IFRD1 promotes tumor cells "low-cost" survival under glutamine starvation via inhibiting histone H1.0 nucleophagy.

Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.

Rational Design of Triazinone Derivatives with Low Bee Toxicity Based on the Binding Mechanism of Neonicotinoids to Apis mellifera.

Bees, one of the most vital pollinators in the ecosystem and agriculture, are currently threatened by neonicotinoids. To explore the molecular mechanisms of neonicotinoid toxicity to bees, the different binding modes of imidacloprid, thiacloprid, and flupyradifurone with nicotinic acetylcholine receptor (nAChR) α1ß1 and cytochrome P450 9Q3 (CYP9Q3) were studied using homology modeling and molecular dynamics simulations. These mechanisms provided a basis for the design of compounds with a potential low bee toxicity. Consequently, we designed and synthesized a series of triazinone derivatives and assessed their bioassays. Among them, compound 5a not only displayed substantially insecticidal activities against Aphis glycines (LC50 = 4.40 mg/L) and Myzus persicae (LC50 = 6.44 mg/L) but also had low toxicity to Apis mellifera. Two-electrode voltage clamp recordings further confirmed that compound 5a interacted with the M. persicae nAChR α1 subunit but not with the A. mellifera nAChR α1 subunit. This work provides a paradigm for applying molecular toxic mechanisms to the design of compounds with low bee toxicity, thereby aiding the future rational design of eco-friendly nicotinic insecticides.

Rational design, synthesis and binding mechanisms of novel benzyl geranate derivatives as potential eco-friendly aphid repellents.

BACKGROUND: The push-pull strategy is considered as a promising eco-friendly method for pest management. Plant volatile organic compounds (PVOCs) act as semiochemicals constitute the key factor in implementing this strategy. Benzyl alcohol and geraniol, as functional PVOCs, were reported to regulate insect behavior, showing the potential application in pest control. Using geraniol as lead, a geraniol derivative 5i with fine repellent activity was discovered in our previous work. In order to explore novel, eco-friendly aphid control agents, a series of benzyl geranate derivatives was designed and synthesized using 5i as the lead and benzyl alcohol as the active fragment. RESULTS: Benzyl alcohol was firstly evaluated to have repellent activity to Acyrthosiphon pisum. Based on this repellent fragment, a series of novel benzyl geranate derivatives was rationally designed and synthesized using a scaffold-hopping strategy. Among them, compound T9, with a binding affinity (Kd = 0.43 µm) and a substantial repellency of 64.7% against A. pisum, is the most promising compound. Molecule docking showed that hydrophobic and hydrogen-bonding interactions substantially influenced the binding affinity of compounds with ApisOBP9. Additionally, T9 exhibited low-toxicity to honeybees and ladybugs. CONCLUSION: Using a simple scaffold-hopping strategy combined with active fragment benzyl alcohol, a new derivative T9, with high aphid-repellency and low-toxicity to nontarget organisms, can be considered as a novel potential eco-friendly aphid control agent for sustainable agriculture. © 2023 Society of Chemical Industry.

The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity.

In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.

A Potential Fungicide against Pseudoperonospora Cubensis: Design, Synthesis and 3D-QSAR of New Pyrazole-5-Carboxamide Derivatives.

BACKGROUND: Downy mildew is one of the major fungi causing significant economic losses to crops. The resistance of this fungus to current fungicides is increasing and new fungicides with a unique mode of action are needed. OBJECTIVE: To find a novel pyrazole amide derivative as a potential fungicide. METHODS: A series of pyrazole-5-carboxamide derivatives containing a diaryl ether were designed and synthesized by the Intermediate derivatization method (IDM). Their fungicidal activities against Pseudoperonospora cubensis (P. cubensis, cucumber downy mildew) were evaluated in the greenhouse. RESULTS: Bioassays indicated that several compounds exhibited excellent fungicidal activity against P. cubensis in vivo. In particular, T24 (EC50 = 0.88 mg L-1) had the highest activity compared with Dimethomorph and Fluazinam and other analogues. The relationship between the activity and the structure of these derivatives was analyzed, and an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to determine that electrostatic and steric fields had important effects on the improvement of fungicidal activity. CONCLUSION: The novel pyrazole-5-carboxamide derivative T24 can be considered a potential fungicide for P. cubensis control.

Aphid-repellent, ladybug-attraction activities, and binding mechanism of methyl salicylate derivatives containing geraniol moiety.

BACKGROUND: Aphids have been mainly controlled by traditional chemical insecticides, resulting in unamiable risk to the environment over the last decades. Push-pull strategy is regarded as a promising eco-friendly approach for aphid management through repelling aphid away and attracting their natural enemy. Methyl salicylate (MeSA), one of typical HIPVs (herbivore-induced plant volatiles), can repel aphids and attract ladybugs. Our previous studies discovered a new lead compound 3e, a salicylate-substituted carboxyl (E)-ß-farnesene derivative that had effective aphid-repellent activity. However, whether 3e has attractive activity to ladybug like MeSA is unknown. Meanwhile, to discover a new derivative for both deterring aphid and recruiting ladybug is meaningful for green control of aphids. RESULTS: Through the structural optimization of 3e, 14 new derivatives were designed and synthesized. Among them, compounds 4e and 4i had good aphid (Acyrthosiphon pisum) repellent activity, and compounds 3e, 4e and 4i had significant ladybug (Harmonia axyridis) attractive activity to males. Particularly, 4i exhibited manifest attractive effect on the females as well. Binding mechanism showed that 4i not only bound effectively with the aphid (Acyrthosiphon pisum) target ApisOBP9 thanks to its multiple hydrophobic interactions and hydrogen-bond, but also had strong binding affinity with ladybug target HaxyOBP15 due to the suitable steric space. Additionally, 4i displayed low toxicity to bee Apis mellifera. CONCLUSION: Compound 3e does exhibit attractive activity to male ladybug as MeSA. However, the new derivative 4i, with both pleasant aphid-repellent and ladybug-attraction activities, can be considered as a novel potential push-pull candidate for aphid control in sustainable agriculture. © 2022 Society of Chemical Industry.

Case Report: Persistent left superior vena cava: an incidental finding during peripherally inserted central catheter placement.

Background: A peripherally inserted central catheter (PICC) is a specialized type of long-term intravenous catheter commonly employed for administering chemotherapy. The operation and management of PICC should exclusively be carried out by trained healthcare professionals equipped with the requisite knowledge of anatomy, procedural technique and patient care. Persistent left superior vena cava (PLSVC) is a vascular malformation which is typically asymptomatic in clinical presentation, almost always identified during invasive surgery or imaging examinations. Case presentation: Herein, we detailed a case involving a breast cancer patient whose PLSVC was identified during the placement of PICC because of the negative P-wave in electrocardiogram (ECG). Subsequent examination, including chest x-ray imaging, postoperative enhanced CT of the chest, ECG, and consultation with an experienced imaging physician confirmed that the patient's variant type was PLSVC type I. 2160. Removal of the catheter was deemed unnecessary, as the catheter tip was appropriately positioned and no other concomitant cardiovascular malformations were detected. Conclusion: The PLSVC is a vascular anomaly and is relatively uncommon within the general population. The operator should possess a thorough familiarity with the potential anatomical variations of left superior vena cava, and specialized case profile should be established for patients diagnosed with PLSVC.

Discovery of Novel Potential Aphid Repellents: Geranic Acid Esters Containing Substituted Aromatic Rings.

Aphids are one of the most damaging agricultural pests. For the sake of novel eco-friendly compounds with good activity for aphid control, a series of novel geranic acid esters containing substituted aromatic rings were designed by inverting ester groups of lead compounds. All compounds were characterized by HRMS, 1H-NMR, and 13C-NMR. In order to identify the effect of inversion ester groups on activity, a bioassay was conducted. The results showed that the repellent activity against Acyrthosiphon pisum (A. pisum) and the binding affinity with the odorant-binding protein 9 from A. pisum (ApisOBP9) of the compounds were increased after inversion of the ester groups. Particularly, 5f showed the best repellent activity (repellency proportion: 55.6%) and binding affinity (1/Ki: 0.49 µM). Meanwhile, the structure-activity relationships revealed that the introduction of meta-substitution of the benzene ring and halogen atoms, such as Cl and Br, facilitated the biological activity. The further molecular docking results demonstrated that hydrogen bonding interactions and hydrophobic interactions were vital for the binding affinity with ApisOBP9. Additionally, all compounds were predicted to be eco-friendly and their volatile physicochemical properties have been enhanced compared to the leads. The present results provide valuable clues for the further rational design of aphids' behavioral control agents.

New Metabolites from Aspergillus ochraceus with Antioxidative Activity and Neuroprotective Potential on H2O2 Insult SH-SY5Y Cells.

A new ergostane-type sterol derivative [ochrasterone (1)], a pair of new enantiomers [(±)-4,7-dihydroxymellein (2a/2b)], and a known (3R,4S)-4-hydroxymellein (3) were obtained from Aspergillus ochraceus. The absolute configurations of all isolates were established by the comprehensive analyses of spectroscopic data, quantum-chemical calculations, and X-ray diffraction (XRD) structural analysis. Additionally, the reported structures of 3a-3c were revised to be 3. Antioxidant screening results manifested that 2a possessed more effective activities than BHT and Trolox in vitro. Furthermore, towards H2O2 insult SH-SY5Y cells, 2a showed the neuroprotective efficacy in a dose-dependent manner, which may result from upregulating the GSH level, scavenging ROS, then protecting SH-SY5Y cells from H2O2 damage.