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Molecular Diversity Jun 2024Succinate dehydrogenase inhibitors (SDHIs) as one of the fastest-growing fungicide categories for plant protection. In this study, a series of N'-phenyl...
Succinate dehydrogenase inhibitors (SDHIs) as one of the fastest-growing fungicide categories for plant protection. In this study, a series of N'-phenyl pyridylcarbohydrazides as analogues of commercial SDHIs were designed and evaluated for inhibition activity on phytopathogenic fungi to search for potential novel SDHIs. The determination of antifungal activity in vitro and in vivo led to the discovery of a series of compounds with high activity and broad-spectrum property. Especially, N'-(4-fluorophenyl)picolinohydrazide (1c) and N'-(3,4-fluorophenyl)picolinohydrazide (1ae) showed 0.041-1.851 μg/mL of EC values on twelve fungi, superior to positive controls carbendazim and boscalid. In vivo activity, 1c at 50 μg/mL showed 61% of control efficacy at the post-treatment 9th day for the infection of P. piricola on apples, slightly smaller than 70% of carbendazim. In terms of action mechanism, 1c showed strong inhibition activity with IC of 0.107 μg/mL on SDH in Alternaria brassicae, superior to positive SDHI boscalid (IC 0.182 μg/mL). Molecular docking indicated that 1c can well bind with the ubiquinone-binding region of SDH mainly by hydrogen bond, carbon hydrogen bond, π-alkyl, amide-π stacking, F-N and F-H interactions. Furthermore, scanning and transmission electron micrographs showed that 1c was able to obviously change the structure of mycelia and cell membrane. Fluorescence staining analysis showed that 1c could increase both the intracellular reactive oxygen species level and mitochondrial membrane potential. Finally, seed germination test, seedling growth test and cytotoxicity assay showed that 1c had very low toxicity to plant growth and mammalian cells. Thus, N'-phenyl pyridylcarbohydrazides especially 1c and 1ae can be considered promising fungicide alternatives for plant protection.
PubMed: 38926303
DOI: 10.1007/s11030-024-10919-4 -
Journal of the Science of Food and... Jun 2024Proteins and anionic octenyl succinic anhydride (OSA)-modified starch (OSA-starch) are common ingredients in food systems. The interactions between OSA-starch and...
Understanding regulating effects of protein-anionic octenyl succinic anhydride-modified starch interactions on the structural, rheological, digestibility and release properties of starch.
BACKGROUND
Proteins and anionic octenyl succinic anhydride (OSA)-modified starch (OSA-starch) are common ingredients in food systems. The interactions between OSA-starch and protein are found to alter the structural and functional properties of the protein-OSA-starch complexes. In this regard, the close understanding of the relationship among the molecular interactions between whey protein isolate (WPI) and OSA-high amylose corn starch (HAS), structure changes and rheological, digestibility and release properties of WPI-OSA-HAS was investigated.
RESULTS
The molecular interactions of WPI-OSA-HAS were significant for increasing the surface rough, solubility, storage modulus and loss modulus, but decreasing the R values. For the nutritional evaluation, the anti-digestibility of WPI-OSA-HAS was enhanced with increased resistant starch + slowly digestible starch contents and decreased equilibrium hydrolysis percentage and kinetic constant. During the digestion, part of the starch granule, OSA groups and WPI were lost, but the loss was lower than for OSA-HAS. Furthermore, the results of curcumin-loaded WPI-OSA-HAS in simulated gastrointestinal fluids demonstrated that curcumin could be gradually released to simulate colonic fluid. Notably, the interaction between WPI and OSA-HAS depended on the WPI concentration with the stronger molecular interactions obtained at 35% concentration.
CONCLUSION
These results provided important information concerning how to adjust the rheological, anti-digestibility and release properties of WPI-OSA-HAS through altering the electrostatic interactions and hydrophobic interactions of WPI-OSA-HAS. © 2024 Society of Chemical Industry.
PubMed: 38925572
DOI: 10.1002/jsfa.13686 -
International Journal of Antimicrobial... Jun 2024Isobavachalcone (IBC) is a natural small-molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our...
Isobavachalcone (IBC) is a natural small-molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our study, IBC showed a good antifungal effect. Through in vitro experiments, its minimum inhibitory concentration (MIC) was 0.5-1 μg/mL. It exhibited the same antifungal effect as Amphotericin B in brain and lung infections in in vivo experiments. IBC also showed a synergistic antifungal effect with emodin with lower toxicity, and C. neoformans did not develop drug resistance to IBC. In the mechanistic study, significantly damaged mitochondria of C. neoformans, a significant reduction in mitochondrial membrane potential and adenosine triphosphate (ATP) production, and an increase in hydrogen peroxide [HO] caused by IBC were observed using transmission electron microscopy. Through drug affinity-responsive target stability combined with phenotype detection, riboflavin synthases of aconitase and succinate dehydrogenase were screened. Molecular docking, quantitative polymerase chain reaction experiments, target inhibitor and agonist intervention, molecular interaction measurements, and MIC detection of the constructed expression strains revealed that IBC targeted the activity of these two enzymes, interfered by the tricarboxylic acid cycle, inhibited the production of ATP, blocked electron transport, reduced mitochondrial membrane potential, and induced antioxidation imbalance and reactive oxygen species accumulation, thus producing an antifungal effect. Therefore, IBC is a promising lead drug and redox antifungal agent for C. neoformans.
PubMed: 38925229
DOI: 10.1016/j.ijantimicag.2024.107253 -
European Journal of Medicinal Chemistry Jun 2024Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma...
Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with ICs of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice.
PubMed: 38925013
DOI: 10.1016/j.ejmech.2024.116598 -
Food Chemistry Jun 2024Phenylalanine (Phe) accelerates fruit wound healing by activating phenylpropanoid metabolism. However, whether Phe affects sucrose and respiratory metabolism in fruit...
Phenylalanine (Phe) accelerates fruit wound healing by activating phenylpropanoid metabolism. However, whether Phe affects sucrose and respiratory metabolism in fruit during wound healing remains unknown. In this research, we found that preharvest Phe spray promoted sucrose degradation and increased glucose and fructose levels by activating acid invertase (AI), neutral invertase (NI), sucrose synthase (SS) and sucrose phosphate synthase (SPS) on harvested muskmelons. The spray also activated hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), malate dehydrogenase (MDH), succinate dehydrogenase (SDH) and glucose-6-phosphate dehydrogenase (G6PDH). In addition, the spray improved energy and reducing power levels in the fruit. Taken together, preharvest Phe spray can provide carbon skeleton, energy and reducing power for wound healing by activating the sucrose metabolism, Embden-Meyerhof-Parnas (EMP) pathway, tricarboxylic acid (TCA) cycle and pentose phosphate (PPP) pathway in muskmelon wounds during healing, which is expected to be developed as a new strategy to accelerate fruit wound healing.
PubMed: 38924917
DOI: 10.1016/j.foodchem.2024.140194 -
Protein Science : a Publication of the... Jul 2024The effect of population bottlenecks and genome reduction on enzyme function is poorly understood. Candidatus Liberibacter solanacearum is a bacterium with a reduced...
The effect of population bottlenecks and genome reduction on enzyme function is poorly understood. Candidatus Liberibacter solanacearum is a bacterium with a reduced genome that is transmitted vertically to the egg of an infected psyllid-a population bottleneck that imposes genetic drift and is predicted to affect protein structure and function. Here, we define the function of Ca. L. solanacearum dihydrodipicolinate synthase (CLsoDHDPS), which catalyzes the committed branchpoint reaction in diaminopimelate and lysine biosynthesis. We demonstrate that CLsoDHDPS is expressed in Ca. L. solanacearum and expression is increased ~2-fold in the insect host compared to in planta. CLsoDHDPS has decreased thermal stability and increased aggregation propensity, implying mutations have destabilized the enzyme but are compensated for through elevated chaperone expression and a stabilized oligomeric state. CLsoDHDPS uses a ternary-complex kinetic mechanism, which is to date unique among DHDPS enzymes, has unusually low catalytic ability, but an unusually high substrate affinity. Structural studies demonstrate that the active site is more open, and the structure of CLsoDHDPS with both pyruvate and the substrate analogue succinic-semialdehyde reveals that the product is both structurally and energetically different and therefore evolution has in this case fashioned a new enzyme. Our study suggests the effects of genome reduction and genetic drift on the function of essential enzymes and provides insights on bacteria-host co-evolutionary associations. We propose that bacteria with endosymbiotic lifestyles present a rich vein of interesting enzymes useful for understanding enzyme function and/or informing protein engineering efforts.
Topics: Lysine; Genome, Bacterial; Symbiosis; Genetic Drift; Hydro-Lyases; Bacterial Proteins; Animals
PubMed: 38924211
DOI: 10.1002/pro.5083 -
Cell Reports Jun 2024Succinate, a citric acid cycle intermediate, serves important functions in energy homeostasis and metabolic regulation. Extracellular succinate acts as a stress signal...
Succinate, a citric acid cycle intermediate, serves important functions in energy homeostasis and metabolic regulation. Extracellular succinate acts as a stress signal through succinate receptor (SUCNR1), a class A G protein-coupled receptor. Research on succinate signaling is hampered by the lack of high-resolution structures of the agonist-bound receptor. We present cryoelectron microscopy (cryo-EM) structures of SUCNR1-Gi complexes bound to succinate and its non-metabolite derivative cis-epoxysuccinate. Key determinants for the recognition of succinate in cis conformation include R281 and Y83, while Y30 and R99 participate in the binding of both succinate and cis-epoxysuccinate. Extracellular loop 2, through F175 in its β-hairpin, forms a hydrogen bond with succinate and caps the binding pocket. At the receptor-Gi interface, agonist binding induces the rearrangement of a hydrophobic network on transmembrane (TM)5 and TM6, leading to TM signaling through TM3 and TM7. These findings extend our understanding of succinate recognition by SUCNR1, aiding the development of therapeutics for the succinate receptor.
PubMed: 38923454
DOI: 10.1016/j.celrep.2024.114381 -
Journal of Food Science Jun 2024In vegetable fermentation, pellicle is a common quality deterioration phenomenon. This study investigates the characteristics of glucose, organic acids, amino acids, and...
In vegetable fermentation, pellicle is a common quality deterioration phenomenon. This study investigates the characteristics of glucose, organic acids, amino acids, and biogenic amines during the pellicle occurrence and disappearance of paocai. The results revealed a slight increase in pH of the fermentation system after pellicle occurred, and glucose was the main carbohydrate that microbial activity primary relied on. The microorganisms responsible for pellicle formation consumed organic acids in brine, but the lactic acid in paocai gradually increased and exceeded 25 mg/g. The appearance of pellicle caused a decrease in total free amino acids from 200.390 mg/100 g to 172.079 when pellicle occurred, whereas its impact on biogenic amines was not apparent. Through Kyoto Encyclopedia of Genes and Genomes pathway enrichment of metagenomics sequencing data, screening, and sorting of the key enzymes involved in organic acid metabolism, it was observed that the composition and species of the key microorganisms capable of metabolizing organic acids were more abundant before the appearance of pellicle. When pellicle occurred, lactic acid may be metabolized by Lactobacillus plantarum; in contrast, Lactobacillus and Pichia were associated with citric acid metabolism, and Lactobacillus, Pichia, Saccharomycodes, and Kazachstania were linked to malic acid metabolism. Moreover, Prevotella, Kazachstania, Lactobacillus, Vibrio, and Siphonobacter were implicated in succinic acid metabolism. Additionally, the production of tartaric acid and oxalic acid in paocai and brine resulted from abiotic effects. This knowledge offers a theoretical basis for precise control of paocai fermentation process. PRACTICAL APPLICATION: Our study revealed the specific situation of the metabolites produced by the microorganisms during the pollution and recovery process of pellicle in paocai fermentation, especially the effect of pellicle on the key process of organic acid metabolism. These research results provided theoretical basis for precise control of paocai fermentation.
PubMed: 38922911
DOI: 10.1111/1750-3841.17178 -
Acta Chimica Slovenica Jun 2024Diabetes mellitus is a chronic metabolic disorder marked by elevated blood sugar levels, leading to organ dysfunction. Curcumin, derived from turmeric, exhibits promise...
Diabetes mellitus is a chronic metabolic disorder marked by elevated blood sugar levels, leading to organ dysfunction. Curcumin, derived from turmeric, exhibits promise in managing type II diabetes. Nanomicelles were created by conjugating curcumin with chitosan through succinic anhydride. Succinyl-curcumin, the resultant compound, was esterified with chitosan to form a polymer prodrug conjugate. Nanomicelles, formed via dialysis, were spherical with a hydrodynamic size of 49.37 nm. In vitro release studies revealed 97% curcumin release at pH 5 in 7 days. A 21-day experiment on diabetic mice compared nanomicelles, standard drug, and free curcumin's impact on fasting blood glucose. The study showcased gradual, controlled curcumin release from nanomicelles, suggesting their potential in type II diabetes treatment.
Topics: Animals; Curcumin; Chitosan; Diabetes Mellitus, Type 2; Micelles; Mice; Mice, Inbred BALB C; Diabetes Mellitus, Experimental; Prodrugs; Nanoparticles; Male; Blood Glucose; Hypoglycemic Agents
PubMed: 38919100
DOI: 10.17344/acsi.2024.8658 -
Biomaterials Jun 2024Drug transmission through the blood-brain barrier (BBB) is considered an arduous challenge for brain injury treatment following the return of spontaneous circulation...
Drug transmission through the blood-brain barrier (BBB) is considered an arduous challenge for brain injury treatment following the return of spontaneous circulation after cardiac arrest (CA-ROSC). Inspired by the propensity of melanoma metastasis to the brain, B16F10 cell membranes are camouflaged on 2-methoxyestradiol (2ME2)-loaded reactive oxygen species (ROS)-triggered "Padlock" nanoparticles that are constructed by phenylboronic acid pinacol esters conjugated D-a-tocopheryl polyethylene glycol succinate (TPGS-PBAP). The biomimetic nanoparticles (BM@TP/2ME2) can be internalized, mainly mediated by the mutual recognition and interaction between CD44v6 expressed on B16F10 cell membranes and hyaluronic acid on cerebral vascular endothelial cells, and they responsively release 2ME2 by the oxidative stress microenvironment. Notably, BM@TP/2ME2 can scavenge excessive ROS to reestablish redox balance, reverse neuroinflammation, and restore autophagic flux in damaged neurons, eventually exerting a remarkable neuroprotective effect after CA-ROSC in vitro and in vivo. This biomimetic drug delivery system is a novel and promising strategy for the treatment of cerebral ischemia-reperfusion injury after CA-ROSC.
PubMed: 38917705
DOI: 10.1016/j.biomaterials.2024.122678