Anticancer, anti-inflammatory and analgesic activities of aminoalcohol-based quinoxaline small molecules.

PURPOSE: Bioactive molecules are relevant to fight cancer and associated conditions. Quinoxaline is a privileged N-heterocycle, notably as anticancer agents. Herein, we report the evaluation of the quinoxaline derivatives DEQX and OAQX as anticancer agents, as well as in function of their anti-inflammatory and analgesic activities. METHODS: Quinoxalines were synthesized and tested as anticancer agents based on cell viability and Annexin V-FITC apoptosis. Anti-inflammatory activity was evaluated from mouse carrageenan peritonitis and levels of interleukin (IL)-1ß and tumor necrosis factor (TNF)-alfa for enzyme-linked immunosorbent assay. Hot-plate and acetic acid-induced writing test were employed to investigate analgesia. RESULTS: Both reduced the Ht-29 cell viability in a dependent-concentration manner (p < 0.001). Total apoptosis was detected for cells treated with 12.5 and 25 µg/mL of both the compounds for 24 and 48 h (all doses, p < 0.0001). DEQX (all doses, p < 0.01) and OAQX (all doses, p < 0.001) acted in leukocyte migration and decreased the IL-1ß and TNF-ß levels (p < 0.05). DEQX (all doses, p < 0.05) and OAQX (5mg/kg, p < 0.001) showed peripheral analgesic effect. CONCLUSIONS: In-vitro and in-vivo results suggest that these quinoxalines are promising for application in pharmacological area due to their anticancer, anti-inflammatory, and peripheric analgesia.

In-vivo and in-vitro toxicity evaluation of 2,3-dimethylquinoxaline: An antimicrobial found in a traditional herbal medicine.

2,3-dimethylquinoxaline (DMQ) is a broad-spectrum antimicrobial phytochemical. This study aims to assess its toxicological profile. In vitro studies conducted in appropriate cell cultures, included assessment of cardiotoxicity, nephrotoxicity, and hepatotoxicity. An in vivo study was conducted in mice to determine acute oral toxicity (AOT), and subacute oral toxicity (SAOT). Acute dermal toxicity (ADT) was conducted in rats. All in-vitro toxicity studies of DMQ had negative results at concentrations ≤100 µM except for a non-significant reduction in the ATP in human hepatocellular carcinoma cell culture. The median lethal dose of DMQ was higher than 2000 mg/kg. All animals survived the scheduled necropsy and none showed any alteration in clinical signs. Biochemistry analysis revealed a significant difference between the satellite and control groups, showing an increase in platelet counts and white blood cell counts by 99.8% and 188.8%, respectively. Histology revealed enlargement of renal corpuscles; hyperplasia of testosterone-secreting cells; and dilatation of coronaries and capillaries. The present data suggests an acceptable safety profile of DMQ in rodents except for thrombocytosis, leukocytosis, and histological changes in high doses that need further investigation.

Erdafitinib in Asian patients with advanced solid tumors: an open-label, single-arm, phase IIa trial.

BACKGROUND: FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer. METHODS: Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics. RESULTS: Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%). CONCLUSIONS: Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

Metal-free internal nucleophile-triggered domino route for synthesis of fused quinoxaline [1,4]-diazepine hybrids and the evaluation of their DNA binding properties.

An unprecedented metal-free synthesis of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine hybrids have been reported under mild conditions through a domino intermolecular SNAr followed by an internal nucleophile-triggered intramolecular SNAr pathway. Our strategy offers the flexibility for the introduction of a broad variety of functionalities at the N-1 position of fused diazepine moiety by using suitable diamine tails to design structurally diverse scaffolds. The DNA binding properties of representative quinoxaline diazepine hybrids were studied using UV-vis absorbance and EtBr displacement assay and were found to be governed by the functionalities at the N-1 position. Interestingly, compound 11f containing the N-1 benzyl substitution demonstrated significant DNA binding (KBH âˆ¼ 2.15 ± 0.25 × 104 M-1 and Ksv âˆ¼ 12.6 ± 1.41 × 103 M-1) accompanied by a bathochromic shift (Δλ âˆ¼ 5 nm). In silico studies indicated possible binding of diazepine hybrid 11f at the GC-rich major groove in the ct-DNA hexamer duplex and showed comparable binding energies to that of ethidium bromide. The antiproliferative activity of compounds was observed in the given order in different cell lines: (HeLa > HT29 > SKOV 3 > HCT116 > HEK293). Lead compound 11f demonstrated maximum cytotoxicity (IC50 value of 13.30 µM) in HeLa cell lines and also caused early apoptosis-mediated cell death in cancer cell lines. We envision that our work will offer newer methodologies for the construction of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine class of molecules.

Effect of 3-hydrazinylquinoxaline-2-thiol hydrogel on skin wound healing process in diabetic rats.

Impaired wound healing in diabetic individuals creates huge social and financial burdens for both diabetic patients and the health system. Unfortunately, the current treatment has not resulted in consistently lower amputation rates. Quinoxalines are heterocyclic compounds with multiple important pharmacological properties. Their effect on wound healing have not been closely studied. In the current work, the wound healing effect of 3-hydrazinylquinoxaline-2-thiol hydrogel is tested topically in a full-thickness excision wound in streptozotocin-induced type 1 diabetic rats. We examined the wound closure rate, expression of inflammatory factors, growth factors in addition to the histological analysis. The results revealed a significant acceleration in wound closure in the treated group compared with the control experimental animals. Histological data demonstrated enhanced re-epithelialization and collagen disposition. The healing effect was additionally evaluated by the inhibition of the inflammatory response of interleukin (IL)-1ß interleukin (IL)-6, tumor necrosis factor (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) with a marked improvement of the transforming growth factor beta (TGFß-1), antioxidant markers and collagen-1. In silico study indicated a favorable drug-like properties and toxicity profile. The present work showed that 3-hydrazinylquinoxaline-2-thiol holds great potential for the treatment of diabetic wounds.

Scaffold Hopping of Pristimerin Provides Derivatives Containing a Privileged Quinoxaline Substructure as Potent Autophagy Inducers in Breast Cancer Cells.

Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities in vitro using the MTT assay. The most potent cytotoxic compound (21o) significantly inhibited the proliferation of MCF-7 cells with an IC50 value of 2.0 µM, 1.5-fold more potent than pristimerin (IC50 = 3.0 µM). Compared with pristimerin, compound 21o displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound 21o. Compound 21o induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound 21o may serve as a lead compound for developing new therapies to treat breast cancer.

Sequential Nucleophilic Aromatic Substitution Reactions of Activated Halogens.

Building blocks have been identified that can be functionalised by sequential nucleophilic aromatic substitution. Some examples are reported that involve the formation of cyclic benzodioxin and phenoxathiine derivatives from 4,5-difluoro-1,2-dinitrobenzene, racemic quinoxaline thioethers, and sulfones from 2,3-dichloroquinoxaline and (2-aminophenylethane)-2,5-dithiophenyl-4-nitrobenzene from 1-(2-aminophenylethane)-2-fluoro-4,5-dinitrobenzene. Four X-ray single-crystal structure determinations are reported, two of which show short intermolecular N-O…N "π hole" contacts.

Targeted Delivery of Quinoxaline-Based Semiconducting Polymers for Tumor Photothermal Therapy.

Photothermal therapy (PTT) holds great potential in the field of cancer treatment due to its high specificity and low invasiveness. However, the low conversion efficiency, inadequate tumor accumulation, and limited cellular uptake continue to impede PTT effectiveness in treating tumors. The present study focuses on the utilization of quinoxaline and its nanoparticles to develop an organic semiconducting photothermal agent (PAQI-BDTT) for tumor photothermal therapy. To achieve this, PAQI-BDTT was encapsulated within liposomes modified with cyclic Arg-Gly-Asp (cRGD) peptide targeting tumors (named T-BDTT-Lipo). Notably, T-BDTT-Lipo demonstrated a positive photothermal conversion efficiency of 74% when exposed to an 808 nm laser, along with NIR-II fluorescence imaging capabilities. The efficacy of T-BDTT-Lipo in tumor tissue accumulation and precise targeting of malignant cells has been confirmed through both in vitro and in vivo experiments guided by fluorescence imaging. Under single dose and 808 nm light irradiation, T-BDTT-Lipo generated local intracellular hyperthermia at the tumor site. The elevated temperature additionally exerted a significant inhibitory effect on tumor growth and recurrence, thereby extending the survival duration of mice harboring tumors. The therapeutic nanosystem (T-BDTT-Lipo) proposed in this work demonstrates the enormous potential of semiconducting photothermal agents in photothermal therapy, laying the foundation for the next clinical application.

Uncovering the Molecular Pathways Implicated in the Anti-Cancer Activity of the Imidazoquinoxaline Derivative EAPB02303 Using a Caenorhabditis elegans Model.

Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used Caenorhabditis elegans transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in C. elegans. Moreover, EAPB02303 significantly reduced the multivulva phenotype in let-60/Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in C. elegans. Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations.

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

Erdafitinib promotes ferroptosis in human uveal melanoma by inducing ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling axis.

Uveal melanoma (UM) is a rare yet lethal primary intraocular malignancy affecting adults. Analysis of data from The Cancer Genome Atlas (TCGA) database revealed that FGFR1 expression was increased in UM tumor tissues and was linked to aggressive behavior and a poor prognosis. This study assessed the anti-tumor effects of Erdafitinib, a selective pan-FGFR inhibitor, in both in vitro and in vivo UM models. Erdafitinib exhibited a robust anti-cancer activity in UM through inducing ferroptosis in the FGFR1-dependent manner. Transcriptomic data revealed that Erdafitinib mediated its anti-cancer effects via modulating the ferritinophagy/lysosome biogenesis. Subsequent research revealed that Erdafitinib exerted its effects by reducing the expression of FGFR1 and inhibiting the activity of mTORC1 in UM cells. Concurrently, it enhanced the dephosphorylation, nuclear translocation, and transcriptional activity of TFEB. The aggregation of TFEB in nucleus triggered FTH1-dependent ferritinophagy, leading to lysosomal activation and iron overload. Conversely, the overexpression of FGFR1 served to mitigate the effects of Erdafitinib on ferritinophagy, lysosome biogenesis, and the activation of the mTORC1/TFEB signaling pathway. In vivo experiments have convincingly shown that Erdafitinib markedly curtails tumor growth in an UM xenograft mouse model, an effect that is closely correlated with a decrease in FGFR1 expression levels. The present study is the first to demonstrate that Erdafitinib powerfully induces ferroptosis in UM by orchestrating the ferritinophagy and lysosome biogenesis via modulating the FGFR1/mTORC1/TFEB signaling. Consequently, Erdafitinib emerges as a strong candidate for clinical trial investigation, and FGFR1 emerges as a novel and promising therapeutic target in the treatment of UM.

Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer.

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.

Exploring quinoxaline derivatives: An overview of a new approach to combat antimicrobial resistance.

Antimicrobial resistance (AMR) has emerged as a long-standing global issue ever since the introduction of penicillin, the first antibiotic. Scientists are constantly working to develop innovative antibiotics that are more effective and superior. Unfortunately, the misuse of antibiotics has resulted in their declining effectiveness over the years. By 2050, it is projected that approximately 10 million lives could be lost annually due to antibiotic resistance. Gaining insight into the mechanisms behind the development and transmission of AMR in well-known bacteria including Escherichia coli, Bacillus pumilus, Enterobacter aerogenes, Salmonella typhimurium, and the gut microbiota is crucial for researchers. Environmental contamination in third world and developing countries also plays a significant role in the increase of AMR. Despite the availability of numerous recognized antibiotics to combat bacterial infections, their effectiveness is diminishing due to the growing problem of AMR. The overuse of antibiotics has led to an increase in resistance rates and negative impacts on global health. This highlights the importance of implementing strong antimicrobial stewardship and improving global monitoring, as emphasized by the World Health Organization (WHO) and other organizations. In the face of these obstacles, quinoxaline derivatives have emerged as promising candidates. They are characterized by their remarkable efficacy against a broad spectrum of harmful bacteria, including strains that are resistant to multiple drugs. These compounds are known for their strong structural stability and adaptability, making them a promising and creative solution to the AMR crisis. This review aims to assess the effectiveness of quinoxaline derivatives in treating drug-resistant infections, with the goal of making a meaningful contribution to the global fight against AMR.

Impaired GPX4 activity elicits ferroptosis in alveolar type II cells promoting PHMG-induced pulmonary fibrosis development.

Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6 J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment.

Design, Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Quinoxaline-2-Oxyacetate Hydrazide.

Plant pathogenic fungi pose a major threat to global food security, ecosystem services, and human livelihoods. Effective and broad-spectrum fungicides are needed to combat these pathogens. In this study, a novel antifungal 2-oxyacetate hydrazide quinoxaline scaffold as a simple analogue was designed and synthesized. Their antifungal activities were evaluated against Botrytis cinerea (B. cinerea), Altemaria solani (A. solani), Gibberella zeae (G. zeae), Rhizoctonia solani (R. solani), Colletotrichum orbiculare (C. orbiculare), and Alternaria alternata (A. alternata). These results demonstrated that most compounds exhibited remarkable inhibitory activities and possessed better efficacy than ridylbacterin, such as compound 15 (EC50 = 0.87 µg/mL against G. zeae, EC50 = 1.01 µg/mL against C. orbiculare) and compound 1 (EC50 = 1.54 µg/mL against A. alternata, EC50 = 0.20 µg/mL against R. solani). The 3D-QSAR analysis of quinoxaline-2-oxyacetate hydrazide derivatives has provided new insights into the design and optimization of novel antifungal drug molecules based on quinoxaline.

New prospective insecticidal agents based on thiazolo[4,5-b]quinoxaline derivatives against cotton leafworm Spodoptera litura (Fabricius): Design, synthesis, toxicological, morphology, histological, and biomedical studies.

In this study, a new series of thiazolo[4,5-b]quinoxaline derivatives 3-8 were synthesized by treating 2,3-dichloroquinoxaline with thiosemicarbazone and thiourea derivatives under reflux conditions. The chemical structure of the newly designed derivatives was conducted using spectroscopic techniques. The insecticidal bioassay of the designed derivatives was evaluated against the 2nd and 4th larvae of S. litura after five days as toxicity agents via median lethal concentration (LC50) and the lethal time values (LT50). The results indicated that all the tested compounds had insecticidal effects against both instar larvae of S. litura with variable values. Among them, thiazolo[4,5-b]quinoxaline derivative 3 was the most toxic, with LC50 = 261.88 and 433.68 ppm against 2nd and 4th instar larvae, respectively. Moreover, the thiazolo[4,5-b]quinoxaline derivative 3 required the least time to kill the 50% population (LT50) of 2nd larvae were 20.88, 13.2, and 15.84 hs with 625, 1250, and 2500 ppm, respectively, while for the 4th larval instar were 2.75, 2.08, and 1.76 days with concentrations of 625, 1250, and 2500 ppm, respectively. Larvae's morphological and histological studies for the most active derivative 3 were investigated. According to SEM analysis, the exterior morphology of the cuticle and head capsule was affected. In addition, there were some histological alterations in the cuticle layers and the midgut tissues. Columnar cells began breaking down, and vacuolization occurred in the peritrophic membrane. Moreover, treating 4th S litura larvae hemolymph with compound 3 showed significant changes in biochemical analysis, such as total proteins, GPT, GOT, acetylcholinesterase (AChE), and alkaline phosphatase (AlP). Finally, the toxicity prediction of the most active derivative revealed non-corrosive, non-irritant to the eye, non-respiratory toxicity, non-sensitivity to the skin, non-hepatotoxic, and don't have toxicity on minnow toxicity and T. pyriformis indicating a good toxicity profile for human.

Fluorinated indeno-quinoxaline bearing thiazole moieties as hypoglycaemic agents targeting α-amylase, and α-glucosidase: synthesis, molecular docking, and ADMET studies.

Inhibition of α-glucosidase and α-amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2-b] quinoxalines-carrying thiazole hybrids 1-17 were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds 4, 6, 8, and 16 were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against α-glucosidase and α-amylase enzymes in vitro. The four hybrids 4, 6, 8, and 16 represented moderate to potent activity with IC50 values 0.982 ± 0.04, to 10.19 ± 0.21 for α-glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 µM for α-amylase inhibition when compared to the standard medication acarbose with IC50=0.316 ± 0.02 µM for α-glucosidase inhibition and 31.56 ± 1.33 µM for α-amylase inhibition. Docking studies as well as in silico ADMT were done.

TRPV1/cPLA2/AA pathway contributes to ferroptosis-mediated acute liver injury in heatstroke.

With the increasing frequency of global heatwaves, the incidence of heatstroke (HS) is significantly rising. The liver plays a crucial role in metabolism and is an organ highly sensitive to temperature. Acute liver injury (ALI) frequently occurs in patients with HS, yet the exact mechanisms driving ALI in HS are still unknown. In this basic study, we investigated the specific molecular mechanisms by which cytosolic phospholipase A2 (cPLA2) mediates ferroptosis, contributing to the development of ALI following HS. We utilized a mouse model of HS and divided the mice into healthy control and HS groups for a series of experiments. Firstly, we assessed oxidative damage markers in tissues and cells, as well as ferroptosis biomarkers. Additionally, we conducted a non-targeted metabolomics analysis to validate the role of key enzymes in metabolism and the ferroptosis pathway. Our results indicated that ferroptosis contributed to the progression of ALI after HS. Administering the ferroptosis inhibitor liproxstatin-1 (10 mg/kg) post-HS onset significantly inhibits HS-induced ALI progression. Mechanistically, heatstroke triggered cPLA2 activation and increased the levels of its metabolic product, arachidonic acid, thereby further promoted the occurrence of ferroptosis. Furthermore, heatstroke mediated cPLA2 activation might involve enhancing transient receptor potential vanilloid subtype 1 (TRPV1) receptor function. Overall, these results highlighted the critical role that cPLA2-mediated ferroptosis plays in the development of ALI following HS, indicating that inhibiting cPLA2 may present a novel therapeutic approach to prevent ALI after HS by limiting liver cell death.

Neuronal ferroptosis and ferroptosis-mediated endoplasmic reticulum stress: Implications in cognitive dysfunction induced by chronic intermittent hypoxia in mice.

Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.

Europium Nanoparticle-Based Lateral Flow Strip Biosensors for the Detection of Quinoxaline Antibiotics and Their Main Metabolites in Fish Feeds and Tissues.

Olaquindox (OLA) and quinocetone (QCT) have been prohibited in aquatic products due to their significant toxicity and side effects. In this study, rapid and visual europium nanoparticle (EuNP)-based lateral flow strip biosensors (LFSBs) were developed for the simultaneous quantitative detection of OLA, QCT, and 3-methyl-quinoxaline-2-carboxylic acid (MQCA) in fish feed and tissue. The EuNP-LFSBs enabled sensitive detection for OLA, QCT, and MQCA with a limit of detection of 0.067, 0.017, and 0.099 ng/mL (R2 ≥ 0.9776) within 10 min. The average recovery of the EuNP-LFSBs was 95.13%, and relative standard deviations were below 9.38%. The method was verified by high-performance liquid chromatography (HPLC), and the test results were consistent. Therefore, the proposed LFSBs serve as a powerful tool to monitor quinoxalines in fish feeds and their residues in fish tissues.