RESUMEN
AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.
RESUMEN
Infidelity has been operationalized inconsistently across studies, and measurement approaches have been employed that are not ideally suited for addressing the stigmatized and subjective nature of infidelity, thereby limiting the conclusions that can be drawn from this body of literature. In 2016, Thompson and O'Sullivan took a step toward addressing these shortcomings by implementing an indirect measurement approach. We extend their findings using a sample of 465 married and divorced individuals via MTurk. Substantially more participants reported having engaged in infidelity via the indirect approach than the direct approach, and results suggest that-in contrast to findings from direct questioning-similar percentages of men and women engage in self-defined infidelity. Implications for research and clinical practice are provided.
Asunto(s)
Divorcio , Matrimonio , Masculino , Humanos , Femenino , Relaciones ExtramatrimonialesRESUMEN
Poor prognosis in the underlying mechanisms involved in lung adenocarcinoma and its treatment leads to low survival rates in patients. Emerging evidence indicates that cancer is primarily a metabolic disease and metabolic reprogramming is a well-established hallmark and driving force of cancer. Oct4, acting as an oncogene, is a major regulator of cell pluripotency. It can reprogram the differentiated cells into cancer stem cells (CSCs) and plays an oncogenic role when pathologically hijacked. However, data that Oct4, the genetic reprogramming factor, could induce metabolic reprogramming have been very limited, and the direct evidence in metabolic level whether Oct4 reprograms metabolome is lacking. In the present study, integrated untargeted and targeted metabolomics analyses were utilized to investigate metabolic changes induced by Oct4 overexpression in lung adenocarcinoma cells. The results suggested that elevated expression levels of Oct4 drive metabolic reprogramming. Oct4 overexpression redirects glucose catabolism to glycolysis pathway and to the oxidative pentose phosphate pathway (PPP). This study identifies unique pathways that are candidate therapeutic targets for the treatment of lung adenocarcinoma. This study also aims to improve our understanding of the cancer-promoting activity of Oct4 and help identify novel diagnostic and therapeutic strategies for cancer treatment.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Glucólisis , Humanos , Neoplasias Pulmonares/metabolismo , Metabolómica , Vía de Pentosa FosfatoRESUMEN
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer (NSCLC), but acquired resistance limits their clinical application. NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy. In this study, we investigated the role of NRF2 in resistance to EGFR-TKIs. We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein. NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells. Furthermore, we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2, and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs. Thus, we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Resistencia a Antineoplásicos/fisiología , Neoplasias Pulmonares/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Superóxido Dismutasa/metabolismo , Carbolinas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/fisiología , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/farmacología , Gefitinib/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/genética , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño/farmacología , Superóxido Dismutasa/genética , Regulación hacia Arriba/fisiologíaRESUMEN
INTRODUCTION: Specific oncogenotypes can produce distinct metabolic changes in cancer. Recently it is considered that metabolic reprograming contributes heavily to drug resistance. Aldehyde dehydrogenase 1A1 (ALDH1A1), is overexpressed in drug resistant lung adenocarcinomas and may be the cause of acquired drug resistance. However, how ALDH1A1 affects metabolic profiling in lung adenocarcinoma cells remains elusive. OBJECTIVE: We sought to investigate metabolic alterations induced by ALDH1A1 in lung adenocarcinoma in order to better understand the reprogramming and metabolic mechanism of resistance induced by ALDH1A1. METHODS: Metabolic alterations in lung adenocarcinoma HCC827-ALDH1A1 cells were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). HCC827-ALDH1A1 metabolic signatures were extracted by univariate and multivariate statistical analysis. Furthermore, metabolite enrichment analysis and pathway analysis were performed using MetaboAnalyst 4.0 software. RESULTS: Twenty-two metabolites were positively identified using authentic standards, including uridine monophosphate (UMP), uridine diphosphate (UDP), adenosine diphosphate (ADP), malic acid, malonyl-coenzyme A, nicotinamide adenine dinucleotide (NAD), coenzyme A and so on. Furthermore, metabolic pathway analysis revealed several dysregulated pathways in HCC827-ALDH1A1 cells, including nucleotide metabolism, urea cycle, tricarboxylic acid (TCA) cycle, and glycerol phospholipid metabolism etc. CONCLUSION: Lung cancer is the most frequent cause of cancer-related deaths worldwide. Nearly all patients eventually undergo disease progression due to acquired resistance. Mechanisms of biological acquired resistance need to be identified. Our study identified altered metabolites in HCC827-ALDH1A1 cells, enhancing our knowledge of lung adenocarcinoma metabolic alterations induced by ALDH1A1, creating a novel therapeutic pathway. These metabolic signatures of ALDH1A1 overexpression may shed light on molecular mechanisms in drug-resistant tumors, and on candidate drug targets. Furthermore, new molecular targets may provide the foundation for potential anticancer strategies for lung cancer therapy.
Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Familia de Aldehído Deshidrogenasa 1/genética , Familia de Aldehído Deshidrogenasa 1/metabolismo , Retinal-Deshidrogenasa/genética , Retinal-Deshidrogenasa/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión/métodos , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Redes y Vías Metabólicas , Metabolómica/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
Adrenoreceptors (ARs) are widely expressed and play essential roles throughout the body. Different subtype adrenoceptors elicit distinct effects on cell proliferation, but knowledge remains scarce about the subtype-specific effects of ß2-ARs on the proliferation of embryonic pluripotent stem (PS) cells that represent different characteristics of proliferation and cell cycle regulation with the somatic cells. Herein, we identified a ß2-AR/AC/cAMP/PKA signaling pathway in embryonic PS cells and found that the pathway stimulation inhibited proliferation and cell cycle progression involving modulating the stem cell growth and cycle regulatory machinery. Embryonic stem (ES) cells and embryonal carcinoma stem (ECS) cells expressed functional ß-ARs coupled to AC/cAMP/PKA signaling. Agonistic activation of ß-ARs led to embryonic PS cell cycle arrest and proliferation inhibition. Pharmacological and genetic analyzes using receptor subtype blocking and RNA interference approaches revealed that this effect selectively depended on ß2-AR signaling involving the regulation of AKT, ERK, Rb, and Cyclin E molecules. Better understanding of the effects of ß2-ARs on embryonic PS cell proliferation and cycle progression may provide new insights into stem cell biology and afford the opportunity for exploiting more selective ligands targeting the receptor subtype for the modulation of stem cells.
Asunto(s)
Células Madre Embrionarias/citología , Proteína Oncogénica v-akt/genética , Células Madre Pluripotentes/citología , Receptores Adrenérgicos beta 2/genética , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Puntos de Control del Ciclo Celular/genética , Proliferación Celular/genética , AMP Cíclico/genética , AMP Cíclico/metabolismo , Células Madre Embrionarias/metabolismo , Humanos , Proteína Oncogénica v-akt/biosíntesis , Células Madre Pluripotentes/metabolismo , Interferencia de ARN , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 × 100 mm, 3.5 µm) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3% formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 µL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67%, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90%. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 ± 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-∞) = 283.1 ± 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/efectos de los fármacos , Cromatografía Liquida , Meptazinol/análogos & derivados , Fenilcarbamatos/análisis , Fenilcarbamatos/farmacocinética , Espectrometría de Masas en Tándem , Animales , Área Bajo la Curva , Encéfalo/metabolismo , Calibración , Química Farmacéutica/métodos , Femenino , Formiatos/química , Masculino , Meptazinol/análisis , Meptazinol/farmacocinética , Ratones , Fenilcarbamatos/química , Control de Calidad , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray , Temperatura , Distribución TisularRESUMEN
The relationship between glomalin-related soil protein (GRSP) and soil aggregation has been a hot topic of research for its close link to soil stability and quality. However, the short-term cultivation of Eucalyptus poses serious threats to soil stability and nutrient stocks, and the effects of GRSP on soil aggregate stability and macronutrient accumulation remain unclear. The aim is to clarify the potential mechanisms affecting soil aggregate stability and macronutrient accumulation in short-term Eucalyptus plantations. Five Eucalyptus urophylla × Eucalyptus grandis plantations with different cultivation periods (1-5 years) in this study were investigated, and a native evergreen broadleaf forest (0 year) was selected as control. The mean weight diameter index increased in the first 3 years and then significantly decreased during 5 years cultivation of Eucalyptus. Soil organic carbon (SOC) and total nitrogen also decreased after planting Eucalyptus for 3 years, but variation in total phosphorus was not obvious. The relative abundance of Glomeraceae and Claroideoglomeraceae decreased in the 5-year-old Eucalyptus plantations and was positively correlated with GRSP content. In pathway modeling, nutrient-acquisition enzyme activities positively affected GRSP and macronutrient content. Total GRSP (T-GRSP) had higher total effects than easily extractable GRSP on soil aggregate stability, and positively correlated with SOC in macroaggregates. Both T-GRSP and SOC had positive and direct effects on soil aggregate stability. Variance partitioning analysis further explained the contribution of GRSP and SOC to aggregate stability, particularly in >2 and 2-0.25 mm macroaggregates. Our results suggested that GRSP was directly associated with SOC content and soil aggregate stability, and was a potential key factor affecting soil aggregate stability in Eucalyptus plantations. Improving T-GRSP and SOC are efficient approaches for preventing the gradual deterioration of soil aggregate stability. Short-term cultivation should be carefully used in Eucalyptus plantations, and a new cultivation period is needed.
Asunto(s)
Eucalyptus , Glomeromycota , Suelo , Proteínas Fúngicas/metabolismo , Carbono , Glicoproteínas/metabolismo , NutrientesRESUMEN
The cGAS-STING pathway has long been recognized as playing a crucial role in immune surveillance and tumor suppression. Here, we show that when the pathway is activated in a cancer-cell-autonomous response manner, it confers drug resistance. Targeted or conventional chemotherapy drugs promoted cytosolic DNA accumulation in cancer cells, activating the cGAS-STING pathway and downstream TBK1-IRF3/NF-κB signaling. This cancer cell-intrinsic response enabled the cells to counteract drug stress, allowing treatment resistance to be acquired and maintained. Blockade of stimulator of interferon genes (STING) signaling delayed and overcame resistance in models in vitro and in vivo. This finding uncovers an alternative face of cGAS-STING signaling other than the well-reported modulation of microenvironmental immune cells. It also implies a caution for the combination of STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.
Asunto(s)
Resistencia a Antineoplásicos , Proteínas de la Membrana , Neoplasias , Nucleotidiltransferasas , ADN/metabolismo , Neoplasias/tratamiento farmacológico , FN-kappa B/metabolismo , Nucleotidiltransferasas/metabolismo , Transducción de Señal , Proteínas de la Membrana/metabolismoRESUMEN
Slash disposal changes soil quality by affecting soil properties and nutrient cycling, and the appropriate disposal approaches remain controversial. This work aimed to explore the impact of different slash disposal methods on soil qualities. For this purpose, a Eucalyptus grandis × Eucalyptus urophylla plantation that had been cultivated in 2002 and felled for the third time in 2016 was established in Hezhou City, China. Burning forest (BF, for moderate intensity fire) and no-burning forest (NF) were set in the plantation, and the native evergreen broadleaf forest near the plantation was used as the control (CK). Soils were sampled quarterly in 2017, and 27 indicators that represent soil physical, chemical, and biological properties were analyzed and compared through the analysis of the sustainability index (SI), which adopts five indices to calculate soil quality. The obtained data showed that the indicators of BF and NF, except for the total potassium content, were much lower than those of CK. The physical properties (Max-WHC, CWHC, Min-WHC, MMC, CPD, TPD) of NF were significantly better (29.07%, 30.98%, 29.61%, 52.08%, 21.89%, 19.76%) than those of BF, unlike the chemical properties of BF (SOM, TN, ACa, AFe, AMn, ACu, AZn) were significantly better than those of NF (45.61%, 81.33%, 12.78%, 23.18%, 96.13%, 144.30%, 114.04%). The enzymatic activities of NF (URE, APHO) were significantly better (43.33%, 156.58%)than those of BF, except the activities of INV (- 25.21%). Results of SI showed that the soil quality of CK was much better than that of BF, and NF the worst. But it exhibited the most unevenness of CK, followed by NF, and BF the best. The change rules of BF and NF were contrasting, and soil quality reached the same level after half a year. In summary, the soil qualities, either BF or CK, were not comparable to that of CK. BF increased the soil quality fleetly and transiently, and NF was sustainable for the eucalyptus plantation.
Asunto(s)
Eucalyptus , Incendios , Suelo/química , Eucalyptus/química , Bosques , ChinaRESUMEN
Mutations in RAS pathway genes are highly prevalent in acute lymphoblastic leukemia (ALL). However, the effects of RAS mutations on ALL cell growth have not been experimentally characterized, and effective RAS-targeting therapies are being sought after. Here, we found that Reh ALL cells bearing the KRAS-G12D mutation showed increased proliferation rates in vitro but displayed severely compromised growth in mice. Exploring this divergence, proliferation assays with multiple ALL cell lines revealed that the KRAS-G12D rewired methionine and arginine metabolism. Isotope tracing results showed that KRAS-G12D promotes catabolism of methionine and arginine to support anabolism of polyamines and proline, respectively. Chemical inhibition of polyamine biosynthesis selectively killed KRAS-G12D B-ALL cells. Finally, chemically inhibiting AKT/mTOR signaling abrogated the altered amino acid metabolism and strongly promoted the in vivo growth of KRAS-G12D cells in B-ALL xenograft. Our study thus illustrates how hyperactivated AKT/mTOR signaling exerts distinct impacts on hematological malignancies vs. solid tumors.
RESUMEN
Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities. SIGNIFICANCE: Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Receptores ErbB , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Transaminasas/metabolismoRESUMEN
BACKGROUND: In recent decades, an increasing number of studies have focused on the clinical translational effect of simulation-based medical education (SBME). However, few scientific bibliometric studies have analyzed the research hotspots and publication trends. This study aimed to investigate research hotspots and future direction in the clinical translational outcome of SBME via bibliometrics. METHOD: Relevant publications on the clinical translational outcomes of SBME from 2011 to 2021 were identified and retrieved from the Web of Science Core Collection (WOSCC). Software including VOSviewer (1.6.17) and CiteSpace (5.8R3) and a platform (bibliometric.com) were employed to conduct bibliographic and visualized analysis on the literature. RESULTS: A total of 1,178 publications were enrolled. An increasing number of publications were observed in the past decades from 48 in 2011 to 175 in 2021. The United States accounted for the largest number of publications (488, 41.4%) and citations (10,432); the University of Toronto and Northwestern University were the leading institutions. Academic Medicine was the most productive journal concerning this field. McGaghie W C and Konge L were the most influential authors in this area. The hot topic of the translational outcome of SBME was divided into 3 stages, laboratory phase, individual skill improvement, and patient outcome involving both technical skills and non-technical skills. Translational research of comprehensive impact and collateral outcomes could be obtained in the future. CONCLUSION: From the overall trend of 10 years of research, we can see that the research is roughly divided into three phases, from laboratory stage, individual skill improvement to the patient outcomes, and comprehensive impacts such as skill retention and collateral effect as cost-effectiveness is a major trend of future research. More objective evaluation measurement should be designed to assess the diverse impact and further meta-analysis and randomized controlled trials are needed to provide more clinical evidence of SBME as translational science.
RESUMEN
BACKGROUND: Glaucoma is a neurodegenerative disease that shares similar pathological mechanisms with Alzheimer's disease (AD). Drug treatments for glaucoma increasingly rely upon both lowering of intraocular pressure (IOP) and optic nerve protection, as lowering of IOP alone has been unsatisfactory. Huperzine A (HupA) is an acetylcholinesterase inhibitor (AChEI) used for AD. This study investigated the potential of HupA as a treatment for glaucoma. METHODS: The ability of HupA to lower IOP via causing pupil constriction was assessed using New Zealand rabbits. The retinal neuroprotective effects of HupA were assessed in vivo using rat retinas subjected to ischemia-reperfusion (I/R) and in vitro using primary retinal neurons (PRNs) suffering from oxygen-glucose deprivation (OGD). RESULTS: HupA caused pupil constriction in a dose-time dependent manner which was reversed by the nonselective muscarinic acetylcholine receptor (mAChR) antagonist atropine and the selective M3 mAChR antagonist 4-DAMP. However, HupA had no effect on isolated iris muscle tension and calcium flow indicating an indirect M3 mAChR mediated effect. HupA exerted a neuroprotective effect against I/R and OGD to attenuate the retinal pathological lesion, improve retinal neuronal cell viability, reverse oxidative stress injury by increasing GSH levels and SOD activity, and decreasing MDA content and reduce the retinal neuronal apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 expression with no effect on the calcium flow tests. The effects were abolished by atropine and the selective M1 mAChR antagonist pirenzepine in OGD-induced PRNs suggesting an indirect M1 mAChR-mediated effect via inhibiting AChE activity to increase endogenous ACh level. Furthermore, HupA increased phosphorylated AKT level and decreased the levels of phosphorylated JNK, P38 MAPK and ERK via M1 mAChR antagonists indicating an involvement of activating the M1 mAChR and the downstream AKT/MAPK signaling pathway in the protective effects of HupA. CONCLUSIONS: HupA could significantly decrease IOP via activating M3 mAChR indirectly and produce retinal neuroprotective effect through M1 mAChR/AKT/MAPK by increasing endogenous ACh level. These investigations demonstrated that HupA was an effective drug in glaucoma treatment and the clinical application of HupA and other AChEIs for glaucoma patients should be further investigated.
RESUMEN
Acquired resistance represents a bottleneck to molecularly targeted therapies such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. A deeper understanding of resistance mechanisms can provide insights into this phenomenon and help to develop additional therapeutic strategies to overcome or delay resistance. Here, we identified a pharmacologically targetable metabolic mechanism that drives resistance to EGFR TKIs in lung cancer cell lines and patient-derived xenograft mice. We demonstrated that aldo-keto reductase family 1 member B1 (AKR1B1) interacts with and activates signal transducer and activator of transcription 3 (STAT3) to up-regulate the cystine transporter solute carrier family 7 member 11 (SLC7A11). This leads to enhanced cystine uptake and flux to glutathione de novo synthesis, reactive oxygen species (ROS) scavenging, protection from cell death, and EGFR TKI drug resistance in lung cancer cell lines and xenograft mouse models. Suppression of AKR1B1 with selective inhibitors, including the clinically approved antidiabetic drug epalrestat, restored the sensitivity of resistant cell lines to EGFR TKIs and delayed resistance in lung cancer patient-derived xenograft mice. Our findings suggest a metabolic mechanism for resistance to a molecularly targeted therapy and provide a potential therapeutic target for overcoming resistance to EGFR TKIs, including the third-generation inhibitor osimertinib.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Aldehído Reductasa , Resistencia a Antineoplásicos , Receptores ErbB/genética , Glutatión , Humanos , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
[This corrects the article DOI: 10.7150/thno.23177.].
RESUMEN
BACKGROUND: With the comprehensive implementation of the second child policy in China, the proportion of multiparous women has increased dramatically in the past few years. As nearly half of them have a history of previous cesarean delivery, there is widespread concern regarding complications of their pregnancy. METHODS: The aim of this study was to evaluate the effect of the previous delivery mode on subsequent pregnancy outcomes in the real world based on data from a Chinese birth registry. Birth registry data from July 1, 2016 to June 30, 2017 among a Chinese population were collected and analyzed retrospectively. This study included 14 representative hospitals from 10 provinces of China. All delivery data were collected by an internet-based system using a birth registration platform. The study enrolled 36,355 multiparas. Information extracted for analysis included basic demographic characteristics, previous delivery mode, current delivery mode, major maternal complications, and neonatal outcomes. Pregnancy outcomes of women with previous cesarean delivery (PCS group, n=14,774) were compared with the outcomes of women with previous vaginal delivery (PVD group, n=21,581). RESULTS: There were statistically significant differences in the major pregnancy outcomes between the PCS group and the PVD group. The PCS group had a higher incidence of cesarean section (CS), placenta previa, postpartum hemorrhage, uterus rupture, hysterectomy, gestational diabetes, gestational hypertension, delivery before 37 weeks of gestation, low birth weight, and Apgar Score at 5 min ≤3. CONCLUSIONS: Women with previous cesarean delivery had poorer pregnancy outcomes than women with previous vaginal delivery. Avoiding unnecessary CS, especially in primiparas is essential to improving maternal and neonatal outcomes in later pregnancies.
RESUMEN
Changes in cellular metabolism accompany tumor therapeutic resistance. Metabolite concentrations specifically reflect the cellular state. Glutathione (GSH) metabolism maintains the redox homeostasis while also confers therapeutic resistance to cancer cells. However, analytical methods for studying GSH metabolism rely on high-resolution-based untargeted metabolomics. Since the aim of untargeted metabolomics studies is covering as much metabolites as possible, these methods lack sensitivity for simultaneous analysis of intracellular GSH-related metabolites with different polarities and structures. In this study, based on cultured lung cancer cells, we described a rapid, robust and sensitive ultra-performance liquid chromatography-triple quadrupole tandem mass spectrographic method (UPLC-QQQ-MS/MS) to simultaneously quantify a repertoire of GSH-related metabolites, including GSH, GSSG, glycine, cysteine, glutamine, glutamate, cystine, γ-glutamyl-cysteine and cysteinyl-glycine. This method avoided the use of derivatization and/or ion-pairing reagents and was validated according to United States Food and Drug Administration (US FDA) criteria. The lower limit of quantification was determined to be 0.5-100 ng/mL with lower limits of detection at 0.14-10.07 ng/mL. The intra- and inter-day precision values for all the analytes were <15% CV, and the accuracy ranged from 85.4% to 114% at three levels of quality control. This method combined simple preparation with rapid analytical procedure (8 min), allowed for high-throughput analysis of GSH metabolism in basic and therapeutic treatment conditions within cultured cells. Our data showed a significant alteration of GSH metabolism in two independent resistant cells compared to sensitive cells. This method monitored the impact of molecularly targeted drugs on GSH metabolism within lung cancer cells and therefore helped identifying potential metabolic vulnerability for the therapeutic resistance in lung cancer.
RESUMEN
Background: Urine samples, which capture an individual's metabolic profile, are ideal for the exploration of non-invasive biomarkers to confirm the amnestic mild cognitive impairment (aMCI) status of patients vs. unimpaired ones. Objective: We aimed to detect differentially metabolized amino acids, which are important objectives in metabolomics, garnering particular attention in biomedical pathogenesis from the urine of aMCI patients, which may give clinicians the possibility to intervene with early treatments that curb Alzheimer's disease (AD). Methods: The study included 208 subjects, 98 of whom were aMCI patients, and 110 who were control subjects without dementia. Urine samples were taken from each participant and supernatant was obtained for analysis. The concentrations of amino acids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Urinary arginine levels in aMCI patients are obviously lower than in normal controls (q < 0.2 and p < 0.05). Meanwhile, aMCI patients had significant reduced urinary global arginine bioavailability ratio (GABR), and GABR in urine displayed a positive correlation with the score of CMMSE. Conclusion: Urinary dysregulated arginine metabolism that may serve as a helpful clinical diagnostic biomarker for aMCI in older adults.