BACKGROUND: This study investigates the potential of eleven 1H-1,2,3-triazol-1,4-naphthoquinone conjugates as virulence factor inhibitors (like Pyocyanin) and their affinity for PhzM, a crucial enzyme for Pyocyanin biosynthesis in Pseudomonas aeruginosa infections.
METHODS: A straightforward synthetic pathway enabled the production of these compounds, which were characterized and structurally confirmed through spectroscopic analyses. Evaluation of their impact on PhzM thermal stability identified promising candidates for PhzM binders.
RESULTS: Concentration-response behavior elucidated their binding affinity, revealing them as the first reported micromolar affinity ligands for PhzM. Structure-activity relationship analysis emphasized the role of specific molecular moieties in binding affinity modulation, paving the way for future advanced inhibitors\' development.
CONCLUSIONS: These findings highlight the potential of naphthoquinone-triazole derivatives as leads for novel therapeutics against P. aeruginosa infections.

Successful plant reproduction depends on the adequate development of flower organs controlled by cell proliferation and other processes. The SCI1 gene regulates cell proliferation and affects the final size of the female reproductive organ. To unravel the molecular mechanism exerted by SCI1 in cell proliferation control, we searched for its interaction partners through semi-in vivo pulldown experiments, uncovering a cyclin-dependent kinase, NtCDKG;2. Bimolecular fluorescence complementation (BiFC) and co-localization experiments showed that SCI1 interacts with NtCDKG;2 and its cognate NtCyclin L in nucleoli and splicing speckles. The screening of a yeast two-hybrid (Y2H) cDNA library using SCI1 as bait revealed a novel DEAD-box RNA helicase (NtRH35). The interaction between the NtCDKG;2-NtCyclin L complex, and NtRH35 was also shown. Subcellular localization experiments showed that SCI1, NtRH35, and the NtCDKG;2-NtCyclin L complex associate with each other within splicing speckles. The Y2H screening of NtCDKG;2 and NtRH35 identified the conserved spliceosome components U2a\', NKAP, and CACTIN. This work presents SCI1 and its interactors NtCDKG;2-NtCyclin L complex, and NtRH35 as new spliceosome-associated proteins. Our findings reveal a network of interactions and suggest that SCI1 may regulate cell proliferation through the splicing process. This study provides new valuable insights into the intricate molecular pathways governing plant development.

Psychedelics have emerged as promising therapeutics for several psychiatric disorders. Hypotheses around their mechanisms have revolved around their partial agonism at the serotonin 2 A receptor, leading to enhanced neuroplasticity and brain connectivity changes that underlie positive mindset shifts. However, these accounts fail to recognise that the gut microbiota, acting via the gut-brain axis, may also have a role in mediating the positive effects of psychedelics on behaviour. In this review, we present existing evidence that the composition of the gut microbiota may be responsive to psychedelic drugs, and in turn, that the effect of psychedelics could be modulated by microbial metabolism. We discuss various alternative mechanistic models and emphasize the importance of incorporating hypotheses that address the contributions of the microbiome in future research. Awareness of the microbial contribution to psychedelic action has the potential to significantly shape clinical practice, for example, by allowing personalised psychedelic therapies based on the heterogeneity of the gut microbiota.

Arsenic-hyperaccumulator Pteris vittata exhibits remarkable absorption ability for chromium (Cr) while beneficial element selenium (Se) helps to reduce Cr-induced stress in plants. However, the effects of Se on the Cr uptake and the associated mechanisms in P. vittata are unclear, which were investigated in this study. P. vittata plants were grown for 14 days in 0.2-strength Hoagland solution containing 10 (Cr10) or 100 μM (Cr100) chromate (CrVI) and 1 μM selenate (Se1). The plant biomass, malondialdehyde contents, total Cr and Se contents, Cr speciation, expression of genes associated with Cr uptake, and Cr subcellular distribution in P. vittata were determined. P. vittata effectively accumulated Cr by concentrating 96-99% in the roots under Cr100 treatment. Further, Se substantially increased its Cr contents by 98% to 11,596 mg kg-1 in the roots, which may result from Se\'s role in reducing its oxidative stress as supported by 27-62% reduction in the malondialdehyde contents. Though supplied with CrVI, up to 98% of the Cr in the roots was reduced to insoluble chromite (CrIII), with 83-89% being distributed on root cell walls. Neither Cr nor Se upregulated the expression of sulfate transporters PvSultr1;1-1;2 or phosphate transporter PvPht1;4, indicating their limited role in Cr uptake. P. vittata effectively accumulates Cr in the roots mainly as CrIII on cell walls and Se effectively enhances its Cr uptake by reducing its oxidative stress. Our study suggests that Se can be used to enhance P. vittata Cr uptake and reduce its oxidative stress, which may have application in phytostabilization of Cr-contaminated soils.

A novel class of pleuromutilin derivatives possessing 1,2,3-triazole as the linker connected to phenyl analogues were designed. The antibacterial properties of the prepared compounds were assessed in vitro against five strains (E. coli, S. aureus, S. epidermidis, and E. faecalis). Most of the tested compounds displayed potent antibacterial activities against gram-positive bacteria and 14-O-[2-(4-((2,4-dinitrophenoxy)-methyl-1H-1,2,3-triazol-1-yl) acetamide)-2-methylpropan-2-yl) thioacetyl]mutilin (7c) exerted antibacterial activities against S. aureus, MRSA and S. epidermidis with MIC values 0.0625 μg/mL, representing 64-fold, 4-fold and 8-fold higher than tiamulin respectively. Compound 6e, 7c and 8c were chosen to carry out killing kinetics, which exhibited concentration-dependent effect. Subsequently, molecular modeling was conducted to further explore the binding of compound 6e, 7a, 7c, 8c and tiamulin with 50S ribosomal subunit from deinococcus radiodurans. The investigation revealed that the main interactions between compound 7c and the ribosomal residues were three hydrogen bonds, π-π, and p-π conjugate effects. Additionally, the free binding energy and docking score of 7c with the ribosome demonstrated the lowest values of -11.90 kcal/mol and -7.97 kcal/mol, respectively, consistent with its superior antibacterial activities.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients often benefit from EGFR inhibitors like gefitinib. However, drug resistance remains a significant challenge in treatment. The unique properties of 1,2,3-triazole, a nitrogen-based compound, hold promise as potential solutions due to its versatile structural attributes and diverse biological effects, including anticancer properties.
METHODS: Our synthesis process involved the huisgen cycloaddition chemical method, which generated diverse icotinib derivatives. We evaluated the anticancer capabilities of these derivatives against various cancer cell lines, with a specific focus on NSCLC cells that exhibit drug resistance. Additionally, we investigated the binding affinity of selected compounds, including 3l, towards wild-type EGFR using surface plasmon resonance (SPR) experiments.
RESULTS: Notably, icotinib derivatives such as derivative 3l demonstrated significant efficacy against different cancer cell lines, including those resistant to conventional therapies. Compound 3l exhibited potent activity with IC50 values below 10 μM against drug-resistant cells. SPR experiments revealed that 3l exhibited enhanced affinity towards wild-type EGFR compared to icotinib. Our research findings suggest that 3l acts as a compelling antagonist for the protein tyrosine kinase of EGFR (EGFR-PTK).
CONCLUSIONS: Icotinib derivative 3l, featuring a 1,2,3-triazole ring, demonstrates potent anticancer effects against drug-resistant NSCLC cells. Its enhanced binding affinity to EGFR and modulation of the EGFR-RAS-RAF-MAPK pathway position 3l as a promising candidate for the future development of anticancer drugs.

Following the publication of this paper, it was drawn to the Editor\'s attention by a concerned reader that the data featured in Figs. 1, 4 and 5 (including western blotting data) were strikingly similar to data that had appeared in a different form in a different article by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been accepted for publication in another article prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 16: 8900‑8906, 2017; DOI: 10.3892/mmr.2017.7680].

Cancer stem cells (CSCs) are a group of tumor cells with high tumorigenic ability and self-renewal potential similar to those of normal stem cells. CSCs are the key \"seeds\" for tumor development, metastasis, and recurrence. A better insight into the key mechanisms underlying CSC survival improves the efficiency of cancer therapy via specific targeting of CSCs. Insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) signaling plays an important role in the maintenance of cancer stemness. However, the effect of IGF/IGF-1R signaling on stemness and CSCs and the underlying mechanisms are still controversial. Based on the similarity between CSCs and normal stem cells, this review discusses emerging data on the functions of IGF/IGF-1R signaling in normal stem cells and CSCs and dissects the underlying mechanisms by which IGF/IGF-1R signaling is involved in CSCs. On the other hand, this review highlighted the role of IGF/IGF-1R signaling blockade in multiple CSCs as a potential strategy to improve CSC-based therapy.

UNASSIGNED: Faidherbia albida, popularly known as gawo in Hausa, is traditionally used to treat jaundice in Zuru emirate of Kebbi State. Herein, the ameliorative effect of F. albida against 2.4-dinitrophenylhydrazine-induced hyperbilirubinemia in Wistar albino rats was investigated.
UNASSIGNED: Thirty healthy rats were administered 75 mg of 2.4-dinitrophenylhydrazine to induce hyperbilirubinemia. Thereafter, groups 1-3 received 500, 750, and 1000 mg/kg body weight of the methanol stem-bark extract, and 15 mg/kg of phenobarbitone (standard drug) was administered to group 4. Groups 5 and 6 served as the untreated and normal controls, respectively. The phytochemical composition was evaluated using standard methods, and acute oral toxicity was evaluated using standard OECD 2008 guidelines.
UNASSIGNED: Phytochemical analysis revealed the presence of alkaloids, phenols, and a substantial amount of tannins. A significant (P<0.05) reduction of direct bilirubin, total bilirubin, and total protein levels for all the doses of the extract and standard drug compared to untreated groups was observed. Similarly, there were significant reductions in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels of the group treated with the standard drug and all extract-treated groups compared to elevated levels observed in untreated controls. However, a significant (P<0.05) increase in serum albumin (ALB) levels, red blood cells, hemoglobin, and pack cell volume was observed in all extract-treated compared to the untreated control in contrast to a significant decrease in MCH levels in treated groups compared to the untreated group.
UNASSIGNED: F. albida ameliorated the hyperbilirubinemia induced by 2.4-dinitrophenylhydrazine in Wistar albino rats, thus providing some support for its use in traditional medicine to treat jaundice.

HPK1 also referred to as MAP4K1, belongs to the category of mammalian STE20-like protein serine/threonine kinases. Its physiological function involves the down-regulation of T cell signals, and it is regarded as a new immune checkpoint of tumor immunology. In this study, we commenced our investigation with the hit compounds, focusing the efforts on structural optimization and SAR exploration to identify a novel class of 2,4-diaminopyrimidine HPK1 inhibitors. Notably, compound 14g exhibited a remarkable inhibitory effect on HPK1 kinase (IC50 = 0.15 nM), significantly suppressed the phosphorylation of the downstream adaptor protein SLP76 (pSLP76 IC50 = 27.92 nM), and effectively stimulated the secretion of the T cell activation marker IL-2 (EC50 = 46.64 nM). In vitro microsomal stability assay, compound 14g showed moderate stability in HLMs with T1/2 = 38.2 min and CLint = 36.4 µL·min-1·mg-1 proteins. In vivo pharmacokinetic studies, compound 14g demonstrated heightened plasma exposure (AUC0-inf = 644 ng·h·mL-1), extended half-life (T1/2 = 9.98 h), and reduced plasma clearance (CL = 52.3 mL·min-1·kg-1) compared to the reference compound after a single intravenous dose of 2 mg/kg in rats. These results indicated that compound 14g emerged as a promising inhibitor of HPK1.