Search

From an aqueous extract of “tian ma” (the steamed and dried rhizomes of Gastrodia elata), ten new compounds gastrodibenzins A−D (1−4) and gastrotribenzins A−F (5−10), along with known analogues (11−20), having structure features coupling between two and three p-hydroxybenzyl-derived units via carbon- and/or ether-bonds, were isolated and characterized by spectroscopic data analysis. Meanwhile, the new compounds 5a, 6a, 8a, 22, and 23, as well as the known derivatives 13a, 14a, 15, 17−21, 24, 25, and p-hydroxybenzyl aldehyde were isolated and identified from a refluxed aqueous solution of p-hydroxybenzyl alcohol. Methylation of 5a and 6a in methanol and ethylation of 6a, 8a, 13a, and 14a in ethanol produced 5 and 6 and 7, 8, 13, and 14, respectively. using ultra-performance liquid chromatography high-resolution electrospray ionization mass spectrometry (UPLC-HRESIMS) analysis of the refluxed solutions of p-hydroxybenzyl alcohol and the refluxed extracts of the fresh G. elata rhizome and “tian ma” extracts indicated consistent production and variation of the dimeric and trimeric derivatives of p-hydroxybenzyl alcohol upon extracting solvents and refluxing time. In various assays, the dimeric and trimeric derivatives showed more potent activities than p-hydroxybenzyl alcohol itself and gastrodin, which are the main known active constituents of “tian ma”. These results revealed for the first time that the more effective dimers and trimers can be produced through condensation of the co-occurring p-hydroxybenzyl alcohol during processing and decocting of the G. elata rhizomes, demonstrating insights into medicinal chemistry behind application protocols of traditional Chinese medicines. Graphic Abstract

A pair of neolignan enantiomers with an unprecedented carbon skeleton, (+)-/(−)-angelignanine [(+)-/(−)-1], was isolated as minor components of an aqueous extract of the Angelica sinensis root heads (guitou). Their structures were determined by spectroscopic data analysis and the absolute configurations were assigned by the circular dichroism (CD) exciton chirality method as well as electronic CD quantum calculations. The enantiomers represent the first 2,7′-cyclo-8,9′-neolignans, of which biosynthetic pathways originating from precursors ferulic acid and coniferyl alcohol is proposed. In an in vivo test, both the enantiomers showed significant hypnotic effects at a dose of 10 mg/kg (i.g.).

Two new folate-derived analogues, named uncarophyllofolic acids A (1) and B (2), respectively, were isolated from the Uncaria rhynchophylla hook bearing stem (Gouteng in Chinese). The distinct stereochemical structures of 1 and 2 were determined by spectroscopic data analysis in combination with acidic hydrolysis and Marfey's derivatization, along with comparison of their specific rotation and Cotton effect (CE) data with those of the biogenetically related known derivatives as well as theoretical calculations of electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway of 1 and 2, associating to folate metabolism and the previously reported orychophragines A-C from Orychophragmus violaceus, is discussed.

Seven indole alkaloid glycosides containing a 1′-(4″-hydroxy-3″,5″-dimethoxyphenyl)ethyl unit (1–7) were isolated from an aqueous extract of Isatis indigotica leaves (da qing ye). Their structures were determined by spectroscopic data analysis combined with enzymatic hydrolysis as well as comparison of their experimental CD (circular dichroism) and calculated ECD (electrostatic circular dichroism) spectra. Based on analysis of [α]D20 and/or Cotton effect (CE) data of 1–7, two simple roles to assign location and/or configuration of β-glycopyranosyloxy and 1′-(phenyl)ethyl units in the indole alkaloid glycosides are proposed. Stereoselectivity in plausible biosynthetic pathways of 1–7 is discussed. Compounds 3 and 4 and their mixture in a 3:2 ratio showed activity against KCNQ2 in CHO cells. The mixture of 5 and 6 (3:2) exhibited antiviral activity against influenza virus H1N1 PR8 with IC50 64.7 μmol/L (ribavirin, IC50 54.3 μmol/L), however, the individual 5 or 6 was inactive. Preliminary structure–activity relationships were observed., Graphical abstract Image 1Seven indole alkaloid glycosides (1–7) were isolated from an aqueous extract of Isatis indigotica leaves (da qing ye), representing the first isomers biogenetically originated from indole glycosides and sinapinic acid in differential stereoselective manners, respectively. The mixture of 5 and 6 (3:2) exhibited antiviral activity against influenza virus H1N1 PR8.

Five new denudatine-type diterpenoid alkaloids (1-5), along with the known analogue aconicarmine (

Seven new monoterpene alkaloids (

Six new triterpenes, uncarinic acids KP (

Five new denudatine-type diterpenoid alkaloids (1–5), along with the known analogue aconicarmine (6), were isolated from an aqueous decoction of the lateral roots of Aconitum carmichaelii (fu-zi). Their structures were determined by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Compound 5 is the first denudatine-type diterpenoid alcohol iminium alkaloid, which could be partially transformed into the aza acetal form in pyridine-d5. Compound 5 inhibited mice writhing in an acetic acid-induced writhing assay.

Seven new monoterpene alkaloids (1−7), along with 18 known analogues, were isolated from an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). Their structures were determined by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Compound 1 is the first monoterpene 22-norindoloquinolizidine alkaloid with a ketene unit, while 2 and 3 are unusual indoloquinolizidine alkaloids having an oxazinane ring.

Six new triterpenes, uncarinic acids K—P (1–6), along with 24 known analogues, were isolated as minor constituents of an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). By comprehensive spectroscopic data analysis, their structures were elucidated as derivatives of olean-12-en-28-oic acid and urs-12-en-28-oic acid with different oxidized forms at C-3, C-6, and/or C-23, respectively. Cell-based preliminary bioassay showed that the (E)-/(Z)-coumaroyloxy and (E)-/(Z)-feruloyloxy units at C-27 of olean-12-en-28-oic acid and urs-12-en-28-oic acid played roles in their bioactivities.

The role of lipoprotein (a) [Lp(a)] in coronary artery diseases (CAD) with special clinical background such as type 2 diabetes mellitus (T2DM) has not been fully determined. The aim of the present study was to investigate the relation of Lp(a) to type 2 diabetic patients with or without CAD.A total of 2040 consecutive patients with T2DM who received selective coronary angiography (CAG) due to angina-like chest pain were enrolled. The patients were subsequently divided into CAD and non-CAD groups according to the results of CAG. The severity of CAD was evaluated by the Gensini Score (GS), number of stenotic vessels, and history of myocardial infarction (MI). Data showed that Lp(a) levels were higher in the CAD group than in the non-CAD group (median: 15.00 mg/dL vs. 11.88 mg/dL, P = 0.025). The results from CAD subgroup analysis indicated that the patients with MI, multiple-vessel disease and high GS had higher Lp(a) levels compared with those in their matched subgroups (P 0.05, respectively). After adjustment for confounders, Lp(a) levels were independently related to the presence and severity of CAD (CAD:OR = 1.564; MI:OR = 1.523; high GS:OR = 1.388; multiple-vessel disease:OR = 1.455; P 0.05, respectively).Elevated Lp(a) levels were independently associated with the presence and severity of CAD in patients with T2DM. More studies are necessary to confirm our findings.

Five new sulfur-enriched alkaloids isatithioetherins A–E (1–5), and two pairs of scalemic enantiomers (+)- and (−)-isatithiopyrin B (6a and 6b) and isoepigoitrin and isogoitrin (7a and 7b), along with the known scalemic enantiomers epigoitrin and goitrin (8a and 8b), were isolated and characterized from an aqueous extract of the Isatis indigotica roots. Their structures were determined by extensive spectroscopic data analysis, including 2D NMR and theoretical calculations of electronic circular dichroism (ECD) spectra based on the quantum-mechanical time-dependent density functional theory (TDDFT). Compounds 1–5 represent a novel group of sulfur-enriched alkaloids, biogenetically originating from stereoselective assemblies of epigoitrin-derived units. Isolation and structure characterization of 6a and 6b support the postulated biosynthetic pathways for the diastereomers 9a and 9bvia a rare thio-Diels–Alder reaction. Compounds 2 and 4 showed antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2, IC50 0.60 and 1.92 μmol/L) and the herpes simplex virus 1 (HSV-1, IC50 3.70 and 2.87 μmol/L), and 2 also inhibited Coxsackie virus B3 (IC50 0.71 μmol/L)., Graphical abstract Five new sulfur-enriched alkaloids (1–5) and two pairs of scalemic enantiomers (+)- and (−)-isatithiopyrin B (6a and 6b), and isoepigoitrin (7a) and isogoitrin (7b) were characterized from an aqueous extract of the Isatis indigotica roots. Compounds 1–5 represent a novel group of sulfur-enriched alkaloids biogenetically originated from epiprogoitrin. Compounds 2 and 4 showed antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2, IC50 0.60 and 1.92 μmol/L) and the herpes simplex virus 1 (HSV-1, IC50 3.70 and 2.87 μmol/L). Compound 2 also inhibited Coxsackie virus B3 (IC50 0.71 μmol/L).fx1

Though type 2 diabetes mellitus (T2DM) is an important and independent risk factor for coronary artery disease (CAD) in the general population, the impact of T2DM on CAD in patients with familial hypercholesterolemia (FH) is less understood. Thus, the current study aimed to examine the features of FH patients with T2DM and explore the effects of T2DM on CAD in FH. A total of 289 clinical heterozygous FH (HeFH) patients diagnosed with Dutch Lipid Clinic Criteria were consecutively recruited and divided into a T2DM group (n = 58) and non-T2DM group (n = 231). Clinical characteristics and laboratory findings were compared between the two groups. Target exome sequencing was used for gene mutation analysis. HeFH patients with T2DM had significantly higher levels of triglycerides, body mass index and free fatty acids than did non-T2DM patients; moreover, patients with T2DM more frequently exhibited hypertension. However, the spectrum of FH-causing mutations was not significantly different (p = 0.061). Notably, patients with T2DM had higher prevalence of CAD (p = 0.012) and higher Gensini Score (p = 0.002). The regression analysis confirmed that HbA1c was an independent risk factor for both the presence and severity of CAD [OR 2.321 (1.098–4.904), p = 0.027; OR 1.349 (1.032–1.762), p = 0.028, respectively] in patients with HeFH. Although there were not many differences in the clinical, lipid and genetic aspects of HeFH patients with and without T2DM, T2DM and HbA1c were associated with worse coronary lesions, suggesting that diabetes and the degree of blood glucose control are also important determinants of cardiovascular disease in these patients.

Eight new C19-diterpenoid alkaloid arabinosides, named aconicarmichosides E–L (1–8), were isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii (Fu Zi). Their structures were determined by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1–8, together with the previously reported four neoline 14-O-arabinosides from the same plant, represent the only examples of glycosidic diterpenoid alkaloids so far. At a dose of 1.0 mg/kg (i.p.), as compared with the black control, compounds 1, 2, and 4–6 exhibited analgesic effects with >65.6% inhibitions against acetic acid-induced writhing of mice. Structure–activity relationship was also discussed., Graphical abstract Eight new C19-diterpenoid alkaloid arabinosides, named aconicarmichosides E−L (1−8), were isolated and characterized from an aqueous extract of the lateral roots of Aconitum carmichaelii (Fu Zi). These compounds, together with the previously reported four neoline 14-O-arabinosides from the same extract, represent the only examples of glycosidic diterpenoid alkaloids from nature. At a dose of 1.0 mg/kg (i.p.), compounds 1, 2, and 4–6 exhibited analgesic effects against acetic acid-induced writhing of mice.fx1

A novel indole alkaloid glycoside with an unprecedented 2-(diphenylpropyl)indole skeleton, isatindigodiphindoside (1), was isolated from an aqueous extract of the roots of Isatis indigotica. The structure was determined by extensive spectroscopic studies, especially by 2D NMR data analysis combined with enzymatic hydrolysis and ECD calculations. Plausible biosynthetic pathways of compound 1 are also discussed.

Four structurally unprecedented aconitane-type C19-diterpenoid alkaloid glycosides with isomeric arabinosyls, named aconicarmichosides A–D (1–4), were isolated from an aqueous extract of “fu zi”, the lateral roots of Aconitum carmichaelii. Their structures were determined as neoline 14-O-α- and 14-O-β- l -arabinopyranosides (1 and 2) and 14-O-α- and 14-O-β- l -arabinofuranosides (3 and 4), by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1–4 represent the first examples of glycosidic diterpenoid alkaloids.

Gastradefurphenol ( 1 ), a minor 9,9′-neolignan with a novel carbon skeleton substituted by two p -hydroxybenzyls was isolated from an aqueous extract of the Gastrodia elata rhizomes (tian ma). Its structure was determined by extensive spectroscopic data analysis. Solvent-dependent free rotational restriction of bonds and equilibrium of two molecular states are discussed by comparison of the NMR spectroscopic data of 1 in acetone- d 6 with those in CD 3 OD. A biogenetic pathway of 1 is postulated to be associated with metabolic processes of l -tyrosine.

Background It has been reported that coronary artery disease (CAD) is characterized by inflammation and non-obstructive CAD (NOCAD) increases the risk of cardiovascular events (CVEs) compared with ones with normal or near-normal coronary arteries (NNCA), even is similar to obstructive CAD (OCAD). We hypothesized that elevated high-sensitivity C-reactive protein (hs-CRP) may be linked to CVEs in those patients with NOCAD. Purpose To investigate the predictive role of hs-CRP in patients with NOCAD. Methods Of 7,746 consecutive patients with angina-like chest pain admissions, 4,662 eligible patients were enrolled who received coronary artery angiography (CAG) and followed up for the CVEs comprising all-cause mortality, myocardial infarction, stroke and late revascularization. According to the results of CAG, the patients were classified as NNCA group (3 mg/L). Proportional hazards models were used to assess the risk of CVEs in all patients enrolled. Results A total of 338 patients (7.3%) experienced CVEs during an average of 13403 person-years follow-up. Patients with NOCAD and OCAD had higher rates of CVEs compared to those with NNCA (p Conclusions Patients with NOCAD had indeed worse outcomes and hs-CRP levels were positively in relation to the CVEs in those with NOCAD, which may help to the risk assessment in ones with NOCAD. Acknowledgement/Funding This study was partly supported by Capital Health Development Fund (201614035) and CAMS Innovation Fund for Medical Sciences (2016-I2M-1-011) awarded

Background Lipoprotein (a) [Lp(a)] is recently recognized as a risk factor of atherosclerosis, and the development of coronary artery disease (CAD) in women is not fully understood. Purpose The present study aimed to examine the association of Lp(a) levels with the presence and severity of (CAD) in female patients pre- and post-menopause. Methods A total of 3712 female patients who received coronary angiography were consecutively enrolled. The level of Lp(a) was measured and compared among patients with and without CAD or myocardial infarction (MI), pre- or post- menopause. The association of Lp(a) with the presence of CAD and the severity of coronary atherosclerosis assessed by Gensini Score were examined. Results The average of Lp(a) levels were elevated as age increased in female subjects. Notably, women after menopause had higher Lp(a) levels compared with that before menopause [16.8 mg/dL (IQR 7.54–41.12 mg/dL) vs. 14.7 mg/dL (IQR 6.72–30.82 mg/dL), p=0.002]. Furthermore, multiple logistic regression analysis identified that Lp(a) >30mg/dL was an independent risk factor of CAD in the postmenopausal female (OR1.38, 95% CI 1.13–1.69, p=0.002). Finally, Lp(a) had a positive correlation with Gensini score (r=0.11, p30mg/dL was an independent risk factor for high Gensini score (OR 1.43, 95% CI 1.14–1.79, p Baseline characteristics of all patients Before menopause (n=525) Post menopause (n=3187) P value Age, (years) 46 (42–49) 62 (58–68) Lp(a) in pre- and post-menopausal women Conclusion The present study indicated that circulating Lp(a) levels were independently associated with the presence and severity of CAD in the postmenopausal female, suggesting that further study may be needed to examine the role of Lp(a) in the development of CAD in female individuals with different menopausal status.

Investigation of the in vivo drug action and metabolic differences of epimer drugs is challenging. Whole-body MSI analysis can visually present the stereoscopic distribution of molecules related to the interaction of drugs and organisms, and can provide more comprehensive organ-specific profiling information. Herein, we developed a whole-body spatially-resolved imaging metabolomics method based on an air flow-assisted ionisation desorption electrospray ionisation (AFADESI)-MSI system coupled with a high-resolution mass spectrometer and highly discriminating imaging software. The epimeric sedative-hypnotic drug candidates YZG-331 and YZG-330 were selected as examples, and rats administered normal or high oral doses were used. By performing multivariate statistical data-mining on the combined MSI data, organ-specific differential ions were screened. By comparing the variations in the relative contents of the drugs, their metabolites, and endogenous neurotransmitters throughout whole-body tissue sections of the rats, rich information that could potentially explain the more significant sedative-hypnotic effects of YZG-330 compared to YZG-331 was obtained. Such as the increased ratio of gamma-aminobutyric acid in the brain and stomach of the rats (0.25, 0.47, 0.68, 0.30, and 0.89 for the control and YZG-331-H, YZG-330-H, YZG-331-L, and YZG-330-L, respectively) were interesting. This study provided a convenient and visual method to investigate in vivo molecular metabolic differences and provide insight towards a better understanding of the pharmacodynamic mechanisms of these sedative-hypnotic drug-candidates.

Two pairs of unusual scalemic enantiomers with a novel carbon skeleton of 2-[1′-(4″-hydroxy-3″,5″-dimethoxyphenyl)ethyl]-2-methoxyindolin-3-one, named isatidifoliumindolinones A–D (1–4), were isolated from an aqueous extract of Isatis indigotica leaves (da qing ye). Their structures including absolute configurations were determined by spectroscopic data analysis combined with comparison of their experimental CD and calculated ECD spectra. Validity of the ECD spectra calculation to assign the absolute configurations is discussed. Plausible biosynthetic pathways of 1–4 are proposed. Stereochemistry-dependent activity against LPS-induced NO production in BV2 cells was observed, and among the stereoisomers compound 4 is most active.

Gastrolatathioneine ( 1 ), an unusual natural product derived from ergothioneine, a fungal amino acid containing an imidazole-2-thione moiety, was isolated from an aqueous extract of “tian ma” (the Gastrodia elata rhizomes). The structure of 1 including the absolute configuration was determined by extensive spectroscopic data analysis, combined with comparison of an experimental circular dichroism spectrum and calculated electronic circular dichroism spectra of stereoisomers, and confirmed by X-ray crystallography. The natural origin of 1 was proved by HPLC-ESIMS analysis of the crude extract. A biogenetic pathway of 1 is proposed on the basis of metabolic post-modification of ergothioneine that is biosynthesized by a symbiotic fungus. The plant and symbiotic fungus are co-producers of 1 .

Three new napelline-type C 20 -diterpenoid alkaloids, named aconicarmichinium A and B trifluoroacetates ( 1 and 2 ) and aconicarmichinium C chloride ( 3 ), were isolated from an aqueous extract of “fu zi”, the lateral roots of Aconitum carmichaelii . Their structures were elucidated by extensive spectroscopic data analysis. Compounds 1 – 3 represent the first examples of napelline-type C 20 -diterpenoid alkaloid alcohol iminiums, of which the structures were fully characterized. In addition, transformation and equilibration between the alcohol iminiums ( 1 – 3 ) and the aza acetals 1a – 3a were investigated by measurements of the NMR spectra in protic and aprotic deuterium solvents including alkali pyridine- d 5 , along with evaporation under reduced pressure and gradual additions of TFA, AcOH, and HCl. The results demonstrated that the transformation and equilibration were solvent-, base-, and acid-dependent. Especially, in aqueous biological fluid, these C 20 -diterpenoid alkaloids would more likely exist as the alcohol iminiums accompanied by anion counterparts in biosystems to increase their solubility, bioavailability, transportations, and functions. The absolute configurations of 1 – 3 were confirmed by X-ray crystallographic analysis of 2a .

Our preliminary study shows that a bibenzyl compound isolated from Gastrodia elata, 2-[4-hydroxy-3-(4-hydroxybenzyl)benzyl]-4-(4-hydroxybenzyl)phenol (designated 20C), protects PC12 cells against H2O2-induced injury. In this study we investigated whether 20C exerted neuroprotective action in a cell model of Parkinson's disease. A cell model of Parkinson's disease was established in PC12 cells by exposure to rotenone (4 μmol/L) for 48 h. Cell viability and apoptosis were assessed, and intracellular ROS level and the mitochondrial membrane potential (MMP) were detected. The expression of apoptosis-related proteins Bax, Bcl-2, cytochrome c, cleaved caspase-3, and oxidative stress-related proteins Nrf2, HO-1 and NQO1 were examined using Western blotting. The mRNA levels of HO-1 and NQO1 were determined with RT-PCR. The nuclear translocation of Nrf2 was observed with immunofluorescence staining. Treatment with rotenone significantly increased the number of apoptotic cells, accompanied by marked increases in the Bax/Bcl-2 ratio, cytochrome c release and caspase-3 activation. Rotenone also increased ROS accumulation, reduced MMP, and increased the nuclear translocation of Nrf2 as well as the mRNA and protein levels of the Nrf2 downstream target genes HO-1 and NQO1 in PC12 cells. Co-treatment with 20C (0.01–1 μmol/L) dose-dependently attenuated rotenone-induced apoptosis and oxidative stress in PC12 cells. Nrf2 knockdown by siRNA partially reversed the protective effects of 20C in rotenone-treated PC12 cells. The bibenzyl compound 20C protects PC12 cells from rotenone-induced apoptosis, at least in part, via activation of the Nrf2/ARE/HO-1 signaling pathway.

Four stereoisomers of 3,5-bis(2-hydroxybut-3-en-1-yl)-1,2,4-thiadiazole, named insatindigothiadiazoles A–D ( 1a – 1d ), were isolated from the roots of Isatis indigotica . Their structures were determined by spectroscopic analysis; specifically, the absolute configurations were assigned by using the MPA determination rule based on Δ δ RS values of MPA esters, and supported by electronic CD (ECD) calculations. Proposed biosynthetic pathways and preliminary investigations of the biological activities of 1a – 1d against influenza virus A (H3N2), Coxsackie virus B3, and/or HSV-1 are also discussed.

It has been reported that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can significantly reduce lipoprotein(a) [Lp(a)], and the mechanism for Lp(a) reduction remains unclear. Recently an interesting clinical research with a small sample showed a positive correlation between plasma PCSK9 and Lp(a) levels in diabetes. Here we aimed to use a relatively large sample to investigate whether such an association exists in Han Chinese. A total of 783 inpatients were consecutively enrolled and composed of 172 patients with type 2 diabetes mellitus (T2DM) and 611 non-T2DM subjects. Plasma PCSK9 level was measured by ELISA, and its association with Lp(a) was assayed by Spearman’s correlation and multiple regression. Clinical and biochemical parameters were determined in all subjects studied. No significant differences in PCSK9 and Lp(a) levels were found between T2DM and non-T2DM patients. PCSK9 level was not related to Lp(a) level either in T2DM or non-T2DM group in bivariate correlation and multiple linear regression analysis. Additionally, no association between the levels of PCSK9 and Lp(a) was found in well, poorly controlled T2DM patients or in T2DM patients with or without coronary artery disease (CAD). Besides, no difference was found among the PCSK9 values across tertiles of Lp(a) level. We found no association of plasma PCSK9 levels with Lp(a) level in Han Chinese with or without T2DM, suggesting that Lp(a) reduction by PCSK9 inhibitors may not be achieved simply through PCSK9 pathway at least in Chinese.

Sixteen lignanoids were isolated from an aqueous extract of the commonly used Chinese traditional medicine Dangshen, the dried roots of Codonopsis pilosula, by using a combination of various chromatographic techniques, including silica gel, macroporous adsorbent resin, MCI resin, sephadex LH-20, and reversed phase semi-preparative HPLC. On the basis of spectral data analysis, their structures were elucidated and identified as（-）-（7R,7’R,8R,8’S）-4,4’-dihydroxy-3,3’,5,5’,7-pentamethoxy-2,7’-cyclolignane（1）,（-）-（7R,8S）- dihydrodehydrodiconiferyl alcohol 4-O-β-D-glucopyranosyl-（1’’’→2’’）-β-D-glucopyranoside（2）,（-）-（7R,8S）- dihydrodehydrodiconiferyl alcohol（3）,（+）-（7S,8R）-dehydrodiconiferyl alcohol（4）,（+）-balanophonin（5）,（+）- demethoxypinoresinol（6）,（+）-pinoresinol（7）,（+）-epipinoresinol（8）,（-）-syringaresinol（9）,（-）-medioresinol（10）,（-）-lariciresinol（11）,（-）-secoisolariciresinol（12）,（-）-ent-isolariciresinol（13）,（+）-（7S,8S）-3-methoxy-3’,7- expoxy-8,4’-neolignan-4,9,9’-triol（14）,（+）-（7S,8R）-3’,4-dihydroxy-3-methoxy-8,4’-neolignan（15）, and（-）-（7R,8R）-3’,4-dihydroxy-3-methoxy-8,4’-neolignan（16）. All these compounds were isolated from C. pilosula for the first time, while compound 1 is a new natural product of 2,7’-cyclolignan and 2 is a new 4’,7-epoxy- 8,3’-neolignan diglucoside. Compound 12 showed activity against Fe(2+)-cysteine induced rat liver microsomal lipid peroxidation with an inhibition ratio of（63.4 ± 8.3） % at 1×10(-5) mol·L(-1).

Three new sesquiterpene glycosides, named codonopsesquilosides A−C (1−3), were isolated from an aqueous extract of the dried roots of Codonopsis pilosula. Their structures including absolute configurations were determined by spectroscopic and chemical methods. These glycosides are categorized as C15 carotenoid (1), gymnomitrane (2), and eudesmane (3) types of sesquiterpenoids, respectively. Compound 1 is the first diglycoside of C15 carotenoids to be reported. Compound 2 represents the second reported example of gymnomitrane-type sesquiterpenoids from higher plants. The absolute configurations were supported by comparison of the experimental circular dichroism (CD) spectra with the calculated electronic CD (ECD) spectra of 1−3, their aglycones, and model compounds based on quantum-mechanical time-dependent density functional theory. The influences of the glycosyls on the calculated ECD spectra of the glycosidic sesquiterpenoids, as well as some nomenclature and descriptive problems with gymnomitrane-type sesquiterpenoids are discussed., Graphical abstract Three new sesquiterpene glycoside codonopsesquilosides A−C (1−3) were isolated from an aqueous extract of the Codonopsis pilosula roots. Their structures including absolute configurations were determined by spectroscopic and chemical methods. Compound 1 is the first diglycoside of C15 carotenoids, and 2 represents the second example of gymnomitrane-type sesquiterpenoids from higher plants. The influences of the glycosyls on the calculated ECD spectra of the glycosidic sesquiterpenoids are discussed. Some suggestions to solve problems with gymnomitrane-type sesquiterpenoids nomenclature and descriptions are proposed.

A pair of indole alkaloid enantiomers with a novel bisindolylacetamide skeleton, insatindibisindolamides A and B (1a and 1b), was isolated from an aqueous extract of Isatis indigotica roots. The enantiomers were separated by chiral HPLC. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, including 2D NMR, X-ray crystallography, and electronic CD (ECD) calculation. The proposed biosynthetic pathway and preliminary investigations of the biological activity of compounds 1a and 1b are also discussed.

Two new 2-(quinonylcarboxamino)benzoates, named aconicarmiquinamides A (1) and B (2), were isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii. Their structures were determined by spectroscopic data analysis, and confirmed by comparison with synthetic methyl 3,6-bis(diethylamino)benzoqunonylcarboxylate (3).

Seven new C14-polyacetylene glucosides codonopilodiynosides A-G (1-7) were isolated from an aqueous extract of the Codonopsis pilosula roots. Their structures were determined by spectroscopic and chemical methods as (-)-(5S,6E,12E)-tetradeca-6,12-dien-8,10-diyn-1,5,14-triol 5-O-β-D-glucopyranoside (1), (-)-(5S,6E,12E)-tetradeca-6,12-dien-8,10-diyn-1,5,14-triol 5-O-β-D-glucopyranosyl-(1″ → 2')-β-D-glucopyranoside (2), (-)-(5S,6E,12E)-tetradeca-6,12-dien-8,10-diyn-1,5,14-triol 5,14-di-O-β-D-glucopyranoside (3), (-)-(5S,6E)-tetradeca-6-en-8,10-diyn-1,5,14-triol 5-O-β-D-glucopyranoside (4), (-)-(5S,6E,12E)-tetradeca-6,12-dien-8,10-diyn-1,5-diol 5-O-β-D-glucopyranosyl-(1″ → 2')-β-D-glucopyranoside (5), (-)-(6S,4E,12E)-tetradeca-4,12-dien-8,10-diyn-1,6-diol 6-O-β-D-glucopyranosyl-(1″ → 2')-β-D-glucopyranoside (6), and (-)-(5S,6E)-tetradeca-6-en-1,5-epoxy-8,10-diyn-14-ol 14-O-β-D-glucopyranosyl-(1″ → 2')-β-D-glucopyranoside (7), respectively. The absolute configurations of 1-7 were assigned by enzymatic hydrolysis followed by isolation of glucose and aglycones (1a and 4a-7a), and subsequent comparison of specific rotation, TLC, and (1)H NMR data of the glucose with an authentic sugar sample and application of modified Mosher's method based on the MPA determination rule of Δδ(RS) values for 1a and 4a, and Δδ(S) values for 6a. The configuration of 7 was assigned by electronic circular dichroism calculations based on the quantum-mechanical time-dependent density functional theory.

Seven new 4-hydroxybenzyl-substituted glutathione derivatives (2-8), together with a known analogue (1), were isolated from the aqueous extract of Gastrodia elata Blume rhizomes. Their structures were determined by using spectroscopic and chemical methods. The absolute configurations of 1-8 were assigned by using Marfey's method, combined with comparing the NMR and CD spectroscopic data of sulfoxide moieties in 3-6 with those of S-(4-hydroxybenzyl)cysteine sulfoxide stereoisomers (9-12) synthesized as authentic samples. The configurations of 9-12 were confirmed by electronic CD calculations based on the quantum-mechanical time-dependent density functional theory. Furthermore, the structures of 1, 3, 5, 7, and 8 were verified by synthesis. Compound 3 was active against serum deprivation-induced PC12 cell damage and synthetic 9-14 exhibited activity against Fe(2+)-cysteine induced rat liver microsomal lipid peroxidation.

Four new acetylenes (1–4) and one new unsaturated ω-hydroxy fatty acid (5), together with 5 known analogues, were isolated from an aqueous extract of Codonopsis pilosula roots. Their structures were determined by spectroscopic and chemical methods. The new acetylenes are categorized as an unusual cyclotetradecatrienynone (1), tetradecenynetriol (2), and rare octenynoic acids (3 and 4), respectively, and 3 and 4 are possibly derived from oxidative metabolic degradation of 1 and/or 2. The absolute configuration of 1 was assigned by comparison of the experimental circular dichroism (CD) spectrum with the calculated electronic circular dichroism (ECD) spectra of stereoisomers based on the quantum-mechanical time-dependent density functional theory, while the configuration of 2 was assigned by using modified Mosher׳s method based on the MPA determination rule of ΔδRS values for diols., Graphical abstract Four new acetylenes (1−4) and one new unsaturated ω-hydroxy fatty acid (5), together with 5 known analogues, were isolated from an aqueous extract of C. pilosula roots. Their structures including absolute configurations were determined by spectroscopic and chemical methods.

20C, a novel bibenzyl compound, is isolated from Gastrodia elata. In our previous study, 20C showed protective effects on tunicamycin-induced endoplasmic reticulum stress, rotenone-induced apoptosis and rotenone-induced oxidative damage. However, the anti-neuroinflammatory effect of 20C is still with limited acquaintance. The objective of this study was to confirm the anti-neuroinflammatory effect of 20C on Lipopolysaccharide (LPS)-activated BV-2 cells and further elucidated the underlying molecular mechanisms. In this study, 20C significantly attenuated the protein levels of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin (IL)-1β, and secretion of nitric oxide (NO) and tumor necrosis factor (TNF)-α induced by Lipopolysaccharide (LPS) in BV-2 cells. Moreover, 20C up-regulated the levels of autophagy-related proteins in LPS-activated BV-2 cells. The requirement of mitogen-activated protein kinases (MAPKs) has been well documented for regulating the process of autophagy. Both 20C and rapamycin enhanced autophagy by suppressing the phosphorylation of MAPKs signaling pathway. Furthermore, 20C treatment significantly inhibited the levels of toll like receptor 4 (TLR4), phosphorylated-protein kinase B (Akt) and phosphorylated-mechanistic target of rapamycin (mTOR), indicating blocking TLR4/Akt/mTOR might be an underlying basis for the anti-inflammatory effect of 20C. These findings suggest that 20C has therapeutic potential for treating neurodegenerative diseases in the future.

Oxidative stress is thought to be involved in the development of Parkinson's disease (PD). We previously reported that 20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ-1, nuclear factor erythroid 2-related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. In this study, we showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β (GSK3β) activation, eventually promoted the nuclear translocation of Nrf2 and induced the expression of hemeoxygenase-1 (HO-1). The antioxidant effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor, respectively. Conclusively, our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for alleviating the consequences of PD in the future.

Seven new aromatic acid derivatives (1-7), together with five known analogs, were isolated from the lateral roots of Aconitum carmichaelii. Structures of the new compounds were determined by spectroscopic and chemical methods as 4-methyl ( - )-(R)-hydroxyeucomate (1), 4-butyl ( - )-(R)-hydroxyeucomate (2), 4-butyl-1-methyl (+)-(R)-2-O-(4'-hydroxy-3'-methoxybenzoyl)malate (3), 1-butyl-4-methyl (+)-(R)-2-O-(4'-hydroxy-3'-methoxybenzoyl)malate (4), dimethyl (+)-(R)-2-O-(4'-hydroxy-3'-methoxybenzoyl)malate (5), dimethyl (+)-(R)-2-O-(4'-hydroxybenzoyl)malate (6), and methyl ( ± )-3-(4'-hydroxy-3'-methoxyphenyl)-3-sulfopropionate (7), respectively. Compounds 1 and 2 are 2-benzylmalates (eucomate derivatives), 3-6 belong to 2-O-benzoylmalates, and 7 is a rare phenylpropionate containing a sulfonic acid group. The absolute configurations of eucomate derivatives were confirmed by X-ray crystallographic analysis of 4-methyl eucomate (11).

A novel diterpenoid with an unprecedented 6/5/7/3 fused-ring skeleton, euphorbactin (1), was isolated from an ethanol extract of the roots of Euphorbia micractina. The structure was determined by extensive spectroscopic studies, especially by 2D NMR and CD data analysis. A proposed biosynthetic pathway and preliminary investigations of the biological activity of compound 1 are also discussed.

Nine new homosecoiridoid alkaloids, named lonijaposides O-W (1-9), along with 19 known compounds, were isolated from an aqueous extract of the flower buds of Lonicera japonica. Their structures and absolute configurations were determined by spectroscopic data analysis and chemical methods. Lonijaposides O-W have structural features that involve amino acid units sharing the N atom with a pyridinium (1-5) or nicotinic acid (6-9) moiety. The absolute configurations of the amino acid units were determined by oxidation of each pyridinium ring moiety with potassium ferricyanide, hydrolysis of the oxidation product, and Marfey's analysis of the hydrolysate. This procedure was validated by oxidizing and hydrolyzing synthetic model compounds. The phenylalanine units in compounds 4, 5, and 9 have the d-configuration, and the other amino acid units in 1-3 and 6-8 possess the l-configuration. Compounds 1, 4, 6, and 9 and the known compounds 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 5'-O-methyladenosine exhibited antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2) with IC50 values of 3.4-11.6 μM, and 4 inhibited Coxsackie virus B3 replication with an IC50 value of 12.3 μM.

Six new glycosides (1-6) have been isolated from the flower buds of Lonicera japonica. Their structures including the absolute configurations were determined by spectroscopic and chemical methods as ( - )-2-hydroxy-5-methoxybenzoic acid 2-O-β-d-(6-O-benzoyl)-glucopyranoside (1), ( - )-4-hydroxy-3,5-dimethoxybenzoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (2), ( - )-(E)-3,5-dimethoxyphenylpropenoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (3), ( - )-(7S,8R)-(4-hydroxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (4), ( - )-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (5), and ( - )-4-hydroxy-3-methoxyphenol β-d-{6-O-[4-O-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (6), respectively.

Six new glycosidic constituents (1-6), together with 10 known analogs, have been isolated from the bark of Machilus robusta. Structures of the new compounds, including the absolute configurations, were determined by spectroscopic and chemical methods as ( - )-nectandrin B-β-d-glucopyranoside (1), ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4-O-β-d-glucopyranoside (2), ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4'-O-β-d-glucopyranoside (3), ( - )-(8S,8'R)-4,4'-dihydroxy-3,3',5'-trimethoxylignan-4'-O-β-d-glucopyranoside (4), ( - )-(7R,8R)-syringylglycerol-8-O-β-d-glucopyranoside (5), and ( - )-3-hydroxy-2-methyl-4-pyrone-3-O-β-d-xylopyranosyl-(1 → 6)-O-β-d-glucopyranoside (6), respectively.

Six new indole alkaloid diglycosides named isatigotindolediosides A-F (1–6), along with three known analogs (7–9), were isolated from an aqueous extract of the Isatis indigotica roots (ban lan gen). Their structures including the absolute configurations were determined by comprehensive spectroscopic data analysis, combined with enzyme or acid hydrolysis, and comparison of experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra. In the preliminary assays, compounds 3, 5, and 8 showed antiviral activity against Coxsackie virus B3.

Accumulation of α-synuclein (α-syn) in the brain is a characteristic of Parkinson's disease (PD). In this study, we investigated whether treatment with tunicamycin, an endoplasmic reticulum (ER) stress inducer, led to the accumulation of α-syn in PC12 cells, and where α-syn protein was accumulated, and finally, whether bibenzyl compound 20c, a novel compound isolated from Gastrodia elata (Tian ma), could alleviate the accumulation of α-syn and ER stress activation in tunicamycin-treated PC12 cells.PC12 cells were treated with tunicamycin for different time (6 h, 12 h, 24 h, 48 h). Cell viability was determined by a MTT assay. Subcellular fractions of ER and mitochondria were extracted with the Tissue Endoplasmic reticulum Isolation Kit. The levels of α-syn protein and ER-stress-associated downstream chaperones were detected using Western blots and immunofluorescence.Treatment of PC12 cells with tunicamycin (0.5-10 μg/mL) dose-dependently increased the accumulation of α-syn monomer (19 kDa) and oligomer (55 kDa), and decreased the cell viability. Accumulation of the two forms of α-syn was observed in both the ER and mitochondria with increasing treatment time. Co-treatment with 20c (10Tunicamycin treatment caused accumulation of α-syn monomer and oligomer in PC12 cells. Bibenzyl compound 20c reduces the accumulation of α-syn and inhibits the activation of ER stress, which protected PC12 cells against the toxicity induced by tunicamycin.

Five new phenylpropene diglycosides (1-5), together with three known analogs, have been isolated from an ethanol extract of the bark of Machilus wangchiana. Their structures were determined by spectroscopic and chemical methods. In the preliminary assay, compounds 2 and 5-8 reduced dl-galactosamine (GalN)-induced hepatocyte (WB-F344 cells) damage with 37-41% inhibitions at 10 μM.

Seventeen new alkaloids (1-17) and 14 known analogues have been isolated from an aqueous extract of the root of Isatis indigotica. The structures and absolute configurations of these compounds were determined by extensive spectroscopic data analysis, including 2D NMR, single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation, and electronic circular dichroism spectra calculations based on the quantum-mechanical time-dependent density functional theory. Compounds 1, 2, and 3 are the first examples of natural products with unique linkages between a molecule of 2-(4-methoxy-1H-indol-3-yl)acetonitrile and 2-(1H-indol-3-yl)acetonitrile, 2-(4-methoxy-1H-indol-3-yl)acetonitrile, and 4-hydroxyphenylethane, respectively. Compounds (-)-4 and (+)-4 represent the first natural products with the pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline skeleton. Some structural assignments for the new alkaloids suggest that the assignments made for certain previously reported alkaloids require revision. Compounds 1-3 and arvelexin (18) show antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2), with IC(50) values of 3.70-12.35 μM, and 17 inhibits Coxsackie virus B3 replication with an IC(50) of 6.87 μM.

Eight new 9,10-anthraquinones (1–8) including three acetonide derivatives of 3-hydroxy-2-hydroxymethyl-9,10-anthraquinones (6–8) were isolated from an ethanol extract of the roots of Knoxia valerianoides. On the basis of chemical transformation reactions of the co-occurring 14 and 15 combined with HPLC–DAD–ESI–MS analysis of the extracts, the previously and newly isolated 2-methoxymethyl- and 2-ethoxymethyl-9,10-anthraquinones (4, 5, and 9–13), as well as the 3-hydroxy-2-hydroxymethyl-9,10-anthraquinone acetonide derivatives (6–8), were shown to be solvolytic artifacts. In the in vitro assays, compound 4 was active to protect hepatocyte (WB-F344) damage.

Homosecoiridoids (1-15) were isolated from the flower buds of Lonicera japonica. Compounds 1-4, designated as loniphenyruviridosides A-D, possess unprecedented skeletons featuring phenylpyruvic acid derived moieties coupled with an iridoid or a secoiridoid nucleus. Compounds 5-15 (lonijaposides D-N) are additional examples of the unusual pyridinium alkaloid-coupled secoiridoids (lonijaposides A-C). The validity of the CD data to determine the configuration of the secoiridoid derivatives is discussed on the basis of detailed CD data analysis and semisynthesis of 2 and 3 with the co-occurring secologanic acid. The configuration of secologanic acid was determined by a single-crystal X-ray crystallographic analysis using anomalous scattering of Cu Kα radiation. Biosynthetic pathways of the homosecoiridoids were postulated. Compounds 1-4 inhibited STAT-3 activity of HELF cells, and lonijaposides F (7), H (9), I (10), and K (12) showed activity against the release of glucuronidase in rat polymorphonuclear leukocytes induced by platelet-activating factor.

Four steroids, a homopregnene (1) and three heptanorergosterane derivatives (2-4), nine tremulane sesquiterpenes (5-13), and 18 known compounds have been isolated from cultures of the fungus Phellinus igniarius. Their structures and absolute configurations were elucidated by spectroscopic data analysis. In preliminary in vitro assays, at 10(-5) M, compounds 8, 9, 13, and 3beta-hydroxy-11,12-O-isopropyldrimene (14) showed significant vascular-relaxing activities against phenylephrine-induced vasoconstriction with relaxing rates of 35.7%, 45.4%, 46.6%, and 32.1%, respectively, as compared with the blank control.