Design and Synthesis of Dimethylaminomethyl-Substituted Curcumin Derivatives: Potent Anti-Inflammatory, Anti-Oxidant, and Radioprotection Activity, Improved Aqueous Solubility Compared with Curcumin.

Although the wide variety of bioactivities of curcumin has been reported by researchers, the clinical application of curcumin is still limited due to its poor aqueous solubility. In view of this, a series of dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized (compounds 1-15). Acetate of these derivatives were prepared (compounds 1a-15a). The Mannich reaction and aldol condensation reaction are the main reactions involved in this study. Compounds 6, 10, 12, 3a, 5a, 6a, 7a, 8a, 10a, 11a, 12a, 13a, 14a, and 15a exhibited better in vitro anti-inflammatory activity compared to curcumin in the RAW264.7 cell line. Compounds 5, 1a, 5a, 8a, and 12a exhibited better in vitro antioxidant activity compared to curcumin in the PC 12 cell line. Compounds 11, 13, 5a, 7a, and 13a exhibited better in vitro radiation protection compared to curcumin in the PC 12 cell line. The aqueous solubilities of all the curcumin derivative acetates were greatly improved compared to curcumin.

Purification of total flavonoids from Ginkgo biloba flowers with resin column chromatography and evaluation of antioxidant activities in vitro.

Purification of total flavonoids from Ginkgo biloba flowers (GBF) extracts were studied using six resins. Adsorption-desorption experiments indicated that polyamide resin is the most suitable resin. The optimal purification process of total flavonoids of GBF was as follows: a loading concentration of 5.85 mg/mL, a loading volume of 1 bed volume (BV), a loading flow rate of 2 BV/h, a water volume of 2.67 BV, and a desorption solution of 40% ethanol. Under these conditions, the maximum purity of total flavonoids was 37.1 ± 1.1%. The antioxidant activity of purified flavonoids was further evaluated in vitro. It showed that the 40% ethanol purified fraction (Fr. B) group had the strongest antioxidant activity of the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity concentration for 50% of maximal effect (EC50, 145.4 ± 13.8 µg/mL) and ferric reducing ability (2.5 ± 0.2 mM FeSO4 equivalent mg-1 Fr. B). In addition, at the concentration of 160 µg/mL, the Fr. B strikingly increased the viability rate of hydrogen peroxide stimulated PC-12 cells to normal levels (***p < 0.001). This method provides a basis for the application and development of GBF resources. It indicated that the purified GBF flavonoids can be used as a source of potential antioxidant.

Phytochemical Constituents from the Seeds of Capsella bursa-pastoris and Their Antioxidant Activities.

Phytochemical investigation of 70% EtOH extract of the seeds of Capsella bursa-pastoris led to the isolation of a new cyclobutane organic acid (1), and fourteen known compounds, including two organosulfur compounds (2, 3), two quinonoids (4, 5), five flavonoids (6-10), three sterols (11-13) and two other types (14, 15). The structures of the compounds were elucidated by extensive spectroscopic analyses as well as comparison of their spectroscopic data with those reported in the literature. The antioxidant capacities of all compounds and extractive fractions were evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging test and ferric reducing antioxidant power (FRAP) assay. Then the antioxidative substances were evaluated for their neuroprotective effects against H2O2-induced HT22 cell injury. The results indicated the strong scavenging ability to free radical of the extractive fractions and compounds 1-3, 8-10 and 13, and the ferric reducing antioxidant power of the extractive fractions and compounds 1-3, 8 and 10, which were close to or higher than that of the positive control trolox. The EtOAc fraction, n-BuOH fraction, and compounds 1, 3 and 8 can protect HT-22 cells from oxidative damage.

Absolute Configuration and Biological Evaluation of Novel Triterpenes as Possible Anti-Inflammatory or Anti-Tumor Agents.

Two new compounds, ardisiapunine B (1) and ardisiapunine C (2), were isolated from Ardisia lindleyana D. Dietr. Their structures were examined using HR-ESI-MS, IR, (1D, 2D) NMR spectroscopic analyses, single-crystal X-ray diffraction, and ECD calculation. It was found that the two new compounds belong to unusual oleanane-type triterpenes, with compound 1 bearing an acetal unit and a C-13-C-18 double bond, and compound 2 bearing a C-28 aldehyde group and a C-18-C-19 double bond. The anti-inflammatory properties of compounds 1 and 2 were tested on NO production and cellular morphology using RAW264.7 cells, and their anti-tumor properties were tested on cytotoxic activities, cellular morphology, cell apoptosis, and cell cycle. The results showed that compound 1 exhibited a potent cytotoxicity against HepG2 cell lines with an IC50 of 12.40 µM. Furthermore, it is possible that compound 1 inhibits cell proliferation by blocking the cell G2/M phase and promoting cell apoptosis. Compound 2 exhibited a potential anti-inflammatory activity by decreasing the production of NO in LPS-stimulated RAW264.7 cells. Comparative analysis of the structures of compounds 1 and 2 revealed that the acetal structure and double bond positions were the main differences between them, and these are presumed to be the main reasons for the extreme differences in their cytotoxicity and anti-inflammatory activities. From these new findings, two promising lead compounds were identified for the future development of potential anti-inflammatory or anti-tumor agents.

Advances in Supercritical Carbon Dioxide Extraction of Bioactive Substances from Different Parts of Ginkgo biloba L.

Ginkgo biloba L. has always been a popular area of research due to its various active ingredients and pharmacological effects. Ginkgo biloba is rich in ginkgo flavonoids, ginkgolides, and ginkgolic acid, with anti-inflammation, antioxidation, neuroprotection, anti-platelet agglutination, hypolipidemic effect, anti-cancer, and anti-radiation properties. There are many methods to extract and separate the active components of ginkgo. Among them, supercritical carbon dioxide fluid extraction (SFE-CO2) is known for its green, clean, and environment-friendly properties. In this paper, the pharmacological activities, the active components, and structures of different parts of ginkgo, the extraction methods of its effective ingredients, and the application of the SFE-CO2 method for the extraction and separation of active ingredients in Ginkgo biloba from leaves, seeds, pollen, and roots were reviewed, in order to make best use of ginkgo resources, and provide support and references for the development of SFE-CO2 of active components from Ginkgo biloba.

Anticancer Effects of Five Biflavonoids from Ginkgo Biloba L. Male Flowers In Vitro.

Ginkgo biloba L., an ancient dioecious gymnosperm, is now cultivated worldwide for landscaping and medical purposes. A novel biflavonoid-amentoflavone 7''-O-ß-D-glucopyranoside (1)-and four known biflavonoids were isolated and identified from the male flowers of Ginkgo. The anti-proliferative activities of five biflavonoids were evaluated on different cancer lines. Bilobetin (3) and isoginkgetin (4) exhibited better anti-proliferative activities on different cancer lines. Their effects were found to be cell-specific and in a dose and time dependent manner for the most sensitive HeLa cells. The significant morphological changes validated their anticancer effects in a dose-dependent manner. They were capable of arresting the G2/M phase of the cell cycle, inducing the apoptosis of HeLa cells dose-dependently and activating the proapoptotic protein Bax and the executor caspase-3. Bilobetin (3) could also inhibit the antiapoptotic protein Bcl-2. These might be the mechanism underlying their anti-proliferation. In short, bilobetin (3) and isoginkgetin (4) might be the early lead compounds for new anticancer agents.

A review on triterpenoid and triterpenoid saponins from Xanthoceras sorbifolium Bung.

Xanthoceras sorbifolium Bunge, also known as Tu-Mu-Gua and Wen-Dan-Ge-Zi, has several applications. Clinical data and experimental studies have shown anti-tumor, anti-inflammatory, anti-bacterial, and anti-oxidant properties of Xanthoceras sorbifolium Bunge that inhibits prostate hyperplasia, lowers blood pressure and lipid level, and treats enuresis and urinary incontinence. It also has neuroprotective effects and can treat Alzheimer's disease and Parkinson's syndrome. The research on the chemical composition and pharmacological effects of Xanthoceras sorbifolium Bunge has been increasing. Triterpenoid and triterpenoid saponins are the main constituents in Xanthoceras sorbifolium Bunge and exhibit biological activities. In this review, we summarized the research progress on triterpenoids and their glycosides in Xanthoceras sorbifolia, including the chemical constituents, pharmacological activities, and biogenic pathways of triterpenoid mother nucleus. The results would provide a reference for further research and development of triterpenoids and their glycosides in Xanthoceras sorbifolia.

Knockdown of microRNA-96-5p resists oxidative stress-induced apoptosis in nucleus pulposus cells.

BACKGROUND: Intervertebral disc degeneration (IVDD) often leads to low back pain, which severely affects people's quality of life. Oxidative stress (OS) can accelerate nucleus pulposus cell (NPCs) senescence and apoptosis. Exploring the mechanism underlying OS-induced apoptosis is of utmost importance to aid in the development of IVDD treatment. METHODS: In the current study, we tested the function of microRNA-96-5p in H2O2-treated NPCs. Apoptosis and mitophagy-related proteins were examined by western blot. Reactive oxygen species (ROS) generation, mitochondrial membrane potential, and apoptosis of NPCs were evaluated by flow cytometry. A luciferase reporter assay was conducted to confirm the interaction between microRNA-96-5p and Forkhead Box Protein O1 (FOXO1). RESULTS: H2O2 treatment enhanced apoptosis in NPCs and upregulated the microRNA-96-5p expression. It was shown that knockdown of microRNA-96-5p attenuated H2O2-induced OS and apoptosis. FOXO1 is a direct target of microRNA-96-5p, and knockdown of microRNA-96-5p enhanced PINK1/Parkin-mediated mitophagy by up-regulating FOXO1. CONCLUSIONS: Collectively, knockdown of microRNA-96-5p enhanced PINK1/Parkin-mediated mitophagy by up-regulating FOXO1. Our results facilitate the understanding of the role of microRNA-96-5p in IVDD and the mechanism of H2O2-induced oxidative damage.

Chelating decorporation agents for internal contamination by actinides: Designs, mechanisms, and advances.

During the wide utilization of the actinides in medicine, energy, military, and other fields, internal contaminations can profoundly endanger human health and public security. Chelating decorporation agents are the most effective therapies to reduce internal contamination that includes radiological and chemical toxicities. This review introduces the structures of chelating decorporation agents including inorganic salts, polyaminocarboxylic acids, peptides, polyphosphonates, siderophores, calixarenes, polyethylenimines, and fullerenes, and highlights ongoing advances in their designs and mechanisms. However, there are still numerous challenges that block their applications including coordination properties, pharmacokinetic properties, oral bioavailability, limited timing of administration, and toxicity. Therefore, additional efforts are needed to push novel decorporation agents with high efficiency and low toxicity for the treatment of internal contamination by actinides.

Orychophragine D:A new 2-piperazinone fused 5-azacytosine type alkaloid with radioprotective activity from the seeds of Orychophragmus violaceus.

A new alkaloid, Orychophragine D (1), together with three known alkaloids, were isolated from the seeds of Orychophragmus violaceus. Orychophragine D represented the first example of 2-piperazinone fused 5-azacytosine skeleton. Their structures and absolute configurations were determined by spectroscopic analyses and X-ray crystallography. Compared to Ex-RAD, compound 1 exhibited a significant radioprotective activity on cell survival of irradiated HUVEC. In vivo experiments showed that 1 not only remarkably enhanced the survival of irradiated mice in 30 days, but also significantly promoted the recovery of the blood system of irradiated mice. These results suggested that 1 was valuable for further research as promising radioprotectors.

Four organosulfur compounds from the seeds of Capsella bursa-pastoris and their anti-inflammatory activities.

Phytochemical investigation of the seeds of Capsella bursa-pastoris led to the isolation of four organosulfur compounds. There were two new compounds, 10-methylsulfinyl-decanamide (1) and 11-methylsulfinyl-undecanamide (2), along with two known compounds (3 - 4), which all have a sulfoxide group and an amide or a nitrile group. Their chemical structures were elucidated by analysing UV, IR, ESI-MS and NMR spectroscopy. In addition, compounds 1 - 4 were evaluated for their anti-inflammatory activities by using LPS-induced RAW 264.7 cells. Compounds 1 - 4 exhibited potential anti-inflammatory activities on NO release characterised by decreasing the mRNA expression levels of inducible NO synthase (iNOS), cytokines cyclooxygenase-2 (COX-2) and interleukin 6 (IL-6).

Discovery of pentacyclic triterpenoid glycosides with anti-proliferative activities from Ardisialindleyana.

One new pentacyclic triterpenoid glycoside, ardisiapunine E (1), along with two known compounds were isolated from the root of Ardisia lindleyana D.Dietr. Their structures were elucidated by 1H and 13C NMR, DEPT, HMBC, HSQC, 1H-1H COSY and NOESY spectroscopic analyses, ESI-MS, and literature. Compounds 1-3 exhibited obvious anti-proliferative activities against the HeLa cell line in a dose- and time-dependent manner by inducing G2/M phase arrest and apoptosis in vitro, both consisting of pentacyclic triterpenes and sugar. Hence, this study identified a new and two known pentacyclic triterpenoid glycosides promoting apoptosis as a potential anti-proliferative agent.

Intriguing roles of reactive intermediates in dissociation chemistry of N-phenylcinnamides.

In mass spectrometry of protonated N-phenylcinnamides, the carbonyl oxygen is the thermodynamically most favorable protonation site and the added proton is initially localized on it. Upon collisional activation, the proton transfers from the carbonyl oxygen to the dissociative protonation site at the amide nitrogen atom or the α-carbon atom, leading to the formation of important reactive intermediates. When the amide nitrogen atom is protonated, the amide bond is facile to rupture to form ion/neutral complex 1, [RC(6)H(4)CH=CHCO(+)/aniline]. Besides the dissociation of the complex, proton transfer reaction from the α-carbon atom to the nitrogen atom within the complex takes place, leading to the formation of protonated aniline. The presence of electron-withdrawing groups favored the proton transfer reaction, whereas electron-donating groups strongly favored the dissociation (aniline loss). When the proton transfers from the carbonyl oxygen to the α-carbon atom, the cleavage of the C(α)-CONHPh bond results in another ion/neutral complex 2, [PhNHCO(+)/RC(6)H(4)CH=CH(2)]. However, in this case, electron-donating groups expedited the proton transfer reaction from the charged to the neutral partner to eliminate phenyl isocyanate. Besides the cleavage of the C(α)-CONHPh bond, intramolecular nucleophilic substitution (a nucleophilic attack of the nitrogen atom at the ß-carbon) and stepwise proton transfer reactions (two 1,2-H shifts) also take place when the α-carbon atom is protonated, resulting in the loss of ketene and RC(6)H(5), respectively. In addition, the H/D exchanges between the external deuterium and the amide hydrogen, vinyl hydrogens and the hydrogens of the phenyl rings were discovered by D-labeling experiments. Density functional theory-based (DFT) calculations were performed to shed light on the mechanisms for these reactions.

Copper-catalyzed domino intramolecular cyclization: a facile and efficient approach to polycyclic indole derivatives.

A mild and efficient Cu(2)O-catalyzed domino intramolecular C-N coupling/C-Y (Y = O, S, N) bond formation was successfully achieved. Thus oxazino[3,2-a]indole, thiazino[3,2-a]indole and indolo[2,1-b]quinazoline derivatives were facilely assembled from readily accessible gem-dibromovinyl systems. The protocol is general and practical, affording a variety of the indole-incorporated products in good to excellent yields even under air atmosphere.

Supercritical CO2 extraction of fermented soybean lipids against erastin-induced ferroptosis in rat pheochromocytoma cells.

The optimum supercritical carbon dioxide (SC-CO2) extraction of fermented soybean lipids (FSE-C) was as follows: 35 °C, 30 MPa, and 2.40 ± 0.19% moisture content using response surface methodology. The fatty acid composition of FSE-C contained more palmitic acid and α-linolenic acid and less linoleic acid than unfermented soybean lipids (SE-C). FSE-C had higher contents of minor active components (phytosterols, squalene, total flavonoid, and total polyphenol) than SE-C. The protective effects of FSE-C on erastin-induced ferroptosis were investigated to reveal the potential mechanisms of action characterized by increasing cell viability and glutathione concentrations, attenuating levels of intracellular Fe2+ ion, lipid peroxidation, and ROS, as well as modifying mRNA expression (GPx4, SLC7A11, ACSL4, and LPCAT3) and lipid metabolism. These findings suggest that FSE-C is a class of active ingredients against erastin-induced ferroptosis and warrants further exploration and utilization as a functional food.

Lipidomics of Serum and Hippocampus Reveal the Protective Effects of Fermented Soybean Lipid on Rats of Microwave-Induced Cognitive Damage.

Fermented soybean lipids (FSE-C) is an extract enriched in active lipid classes. To explore whether FSE-C can alleviate cognitive damage triggered by the exposure to microwave radiation through regulating lipid metabolism, we employed lipidomic profiling based on a UPLC-MS to investigate differential lipid metabolites in the serum and hippocampus of rats. The results showed that orally administered FSE-C could protect from cognitive damage in microwave-induced rats. Serum lipidomics indicated that FSE-C effectively facilitated the recovery of 43 differential lipid metabolites including 6 phosphatidylcholines (PCs), 5 phosphatidylethanolamines (PEs), 1 phosphatidylinositol, 3 lysophosphatidylcholines (LPCs), 6 lysophosphatidylethanolamines (LPEs), and 22 triglycerides (TGs), which was consistent with the analysis of serum TG levels. Moreover, FSE-C positively coordinated hexacosanoic acid, 2 PCs, 4 sphingomyelins (SMs), and 11 TGs, through the hippocampal lipidomics. Collectively, these findings suggested that phospholipid and TG metabolisms were significantly modified in microwave-exposed rats. TGs may be regarded as potential biomarkers to further investigate and evaluate the roles and functions of FSE-C on the attenuation of cognitive damage induced by microwave radiation.

The relationship between microwave radiation injury and abnormal lipid metabolism.

Microwave radiation can lead to some biological effects, mainly involving the nervous and reproductive systems. However, its lipid metabolic mechanism remains unclear. Here, we performed an untargeted metabolomics approach to analyze lipid metabolic changes caused by microwave radiation using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Then, multivariate analysis was used to reveal the different lipid metabolites and metabolic pathways. Compared with the sham group, biochemical parameters of the microwave group had significant changes in triglyceride (TG) and high-density lipoprotein (HDL) levels. Sixty-eight abnormal lipids were identified, which were mainly distributed in linoleic acid metabolism, glycerophospholipid metabolism, glycerolipid metabolism and glycosylphosphatidylinositol (GPI)-anchor biosynthesis. Among them, phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC) and linoleic acid showed mainly upregulated expression, while sphingomyelin (SM), cholesterol esters (CE) and some free fatty acids (FFAs) showed downregulated expression. Phosphatidylcholine (PC) and triacylglycerol (TG) were increased or decreased. Furthermore, we obtained significant links between lipid metabolic changes and cognitive damage caused by microwave radiation. Together, our results suggested that microwave radiation could cause changes in lipid metabolism and provided a novel insight into the role of lipids in microwave radiation. Targeting lipid metabolism may provide a new therapeutic strategy for microwave radiation injury.

Orychophragines A-C, Three Biologically Active Alkaloids from Orychophragmus violaceus.

Orychophragines A-C (1-3), three new alkaloids with an novel 2-piperazinone-fused 2,4-dioxohexahydro-1,3,5-triazine skeleton, were isolated from the seeds of Orychophragmus violaceus. Their structures were established on the basis of spectroscopic analysis and X-ray crystallographic analysis. Orychophragines A (1) exhibited remarkable cytotoxicity against HepG2, A549, Hela, and HCT-116 cells with IC50 values of 7.73, 10.79, 11.91, and 9.93 µM, respectively. Orychophragines C (3) showed moderate 60Co γ radiation protection activity in HUVEC cells. A plausible biosynthetic pathway for 1-3 was proposed.

Anti-inflammatory and Anti-oxidative Activities of Paeonol and Its Metabolites Through Blocking MAPK/ERK/p38 Signaling Pathway.

The possible protective and curative effects of paeonol on carrageenan-induced acute hind paw edema in rats and dextran sulfate sodium (DSS)-induced colitis in mice have been evaluated. After oral administration, paeonol (20 and 40 mg/kg) reduced the edema increase in paw volumes and also the development of DSS-induced murine colitis. Furthermore, anti-inflammatory and anti-oxidant activities of paeonol (1) together with its 10 metabolites (M2~M11) were investigated by using in vitro anti-inflammatory and anti-oxidant assays. M3 and M11 exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities (with EC50 values of 93.44 and 23.24 µM, respectively). All the metabolites except M8 showed hydroxyl radical scavenging activities, and M3 and M11 were the most potent agents (with EC50 values of 336.02 and 124.05 µM, respectively). Inhibitory effects of paeonol, M2~M11 on the overproduction of nitric oxide (NO), and the release of TNF-α were also tested. M3 and M11 potently inhibited lipopolysaccharide (LPS)-induced overproduction of NO in macrophage RAW 264.7. Western blot results demonstrated that paeonol, M3, and M11 downregulated the high expression of inducible nitric oxide synthase (iNOS) and COX-2 proteins, and the effects of M3 and M11 were more potent when compared with paeonol. These findings indicated that paeonol may play anti-inflammatory and anti-oxidant roles by changing to its active metabolites after absorption. In addition, further investigations on the mechanism showed that paeonol, M3, and M11 blocked the phosphorylation of MAPK/ERK 1/2 and p38, whereas they showed no effect on the phosphorylation of JNK. The above results suggested that pre-treatment with paeonol might be an effective therapeutic intervention against inflammatory diseases including colitis.