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Frontiers in Plant Science 2023The chemical composition, insect antifeedant, nematicidal activity, phytotoxicity, and nematicidal activity of the essential oil (EO) of the African medicinal plant...
The chemical composition, insect antifeedant, nematicidal activity, phytotoxicity, and nematicidal activity of the essential oil (EO) of the African medicinal plant were studied. Chemical analysis using GC/MS indicated that benzyl isothiocyanate (96.23%) was the major compound, followed by benzyl cyanide (1.38%). The biocidal effects of this oil were tested against insect pests and root-knot nematodes. All the insect species tested were significantly affected by the oil according to their feeding adaptations ( and were less affected than ) with efficient doses (EC) of 29.4 8.3 μg/cm, 14.744 8.3 μg/cm, and 8.3 μg/cm, respectively. The oil was highly effective against juveniles J2 of the nematode , with LC-LC values of 0.007 mg/mL-0.0113 mg/mL. EO at minimum lethal concentrations (MLC) and below strongly inhibited egg hatching , whereas soil treatment caused a strong suppression of nematode population, infection frequency, and multiplication rate. The EO inhibited ryegrass () germination at 0.4 mg/mL, while at 0.1 mg/mL, its effects on germination, root and leaf growth were moderate (32.4%, 8.4%, and 18.3%, respectively). The tomato () germination was not affected by the EO, but the root growth was reduced (56% at 0.1 mg/mL) at a dose 10 times higher than the LD calculated for J2 mortality. Molecular docking of the nematicidal effects of the oil using PyRx revealed a strong interaction between potassium chloride transporting KCC3 (PDB ID: 7D90) and benzyl cyanide at a distance of 2.20 A° with GLN C:350, followed by benzyl isothiocyanate at a distance of 2.78 A° with ARG B:294. The nematicidal effects of EO on penetration and reproduction in tomato roots further support the potential of this EO as a nematicidal agent with insect antifeedant effects, which could be used by local farmers for crop protection.
PubMed: 38098790
DOI: 10.3389/fpls.2023.1260360 -
Brain and Nerve = Shinkei Kenkyu No... Dec 2023And Then There Were None and Sparkling Cyanide, two of Agatha Christie's famous novels describe potassium cyanide-induced deaths. Cyanide, a tasteless, odorless,...
And Then There Were None and Sparkling Cyanide, two of Agatha Christie's famous novels describe potassium cyanide-induced deaths. Cyanide, a tasteless, odorless, strongly alkaline poison is a powerful gastrointestinal irritant, following oral ingestion. It reacts with hydrochloric acid in the gastric juice to produce hydrogen cyanide gas, which is absorbed and inhibits the mitochondrial electron transfer system and consequently suppresses adenosine triphosphate (ATP) production. Therefore, the central nervous system, which consumes a large amount of ATP, is first affected and symptoms of poisoning manifest as dizziness, disorientation, coma, and convulsions. The orally lethal dose is approximately 300 mg.
Topics: Humans; Cyanides; Antidotes; Seizures; Adenosine Triphosphate
PubMed: 38097219
DOI: 10.11477/mf.1416202529 -
Drug Metabolism and Bioanalysis Letters Dec 2023Everolimus, an allosteric mechanistic target of rapamycin (mTOR) inhibitor, recently demonstrated the therapeutic value of mTOR inhibitors for Central Nervous System...
BACKGROUND
Everolimus, an allosteric mechanistic target of rapamycin (mTOR) inhibitor, recently demonstrated the therapeutic value of mTOR inhibitors for Central Nervous System (CNS) indications driven by hyperactivation of mTOR. A newer, potent brain-penetrant analog of everolimus, referred to as (1) in this manuscript [(S)-3-methyl-4-(7-((R)-3-methylmorpholino)-2-(thiazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)morpholine,(1)] catalytically inhibits mTOR function in the brain and increases the lifespan of mice with neuronal mTOR hyperactivation.
INTRODUCTION
Early evaluation of the safety of 1 was conducted in cynomolgus monkeys in which oral doses were administered to three animals in a rising-dose fashion (from 2 to 30 mg/kg/day). 1 produced severe toxicity including the evidence of hepatic toxicity, along with non-dose proportional increases in drug exposure. Investigations of cross-species hepatic bioactivation of 1 were conducted to assess whether the formation of reactive drug metabolites was associated with the mechanism of liver toxicity.
METHOD
1 contained two morpholine rings known as structural alerts and can potentially form reactive intermediates through oxidative metabolism. Bioactivation of 1 was investigated in rat, human and monkey liver microsomes fortified with trapping agents such as methoxylamine or potassium cyanide.
RESULTS
Our results suggest that bioactivation of the morpholine moieties to reactive intermediates may have been involved in the mechanism of liver toxicity observed with 1. Aldehyde intermediates trappable by methoxylamine were identified in rat and monkey liver microsomal studies. In addition, a total of four cyano conjugates arising from the formation of iminium ion intermediates were observed and identified. These findings may potentially explain the observed monkey toxicity. Interestingly, methoxylamine or cyano adducts of 1 were not observed in human liver microsomes.
CONCLUSION
The bioactivation of 1 appears to be species-specific. Circumstantial evidence for the toxicity derived from 1 point to the formation of iminium ion intermediates trappable by cyanide in monkey liver microsomes. The cyano conjugates were only observed in monkey liver microsomes, potentially pointing to cause at least the hepatotoxicity observed in monkeys. In contrast, methoxylamine conjugates were detected in both rat and monkey liver microsomes, with only a trace amount in human liver microsomes. Cyano conjugates were not observed in human liver microsomes, challenging the team on the drugability and progressivity of 1 through drug development. The mechanisms for drug-induced liver toxicity are multifactorial. These results are highly suggestive that the iminium ion may be an important component in the mechanism of liver toxicity 1 observed in the monkey.
PubMed: 38047363
DOI: 10.2174/0118723128260455231104180653 -
Life (Basel, Switzerland) Oct 2023Baicalin is the foremost prevalent flavonoid found in . It also frequently occurs in many multi-herbal preparations utilized in Eastern countries. The current research...
Baicalin is the foremost prevalent flavonoid found in . It also frequently occurs in many multi-herbal preparations utilized in Eastern countries. The current research has assessed and compared the antioxidant, antidiabetic, anticholinergic, and antiglaucoma properties of baicalin hydrate. Baicalin hydrate was tested for its antioxidant capacity using a variety of techniques, including N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD) scavenging activity, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS) scavenging activity, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activity, potassium ferric cyanide reduction ability, and cupric ions (Cu) reducing activities. Also, for comparative purposes, reference antioxidants, such as butylated hydroxyanisole (BHA), Trolox, α-Tocopherol, and butylated hydroxytoluene (BHT) were employed. Baicalin hydrate had an IC value of 13.40 μg/mL (r: 0.9940) for DPPH radical scavenging, whereas BHA, BHT, Trolox, and α-Tocopherol had IC values of 10.10, 25.95, 7.059, and 11.31 μg/mL for DPPH scavenging, respectively. These findings showed that baicalin hydrate had comparably close and similar DPPH scavenging capability to BHA, α-tocopherol, and Trolox, but it performed better than BHT. Additionally, apart from these studies, baicalin hydrate was tested for its ability to inhibit a number of metabolic enzymes, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II), and α-glycosidase, which have been linked to several serious illnesses, such as Alzheimer's disease (AD), glaucoma, and diabetes, where the K values of baicalin hydrate toward the aforementioned enzymes were 10.01 ± 2.86, 3.50 ± 0.68, 19.25 ± 1.79, and 26.98 ± 9.91 nM, respectively.
PubMed: 38004276
DOI: 10.3390/life13112136 -
Folia Microbiologica Feb 2024Endophytic microbes are plant-associated microorganisms that reside in the interior tissue of plants without causing damage to the host plant. Endophytic microbes can... (Review)
Review
Endophytic microbes are plant-associated microorganisms that reside in the interior tissue of plants without causing damage to the host plant. Endophytic microbes can boost the availability of nutrient for plant by using a variety of mechanisms such as fixing nitrogen, solubilizing phosphorus, potassium, and zinc, and producing siderophores, ammonia, hydrogen cyanide, and phytohormones that help plant for growth and protection against various abiotic and biotic stresses. The microbial endophytes have attained the mechanism of producing various hydrolytic enzymes such as cellulase, pectinase, xylanase, amylase, gelatinase, and bioactive compounds for plant growth promotion and protection. The efficient plant growth promoting endophytic microbes could be used as an alternative of chemical fertilizers for agro-environmental sustainability. Endophytic microbes belong to different phyla including Euryarchaeota, Ascomycota, Basidiomycota, Mucoromycota, Firmicutes, Proteobacteria, and Actinobacteria. The most pre-dominant group of bacteria belongs to Proteobacteria including α-, β-, γ-, and δ-Proteobacteria. The least diversity of the endophytic microbes have been revealed from Bacteroidetes, Deinococcus-Thermus, and Acidobacteria. Among reported genera, Achromobacter, Burkholderia, Bacillus, Enterobacter, Herbaspirillum, Pseudomonas, Pantoea, Rhizobium, and Streptomyces were dominant in most host plants. The present review deals with plant endophytic diversity, mechanisms of plant growth promotion, protection, and their role for agro-environmental sustainability. In the future, application of endophytic microbes have potential role in enhancement of crop productivity and maintaining the soil health in sustainable manner.
Topics: Endophytes; Bacteria; Bacillus; Basidiomycota; Ascomycota
PubMed: 37747637
DOI: 10.1007/s12223-023-01092-6 -
Applied and Environmental Microbiology Oct 2023grows as a biofilm under many environmental conditions, and the bacterium can disperse from biofilms via highly regulated, dynamic processes. However, physiologic...
grows as a biofilm under many environmental conditions, and the bacterium can disperse from biofilms via highly regulated, dynamic processes. However, physiologic triggers of biofilm dispersal remain poorly understood. Based on prior literature describing dispersal triggered by forms of starvation, we tested bacterial respiratory inhibitors for biofilm dispersal in two models resembling chronic airway infections. Our underlying hypothesis was that respiratory inhibitors could serve as a model for the downstream effects of starvation. We used two experimental conditions. In the first condition, biofilms were grown and dispersed from the surface of airway epithelial cells, and the second condition was a model where biofilms were grown on glass in cell culture media supplemented with host-relevant iron sources. In both biofilm models, the respiratory inhibitors potassium cyanide and sodium azide each triggered biofilm dispersal. We hypothesized that cyanide-induced dispersal was due to respiratory inhibition rather than signaling via an alternative mechanism, and, indeed, if respiration was supported by overexpression of cyanide-insensitive oxidase, dispersal was prevented. Dispersal required the activity of the cyclic-di-GMP regulated protease LapG, reinforcing the role of matrix degradation in dispersal. Finally, we examined the roles of individual phosphodiesterases, previously implicated in dispersal to specific triggers, and found signaling to be highly redundant. Combined deletion of the phosphodiesterases , , and was required to attenuate the dispersal phenotype. In summary, this work adds insight into the physiology of biofilm dispersal under environmental conditions in which bacterial respiration is abruptly limited. IMPORTANCE The bacterium grows in biofilm communities that are very difficult to treat in human infections. Growing as a biofilm can protect bacteria from antibiotics and the immune system. Bacteria can leave a biofilm through a process called "dispersal." Dispersed bacteria seed new growth areas and are more susceptible to killing by antibiotics. The triggers for biofilm dispersal are not well understood, and if we understood dispersal better it might lead to the development of new treatments for infection. In this paper, we find that inhibiting ability to respire (generate energy) can trigger dispersal from a biofilm grown in association with human respiratory epithelial cells in culture. The dispersal process requires a protease which is previously known to degrade the biofilm matrix. These findings give us a better understanding of how the biofilm dispersal process works so that future research can discover better ways of clearing bacteria growing in biofilms.
Topics: Humans; Pseudomonas aeruginosa; Biofilms; Phosphoric Diester Hydrolases; Anti-Bacterial Agents; Peptide Hydrolases; Cyanides; Gene Expression Regulation, Bacterial; Bacterial Proteins; Cyclic GMP
PubMed: 37728340
DOI: 10.1128/aem.01101-23 -
Journal of Labelled Compounds &... Nov 2023Stable isotope labeled Iclepertin (BI 425809, 1) and its major metabolites are needed as internal standards in bioanalytical studies. BI 425809 consists of two main...
Stable isotope labeled Iclepertin (BI 425809, 1) and its major metabolites are needed as internal standards in bioanalytical studies. BI 425809 consists of two main building blocks, 5-methylsulfonyl-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]benzoic acid (2) and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. We used fluoro[ C ]benzene as the starting material in the preparation of [ C ]-2. This intermediate was then employed to access carbon 13 labeled Iclepertin ([ C ]-1) and other metabolites. The major metabolite BI 761036 (6), which resulted from cytochrome P450 oxidation and amide hydrolysis of BI 425809, was prepared labeled with carbon 13 and nitrogen 15 via two synthetic routes. In the first route, diethyl [ C ]malonate, [ C]methyl iodide, and hydroxyl[ N]amine were used to provide [ C , N]-BI 761036 ([ C , N]-6a) in 13 steps in 6% overall yield, whereas in the second route, [ C ]propargyl alcohol, potassium [ C]cyanide, and [ N]ammonia were used to furnish [ C , N]-BI 761036 ([ C , N]-6b) in 11 steps in 1% overall yield. The detailed stable isotope synthesis of 1 and its major metabolites is described.
Topics: Glycine Plasma Membrane Transport Proteins; Carbon Isotopes; Amides
PubMed: 37727936
DOI: 10.1002/jlcr.4063 -
Saudi Pharmaceutical Journal : SPJ :... Oct 2023Onion contains many dietary and bioactive components including phenolics and flavonoids. Spiraeoside (quercetin-4-O-β-D-glucoside) is one of the most putative...
Onion contains many dietary and bioactive components including phenolics and flavonoids. Spiraeoside (quercetin-4-O-β-D-glucoside) is one of the most putative flavonoids in onion. Several antioxidant techniques were used in this investigation to assess the antioxidant capabilities of spiraeoside, including 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·) scavenging, N,N-dimethyl-p-phenylenediamine radical (DMPD) scavenging, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS) scavenging activities, cupric ions (Cu) reducing and potassium ferric cyanide reduction abilities. In contrast, the water-soluble α-tocopherol analogue trolox and the conventional antioxidants butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and α-tocopherol were utilized as the standards for evaluation. Spiraeoside scavenged the DPPH radicals an IC of 28.51 μg/mL (r: 0.9705) meanwhile BHA, BHT, trolox, and α-tocopherol displayed IC of 10.10 μg/mL (r: 0.9015), 25.95 μg/mL (r: 0.9221), 7.059 μg/mL (r: 0.9614) and 11.31 μg/mL (r: 0.9642), accordingly. The results exhibited that spiraeoside had effects similar to BHT, but less potent than α-tocopherol, trolox and BHA. Also, inhibitory effects of spiraeoside were evaluated toward some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II) and α-glycosidase, which are related to a number of illnesses, such as Alzheimer's disease (AD), diabetes mellitus and glaucoma disorder. Spiraeoside exhibited IC values of 4.44 nM (r: 0.9610), 7.88 nM (r: 0.9784), 19.42 nM (r: 0.9673) and 29.17 mM (r: 0.9209), respectively against these enzymes. Enzyme inhibition abilities were compared to clinical used inhibitors including acetazolamide (for CA II), tacrine (for AChE and BChE) and acarbose (for α-glycosidase). Spiraeoside demonstrated effective antioxidant, anticholinergic, antidiabetic and antiglaucoma activities. With these properties, it has shown that Spiraeoside has the potential to be a medicine for some metabolic diseases.
PubMed: 37693735
DOI: 10.1016/j.jsps.2023.101760 -
ACS Omega Aug 2023Current flotation practices using lime or cyanide as depressants in chalcopyrite and pyrite separation have significant disadvantages, such as substantial reagent...
Current flotation practices using lime or cyanide as depressants in chalcopyrite and pyrite separation have significant disadvantages, such as substantial reagent consumption, high slurry pH, and environmental hazards. This work aimed to explore the utilization and mechanisms of tannic acid (TA) as an eco-friendly alternative to lime or cyanide in chalcopyrite-pyrite separation. Flotation results showed that TA selectively depressed pyrite yet allowed chalcopyrite to float at neutral or alkaline pH. Adsorption density and zeta potential results indicated that TA adsorbed intensely on pyrite but minorly on chalcopyrite. Besides, potassium ethyl xanthate was still largely adsorbed on chalcopyrite but not on pyrite after TA adsorption. Surface analysis by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy further showed that the oxidation species of FeOOH and Fe (SO), particularly FeOOH were the main active sites for TA chemical adsorption. Owing to the greater and faster oxidation of pyrite, more FeOOH and Fe (SO) were generated on the pyrite surface, and the chemical adsorption of TA was more pronounced on the pyrite surface than on the chalcopyrite surface.
PubMed: 37636951
DOI: 10.1021/acsomega.3c03663 -
Heliyon Jun 2023Spebrutinib is a new Bruton tyrosine kinase inhibitor developed by Avila Therapeutics and Celgene. Spebrutinib (SPB) is currently in phase Ib clinical trials for the...
Spebrutinib is a new Bruton tyrosine kinase inhibitor developed by Avila Therapeutics and Celgene. Spebrutinib (SPB) is currently in phase Ib clinical trials for the treatment of lymphoma in the United States. Preliminary studies were first performed to predict susceptible sites of metabolism, reactivity pathways and structural alerts for toxicities by StarDrop WhichP450™ module, Xenosite web predictor tool and DEREK software; respectively. SPB metabolites and adducts were characterized from rat liver microsomes (RLM) using LC-MS/MS. Formation of reactive intermediates was investigated using potassium cyanide (KCN), glutathione (GSH) and methoxylamine as trapping nucleophiles for the unstable and reactive iminium, iminoquinone and aldehyde intermediates, respectively, with the aim to produce stable adducts that can be detected and characterized using mass spectrometry. Fourteen phase I metabolites, four cyanide adducts, six GSH adducts and three methoxylamine adducts of SPB were identified and characterized. The proposed metabolic pathways involved in generation of phase I metabolites of SPB are oxidation, hydroxylation, -dealkylation, epoxidation, defluorination and reduction. Several reactive intermediates were identified and characterized, the formation of which can aid in explaining the adverse drug reactions of SPB. Several iminium, 2-iminopyrimidin-5()-one and aldehyde intermediates of SPB were revealed. Acrylamide is identified as a structural alert for toxicity by DEREK report and was found to be involved in the formation of several glycidamide and aldehyde reactive intermediates.
PubMed: 37484253
DOI: 10.1016/j.heliyon.2023.e17058