Monoterpenoid indole alkaloids from the fruits of Gelsemium elegans and their anti-inflammatory activities.

Two novel monoterpenoid indole alkaloids (MIAs), gelsechizines A-B (1-2), along with four known ones (3-6) were isolated from the fruits of Gelsemium elegans. Compound 1 features a new carbon skeleton with two additional carbon atoms forming a 4-methylpyridine unit. Their structures with absolute configurations were elucidated by NMR, MS, X-ray diffraction and electronic circular dichroism (ECD) calculations. Compounds 1-3 showed significant anti-inflammatory effects in vivo and in vitro, which may be related to the inhibition of the trecruitment of neutrophils and macrophages as well as the secretion of TNF-α and IL-6. Preliminary structure-activity relationship analysis revealed that the ß-N-acrylate moiety plays an important role in the anti-inflammatory effect.

Rearranged Phloroglucinol-Monoterpenoid Adducts from Callistemon rigidus.

Callisretones A (1) and B (2), two rearranged phloroglucinol-monoterpenoid adducts featuring an unprecedented isopropylcyclopenta[b]benzofuran backbone, together with their postulated biosynthetic precursors (3-9), were isolated from Callistemon rigidus. The previously assigned absolute configurations of viminalins H (7), L (8), and N (9) were revised and unequivocally established by X-ray diffraction data. A putative biosynthetic pathway toward callisretones A and B involving the rearrangement of the terpenoid motif is proposed. In addition, 1 and 2 showed inhibitory effects on nitric oxide production with IC50 values of 15.3 ± 1.0 and 17.7 ± 1.1 µM, respectively.

Antiviral Triketone-Phloroglucinol-Monoterpene Adducts from Callistemon rigidus.

Callistrilones F - K (1 - 6), six new triketone-phloroglucinol-monoterpene hybrids were isolated from the twigs and leaves of Callistemon rigidus. Their structures with absolute configurations were established by a combination analysis of NMR spectra, X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 3 and 4 exhibited moderate inhibitory activities against herpes simplex virus (HSV-1) with IC50 values of 10.00 ± 2.50 and 12.50 ± 1.30 µm, respectively.

Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF-7, A-549, HCT-116, and BGC-823 cell lines.

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents.

Intraoperative Correction of Femoral Rotational Deformity Using a Conventional Navigation System and a Smartphone: A Novel Technique.

The intraoperatively rotational control of femoral shaft fractures treated with a closed intramedullary interlocking nailing is a challenging problem. A novel surgical technique that includes respective insertions of guidewires into the proximal and distal femur under the guidance of a 2-dimensional fluoroscopy-based navigation system and the measurements of the intersection angle subtended by the proximal and distal guidewires with the smartphone positional software has been designed to provide intraoperatively quantitative parameters of femoral rotation deformation. The comparison of these parameters with preoperative measurement values of the contralateral intact femur on computed tomography images was used to align the proximal and distal femur fragments based on periaxial rotation. The purpose of this study was to evaluate its clinical suitability. Ten adult patients with femoral shaft fractures were attempted to correct intraoperatively femoral rotational deformity using this novel technique. The additional operation time was 20.04 ± 3.27 minutes. The angle of femoral anteversion was 20.85° ± 4.22°, 38.14° ± 19.07°, and 22.77° ± 3.38° in the contralateral intact and preoperatively and postoperatively injured femur, respectively. The mean absolute difference between both limbs was preoperatively 21.55° ± 10.14° with a statistically significant difference ( P = .005) and postoperatively 3.24° ± 1.69° with no statistically significant difference ( P = .092). Our results showed this novel technique could become an effective tool to correct intraoperatively rotational malalignment of femoral fractures.

Novel dammarane-type triterpenes isolated from hydrolyzate of total Gynostemma pentaphyllum saponins.

In this study, five novel triterpenes were isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum and identified as gypensapogenin H (1), gypensapogenin I (2), gypensapogenin L (3), gypensapogenin J (4) and gypensapogenin K (5), three of which (1-3) possess unprecedented ring A. All the isolated compounds were evaluated for cytotoxic activities in five cell lines and all the tested compounds showed significant anti-cancer activities against a series of human cancer cell lines, while having much weaker effect on the growth of normal cell. Among them, compound 1 showed strong inhibition toward MCF-7 human breast cancer cells (IC50 values 6.85 µM). Further mechanistic study demonstrated that compound 1 significantly induced MCF-7 cell apoptosis. Our results indicated that compound 1 may be a promising lead agent for further study.

Novel 25-hydroxyprotopanaxadiol derivatives incorporating chloroacetyl chloride and their anti-tumor evaluation.

In the current work, 12 novel 25-hydroxyprotopanaxadiol (25-OH-PPD) derivatives were synthesized by reacting with chloroacetyl chloride. And their in vitro antitumor activities were evaluated on six human tumor cell lines by MTT assay. The results demonstrated that, as compared with 25-OH-PPD, compounds 4, 6 and 7 exhibited higher cytotoxic activity on all tested cell lines. Of them, compound 4 showed strongly inhibition against MCF-7, HCT-116 and Lovo cells with IC50 values of 1.7, 1.6 and 2.1 µM, respectively. The IC50 values of compound 6 against HCT-116 and 7 against MCF-7 were the lowest (1.2 and 1.6 µM, respectively). It was also noted that compound 4 showed a 20- to 100-fold greater growth inhibition than ginsenoside-Rg3 (an anti-cancer regular drug in China). In conclusion, the data revealed that compounds 4, 6 and 7 were potential candidates for anti-tumor treatment and may be useful for the development of novel antiproliferative agents.

Protein tyrosine phosphatase 1B inhibitory effect by dammarane-type triterpenes from hydrolyzate of total Gynostemma pentaphyllum saponins.

Protein tyrosine phosphatase 1B (PTP1B) is an important factor in non-insulin-dependent diabetes mellitus (type-2 diabetes), and a promising target for treatment of diabetes and obesity. Therefore, the aim of this study is to investigate the inhibitory activities of constituents (three new together with twelve known triterpenes compounds) isolated from the hydrolyzate of total saponins from Gynostemma pentaphyllum. Their structures were accomplished mainly base on the spectroscopic methods, and then were further confirmed by X-ray crystal diffraction. All the compounds were evaluated for inhibitory activity against PTP1B. Current data suggested that the compounds 1, 3, 12, 13 and 14 were considered to be potential as antidiabetic agents, in which they could significantly inhibit the PTP1B enzyme activity in a dose-dependent manner.

Differences in metabolic improvement after metabolic surgery are linked to the gut microbiota in non-obese diabetic rats.

BACKGROUND: Different metabolic/bariatric surgery approaches vary in their effect on weight loss and glucose levels, although the underlying mechanism is unclear. Studies have demonstrated that the gut microbiota might be an important mechanism of improved metabolism after metabolic/bariatric surgery. AIM: To investigate the relationship between the improvement in metabolic disturbances and the changes in gut microbiota after gastric or intestinal bypass. METHODS: We performed sleeve gastrectomy (SG), distal small intestine bypass (DSIB) or sham surgery in nonobese rats with diabetes induced by 60 mg/kg streptozotocin (STZ-DM). RESULTS: The group comparisons revealed that both SG and DSIB induced a reduction in body weight and significant improvements in glucose and lipid metabolism in the STZ-DM rats. Furthermore, DSIB exhibited a stronger glucose-lowering and lipid-reducing effect on STZ-DM rats than SG. 16S ribosomal RNA gene sequencing revealed the gut abundance of some Lactobacillus spp. increased in both the SG and DSIB groups after surgery. However, the DSIB group exhibited a more pronounced increase in the gut abundance of Lactobacillus spp. compared to the SG group, with more Lactobacillus spp. types increased in the gut. CONCLUSION: The gut abundance of Lactobacillus was significantly correlated with the improvement in glycolipid metabolism and the change in serum fibroblast growth factor 21 levels.

Enhanced glucose homeostasis via Clostridium symbiosum-mediated glucagon-like peptide 1 inhibition of hepatic gluconeogenesis in mid-intestinal bypass surgery.

BACKGROUND: The small intestine is known to play a crucial role in the development and remission of diabetes mellitus (DM). However, the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood. AIM: To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism. METHODS: Streptozotocin (STZ) was used to induce DM in Sprague-Dawley (SD) rats at a dose of 60 mg/kg. The rats were then randomly divided into two groups: The mid-small intestine bypass (MSIB) group and the sham group (underwent switch laparotomy). Following a 6-wk recovery period post-surgery, the rats underwent various assessments, including metabolic parameter testing, analysis of liver glycogen levels, measurement of key gluconeogenic enzyme activity, characterization of the gut microbiota composition, evaluation of hormone levels, determination of bile acid concentrations, and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor. RESULTS: The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism, along with increased hepatic glycogen content. Furthermore, there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase. Importantly, the MSIB group exhibited a substantial increase in the abundances of intestinal Lactobacillus, Clostridium symbiosum, Ruminococcus gnavus, and Bilophila. Moreover, higher levels of secondary bile acids, such as intestinal lithocholic acid, were observed in this group. Remarkably, the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1 (GLP-1) at 6 wk postoperatively, highlighting their potential role in glucose regulation. These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota. CONCLUSION: The findings of this study demonstrate that the introduction of postoperative intestinal Clostridium symbiosum in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats. This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1, resulting in a favorable modulation of glucose homeostasis.

New antitumor compounds from Carya cathayensis.

A new lignan (7R,8S,8'R)-4,4',9-trihydroxy-7,9'-epoxy-8,8'-lignan, and three new phenolics, carayensin-A, carayensin-B, and carayensin-C, together with 13 known compounds were isolated from the shells of Carya cathayensis. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. All the compounds were evaluated for cytotoxicity against several human tumor types including human colorectal cancer cell lines (HCT-116, HT-29), human lung cancer cell line (A549), and human breast cancer cell line (MCF-7). The compounds 1, 5, 6, and 16 are considered to be potential as antitumor agents, which could significantly inhibit the cancer cell growth in a dose-dependent manner.

Triterpenoid saponins from Gynostemma pentaphyllum.

Four new dammarane-type triterpene saponins, 1-4, were isolated from the aerial parts of Gynostemma pentaphyllum (Thunb.) Makino. Their structural elucidations were accomplished mainly on the basis of spectroscopic methods, such as IR, HR-TOF-MS, and NMR. Compounds 1-4 showed moderate cytotoxic activities against cancer cell lines HL-60, Colon205, and Du145 in vitro.

Four New Phloroglucinol-Terpene Adducts from the Leaves of Myrciaria cauliflora.

Myrcauones A-D (1-4), four new phloroglucinol-terpene adducts were isolated from the leaves of Myrciaria cauliflora. Their structures with absolute configurations were elucidated by combination of spectroscopic analysis, single crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compound 1 was a rearranged isobutylphloroglucinol-pinene adduct featuring an unusual 2,3,4,4a,10,11-hexahydro-1H-3,11a-methanodibenzo[b,f]oxepin backbone. Compound 4 showed moderate antibacterial activity against Gram-positive bacteria including multiresistant strains.

Methionine represses the autophagy of gastric cancer stem cells via promoting the methylation and phosphorylation of RAB37.

This study focused on the role of methionine (MET) in the autophagy of gastric cancer stem cells (GCSCs) and aims to elaborate its regulatory mechanism. In the present study, the GCSCs were isolated from human gastric cancer cell lines using an anti-CD44 antibody, and then cultured in MET+ homocysteine (HCY)- or MET-HCY+ medium. In MET+HCY-treated GCSCs, autophagy was suppressed, the methylation and phosphorylation of RAB37 were elevated, and miR-200b expression was down-regulated. Lentiviral vector (LV-) carrying methionine-γ lyase (an enzyme that could specifically lyse MET; Metase) promoted autophagy, reduced the methylation and phosphorylation of RAB37, and up-regulated miR-200b expression in MET+HCY--treated GCSCs. Then, we found that miR-200b suppressed the expression of protein kinase C α (PKCα), a protein that could inactivate RAB37 through promoting its phosphorylation. LV-Metase down-regulated RAB37 phosphorylation via miR-200b/PKCα, thus promoting the RAB37-mediated autophagy and suppressing cell viability in MET+HCY-treated GCSCs. Finally, the in vivo study proved that LV-Metase treatment inhibited tumor growth through up-regulating RAB37 expression. In conclusion, MET suppressed RAB37 expression via enhancing its methylation and suppressed RAB37 activity via miR-200b/PKCα axis, thus repressing RAB37-mediated autophagy in GCSCs. The supplementation of Metase lysed MET, thus inducing the autophagy of GCSCs and inhibiting tumor growth.

Isolation, Structure Elucidation, and Total Synthesis of Myrtuspirone A from Myrtus communis.

A pair of enantiomeric triketone-phloroglucinol hybrids, (+)- and (-)-myrtuspirone A (1), featuring an unprecedented 3-isopropyl-3 H-spiro[benzofuran-2,1'-cyclohexane] backbone, were isolated from the leaves of Myrtus communis. The absolute configuration of each enantiomer of 1 was determined by X-ray diffraction and chemical calculations. Furthermore, the gram-scale total syntheses of (±)-1 and (-)-1 were conducted in four steps using a Michael- N-iodosuccinimide (NIS)-mediated (3 + 2)-annulation reaction. Both (+)- and (-)-1 exhibited antibacterial activities against Gram-positive bacteria including multidrug-resistant strains.

[Studies on flavonoids from Blumea riparia].

OBJECTIVE: To separate and identify the chemical constituents of Blumea riparia. METHOD: The compounds were separated and purified by repeated silica gel, Sephadex LH -20 column chromatographiy. The structures of these compounds isolated were identified by analysis of their spectral data, physical and chemical properties. RESULT: Six flavonoids were isolated from B. riparia. and their structures were identified as eriodictyol-7, 4'-dimethyl ether (1), eriodictyol-7, 3'-dimethyl ether (2), eriodictyol-7-methyl ether (3), quercetin-7, 3', 4'-trimethyl ether (4), tamarixetin (5), rhamnocitrin (6). CONCLUSION: Compound 1-6 were obtained from B. riparia for the first time.

Catalytic asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E.

Herein, we describe a concise catalytic approach to the first asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E. The syntheses proceed in only 5-7 steps from the readily available compound 11, without the need for protecting groups. Key features of the syntheses include a unique organocatalytic asymmetric Friedel-Crafts-type Michael addition with high enantioselectivity and a broad substrate scope, a novel Michael-ketalization-annulation cascade reaction, and an oxidative [3 + 2] cycloaddition. Furthermore, the new compound 7 exhibited potent antibacterial activities against several multidrug-resistant strains (MRSA, VISA and VRE), and showed greater potency than vancomycin.

A new piperazine-2,5-dione from the marine fungus Gliocladium sp.

A new piperazine-2,5-dione, named gliocladride, was isolated from marine fungus Gliocladium sp. The structure was established on the basis of spectral data, and the stereochemical assignments were made by 1H NMR spectrum and chiral HPLC of the hydrolyzed compound. Gliocladride showed a cytotoxic effect with an IC50 value of 3.86 microg/ml against human A375-S2 melanoma cell line.

Using a Novel CD133+ Immune Magnetic Particle to Separate Gastric Adenocarcinoma Stem Cells from Peripheral Blood and the Pluripotency Study About the Separated Cells.

Background: Stem cells isolated from peripheral blood of gastric adenocarcinoma patients have noninvasive advantages. However, at present, there is no simple and effective separation technique. Purpose: In this study, CD133+ cells were isolated from peripheral blood of patients with gastric adenocarcinoma by using specific immunomagnetic particles, and the immunology of subcultured cells was identified to evaluate whether the immune magnetic particle separation had any effect on the cells themselves. Methods: Immune magnetic particles, made by a specific technique, are used to sort out the cells whose membrane could express CD133 from peripheral blood of gastric adenocarcinoma patients. By observing the sorted cells within serum-free culturing, we compare the differences in morphology and proliferation ability between the collected cells and cells from a standard tumor cell line. At the same time, an immunofluorescence method is used to detect the expression of the CD133 antibody. Moreover, this study explores the inhibition effect on gastric adenocarcinoma stem cell growth when combining 5-fluorouracil and methionine enzymes. Results and Conclusions: The specific immunomagnetic particles have a small diameter and strong sorting characteristics. In the experiment, there were 20 patients with gastric adenocarcinoma. CD133+ cells were separated successfully from peripheral blood of 13 patients (65%), among which subcultured cells of 9 cases (69.2%) were found to express CD44+ antigens. The sorted cells grew vigorously with a variety of morphologies in non-inducing culture, while the cells induced by ß transforming growth factor presented slow growth and uniform morphology. There was a significant difference (P < 0.05) in cell proliferation between these two groups and the standard tumor cell line. In addition, 5-fluorouracil combined with methionine enzyme inhibited the growth of gastric adenocarcinoma stem cells significantly (P < 0.05). Accordingly, the CD133+/CD44+ cells from peripheral blood of gastric adenocarcinoma patients, sorted by specific immune magnetic particles, had clear stem cell properties as determined by cell function and structure. This lays a foundation for gastric adenocarcinoma stem cell extraction, culture and further research on stem cell characteristics.

One-pot synthesis, anti-tumor evaluation and structure-activity relationships of novel 25-OCH3-PPD derivatives.

Based on the fact that 25-OCH3-PPD, a natural ginsengenin isolated from the leaves of Panax ginseng, is a promising lead compound, novel 25-OCH3-PPD derivatives were synthesized to find more potent anti-tumor agents by a simple and facile synthetic method. These derivatives were classified into three types and screened for their cytotoxic activities against seven human cancer cell lines. Compared with 25-OCH3-PPD, compounds a5, a7, b5 and b7 exhibited higher anti-tumor activities on all tested cell lines with almost 5-fold to 15-fold increases. In particular, compound a7 showed the greatest cytotoxic activity against α-2 cells (IC50 = 2.4 ± 0.4 µM). The preliminary study on the mechanisms indicated that compound a7 could induce α-2 cell apoptosis. Structure-activity relationships demonstrated that the carbon-carbon double bond at the C-20 position could enhance the antiproliferative activity. In conclusion, the novel derivatives a5, a7, b5 and b7 could be further studied as potential candidates for the treatment of cancer. This research provides a theoretical reference for the exploration of new antiproliferative agents.