Curcuma wenyujin rhizomes extract ameliorates lipid accumulation.

Curcuma wenyujin (C. wenyujin) is a medicinal plant that is traditionally used to treat blood stagnation, liver fibrosis, pain, and jaundice. In this study, we examined the effect of C. wenyujin rhizome extract on hepatic lipid accumulation both in vivo and in vitro. We found that the petroleum ether fraction of C. wenyujin rhizome extract (CWP) considerably reduced the accumulation of lipids in HepG2 cells treated with oleic and palmitic acid. Ultra-high-performance liquid chromatography coupled with LTQ-Orbitrap mass spectrometry was used to analyze the main chemical constituents of CWP, and 21 sesquiterpenes were identified. In vivo experiments revealed that the administration of CWP significantly reduced the body weight and serum total cholesterol (TC) level of low-density-lipoprotein receptor knockout mice treated with a high-fat diet without affecting their food intake. CWP also significantly reduced the levels of liver TC, liver triglycerides, aspartate transaminase, and alanine transaminase. Histological examination revealed that CWP dose-dependently reduced steatosis in liver tissue, significantly downregulated the expression of lipogenesis genes, and increased the ß-oxidation of fatty acids. CWP also significantly increased autophagy-related proteins. In conclusion, CWP rich in sesquiterpenes reduces the accumulation of lipids in vivo and in vitro by improving lipid metabolism and activating autophagy.

Bavachinin selectively modulates PPAR γ and maintains bone homeostasis in Type 2 Diabetes.

Full peroxisome proliferator-activated receptor (PPAR) γ agonists, Thiazolidinediones (TZDs), effectively prevent the process of Type 2 Diabetes Mellitus (T2DM), but their side effects have curtailed use in the clinic, including weight gain and bone loss. Here, we identified that a selective PPAR γ modulator, Bavachinin (BVC), isolated from the seeds of Psoralea Corylifolia L., could potently regulate bone homeostasis. MC3T3-E1 pre-osteoblast cells and C3H10T1/2 mesenchymal stem cells were assessed for osteogenic differentiation activities, and receptor activator of NF-κB ligand (RANKL)-induced RAW 264.7 cells were assessed osteoclasts formation. Leptin receptor-deficient mice and diet-induced obesity mice were applied to evaluate the effect of BVC on bone homeostasis in vivo. Compared to full PPAR γ agonist rosiglitazone, BVC significantly increased the osteogenesis differentiation activities under normal and high glucose conditions in MC3T3-E1 cells. Moreover, BVC could alleviate osteoclast differentiation in RANKL-induced RAW 264.7 cells. In vivo, synthesized BVC prodrug (BN) has been applied to improve water solubility, increase the extent of oral absorption of BVC and prolong its residence time in blood circulation. BN could prevent weight gain, ameliorate lipid metabolism disorders, improve insulin sensitivity, and maintain bone mass and bone biomechanical properties. BVC, a unique PPAR γ selective modulator, could maintain bone homeostasis, and its prodrug (BN) exhibits insulin sensitizer activity while circumventing the side effects of the TZDs, including bone loss and undesirable weight gain.

Structures, Sources, Identification/Quantification Methods, Health Benefits, Bioaccessibility, and Products of Isorhamnetin Glycosides as Phytonutrients.

In recent years, people have tended to consume phytonutrients and nutrients in their daily diets. Isorhamnetin glycosides (IGs) are an essential class of flavonoids derived from dietary and medicinal plants such as Opuntia ficus-indica, Hippophae rhamnoides, and Ginkgo biloba. This review summarizes the structures, sources, quantitative and qualitative analysis technologies, health benefits, bioaccessibility, and marketed products of IGs. Routine and innovative assay methods, such as IR, TLC, NMR, UV, MS, HPLC, UPLC, and HSCCC, have been widely used for the characterization and quantification of IGs. All of the therapeutic effects of IGs discovered to date are collected and discussed in this study, with an emphasis on the relevant mechanisms of their health-promoting effects. IGs exhibit diverse biological activities against cancer, diabetes, hepatic diseases, obesity, and thrombosis. They exert therapeutic effects through multiple networks of underlying molecular signaling pathways. Owing to these benefits, IGs could be utilized to make foods and functional foods. IGs exhibit higher bioaccessibility and plasma concentrations and longer average residence time in blood than aglycones. Overall, IGs as phytonutrients are very promising and have excellent application potential.

Four new sesquiterpenes from Curcuma wenyujin.

Four new sesquiterpenes including two guaianes (1 and 2), one germacrene (3), and one nor-sesquiterpene (4), which were named as wenyujinols M-P, along with nine known sesquiterpenes (5-13) and three monoterpenes (14-16), were isolated from the rhizomes of Curcuma wenyujin. The chemical structures of 1-4 were elucidated by NMR spectroscopic, mass spectrometric data, and electronic circular dichroism (ECD) spectra analysis. The isolated compounds were evaluated for antioxidant activity via activating the transcription of Nrf2 in 293 T cells. As a result, compounds 6, 13 and 14 exhibited the Nrf2 agonist activity dose-dependently.

A bavachinin analog, D36, induces cell death by targeting both autophagy and apoptosis pathway in acute myeloid leukemia cells.

PURPOSE: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality, and it is urgent to find new and optimized treatment strategies for AML. In this study, bavachinin, isolated from Psoralea corylifolia L. exhibiting extensive anti-tumor activity in many solid tumors and a series of its synthesized analogs, were screened for their anti-cancer activity on AML cell lines. METHODS: The cell viability of AML cells was measured using CCK-8 assays. Cell apoptosis and cell cycle were detected by flow cytometry. The expression of apoptosis-related protein and autophagy-related protein/gene was detected by western blot, immunofluorescence or RT-PCR. Subcutaneous mice tumor model was used to evaluate the anti-cancer activity of D36 in vivo. RESULTS: D36 robustly induced AML cells death in a dose-dependent manner with the IC50 value of 1.0 µM for HL-60 cells and 0.81 µM for MV4-11 cells at 24 h. D36 activated autophagy by inducing the accumulation of LC3B and promoting the autophagy flux. In addition, D36 triggered the extrinsic apoptosis by upregulating the protein level of FAS, cleaved-caspase 8, cleaved-caspase 3 and cleaved-PARP. D36 also blocked the cell cycle at S phase or G2/M phase in AML cells. In addition, we find that activation of caspase cascade induced apoptosis and meanwhile activated autophagy, autophagy activation in turns contributes to apoptosis. Furthermore, D36 suppressed the tumor growth in HL-60 AML-bearing mice without obvious side effects. CONCLUSION: This study suggests that D36 is a promising small-molecule for the treatment of acute myeloid leukemia.

Guaiane-type sesquiterpenes from Curcumawenyujin.

Eight undescribed sesquiterpenes including seven guaianes and one pseudoguaiane which were named as wenyujinols A-H, along with ten known guaianes, were isolated from rhizomes of Curcuma wenyujin Y. H. Chen et C. Ling. The structures of wenyujinols A-H were elucidated by 1D and 2D nuclear magnetic resonance (NMR) data, high resolution mass spectrum (HRMS), electronic circular dichroism (ECD) spectra, and X-ray single crystallographic analysis. All of the isolated compounds were evaluated for antioxidant activity via activation of the Nrf2-ARE pathway in human embryonic kidney (HEK) 293 cells, for inhibitory effects on NO production in RAW 264.7 cells, and for cytotoxicity against three human cancer cell lines A549, HL60, and MCF7 in vitro. The results indicated that procurcumenol (50-200 µM) and 9-oxo-neoprocurcumenol (25-200 µM) exhibited antioxidant activity via activation of the Nrf2-ARE pathway in a dose-dependent manner.

Nine new sesquiterpenes from Curcuma wenyujin rhizomes.

Nine new sesquiterpenes wenyujinones A-I (1-9), along with ten known ones (10-19), were isolated from the rhizomes of Curcuma wenyujin Y. H. Chen et C. Ling (C. wenyujin). The chemical structures of compounds 1-9 were elucidated by NMR spectroscopic and mass spectrometric data, electronic circular dichroism (ECD) spectra analysis. Furthermore, all compounds were evaluated for the protective effects against hydrogen peroxide (H2O2)-induced injury in human hepatic L02 cells, for the inhibitory effects on nitric oxide (NO) production in RAW 264.7 cells, and for their cytotoxicity against three human cancer cell lines A549, HL60, and MCF7 in vitro. As a result, compounds 2, 4, 14 markedly weakened the oxidative damage induced by H2O2 in L02 cells via strengthening the cell viability.

Flavonoids extract from the seeds of Psoralea corylifolia L. (PFE) alleviates atherosclerosis in high-fat diet-induced LDLR-/- mice.

BACKGROUND: The seeds of Psoralea corylifolia L., a traditional medicine popular used in China and India, have been recommended in the treatment of leucoderma, psoriasis, osteoporosis, and gynecological bleeding. Our previous studies have found that flavonoid extract from the seeds of Psoralea corylifolia L. could activate fat browning and correct the disorder of glucose and lipid metabolism in obese mice. PURPOSE: The present study aimed to investigate the anti-atherosclerosis of flavonoids extract from the seeds of Psoralea corylifolia L. METHODS: Leukocyte adhesion assay, RT-PCR, Western blot analysis, and immunofluorescent assay were carried out in ox-LDL induced endothelium injury and foam cells formation in vitro. Flavonoids from the seeds of P. corylifolia L. (PFE) was administrated 150 and 300 mg/kg/day in HFD-induced LDLR-/- mice for 12 weeks. RESULTS: Flavonoids from the seeds of P. corylifolia L. (PFE) could prevent leukocyte adhesion to the endothelium by inhibiting mRNA and protein expression of these adhesion molecules (VCAM-1, ICAM-1, and E-selectin). PFE could also prevent ox-LDL stimulated inflammation in HUVECs by inhibiting the NF-κB pathway. In addition, PFE significantly ameliorated ox-LDL induced macrophages-oriented foam cells formation through inducing cholesterol efflux via PPARγ-ABCA1/ABCG1. In HFD-induced LDLR-/- mice, PFE reversed the serum profile and circulated inflammation level. Meanwhile, PFE could remarkably alleviate atherosclerotic lesion sizes and intraplaque macrophage infiltration in aortic roots. CONCLUSION: Flavonoids from the seeds of P. corylifolia L. could alleviate atherosclerosis by preventing endothelium injury, attenuating vascular inflammation, and alleviating the formation of foam cells.

Isolation and structural characterization of eight impurities in aztreonam.

To comply with regulatory requirements, it is necessary to detect and separate the impurities generated during aztreonam synthesis or storage. The chromatogram of aztreonam revealed eight major impurities, which were purified through medium-pressure reversed-phase column and preparative High Performance Liquid Chromatography (HPLC). Through high resolution electrospray ionization mass spectroscopy (HRESIMS), as well as one- and two-dimensional nuclear magnetic resonance (NMR), their structures were confirmed as aztreonam acetate (Ⅰ), desulfated aztreonam (Ⅱ), anti-aztreonam (Ⅲ), open-ring aztreonam (Ⅳ), open-ring desulfated aztreonam (Ⅴ), open-ring desulfated aztreonam ethyl ester (VI), cis-deamino open-ring desulfated aztreonam (VII), and trans-deamino open-ring desulfated aztreonam (Ⅷ). Their exact concentrations were determined through quantitative nuclear magnetic resonance (qNMR) technique. Structural elucidation of the eight impurities through 1H NMR, 13C NMR, the 1H-1H COSY, NOESY, HSQC, HMBC NMR and MS spectra was conducted. Especially, ⅥI and Ⅷ were identified as undescribed impurities here.

Synthesis of Four Pentacyclic Triterpene-Sialylglycopeptide Conjugates and Their Affinity Assays with Hemagglutinin.

Influenza outbreaks pose a serious threat to human health. Hemagglutinin (HA) is an important target for influenza virus entry inhibitors. In this study, we synthesized four pentacyclic triterpene conjugates with a sialylglycopeptide scaffold through the Cu(I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC) and prepared affinity assays of these conjugates with two HAs, namely H1N1 (A/WSN/1933) and H5N1 (A/Hong Kong/483/97), respectively. With a dissociation constant (KD) of 6.89 µM, SCT-Asn-betulinic acid exhibited the strongest affinity with the H1N1 protein. Furthermore, with a KD value of 9.10 µM, SCT-Asn-oleanolic acid exhibited the strongest affinity with the H5N1 protein. The conjugates considerably enhanced antiviral activity, which indicates that pentacyclic triterpenes can be used as a ligand to improve the anti-influenza ability of the sialylglycopeptide molecule by acting on the HA protein.

Inhibitors of BRD4 protein from the roots of Astilbe grandis stapf ex E.H. Wilson.

A new monoterpene (1) along with eight known compounds were isolated from the roots of Astilbe grandis Stapf ex E.H. Wilson. Their structures were determined by extensive spectroscopic analysis and ECD experiments as (S)-3-(2-hydroxyethyl)-5-(2-methylprop-1-en-1-yl)furan-2(5H)-one (1), caffeic acid (2), mandelic acid (3), sonchifolinin B (4), α-viniferin (5), euscaphic acid (6), cianidanol (7), ß-sitosterol (8), and stigmasterol (9), respectively. Compounds 5 and 6 exhibited inhibitory effects against BRD4 protein with IC50 values of 13.20 and 17.39 µM, respectively. In vitro, compounds 5 and 6 showed moderate cytotoxicity to A549 cells, HCC827 cells and Hela cells with IC50 values ranging from 31.98 to 154.90 µM.

Review of the traditional uses, phytochemistry, and pharmacology of Curcuma wenyujin Y. H. Chen et C. Ling.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma wenyujin is a multifunctional medicinal plant belonging to the ginger family (Zingiberaceae). It has been used to treat blood stasis, promote the flow of qi, dredge the meridians, and relieve pain for more than 1500 years. Its raw rhizomes, steamed rhizomes, and steamed roots constitute three herbal medicines currently listed in the Chinese Pharmacopoeia: pian-jiang-huang (), wen-e-zhu () and wen-yu-jin (), respectively. AIM OF THE REVIEW: The aim of this review was to comprehensively summarize the traditional use, phytochemistry, and pharmacology of C. wenyujin in order to provide theoretical support for its further investigation and utilization. MATERIALS AND METHODS: Multiple databases (Scifinder, CNKI, Web of Science, PubMed, Google Scholar, and Baidu Scholar) were searched. Some information was also obtained from the literatures on traditional Chinese medicine. RESULTS: A total of 169 compounds have been isolated from C. wenyujin so far. Sesquiterpenoids are the major constituents and are crucial chemotaxonomic markers. Modern pharmacological studies and clinical trials have demonstrated that the extracts or active compounds from C. wenyujin have anti-inflammatory, antitumor, antioxidant, antibacterial, antiviral, and hepatoprotective properties. CONCLUSIONS: Until now, significant progress has been witnessed in phytochemistry and pharmacology of C. wenyujin. Some traditional uses of C. wenyujin have been supported by modern pharmacological studies. However, the establishment of quality control standards and additional clinical studies are warranted.

Four undescribed sulfur-containing indole alkaloids with nitric oxide inhibitory activities from Isatis tinctoria L. roots.

Four undescribed sulfur-containing indole alkaloids, isatisindigoticanines H, I and isatindigosides F, G along with three known analogues were obtained from Isatis tinctoria L. roots. Isatisindigoticanines H and I contained an unusual 1-(thiazol-4-yl)butane-1,2,3,4-tetraol moiety while isatindigosides F and G possessed a new 3-[3-(1H-indole-2-yl)azet-2-yl]-1H-indole skeleton. The putative biosynthetic pathways of isatisindigoticanines H, I and isatindigosides F, G are proposed. The isolated compounds showed nitric oxide inhibitory effects with IC50 values ranging from 4.3 to 70.3 µM.

Ruthenium(II)-Catalyzed Regioselective Ortho C-H Allenylation of Electron-Rich Aniline and Phenol Derivatives.

Ortho C-H allenylation of electron-rich benzene derivatives with propargylic alcohol derivatives has been a challenge, due to their great innate tendency toward a para C-H allenylation via an SN2'-type substitution process. Here, we described a Ru(II)-catalyzed regioselective ortho C-H allenylation of electron-rich aniline and phenol derivatives, which allows the previously challenging synthesis of a broad range of ortho allenylated aniline and phenol derivatives. More significantly, highly optically active fully substituted allenes can also be prepared with high enantiomeric excess via a highly efficient chirality transfer. No para C-H allenylation product was observed in the current catalytic system, thus showing a complete reversibility of the regioselectivity.

Alkaloid Enantiomers from the Roots of Isatis indigotica.

Five pairs of alkaloid enantiomers (1a/1b-5a/5b) were obtained from Isatis indigotica (I. indigotica) roots. Among them, 1a/1b, 2a/2b and 3a/3b were determined as three pairs of new alkaloid enantiomers. Their structures were elucidated by physicochemical properties and spectroscopic methods. The absolute configurations were deduced by comparison of their experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra, as well as by single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation. Alkaloids 1a and 1b possess an unpresented carbon skeleton and their putative biosynthetic pathways are discussed. Moreover, all of the alkaloids were tested for their nitric oxide (NO) inhibitory effects in RAW 264.7 cells, and 4a and 4b showed inhibitory effects with IC50 values of 76.97 µM and 65.88 µM, respectively.

Bromodomain-Containing Protein 4: A Druggable Target.

Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extraterminal family. BRD4 inhibitors can regulate acetylated lysine and form protein complexes that initiate transcriptional programs as an epigenetic regulator of the histone code. BRD4 was initially considered to be one of the most promising targets for combating malignant tumors. However, many recent studies have shown that BRD4 plays a crucial role in various kinds of diseases, including cancer, coronary heart disease, neurological disorder, and obesity. Currently, several BRD4 inhibitors are undergoing clinical trials. A search for new BRD4 inhibitors appears to be of great utility for developing novel drugs. In this mini-review, we highlight the inhibitors of BRD4 from natural products and synthesized sources, as well as their applications in cancer, glucolipid metabolism, inflammation, neuronal stimulation activation, human immunodeficiency virus and renal fibrosis.

Scrodentoid A Inhibits Mast Cell-Mediated Allergic Response by Blocking the Lyn-FcεRIß Interaction.

Background: Mast cells are considered an attractive therapeutic target for treating allergic diseases, and the Lyn-FcεRIß interaction is essential for mast cell activation. This study investigated the antiallergic effect of scrodentoid A (SA) on mast cells and mast cell-mediated anaphylaxis. Methods: For in vitro experiments, mast cells were treated with SA. Cell proliferation was tested using the XTT assay. The mRNA expression of various cytokines and chemokines was measured using qPCR. The levels of histamine, eicosanoids (PGD2, LTC4), and cytokines were measured using enzyme immunoassay kits. Signaling was investigated using Western blotting and immunoprecipitation. For in vivo experiments, the antiallergic activity of SA was evaluated using two mouse models of passive anaphylaxis as passive cutaneous and systemic anaphylaxis. The mechanism was investigated through immunohistochemistry and immunofluorescence. Results: SA considerably inhibited immunoglobulin (Ig) E-mediated mast cell activation, including ß-hexosaminidase release, mRNA and protein expression of various cytokines, and PGD2 and LTC4 release. Oral administration of SA effectively and dose-dependently suppressed mast cell-mediated passive cutaneous and systemic anaphylaxis. SA significantly attenuated the activation of Lyn, Syk, LAT, PLCγ, JNK, Erk1/2, and Ca2+ mobilization without Fyn, Akt, and P38 activation by blocking the Lyn-FcεRIß interaction. Conclusions: SA suppresses mast cell-mediated allergic response by blocking the Lyn-FcεRIß interaction in vitro and in vivo. SA may be a promising therapeutic agent for allergic and other mast cell-related diseases.

Prenylated flavonoid-standardized extract from seeds of Psoralea corylifolia L. activated fat browning in high-fat diet-induced obese mice.

We investigated the effects of the prenylated flavonoid-standardized extract (PFE) from the seeds of Psoralea corylifolia L. on countering obesity, which increases energy expenditure and stimulates thermogenesis in subcutaneous white adipose tissue (sWAT) and brown adipose tissue (BAT). For 12 weeks, C57BL/6 mice were fed a controlled high-fat diet (HFD) or HFDs with 0.2% or 0.5% w/w PFE. In vitro, the differentiation of 3 T3-L1 cells was used to elicit thermogenesis in the presence of PFE. PFE obviously reduced body weight and fat mass in a dose-dependent manner, increased energy expenditure, improved insulin sensitivity, and prevented hepatic steatosis by increasing lipid oxidation and secretion in HFD-fed mice. Moreover, PFE induced clear browning in sWAT, significantly increased phosphorylation of AMPKα1/2 and p38, increased BAT activity and the differentiation of 3 T3-L1 by increasing the expression of uncoupling protein 1 and other thermogenic genes. Our study showed that PFE prevented obesity by increasing browning and activating thermogenic genes in sWAT and BAT, improving glucose homeostasis, and protecting hepatic steatosis.

Establishment of an in vitro system based on AGM-S3 co-culture for screening traditional herbal medicines that stimulate hematopoiesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Spatholobus suberectus Dunn is a traditional Chinese medicine (TCM) that can activate blood, dispel stasis, inhibit platelet aggregation, and stimulate hematopoiesis, and thereby treat anemia and diseases related to blood stasis syndrome (BSS). However, its hematopoiesis-stimulating activity is not well understood. AIM OF STUDY: Four phenolic compounds (daidzein, formononetin, catechin, and procyandin B2) were isolated and purified from stems of S. suberectus, and tested using an in vitro hematopoiesis system. MATERIALS AND METHODS: An AGM-S3 co-culture system for hematopoiesis derived from human embryonic stem cells (hESCs) was employed to explore effects on hematopoiesis. At different stages, extracts from Spatholobus suberectus Dunn were added to the co-culture system at concentrations of 2, 10, or 50 µM, and fluorescence-activated cell sorting (FACS), hematopoietic colony culturing, and quantitative reverse transcription PCR (qRT-PCR) were used to probe changes in hematopoietic progenitors and erythroid progenitors. RESULTS: When H1 hESCs co-cultured with AGM-S3 were added along with 10 µM catechin from day 12 (D12), proliferation and differentiation of hematopoietic and erythroid progenitors from hESCs was increased based on FACS with antibodies recognizing CD34/CD45 and GPA/CD71. Hematopoiesis colony culturing further confirmed the promotion effect of catechin on hematopoiesis, and other active fractions did not significantly promote hematopoiesis. qRT-PCR revealed that some important genes related to hematopoiesis and erythroid were up-regulated followed catechin exposure. CONCLUSIONS: Our results demonstrate that catechin, an active ingredient of Spatholobus suberectus Dunn, can increase the efficiency of hematopoiesis, including hematopoietic and erythroid progenitors, consistent with previous reports. The AGM-S3 co-culture system could provide an effective tool for screening active compounds in TCMs that promote hematopoiesis, and may be of clinical and pharmaceutical use.

Two new 19-norbufadienolides with cardiotonic activity isolated from the venom of Bufo bufo gargarizans.

Two new 19-norbufadienolides (1 and 2) and one new 14,15-epoxy bufadienolide (3) alongside 16 known bufadienolides (4-19) were isolated from Bufonis Venenum that originated from the skin and parotid venom glands of an Asiatic toad (Bufo bufo gargarizans Cantor). The structures of these bufadienolides were elucidated based on the interpretation of their HRESIMS and NMR data. Compound 1, which had a unique peroxide, was established through extensive single-crystal X-ray diffraction. The two 19-norbufadienolides exhibited more potent cardiotonic activity in the isolated toad heart model and lower cytotoxicity against U87, U251, and LN-18 cell lines than other bufadienolides, such as bufalin and bufotalin. The results suggested that 19-norbufadienolides might be more suitable for developing cardiotonic agents with low cytotoxicity.