Drug metabolism and disposition diversity of Ranunculales phytometabolites: a systems perspective

<p><b>Introduction</b>: Although investigations in metabolism and pharmacokinetics of Ranunculales phytometabolites are booming, data obtained from human and animal studies have not been summarized as a whole to outline current trends and to predict future development.</p> <p><b>Areas covered</b>: Here, we highlight the current knowledge, as well as the challenges around the DMPK (drug metabolism and pharmacokinetics) associated concerns in streamlining drug research and therapeutic use of Ranunculales phytometabolites. Data from various <i>in vivo</i> and <i>in vitro</i> models are classified and discussed. DMPK characteristics of Ranunculales phytometabolites are summarized and presented according to the phylogenetic relationship of families and genera. This review also presents an overview of the complex interaction between drug metabolizing enzymes/transporters and phytochemicals, as well as of the most advanced approaches in the relevant field.</p> <p><b>Expert opinion</b>: Since species-specific differences in DMPK exist, data obtained from animal studies may not be sufficient to predict drug metabolism reactions in humans. Omics-based methodologies (genomics, epigenomics, transcriptomics, proteomics, microbiomics, and metabolomics) should be used to enhance the reliability of DMPK prediction. The fluorescent probes may bridge the gap between conventional models and <i>in vivo</i> clinical studies in humans and provide a consistent basis for DMPK assay development.</p

Table_1_Altered resting-state brain functional activities and networks in Crohn’s disease: a systematic review.DOCX

BackgroundCrohn’s disease (CD) is a non-specific chronic inflammatory disease of the gastrointestinal tract and is a phenotype of inflammatory bowel disease (IBD). The current study sought to compile the resting-state functional differences in the brain between CD patients and healthy controls.MethodsThe online databases PubMed, Web of Science Core, and EMBASE were used to find the published neuroimage studies. The search period was from the beginning through December 15, 2023. The predetermined inclusion and exclusion criteria allowed for the identification of the studies. The studies were assembled by two impartial reviewers, who also assessed their quality and bias.ResultsThis review comprised 16 resting-state fMRI studies in total. The included studies generally had modest levels of bias. According to the research, emotional processing and pain processing were largely linked to increased or decreased brain activity in patients with CD. The DMN, CEN, and limbic systems may have abnormalities in patients with CD, according to research on brain networks. Several brain regions showed functional changes in the active CD group compared to the inactive CD group and the healthy control group, respectively. The abnormalities in brain areas were linked to changes in mood fluctuations (anxiety, melancholy) in patients with CD.ConclusionFunctional neuroimaging helps provide a better understanding of the underlying neuropathological processes in patients with CD. In this review, we summarize as follows: First, these findings indicate alterations in brain function in patients with CD, specifically affecting brain regions associated with pain, emotion, cognition, and visceral sensation; second, disease activity may have an impact on brain functions in patients with CD; and third, psychological factors may be associated with altered brain functions in patients with CD.</p

Theoretical Studies on the Catalytic Cycle of Histidine Acid Phosphatases Revealing an Acid Proof Mechanism

After reporting the mechanisms of purple acid phosphatases against acid environments and alkaline phosphatases against alkaline environments, in the present work, we continued investigating the relationship between catalytic structures of histidine acid phosphatases (HAPs) and acid environments. On the basis of the comparison of the crystal structures of several HAP members, a series of models were constructed and calculated using density functional theory. Our calculations describe a complete catalytic cycle of HAPs, including a free stage and a catalytic reaction stage. This cycle reveals a definite mechanism for HAPs to survive in acidic environments, which can be used to nicely interpret acidic pH optima of HAPs. It also suggests that a free water molecule from a solvent should be the nucleophile for hydrolyzing the phosphohistidine intermediate. Our studies are focused on the biological significance of enzymatic mechanisms and raise two concrete criteria: the logic-complete catalytic cycle and the evolutional relation with family members and molecular environments

UGT1A10 Is a High Activity and Important Extrahepatic Enzyme: Why Has Its Role in Intestinal Glucuronidation Been Frequently Underestimated?

The aim of this work was to highlight a considerable and broad problem in UGT1A10 activity assessment that has led to underestimation of its role in intestinal glucuronidation of drugs and other xenobiotics. The reason appears to be poor activity of the commercial UGT1A10 that is used by many laboratories, and here we have tested it by comparison with our recombinant His-tagged UGT1A10 (designated as UGT1A10-H), both expressed in insect cells. The glucuronidation rates of morphine, estradiol, estrone, SN-38, diclofenac, 4-methylumbelliferone, 7-amino-4-methylcoumarin, <i>N</i>-(3-carboxypropyl)-4-hydroxy-1,8-naphthalimide, and bavachinin were assayed. The results revealed that the activity of commercial UGT1A10 was low, very low, and in the cases of morphine, estrone, 7-methyl-4-aminocoumarin, and bavachinin it was below the detection limit. On the other hand, under the same conditions, UGT1A10-H exhibited high glucuronidation rates toward all these compounds. Moreover, using estradiol, morphine, and estrone, in the presence and absence of suitable inhibitors, nilotinib or atractylenolide I, it was demonstrated that UGT1A10-H, but not the commercial UGT1A10, provides a good tool to study the role of native UGT1A10 in the human intestine. The results also suggest that much of the data in the literature on UGT1A10 activity may have to be re-evaluated

Substrate Effects in the Supramolecular Self-Assembly of 2,4,6-Tris(4-bromophenyl)-1,3,5-triazine on Graphite and Graphene

Two-dimensional self-assembly of star-shaped 2,4,6-tris­(4-bromophenyl)-1,3,5-triazine (BPT) molecule is investigated both on highly oriented pyrolytic graphite (HOPG) and single-layer graphene (SLG) grown on a polycrystalline Cu foil. Scanning tunneling microscopy (STM) reveals that this molecule can form different self-assembling structures on these two different surfaces. On the basis of high-resolution STM images, we find that BPT molecules can form compact and loose assembly patterns with different packing densities on HOPG surface and a porous structure with hexagonal-like cavities on SLG surface. A combination of STM and density functional theory calculations elucidates the interplay of molecule–molecule and molecule–substrate interactions on the assembling behavior on both substrates

MiR-9-3p augments apoptosis induced by H₂O₂ through down regulation of Herpud1 in glioma - Fig 5

<p>Relative luciferase activities of Herpud1 wild type (wt) UTRs (A) and three mutant UTRs of Herpud1 (B) were obtained by co-transfection of negative control miRNA or miR-9-3p mimics and pRL-CMV plasmid. Relative luciferase activity was calculated as the ratio of firefly/Renilla activities in the cells and normalized to those of the control. The results are presented as mean±SD from three independent experiments. ***P<0.001.</p

Heat map of differential miRNA expression in glioma and non-tumor tissues.

<p>Both down-regulated (red) and up-regulated (blue) miRNAs were identified in glioma tissues (N = 3) versus non-tumor tissues (N = 3).</p

Schematic diagram of the putative miR-9-3p binding site in the UTRs of Herpud1.

<p>The seed sequence of miR-9-3p matches the UTRs of Herpud1. The 3 mutated nucleotides of the Herpud1-UTR are in bold and underlined.</p

Herpud1 levels in U251 cells and glioma tissues.

<p>(A) U251 cells were transfected with 200 nM negative control miRNA (NC) and miR-9-3p mimics. Expression of Herpud1 was normalized by GAPDH using the 2^-ΔΔct method. **P<0.01; (B) and the protein level of HERPUD1 was detected by westernblot. (C) Relative expression levels of Herpud1 were measured by using qRT-PCR with GAPDH as an internal control. The box extends from the 25^th to the 75^th percentile; the bar in the middle indicates the 50^th percentile; the whisker caps indicate the maximum and the minimum values. S: significant; NS: not significant. *P<0.05.</p

MiR-9-3p augments H₂O₂ induced apoptosis through Herpud1.

<p>(A) Cell proliferation of transfected U251 cells was determined using CCK8 assay at 24h, 48 and 72h. U251 cells were treated with 500μM H₂O₂ for 4, 6, 8 and 24h after transfected with miR-9-3p mimics (B) or HERPUD1-RNAi plasmids (D) for 48h. Apoptotic cells were detected by staining with FITC-Annexin V and propidium iodide. (C) U251 cells were transfected with 2μg HERPUD1-RNAi-CON. and three RNAi plasmids. The protein level of HERPUD1 was detected by westernblot.</p