The dynamically evolving science of pharmacology requires AI technology to advance a new path for drug development. The author proposes generative AI for future drugs, identifying suitable drug molecules, uncharacteristically to previous generations of medicines, incorporating the wisdom, experience, and intuit of traditional materia medica and the respective traditional medicine practitioners. This paper describes the guiding principles of the new drug development, springing from the tradition and practice of Tibetan medicine, defined as the Interactive Nutrient Process (INP). The INP provides traditional knowledge and practitioner\'s experience, contextualizing and teaching the new drug therapy. An illustrative example of the outcome of the INP is a potential small molecule drug, 6-Shogaol and related shogaol derivatives, from ginger roots (Zingiber officinalis fam. Zingiberaceae) evaluated clinically for 12 months for biological markers of iron homeostasis in patients with the myelodysplastic syndromes (MDS). The study\'s preliminary results indicate that 6-Shogaol and related shogaols may improve iron homeostasis in low-risk/intermediate-1 MDS patients without objective or subjective side effects.

The plant hormone salicylic acid (SA) plays critical roles in plant innate immunity. Several SA derivatives and associated modification are identified, whereas the range and modes of action of SA-related metabolites remain elusive. Here, the study discovered 2,4-dihydroxybenzoic acid (2,4-DHBA) and its glycosylated form as native SA derivatives in plants whose accumulation is largely induced by SA application and Ps. camelliae-sinensis (Pcs) infection. CsSH1, a 4/5-hydroxylase, catalyzes the hydroxylation of SA to 2,4-DHBA, and UDP-glucosyltransferase UGT95B17 catalyzes the formation of 2,4-DHBA glucoside. Down-regulation reduced the accumulation of 2,4-DHBA glucosides and enhanced the sensitivity of tea plants to Pcs. Conversely, overexpression of UGT95B17 increased plant disease resistance. The exogenous application of 2,4-DHBA and 2,5-DHBA, as well as the accumulation of DHBA and plant resistance comparison, indicate that 2,4-DHBA functions as a potentially bioactive molecule and is stored mainly as a glucose conjugate in tea plants, differs from the mechanism described in Arabidopsis. When 2,4-DHBA is applied exogenously, UGT95B17-silenced tea plants accumulated more 2,4-DHBA than SA and showed induced resistance to Pcs infection. These results indicate that 2,4-DHBA glucosylation positively regulates disease resistance and highlight the role of 2,4-DHBA as potentially bioactive molecule in the establishment of basal resistance in tea plants.

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The ultimate goal in the understanding of complex chemical processes is a complete description of the underlying reaction mechanism. In the present study and for this purpose, a novel experimental platform is introduced that builds upon electrochemistry capable of generating reactive intermediate species at the electrode surface. The atmospherically relevant nitration of catechols is taken as a case example. First, we confirm the recently proposed nitration mechanism, advancing the understanding of atmospheric brown carbon formation in the dark. We are able to selectively quantify aromatic isomers, which is beyond the limits of conventional electroanalysis. Second, we identify a new pathway of nitrocatechol hydroxylation, which proceeds simply by oxidation and the addition of water. This pathway can be environmentally significant in the dark aqueous-phase formation of secondary organic aerosols. Third, the developed methodology is capable of selectively detecting a wide range of nitroaromatics; a possible application in environmental monitoring is proposed.

METHODS: Catechol moieties are commonly present in dietary natural products that exert cancer chemopreventive activity. While the oxidative conversion of catechols into their corresponding o-quinones is generally considered to contribute to their cancer chemopreventive effects, the mechanism of the intracellular conversion has not been fully elucidated.
RESULTS: Among resveratrol and its hydroxylated analogs examined, only 3,4-dihydroxy-trans-stilbene exerted cytoprotective effects against t-butylhydroperoxide-induced death of HepG2 cells. This resveratrol analog activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway through stimulating phosphorylation of Akt and inducing keap1 modification, thereby resulting in its nuclear translocation and subsequent transcriptional induction of phase II detoxifying enzymes. Its cytoprotective effect through Nrf2 activation was largely abrogated by pretreatment of cells with DTT, a sulfhydryl-containing nucleophile, and neocuproine, a specific chelating agent for copper ions.
CONCLUSIONS: We identified 3,4-dihydroxy-trans-stilbene as a novel Nrf2 activator that is converted intracellularly into its corresponding o-quinone electrophile by copper ions. The copper-mediated oxidation was required for the Nrf2 activation, subsequent transcriptional induction of phase II detoxifying enzymes and ultimately for cytoprotection. The findings demonstrate a previously underrecognized role for intracellular copper ions in the cancer chemopreventive effects of catechol-containing dietary natural products.

A new method based on nano-liquid chromatography coupled to time-of-flight mass spectrometry (nano-LC-TOF-MS) using lock-mass calibration was developed to facilitate the accurate and routine characterization and quantification of phenolic compounds. Thus, it was applied to study cranberry syrups, in which, using negative ionization mode, a total of nine phenolic compounds were unequivocally identified using standards and 38 tentatively taking into account their retention time, accurate mass (errors<5 ppm) data and isotope pattern, as well as literature. Among them, 13 compounds, belonging to flavonols and iridoids conjugated with phenolic acids, were reported for first time in cranberry or cranberry based-products. The analytical method was also validated using chlorogenic acid, p-coumaric acid, (+)-catechin, (-)-epicatechin, procyanidin A2, quercetin 3-O-glucoside, quercetin 3-O-rhamnoside, quercetin, and myricetin standards. In this way, the analytical method showed adequate linearity, with R(2) above 0.99, and acceptable values of intra- and inter-day repeatability of the retention time and peak area. The detection limits and quantification were between 1.0-15.6 ng mL(-1) and 2.0-62.5 ng mL(-1), respectively. The method can be extended to characterize phenolic compounds in other food and plant matrices, and as well biological samples.

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Due to regulatory constraints and ethical considerations, the quest for alternatives to animal testing has gained a new momentum. In general, animal welfare considerations and compliance with regulations are the key drivers for this research. Mechanistically based in vitro tests addressing specific toxicological questions can yield new information, for example on reactive components, and thus in certain cases the in vitro tests are not only second choice replacements of a \'gold standard\' animal test but can also be used to develop safer products. Here we report a case study from the in vitro investigation on the commercial fragrance chemical Azurone. This compound was found to be a moderate skin sensitizer in the LLNA, whereas the structurally closely similar compound Calone is a non-sensitizer. A peptide reactivity assay indicated, that indeed Azurone yields peptide depletion, thus the in vitro assays confirmed the animal test result. LC-MS analysis of the peptide reactivity sample showed the presence of peptide adducts of unexpected molecular weight. They were consistent with the reaction of the peptide with a catechol related to Azurone. Detailed analytics indicated that indeed this catechol is present in the original batches as an impurity, but it has escaped quality control analysis, as it is not detectable in routine GC-analysis. A new purified batch was prepared, re-tested in the in vitro assays and predicted by the tests to be a non-sensitizer. A confirmatory LLNA test indeed yielded a significantly (10-fold) higher EC3 value of the new batch, but the LLNA was still positive. A dose-response study in the EpiSkin assay indicated that this molecule still has a significant skin irritation potential, which may generate the weak positive signal in the LLNA. This case study illustrates how the mechanistically based in vitro LC-MS peptide reactivity assay can be used to contribute to the understanding of the sensitization mechanism of a commercial product and help to define a safer product specification.

Many industries employ the activated sludge process for biological removal of pollutants present in wastewater. Yet, treatment plants do notfunction at optimum potential. The biological component of such systems remains a black box, and reasons responsible for poor performance have not been identified. We have used genomic and physiological tools to understand the process and propose that analysis of catabolic signatures and nutrient levels, are crucial parameters in assessing and monitoring the performance of an effluent treatment plant. In this study, we use activated sludge collected from a refinery running at a capacity of 8 million metric tonnes of wastewater as a model. The presence of hydroxylases, oxygenases, and dioxygenases in the biomass was demonstrated by polymerase chain reaction and sequence analysis of aromatic-ring hydroxylating dioxygenase clones extracted from the metagenome, suggests the presence of hitherto unreported enzymes. The actual degradative state of the biomass was demonstrated by respirometric analysis using 11 substrates expected in refinery wastewater. Nutrient-levels required for the microbial population were estimated by on-site analysis. Diagnosis of the degradative potential of activated sludge can be carried out by incorporating these tools in regular monitoring procedures and can setthe rules for improving the efficiency of treatment

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