RESUMO
Mobocertinib (formerly known as TAK-788) is a targeted covalent tyrosine kinase inhibitor of epidermal growth factor receptor with exon 20 insertion mutations. This article describes the metabolism and excretion of mobocertinib in healthy male subjects after a single oral administration of [14C]mobocertinib. Mobocertinib related materials were highly covalently bound to plasma proteins such as human serum albumin. The mean extraction recovery of total radioactivity was only 3.9% for 6 individual Hamilton pooled plasma samples. After extraction, mobocertinib was the most abundant component accounting for 7.7% of total extracted circulating radioactivity (TECRA) in the supernatant. Each of identified metabolites accounted for <10% of TECRA. Mobocertinib underwent extensive first-pass metabolism with the fraction of the dose absorbed estimated to be approximately 91.7%. Fecal excretion of mobocertinib metabolites was the major elimination route. Mobocertinib was mainly eliminated via oxidative metabolism with a fraction of approximately 88% metabolized by CYP3A4/5. The other minor elimination pathways included cysteine conjugation, metabolism by other CYPs, and renal excretion of unchanged mobocertinib. Significance Statement This manuscript describes the metabolism and excretion of a targeted covalent inhibitor mobocertinib in humans after a single oral administration of [14C]mobocertinib. Mobocertinib was highly covalently bound to human plasma proteins. No metabolite accounted for >10% of total extracted circulating radioactivity in human plasma. Mobocertinib was mainly eliminated via CYP3A4/5 mediated oxidative metabolism followed by fecal excretion after approximately 91.7% of the dose was absorbed.
RESUMO
Background: This randomized controlled trial aimed to compare the effects of butorphanol and sufentanil on early post-operative cognitive dysfunction (POCD) and systemic inflammation in older surgical patients. Methods: Patients (aged 65 years or above) undergoing surgeries with general anesthesia were randomized to either the butorphanol group (40 µg/kg during anesthesia induction) or the sufentanil group (0.4 µg/kg). Cognitive function changes during the perioperative period were assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) scale up to 3 days after surgery. POCD was defined as a Z-score or composite Z-score greater than 1.96 for both MMSE and MoCA scores. Circulating inflammatory factors, including tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 10 (IL-10), were measured using enzyme-linked immunosorbent assay. Results: The study included 114 patients (median age: 71 years, 57.7% male). Compared to sufentanil, butorphanol significantly reduced the incidence of POCD on the first (11.5% versus 32.7%, p = 0.017) and third day (3.8% versus 15.4%, p = 0.046) after surgery. Additionally, patients receiving butorphanol had significantly lower circulating levels of TNF-α and IL-1ß at the time of discharge from the post-anesthesia care unit and on the first and third day after surgery (p < 0.05 for all comparisons). Furthermore, circulating IL-10 levels were significantly higher in patients receiving butorphanol (p < 0.05 for all comparisons). Conclusion: Administration of butorphanol during anesthesia induction, as opposed to sufentanil, was associated with a significant reduction in the early incidence of POCD in older surgical patients, possibly attributed to its impact on systemic inflammation.Clinical trial registration: The present study was registered in the China Clinical Trial Center (ChiCTR2300070805, 24/04/2023).
RESUMO
One of the hallmarks of cancer is metabolic reprogramming in tumor cells, and aerobic glycolysis is the primary mechanism by which glucose is quickly transformed into lactate. As one of the primary rate-limiting enzymes, pyruvate kinase (PK) M is engaged in the last phase of aerobic glycolysis. Alternative splicing is a crucial mechanism for protein diversity, and it promotes PKM precursor mRNA splicing to produce PKM2 dominance, resulting in low PKM1 expression. Specific splicing isoforms are produced in various tissues or illness situations, and the post-translational modifications are linked to numerous disorders, including cancers. hnRNPs are one of the main components of the splicing factor families. However, there have been no comprehensive studies on hnRNPs regulating PKM alternative splicing. Therefore, this review focuses on the regulatory network of hnRNPs on PKM pre-mRNA alternative splicing in tumors and clinical drug research. We elucidate the role of alternative splicing in tumor progression, prognosis, and the potential mechanism of abnormal RNA splicing. We also summarize the drug targets retarding tumorous splicing events, which may be critical to improving the specificity and effectiveness of current therapeutic interventions.
Assuntos
Processamento Alternativo , Ribonucleoproteínas Nucleares Heterogêneas , Neoplasias , Piruvato Quinase , Humanos , Processamento Alternativo/genética , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , AnimaisRESUMO
Leguminosae is one of the three largest families of angiosperms after Compositae and Orchidaceae. It is widely distributed and grows in a variety of environments, including plains, mountains, deserts, forests, grasslands, and even waters where almost all legumes can be found. It is one of the most important sources of starch, protein and oil in the food of mankind and also an important source of high-quality forage material for animals, which has important economic significance. In our study, the codon usage patterns and variation sources of the chloroplast genome of nine important forage legumes were systematically analyzed. Meanwhile, we also constructed a phylogenetic tree based on the whole chloroplast genomes and protein coding sequences of these nine forage legumes. Our results showed that the chloroplast genomes of nine forage legumes end with A/T bases, and seven identical high-frequency (HF) codons were detected among the nine forage legumes. ENC-GC3s mapping, PR2 analysis, and neutral analysis showed that the codon bias of nine forage legumes was influenced by many factors, among which natural selection was the main influencing factor. The codon usage frequency showed that the Nicotiana tabacum and Saccharomyces cerevisiae can be considered as receptors for the exogenous expression of chloroplast genes of these nine forage legumes. The phylogenetic relationships of the chloroplast genomes and protein coding genes were highly similar, and the nine forage legumes were divided into three major clades. Among the clades Melilotus officinalis was more closely related to Medicago sativa, and Galega officinalis was more closely related to Galega orientalis. This study provides a scientific basis for the molecular markers research, species identification and phylogenetic studies of forage legumes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01421-0.
RESUMO
Enzyme-mimetic photocatalysis has been attracting much attention in bionic research, in which carbon monoxide dehydrogenase (CODH) is a suitable prototype for simulation to meet environmental and energy needs. In this study, we utilized the structural memory effect of layered double hydroxides (LDHs) to build inorganic intergrowth bulk heterojunctions (IIBHs) NiS/FeS@MgFe-LDHs via a pyrolytic topological vulcanization (PTV) method that imitated active C-clusters [Ni-4Fe-4S] in CODH. Enzyme mimicry was evaluated in terms of the microstructure and catalytic reaction site. The similarity between the microstructure of NiS/FeS@MgFe-LDHs and the CODH active group was demonstrated through XRD, XAFS and other characterisations. Subsequently, the obtained in situ irradiated X-ray photoelectron spectra and transient absorption spectra indicated the photogenerated electron transfer of the IIBH, wherein electrons finally accumulated in the conduction band of the NiS domain for the photocatalytic CO2 reduction reaction, which was similar to that of C-clusters [Ni-4Fe-4S] in which the Ni2+ ion was the reactive site. As a result, NiS/FeS@MgFe-LDHs achieved a high yield of CO at a rate of 2151.974 µmol g-1 h-1, which was 39.8 and 9.7 times more than that of NiMgFe-LDHs and NiMgFe-MMO, respectively. The study offers an innovative design route for developing IIBHs, providing novel opportunities for enzyme-mimetic photocatalysis.
RESUMO
AIMS: Our aim was to determine the absolute bioavailability, mass balance, metabolism and excretion of soticlestat (TAK-935). METHODS: An open-label, two-period, single-site, phase 1 study was conducted in six healthy men. In Period 1, a single 300 mg dose of soticlestat was administered orally, followed by a 15-min intravenous infusion of [14 C]soticlestat 50 µg (~1 µCi) 10 min later. In Period 2, a single 300 mg dose (~100 µCi) of [14 C]soticlestat in solution was administered orally. Samples were collected, analysed for radioactivity or unchanged soticlestat, and profiled for metabolites. RESULTS: In Period 1, soticlestat had an absolute bioavailability of 12.6% (90% confidence interval, 7.81-20.23%). In Period 2, there was near-complete recovery of total radioactivity (TRA) following a 300 mg dose of [14 C]soticlestat: urine, 94.8% (standard deviation [SD], 1.35%); faeces, 2.7% (SD, 1.67%). Of TRA, 0.1% (SD, 0.09%) and 0.6% (SD, 0.21%) were recovered as soticlestat and metabolite M-I in urine, respectively. In plasma, soticlestat and M-I reached geometric mean maximum observed concentrations of 1352 ng/mL (geometric percent coefficient of variation [gCV%], 61.3) and 253.2 ng/mL (gCV%, 44.1) after 25 min and declined with mean terminal half-lives (SD) of 5.7 (2.90) and 2.0 (0.15) h, respectively. Soticlestat represented 4.9% of TRA in plasma. Soticlestat was rapidly eliminated primarily via O-glucuronidation to metabolite M3, which was the dominant species in plasma (92.6%) and urine (86%). CONCLUSIONS: This study indicates that soticlestat and its metabolites are rapidly cleared and eliminated, lowering the risk of dose accumulation from repeated dosing and supporting further investigation of soticlestat.
Assuntos
Piperidinas , Piridinas , Humanos , Masculino , Administração Oral , Disponibilidade Biológica , Colesterol 24-Hidroxilase , Voluntários SaudáveisRESUMO
BACKGROUND AND OBJECTIVE: Felcisetrag (previously TAK-954 or TD-8954) is a highly selective and potent 5-HT4 receptor agonist in clinical development for prophylaxis and treatment of postoperative gastrointestinal dysfunction (POGD). The rat, dog, and human absorption, distribution, metabolism, and excretion (ADME) properties of felcisetrag were investigated. METHODS: The metabolism and victim and perpetrator drug interaction potentials towards cytochrome P450s (CYP) and transporters were determined using in vitro models. The excretion, metabolite profile, and pharmacokinetics were determined during unlabeled and radiolabeled ADME studies in rat and dog for comparison with human. Due to a low clinical dose (0.5 mg) and radioactivity (~ 1.5 µCi), a combination of liquid scintillation counting and accelerator mass spectrometry was used for analysis of samples in this study. RESULTS: The ADME properties, including metabolite profile, for felcisetrag are generally conserved across species. Felcisetrag is primarily cleared through renal excretion (0.443) and metabolism in humans (0.420), with intact parent as the predominant species in circulation. There are multiple metabolites, each representing < 10% of the circulating radioactivity, confirming no metabolites in safety testing (MIST) liabilities. Metabolites were also detected in animals. The potential for major CYP- and transporter-based drug-drug interaction (DDI) of felcisetrag as a victim or perpetrator is considered to be low. CONCLUSIONS: Felcisetrag is primarily cleared in humans through renal excretion. Although the metabolism of felcisetrag is primarily through CYP3A, the potential for clinically relevant DDI as a victim is significantly reduced as metabolism plays a minor role in the overall clearance.
Assuntos
Sistema Enzimático do Citocromo P-450 , Serotonina , Animais , Cães , Interações Medicamentosas , Humanos , RatosRESUMO
BACKGROUND: Radioresistance is still the major cause of radiotherapy failure and poor prognosis in patients with non-small cell lung cancer (NSCLC). Apatinib (AP) is a highly selective inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2). Whether and how AP affects radiosensitivity in NSCLC remains unknown. The present study aimed to explore the radiosensitization effect of AP in NSCLC and its underlying mechanism as a radiosensitizer. METHODS: The NSCLC cell lines A549 and LK2 were treated with AP, ionizing radiation (IR), or both AP and IR. Expression of VEGFR2 was analyzed by western blot and RT-PCR. Cell proliferation was measured using CCK-8 and colony formation assays. Apoptosis and cell cycle distribution in NSCLC cells were analyzed by flow cytometry. Nuclear phosphorylated histone H2AX foci immunofluorescence staining was performed to evaluate the efficacy of the combination treatment. Western blot was used to explore the potential mechanisms of action. RESULTS: AP inhibited cell proliferation in a dose- and time-dependent manner. Flow cytometry analysis indicated that AP significantly increased radiation-induced apoptosis. Colony formation assays revealed that AP enhanced the radiosensitivity of NSCLC cells. AP strongly restored radiosensitivity by increasing IR-induced G2/M phase arrest. AP effectively inhibited repair of radiation-induced DNA double-strand breaks. Western blot analysis showed that AP enhanced radiosensitivity by downregulating AKT and extracellular signal-regulated kinase (ERK) signaling. CONCLUSION: Our findings suggest that AP may enhance radiosensitivity in NSCLC cells by blocking AKT and ERK signaling. Therefore, AP may be a potential clinical radiotherapy synergist and a novel small-molecule radiosensitizer in NSCLC. Our study fills a gap in the field of anti-angiogenic drugs and radiosensitivity.
RESUMO
BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors with high mortality rates and a poor prognosis. There is an urgent need to determine the molecular mechanism of PAAD tumorigenesis and identify promising biomarkers for the diagnosis and targeted therapy of the disease. METHODS: Three GEO datasets (GSE62165, GSE15471 and GSE62452) were analyzed to obtain differentially expressed genes (DEGs). The PPI networks and hub genes were identified through the STRING database and MCODE plugin in Cytoscape software. GO and KEGG enrichment pathways were analyzed by the DAVID database. The GEPIA database was utilized to estimate the prognostic value of hub genes. Furthermore, the roles of MMP14 and COL12A1 in immune infiltration and tumor-immune interaction and their biological functions in PAAD were explored by TIMER, TISIDB, GeneMANIA, Metascape and GSEA. RESULTS: A total of 209 common DEGs in the three datasets were obtained. GO function analysis showed that the 209 DEGs were significantly enriched in calcium ion binding, serine-type endopeptidase activity, integrin binding, extracellular matrix structural constituent and collagen binding. KEGG pathway analysis showed that DEGs were mainly enriched in focal adhesion, protein digestion and absorption and ECM-receptor interaction. The 14 genes with the highest degree of connectivity were defined as the hub genes of PAAD development. GEPIA revealed that PAAD patients with upregulated MMP14 and COL12A1 expression had poor prognoses. In addition, TIMER analysis revealed that MMP14 and COL12A1 were closely associated with the infiltration levels of macrophages, neutrophils and dendritic cells in PAAD. TISIDB revealed that MMP14 was strongly positively correlated with CD276, TNFSF4, CD70 and TNFSF9, while COL12A1 was strongly positively correlated with TNFSF4, CD276, ENTPD1 and CD70. GSEA revealed that MMP14 and COL12A1 were significantly enriched in epithelial mesenchymal transition, extracellular matrix receptor interaction, apical junction, and focal adhesion in PAAD development. CONCLUSIONS: Our study revealed that overexpression of MMP14 and COL12A1 is significantly correlated with PAAD patient poor prognosis. MMP14 and COL12A1 participate in regulating tumor immune interactions and might become promising biomarkers for PAAD.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/genética , Antígenos B7 , Biomarcadores Tumorais/genética , Colágeno Tipo XII/genética , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinase 14 da Matriz/genética , Ligante OX40 , Neoplasias Pancreáticas/genética , Mapas de Interação de ProteínasRESUMO
Herein, a distinctive dual-carbon-confined nanoarchitecture, composed of an inner highly conductive, robust carbon nanotube (CNT) support and outer well-designed porous carbon (PC) coating, was demonstrated to efficiently improve the electrochemical properties of CoO nanoparticles for the first time, and the CoO nanoparticles were confined between the CNTs and porous carbon. The well-designed porous carbon coating showed significant superiority compared to common non-porous carbon coatings, due to its distinctive characteristics such as high flexibility, rich free space and open tunnel-like structure. Therefore, the synergistic effects of the CNT core and the porous carbon sheath endowed the CoO-based composite (CNTs@CoO@PC) with improved electrochemical reaction kinetics, large pseudocapacitive contribution and superior structural stability. As a result, the CNTs@CoO@PC showed outstanding performance with 1090, 571 and 242 mA h g-1 at 200, 1000 and 5000 mA g-1 after 300, 600 and 1000 cycles, respectively. Furthermore, this strategy may be used to improve other metal oxide anode materials for lithium storage.
RESUMO
In order to reduce the negative impact of the extra carbon coating on the electrochemical properties of the commonly sandwiched carbon nanotubes@tin dioxide@carbon (CNT@SnO2@C) composites, the external C coating has been designed as a porous carbon in this work. The well-designed porous carbon coating offers an attractive advantage compared to the common carbon coatings, namely, it can not only better mitigate the volumetric variation of SnO2 by means of its spongy structure with better flexibility and rich free space, but also accelerate the lithium-ions diffusion by virtue of its open tunnel-like architecture. For this reason, this composite prepared here shows outstanding electrochemical performance stemming from the cooperative effect of inner CNT supporting and externally porous carbon coating, displaying 819.3 and 576.0 mAh g-1 at 200 and even 1000 mA g-1 after even 500 cycles, respectively. This surface engineering strategy may be valuable for enhancing the cyclical durability of other metal oxides with higher theoretical specific capacities.
RESUMO
BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a deadly tumor with a high recurrence rate and poor prognosis. Keratin 7 (KRT7) is a member of the keratin gene family that is involved in the regulation of cell growth, migration and apoptosis in many cancers. However, the role of KRT7 and its biological functions in PAAD remain unclear. We systemically analyzed the expression and clinical values of KRT7 in PAAD. METHODS: The Gene Expression Profiling Interactive Analysis (GEPIA), Oncomine and Human Protein Atlas (HPA) databases were used to analyze the mRNA and protein expression of KRT7 in PAAD. The prognosis and subgroup analysis of KRT7 in PAAD patients was performed using the GEPIA, PROGgeneV2 and UALCAN databases. Later, the correlation between KRT7 expression and tumor immune molecules in PAAD was evaluated using the Immune Cell Abundance Identifier (ImmuCellAI) and TISIDB databases. Finally, the functional enrichment pathway of KRT7 and its coexpressed genes were analyzed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Metascape databases and Gene Set Enrichment Analysis (GSEA). RESULTS: The mRNA and protein expression of KRT7 was increased in PAAD tissues compared with normal tissues. High KRT7 expression was closely associated with tumor grade, TP53 mutations and poor prognosis in PAAD patients. Cox regression analysis proved that overexpressed KRT7 was an important and independent risk factor for poor overall survival (P = 0.006, HR =1.87) and disease-free survival (P = 0.019, HR =1.793) in PAAD. Additionally, KRT7 expression was significantly associated with immune infiltration of tumor immune cells and immunomodulators. Functional enrichment analyses and GSEA indicated that KRT7 might be involved in the regulation of the p53 pathway in PAAD. CONCLUSION: Overexpressed KRT7 could be a promising prognostic and therapeutic target biomarker for PAAD by bioinformatics analysis.
RESUMO
Sepsis is a fatal organ dysfunction resulting from a disordered host response to infection. Endothelial cells (ECs) are usually the primary targets of inflammatory mediators in sepsis; damage to ECs plays a pivotal part in vital organ failure. In recent studies, autophagy was suggested to play a critical role in the ECs injury although the mechanisms by which ECs are injured in sepsis are not well elucidated. Autophagy is a highly conserved catabolic process that includes sequestrating plasma contents and transporting cargo to lysosomes for recycling the vital substrates required for metabolism. This pathway also counteracts microbial invasion to balance and retain homeostasis, especially during sepsis. Increasing evidence indicates that autophagy is closely associated with endothelial function. The role of autophagy in sepsis may or may not be favorable depending upon conditions. In the present review, the current knowledge of autophagy in the process of sepsis and its influence on ECs was evaluated. In addition, the potential of targeting EC autophagy for clinical treatment of sepsis was discussed.
Assuntos
Autofagia , Células Endoteliais/patologia , Sepse/patologia , Animais , HumanosRESUMO
Objectives: Radiotherapy has played a limited role in the treatment of non-small cell lung cancer (NSCLC) due to the risk of tumour radioresistance. We previously established the radioresistant non-small cell lung cancer (NSCLC) cell line H460R. In this study, we identified differentially expressed genes between these radioresistant H460R cells and their radiosensitive parent line. We further evaluated the role of a differentially expressed gene, ITGB1, in NSCLC cell radioresistance and as a potential target for improving radiosensitivity. Materials and Methods: The radiosensitivity of NSCLC cells was evaluated by flow cytometry, colony formation assays, immunofluorescence, and Western blotting. Bioinformatics assay was used to identify the effect of ITGB1 and YAP1 expression in NSCLC tissues. Results: ITGB1 mRNA and protein expression levels were higher in H460R than in the parental H460 cells. We observed lower clonogenic survival and cell viability and a higher rate of apoptosis of ITGB1-knockdown A549 and H460R cells than of wild type cells post-irradiation. Transfection with an ITGB1 short hairpin (sh) RNA enhanced radiation-induced DNA damage and G2/M phase arrest. Moreover, ITGB1 induced epithelial-mesenchymal transition (EMT) of NSCLC cells. Silencing ITGB1 suppressed the expression and intracellular translocation of Yes-associated protein 1 (YAP1), a downstream effector of ITGB1. Conclusions: ITGB1 may induce radioresistance via affecting DNA repair and YAP1-induced EMT. Taken together, our data suggest that ITGB1 is an attractive therapeutic target to overcome NSCLC cell radioresistance.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Integrina beta1/metabolismo , Neoplasias Pulmonares/metabolismo , Tolerância a Radiação , Proteínas de Sinalização YAP/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Reparo do DNA , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapiaRESUMO
Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366 .
Assuntos
Ciclopentanos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Proteína NEDD8/antagonistas & inibidores , Pirimidinas/farmacocinética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Área Sob a Curva , Ciclopentanos/uso terapêutico , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/uso terapêutico , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Compostos RadiofarmacêuticosRESUMO
Pancreatitis is an inflammatory disease of the pancreas characterized by acinar cell injury and is associated with the abnormal release of trypsin, which results in high mortality due to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). The inflammatory response, impaired autophagic flux, endoplasmic reticulum stress (ERS) and their interactions are involved in the development of pancreatitis. Molecular hydrogen (H2) is a novel antioxidant that possesses the features of selective scavenging of oxygen free radicals and nontoxic metabolites and has been shown to be efficacious for treating infection, injury, tumors, ischemia-reperfusion organ injury, metabolic disease and several other diseases. Recent studies have found that H2 is also useful in the treatment of pancreatitis, which may be related to the mechanism of antioxidative stress, anti-inflammation, anti-apoptosis, regulation of immunity and regulation of molecular pathways. This review focuses on the pathogenesis of pancreatitis and the research progress and potential mechanisms of H2 against pancreatitis to provide theoretical bases for future research and clinical application of H2 therapy for pancreatitis.
Assuntos
Hidrogênio/uso terapêutico , Pancreatite/terapia , Animais , Antioxidantes/metabolismo , Apoptose , Autofagia/efeitos dos fármacos , Morte Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Inflamação , Sistema de Sinalização das MAP Quinases , Insuficiência de Múltiplos Órgãos , Estresse Oxidativo , Pâncreas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Tripsina/químicaRESUMO
Sepsis is a life-threatening systemic inflammatory response syndrome (SIRS) caused by the host's maladjustment response to infection, which eventually leads to septic shock and multiple organ failure. Pancreatic injury was found to be an important pathological change in sepsis. Autophagy is a crucial way to maintain the normal metabolism of cell substances and energy, which plays an important role in many diseases. Recent studies have found that autophagy plays a dual role in pancreatic injury in sepsis. Moderate autophagy can protect the pancreas and reduce the injury, while excessive autophagy can cause apoptosis-related autophagic cell death and aggravate the pancreatic injury. In sepsis, activated nuclear factor-κB (NF-κB) has a promoting effect on autophagy, and lysosome associated membrane protein (LAMP) degradation can result in impaired autophagy flux and aggravate pancreatic injury. The exploration of the mechanism of autophagy in pancreatic injury of sepsis will help to restore the normal autophagy function, so as to find a new target for the treatment of pancreatic injury of sepsis.
Assuntos
Autofagia , Pâncreas/lesões , Sepse , Apoptose , Humanos , Lisossomos , NF-kappa BRESUMO
BACKGROUND: The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX, which are important in the development of various tissues and organs in mammals. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers. However, the expression levels and distinctive prognostic values of the NFI family remain poorly explored in most cancers. MATERIALS AND METHODS: In the present study, the differences in mRNA expression of the NFI family in various cancers were investigated using the Oncomine and TCGA databases, and the mRNA expression, genetic alteration and DNA methylation of the NFI family members in various cancers were examined using cBioPortal for Cancer Genomics. In addition, the prognostic significance of the NFI family was assessed in multiple cancers using the Kaplan-Meier plotter (KM plotter) and SurvExpress databases. RESULTS: The mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression. Although NFIX expression was not downregulated in kidney, colorectal and prostate cancers. Furthermore, NFIB expression was upregulated in gastric cancer. Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers. Decreased expression levels of NFIA, NFIB and NFIC were associated with poor overall survival (OS) in head and neck cancer. Low mRNA expression of NFIA and NFIB was significantly associated with OS and first progression in lung adenocarcinoma, but not in lung squamous cell carcinoma. In addition, potential correlations between NFI family members and survival outcomes were also observed in liver, esophageal, kidney and cervical cancer. CONCLUSION: The results from the present study indicated certain members of the NFI family could be promising therapeutic targets and novel prognostic biomarkers for human cancers.
RESUMO
Alisertib (MLN8237) is an investigational, orally available, selective aurora A kinase inhibitor in clinical development for the treatment of solid tumors and hematologic malignancies. This metabolic profiling analysis was conducted as part of a broader phase 1 study evaluating mass balance, pharmacokinetics, metabolism, and routes of excretion of alisertib following a single 35-mg dose of [14C]alisertib oral solution (â¼80 µCi) in three patients with advanced malignancies. On average, 87.8% and 2.7% of the administered dose was recovered in feces and urine, respectively, for a total recovery of 90.5% by 14 days postdose. Unchanged [14C]alisertib was the predominant drug-related component in plasma, followed by O-desmethyl alisertib (M2), and alisertib acyl glucuronide (M1), which were present at 47.8%, 34.6%, and 12.0% of total plasma radioactivity. In urine, of the 2.7% of the dose excreted, unchanged [14C]alisertib was a negligible component (trace), with M1 (0.84% of dose) and glucuronide conjugate of hydroxy alisertib (M9; 0.66% of dose) representing the primary drug-related components in urine. Hydroxy alisertib (M3; 20.8% of the dose administered) and unchanged [14C]alisertib (26.3% of the dose administered) were the major drug-related components in feces. In vitro, oxidative metabolism of alisertib was primarily mediated by CYP3A. The acyl glucuronidation of alisertib was primarily mediated by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A3, and 1A8 and was stable in 0.1 M phosphate buffer and in plasma and urine. Further in vitro evaluation of alisertib and its metabolites M1 and M2 for cytochrome P450-based drug-drug interaction (DDI) showed minimal potential for perpetrating DDI with coadministered drugs. Overall, renal elimination played an insignificant role in the disposition of alisertib, and metabolites resulting from phase 1 oxidative pathways contributed to >58% of the alisertib dose recovered in urine and feces over 192 hours postdose. SIGNIFICANCE STATEMENT: This study describes the primary clearance pathways of alisertib and illustrates the value of timely conduct of human absorption, distribution, metabolism, and excretion studies in providing guidance to the clinical pharmacology development program for oncology drugs, for which a careful understanding of sources of exposure variability is crucial to inform risk management for drug-drug interactions given the generally limited therapeutic window for anticancer drugs and polypharmacy that is common in cancer patients.
Assuntos
Aurora Quinase A/metabolismo , Azepinas/metabolismo , Biotransformação/fisiologia , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/metabolismo , Administração Oral , Idoso , Antineoplásicos/metabolismo , Citocromo P-450 CYP3A/metabolismo , Fezes , Feminino , Glucuronídeos/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Radioresistance remains the most challenging issue leading to radiotherapy failure in the treatment of non-small cell lung cancer (NSCLC). The nuclear factor IA (NFIA) is associated with tumor response to treatments in many cancers, but its role in NSCLC radioresistance remains unclear. Here, we established two radioresistant NSCLC cell lines, H226R and H460R, by dose-gradient irradiation to investigate the function of NFIA in NSCLC radioresistance. The results showed a dramatically reduced expression of NFIA in radioresistant cells accompanied with elevated phosphorylation of AKT and ERK, when compared with their parental cells. Overexpression of NFIA restored the sensitivity of radioresistant cells to radiation through increased ionizing radiation (IR)-induced apoptosis and DNA damage by downregulating p-AKT and p-ERK, whereas knockdown of NFIA promoted radioresistance of the parental cells. Our findings suggested that NFIA enhanced cell radiosensitivity by downregulating p-AKT and p-ERK in NSCLC. Our study fills a gap in the field of NFIA and radioresistance, and establishes a mechanistic foundation to improve radiotherapy efficiency in NSCLC patients.