parameters of fruits and leaves of C.officinalis genotypes, C. officinalis × C. mas hybrid ‘Etude’ and genotype from the grafting C. officinalis on C.mas under cultivation in the M.M. Gryshko National Botanical Garden, National Academy of Sciences of Ukraine, and to determine the degree of adaptation of C. officinalis to the climatic conditions of Ukraine (in particular, Right-Bank Forest Steppe) for selection of promising genotypes for further breeding work. Material and methods. We used: a) 26-year-old maternal plant obtained from a two-year-old seedling in 1993 received from the nursery “Northwoods Wholesale Nursery” Mollala (Oregon, USA), where it was grown as an ornamental plant; b) seedlings of the maternal plant; c) cultivar Etude, which is an artificial hybrid from crossing C. officinalis × C. mas; and d) genotype obtained from grafting C.officinalis on C.mas. In our experiment, the maternal plant is indicated as G-01, while other plants – as G-02–G-08 genotypes. We determined the biometric parameters of the fruit (length, diameter, and weight), endocarp (length, diameter, and weight), pedicel (length and thickness), leaf blade (length, width, and the number of lateral veins) and petiole (length, width, and thickness). We examined the dynamics of fruit and endocarp formation during the season (genotypes G-01–G-03 and G-05) and compared the biometric characteristics of the fruit of genotypes G-01–G-05 from crops of two years, 2010 and 2018, which were most favorable in weather conditions. We have processed quantitative data in the PAST 2.10 software. The differences between the samples were estimated using the Tukey-Kramer test. The degree of variability was determined by the coefficient of variation. To assess the level of variability, we used the classification of Mamaev (1975). Results. We have found that the largest fruits in 2010 were observed in the genotype G-01 and the smallest – in the genotype G-03. The coefficient of variation of the linear parameters of the fruit and endocarp was in the range 5.7–10.1 %; the level of variability was very low or low. The variability of fruit weight and endocarp was high; the coefficient of variation was from 7.0 up to 28.3 %. The amplitude of the linear parameters of the leaf was wide (coefficient of variation was from 9.8 to 31.0 %). The cultivar Etude differed from other C. officinalis genotypes in size and weight of (M = 1800 mg, max = 2400mg) and a much wider amplitude of variation in the length (17.9–22.6 vs. 14.3–18.2mm) of the fruit. The largest leaves were in the genotypes G-08 and G-01, and the smallest – in the genotype G-02. The cultivar Etude did not differ so much by the mean leaf morphometric indices and number of veins, but it demonstrated one of the broadest leaf blades (51.5mm). Conclusions. The data obtained in this study is important for the commercial use of C. officinalis and the cultivar Etude as food and medicinal plant, as well as for breeding in climatic conditions of Ukraine and analysis of hybridization features in the genus Cornus in general.

Medicinal plants have been used worldwide as primary alternative healthcare supplements. Cornus officinalis (CO) and Ribes fasciculatum (RF) are traditional medicinal plants applied in East Asia to treat human diseases such as hepatitis, osteoporosis, oxidative stress and allergy. The aim of this study was to examine the anti-obesity effect of CO and RF on preadipocyte 3T3-L1 cells in vitro and high-fat diet (HFD)-induced obesity mice in vivo. Combination treatment of CO and RF in differentiated 3T3-L1 cells inhibited adipocyte differentiation through downregulation of adipogenesis-associated genes such as CCAAT/enhancer-binding protein alpha (Cebpa), fatty acid binding protein 4 (Fabp4), peroxisome proliferator-activated receptor gamma (Pparg) and sterol regulatory element binding protein (Srebp1). In vivo animal models showed that a mixture of CO and RF inhibited HFD-induced weight gain, resulting in decreased abdominal visceral fat tissues and fatty hepatocyte deposition. In addition, CO+RF treatment decreased HFD-induced adipogenesis-associated genes in abdominal white fat tissue. These results suggest that administration of a CO and RF mixture prevented adipocyte differentiation and lipid accumulation in preadipocyte cells and HFD-induced body weight in obesity mice. Therefore, combined therapy of CO and RF may be a protective therapeutic agent against obesity.

Type 1 diabetes (T1D) results in the loss of pancreatic beta cells and subsequent loss of insulin production. Exogenous insulin is the only effective treatment, but there is still no cure or interventional therapy available to inhibit progression of T1D. Successful T1D interventional therapy must protect pancreatic beta cells from autoimmunity while enhancing beta cell survival and function. Our data suggests Cornus officinalis (CO) may be a candidate for interventional therapy to protect pancreatic beta cells from autoimmune attack and increase their function. CO has been used in traditional Chinese medicine (TCM) for over 2,000 years and has shown characteristics of anti-diabetic effects in vitro and in vivo but never examined in the application of T1D. Our prior publication (Mol. and Cell. Endo.2019:494:110491), has shown increased proliferation and protection against Th1 cytokine attack upon CO treatment using a human pancreatic beta cell line, 1.1B4. From this, we sought to define precise molecular mechanism by employing a global and phosphorylation mass spectrometry (MS) approach. We applied CO to 1.1B4 cells for 2, 6, 12, and 24h then collected the cell lysates for MS analysis. Our global MS analysis revealed a 12-fold increase in beta cell functional regulator, IGFBP2, at multiple time points. IGFBP2 has been shown to display a T2D protective effect and regulate glucose metabolism. The ingenuity pathway analysis program (IPA) predicted an increase in insulin starting at 2h and the NRF2-mediated oxidative stress pathway at 12h and 24h. Furthermore, NRF2 is an upstream regulator of P62 which was significantly hyperphosphorylated at multiple timepoints from our MS analysis. Nrf2 is responsible for activating antioxidant enzymes upon oxidative stress, which is caused by proinflammatory cytokines in T1D. P62 aids in this pathway by targeting proteins for autophagy upon oxidative stress in order to keep cellular homeostasis within beta cells rather than cells progressing through apoptosis. Autophagy is critical for beta cell function and survival as it promotes survival under beta cell stress which would otherwise lead to cell death. The recovery and protection of autophagy in beta cells of patients in the pre-diagnosed stages of T1D could provide a beneficial interventional therapy in order to delay or inhibit the onset of T1D. Altogether, our proteomic analysis revealed an increase in IGFBP2 and predicted an increase in the NRf2-mediated oxidative stress pathway upon CO induction. Further analysis will examine the IGFBP2 and Nrf2-mediated oxidative pathway as a mechanism of CO induced protective and proliferative effects in pancreatic beta cells.

Cornus officinalis, an important traditional medicinal plant, is used as major constituents of tonics, analgesics, and diuretics. While several studies have focused on its characteristic bioactive compounds, little is known on their biosynthesis. In this study, we performed LC-QTOF-MS-based metabolome and RNA-seq-based transcriptome profiling for seven tissues of C. officinalis. Untargeted metabolome analysis assigned chemical identities to 1,215 metabolites and showed tissue-specific accumulation for specialized metabolites with medicinal properties. De novo transcriptome assembly established for C. officinalis showed 96% of transcriptome completeness. Co-expression analysis identified candidate genes involved in the biosynthesis of iridoids, triterpenoids, and gallotannins, the major group of bioactive metabolites identified in C. officinalis. Integrative omics analysis identified 45 cytochrome P450s genes correlated with iridoids accumulation in C. officinalis. Network-based integration of genes assigned to iridoids biosynthesis pathways with these candidate CYPs further identified seven promising CYPs associated with iridoids’ metabolism. This study provides a valuable resource for further investigation of specialized metabolites’ biosynthesis in C. officinalis.

Five new secoiridoid glycosides, cornusphenosides E-I (1–5), were isolated and characterized from an active fraction of ethanol extract of the fruits of Cornus officinalis. Their structures were determined by extensive spectroscopic data analysis, including 2 D NMR and HRESIMS experiments. In the preliminary assay, compound 5 (when evaluated at 10 μM) showed the neuroprotective effect against H2O2-induced SH-SY5Y cell damage.