- Anti-BACE1 and anti-AchE activities of undescribed spiro-dioxolane-containing meroterpenoids from the endophytic fungus Aspergillus terreus Thom. [Journal Article]
- PPhytochemistry 2019 Jun 13; 165:112041
- Spiroterreusnoids A-F, six undescribed spiro-dioxolane-containing adducts bearing 3,5-dimethylorsellinic acid-based meroterpenoid and 2,3-butanediol moieties were isolated from the endophytic fungus …
Spiroterreusnoids A-F, six undescribed spiro-dioxolane-containing adducts bearing 3,5-dimethylorsellinic acid-based meroterpenoid and 2,3-butanediol moieties were isolated from the endophytic fungus Aspergillus terreus Thom from Tripterygium wilfordii Hook. f. (Celastraceae). The structures of these adducts were established by spectroscopy, single-crystal X-ray diffraction, and experimental electronic circular dichroism (ECD) measurements. Spiroterreusnoids A-F represent the first examples of adducts composed of 3,5-dimethylorsellinic acid-based meroterpenoids. It is noteworthy that spiroterreusnoids A-F possessing a spiro-dioxolane moiety exhibited potential abilities in inhibiting BACE1 (IC50 values ranging from 5.86 to 27.16 μM) and AchE (IC50 values ranging from 22.18 to 32.51 μM), while the other analogues without this fragment displayed no such activities. Taken together, spiroterreusnoids A-F represent the first multitargeted natural adducts that could inhibit BACE1 and AchE, and might provide a new template for the development of new anti-Alzheimer's disease drugs.
- Structure-Guided Generation of a Redox-Independent Blue Fluorescent Protein from mBFP. [Journal Article]
- JMJ Mol Biol 2019 Jun 13
- Fluorescent proteins, such as the green fluorescent protein (GFP), are used for detection of cellular components and events. However, GFP and its derivatives have limited usage under anaerobic condit…
Fluorescent proteins, such as the green fluorescent protein (GFP), are used for detection of cellular components and events. However, GFP and its derivatives have limited usage under anaerobic conditions and require a long maturation time. On the other hand, the NADPH-dependent blue fluorescent protein (BFP) without oxidative modification of residues is instantly functional in both aerobic and anaerobic systems. BFP proteins belong to a short-chain dehydrogenase/reductase (SDR) protein family, and their fluorescent property changes with reaction time in the presence of a substrate. With the aim of developing a better fluorescent reporter independent of redox state, we elucidated the crystal structure of a tetrameric mBFP from soil metagenomes with and without NADPH. Apart from the previously known regions, structure-guided mutational studies have identified several residues that contribute to the fluorescence of mBFP, including two aromatic residues (F97 and Y157) near the nicotinamide moiety of the bound NADPH. A single histidine mutation at Y157 (Y157H) has conferred more stabilized, time-independent fluorescence even in the presence of substrates. Furthermore, we discovered another SDR protein that can also emit blue fluorescence. These results open a new possibility for the development of BFP as a stable cellular reporter for widespread use, independent of subcellular environments.
- Neurostatin and other O-acetylated gangliosides show anti-neuroinflammatory activity involving the NFκB pathway. [Journal Article]
- TAToxicol Appl Pharmacol 2019 Jun 13; :114627
- In many neuropathologies activated microglia and macrophages cause neurotoxicity and prolong the inflammatory response. We have previously characterized the glycosphingolipid Neurostatin (Nst), which…
In many neuropathologies activated microglia and macrophages cause neurotoxicity and prolong the inflammatory response. We have previously characterized the glycosphingolipid Neurostatin (Nst), which potentially reduces these detrimental mechanisms. Nst, isolated from mammalian brain, is the GD1b ganglioside with O-acetylation of the outer sialic acid residue. Using the enzyme sialate-O-acetyltransferase (SOAT), we obtained several O-acetylated gangliosides and O-propionylated GD1b (PrGD1b). In the present study we investigated the anti-inflammatory effects of these compounds. Nst and other O-acetylated gangliosides reduced nitrite production in microglial cells which were activated with lipopolysaccharide (LPS), but did not affect nitrite production after their stimulation with interferon gamma (IFNγ). Structure-activity relationship analysis showed that Nst was the most active ganglioside as inhibitor of nitrite production. Its ceramide moiety is essential for this, and both, the O-acetylation and the monosaccharide chain are important for the anti-inflammatory activity of the gangliosides. We also found that Nst reduced iNOS, IL-6 and IL-12 transcription in LPS-induced microglia, likely by inhibiting nuclear localization of NFκB. In co-cultures, Nst reduced neuronal cell death caused by LPS-activated microglia. In vivo, Nst diminished microglia activation in a mouse model of acute neuroinflammation. We propose that Nst and other O-acetylated gangliosides are neuroprotective regulators of microglia activity under both physiological and pathological conditions.
- A structure optimized fluorescent probe for highly sensitive monitoring drug induced lysosomal pH value changes. [Journal Article]
- TTalanta 2019 Oct 01; 203:1-8
- Lysosomes generally maintain the weak acidic microenvironment, to ensure highly efficient activity and functions of hydrolytic enzymes and proteins. Aberrations of the lysosomal pH may result in cell…
Lysosomes generally maintain the weak acidic microenvironment, to ensure highly efficient activity and functions of hydrolytic enzymes and proteins. Aberrations of the lysosomal pH may result in cellular functional changes and influence human physiology, possibly causing serious diseases. Small-molecular fluorescent probes based imaging techniques capable of providing information on target locations are considerably appreciated. Herein, by reducing the size of the typical lysosome targetable group 4-(2-aminoethyl) morpholine, we rationally designed a rhodamine analogue probe Ly-HN2AM with N-Aminomorpholine as the ring-closed switch and the lysosome targetable moiety for visualizing lysosomal pH changes. With the benefit of constructing multi-pentacyclic intramolecular hydrogen bond when binding with the H+, Ly-HN2AM gives a highly sensitive response towards pH values ranging from 4.79 to 6.07, with a remarkable higher pKa 5.35 over the typical 4-(2-aminoethyl) morpholine modified probes. The new probe was successfully applied to visualize pH value changes in lysosome-associated physiological and pathological processes with excellent photostability and low cytotoxicity, indicating the potential applications of lysosome specific bioimaging.
- Structural elucidation of the ellagitannin with a molecular weight of 2038 isolated from strawberry fruit (Fragaria ananassa Duch.) and named fragariin A. [Journal Article]
- FCFood Chem 2019 Oct 30; 296:109-115
- The structure of the ellagitannin (ET) with a molecular weight (MW) of 2038 isolated from strawberry fruit was elucidated on the basis of mass spectrometry data and nuclear magnetic resonance studies…
The structure of the ellagitannin (ET) with a molecular weight (MW) of 2038 isolated from strawberry fruit was elucidated on the basis of mass spectrometry data and nuclear magnetic resonance studies, with the newly determined compound being named fragariin A. Similarly to the main strawberry ET, agrimoniin (MW 1870), fragariin A was shown to contain a bis-HHDP-glucose moiety (MW 784). It exhibited the same three fragmentation ions with m/z 1567, 1265 and 633, arising from the detachment of consecutive hexahydroxydiphenoyl (HHDP) units from the structure with MW 1870. Based on spectroscopic studies, it was found that, in the tested ET (MW 2038), a free gallic acid is connected by a DOG-type bond to the 4,6-HHDP unit of the second glucose moiety of agrimoniin.
- White light emitting lanthanide based carbon quantum dots as toxic Cr (VI) and pH sensor. [Journal Article]
- JCJ Colloid Interface Sci 2019 Jun 04; 553:177-185
- Although, great attention is paid to synthesize fluorescent carbon quantum dots (CQDs) for versatile applications, the field remains still attractive to achieve white light using these nano materials…
Although, great attention is paid to synthesize fluorescent carbon quantum dots (CQDs) for versatile applications, the field remains still attractive to achieve white light using these nano materials. In the present work, CQDs are synthesized from citric acid and lanthanide ions viz. Europium (Eu) and Terbium (Tb) are doped in CQD moiety to explore superior optical response for multifunctional applications. By proper tuning of excitation wavelength, perfect white light with Commission Internationale de l'Elcairage (CIE) index (0.345, 0.344) is obtained using these Europium Terbium co-doped CQDs (Eu-Tb-CQD). The observed photoluminescence of white light emitting lanthanide based CQD is pH dependent and will be used as a visual pH sensor. These luminescent Eu and Tb co-doped CQDs are also very useful to detect toxic Cr (VI) with excellent selectivity and sensitivity as compared to pure CQDs. It shows high quenching efficiency (∼95%) in presence of only 160 µM Cr(VI). The selectivity and lower detection limit are also obtained as ∼80% and 0.175 µM respectively.
- Oligostilbenes from the leaves of Gnetum latifolium and their biological potential to inhibit neuroinflammation. [Journal Article]
- PPhytochemistry 2019 Jun 12; 165:112044
- Oligostilbenes are polyphenol oligomers derived from resveratrol and are commonly produced by members of the Gnetaceae family, and many researchers have focused on their anti-inflammatory activities.…
Oligostilbenes are polyphenol oligomers derived from resveratrol and are commonly produced by members of the Gnetaceae family, and many researchers have focused on their anti-inflammatory activities. The EtOAc fraction of a Gnetum latifolium extract showed inhibitory activity against neuroinflammation induced by the transfection of Aβ1-42 into microglial BV-2 cells. The bioassay-guided isolation of the 70% EtOH extract of this plant resulted in three previously undescribed resveratrol oligostilbenes and ten known stilbene derivatives. The structures of the isolated compounds were established based on extensive NMR spectroscopic analysis. The absolute configurations of the three undescribed compounds were confirmed by comparison with available compounds with known stereochemistry and by ECD calculations and molecular modelling. Latifoliols A and B are the first reported oligostilbenes with a bridged 3-oxabicyclo[3.3.0]octane moiety, and latifoliol C was formed by the condensation of gnemontanin G with oxyresveratrol. Moreover, the hypothetical biogenetic pathway of latifoliols A, B and C was proposed. The potential anti-inflammatory activities of the thirteen isolated compounds were tested by measuring their effect on the secreted NO concentrations induced by transfection with plasmids expressing the Aβ1-42 gene in the BV-2 cell line. Interestingly, cis- and trans-shegansu B and latifolol, whose structures contained double bonds, strongly inhibited NO secretion in BV-2 cells, supporting the double binding effect of the stilbene derivative on inhibitory activity.
- DNA-binding and in vitro cytotoxic activity of platinum(II) complexes of curcumin and caffeine. [Journal Article]
- JIJ Inorg Biochem 2019 Jun 07; 198:110749
- Three Pt(II) complexes containing the natural ligands curcumin and caffeine, namely [Pt(curc)(PPh3)2]Cl (1), [PtCl(curc)(DMSO)] (2) (curc = deprotonated curcumin) and trans-[Pt(caffeine)Cl2(DMSO)] (3…
Three Pt(II) complexes containing the natural ligands curcumin and caffeine, namely [Pt(curc)(PPh3)2]Cl (1), [PtCl(curc)(DMSO)] (2) (curc = deprotonated curcumin) and trans-[Pt(caffeine)Cl2(DMSO)] (3), were synthesized and fully characterized. The data obtained suggest that, for both 1 and 2, the anion of curcumin is coordinated to the platinum ion via the oxygen atoms of the β-diketonate moiety. Spectroscopic features reveal that in 2 and 3, a DMSO molecule is S-bonded to the metal centre. For 3, all data indicate a square-planar geometry formed by a 9-N bonded caffeine, two trans chloride anions and a DMSO. The three complexes undergo changes in solution upon incubation for 24 h; 1 and 2 release curcumin while 3 isomerizes from trans to cis configuration. The DNA-binding and cytotoxic properties of 1-3 were evaluated in vitro. Despite their structural similarity, curcuminate-containing 1 and 2 exhibit distinct DNA interactions. While 1 appears to intercalate between nucleobase pairs, inducing the oxidative degradation of the biomolecule, 2 behaves as a groove binder, by means of electrostatic forces. Caffeine-containing 3 exhibits a behaviour that is comparable to that of 2. Complexes 1 and 2 showed moderate to high cytotoxicity and selectivity against several cancer cell lines, while 3 is inactive. Compounds 1 and 2 can be further activated by visible-light irradiation.
- Discovery of novel (+)-Usnic acid derivatives as potential anti-leukemia agents with pan-Pim kinases inhibitory activity. [Journal Article]
- BCBioorg Chem 2019 May 02; 89:102971
- Usnic acid (UA) is the main secondary metabolite isolated from lichens, with moderate anticancer activity. A small group of (+)-UA derivatives characterized with flavanone moiety was designed and syn…
Usnic acid (UA) is the main secondary metabolite isolated from lichens, with moderate anticancer activity. A small group of (+)-UA derivatives characterized with flavanone moiety was designed and synthesized, and their anticancer activities were evaluated in leukemia cells. It was demonstrated that (+)-UA derivatives 6a-6g inhibited the proliferation of leukemia cells HL-60 and K562 with low micromolar IC50 values. Mechanisms of action were investigated to find that 6g induced apoptosis in HL-60 and K562 cell lines, and affected the expression of MNK/eIF4E axis-related proteins, such as Mcl-1, p-eIF4E, p-4E-BP1. Finally, kinase inhibition assay suggested 6g was a potential inhibitor of pan-Pim kinases. Meanwhile, the blocking of phosphorylation of BAD and 4E-BP1 by 6g, together with the proposed binding mode of 6g with Pim-1 further confirmed its Pim inhibition effects. Our finding provides the sight towards the potential mechanism of (+)-UA derivatives 6g as anti-leukemia agents.
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- Bis(1,3-dithiol-2-ylidene)-substituted Subtriazachlorin: A Subphthalocyanine Analogue with Unique Redox Properties. [Journal Article]
- ACAngew Chem Int Ed Engl 2019 Jun 14
- Bis(1,3-dithiol-2-ylidene)-substituted subtriazachlorin was formed due to an unusual deformation of 1,3-dithiole-2-one-fused subphthalocyanine in a regular triethylphosphite-mediated tetrathiafulvale…
Bis(1,3-dithiol-2-ylidene)-substituted subtriazachlorin was formed due to an unusual deformation of 1,3-dithiole-2-one-fused subphthalocyanine in a regular triethylphosphite-mediated tetrathiafulvalene synthesis. In this novel molecule, bis(1,3-dithiol-2-ylidene)ethane moiety and subtriazachlorin structures are mutually merged to emerge electron-donating ability and broad absorption in the near-infrared region.