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The delivery of electrical pulses to the brain via penetrating electrodes, known as brain stimulation, has been recognized as an effective clinical approach for treating neurological disorders. Resident brain neural precursor cells (NPCs) are electrosensitive cells that respond to electrical stimulation by expanding in number, migrating and differentiating which are important characteristics that support neural repair. Here, we report the design of a conductive cryogel brain stimulation electrode specifically developed for NPC activation. The cryogel electrode has a modulus switching mechanism permitting facile penetration and reducing the mechanical mismatch between brain tissue and the penetrating electrode. The cryogel demonstrated good in vivo biocompatibility and reduced the interfacial impedance to deliver the stimulating electric field with lower voltage under charge-balanced current controlled stimulation. An ex vivo assay reveals that electrical stimulation using the cryogel electrodes results in significant expansion in the size of NPC pool. Hence, the cryogel electrodes have the potential to be used for NPC activation to support endogenous neural repair. STATEMENT OF SIGNIFICANCE: The objective of this study is to develop a cryogel-based stimulation electrode as an alternative to traditional electrode materials to be used in regenerative medicine applications for enhancing neural regeneration in brain. The electrode offers benefits such as adaptive modulus for implantation, high charge storage and injection capacities, and modulus matching with brain tissue, allowing for stable delivery of electric field for long-term neuromodulation. The electrochemical properties of cryogel electrodes were characterized in living tissue with an ex vivo set-up, providing a deeper understanding of stimulation capacity in brain environments. The cryogel electrode is biocompatible and enables low voltage, current-controlled stimulation for effective activation of endogenous neural precursor cells, revealing their potential utility in neural stem cell-mediated brain repair.
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Criogeles , Células-Madre Neurales , Electrodos , Neuronas/fisiología , Conductividad Eléctrica , Estimulación Eléctrica , Electrodos ImplantadosRESUMEN
Many digestive system malignant tumors are characterized by high incidence and mortality rate. Increasing evidence has revealed that the tumor microenvironment (TME) is involved in cancer initiation and tumor progression. Tumor-associated macrophages (TAMs) are a predominant constituent of the TME, and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer. TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype. The latter especially are crucial drivers of tumor invasion, growth, angiogenesis, metastasis, immunosuppression, and resistance to therapy. TAMs are of importance in the occurrence, development, diagnosis, prognosis, and treatment of common digestive system malignant tumors. In this review, we summarize the role of TAMs in common digestive system malignant tumors, including esophageal, gastric, colorectal, pancreatic and liver cancers. How TAMs promote the development of tumors, and how they act as potential therapeutic targets and their clinical applications are also described.
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Hepatocellular carcinoma (HCC) is a common malignant tumor. At present, early diagnosis of HCC is difficult and therapeutic methods are limited. Radiomics can achieve accurate quantitative evaluation of the lesions without invasion, and has important value in the diagnosis and treatment of HCC. Radiomics features can predict the development of cancer in patients, serve as the basis for risk stratification of HCC patients, and help clinicians distinguish similar diseases, thus improving the diagnostic accuracy. Furthermore, the prediction of the treatment outcomes helps determine the treatment plan. Radiomics is also helpful in predicting the HCC recurrence, disease-free survival and overall survival. This review summarized the role of radiomics in the diagnosis, treatment and prognosis of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Pronóstico , Humanos , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Pulmonary tuberculosis (TB) is a serious infectious disease that lacks robust blood-based biomarkers to identify cured TB. Some discharged patients are not fully cured and may relapse or even develop multidrug-resistant TB. This study is committed to finding proteomic-based plasma biomarkers to support establishing laboratory standards for clinical TB cure. METHODS: Data-independent acquisition (DIA) was used to obtain the plasma protein expression profiles of TB patients at different treatment stages compared with healthy controls. Multivariate statistical methods and bioinformatics were used to analyze the data. RESULTS: Bioinformatic analysis suggests coagulation dysfunction and vitamin and lipid metabolism disturbances in TB. Albumin (ALB), haptoglobin (HP), out at first protein homolog (OAF), and retinol-binding protein 4 (RBP4) can be used to establish a diagnostic model for the efficacy evaluation of TB with an area under the curve of 0.963, which could effectively distinguish untreated TB patients from cured patients. CONCLUSIONS: Our research demonstrated that ALB, HP, OAF and RBP4 can be potential biomarkers for evaluating the efficacy of TB. These findings may provide experimental data for establishing the laboratory indicators of clinical TB cure and providing clinicians with new targets for exploring the underlying mechanisms of TB pathogenesis.
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Tuberculosis Pulmonar , Humanos , Albúminas/análisis , Biomarcadores/sangre , Haptoglobinas/análisis , Proteómica , Proteínas Plasmáticas de Unión al Retinol/análisis , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológicoRESUMEN
The growing evidence over the past few decades has indicated that the photodynamic antitumor activity of transition metal complexes, and Re(I) compounds are potential candidates for photodynamic therapy. This study reports the synthesis, characterization, and anti-tumor activity of three new Re(I)-guadinium complexes. Cytotoxicity tests reveal that complex Re1 increased cytotoxicity by 145-fold from IC50 > 180 µM in the dark to 1.3 ± 0.7 µM following 10â¯min of light irradiation (425 nm) in HeLa cells. Further, the mechanism by which Re1 induces apoptosis in the presence or absence of light irradiation was investigated, and results indicate that cell death was caused through different pathways. Upon irradiation, Re1 first accumulates on the cell membrane and interacts with death receptors to activate the extrinsic death receptor-mediated signaling pathway, and then is transported into the cell cytoplasm. Most of the intracellular Re1 locates within mitochondria, improving the reactive oxygen species level, and decreasing mitochondrial membrane potential and ATP levels, and inducing the activation of caspase-9 and, thus, apoptosis. Subsequently, the residual Re1 can translocate into the cell nucleus, and activates the p53 pathway, causing cell cycle arrest and eventually cell death.
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Fármacos Fotosensibilizantes , Renio , Apoptosis , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Guanidina/farmacología , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Fármacos Fotosensibilizantes/metabolismo , Fármacos Fotosensibilizantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptores de Muerte Celular/metabolismo , Renio/farmacologíaRESUMEN
BACKGROUND: Pulmonary tuberculosis (TB) is a serious disease burden worldwide, and its effective early diagnosis is still facing challenges. Knowledge, acquired from multi-omics integration analysis about the association between different types of differentially expressed molecules in the plasma of TB patients and the disease traits, is anticipated to improve the accuracy of TB diagnosis through the "integrative pattern". METHODS: In this study, the lncRNA-miRNA-mRNA interaction network was constructed based on the competing endogenous RNA (ceRNA) hypothesis by integrating our previous data sets of lncRNA, mRNA, miRNA, and metabolites. Moreover, the key regulatory axis was established by co-expression analysis and verified at the level of metabolites. RESULTS: A ceRNA regulatory network consisting of 23 lncRNAs, 10 miRNAs, and 113 mRNAs was constructed. The analysis results suggested that lncRNA (OSBPL10-AS1), miRNA (has-miR-485-5p), and mRNA (SLC23A2) might be involved in the regulation of vitamin metabolism in patients with TB. Metabolite analysis showed that compared with the normal control group, TB patients had abnormal vitamin metabolism, and the expression levels of pyridoxal phosphate, pyridoxamine phosphate, and folic acid were significantly different between the two groups (p < 0.05). CONCLUSION: Integrated multi-omics analysis showed that vitamin metabolism disorder may be one of the pathological characteristic of TB. OSBPL10-AS1, hsa-miR-485-5p, SLC23A2, pyridoxal phosphate, pyridoxamine phosphate, and folic acid may collectively constitute the "integrative pattern" of multiple biomarkers, which may provide an accurate diagnosis of TB.
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MicroARNs , ARN Largo no Codificante , Tuberculosis Pulmonar , Biomarcadores , Ácido Fólico , Redes Reguladoras de Genes , Humanos , MicroARNs/genética , Fosfato de Piridoxal/genética , Piridoxamina/análogos & derivados , ARN Largo no Codificante/genética , ARN Mensajero/genética , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/genética , VitaminasRESUMEN
Ruthenium complexes with good biological properties have attracted increasing attention in recent decades. In this work, three ruthenium polypyridine complexes containing 5-fluorouracil derivatives as ligands, [Ru(bpy)2(L)]2+ (Ru1), [Ru(phen)2(L)]2+ (Ru2), [Ru(dip)2(L)]2+ (Ru3) (L = 1-((1,10-phenanthroline-5-amino) pentyl)-5-fluorouracil; bpy = 2,2'-bipyridine; phen =1,10-phenanthroline; dip = 4,7-diphenyl-1,10-phenanthroline), were synthesized and characterized. Based on in vitro cytotoxicity tests, Ru3 (IC50 = 7.35 ± 0.39 µM) showed the best anticancer activity among three compounds in the selected cell lines. It is worth noting that Ru3 also exerts less cytotoxicity on LO2 cell lines, with an IC50 value 5 times higher than that on HeLa cells, indicating its selective activity. Mechanism studies revealed that Ru3 can specifically target lysosomes and induce cell apoptosis in a caspase-dependent manner. Specifically, Ru3 can arrest cell cycle at the G0/G1 phase, increase the intracellular reactive oxygen species (ROS) level, and then damage DNA. In short, Ru3 can eventually cause cell death through the synergy of inducing apoptosis and autophagy, which was further proven by western blot assay results.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Complejos de Coordinación/farmacología , Lisosomas/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/efectos de la radiación , Daño del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Fluorouracilo/análogos & derivados , Fluorouracilo/farmacología , Fluorouracilo/toxicidad , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Ligandos , Piridinas/síntesis química , Piridinas/farmacología , Piridinas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Rutenio/químicaRESUMEN
Lung cancer is characterized by a high incidence rate and low survival rate. It is important to achieve early diagnosis of the disease. We applied ultra-high performance liquid chromatography tandem mass spectrometry to screen plasma lipid spectrum in non-small cell lung cancer (NSCLC) patients, healthy controls (HC), and community-acquired pneumonia (CAP) patients. Modeling employing orthogonal partial least squares-discriminant analysis combined with t-test was used to screen the differential lipids. Logistic regression analysis was used to establish the diagnostic model, while the accuracy was verified by 10-fold cross-validation. The results showed that the abnormal metabolism of lipid in NSCLC mainly comprised fatty acid metabolism, phospholipid metabolism, and glyceride metabolism. Four potential biomarkers, including LPC (14:0/0:0), LPI (14:1/0:0), DG (14:0/18:2/0:0), and LPC (16:1/0:0), were fitted by the receiver operating characteristic curve model with the area under curve (AUC) value of 0.856, and the specificity and sensitivity were 87.0 and 78.0%, respectively. The results of cross validation showed that the AUC value of the model was 0.812, the sensitivity was 72.9%, and the specificity was 82.6%. The positive rate of four potential lipid biomarkers in this study (>60.0%) was higher than that of existing tumor biomarkers in the clinical application. We investigated the plasma lipid profile of NSCLC patients and identified lipid biomarkers with potential diagnostic values. From the lipidomics perspective, our study may lay a foundation for the biomarker-based early diagnosis of lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Biomarcadores , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Cromatografía Líquida de Alta Presión/métodos , Detección Precoz del Cáncer , Humanos , Lípidos , Neoplasias Pulmonares/diagnóstico , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant disease, and it is characterized by rapid progression and low five-year survival rate. At present, there are no effective methods for monitoring the treatment and prognosis of HCC. METHODS: The transcriptome and gene expression profiles of HCC were obtained from the Cancer Genome Atlas (TCGA) program, International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. The random forest method was applied to construct a four-gene prognostic model based on RNA terminal phosphate cyclase like 1 (RCL1) expression. The Kaplan-Meier method was performed to evaluate the prognostic value of RCL1, long noncoding RNAs (AC079061, AL354872, and LINC01093), and four-gene signature (SPP1, MYBL2, TRNP1, and FTCD). We examined the relationship between RCL1 expression and immune cells infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). RESULTS: The results of multiple databases indicated that the aberrant expression of RCL1 was associated with clinical outcome, immune cells infiltration, TMB, and MSI in HCC patients. Meanwhile, we found that long noncoding RNAs (AC079061, AL354872, and LINC01093) and RCL1 were significantly coexpressed in HCC patients. We also confirmed that the four-gene signature was an independent prognostic factor for HCC patients. Ferroptosis potential index, immune checkpoint molecules, and clinical feature were found to have obvious correlations with risk score. The area under the receiver operating characteristic curve values for the model were 0.7-0.8 in the training set and the validation set, suggesting high robustness of the four-gene signature. We then built a nomogram for facilitating the use in clinical practice. CONCLUSION: Our study demonstrated that RCL1 and a novel four-gene signature can be used as prognostic biomarkers for predicting clinical outcome in HCC patients; and this model may assist in individualized treatment monitoring of HCC patients in clinical practice.
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Postpartum depression (PPD) is a serious health issue that can affect about 15% of the female population within after giving birth. It often conveys significant negative consequences to the offsprings. The symptoms and risk factors are somewhat similar to those found in non-postpartum depression. The main difference resides in the fact that PPD is triggered by postpartum specific factors, including especially biological changes in the hormone levels. Patients are usually diagnosed using a questionnaire onsite or in a clinic. Treatment of PPD often involves psychotherapy and antidepressant medications. In recent years, there have been more researches on the identification of biological markers for PPD. In this review, we will focus on the current research status of PPD, with an emphasis on the recent progress made on the identification of PPD biomarkers.
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This paper describes a visible-light-mediated oxidative cyclization of 2-aminobenzyl alcohols and secondary alcohols to produce quinolines at room temperature. This photocatalytic method employed anthraquinone as an organic small-molecule catalyst and DMSO as an oxidant. According to this present procedure, a series of quinolines were prepared in satisfactory yields.
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Mitochondrial damage will hinder the energy production of cells and produce excessive ROS (reactive oxygen species), resulting in cell death through autophagy or apoptosis. In this paper, four cyclometalated iridium(III) complexes (Ir1: [Ir(piq)2L]PF6; Ir2: [Ir(bzq)2L]PF6; Ir3: [Ir(dfppy)2L]PF6; Ir4: [Ir(thpy)2L]PF6; piq = 1-phenylisoquinoline; bzq = benzo[h]quinoline; dfppy = 2-(2,4-difluorophenyl)pyridine;thpy = 2-(2-thienyl)pyridine; L = 1,10-phenanthroline-5-amine) were synthesized and characterized. Cytotoxicity tests show that these complexes have excellent cytotoxicity to cancer cells, and mechanism studies indicatethat these complexes can specifically target mitochondria. Complexes Ir1 and Ir2 can damage the function of mitochondria, subsequently increasing intracellular levels of ROS, decreasing MMP (mitochondrial membrane potential), and interfering with ATP energy production, which leads to autophagy and apoptosis. Furthermore, autophagy induced by Ir1 and Ir2 can promote cell death in coordination with apoptosis. Surprisingly, these four complexes also showed moderate antibacterial activity to S. aureusand P. aeruginosa.
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Antibacterianos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Complejos de Coordinación/farmacología , Iridio/química , Mitocondrias/metabolismo , Células A549 , Antibacterianos/química , Antineoplásicos/química , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Complejos de Coordinación/química , Humanos , Espectroscopía de Resonancia Magnética/métodos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Quinolinas/química , Especies Reactivas de Oxígeno/metabolismo , Espectrometría de Masa por Ionización de Electrospray/métodos , Staphylococcus aureus/efectos de los fármacosRESUMEN
Currently, the management of pulmonary tuberculosis (TB) lacks potent medications and accurate efficacy evaluation biomarkers. In view of the fact that the host lipids are the important energy source of Mycobacterium tuberculosis (Mtb), UPLC-MS/MS based on lipid metabolism was used to monitor the plasma lipid spectrum of TB patients from the initial diagnosis to cured. The analysis showed that TB patients presented aberrant metabolism of phospholipids, glycerides, and sphingolipids. Upon the treatment, the abnormal expression of Cer (d18:1/24:0), CerP (d18:1/20:3), LPE (0:0/22:0), LPA (0:0/16:0), and LPA (0:0/18:0) in TB patients were gradually normalized, indicating that the intervention of lipid metabolism could block energy metabolism and inhibit the cell wall synthesis of Mtb. Furthermore, the increase in ceramide (Cer) levels could promote autophagosome-lysosome fusion. LPA (0:0/16:0) and LPA (0:0/18:0) had a great potential in the early diagnosis (both sensitivity and specificity were 100%) and efficacy evaluation (both sensitivity and specificity were 100%) of TB, indicating that the above lipid metabolites could be used as potential biomarkers for TB.
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Metabolismo de los Lípidos , Lípidos/sangre , Mycobacterium tuberculosis/metabolismo , Tuberculosis Pulmonar/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Early diagnosis of active pulmonary tuberculosis (TB) is the key to controlling the disease. Host lipids are nutrient sources for the metabolism of Mycobacterium tuberculosis. In this research work, we used ultra-high-performance liquid chromatography-tandem mass spectrometry to screen plasma lipids in TB patients, lung cancer patients, community-acquired pneumonia patients, and normal healthy controls. Principal component analysis, orthogonal partial least squares discriminant analysis, and K-means clustering algorithm analysis were used to identify lipids with differential abundance. A total of 22 differential lipids were filtered out among all subjects. The plasma phospholipid levels were decreased, while the cholesterol ester levels were increased in patients with TB. We speculate that the infection of M. tuberculosis may regulate the lipid metabolism of TB patients and may promote host-assisted bacterial degradation of phospholipids and accumulation of cholesterol esters. This may be related to the formation of lung cavities with caseous necrosis. The results of receiver operating characteristic curve analysis revealed four lipids such as phosphatidylcholine (PC, 12:0/22:2), PC (16:0/18:2), cholesteryl ester (20:3), and sphingomyelin (d18:0/18:1) as potential biomarkers for early diagnosis of TB. The diagnostic model was fitted by using logistic regression analysis and combining the above four lipids with a sensitivity of 92.9%, a specificity of 82.4%, and the area under the curve (AUC) value of 0.934 (95% CI 0.873 - 0.971). The machine learning method (10-fold cross-validation) demonstrated that the model had good accuracy (0.908 AUC, 85.3% sensitivity, and 85.9% specificity). The lipids identified in this study may serve as novel biomarkers in TB diagnosis. Our research may pave the foundation for understanding the pathogenesis of TB.
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Lípidos/sangre , Espectrometría de Masas en Tándem , Tuberculosis Pulmonar/sangre , Adulto , Biomarcadores/sangre , Cromatografía Líquida de Alta Presión , Progresión de la Enfermedad , Femenino , Humanos , Metabolismo de los Lípidos , Lipidómica , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Modelos Estadísticos , Análisis Multivariante , Curva ROC , Tuberculosis Pulmonar/diagnósticoRESUMEN
As the "powerhouse" of a cell, mitochondria maintain energy homeostasis, synthesize ATP via oxidative phosphorylation, generate ROS signaling molecules, and modulate cell apoptosis. Herein, three Re(I) complexes bearing guanidinium derivatives have been synthesized and characterized. All of these complexes exhibit moderate anticancer activity in HepG2, HeLa, MCF-7, and A549 cancer cells. Mechanism studies indicate that complex 3, [Re(CO)3(L)(Im)](PF6)2, can selectively localize in the mitochondria and induce cancer cell death through mitochondria-associated pathways. In addition, complex 3 can effectively depress the ability of cell migration, cell invasion, and colony formation.
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Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Guanidina/química , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Renio/química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Ligandos , Invasividad Neoplásica , Relación Estructura-ActividadRESUMEN
PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425â¯nm. Notably, Ir1 conferred almost no dark toxicity (IC50â¯>â¯100⯵M) to HepG2 cells, but the value decreased by 387-fold to 0.36⯵M following 10â¯min of light irradiation (425â¯nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425â¯nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.
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Antineoplásicos/farmacología , Guanidina/farmacología , Iridio/farmacología , Mitocondrias/efectos de los fármacos , Imagen Óptica , Compuestos Organometálicos/farmacología , Fármacos Fotosensibilizantes/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Guanidina/química , Células Hep G2 , Humanos , Iridio/química , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/patología , Ratones , Mitocondrias/patología , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Relación Estructura-ActividadRESUMEN
Titanium (Ti) and its corresponding alloys have been widely applied in dental and orthopedic implants. Owing to abrasion and corrosion of implants in the unfavorable electrolytic aqueous environment of the host body, Ti ions could be released from implants and accumulated in local tissues. Recent studies have found that excessive Ti ions were toxic to osteoblasts in adjacent bone tissues and subsequently influenced long-term effects on implant prostheses. However, the potential molecular mechanisms underlying the damage to osteoblasts induced by Ti ions remained unclear. Hippo signaling has been confirmed to be involved in organ size and tissue regeneration in many organs, while its roles in osteoblasts differentiation and bone repair remained elusive. Therefore, we hypothesize that YAP, a regulator of Hippo pathway, inhibited osteoblast growth, skeletal development and bone repair, as well as excessive Ti ions promoted the progression of YAP activation. This study aimed to explore the role of Hippo/YAP signaling pathway in the biotoxicity effect of Ti ions on osteoblast behaviors. Here, we confirmed that 10 ppm Ti ions, a minimum concentration gradient previously reported that was capable of suppressing osteoblasts growth, induced nuclear expression of YAP in osteoblasts in our study. Furthermore, 10 ppm Ti ion-induced YAP activation was found to downregulate osteogenic differentiation of MC3T3-E1 cells. Most importantly, the hypothesis we proposed that knockdown of YAP did reverse the inhibitory effect of 10 ppm Ti ions on osteogenesis has been verified. Taken together, our work provides insights into the mechanism of which YAP is involved in regulating osteoblast behaviors under the effect of Ti ions, which may help to develop therapeutic applications for Ti implant failures and peri-implantitis.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Osteoblastos/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Titanio/toxicidad , Células 3T3 , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular/genética , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica , Vía de Señalización Hippo , Ratones , Osteoblastos/metabolismo , Osteoblastos/patología , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Fosforilación , Proteínas Señalizadoras YAPRESUMEN
The albumin/globulin ratio (AGR) has been widely reported to be a potential predictor of prognosis in digestive system cancers (DSCs), but convincing conclusions have not been made. Therefore, herein, we performed a meta-analysis of relevant studies regarding this topic to evaluate the prognostic value of AGR in patients with DSCs. Three databases, including PubMed, EMBase, and Web of science, were searched comprehensively for eligible studies through September 8, 2017. The outcomes of interest included overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). In our meta-analysis, pooled analysis of 13 studies with 9269 patients showed that a low AGR was significantly correlated with poor OS (HR = 1.94; 95% CI: 1.57-2.38; P <0.001). Five studies with 6538 participants involved DFS, and our pooled analysis of these studies also demonstrated that there was a significant association of a low AGR with worse DFS (HR = 1.49; 95% CI: 1.10 to 2.00; P < 0.001). In addition, only 2 studies referred to CSS, and we also detected a significant relationship between a low AGR and worse CSS from the results of our meta-analysis. In summary, a low pretreatment AGR was related to unfavorable survival in human digestive system cancers. A low pretreatment AGR may be a useful predictive prognostic biomarker in human digestive system cancers.
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Albúminas/metabolismo , Biomarcadores de Tumor/sangre , Neoplasias del Sistema Digestivo/patología , Globulinas/metabolismo , Neoplasias del Sistema Digestivo/sangre , Humanos , Pronóstico , Tasa de SupervivenciaRESUMEN
DESCRIPTION: Two new ruthenium(II) complexes containing guanidinium as ligands, [Ru(dip)2 (L1)]3+ (Ru1) and [Ru(dip)2(L2)]3+ (Ru2) (dip=4,7-diphenyl-1,10-phenanthroline; L1=1-(4-(1H-imidazo[4,5- f][1,10]phenanthrolin-2-yl)phenyl)guanidine cation; L2 = 1-(3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl) phenyl)guanidine cation) have been synthesized and characterized. Both complexes display higher cytotoxicity against several cancer cell lines compared to cisplatin and are less cytotoxic on the nontumorigenic cell line LO2. Intracellular distribution studies show that these complexes are selectively localized in the cytoplasm. FINDINGS: Further analysis revealed that Ru1 and Ru2 had no obvious effects on the cell cycle and induced apoptosis in HeLa cells via the mitochondrial pathway, which involved reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and Bcl-2 family member activation. Taken together, the two complexes have the potential to be utilized as anticancer agents.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Guanidina/farmacología , Rutenio/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Guanidina/química , Humanos , Ligandos , Estructura Molecular , Rutenio/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Guanidinium-functionalized molecules are commonly studied for their use as pharmaceutically active compounds and drugs carriers. Herein, four cyclometalated iridium(III) complexes containing guanidinium ligands have been synthesized and characterized as potential anticancer agents. These complexes exhibit moderate antitumor activity in HeLa, MCF-7, HepG2, CNE-2, and A549 human tumor cells. Interestingly, all complexes showed higher cytotoxicity than cisplatin against a cisplatin-resistant cell line A549R, and less cytotoxicity on the nontumorigenic LO2 cells. Intracellular distribution studies suggest that these complexes are selectively localized in the mitochondria. Mechanism studies indicate that these complexes arrested the cell cycle in the G0/G1 phase and can influence mitochondrial integrity, inducing cancer cell death through reactive oxygen species (ROS)-dependent pathways.