RESUMEN

After seizures, the hyperactivation of extracellular signal-regulated kinases (ERK1/2) causes mitochondrial dysfunction. Through the guidance of dynamin-related protein 1 (DRP1), ERK1/2 plays a role in the pathogenesis of several illnesses. Herein, we speculate that ERK1/2 affects mitochondrial division and participates in the pathogenesis of epilepsy by regulating the activity of DRP1. LiCl-Pilocarpine was injected intraperitoneally to establish a rat model of status epilepticus (SE) for this study. Before SE induction, PD98059 and Mdivi-1 were injected intraperitoneally. The number of seizures and the latency period before the onset of the first seizure were then monitored. The analysis of Western blot was also used to measure the phosphorylated and total ERK1/2 and DRP1 protein expression levels in the rat hippocampus. In addition, immunohistochemistry revealed the distribution of ERK1/2 and DRP1 in neurons of hippocampal CA1 and CA3. Both PD98059 and Mdivi-1 reduced the susceptibility of rats to epileptic seizures, according to behavioral findings. By inhibiting ERK1/2 phosphorylation, the Western blot revealed that PD98059 indirectly reduced the phosphorylation of DRP1 at Ser616 (p-DRP1-Ser616). Eventually, the ERK1/2 and DRP1 were distributed in the cytoplasm of neurons by immunohistochemistry. Inhibition of ERK1/2 signaling pathways downregulates p-DRP1-Ser616 expression, which could inhibit DRP1-mediated excessive mitochondrial fission and then regulate the pathogenesis of epilepsy.

Asunto(s)

Dinaminas , Flavonoides , Dinámicas Mitocondriales , Pilocarpina , Quinazolinonas , Ratas Sprague-Dawley , Estado Epiléptico , Animales , Dinaminas/metabolismo , Dinaminas/genética , Dinámicas Mitocondriales/fisiología , Dinámicas Mitocondriales/efectos de los fármacos , Masculino , Pilocarpina/toxicidad , Estado Epiléptico/metabolismo , Estado Epiléptico/inducido químicamente , Flavonoides/farmacología , Quinazolinonas/farmacología , Sistema de Señalización de MAP Quinasas/fisiología , Ratas , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Convulsiones/metabolismo , Cloruro de Litio/farmacología , Modelos Animales de Enfermedad , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Fosforilación

RESUMEN

Chronic hepatitis B virus (HBV) infection continues to be a prominent cause of liver fibrosis and end-stage liver disease in China, necessitating the development of effective therapeutic strategies. This study investigated the potential of targeting TGR5 to alleviate liver fibrosis by impeding the activation of hepatic stellate cells (HSCs), which play a pivotal role in fibrotic progression. Using the human hepatic stellate cell line LX-2 overexpressing hepatitis B virus X protein (HBX), this study revealed that TGR5 activation through INT-777 inhibits HBX-induced LX-2 cell activation, thereby ameliorating liver fibrosis, which is associated with the attenuation of mitochondrial fission and introduces a novel regulatory pathway in liver fibrosis. Additional experiments with mitochondrial fission inducers and inhibitors confirm the crucial role of mitochondrial dynamics in TGR5-mediated effects. In vivo studies using TGR5 knockout mice substantiate these findings, demonstrating exacerbated fibrosis in the absence of TGR5 and its alleviation with the mitochondrial fission inhibitor Mdivi-1. Overall, this study provides insights into TGR5-mediated regulation of liver fibrosis through the modulation of mitochondrial fission in HSCs, suggesting potential therapeutic strategies for liver fibrosis intervention.

Asunto(s)

Células Estrelladas Hepáticas , Cirrosis Hepática , Dinámicas Mitocondriales , Receptores Acoplados a Proteínas G , Animales , Humanos , Masculino , Ratones , Línea Celular , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Quinazolinonas/farmacología , Quinazolinonas/uso terapéutico , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética

RESUMEN

Ghrelin modulates several biological functions via selective activation of the growth hormone secretagogue receptor (GHSR). GHSR agonists may be useful for the treatment of anorexia and cachexia, while antagonists and inverse agonists may represent new drugs for the treatment of metabolic and substance use disorders. Thus, the identification and pharmacodynamic characterization of new GHSR ligands is of high interest. In the present work the label-free dynamic mass redistribution (DMR) assay has been used to evaluate the pharmacological activity of a panel of GHSR ligands. This includes the endogenous peptides ghrelin, desacyl-ghrelin and LEAP2(1-14). Among synthetic compounds, the agonists anamorelin and HM01, the antagonists HM04 and YIL-781, and the inverse agonist PF-05190457 have been tested, together with HM03, R011, and H1498 from patent literature. The DMR results have been compared to those obtained in parallel experiments with the calcium mobilization assay. Ghrelin, anamorelin, HM01, and HM03 behaved as potent full GHSR agonists. YIL-781 behaved as a partial GHSR agonist and R011 as antagonist in both the assays. LEAP2(1-14) resulted a GHSR inverse agonist in DMR but not in calcium mobilization assay. PF-05190457, HM04, and H1498 behaved as GHSR inverse agonists in DMR experiments, while they acted as antagonists in calcium mobilization studies. In conclusion, this study provided a systematic pharmacodynamic characterization of several GHSR ligands in two different pharmacological assays. It demonstrated that the DMR assay can be successfully used particularly to discriminate between antagonists and inverse agonists. This study may be useful for the selection of the most appropriate compounds to be used in future studies.

Asunto(s)

Calcio , Ghrelina , Receptores de Ghrelina , Receptores de Ghrelina/agonistas , Receptores de Ghrelina/metabolismo , Receptores de Ghrelina/antagonistas & inhibidores , Ligandos , Ghrelina/farmacología , Ghrelina/metabolismo , Calcio/metabolismo , Humanos , Animales , Cricetulus , Células CHO , Oligopéptidos/farmacología , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/metabolismo , Hidrazinas , Piperidinas , Quinazolinonas

RESUMEN

Several human diseases, including cancer and neurodegeneration, are associated with excessive mitochondrial fragmentation. In this context, mitochondrial division inhibitor (Mdivi-1) has been tested as a therapeutic to block the fission-related protein dynamin-like protein-1 (Drp1). Recent studies suggest that Mdivi-1 interferes with mitochondrial bioenergetics and complex I function. Here we show that the molecular mechanism of Mdivi-1 is based on inhibition of complex I at the IQ site. This leads to the destabilization of complex I, impairs the assembly of N- and Q-respirasomes, and is associated with increased ROS production and reduced efficiency of ATP generation. Second, the calcium homeostasis of cells is impaired, which for example affects the electrical activity of neurons. Given the results presented here, a potential therapeutic application of Mdivi-1 is challenging because of its potential impact on synaptic activity. Similar to the Complex I inhibitor rotenone, Mdivi-1 may lead to neurodegenerative effects in the long term.

Asunto(s)

Complejo I de Transporte de Electrón , Mitocondrias , Quinazolinonas , Complejo I de Transporte de Electrón/metabolismo , Humanos , Quinazolinonas/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Animales , Especies Reactivas de Oxígeno/metabolismo , Calcio/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Ratones

RESUMEN

Vascular dementia (VD) is one of the most common forms of dementia worldwide, characterized by problems with reasoning, planning, judgment, and memory. This study investigated the effect of a histone methyltransferase inhibitor on cognition and mitochondrial function in a rat model of VD, as well as its impact on H2O2-induced neurotoxicity in hippocampal neuronal cultures. In the in vivo experiments, VD was induced by bilateral occlusion of the common carotid artery (CCA) for one month. The histone methyltransferase inhibitor, BIX01294, was administered intracerebroventricularly for one month (22.5 µg.kg-1 three times/week). On day 30, behavioral tests, including the novel object recognition test and elevated plus maze test, were conducted. Mitochondrial enzyme activities, including aconitase, α-ketoglutarate dehydrogenase (α-KG), complex I, and complex IV, were evaluated in the hippocampus of rats following CCA ligation. In the in vitro experiments, the effect of BIX01294 (50-600 µM) on H2O2 (400 µM)-induced cytotoxicity in hippocampal neuronal cells was assessed using the MTT assay. Flow cytometry was performed to evaluate apoptosis. Our findings revealed that BIX01294 effectively improved memory function, Krebs cycle enzyme activity, and mitochondrial function in the rat model of VD. Moreover, in vitro results showed that BIX01294 at a concentration of 100 µM significantly reversed the cytotoxicity and apoptosis induced by H2O2 in neuronal cells. These findings suggest that BIX01294 may have the potential to improve VD complications by reducing oxidative stress and inhibiting histone methylation.

Asunto(s)

Demencia Vascular , Modelos Animales de Enfermedad , Hipocampo , Mitocondrias , Animales , Demencia Vascular/tratamiento farmacológico , Demencia Vascular/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Cognición/efectos de los fármacos , Histona Metiltransferasas/metabolismo , Histona Metiltransferasas/antagonistas & inhibidores , Ratas Sprague-Dawley , Peróxido de Hidrógeno/farmacología , Quinazolinonas/farmacología , Inhibidores Enzimáticos/farmacología , Apoptosis/efectos de los fármacos , Azepinas , Quinazolinas

RESUMEN

There exist very limited non-hazardous therapeutic strategies except for surgical resection and lymphadenectomy against gastric cancer (GC) despite being the third leading cause of cancer deaths worldwide. This study proposes an innovative treatment approach against GC using a drug combination strategy that manipulates mitochondrial dynamics in conjunction with the induction of mitochondrial pathology-mediated cell death. Comparative analysis was done with gastric adenocarcinoma and normal cells by qPCR, western blot, microscopic immunocytochemistry, and live cell imaging. In this study, impairment of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission by Mdivi-1 created an imbalance in mitochondrial structural dynamics in indomethacin-treated AGS cells in which mitophagy-regulator protein PINK1 is downregulated. These drug combinations with the individual sub-lethal doses ultimately led to the activation of cell death machinery upregulating pro-apoptotic proteins like Bax, Puma, and Noxa. Interestingly, this combinatorial therapy did not affect normal gastric epithelial cells significantly and also no significant upregulation of death markers was observed. Moreover, the drug combination strategy also retarded cell migration and reduced stemness in GC cells. In summary, this study offers a pioneering specific therapeutic strategy for GC treatment, sparing normal cells providing opportunities for minimal drug-mediated toxicity utilizing mitochondria as a viable and specific target for anti-cancer therapy in gastric cancer.

Asunto(s)

Adenocarcinoma , Mitocondrias , Proteínas Quinasas , Neoplasias Gástricas , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Línea Celular Tumoral , Proteínas Quinasas/metabolismo , Indometacina/farmacología , Dinámicas Mitocondriales/efectos de los fármacos , Dinaminas/metabolismo , Dinaminas/genética , Apoptosis/efectos de los fármacos , Mitofagia/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Antineoplásicos/farmacología , Quinazolinonas

RESUMEN

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.

Asunto(s)

Obesidad , Fenotipo , Piperidinas , Proteínas Serina-Treonina Quinasas , Quinazolinonas , Transducción de Señal , eIF-2 Quinasa , Animales , Quinazolinonas/farmacología , Piperidinas/farmacología , Ratones , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Obesidad/patología , Obesidad/metabolismo , Obesidad/prevención & control , Obesidad/genética , Transducción de Señal/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ratones Endogámicos C57BL , Masculino , Resistencia a la Insulina , Insulina/metabolismo , Insulina/sangre , Estrés Fisiológico/efectos de los fármacos , Modelos Animales de Enfermedad , Dieta Alta en Grasa/efectos adversos , Diabetes Mellitus/patología , Diabetes Mellitus/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/prevención & control , Intolerancia a la Glucosa/tratamiento farmacológico , Adenina/análogos & derivados , Indoles

RESUMEN

A series of novel 2-substituted 2, 3-dihydroquinazolin-4(1H)-one derivatives were designed, synthesized and estimated for their in vitro antiproliferative activities against HepG2, U251, PANC-1, A549 and A375 cell lines. Among them, compound 32 was the most promising candidate, and displayed strong broad-spectrum anticancer activity. The mechanism studies revealed that compound 32 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, and induced apoptosis by up-regulating the expression of cleaved PARP-1 and caspase-3. Furthermore, molecular docking analysis suggested that compound 32 well occupied the binding site of tubulin. In addition, compound 32 exhibited no significant activity against 30 different kinases respectively, indicating considerable selectivity. Moreover, compound 32 significantly inhibited the tumour growth of the HepG2 xenograft in a nude mouse model by oral gavage without apparent toxicity. These results demonstrated that some 2-substituted 2, 3- dihydroquinazolin-4(1H)-one derivatives bearing phenyl, biphenyl, naphthyl or indolyl side chain at C2-position might be potentially novel antitumor agents as tubulin polymerization inhibitors.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Ratones Desnudos , Polimerizacion , Quinazolinonas , Moduladores de Tubulina , Tubulina (Proteína) , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Proliferación Celular/efectos de los fármacos , Ratones , Relación Estructura-Actividad , Quinazolinonas/farmacología , Quinazolinonas/química , Quinazolinonas/síntesis química , Polimerizacion/efectos de los fármacos , Apoptosis/efectos de los fármacos , Estructura Molecular , Simulación del Acoplamiento Molecular , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Línea Celular Tumoral , Ratones Endogámicos BALB C

RESUMEN

To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound S-WJM992, were shown to inhibit PfATP4-associated Na+-ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, S-WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.

Asunto(s)

Antimaláricos , Plasmodium falciparum , Quinazolinonas , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/farmacocinética , Animales , Plasmodium falciparum/efectos de los fármacos , Quinazolinonas/farmacología , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratones , Administración Oral , Relación Estructura-Actividad , Humanos , Malaria/tratamiento farmacológico , Femenino , Solubilidad

RESUMEN

BACKGROUND: Spinal cord injury (SCI) is considered a central nervous system (CNS) disorder. Nuclear factor kappa B (NF-κB) regulates inflammatory responses in the CNS and is implicated in SCI pathogenesis. The mechanism(s) through which NF-κB contributes to the neuroinflammation observed during SCI however remains unclear. METHODS: SCI rat models were created using the weight drop method and separated into Sham, SCI and SCI+NF-κB inhibitor groups (n = 6 rats per-group). We used Hematoxylin-Eosin Staining (H&E) and Nissl staining for detecting histological changes in the spinal cord. Basso-Beattie-Bresnahan (BBB) behavioral scores were utilized for assessing functional locomotion recovery. Mouse BV2 microglia were exposed to lipopolysaccharide (LPS) to mimic SCI-induced microglial inflammation in vitro. RESULTS: Inhibition of NF-κB using JSH-23 alleviated inflammation and neuronal injury in SCI rats' spinal cords, leading to improved locomotion recovery (p < 0.05). NF-κB inhibition reduced expression levels of CD86, interleukin-6 (IL-6), IL-1ß, and inducible Nitric Oxide Synthase (iNOS), and improved expression levels of CD206, IL-4, and tissue growth factor-beta (TGF-ß) in both LPS-treated microglia and SCI rats' spinal cords (p < 0.05). Inhibition of NF-κB also effectively suppressed mitochondrial fission, evidenced by the reduced phosphorylation of dynamin-related protein 1 (DRP1) at Ser616 (p < 0.001). CONCLUSION: We show that inhibition of the NF-κB/DRP1 axis prevents mitochondrial fission and suppresses pro-inflammatory microglia polarization, promoting neurological recovery in SCI. Targeting the NF-κB/DRP1 axis therefore represents a novel approach for SCI.

Asunto(s)

Dinaminas , Microglía , FN-kappa B , Traumatismos de la Médula Espinal , Animales , Masculino , Ratones , Ratas , Línea Celular , Polaridad Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Dinaminas/metabolismo , Dinaminas/genética , Inflamación/metabolismo , Lipopolisacáridos , Locomoción/efectos de los fármacos , Microglía/metabolismo , Microglía/efectos de los fármacos , Neuroprotección , FN-kappa B/metabolismo , Quinazolinonas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/patología

RESUMEN

The PI3K signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110γ and p110δ are highly enriched in leukocytes, providing an additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kδ inhibitor idelalisib was the first of four PI3K inhibitors (PI3Ki) to receive regulatory approval for relapsed B-cell malignancies. This was followed by approvals of the pan-class I inhibitor copanlisib (2017), the dual PI3Kγ/δ inhibitor duvelisib (2018), and the PI3Kδ and casein kinase 1ε inhibitor umbralisib (2021). Copanlisib and umbralisib received accelerated approvals, whereas idelalisib and duvelisib received initial accelerated approvals followed by full approvals. The accelerated approvals were based on overall response rates; however, follow-up studies showed increased risk of death and serious side effects. Furthermore, the confirmatory trial with copanlisib failed to show an improvement in progression-free survival when compared with chemoimmunotherapy. These developments led to black box warnings for idelalisib and duvelisib and withdrawal of copanlisib and umbralisib from the market by their manufacturers. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3Kis. In this study, we review the development and current status of PI3Kis in hematology, limitations to their use, and our perspective on whether there is a future for PI3Kis in hematology.

Asunto(s)

Inhibidores de las Quinasa Fosfoinosítidos-3 , Humanos , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Neoplasias Hematológicas/tratamiento farmacológico , Quinazolinonas/uso terapéutico , Quinazolinonas/efectos adversos , Purinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Transducción de Señal/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Quinazolinas

RESUMEN

Background: Development of an inhalable nanoformulation of dacomitinib (DMB) encapsulated in poly-(lactic-co-glycolic acid) nanoparticles (NPs) to improve solubility, facilitate direct lung delivery and overcome the systemic adverse effects.Methods: DMB-loaded poly-(lactic-co-glycolic acid) NPs were prepared using solvent evaporation and characterized for particle size, polydispersity index and zeta-potential. The NPs were evaluated for in vitro drug release, aerosolization performance and in vitro efficacy studies.Results: The NPs showed excellent particle characteristics and displayed a cumulative release of ∼40% in 5 days. The NPs demonstrated a mass median aerodynamic diameter of ∼3 µm and fine particle fraction of ∼80%. Further, in vitro cell culture studies showed improved cytotoxic potential of DMB-loaded NPs compared with free drug.Conclusion: The study underscores the potential of DMB-loaded NPs as a viable approach for non-small cell lung cancer treatment.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Portadores de Fármacos , Liberación de Fármacos , Neoplasias Pulmonares , Nanopartículas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Quinazolinonas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Administración por Inhalación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Portadores de Fármacos/química , Quinazolinonas/química , Quinazolinonas/administración & dosificación , Quinazolinonas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Administración Oral , Línea Celular Tumoral , Ácido Poliglicólico/química , Ácido Láctico/química

RESUMEN

RATIONALE: Acquired resistance still inevitably occurs in patients treated with third-generation TKI osimertinib. Although the EGFR L718Q mutation has been reported as a scarce mechanism of osimertinib resistance, advanced therapeutic strategies are still in development. In this report, we included 2 cases of patients who acquired EGFR L858R/L718Q mutation after osimertinib and were overcome by dacomitinib. PATIENT CONCERNS: Case 1: A 77-year-old woman was diagnosed with stage IV lung adenocarcinoma. Case 2: A 64-year-old woman was diagnosed with stage IV lung adenocarcinoma. DIAGNOSES: Case 1: The patient was diagnosed with adenocarcinoma with EGFR L858R mutation. Since then, treatment with gefitinib was administrated, leading to a progression-free survival of 18 months. The treatment was switched to osimertinib based on the detection of EGFR T790M mutation, resulting in a progression-free survival of 24 months. Subsequently, EGFR L718Q mutation was detected. Case 2: The patient was diagnosed with adenocarcinoma with EGFR L858R mutation. Icotinib was used as the first-line treatment for 7 months. Osimertinib was applied as the second-line treatment for 13 months based on the EGFR T790M mutation. Subsequently, EGFR L718Q mutation was detected. INTERVENTIONS: Case 1: Dacomitinib was administered. Case 2: Dacomitinib was administered. OUTCOMES: Case 1:The progression-free survival was 8 months. Case 2: The progression-free survival was 3 months. LESSONS: Dacomitinib is a potential treatment option for NSCLC patients with EGFR L718Q mutation after resistance to Osimertinib. Further research is needed to validate the efficacy of Dacomitinib in this context.

Asunto(s)

Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Mutación , Quinazolinonas , Humanos , Femenino , Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Receptores ErbB/genética , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Resistencia a Antineoplásicos/genética , Quinazolinonas/uso terapéutico , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Indoles , Pirimidinas

RESUMEN

In this study, a new series of cis and trans 5-substituted-3-(dibenzyloxyphosphoryl)isoxazolidines 16a-g were synthesized by the 1,3-dipolar cycloaddition reaction of N-benzyl-C-(dibenzyloxyphosphoryl)nitrone and selected N1-allyl-N3-benzylquinazoline-2,4-diones. All the obtained trans-isoxazolidines 16a-g and the samples enriched in respective cis-isomers were evaluated for anticancer activity against three tumor cell lines. All the tested compounds exhibited high activity against the prostate cancer cell line (PC-3). Isoxazolidines trans-16a and trans-16b and diastereoisomeric mixtures of isoxazolidines enriched in cis-isomer using HPLC, namely cis-16a/trans-16a (97:3) and cis-16b/trans-16b (90:10), showed the highest antiproliferative properties towards the PC-3 cell line (IC50 = 9.84 ± 3.69-12.67 ± 3.45 µM). For the most active compounds, induction apoptosis tests and an evaluation of toxicity were conducted. Isoxazolidine trans-16b showed the highest induction of apoptosis. Moreover, the most active compounds turned out safe in vitro as none affected the cell viability in the HEK293, HepG2, and HSF cellular models at all the tested concentrations. The results indicated isoxazolidine trans-16b as a promising new lead structure in the search for effective anticancer drugs.

Asunto(s)

Antineoplásicos , Proliferación Celular , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Isoxazoles/química , Isoxazoles/farmacología , Células PC-3 , Ensayos de Selección de Medicamentos Antitumorales , Quinazolinonas/química , Quinazolinonas/farmacología , Quinazolinonas/síntesis química , Estructura Molecular , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos

RESUMEN

In this study, we synthesized 15 novel quinazoline-morpholinobenzylideneamino hybrid compounds from methyl anthranilate and we assessed their cytotoxicity via in vitro assays against A549 and BEAS-2B cell lines. Molecular docking studies were conducted to evaluate the protein-ligand interactions and inhibition mechanisms on nine different molecular targets, while molecular dynamics (MD) simulations were carried out to assess the stability of the best docked ligand-protein complexes. Additionally, ADME prediction was carried out to determine physicochemical parameters and drug likeness. According to the cytotoxicity assays, compound 1 (IC50 = 2.83 µM) was found to be the most active inhibitor against A549 cells. While the selectivity index (SI) of compound 1 is 29, the SI of the reference drugs paclitaxel and sorafenib, used in this study, are 2.40 and 4.92, respectively. Among the hybrid compounds, 1 has the best docking scores against VEGFR1 (-11.744 kcal/mol), VEGFR2 (-12.407 kcal/mol) and EGFR (-10.359 kcal/mol). During MD simulations, compound 1 consistently exhibited strong hydrogen bond interactions with the active sites of VEGFR1 and 2, and these interactions were maintained for more than 90% of the simulation time. Additionally, the RMSD and RMSF values of the ligand-protein complexes exhibited high stability at their minimum levels around 1-2 Å. In conclusion, these findings suggest that compound 1 may be a potent and selective inhibitor candidate for lung cancer treatment and inhibition of VEGFR2, especially.

Asunto(s)

Antineoplásicos , Neoplasias Pulmonares , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Morfolinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Morfolinas/química , Morfolinas/farmacología , Línea Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Células A549 , Quinazolinonas/química , Quinazolinonas/farmacología , Quinazolinonas/metabolismo , Quinazolinonas/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Quinazolinas/química , Quinazolinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/metabolismo , Sitios de Unión , Ensayos de Selección de Medicamentos Antitumorales , Enlace de Hidrógeno

RESUMEN

BACKGROUND: Pediatric postoperative cognitive dysfunction (POCD) is a prevalent complication following anesthesia and surgery. Hypoxia and propofol are the primary risk factors contributing to pediatric POCD. Our previous in vivo animal research has demonstrated that cognitive dysfunction in immature Sprague-Dawley (SD) rats, induced by hypoxia combined with propofol (HCWP), is closely associated with hippocampal neuron ferroptosis. METHODS AND RESULTS: In vivo transcriptome sequencing and KEGG functional analysis revealed significant enrichment of the mitophagy pathway. To further elucidate the relationship between mitophagy and ferroptosis, HT22 cells were selected to construct an in vitro HCWP model. Our findings indicate that HCWP activates excessive mitophagy in HT22 cells, leading to decreased mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) burst, mitochondrial fragmentation, and the induction of ferroptosis. To explore this causal relationship further, we employed Mdivi-1, a mitophagy inhibitor. Notably, low-dose Mdivi-1 (10 µM) effectively suppressed excessive mitophagy in HT22 cells, improved mitochondrial function and morphology, and mitigated markers associated with ferroptosis. The mechanism by which Mdivi-1 alleviates HCWP-induced ferroptosis in HT22 cells is likely due to its inhibition of excessive mitophagy, thereby promoting mitochondrial homeostasis. CONCLUSIONS: Our study suggests that mitophagy may be an upstream event in HCWP-induced ferroptosis in HT22 cells. Consequently, targeted regulation of mitophagy by Mdivi-1 may represent a promising approach to prevent cognitive dysfunction following HCWP exposure.

Asunto(s)

Ferroptosis , Potencial de la Membrana Mitocondrial , Mitofagia , Propofol , Quinazolinonas , Especies Reactivas de Oxígeno , Mitofagia/efectos de los fármacos , Propofol/farmacología , Ferroptosis/efectos de los fármacos , Animales , Quinazolinonas/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ratas , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Línea Celular , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratones , Hipoxia/metabolismo , Hipoxia/complicaciones , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Ratas Sprague-Dawley , Hipoxia de la Célula/efectos de los fármacos , Complicaciones Cognitivas Postoperatorias/metabolismo

RESUMEN

Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.

Asunto(s)

Esclerosis Amiotrófica Lateral , Modelos Animales de Enfermedad , Dinámicas Mitocondriales , Neuronas Motoras , Animales , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Dinámicas Mitocondriales/efectos de los fármacos , Ratones , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/patología , Toxina del Cólera/metabolismo , Saporinas , Quinazolinonas/farmacología , Plasticidad Neuronal/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo

RESUMEN

Autosomal dominant optic atrophy plus (ADOA+) is characterized by primary optic nerve atrophy accompanied by a spectrum of degenerative neurological symptoms. Despite ongoing research, no effective treatments are currently available for this condition. Our study provided evidence for the pathogenicity of an unreported c.1780T>C variant in the OPA1 gene through patient-derived skin fibroblasts and an engineered HEK293T cell line with OPA1 downregulation. We demonstrate that OPA1 insufficiency promoted mitochondrial fragmentation and increased DRP1 expression, disrupting mitochondrial dynamics. Consequently, this disruption enhanced mitophagy and caused mitochondrial dysfunction, contributing to the ADOA+ phenotype. Notably, the Drp1 inhibitor, mitochondrial division inhibitor-1 (Mdivi-1), effectively mitigated the adverse effects of OPA1 impairment. These effects included reduced Drp1 phosphorylation, decreased mitochondrial fragmentation, and balanced mitophagy. Thus, we propose that intervening in DRP1 with Mdivi-1 could correct mitochondrial abnormalities, offering a promising therapeutic approach for managing ADOA+.

Asunto(s)

Dinaminas , Fibroblastos , GTP Fosfohidrolasas , Mitocondrias , Mitofagia , Atrofia Óptica Autosómica Dominante , Quinazolinonas , Humanos , Dinaminas/genética , Dinaminas/metabolismo , Dinaminas/antagonistas & inhibidores , Quinazolinonas/farmacología , Quinazolinonas/uso terapéutico , Atrofia Óptica Autosómica Dominante/genética , Atrofia Óptica Autosómica Dominante/patología , Atrofia Óptica Autosómica Dominante/tratamiento farmacológico , Atrofia Óptica Autosómica Dominante/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Mitofagia/efectos de los fármacos , Células HEK293 , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Masculino , Femenino

RESUMEN

Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABAA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABAA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABAA receptor modulation through transmembrane binding sites.

Asunto(s)

Microscopía por Crioelectrón , Receptores de GABA-A , Receptores de GABA-A/metabolismo , Receptores de GABA-A/química , Sitios de Unión , Humanos , Animales , Etomidato/farmacología , Etomidato/análogos & derivados , Propofol/farmacología , Propofol/química , Quinazolinonas/farmacología , Quinazolinonas/química , Regulación Alostérica/efectos de los fármacos , Células HEK293 , Hipnóticos y Sedantes/farmacología

RESUMEN

The Re(I) organometallic compounds [(Re(CO)3L1-6 )Cl], where Ligand(L) = Tryptanthrin derivatives were prepared and characterized by various spectroscopic techniques. To assess the binding capacities and binding manner, tests of Calf thymus DNA under the impact of organometallic complexes were conducted using absorption titration and viscosity measuring techniques. Data from the research mentioned above point to an intercalation type of binding, which was verified by the docking study. Swiss ADME tools carried out an ADME study. The work focuses on computing the molecular orbital energies for the synthesized compounds using the density functional theory (DFT). The compounds were tested against the MCF-7 cell line to determine their anticancer effects. It was observed that their IC50 values were equivalent to those of the standard medication, indicating that they had a similar antiproliferative impact.

Asunto(s)

Antineoplásicos , Renio , Renio/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Células MCF-7 , Proliferación Celular/efectos de los fármacos , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Simulación del Acoplamiento Molecular , ADN/metabolismo , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Teoría Funcional de la Densidad , Bovinos , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Quinazolinonas/química , Estructura Molecular , Animales , Indoles/farmacología , Indoles/química , Indoles/síntesis química