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1.
Proc Natl Acad Sci U S A ; 121(21): e2309905121, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38753505

ABSTRACT

Interest in logics with some notion of real-valued truths has existed since at least Boole and has been increasing in AI due to the emergence of neuro-symbolic approaches, though often their logical inference capabilities are characterized only qualitatively. We provide foundations for establishing the correctness and power of such systems. We introduce a rich class of multidimensional sentences, with a sound and complete axiomatization that can be parameterized to cover many real-valued logics, including all the common fuzzy logics, and extend these to weighted versions, and to the case where the truth values are probabilities. Our multidimensional sentences form a very rich class. Each of our multidimensional sentences describes a set of possible truth values for a collection of formulas of the real-valued logic, including which combinations of truth values are possible. Our completeness result is strong, in the sense that it allows us to derive exactly what information can be inferred about the combinations of truth values of a collection of formulas given information about the combinations of truth values of a finite number of other collections of formulas. We give a decision procedure based on linear programming for deciding, for certain real-valued logics and under certain natural assumptions, whether a set of our sentences logically implies another of our sentences. The generality of this work, compared to many previous works on special cases, may provide insights for both existing and new real-valued logics whose inference properties have never been characterized. This work may also provide insights into the reasoning capabilities of deep learning models.

2.
Mol Cell ; 68(3): 566-580.e10, 2017 Nov 02.
Article in English | MEDLINE | ID: mdl-29056325

ABSTRACT

The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2, which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P2 levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P2 in the phenotype caused by loss-of-function mutations or deletions in PTEN.


Subject(s)
Breast Neoplasms/enzymology , Class I Phosphatidylinositol 3-Kinases/metabolism , PTEN Phosphohydrolase/metabolism , Phosphatidylinositols/metabolism , Prostatic Neoplasms/enzymology , Second Messenger Systems , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Epidermal Growth Factor/pharmacology , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Humans , Male , Mice, Inbred C57BL , Mice, Knockout , Mutation , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , Phenotype , Phosphoric Monoester Hydrolases/genetics , Phosphoric Monoester Hydrolases/metabolism , Phosphorylation , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Second Messenger Systems/drug effects , Time Factors
3.
Exp Parasitol ; 266: 108844, 2024 Nov.
Article in English | MEDLINE | ID: mdl-39374896

ABSTRACT

Ten compounds, six extracts and five fractions obtained from three Nigerian plants were assayed for their in vitro antitrypanosomal and antileishmanial activities. Each plant was extacted with hexane, ethyl acetate, and methanol. Isolated compounds were characterized and identified based on their NMR chemical shifts and comparison to literature reports. The crude extracts, fractions and isolated compounds were tested against the kinetoplastid parasites: bloodstream forms of Trypanosoma brucei Lister 427WT and the derived multi-drug resistant clone B48, and promastigote forms of Leishmania mexicana cas9/T7 and the derived clone cas9ΔNT1. Column chromatography of the extracts using silica gel yielded ten compounds identified as curzerenone, epi-curzerenone, chloranthene F, isofuranodienone, 8(17)-12E-labdadiene-15, 16-dial and 15-hydroxy-8(17),12E-labdadiene-16-al from Siphonochilus aetiopicus, lupeol, linalolic acid and spinasterone from Calliandra portoricensis, and abruquinone B from Abrus precatorius. The assay results showed that the Siphonochilus aetiopicus and Calliandra portoricensis crude extracts, fractions and compounds displayed moderate activity against the Trypanosoma brucei but showed less activity against Leishmania mexicana. Abrus precatorius crude extract, fraction, and isolated compound exhibited only weak trypanocidal and leishmanicidal activities against both kinetoplastid parasites tested. These findings have provided evidence for the use of Siphonochilus aetiopicus and Calliandra portoricensis in traditional medicine relating to parasitic diseases.


Subject(s)
Leishmania mexicana , Plant Extracts , Trypanocidal Agents , Trypanosoma brucei brucei , Trypanosoma brucei brucei/drug effects , Plant Extracts/pharmacology , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Nigeria , Leishmania mexicana/drug effects , Trypanocidal Agents/pharmacology , Trypanocidal Agents/isolation & purification , Trypanocidal Agents/chemistry , Animals , Pentacyclic Triterpenes/pharmacology , Pentacyclic Triterpenes/isolation & purification , Pentacyclic Triterpenes/chemistry , Inhibitory Concentration 50 , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/isolation & purification , Antiprotozoal Agents/chemistry , Mice , Plants, Medicinal/chemistry , Lupanes
4.
Exp Parasitol ; 263-264: 108807, 2024.
Article in English | MEDLINE | ID: mdl-39043327

ABSTRACT

African trypanosomiasis and malaria are among the most severe health challenges to humans and livestock in Africa and new drugs are needed. Leaves of Hyptis suaveolens Kuntze (Lamiaceae) and Momordica charantia L. (Cucurbitaceae) were extracted with hexane, ethyl acetate, and then methanol, and subjected to silica gel column chromatography. Structures of six isolated compounds were elucidated through NMR and HR-EIMS spectrometry. Callistrisic acid, dehydroabietinol, suaveolic acid, suaveolol, and a mixture of suaveolol and suaveolic acid (SSA) were obtained from H. suaveolens, while karavilagenin D and momordicin I acetate were obtained from M. charantia. The isolated biomolecules were tested against trypomastigotes of Trypanosoma brucei brucei and T. congolense, and against Plasmodium falciparum. The most promising EC50 values were obtained for the purified suaveolol fraction, at 2.71 ± 0.36 µg/mL, and SSA, exhibiting an EC50 of 1.56 ± 0.17 µg/mL against T. b. brucei trypomastigotes. Suaveolic acid had low activity against T. b. brucei but displayed moderate activity against T. congolense trypomastigotes at 11.1 ± 0.5 µg/mL. Suaveolol and SSA were also tested against T. evansi, T. equiperdum, Leishmania major and L. mexicana but the antileishmanial activity was low. Neither of the active compounds, nor the mixture of the two, displayed any cytotoxic effect on human foreskin fibroblast (HFF) cells at even the highest concentration tested, being 200 µg/mL. We conclude that suaveolol and its mixture possessed significant and selective trypanocidal activity.


Subject(s)
Hyptis , Momordica charantia , Plant Extracts , Plant Leaves , Plasmodium falciparum , Trypanosoma brucei brucei , Trypanosoma brucei brucei/drug effects , Plant Extracts/pharmacology , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Plasmodium falciparum/drug effects , Momordica charantia/chemistry , Plant Leaves/chemistry , Hyptis/chemistry , Trypanosomiasis, African/drug therapy , Trypanosomiasis, African/parasitology , Animals , Trypanosoma congolense/drug effects , Triterpenes/pharmacology , Triterpenes/chemistry , Triterpenes/isolation & purification , Humans , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/isolation & purification
5.
Nature ; 548(7665): 112-116, 2017 08 03.
Article in English | MEDLINE | ID: mdl-28723898

ABSTRACT

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Fructose-Bisphosphate Aldolase/metabolism , Fructosediphosphates/metabolism , Glucose/metabolism , AMP-Activated Protein Kinase Kinases , Adenosine Diphosphate/metabolism , Adenosine Monophosphate/metabolism , Adenosine Triphosphatases/metabolism , Adenosine Triphosphate/metabolism , Animals , Axin Protein/metabolism , Binding Sites , Enzyme Activation , Fibroblasts , Fructose-Bisphosphate Aldolase/genetics , Glucose/deficiency , Humans , Male , Mice , Phosphorylation , Protein Serine-Threonine Kinases/metabolism
6.
Adv Exp Med Biol ; 1397: 113-134, 2023.
Article in English | MEDLINE | ID: mdl-36522596

ABSTRACT

The creation of interactive livestreaming post-mortem examination sessions for veterinary students is described, including the technological and pedagogical issues that were considered and a detailed description of the solution developed. We used the Hero 7 Go Pro camera ( https://gopro.com/en/gb ) and livestreamed using Zoom ( https://explore.zoom.us/en/about/ ). We completed a thorough quantitative and qualitative analysis of the student perception of the value of the streaming platform and the sessions that were delivered to the second and third year students in the Bachelor of Veterinary Medicine and Surgery (BVMS) programme at the University of Glasgow. JISC Online surveys to BVMS2 and BVMS3 were central to the quantitative and qualitative analysis (MVLS Ethics reference 200,190,190).Students who responded to the survey found the material interesting, were able to interact effectively with the pathologists, enjoyed the "pathologists' eye" view that the system afforded, and enjoyed the ability to review and revise the video recording. The disadvantage some mentioned was not being in the appropriate professional space, i.e. the post-mortem facility, although a few students found this advantageous and suggested that this was a useful introduction to the post-mortem facility but without the cold/smell/noise to detract from their learning. In addition, a short explanation of additional uses of the Zoom Go Pro to teach BVMS4 and Veterinary Bioscience BSc Level 3 students and use for extracurricular student activities, e.g. Pathology Club, Student Chapter of the American Veterinary Medical Association at the University of Glasgow School of Veterinary Medicine, is given. The authors also consider other roles for the platform in the future, in particular the induction of students to the post-mortem facility environment.


Subject(s)
Education, Veterinary , Medicine , Humans , Autopsy/veterinary , Students , Learning
7.
Molecules ; 28(2)2023 Jan 07.
Article in English | MEDLINE | ID: mdl-36677679

ABSTRACT

Propolis is a resin that is gathered by bees from exudates produced by various plants. Its exact chemical composition depends on the plants available near the hive. Bees use propolis to coat the surfaces of the hive, where it acts as an anti-infective. Regardless of the chemical composition of propolis, it is always anti-protozoal, probably because protozoan parasites, particularly Lotmarium passim, are widespread in bee populations. The protozoa Trypanosoma brucei and T. congolense cause disease in humans and/or animals. The existing drugs for treating these diseases are old and resistance is an increasingly severe problem. The many types of propolis present a rich source of anti-trypanosomal compounds-from a material gathered by bees in an environmentally friendly way. In the current work, red Nigerian propolis from Rivers State, Nigeria was tested against T. brucei and T. congolense and found to be highly active (EC50 1.66 and 4.00 µg/mL, respectively). Four isoflavonoids, vestitol, neovestitol, 7-methylvestitol and medicarpin, were isolated from the propolis. The isolated compounds were also tested against T. brucei and T. congolense, and vestitol displayed the highest activity at 3.86 and 4.36 µg/mL, respectively. Activities against drug-resistant forms of T. brucei and T. congolense were similar to those against wild type.


Subject(s)
Anti-Infective Agents , Propolis , Trypanosoma brucei brucei , Trypanosoma congolense , Trypanosomiasis, African , Humans , Animals , Propolis/pharmacology , Propolis/chemistry , Nigeria , Trypanosomiasis, African/drug therapy
8.
Molecules ; 27(5)2022 Mar 01.
Article in English | MEDLINE | ID: mdl-35268726

ABSTRACT

Profiling a propolis sample from Papua New Guinea (PNG) using high-resolution mass spectrometry indicated that it contained several triterpenoids. Further fractionation by column chromatography and medium-pressure liquid chromatography (MPLC) followed by nuclear magnetic resonance spectroscopy (NMR) identified 12 triterpenoids. Five of these were obtained pure and the others as mixtures of two or three compounds. The compounds identified were: mangiferonic acid, ambonic acid, isomangiferolic acid, ambolic acid, 27-hydroxyisomangiferolic acid, cycloartenol, cycloeucalenol, 24-methylenecycloartenol, 20-hydroxybetulin, betulin, betulinic acid and madecassic acid. The fractions from the propolis and the purified compounds were tested in vitro against Crithidia fasciculata, Trypanosoma congolense, drug-resistant Trypanosoma congolense, Trypanosoma b. brucei and multidrug-resistant Trypanosoma b. brucei (B48). They were also assayed for their toxicity against U947 cells. The compounds and fractions displayed moderate to high activity against parasitic protozoa but only low cytotoxicity against the mammalian cells. The most active isolated compound, 20-hydroxybetulin, was found to be trypanostatic when different concentrations were tested against T. b. brucei growth.


Subject(s)
Propolis
9.
FASEB J ; 34(5): 6284-6301, 2020 05.
Article in English | MEDLINE | ID: mdl-32201986

ABSTRACT

Mitophagy is a key process regulating mitochondrial quality control. Several mechanisms have been proposed to regulate mitophagy, but these have mostly been studied using stably expressed non-native proteins in immortalized cell lines. In skeletal muscle, mitophagy and its molecular mechanisms require more thorough investigation. To measure mitophagy directly, we generated a stable skeletal muscle C2C12 cell line, expressing a mitophagy reporter construct (mCherry-green fluorescence protein-mtFIS1101-152 ). Here, we report that both carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment and adenosine monophosphate activated protein kinase (AMPK) activation by 991 promote mitochondrial fission via phosphorylation of MFF and induce mitophagy by ~20%. Upon CCCP treatment, but not 991, ubiquitin phosphorylation, a read-out of PTEN-induced kinase 1 (PINK1) activity, and Parkin E3 ligase activity toward CDGSH iron sulfur domain 1 (CISD1) were increased. Although the PINK1-Parkin signaling pathway is active in response to CCCP treatment, we observed no change in markers of mitochondrial protein content. Interestingly, our data shows that TANK-binding kinase 1 (TBK1) phosphorylation is increased after both CCCP and 991 treatments, suggesting TBK1 activation to be independent of both PINK1 and Parkin. Finally, we confirmed in non-muscle cell lines that TBK1 phosphorylation occurs in the absence of PINK1 and is regulated by AMPK-dependent signaling. Thus, AMPK activation promotes mitophagy by enhancing mitochondrial fission (via MFF phosphorylation) and autophagosomal engulfment (via TBK1 activation) in a PINK1-Parkin independent manner.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Mitochondrial Dynamics , Mitophagy , Muscle, Skeletal/pathology , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Ubiquitin-Protein Ligases/metabolism , AMP-Activated Protein Kinases/genetics , Animals , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Enzyme Activation , HeLa Cells , Humans , Mice , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Protein Kinases/genetics , Protein Serine-Threonine Kinases/genetics , Proton Ionophores/pharmacology , Signal Transduction , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination
10.
Int J Legal Med ; 135(1): 63-72, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32621147

ABSTRACT

Inhibition of PCR by metal ions can pose a serious challenge in the process of forensic DNA analysis. Samples contaminated with various types of metal ions encountered at crime scenes include swabs from metal surfaces such as bullets, cartridge casings, weapons (including guns and knives), metal wires and surfaces as well as bone samples which contain calcium. The mechanism behind the impact of metal ions on DNA recovery, extraction and subsequent amplification is not fully understood. In this study, we assessed the inhibitory effects of commonly encountered metals on DNA amplification. Of the nine tested metals, zinc, tin, iron(II) and copper were shown to have the strongest inhibitory properties having IC50 values significantly below 1 mM. In the second part of the study, three commercially available DNA polymerases were tested for their susceptibility to metal inhibition. We found that KOD polymerase was the most resistant to metal inhibition when compared with Q5 and Taq polymerase. We also demonstrate how the calcium chelator ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) can be used as an easy and non-destructive method of reversing calcium-induced inhibition of PCR reactions.


Subject(s)
DNA Fingerprinting , Ions/chemistry , Metals/chemistry , Polymerase Chain Reaction , DNA-Directed DNA Polymerase/metabolism , Humans
11.
Nanotechnology ; 31(19): 195101, 2020 May 08.
Article in English | MEDLINE | ID: mdl-31958777

ABSTRACT

Natural products have been successfully used to treat various ailments since ancient times and currently several anticancer agents based on natural products are used as the main therapy to treat cancer patients, or as a complimentary treatment to chemotherapy or radiation. Balanocarpol, which is a promising natural product that has been isolated from Hopea dryobalanoides, has been studied as a potential anticancer agent but its application is limited due to its high toxicity, low water solubility, and poor bioavailability. Therefore, the aim of this study is to improve the characteristics of balanocarpol and increase its anticancer activity through its encapsulation in a bilayer structure of a lipid-based nanoparticle drug delivery system where the application of nanotechnology can help improve the limitations of balanocarpol. The compound was first extracted and isolated from H. dryobalanoides. Niosome nanoparticles composed of Span 80 (SP80) and cholesterol were formulated through an innovative microfluidic mixing method for the encapsulation and delivery of balanocarpol. The prepared particles were spherical, small, and uniform with an average particles size and polydispersity index ∼175 nm and 0.088, respectively. The encapsulation of balanocarpol into the SP80 niosomes resulted in an encapsulation efficiency of ∼40%. The niosomes formulation loaded with balanocarpol showed a superior anticancer effect over the free compound when tested in vitro on human ovarian carcinoma (A2780) and human breast carcinoma (ZR-75-1). This is the first study to report the use of SP80 niosomes for the successful encapsulation and delivery of balanocarpol into cancer cells.


Subject(s)
Breast Neoplasms/drug therapy , Dipterocarpaceae/chemistry , Ovarian Neoplasms/drug therapy , Polyphenols/isolation & purification , Polyphenols/pharmacology , Capsules , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cholesterol/chemistry , Female , Hexoses/chemistry , Humans , Liposomes , Plant Extracts/chemistry , Polyphenols/chemistry
12.
Nano Lett ; 19(11): 8311-8317, 2019 11 13.
Article in English | MEDLINE | ID: mdl-31644875

ABSTRACT

Artificial complex-oxide heterostructures containing ultrathin buried layers grown along the pseudocubic [111] direction have been predicted to host a plethora of exotic quantum states arising from the graphene-like lattice geometry and the interplay between strong electronic correlations and band topology. To date, however, electronic-structural investigations of such atomic layers remain an immense challenge due to the shortcomings of conventional surface-sensitive probes with typical information depths of a few angstroms. Here, we use a combination of bulk-sensitive soft X-ray angle-resolved photoelectron spectroscopy (SX-ARPES), hard X-ray photoelectron spectroscopy (HAXPES), and state-of-the-art first-principles calculations to demonstrate a direct and robust method for extracting momentum-resolved and angle-integrated valence-band electronic structure of an ultrathin buckled graphene-like layer of NdNiO3 confined between two 4-unit cell-thick layers of insulating LaAlO3. The momentum-resolved dispersion of the buried Ni d states near the Fermi level obtained via SX-ARPES is in excellent agreement with the first-principles calculations and establishes the realization of an antiferro-orbital order in this artificial lattice. The HAXPES measurements reveal the presence of a valence-band bandgap of 265 meV. Our findings open a promising avenue for designing and investigating quantum states of matter with exotic order and topology in a few buried layers.

13.
Emerg Infect Dis ; 25(12): 2257-2260, 2019 12.
Article in English | MEDLINE | ID: mdl-31742518

ABSTRACT

Babesia venatorum is an increasingly prominent zoonotic parasite that predominantly infects wild deer. Our molecular examination of Babesia infecting mammals in the United Kingdom identified 18S sequences in domestic sheep isolates identical to zoonotic B. venatorum. Identification of this parasite in livestock raises concerns for public health and farming policy in Europe.


Subject(s)
Babesia/classification , Babesiosis/epidemiology , Babesiosis/parasitology , Host Specificity , Zoonoses/epidemiology , Zoonoses/parasitology , Animals , Babesia/genetics , Polymerase Chain Reaction , Public Health Surveillance , RNA, Protozoan , RNA, Ribosomal, 18S/genetics , Sheep , United Kingdom/epidemiology
14.
Biochem J ; 475(18): 2969-2983, 2018 09 25.
Article in English | MEDLINE | ID: mdl-30135087

ABSTRACT

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake. Here, we show AMPK heterotrimers containing the α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosine-binding (PTB) domains of TBC1D1 and is increased by two different pharmacological activators of AMPK (AICAR and A769962). The interaction enhances the efficiency by which AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237 Furthermore, the interaction is reduced by a naturally occurring R125W mutation in the PTB1 domain of TBC1D1, previously found to be associated with severe familial obesity in females, with a concomitant reduction in Ser237 phosphorylation. Our observations provide evidence for a functional difference between AMPK α-subunits and extend the repertoire of protein kinases that interact with substrates via stabilisation mechanisms that modify the efficacy of substrate phosphorylation.


Subject(s)
AMP-Activated Protein Kinases/metabolism , GTPase-Activating Proteins/metabolism , Mutation, Missense , Obesity/enzymology , AMP-Activated Protein Kinases/genetics , Amino Acid Substitution , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/metabolism , Animals , Female , GTPase-Activating Proteins/genetics , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Mice , Mice, Transgenic , Obesity/genetics , Phosphorylation , Ribonucleotides/genetics , Ribonucleotides/metabolism , Sex Characteristics
15.
Molecules ; 24(6)2019 Mar 15.
Article in English | MEDLINE | ID: mdl-30884752

ABSTRACT

Twelve propolis samples from different parts of Libya were investigated for their phytochemical constituents. Ethanol extracts of the samples and some purified compounds were tested against Trypanosoma brucei, Plasmodium falciparum and against two helminth species, Trichinella spiralis and Caenorhabditis elegans, showing various degrees of activity. Fourteen compounds were isolated from the propolis samples, including a novel compound Taxifolin-3-acetyl-4'-methyl ether (4), a flavanonol derivative. The crude extracts showed moderate activity against T. spiralis and C. elegans, while the purified compounds had low activity against P. falciparum. Anti-trypanosomal activity (EC50 = 0.7 µg/mL) was exhibited by a fraction containing a cardol identified as bilobol (10) and this fraction had no effect on Human Foreskin Fibroblasts (HFF), even at 2.0 mg/mL, thus demonstrating excellent selectivity. A metabolomics study was used to explore the mechanism of action of the fraction and it revealed significant disturbances in trypanosomal phospholipid metabolism, especially the formation of choline phospholipids. We conclude that a potent and highly selective new trypanocide may be present in the fraction.


Subject(s)
Antiprotozoal Agents/chemistry , Cell Proliferation/drug effects , Propolis/chemistry , Trypanosoma brucei brucei/drug effects , Animals , Antiprotozoal Agents/pharmacology , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/pathogenicity , Cell Line , Fibroblasts/drug effects , Humans , Libya , Metabolomics , Plasmodium falciparum/drug effects , Plasmodium falciparum/pathogenicity , Polyphenols/chemistry , Polyphenols/pharmacology , Propolis/pharmacology , Trichinella spiralis/drug effects , Trichinella spiralis/pathogenicity , Trypanosoma brucei brucei/pathogenicity
16.
Nano Lett ; 17(2): 794-799, 2017 02 08.
Article in English | MEDLINE | ID: mdl-28103040

ABSTRACT

We demonstrate a novel pathway to control and stabilize oxygen vacancies in complex transition-metal oxide thin films. Using atomic layer-by-layer pulsed laser deposition (PLD) from two separate targets, we synthesize high-quality single-crystalline CaMnO3 films with systematically varying oxygen vacancy defect formation energies as controlled by coherent tensile strain. The systematic increase of the oxygen vacancy content in CaMnO3 as a function of applied in-plane strain is observed and confirmed experimentally using high-resolution soft X-ray absorption spectroscopy (XAS) in conjunction with bulk-sensitive hard X-ray photoemission spectroscopy (HAXPES). The relevant defect states in the densities of states are identified and the vacancy content in the films quantified using the combination of first-principles theory and core-hole multiplet calculations with holistic fitting. Our findings open up a promising avenue for designing and controlling new ionically active properties and functionalities of complex transition-metal oxides via strain-induced oxygen-vacancy formation and ordering.

17.
Nano Lett ; 17(4): 2426-2432, 2017 04 12.
Article in English | MEDLINE | ID: mdl-28272897

ABSTRACT

Light-matter interaction at the nanoscale in magnetic materials is a topic of intense research in view of potential applications in next-generation high-density magnetic recording. Laser-assisted switching provides a pathway for overcoming the material constraints of high-anisotropy and high-packing density media, though much about the dynamics of the switching process remains unexplored. We use ultrafast small-angle X-ray scattering at an X-ray free-electron laser to probe the magnetic switching dynamics of FePt nanoparticles embedded in a carbon matrix following excitation by an optical femtosecond laser pulse. We observe that the combination of laser excitation and applied static magnetic field, 1 order of magnitude smaller than the coercive field, can overcome the magnetic anisotropy barrier between "up" and "down" magnetization, enabling magnetization switching. This magnetic switching is found to be inhomogeneous throughout the material with some individual FePt nanoparticles neither switching nor demagnetizing. The origin of this behavior is identified as the near-field modification of the incident laser radiation around FePt nanoparticles. The fraction of not-switching nanoparticles is influenced by the heat flow between FePt and a heat-sink layer.

18.
Phytochem Anal ; 27(3-4): 217-21, 2016 May.
Article in English | MEDLINE | ID: mdl-27313159

ABSTRACT

INTRODUCTION: Several taccalonolides with various bioactivities have been isolated from Tacca species but no studies to isolate taccalonolides with anti-trypanosomal activity from Tacca leontopetaloides have been reported. OBJECTIVES: To analyse extracts of the roots of Tacca leontopetaloides, purify the extracts by column chromatography and identify isolated compounds by spectroscopic methods. The compounds and fractions will be tested for antitrypanosomal activity in vitro against Trypanosoma brucei brucei. MATERIAL AND METHODS: Dried roots or tubers of Tacca leontopetaloides, chromatographic separation and spectroscopic identification. RESULTS: A novel taccalonolide A propanoate and some known taccalonolides were isolated and their structures were determined by NMR and mass spectrometry CONCLUSION: Several taccalonolides were isolated from Tacca leontopetaloides and were found to have in vitro antitrypanosomal activity against Trypanosoma brucei brucei and EC50 values for the isolated compounds were from 0.79 µg/mL. Copyright © 2016 John Wiley & Sons, Ltd.


Subject(s)
Dioscoreaceae/chemistry , Plant Extracts/pharmacology , Steroids/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Mass Spectrometry , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Roots/chemistry , Plant Tubers/chemistry , Propionates/chemistry , Propionates/isolation & purification , Propionates/pharmacology , Steroids/chemistry , Steroids/isolation & purification , Trypanocidal Agents/chemistry , Trypanocidal Agents/isolation & purification
19.
Phytochem Anal ; 27(2): 107-15, 2016.
Article in English | MEDLINE | ID: mdl-26662866

ABSTRACT

INTRODUCTION: A previous study showed the unique character of Nigerian red propolis from Rivers State, Nigeria (RSN), with regards to chemical composition and activity against Trypanosoma brucei in comparison with other African propolis. OBJECTIVE: To carry out fractionation and biological testing of Nigerian propolis in order to isolate compounds with anti-trypanosomal activity. To compare the composition of the RSN propolis with the composition of Brazilian red propolis. METHODOLOGY: Profiling was carried out using HPLC-UV-ELSD and HPLC-Orbitrap-FTMS on extracts of two samples collected from RSN with data extraction using MZmine software. Isolation was carried out by normal phase and reversed phase MPLC. Elucidation of the compounds with a purity > 95% was performed by 1D/2D NMR HRMS and HRLC-MS(n) . RESULTS: Ten phenolic compounds were isolated or in the case of liquiritigenin partially purified. Data for nine of these correlated with literature reports of known compounds i.e. one isoflavanone, calycosin (1); two flavanones, liquiritigenin (2) and pinocembrin (5); an isoflavan, vestitol (3); a pterocarpan, medicarpin (4); two prenylflavanones, 8-prenylnaringenin (7) and 6-prenylnaringenin (8); and two geranyl flavonoids, propolin D (9) and macarangin (10). The tenth was elucidated as a previously undescribed dihydrobenzofuran (6). The isolated compounds were tested against Trypanosoma brucei and displayed moderate to high activity. Some of the compounds tested had similar activity against wild type T. brucei and two strains displaying pentamidine resistance. CONCLUSION: Nigerian propolis from RSN has some similarities with Brazilian red propolis. The propolis displayed anti-trypanosomal activity at a potentially useful level.


Subject(s)
Propolis/pharmacology , Trypanosoma brucei brucei/drug effects , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Chromatography, High Pressure Liquid , Molecular Structure , Propolis/chemistry , Spectrophotometry, Ultraviolet
20.
Opt Express ; 23(4): 4340-7, 2015 Feb 23.
Article in English | MEDLINE | ID: mdl-25836470

ABSTRACT

Nonlinear spectroscopy in the extreme ultraviolet (EUV) and soft x-ray spectral range offers the opportunity for element selective probing of ultrafast dynamics using core-valence transitions (Mukamel et al., Acc. Chem. Res. 42, 553 (2009)). We demonstrate a step on this path showing core-valence sensitivity in transient grating spectroscopy with EUV probing. We study the optically induced insulator-to-metal transition (IMT) of a VO(2) film with EUV diffraction from the optically excited sample. The VO(2) exhibits a change in the 3p-3d resonance of V accompanied by an acoustic response. Due to the broadband probing we are able to separate the two features.

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