Discovery of Three New Monoterpenoid Indole Alkaloids from the Leaves of Gardneria multiflora and Their Vasorelaxant and AChE Inhibitory Activities.

Three novel monoterpenoid indole alkaloids gardflorine A (1), gardflorine B (2), and gardflorine C (3) were isolated from the leaves of Gardneria multiflora. Their structures, including absolute configurations, were established on the basis of spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and circular dichroism experiments. All the compounds were evaluated for their vasorelaxant and acetylcholinesterase (AChE) inhibitory activities. Compound 1 exhibited potent vasorelaxant activity, with an EC50 value of 8.7 µM, and compounds 2 and 3 showed moderate acetylcholinesterase (AChE) inhibitory activities, with IC50 values of 26.8 and 29.2 µM, respectively.

Bioactive Limonoids and Triterpenoids from the Fruits of Melia azedarach.

Nine new limonoids, meliazedarines A-I (1-9), seven known analogues (10-16), and five known triterpenoids (17-21) were isolated from the fruits of Melia azedarach. Their structures were determined by analysis of 1D and 2D NMR, HRESIMS, X-ray diffraction, and electronic circular dichroism (ECD) data. Compound 7 showed significant cytotoxicity against the HCT116 cell line with IC50 values of 0.3 ± 0.1 µM.

Simultaneous Determination of α-Glucosidase Inhibitory Triterpenoids in Psidium guajava Using HPLC-DAD-ELSD and Pressurized Liquid Extraction.

Psidium guajava, a popular food and medicine dual purposes plant cultivated in tropical and subtropical regions, has been widely used as food crop and folk medicine, such as anti-diabetes agent, around the world. Triterpenoids have been considered as the major active ingredients of P. guajava. In the present study, a high-performance liquid chromatography coupled with diode array and evaporative light scattering detectors (HPLC-DAD-ELSD) method was developed for simultaneous determination of nine triterpenoids in P. guajava. Pressurized liquid extraction (PLE) was performed for sample preparation, and the analysis was achieved on a Cosmosil 5C18-MS-II (Nacalai Tesque, Kyoto, Japan) column eluted with gradient 0.1% aqueous formic acid-methanol system. The drift tube temperature of ELSD was set at 40 °C, and nitrogen flow-rate was at 1.6 L/min. All calibration curves for the analytes showed good linear regression (R2 > 0.9992) within test ranges. The established method was validated for intra-day and inter-day precisions (RSDs < 5%) and accuracy (recovery 94.23-106.87%). The validated method was successfully applied to determinate nine triterpenoids in 15 samples from the leave or fruit of P. guajava. In addition, the α-glucosidase inhibition assay showed good α-glucosidase inhibition activity in almost all the determined triterpenoids. The present study suggested that triterpenoids should be the quality control markers for P. guajava and HPLC-DAD-ELSD was an effective tool for the quality control of P. guajava.

Ruthenium-Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2.

A Ru-catalyzed direct asymmetric reductive amination of ortho-OH-substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93->99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible -OH group.

Hunterines A-C, Three Unusual Monoterpenoid Indole Alkaloids from Hunteria zeylanica.

Three new monoterpenoid indole alkaloids (MIAs), hunterines A-C (1-3), were isolated from Hunteria zeylanica. Compound 1 possesses a unique skeleton with an unprecedented azabicyclo[4.3.1]decane ring system. Compounds 2 and 3 are a pair of epimeric vobasinylindole alkaloid heterodimers. Their structures including absolute configurations were established by spectroscopic analyses, X-ray diffraction, computational calculation, and the modified Mosher's method. Plausible biogenetic pathways of 1-3 were also proposed. Alkaloid 1 showed moderate cytotoxic activity against the HepG2 cell line.

Synthesis of novel 6,7-dimethoxy-4-anilinoquinolines as potent c-Met inhibitors.

HGF/c-Met signalling pathway plays an important role in the development of cancers. A series of 6,7-dimethoxy-4-anilinoquinolines possessing benzimidazole moiety were synthesised and identified as potent inhibitors of the tyrosine kinase c-Met. Their in vitro biological activities against three cancer cell lines (A549, MCF-7, and MKN-45) were also evaluated. Most of these compounds exhibited moderate to remarkable potency. Among them, compound 12n showed the most potent inhibitory activity against c-Met with IC50 value of 0.030 ± 0.008 µM and it also showed excellent anticancer activity against the tested cancer cell lines at low micromolar concentration. Molecular docking verified the results and revealed the possible binding mode of the most promising compound 12n into the ATP-binding site of c-Met kinase.

Risk factors associated with osteonecrosis of femoral head after internal fixation of femoral neck fracture:a systematic review and meta-analysis.

BACKGROUND: Although the risk factors associated with osteonecrosis of femoral head (ONFH) after internal fixation of femoral neck fracture (IFFNF) have been frequently reported, the results remain controversial. Therefore, its related risk factors were systematically evaluated and meta-classified in this study. METHODS: Literature on risk factors of ONFH caused by IFFNF was retrieved in PubMed, Embase and Cochrane Library due June 2019. Review Manager 5.3 software was applied to data synthesis, and Stata 13.0 software was adopted for analyses of publication bias and sensitivity. RESULTS: A total of 17 case-control studies with 2065 patients were included. The risk of ONFH after IF was 0.40-fold higher in patients with Garden III-IV FNF than that in patients with Garden I-II (OR: 0.40, 95%CI: 0.29-0.55). The risk of OFNH with retained IF was uplifted by 0.04 times (OR: 0.04, 95%CI: 0.02-0.07). There was nonsignificant relationship between gender and ONFH after IFFNF (OR: 1.27, 95%CI: 0.84-1.94). Moreover, ONFH after IFFNF presented no association with age (OR:1.66, 95%CI: 0.89-3.11), injury-operation interval (OR:1.29, 95%CI: 0.82-2.04), fracture reduction mode (OR:1.98, 95%CI: 0.92-4.26), preoperative traction (OR:1.69, 95%CI: 0.29-9.98) and mechanism of injury (OR:0.53, 95%CI: 0.06-4.83). Egger's and Begg's tests indicated a publication bias (P = 0.001). CONCLUSION: It was demonstrated that Garden classification and retained IF were important influencing factors of ONFH after IFFNF. Gender, age, injury-operation interval, fracture reduction mode, preoperative traction and the mechanism of ONFH were irrelevant to the complication.

Eleven New Triterpenoid Glycosides from the Roots of Ilex asprella.

Asprellosides A-K, nine new ursane-type triterpenoid glycosides (1-9), and two new oleanane-type triterpenoid glycosides (10 and 11), including six rare sulfated triterpenoid glycosides, were isolated from the roots of Ilex asprella. Their structures were determined on the basis of comprehensive spectroscopic analysis and chemical methods. Among these compounds, asprelloside B (2) and asprelloside C (3) are the first examples of triterpenoid glycosides bearing a rare 3,4-O-disulfo-xylopyranosyl residue. All the saponins isolated showed no significant effects against respiratory syncytial virus (RSV) and lipopolysaccharide-induced nitric oxide production in Raw264.7 macrophages.

Cablinosides A and B, Two Glycosidic Phenylacetic Acid Derivatives from the Leaves of Pogostemon cablin.

A pair of new glycosidic epimers, cablinosides A (1a) and B (1b) were isolated from the leaves of Pogostemon cablin. The structures with absolute configurations of 1a and 1b were elucidated by extensive NMR investigation, and quantum chemical CD calculations. The epimer mixture 1 showed moderate α-glucosidase inhibitory activity and no significant cytotoxic activity against HepG2 cells.

Design, Synthesis and Anti-Platelet Aggregation Activity Study of Ginkgolide-1,2,3-triazole Derivatives.

Ginkgolides are the major active component of Ginkgo biloba for inhibition of platelet activating factor receptor. An azide-alkyne Huisgen cycloaddition reaction was used to introduce a triazole nucleus into the target ginkgolide molecules. A series of ginkgolide-1,2,3-triazole conjugates with varied functional groups including benzyl, phenyl and heterocycle moieties was thus synthesized. Many of the designed derivatives showed potent antiplatelet aggregation activities with IC50 values of 5~21 nM.

Ervadivamines A and B, Two Unusual Trimeric Monoterpenoid Indole Alkaloids from Ervatamia divaricata.

Ervadivamines A (1) and B (2), two unprecedented trimeric monoterpenoid indole alkaloids, were isolated from Ervatamia divaricata. They are the first examples of vobasine-iboga-vobasine-type alkaloid with both C-C and C-N linkage patterns. Their structures including absolute configurations were fully accomplished by extensive spectroscopic analysis, single-crystal X-ray diffraction, and electric circular dichroism methods. The plausible biogenetic pathways of these trimeric alkaloids were also proposed. In addition, compound 1 exhibited significant cytotoxicity against four cancer cells.

Prognostic analysis of different morphology of the necrotic-viable interface in osteonecrosis of the femoral head.

PURPOSE: The purpose of this study was to investigate the collapse progression in different morphologies of the necrotic-viable interface in osteonecrosis of the femoral head (ONFH). METHODS: A total of 168 patients (202 hips) with Association Research Circulation Osseous (ARCO) stage II ONFH were included. Ending with the collapse of the femoral head, all patients received conservative treatment but without surgical intervention and were followed for three to 91 months. Bilateral hip-joint radiographs and magnetic resonance imaging (MRI) were examined, and the largest layer of necrosis within the coronal section of MRI images was selected together with its anteroposterior radiograph to observe the morphology of the necrotic-viable interface. The morphology was divided into four types: I, type transverse; II, type "V"; III, type zigzag; IV, type closed. The collapse rate and the time to collapse in different morphologies were assessed. RESULTS: A total of 120 hips collapsed in two years or less, 61 were type-I, 51 were type-II, and 8 were type-III. Non-collapse occurred in all 17 hips with type-IV ONFH during long-term follow-up. In 202 hips with ARCO stage-II ONFH, the collapse rate in type-I ONFH was significantly higher than that of type-II and type-III ONFH (P < 0.01 for both). The time to collapse was markedly shortened. CONCLUSIONS: The risk of ONFH-induced collapse is influenced by the morphology of the necrotic-viable interface. Effective mechanical support for preventing the collapse of the femoral head is necessary when the morphology of the necrotic-viable interface is type transverse.

Preparation and Application of Standardized Typical Volatile Components Fraction from Turmeric (Curcuma longa L.) by Supercritical Fluid Extraction and Step Molecular Distillation.

A green and reliable method using supercritical fluid extraction (SFE) and molecular distillation (MD) was optimized for the separation and purification of standardized typical volatile components fraction (STVCF) from turmeric to solve the shortage of reference compounds in quality control (QC) of volatile components. A high quality essential oil with 76.0% typical components of turmeric was extracted by SFE. A sequential distillation strategy was performed by MD. The total recovery and purity of prepared STVCF were 97.3% and 90.3%, respectively. Additionally, a strategy, i.e., STVCF-based qualification and quantitative evaluation of major bioactive analytes by multiple calibrated components, was proposed to easily and effectively control the quality of turmeric. Compared with the individual calibration curve method, the STVCF-based quantification method was demonstrated to be credible and was effectively adapted for solving the shortage of reference volatile compounds and improving the QC of typical volatile components in turmeric, especially its functional products.

Simultaneous Quantification of Three Curcuminoids and Three Volatile Components of Curcuma longa Using Pressurized Liquid Extraction and High-Performance Liquid Chromatography.

A high-performance liquid chromatography (HPLC) method was investigated for the simultaneous quantification of two chemical types of bioactive compounds in the rhizome of Curcuma longa Linn. (turmeric), including three curcuminoids: Curcumin, bisdemethoxycurcumin, and demethoxycurcumin; and three volatile components: ar-turmerone, ß-turmerone, and α-turmerone. In the present study, the sample extraction system was optimized by a pressurized liquid extraction (PLE) process for further HPLC analysis. The established HPLC analysis conditions were achieved using a Zorbax SB-C18 column (250 mm × 4.6 mm i.d., 5 µm) and a gradient mobile phase comprised of acetonitrile and 0.4% (v/v) aqueous acetic acid with an eluting rate of 1.0 mL/min. The curcuminoids and volatile components were detected at 430 nm and 240 nm, respectively. Moreover, the method was validated in terms of linearity, sensitivity, precision, stability and accuracy. The validated method was successfully applied to evaluate the quality of twelve commercial turmeric samples.

Candida xinjiangensis sp. nov., a new anamorphic yeast species isolated from Scolytus scheryrewi Semenov in China.

Three yeast strains designated as S44, XF1 and XF2, respectively, were isolated from Scolytus scheryrewi Semenov of apricot tree in Shule County, Xinjiang, China, and were demonstrated to be a new member of the genus Candida by sequence comparisons of 26S rRNA gene D1/D2 domain and internal transcribed spacer (ITS) region. BLASTn alignments on NCBI showed that the similarity of 26S rRNA gene sequences of S44 (type strain) to all sequences of other Candida yeasts was very low (≦93 %). The phylogenetic tree based on the 26S rRNA gene D1/D2 domain and ITS region sequences revealed that the strain S44 is closely related to C. blattae, C. dosseyi, C. pruni, C. asparagi, C. fructus and C. musae. However, the strain S44 is distinguished from these Candida species by the physiological characteristics. Moreover, the strain S44 formed typical pseudohyphae when grown on cornmeal agar at 25 °C for 7 days, but did not form ascospores in sporulation medium for 3-4 weeks. Therefore, the name Candida xinjiangensis is proposed for the novel species, with S44 (=KCTCT27747) as the type strain.

Norditerpenoids and Dinorditerpenoids from the Seeds of Podocarpus nagi as Cytotoxic Agents and Autophagy Inducers.

Nine new norditerpenoids and dinorditerpenoids, 2-oxonagilactone A (1), 7ß-hydroxynagilactone D (2), nagilactones K and L (3 and 4), 3ß-hydroxynagilactone L (5), 2ß-hydroxynagilactone L (6), 3-epi-15-hydroxynagilactone D (7), 1α-chloro-2ß,3ß,15-trihydroxynagilactone L (8), and 15-hydroxynagilactone L (9), were isolated from the seeds of Podocarpus nagi, along with eight known analogues. The structures of the new compounds were established based on detailed NMR and HRESIMS analysis, as well as from their ECD spectra. The absolute configuration of the known compound 1-deoxy-2α-hydroxynagilactone A (16) was confirmed by single-crystal X-ray diffraction. All of the isolates were tested for their cytotoxic activities against cancer cells. The results indicated that compounds 4 and 6, as well as several known compounds, displayed cytotoxicity against A2780 and HEY cancer cells. Among the new compounds, 2ß-hydroxynagilactone L (6) showed IC50 values of less than 2.5 µM against the two cell lines used. Furthermore, compound 6 induced autophagic flux in A2780 cells, as evidenced by an enhanced expression level of the autophagy marker phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II) and increased mRFP-GFP-LC3 puncta. Also, compound 6 activated the c-Jun N-terminal kinase (JNK) pathway, while pretreatment with the JNK inhibitor SP600125 decreased compound 6-induced autophagy.

A Novel Strategy for Quantitative Analysis of Major Ginsenosides in Panacis Japonici Rhizoma with a Standardized Reference Fraction.

Panacis Japonici Rhizoma (Zhu-Jie-Shen in Chinese), the root of P. japonicus C.A. Mey., is commonly used in traditional Chinese Medicine. Saponins are the major bioactive compounds in this herb. The similarity of polarity and structure of the natural products in herb caused the difficulty of purification and resulted in the shortage and high cost of the reference compounds, which has greatly hindered efforts toward quantification in quality control. A novel strategy using a standardized reference fraction for qualification of the major saponins in Panacis Japonici Rhizoma was proposed to easily and effectively control the quality of PJR. The strategy is feasible and reliable, and the methodology of the developed approach is also validated. The standardized reference fraction was used for quantification, which might solve the shortage of the pure reference compounds in the quality control of herbal medicines.

Discovery of xanthine oxidase inhibitors from a complex mixture using an online, restricted-access material coupled with column-switching liquid chromatography with a diode-array detection system.

To find potential lead compounds for antigout drug discovery, an automated online, restricted-access material coupled with column-switching liquid chromatography with a diode-array detection (RAM-LC-DAD) system was developed for screening of xanthine oxidase (XO) inhibitors and their affinity rankings in complex mixtures. The system was first evaluated by analyzing a mixture of six compounds with known inhibition of XO. Nonspecific binding to the denatured XO was investigated and used as the control for screening. Subsequently, the newly developed system was applied to screening of a natural product, Oroxylum indicum extract, and four compounds which could specifically interact with XO were found and identified as oroxin B, oroxin A, baicalin, and baicalein. The results were verified by a competitive binding test using the known competitive inhibitor allopurinol and were further validated by an inhibition assay in vitro. The online RAM-LC-DAD system developed was shown to be a simple and effective strategy for the rapid screening of bioactive compounds from a complex mixture.

A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.

α-Glucosidase inhibitory effect and simultaneous quantification of three major flavonoid glycosides in Microctis folium.

Microctis Folium, the leaves of Microcos paniculata L., is a commonly used herbal tea material. The methanol extract of Microctis Folium and its principle compounds vitexin (1), isovitexin (2) and isorhamnetin 3-O-ß-D-rutinoside (3) were investigated for their α-glucosidase inhibitory effects. The extract showed strong α-glucosidase inhibitory effect (IC50 = 61.30 µg/mL) and the three flavonoid glycosides 1-3 exerted satisfactory α-glucosidase inhibitory effects, with IC50 values of 244.0 µM, 266.2 µM and 275.4 µM, respectively. A simple and reliable HPLC-DAD method was developed for the quantification of the three flavonoid glycosides in Microctis Folium and applied successfully to determine contents of these components in samples collected from different locations. This study suggested that Microctis Folium may be a promising candidate for development of herbal antidiabetes drugs, and vitexin, isovitexin and isorhamnetin 3-O-ß-D-rutinoside can be the biomarkers and chemical markers for this plant substance.