RESUMEN
The treatment of organophosphate (OP) anticholinesterases currently lacks an effective oxime reactivator of OP-inhibited acetylcholinesterase (AChE) which can penetrate the blood-brain barrier (BBB). Our laboratories have synthesized novel substituted phenoxyalkyl pyridinium oximes and tested them for their ability to promote survival of rats challenged with lethal doses of nerve agent surrogates. These previous studies demonstrated the ability of some of these oximes to promote 24-h survival to rats challenged with a lethal level of highly relevant surrogates for sarin and VX. The reactivation of OP-inhibited AChE in peripheral tissues was likely to be a major contributor to their efficacy in survival of lethal OP challenges. In the present study, twenty of these novel oximes were screened in vitro for reactivation ability for AChE in rat skeletal muscle and serum using two nerve agent surrogates: phthalimidyl isopropyl methylphosphonate (PIMP, a sarin surrogate) and 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate). The oximes demonstrated a range of 23%-102% reactivation of AChE in vitro across both tissue types. Some of the novel oximes tested in the present study demonstrated the ability to more effectively reactivate AChE in serum than the currently approved oxime, 2-PAM. Therefore, some of these novel oximes have the potential to reverse AChE inhibition in peripheral target tissues and contribute to survival efficacy.
Asunto(s)
Acetilcolinesterasa , Inhibidores de la Colinesterasa , Reactivadores de la Colinesterasa , Músculo Esquelético , Organofosfatos , Oximas , Animales , Oximas/farmacología , Oximas/química , Ratas , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/sangre , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/toxicidad , Organofosfatos/toxicidad , Masculino , Reactivadores de la Colinesterasa/farmacología , Reactivadores de la Colinesterasa/química , Compuestos de Piridinio/farmacología , Ratas Sprague-DawleyRESUMEN
Purpose: Glucocorticoid-induced glaucoma (GIG) is a prevalent complication associated with glucocorticoids (GCs), resulting in irreversible blindness. GIG is characterized by the abnormal deposition of extracellular matrix (ECM) in the trabecular meshwork (TM), elevation of intraocular pressure (IOP), and loss of retinal ganglion cells (RGCs). The objective of this study is to investigate the effects of nicotinamide riboside (NR) on TM in GIG. Methods: Primary human TM cells (pHTMs) and C57BL/6J mice responsive to GCs were utilized to establish in vitro and in vivo GIG models, respectively. The study assessed the expression of ECM-related proteins in TM and the functions of pHTMs to reflect the effects of NR. Mitochondrial morphology and function were also examined in the GIG cell model. GIG progression was monitored through IOP, RGCs, and mitochondrial morphology. Intracellular nicotinamide adenine dinucleotide (NAD+) levels of pHTMs were enzymatically assayed. Results: NR significantly prevented the expression of ECM-related proteins and alleviated dysfunction in pHTMs after dexamethasone treatment. Importantly, NR protected damaged ATP synthesis, preventing overexpression of mitochondrial reactive oxygen species (ROS), and also protect against decreased mitochondrial membrane potential induced by GCs in vitro. In the GIG mouse model, NR partially prevented the elevation of IOP and the loss of RGCs. Furthermore, NR effectively suppressed the excessive expression of ECM-associated proteins and mitigated mitochondrial damage in vivo. Conclusions: Based on the results, NR effectively enhances intracellular levels of NAD+, thereby mitigating abnormal ECM deposition and TM dysfunction in GIG by attenuating mitochondrial damage induced by GCs. Thus, NR has promising potential as a therapeutic candidate for GIG treatment.
Asunto(s)
Modelos Animales de Enfermedad , Matriz Extracelular , Glaucoma , Glucocorticoides , Presión Intraocular , Ratones Endogámicos C57BL , Mitocondrias , Niacinamida , Compuestos de Piridinio , Malla Trabecular , Animales , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Piridinio/farmacología , Glucocorticoides/toxicidad , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Ratones , Glaucoma/metabolismo , Glaucoma/tratamiento farmacológico , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Presión Intraocular/efectos de los fármacos , Humanos , Malla Trabecular/metabolismo , Malla Trabecular/efectos de los fármacos , Malla Trabecular/patología , Células Cultivadas , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Especies Reactivas de Oxígeno/metabolismo , Dexametasona/farmacología , MasculinoRESUMEN
This study demonstrates the potential of gelatin nanoparticles as a nanodelivery system for antagonists of nicotinic acetylcholine receptors (nAChRs) to improve chemotherapy efficacy and reduce off-target effects. Too often, chemotherapy for lung cancer does not lead to satisfactory results. Therefore, new approaches directed at multiple pharmacological targets in cancer therapy are being developed. Following the activation of nAChRs (e.g. by nicotine), cancer cells begin to proliferate and become more resistant to chemotherapy-induced apoptosis. This work shows that the 3-alkylpyridinium salt, APS7, a synthetic analog of a toxin from the marine sponge Haliclona (Rhizoneira) sarai, acts as an nAChR antagonist that inhibits the pro-proliferative and anti-apoptotic effects of nicotine on A549 human lung adenocarcinoma cells. In this study, gelatin-based nanoparticles filled with APS7 (APS7-GNPs) were prepared and their effects on A549 cells were compared with that of free APS7. Both APS7 and APS7-GNPs inhibited Ca2+ influx and increased the efficacy of cisplatin chemotherapy in nicotine-stimulated A549 cells. However, significant benefits from APS7-GNPs were observed - a stronger reduction in the proliferation of A549 lung cancer cells and a much higher selectivity in cytotoxicity towards cancer cells compared with non-tumorigenic lung epithelial BEAS-2B cells.
Asunto(s)
Proliferación Celular , Gelatina , Neoplasias Pulmonares , Nanopartículas , Humanos , Gelatina/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Células A549 , Nanopartículas/química , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/química , Cisplatino/farmacología , Nicotina/farmacología , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/química , Línea Celular TumoralRESUMEN
N-methylpyridinium (NMP) is produced through the pyrolysis of trigonelline during the coffee bean roasting process. Preliminary studies suggest that NMP may have health benefits, thanks to its antioxidant properties. Based on this background, the aim of this study was to evaluate whether NMP could have a protective effect against LPS-induced neuroinflammation in human glioblastoma cells (U87MG). With this aim, U87MG cells were pre-treated with NMP (0.5 µM) for 1 h and then exposed to LPS (1 µg/mL) for 24 h. Our findings show that NMP attenuates LPS-induced neuroinflammation by reducing the expression of pro-inflammatory cytokines, such as IL-1ß, TNF-α and IL-6, through the inhibition of the NF-κB signaling pathway, which is critical in regulating inflammatory responses. NMP is able to suppress the activation of the NF-κB signaling pathway, suggesting its potential in preventing neuroinflammatory conditions. These outcomes support the notion that regular consumption of NMP, possibly through coffee consumption, may offer protection against neuroinflammatory states implicated in neurological disorders.
Asunto(s)
Lipopolisacáridos , FN-kappa B , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Compuestos de Piridinio , Transducción de Señal , Humanos , Fármacos Neuroprotectores/farmacología , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Transducción de Señal/efectos de los fármacos , Compuestos de Piridinio/farmacología , Línea Celular Tumoral , Citocinas/metabolismoRESUMEN
Nicotinamide riboside (NR) is a precursor and exogenous supplement of nicotinamide adenine dinucleotide (NAD+). NR has been shown to play a beneficial role in a variety of neurodegenerative diseases. A phase 1 clinical trial identified NR as a potential neuroprotective therapy for Parkinson's disease (PD). However, the mechanism of action of NR in PD has not been fully elucidated. Therefore, the present study aimed to investigate the potential effects of NR on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish and its underlying mechanisms. The results showed that NR improved motor dysfunction, survival time, dopamine neurons, and peripheral neurons, as well as the NAD+ levels in the MPTP-affected PD zebrafish model. In addition, transcriptome sequencing analysis revealed that, after NR treatment, differentially expressed genes were significantly enriched in the glucose metabolism and protein processing pathways in the endoplasmic reticulum (ER). Quantitative PCR (qPCR) revealed that the mRNA levels of the glycoheterotrophic enzyme (involved in glucose metabolism) were significantly decreased, and the glycolytic enzyme mRNA expression levels were significantly increased. The results of the non-targeted metabolomic analysis showed that NR treatment significantly increased the levels of metabolites such as nicotinic acid ,nicotinamide, d-glucose (from the gluconeogenesis and glycolysis metabolism pathways) and some glucogenic amino acids, such as glutamine. Importantly, NR ameliorated MPTP-induced endoplasmic reticulum stress (ERS) in the PD zebrafish model through the Perk-Eif2α-Atf4-Chop pathway. These results highlight the neuroprotective effect of NR in the present PD zebrafish model through modulation of glucose metabolism and ERS via the Perk-Eif2α-Atf4-Chop pathway and provide valuable mechanistic insights into the treatment of PD.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Glucosa , Niacinamida , Compuestos de Piridinio , Pez Cebra , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/uso terapéutico , Glucosa/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Actividad Motora/efectos de los fármacos , MasculinoRESUMEN
Coumarin is a natural product known for its diverse biological activities. While its antifungal properties in agricultural chemistry have been extensively studied, there is limited research on its antibacterial potential. In this study, we developed several novel coumarin derivatives by combining coumarin with pyridinium salt through molecular hybridization and chemical synthesis. Our findings reveal that most of these derivatives exhibit promising antibacterial activity. Among them, derivative A25 has been identified as the most effective compound based on three-dimensional quantitative structure-activity relationships. It demonstrates significant in vitro and in vivo activity against Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas oryzae pv. oryzicola (Xoc), and Xanthomonas campestris pv. citri (Xac), outperforming the commercially available thiediazole copper. Initial investigations into its mechanism of action suggest that A25 disrupts the cell membranes of Xoc and Xoo, thereby inhibiting bacterial growth. Additionally, A25 enhances the activity of defense enzymes in rice and modulates the expression of proteins related to the pyruvate metabolism pathway. This dual action contributes to rice's resistance against bacterial infestation. We anticipate that this study will serve as a foundation for the development of coumarin-based bactericides.
Asunto(s)
Antibacterianos , Cumarinas , Pruebas de Sensibilidad Microbiana , Oryza , Xanthomonas , Cumarinas/farmacología , Cumarinas/síntesis química , Cumarinas/química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Xanthomonas/efectos de los fármacos , Oryza/microbiología , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/química , Compuestos de Piridinio/síntesis química , Xanthomonas campestris/efectos de los fármacos , Diseño de Fármacos , Sales (Química)/farmacología , Sales (Química)/química , Relación Estructura-ActividadRESUMEN
Polymeric materials with antibacterial properties hold great promise for combating multidrug-resistant bacteria, which pose a significant threat to public health. However, the synthesis of most antibacterial polymers typically involves complicated and time-consuming procedures. In this study, we demonstrate a simple and efficient strategy for synthesizing functional poly(vinylpyridinium salt)s via pyridinium-yne click polymerization. This click polymerization could proceed with high atom economy under mild conditions without any external catalyst, yielding soluble and thermally stable poly(vinylpyridinium salt)s with satisfactory molecular weights and well-defined structures in excellent yields. Additionally, the incorporation of luminescent units such as fluorene, tetraphenylethylene, and triphenylamine into the polymer backbone confers excellent aggregation-enhanced emission properties upon the resulting polymers, rendering them suitable for bacterial staining. Moreover, the existence of pyridinium salt imparts intrinsic antibacterial activity against multidrug-resistant bacteria to the polymers, enabling them to effectively inhibit wound bacterial infection and significantly expedite the healing process. This work not only provides an efficient method to prepare antibacterial polymers, but also opens up the possibility of various applications of polymers in healthcare and other antibacterial fields.
Asunto(s)
Antibacterianos , Química Clic , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Polimerizacion , Compuestos de Piridinio , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Compuestos de Piridinio/química , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/síntesis química , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Polímeros/química , Polímeros/farmacología , Polímeros/síntesis químicaRESUMEN
Desensitization of nicotinic acetylcholine receptors (nAChRs) can be induced by overstimulation with acetylcholine (ACh) caused by an insufficient degradation of ACh after poisoning with organophosphorus compounds (OPCs). Currently, there is no generally applicable treatment for OPC poisoning that directly targets the desensitized nAChR. The bispyridinium compound MB327, an allosteric modulator of nAChR, has been shown to act as a resensitizer of nAChRs, indicating that drugs binding directly to nAChRs can have beneficial effects after OPC poisoning. However, MB327 also acts as an inhibitor of nAChRs at higher concentrations and can thus not be used for OPC poisoning treatment. Consequently, novel, more potent resensitizers are required. To successfully design novel ligands, the knowledge of the binding site is of utmost importance. Recently, we performed in silico studies to identify a new potential binding site of MB327, MB327-PAM-1, for which a more affine ligand, UNC0646, has been described. In this work, we performed ligand-based screening approaches to identify novel analogs of UNC0646 to help further understand the structure-affinity relationship of this compound class. Furthermore, we used structure-based screenings and identified compounds representing four new chemotypes binding to MB327-PAM-1. One of these compounds, cycloguanil, is the active metabolite of the antimalaria drug proguanil and shows a higher affinity towards MB327-PAM-1 than MB327. Furthermore, cycloguanil can reestablish the muscle force in soman-inhibited rat muscles. These results can act as a starting point to develop more potent resensitizers of nAChR and to close the gap in the treatment after OPC poisoning.
Asunto(s)
Receptores Nicotínicos , Animales , Ligandos , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Sitios de Unión , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/química , Ratas , Relación Estructura-Actividad , Masculino , Unión Proteica , Simulación del Acoplamiento Molecular , Soman , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/químicaRESUMEN
Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats.
Asunto(s)
Acetilcolinesterasa , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Reactivadores de la Colinesterasa , Agentes Nerviosos , Compuestos Organotiofosforados , Oximas , Sarín , Animales , Oximas/farmacología , Oximas/química , Reactivadores de la Colinesterasa/farmacología , Reactivadores de la Colinesterasa/química , Inhibidores de la Colinesterasa/toxicidad , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/efectos de los fármacos , Butirilcolinesterasa/metabolismo , Ratas , Masculino , Compuestos Organotiofosforados/toxicidad , Sarín/toxicidad , Agentes Nerviosos/toxicidad , Ratas Wistar , Halogenación , Sustancias para la Guerra Química/toxicidad , Compuestos de Piridinio/farmacología , Estabilidad de MedicamentosRESUMEN
Chronic cerebral hypoperfusion (CCH) is an enduring inadequate blood flow to the brain, resulting in vascular dementia (VaD). However, the effective treatment strategies are lacking. Supplementing with nicotinamide adenine dinucleotide (NAD+) has shown neuroprotective benefits in other neurodegenerative disorders. Nicotinamide riboside (NR), as a precursor of NAD+, is believed to hold promise in improving mitochondrial health, autophagy, and cognitive function. Meanwhile, NR has unique oral bioavailability, good tolerability, and minimal side effects, and it is the most promising for clinical translation. However, the effectiveness of NR in treating CCH-related VaD is still uncertain. The present study examined the neuroprotective effects of NR supplementation and its underlying mechanisms in a CCH rat model. The rats with CCH were given NR at a daily dosage of 400 mg/kg for 3 months. NR supplementation increased blood and brain NAD+ levels and improved brain function in CCH rats, including cognitive function and oxygenation capacity. It also reduced hippocampal neuronal loss and abnormalities and mitigated the decrease in dendritic spine density. The analysis of RNA sequencing in hippocampal tissue supports these findings. Electron microscopy and protein detection results suggest that NR may maintain mitochondrial structural integrity and exert a protective role by attenuating mitochondrial fission and impaired autophagy flux caused by CCH. In conclusion, these findings offer evidence for the neuroprotective potential of NR supplementation in ameliorating cognitive impairment induced by CCH.
Asunto(s)
Mitocondrias , Fármacos Neuroprotectores , Niacinamida , Compuestos de Piridinio , Animales , Niacinamida/farmacología , Niacinamida/análogos & derivados , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Compuestos de Piridinio/farmacología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas Sprague-Dawley , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Enfermedad Crónica , Circulación Cerebrovascular/efectos de los fármacosRESUMEN
Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2'-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20â¯Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR.
Asunto(s)
Diafragma , Agentes Nerviosos , Compuestos de Piridinio , Animales , Diafragma/efectos de los fármacos , Diafragma/inervación , Agentes Nerviosos/toxicidad , Masculino , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/química , Transmisión Sináptica/efectos de los fármacos , Relación Estructura-Actividad , Unión Neuromuscular/efectos de los fármacos , Ratas , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Ratas Wistar , Intoxicación por Organofosfatos/tratamiento farmacológico , Oximas/farmacología , Oximas/química , Ratas Sprague-Dawley , Estructura MolecularRESUMEN
Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising MB327 analogs with a 4-aminopyridinium ion partial structure (PTM0056, PTM0062, and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new analogs of the aforementioned compounds with a 4-aminopyridinium ion partial structure (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90-0012 and PTMD90-0015) designed to substitute entropically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research.
Asunto(s)
Receptores Nicotínicos , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Animales , Masculino , Agentes Nerviosos/toxicidad , Ratas Wistar , Ratas , Intoxicación por Organofosfatos/tratamiento farmacológico , Diafragma/efectos de los fármacos , Diafragma/metabolismo , Relación Estructura-Actividad , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/química , Contracción Muscular/efectos de los fármacos , Unión Neuromuscular/efectos de los fármacos , Sitios de UniónRESUMEN
Introduction: Cigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD+) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR. Methods: C57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks. Results: Our results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD+ signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling. Conclusion: We conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS.
Asunto(s)
Ratones Endogámicos C57BL , Niacinamida , Nicotina , Compuestos de Piridinio , Animales , Compuestos de Piridinio/farmacología , Ratones , Niacinamida/análogos & derivados , Niacinamida/farmacología , Masculino , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Hígado Graso/prevención & control , Hígado Graso/metabolismo , Hígado Graso/inducido químicamente , Jarabe de Maíz Alto en Fructosa/efectos adversos , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Ischemic heart disease invariably leads to devastating damage to human health. Nicotinamide ribose (NR), as one of the precursors of NAD+ synthesis, has been discovered to exert a protective role in various neurological and cardiovascular disorders. Our findings demonstrated that pretreatment with 200â¯mg/kg NR for 3â¯h significantly reduced myocardial infarct area, decreased levels of CK-MB and LDH in serum, and improved cardiac function in the rats during myocardial ischemia-reperfusion (I/R) injury. Meanwhile, 0.5â¯mM NR also effectively increased the viability and decreased the LDH release of H9c2 cells during OGD/R. We had provided evidence that NR pretreatment could decrease mitochondrial reactive oxygen species (mtROS) production and MDA content, and enhance SOD activity, thereby mitigating mitochondrial damage and inhibiting apoptosis during myocardial I/R injury. Further investigations revealed that NR increased NAD+ content and upregulated SIRT3 protein expression in myocardium. Through using of SIRT3 small interfering RNA and the SIRT3 deacetylase activity inhibitor 3-TYP, we had confirmed that the cardioprotective effect of NR on cardiomyocytes was largely dependent on the inhibition of mitochondrial oxidative stress via SIRT3-SOD2 axis. Overall, our study suggested that exogenous supplementation with NR mitigated mitochondrial damage and inhibited apoptosis during myocardial I/R injury by reducing mitochondrial oxidative stress via SIRT3-SOD2-mtROS pathway.
Asunto(s)
Apoptosis , Daño por Reperfusión Miocárdica , Niacinamida , Estrés Oxidativo , Compuestos de Piridinio , Ratas Sprague-Dawley , Transducción de Señal , Sirtuina 3 , Superóxido Dismutasa , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Sirtuina 3/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Niacinamida/farmacología , Niacinamida/análogos & derivados , Superóxido Dismutasa/metabolismo , Ratas , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Compuestos de Piridinio/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Cardiotónicos/farmacología , SirtuinasRESUMEN
Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.
Asunto(s)
Hígado , Metaboloma , Ratones Endogámicos C57BL , Niacinamida , Mononucleótido de Nicotinamida , Enfermedad del Hígado Graso no Alcohólico , Compuestos de Piridinio , Transcriptoma , Animales , Niacinamida/farmacología , Niacinamida/uso terapéutico , Niacinamida/análogos & derivados , Compuestos de Piridinio/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Mononucleótido de Nicotinamida/farmacología , Mononucleótido de Nicotinamida/uso terapéutico , Masculino , Transcriptoma/efectos de los fármacos , Metaboloma/efectos de los fármacos , Ratones , Hígado/metabolismo , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Dieta Alta en Grasa/efectos adversosRESUMEN
Thromboembolic events are complications in cancer patients and hypercoagulability has been linked to the tissue factor (TF) pathway, making this an attractive target. Here, we investigated the effects of chemotherapeutics and CDK inhibitors (CDKI) abemaciclib/palbociclib (CDK4/6), THZ-1 (CDK7/12/13), and dinaciclib (CDK1/2/5/9) alone and in combination regimens on TF abundance and coagulation. The human colorectal cancer (CRC) cell line HROC173 was treated with 5-FU or gemcitabine to stimulate TF expression. TF+ cells were sorted, recultured, and re-analyzed. The effect of treatment alone or in combination was assessed by functional assays. Low-dose chemotherapy induced a hypercoagulable state and significantly upregulated TF, even after reculture without treatment. Cells exhibited characteristics of epithelial-mesenchymal transition, including high expression of vimentin and mucin. Dinaciclib and THZ-1 also upregulated TF, while abemaciclib and palbociclib downregulated it. Similar results were observed in coagulation assays. The same anticoagulant activity of abemaciclib was seen after incubation with peripheral immune cells from healthy donors and CRC patients. Abemaciclib reversed 5-FU-induced TF upregulation and prolonged clotting times in second-line treatment. Effects were independent of cytotoxicity, senescence, and p27kip1 induction. TF-antibody blocking experiments confirmed the importance of TF in plasma coagulation, with Factor XII playing a minor role. Short-term abemaciclib counteracts 5-FU-induced hypercoagulation and eventually even prevents thromboembolic events.
Asunto(s)
Neoplasias del Colon , Quinasas Ciclina-Dependientes , Fluorouracilo , Tromboplastina , Regulación hacia Arriba , Humanos , Tromboplastina/metabolismo , Tromboplastina/genética , Línea Celular Tumoral , Fluorouracilo/farmacología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Regulación hacia Arriba/efectos de los fármacos , Quinasas Ciclina-Dependientes/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Aminopiridinas/farmacología , Bencimidazoles/farmacología , Compuestos de Piridinio/farmacología , Óxidos N-Cíclicos/farmacología , Indolizinas/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacosRESUMEN
Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.
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Quinasa 9 Dependiente de la Ciclina , Indolizinas , Neoplasias Pulmonares , Compuestos de Piridinio , Carcinoma Pulmonar de Células Pequeñas , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Humanos , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Línea Celular Tumoral , Ratones , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/uso terapéutico , Indolizinas/farmacología , Óxidos N-Cíclicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
PURPOSE: This study examined the effects of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) on folliculogenesis and mitochondrial dynamics (fission and fusion mechanisms) in ovaries of middle-aged female rats. METHODS: Experimental groups were young, middle-aged (control), middle-aged + NMN and middle-aged + NR. NMN was administered at a concentration of 500 mg/kg intraperitoneally but NR at a concentration of 200 mg/kg by gavage. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were analyzed by ELISA. Hematoxylin-eosin staining sections were used for histopathological examination and follicles-counting. Expression levels of mitochondrial fission (Drp1, Mff and Fis1) and fusion (Mfn1, Mfn2, Opa1, Fam73a and Fam73b) genes as well as Sirt1 gene were analyzed by RT-PCR. Expression levels of fission-related proteins (DRP1, MFF, FIS1 and SIRT1) were analyzed by Western Blot. RESULTS: Higher ovarian index, more corpus luteum and antral follicles were detected in NMN and NR groups compared to the control. NMN or NR could rebalance LH/FSH ratio. The control group was determined to possess higher expression levels of fission genes and lower expression levels of fusion genes when compared the young group. In comparison with the control group, both NMN and NR group were found to exhibit less mitochondrial fission but more mitochondrial fussion. Higher gene and protein levels for Sirt1 were measured in NMN and NR groups compared to the control group. CONCLUSION: This study reveals that NMN alone or NR alone can rebalance mitochondrial dynamics by decreasing excessive fission in middle-aged rat ovaries, thus alleviating mitochondrial stress and correcting aging-induced folliculogenesis abnormalities.
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Envejecimiento , Dinámicas Mitocondriales , Niacinamida , Mononucleótido de Nicotinamida , Ovario , Compuestos de Piridinio , Animales , Femenino , Dinámicas Mitocondriales/efectos de los fármacos , Niacinamida/análogos & derivados , Niacinamida/farmacología , Ovario/efectos de los fármacos , Ovario/metabolismo , Mononucleótido de Nicotinamida/farmacología , Mononucleótido de Nicotinamida/metabolismo , Ratas , Compuestos de Piridinio/farmacología , Sirtuina 1/metabolismo , Sirtuina 1/genética , Hormona Luteinizante/metabolismo , Hormona Luteinizante/sangre , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/metabolismo , Ratas Sprague-Dawley , Hormona Folículo Estimulante/metabolismo , DinaminasRESUMEN
BACKGROUND: Bacterial virulence factors are involved in various biological processes and mediate persistent bacterial infections. Focusing on virulence factors of phytopathogenic bacteria is an attractive strategy and crucial direction in pesticide discovery to prevent invasive and persistent bacterial infection. Hence, discovery and development of novel agrochemicals with high activity, low-risk, and potent anti-virulence is urgently needed to control plant bacterial diseases. RESULTS: A series of novel ß-hydroxy pyridinium cation decorated pterostilbene derivatives were prepared and their antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) were systematacially assessed. Among these pterostilbene derivatives, compound 4S exhibited the best antibacterial activity against Xoo in vitro, with an half maximal effective concentration (EC50) value of 0.28 µg mL-1. A series of biochemical assays including scanning electron microscopy, crystal violet staining, and analysis of biofilm formation, swimming motility, and related virulence factor gene expression levels demonstrated that compound 4S could function as a new anti-virulence factor inhibitor by interfering with the bacterial infection process. Furthermore, the pot experiments provided convinced evidence that compound 4S had the high control efficacy (curative activity: 71.4%, protective activity: 72.6%), and could be used to effectively manage rice bacterial leaf blight in vivo. CONCLUSION: Compounds 4S is an attractive virulence factor inhibitor with potential for application in treating plant bacterial diseases by suppressing production of several virulence factors. © 2024 Society of Chemical Industry.
Asunto(s)
Antibacterianos , Estilbenos , Factores de Virulencia , Xanthomonas , Xanthomonas/efectos de los fármacos , Xanthomonas/patogenicidad , Estilbenos/farmacología , Estilbenos/química , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Antibacterianos/farmacología , Antibacterianos/química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/química , Oryza/microbiología , Amino Alcoholes/farmacología , Amino Alcoholes/química , Biopelículas/efectos de los fármacosRESUMEN
Oxaliplatin (OHP) is effective in colorectal cancer treatment but induces peripheral neurotoxicity (OHP-induced peripheral neurotoxicity, OIPN), diminishing survivor quality of life. Organic cation transporter 2 (OCT2) is a key OHP uptake pathway in dorsal root ganglia. Competing for OCT2-mediated OHP uptake, such as with the tyrosine kinase inhibitor dasatinib, may mitigate OHP side effects. We investigated OHP and dasatinib interaction with OCT2 in human embryonic kidney 293 (HEK293) cells expressing OCT2 within a 10-3 to 10-7 M concentration range. Uptake competition experiments using fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (ASP+, 1 µM) and mass spectrometry (MS) to determine cellular platinum content indicated that OHP (100 µM) is an OCT2 substrate, mediating OHP cellular toxicity. ASP+ and MS analysis revealed dasatinib as a non-transported inhibitor of hOCT2 (IC50 = 5.9 µM) and as a regulator of OCT2 activity. Dasatinib reduced transporter Vmax, potentially via Y544 phosphorylation suppression. MS analysis showed cellular dasatinib accumulation independent of hOCT2. Although 3 µM dasatinib reduced 100 µM OHP accumulation in hOCT2-HEK293 cells, co-incubation with dasatinib and OHP did not prevent OHP toxicity, possibly due to dasatinib-induced cell viability reduction. In summary, this study demonstrates OHP as an OCT2 substrate and dasatinib as a non-transported inhibitor and regulator of OCT2, offering potential for OIPN mitigation.