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Yakugaku Zasshi : Journal of the... 2018We investigated the electric and viscoelastic properties for the aqueous solution of cyanobacterial megamolecules, named sacran. Sacran is an anionic polyelectrolyte... (Review)
Review
We investigated the electric and viscoelastic properties for the aqueous solution of cyanobacterial megamolecules, named sacran. Sacran is an anionic polyelectrolyte that has carboxylate and sulfate groups on the saccharide chain. The electric conductivity and shear viscosity demonstrated three crossover concentrations; overlap concentration at 0.004 wt%, entanglement concentration at 0.02 wt%, and gelation concentration at 0.1 wt%. The decrease in the charge density of the sacran chains reduces the repulsive force between the chains and this would cause transformation from the dilute to condensed states. At extremely low flow rates, sacran demonstrated a behavior called negative thixotropy in which the shear viscosity increased over time. In this review, the conformation of sacran chain in pure water is discussed and its negative thixotropy is briefly described.
Topics: Chemical Phenomena; Cyanobacteria; Electric Conductivity; Gels; Polyelectrolytes; Polysaccharides; Pyrimidinones; Solutions; Thiones; Viscosity; Water
PubMed: 29607995
DOI: 10.1248/yakushi.17-00201-2 -
Journal of Natural Products Dec 2021A straightforward access to 2-unsubstituted imidazole -oxides with subsequent deoxygenation by treatment with Raney-nickel followed by -benzylation opens up a convenient... (Comparative Study)
Comparative Study
A straightforward access to 2-unsubstituted imidazole -oxides with subsequent deoxygenation by treatment with Raney-nickel followed by -benzylation opens up a convenient route to lepidilines A and C. Both imidazolium salts were used to generate in situ the corresponding imidazol-2-ylidenes, which smoothly reacted with elemental sulfur, yielding imidazole-2-thiones. These reactions were performed either under classical conditions in pyridine solutions or mechanochemically using solid CsCO as a base. The structure of lepidiline C was unambiguously confirmed by X-ray analysis of its hexafluorophosphate. An analogous protocol toward lepidilines B and D and their 4,5-diphenyl analogues is less efficient due to observed instability of the key precursors, i.e., the respective 2-methylimidazole -oxides. Comparison of cytotoxic activity against HL-60 and MCF-7 cell lines of all lepidilines, as well as their selected structural analogues (e.g., 4,5-diphenyl derivatives and PF salts), revealed slightly more potent activity of the 2-methylated series, irrespectively of the type of counterion present in the imidazolium salt. Remarkably, the well-known 1,3-diadamantylimidazolium bromide (the "Arduengo salt"), known as the precursor of the first, shelf-stable NHC representative, and its adamantyloxy analogue displayed the most significant cytotoxic activity in the studied series.
Topics: Biological Products; Crystallography, X-Ray; Humans; Imidazoles; MCF-7 Cells; Molecular Structure; Structure-Activity Relationship; Thiones
PubMed: 34808062
DOI: 10.1021/acs.jnatprod.1c00797 -
ACS Chemical Neuroscience Sep 2017The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of...
The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer's disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Aβ toxicity by reducing Aβ levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Aβ in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Aβ peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Aβ toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off-target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies.
Topics: Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Clioquinol; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Homeostasis; Ions; Metals; Mitochondria; Neurodegenerative Diseases; Neuroprotective Agents; Reactive Oxygen Species; Structure-Activity Relationship; Thiones; Yeasts
PubMed: 28628299
DOI: 10.1021/acschemneuro.7b00187 -
The Journal of Endocrinology Jun 2018Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease...
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease worldwide. High-fat (HF) diets promote an increased uptake and storage of free fatty acids (FFAs) and triglycerides (TGs) in hepatocytes, which initiates steatosis and induces lipotoxicity, inflammation and insulin resistance. Activation and signaling of Toll-like receptor 4 (TLR4) by FFAs induces inflammation evident in NAFLD and insulin resistance. Currently, there are no effective treatments to specifically target inflammation associated with this disease. We have established the efficacy of phenylmethimazole (C10) to prevent lipopolysaccharide and palmitate-induced TLR4 signaling. Because TLR4 is a key mediator in pro-inflammatory responses, it is a potential therapeutic target for NAFLD. Here, we show that treatment with C10 inhibits HF diet-induced inflammation in both liver and mesenteric adipose tissue measured by a decrease in mRNA levels of pro-inflammatory cytokines. Additionally, C10 treatment improves glucose tolerance and hepatic steatosis despite the development of obesity due to HF diet feeding. Administration of C10 after 16 weeks of HF diet feeding reversed glucose intolerance, hepatic inflammation, and improved hepatic steatosis. Thus, our findings establish C10 as a potential therapeutic for the treatment of NAFLD.
Topics: Adipose Tissue; Animals; Cells, Cultured; Cytoprotection; Diet; Glucose Intolerance; Hep G2 Cells; Hepatocytes; Humans; Inflammation; Liver; Male; Methimazole; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Thiones; Triglycerides
PubMed: 29666152
DOI: 10.1530/JOE-18-0078 -
Molecular Psychiatry Dec 2018Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with...
Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days.
Topics: Animals; Antidepressive Agents; Autophagy; Bridged-Ring Compounds; Ceramides; Corticosterone; Depressive Disorder, Major; Endoplasmic Reticulum; Female; Lysosomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Norbornanes; Protein Phosphatase 2; Sphingomyelin Phosphodiesterase; Sphingomyelins; Thiocarbamates; Thiones
PubMed: 30038230
DOI: 10.1038/s41380-018-0090-9 -
International Journal of Cancer Aug 2020Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant...
Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA-1 drug inhibits growth and tumor establishment synergistically in a mutant-p53 dependent manner. The Cancer Genome Atlas (TCGA) data and serous ovarian tumors were evaluated for TP53 and HSPA9/mortalin status. SHetA2 and PRIMA-1 were tested in ovarian cancer cell lines and fallopian tube secretory epithelial cells using isobolograms, fluorescent cytometry, Western blots and ELISAs. Drugs were administered to mice after peritoneal injection of MESOV mutant p53 ovarian cancer cells and prior to tumor establishment, which was evaluated by logistic regression. Fifty-eight percent of TP53 mutations were missense and there were no mortalin mutations in TCGA high-grade serous ovarian cancers. Mortalin levels were sequentially increased in serous benign, borderline and carcinoma tumors. SHetA2 caused p53 nuclear and mitochondrial accumulation in cancer, but not in healthy, cells. Endogenous or exogenous mutant p53 increased SHetA2 resistance. PRIMA-1 decreased this resistance and interacted synergistically with SHetA2 in mutant and wild type p53-expressing cell lines in association with elevated reactive oxygen species/ATP ratios. Tumor-free rates in animals were 0% (controls), 25% (PRIMA1 ), 42% (SHetA2) and 67% (combination). SHetA2 (p = 0.004) and PRIMA1 (p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA-1 alone and in combination for ovarian cancer maintenance therapy.
Topics: Animals; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Chromans; Female; HSP70 Heat-Shock Proteins; Humans; Maintenance Chemotherapy; Mice, Nude; Molecular Targeted Therapy; Mutation; Ovarian Neoplasms; Thiones; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 31845320
DOI: 10.1002/ijc.32830 -
Chimia Feb 2020The degenerative xanthate addition transfer to alkenes allows the synthesis of a broad range of protected, and in some cases enantiopure, α, β, and γ-amino acids,...
The degenerative xanthate addition transfer to alkenes allows the synthesis of a broad range of protected, and in some cases enantiopure, α, β, and γ-amino acids, including proline and pipecolic derivatives, as well as fluorinated congeners and β-lactams. The radical addition furnishes naturally latent mercapto-α-amino acids that are ideally equipped for native chemical ligation. Most of the amino acid structures accessible rapidly by this chemistry would otherwise require tedious multi-step syntheses.
Topics: Amino Acids; Bridged-Ring Compounds; Stereoisomerism; Thiones
PubMed: 32200781
DOI: 10.2533/chimia.2020.9 -
Molecules (Basel, Switzerland) Sep 2022In this study, pumice is used as a novel natural heterogeneous catalyst for the synthesis of 3,4-dihydropyrimidine-2-(1)-ones/thiones via the one-pot multi-component...
In this study, pumice is used as a novel natural heterogeneous catalyst for the synthesis of 3,4-dihydropyrimidine-2-(1)-ones/thiones via the one-pot multi-component condensation of aromatic aldehydes, urea/thiourea, and ethyl acetoacetate or acetylacetone in excellent yields (up to 98%). The physical and chemical properties of the catalyst were studied. Their geochemical analysis revealed a basaltic composition. Furthermore, X-ray diffraction showed that it is composed of amorphous materials with clinoptilolite and heulandites zeolite minerals in its pores. Moreover, pumice has a porosity range from 78.2-83.9% (by volume) and is characterized by a mesoporous structure (pore size range from 21.1 to 64.5 nm). Additionally, it has a pore volume between 0.00531 and 0.00781 m/g and a surface area between 0.053 and 1.47 m/g. The latter facilitated the reaction to proceed in a short time frame as well as in excellent yields. It is worth noting that our strategy tolerates the use of readily available, cheap, non-toxic, and thermally stable pumice catalyst. The reactions proceeded smoothly under solvent-free conditions, and products were isolated without tedious workup procedures in good yields and high purity. Indeed, pumice can be reused for at least five reuse cycles without affecting its activity.
Topics: Aldehydes; Catalysis; Silicates; Solvents; Thiones; Thiourea; Urea; Zeolites
PubMed: 36144781
DOI: 10.3390/molecules27186044 -
Plant Physiology Jun 2021The phragmoplast separates daughter cells during cytokinesis by constructing the cell plate, which depends on interaction between cytoskeleton and membrane compartments....
The phragmoplast separates daughter cells during cytokinesis by constructing the cell plate, which depends on interaction between cytoskeleton and membrane compartments. Proteins responsible for these interactions remain unknown, but formins can link cytoskeleton with membranes and several members of formin protein family localize to the cell plate. Progress in functional characterization of formins in cytokinesis is hindered by functional redundancies within the large formin gene family. We addressed this limitation by employing Small Molecular Inhibitor of Formin Homology 2 (SMIFH2), a small-molecule inhibitor of formins. Treatment of tobacco (Nicotiana tabacum) tissue culture cells with SMIFH2 perturbed localization of actin at the cell plate; slowed down both microtubule polymerization and phragmoplast expansion; diminished association of dynamin-related proteins with the cell plate independently of actin and microtubules; and caused cell plate swelling. Another impact of SMIFH2 was shortening of the END BINDING1b (EB1b) and EB1c comets on the growing microtubule plus ends in N. tabacum tissue culture cells and Arabidopsis thaliana cotyledon epidermis cells. The shape of the EB1 comets in the SMIFH2-treated cells resembled that of the knockdown mutant of plant Xenopus Microtubule-Associated protein of 215 kDa (XMAP215) homolog MICROTUBULE ORGANIZATION 1/GEMINI 1 (MOR1/GEM1). This outcome suggests that formins promote elongation of tubulin flares on the growing plus ends. Formins AtFH1 (A. thaliana Formin Homology 1) and AtFH8 can also interact with EB1. Besides cytokinesis, formins function in the mitotic spindle assembly and metaphase to anaphase transition. Our data suggest that during cytokinesis formins function in: (1) promoting microtubule polymerization; (2) nucleating F-actin at the cell plate; (3) retaining dynamin-related proteins at the cell plate; and (4) remodeling of the cell plate membrane.
Topics: Actins; Arabidopsis; Cytokinesis; Cytoskeleton; Formins; Microtubules; Thiones; Nicotiana; Tubulin; Uracil
PubMed: 33620500
DOI: 10.1093/plphys/kiab085 -
Neurochemical Research Feb 2021Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were...
Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED values) and acute neurotoxic effects of TPL-16 (as TD values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD and ED values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing.
Topics: Animals; Anticonvulsants; Carbamazepine; Drug Synergism; Male; Mice; Muscle Strength; Phenobarbital; Phenytoin; Rotarod Performance Test; Seizures; Thiones; Triazoles; Valproic Acid
PubMed: 33206316
DOI: 10.1007/s11064-020-03175-z