Curcumin Inhibits Lysophosphatidic Acid Mediated MCP-1 Expression via Blocking ROCK Signalling

Curcumin is a natural compound that has been widely used as a food additive and medicine in Asian countries. Over several decades, diverse biological effects of curcumin have been elucidated, such as anti-inflammatory and anti-oxidative activities. Monocyte chemoattractant protein-1 (MCP-1) is a key inflammatory marker during the development of atherosclerosis, and curcumin blocks MCP-1 expression stimulated by various ligands. Hence, we studied the action of curcumin on lysophosphatidic acid (LPA) mediated MCP-1 expression and explored the specific underlying mechanisms. In human vascular smooth muscle cells, LPA induces Rho-associated protein kinase (ROCK) dependent transforming growth factor receptor (TGFBR1) transactivation, leading to glycosaminoglycan chain elongation. We found that LPA also signals via the TGFBR1 transactivation pathway to regulate MCP-1 expression. Curcumin blocks LPA mediated TGFBR1 transactivation and subsequent MCP-1 expression by blocking the ROCK signalling. In the vasculature, ROCK signalling regulates smooth muscle cell contraction, inflammatory cell recruitment, endothelial dysfunction and vascular remodelling. Therefore, curcumin as a ROCK signalling inhibitor has the potential to prevent atherogenesis via multiple ways.     

Glycyrrhizic Acid Inhibits SARS-CoV-2 Infection by Blocking Spike Protein-Mediated Cell Attachment

Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of Glycyrrhiza species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.     

Interaction Between Ginkgolic Acid and Human Serum Albumin by Spectroscopy and Molecular Modeling Methods

The interaction of ginkgolic acid (15:1, GA) with human serum albumin (HSA) was investigated by FT–IR, CD and fluorescence spectroscopic methods as well as molecular modeling. FT–IR and CD spectroscopic showed that complexation with the drug alters the protein’s conformation by a major reduction of α-helix from 54 % (free HSA) to 46–31 % (drug–complex), inducing a partial protein destabilization. Fluorescence emission spectra demonstrated that the fluorescence quenching of HSA by GA was by a static quenching process with binding constants on the order of 10⁵ L·mol^?1. The thermodynamic parameters (ΔH = ?28.26 kJ·mol^?1, ΔS = 11.55 J·mol^?1·K^?1) indicate that hydrophobic forces play a leading role in the formation of the GA–HSA complex. The ratio of GA and HSA in the complex is 1:1 and the binding distance between them was calculated as 2.2 nm based on the Förster theory, which indicates that the energy transfer from the tryptophan residue in HSA to GA occurs with high probability. On the other hand, molecular docking studies reveal that GA binds to Site II of HSA (sub-domain IIIA), and it also shows that several amino acids participate in drug–protein complexation, which is stabilized by H-bonding.     

铝热还原法制备铝-稀土中间合金的研究

以混合稀土碳酸盐为原料,Al为还原剂,还原时间为2 h,在温度范围为1000～1200℃的冰晶石熔体中,分别制备了RE含量为2.11%～9.75%(质量分数)的Al-RE中间合金.研究发现,Al-RE合金中的RE含量与温度的关系可近似用公式y=-0.74673-0.02813X 3.07273×10-5X2描述;合金中存在着La,Ce,Pr,Nd和Pm等稀土元素.分析了还原温度对合金中稀土含量的影响,分析了[RE2O3]的活度、[Al2O3]的活度、Al-RE合金中的[RE]的活度及[Al]的活度对反应的影响;讨论了Al-RE中间合金形成的热力学及动力学条件,对Al-RE中间合金的形成机制进行了探讨.     

荧光分析法测定银杏酚酸

根据银杏酚酸在紫外光激发下能产生荧光的性质，建立了检测银杏酚酸的荧光分光光度法。以80％乙醇80℃回流8h提取银杏外种皮，提取液经硅胶柱层析后得酚酸样品。以白果酸为标样，激发波长345nm、发射波长420nm测定银杏酚酸。线性回归方程为，y=2．5024x＋0．4152；线性范围为0．50～100mg／L，相关系数r=0．9922，相对标准偏差2．6％；检出限0．11mg／L。     

荧光分析法测定银杏酚酸

根据银杏酚酸在紫外光激发下能产生荧光的性质,建立了检测银杏酚酸的荧光分光光度法.以80%乙醇80℃回流8 h提取银杏外种皮,提取液经硅胶柱层析后得酚酸样品.以白果酸为标样,激发波长345 nm、发射波长420 nm测定银杏酚酸.线性回归方程为y=2.5024x+0.4152;线性范围为0.50～100 mg/L,相关系数r=0.9922,相对标准偏差2.6%;检出限0.11 mg/L.     

Activation of the Surface of Polymetallic Carriers by the Formation of Intermediate Intermetallic Phases

A method for the conversion of a surface layer of monolithic polymetallic carriers into highly active catalytic phases with a high specific surface area, which contain nanosized formations, was developed. An intermetallide layer was formed in the course of the high-temperature aluminum coating of the carrier surface; this layer was transformed into an active form by leaching and stabilization. A method was proposed for the enrichment of the aluminized layer in alloy additives. The microstructure of the intermetallide layer and the distribution of elements in it were studied with the use of chrome-nickel stainless steel gauze as an example. The physicochemical characteristics of the active phase were examined using a BET method, scanning electron microscopy, and X-ray diffraction analysis. The catalytic properties of the samples were studied in the processes of the deep oxidation of CO and propane and the hydrogenation of CO₂.     

Inhibitory Effect of Lithospermic Acid on the HIV-1 Nucleocapsid Protein

The HIV-1 nucleocapsid protein (NC) is a desirable target in antiretroviral therapy due to its high conservation among HIV-1 strains, and to its multiple and crucial roles in the HIV-1 replication cycle. Natural products represent a valuable source of NC inhibitors, with the catechol group being a privileged scaffold in NC inhibition. By coupling molecular modeling with NMR spectroscopy and fluorescence-based assays, we disclosed lithospermic acid, a catechol derivative extracted from Salvia miltiorrhizza, as a potent and chemically stable non-covalent inhibitor of the NC. Being different from other catechol derivative reported so far, lithospermic acid does not undergo spontaneous oxidation in physiological conditions, thus becoming a profitable starting point for the development of efficient NC inhibitors.     

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis

Novel therapeutic strategies for ovarian cancer treatment are in critical need due to the chemoresistance and adverse side effects of platinum-based chemotherapy. Theasaponin E₁ (TSE1) is an oleanane-type saponin from Camellia sinensis seeds. Its apoptosis-inducing, cell cycle arresting and antiangiogenesis activities against platinum-resistant ovarian cancer cells were elucidated in vitro and using the chicken chorioallantoic membrane (CAM) assay. The results showed that TSE1 had more potent cell growth inhibitory effects on ovarian cancer OVCAR-3 and A2780/CP70 cells than cisplatin and was lower in cytotoxicity to normal ovarian IOSE-364 cells. TSE1 significantly induced OVCAR-3 cell apoptosis via the intrinsic and extrinsic apoptotic pathways, slightly arresting cell cycle at the G2/M phase, and obviously inhibited OVCAR-3 cell migration and angiogenesis with reducing the protein secretion and expression of vascular endothelial growth factor (VEGF). Western bolt assay showed that Serine/threonine Kinase (Akt) signaling related proteins including Ataxia telangiectasia mutated kinase (ATM), Phosphatase and tensin homolog (PTEN), Akt, Mammalian target of rapamycin (mTOR), Ribosome S6 protein kinase (p70S6K) and e IF4E-binding protein 1(4E-BP1) were regulated, and Hypoxia inducible factor-1α (HIF-1α) protein expression was decreased by TSE1 in OVCAR-3 cells. Moreover, TSE1 treatment potently downregulated protein expression of the Notch ligands including Delta-like protein 4 (Dll4) and Jagged1, and reduced the protein level of the intracellular domain (NICD) of Notch1. Combination treatment of TSE1 with the Notch1 signaling inhibitor tert-butyl (2S)-2-[[(2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoyl]amino]-2-phenylacetate (DAPT), or the Akt signaling inhibitor wortmannin, showed a stronger inhibition toward HIF-1α activation compared with single compound treatment. Taken together, TSE1 might be a potential candidate compound for improving platinum-resistant ovarian cancer treatment via Dll4/Jagged1-Notch1-Akt-HIF-1α axis.     

Functionalized Hydroperoxide Formation from the Reaction of Methacrolein-Oxide,an Isoprene-Derived Criegee Intermediate,with Formic Acid: Experiment and Theory

Methacrolein oxide (MACR-oxide) is a four-carbon, resonance-stabilized Criegee intermediate produced from isoprene ozonolysis, yet its reactivity is not well understood. This study identifies the functionalized hydroperoxide species, 1-hydroperoxy-2-methylallyl formate (HPMAF), generated from the reaction of MACR-oxide with formic acid using multiplexed photoionization mass spectrometry (MPIMS, 298 K = 25 °C, 10 torr = 13.3 hPa). Electronic structure calculations indicate the reaction proceeds via an energetically favorable 1,4-addition mechanism. The formation of HPMAF is observed by the rapid appearance of a fragment ion at m/z 99, consistent with the proposed mechanism and characteristic loss of HO₂ upon photoionization of functional hydroperoxides. The identification of HPMAF is confirmed by comparison of the appearance energy of the fragment ion with theoretical predictions of its photoionization threshold. The results are compared to analogous studies on the reaction of formic acid with methyl vinyl ketone oxide (MVK-oxide), the other four-carbon Criegee intermediate in isoprene ozonolysis.     

Formation of Methylphosphonous Acid by Alkylation of Yellow Phosphorus

Methylphosphonous acid is a key intermediate in the synthesis of phosphinic acid salts, a new class of halogen-free flame retardants. This paper describes a novel and simple synthesis of this synthon: By alkylation of elemental yellow phosphorus with methyl chloride under phase-transfer conditions, methylphosphonous acid alkali salt is formed as the main product. Most of the by-products were identified. The mechanism of the reaction is discussed.     

A Protein from Aloe vera that Inhibits the Cleavage of Human Fibrin(ogen) by Plasmin

A protease inhibitor protein with the molecular mass of 11,804.931 Da (analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) was isolated from Aloe vera leaf gel and designated as AVPI-12. The isoelectric point of the protein is about 7.43. The first ten amino acid sequence from the N-terminal was found to be R–D–W–A–E–P–N–D–G–Y, which did not match other protease inhibitors in database searches and other publications, indicating AVPI-12 is a novel protease inhibitor. The band protein of AVPI-12 migrated further on nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) than reducing SDS-PAGE. This result indicated that the molecule of AVPI-12 did not contain interchain disulfide bonds, but appeared to have intrachain disulfide bonds instead. AVPI-12 strongly resisted digestion by the serine proteases human plasmin and bovine trypsin. The protein could protect the γ-subunit of human fibrinogen from plasmin and trypsin digestion, similar to the natural plasma serine protease inhibitor α₂-macroglobulin. The protein also could protect the γ-subunit of fibrinogen from the cysteine protease papain. AVPI-12 also exhibited dose-dependent inhibition of the fibrinogenolytic activity of plasmin, similar to α₂-macroglobulin. The fibrinolytic inhibitory activity of AVPI-12 and the small-angle X-ray scattering showed that the protein could protect human fibrin clot from complete degradation by plasmin. The inhibition of the fibrinogenolytic and fibrinolytic activities of plasmin by AVPI-12 suggests that the inhibitor has potential for use in antifibrinolytic treatment.     

溶解态菲及其中间代谢产物1-羟基-2-萘甲酸的同时测定

运用导数-同步荧光光谱建立了快速同时测定溶解态菲(Phenanthrene,Phe)及其中间代谢产物1-羟基-2-萘甲酸(1-Hydroxy-2-naphthoic acid,1H2NA)的分析方法。所建方法同时测定Phe与1H2NA的线性范围分别为4.0~1.0×103μg/L和4.0~1.2×103μg/L,检出限分别为0.08μg/L和0.07μg/L,加标回收率分别为96.5%~105.3%和99.2%~106.5%,相对标准偏差均小于1.0%。该方法可应用于实验室条件下溶解态Phe微生物降解过程中Phe和1H2NA的测定,具备原位研究Phe降解过程中间代谢产物1H2NA的应用潜力。     

5,2′-Dibromo-2,4′,5′-trihydroxydiphenylmethanone Inhibits LPS-Induced Vascular Inflammation by Targeting the Cav1 Protein

Vascular inflammation is directly responsible for atherosclerosis. 5,2′-Dibromo-2,4′,5′-trihydroxydiphenylmethanone (TDD), a synthetic bromophenol derivative, exhibits anti-atherosclerosis and anti-inflammatory effects. However, the underlying pathways are not yet clear. In this study, we first examined the effects of TDD on toll-like receptor-4 (TLR4) activity, the signaling receptor for lipopolysaccharide (LPS), and found that TDD does not inhibit LPS-induced TLR4 expression in EA.hy926 cells and the vascular wall in vivo. Next, we investigated the global protein alterations and the mechanisms underlying the action of TDD in LPS-treated EA.hy926 cells using an isobaric tag for the relative and absolute quantification technique. Western blot analysis revealed that TDD inhibited NF-κB activation by regulating the phosphorylation and subsequent degradation IκBα. Among the differentially expressed proteins, TDD concentration-dependently inhibited Caveolin 1(Cav1) expression. The interaction between Cav1 and TDD was determined by using biolayer interference assay, UV-vis absorption spectra, fluorescence spectrum, and molecular docking. We found that TDD can directly bind to Cav1 through hydrogen bonds and van der Waals forces. In conclusion, our results showed that TDD inhibited LPS-induced vascular inflammation and the NF-κB signaling pathway by specifically targeting the Cav1 protein. TDD may be a novel anti-inflammatory compound, especially for the treatment of atherosclerosis.     

Chemistry of 1-Alkoxy-1-glycosyl Radicals: Formation of beta-Mannopyranosides by Radical Decarboxylation and Decarbonylation of manno-Heptulosonic Acid Glycoside Derivatives

A method for the preparation of highly enriched beta-mannopyranosides is described. A glycosyl donor 28 is prepared from tetraallyl mannonolactone by standard means and coupled to a number of primary carbohydrate alcohols, resulting in the isolation in excellent yields of axial disaccharides. Following exchange of the allyl groups for acetyl esters, the furan is oxidatively cleaved with catalytic RuO(2) and NaIO(4) and the resulting acid subjected to the Barton decarboxylation. Coupling of 28 to a secondary alcohol, methyl 2,3-isopropylidene-alpha-L-rhamnopyranoside, resulted in an apparent inversion of anomeric stereochemistry and isolation of an equatorial disaccharide.