RESUMEN
A copper-catalyzed [3+2] annulation reaction of exocyclic enamines/enol ethers with 1,4-benzoquinone esters has been developed, providing facile access to N,O-spiroketals and spiroketals under mild conditions with broad substrate scope (26 examples, 71-94 % yields). Gram scale synthesis and chemical transformations demonstrated that this method is potentially useful in the synthesis of natural products and drugs containing a N,O- spiroketal moiety. The chiral N,O-spiroketal could be obtained with 98 % ee after recrystallization, when a chiral SaBOX ligand was employed.
RESUMEN
Spatial transcriptomics technologies developed in recent years can provide various information including tissue heterogeneity, which is fundamental in biological and medical research, and have been making significant breakthroughs. Single-cell RNA sequencing (scRNA-seq) cannot provide spatial information, while spatial transcriptomics technologies allow gene expression information to be obtained from intact tissue sections in the original physiological context at a spatial resolution. Various biological insights can be generated into tissue architecture and further the elucidation of the interaction between cells and the microenvironment. Thus, we can gain a general understanding of histogenesis processes and disease pathogenesis, etc. Furthermore, in silico methods involving the widely distributed R and Python packages for data analysis play essential roles in deriving indispensable bioinformation and eliminating technological limitations. In this review, we summarize available technologies of spatial transcriptomics, probe into several applications, discuss the computational strategies and raise future perspectives, highlighting the developmental potential.
Asunto(s)
Investigación Biomédica , Transcriptoma , Transcriptoma/genética , Perfilación de la Expresión Génica , Análisis de Datos , Análisis de la Célula Individual , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/tratamiento farmacológico , alfa-Fetoproteínas , Estudios Retrospectivos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Recurrencia Local de Neoplasia/diagnóstico por imagen , Inmunoterapia , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Supplemental oxygen impairs lung development in newborn infants with respiratory distress. Lactobacillus johnsonii supplementation attenuates respiratory viral infection in mice and exhibits anti-inflammatory effects. This study investigated the protective effects of intranasal administration of L. johnsonii on lung development in hyperoxia-exposed neonatal mice. METHODS: Neonatal C57BL/6N mice were reared in either room air (RA) or hyperoxia condition (85% O2). From postnatal days 0 to 6, they were administered intranasal 10 µL L. johnsonii at a dose of 1 × 105 colony-forming units. Control mice received an equal volume of normal saline (NS). We evaluated the following four study groups: RA + NS, RA + probiotic, O2 + NS, and O2 + probiotic. On postnatal day 7, lung and intestinal microbiota were sampled from the left lung and lower gastrointestinal tract, respectively. The right lung of each mouse was harvested for Western blot, cytokine, and histology analyses. RESULTS: The O2 + NS group exhibited significantly lower body weight and vascular density and significantly higher mean linear intercept (MLI) and lung cytokine levels compared with the RA + NS and RA + probiotic groups. At the genus level of the gut microbiota, the O2 + NS group exhibited significantly higher Staphylococcus and Enterobacter abundance and significantly lower Lactobacillus abundance compared with the RA + NS and RA + probiotic groups. Intranasal L. johnsonii treatment increased the vascular density, decreased the MLI and cytokine levels, and restored the gut microbiota in hyperoxia-exposed neonatal mice. CONCLUSIONS: Intranasal administration of L. johnsonii protects against hyperoxia-induced lung injury and modulates the gut microbiota.
Asunto(s)
Microbioma Gastrointestinal , Hiperoxia , Lactobacillus johnsonii , Lesión Pulmonar , Ratas , Animales , Ratones , Hiperoxia/complicaciones , Hiperoxia/patología , Animales Recién Nacidos , Lesión Pulmonar/prevención & control , Lesión Pulmonar/patología , Ratas Sprague-Dawley , Administración Intranasal , Ratones Endogámicos C57BL , Pulmón/patología , CitocinasRESUMEN
BACKGROUND: Members of the genus Novius Mulsant, 1846 (= Rodolia Mulsant, 1850) (Coleoptera, Coccinellidae), play important roles in the biological control of cotton cushion scale pests, especially those belonging to Icerya. Since the best-known species, the vedalia beetle Novius cardinalis (Mulsant, 1850) was introduced into California from Australia, more than a century of successful use in classical biological control, some species of Novius have begun to exhibit some field adaptations to novel but related prey species. Despite their economic importance, relatively little is known about the underlying genetic adaptations associated with their feeding habits. Knowledge of the genome sequence of Novius is a major step towards further understanding its biology and potential applications in pest control. RESULTS: We report the first high-quality genome sequence for Novius pumilus (Weise, 1892), a representative specialist of Novius. Computational Analysis of gene Family Evolution (CAFE) analysis showed that several orthogroups encoding chemosensors, digestive, and immunity-related enzymes were significantly expanded (P < 0.05) in N. pumilus compared to the published genomes of other four ladybirds. Furthermore, some of these orthogroups were under significant positive selection pressure (P < 0.05). Notably, transcriptome profiling demonstrated that many genes among the significantly expanded and positively selected orthogroups, as well as genes related to detoxification were differentially expressed, when N. pumilus feeding on the nature prey Icerya compared with the no feeding set. We speculate that these genes are vital in the Icerya adaptation of Novius species. CONCLUSIONS: We report the first Novius genome thus far. In addition, we provide comprehensive transcriptomic resources for N. pumilus. The results from this study may be helpful for understanding the association of the evolution of genes related to chemosensing, digestion, detoxification and immunity with the prey adaptation of insect predators. This will provide a reference for future research and utilization of Novius in biological control programs. Moreover, understanding the possible molecular mechanisms of prey adaptation also inform mass rearing of N. pumilus and other Novius, which may benefit pest control.
Asunto(s)
Escarabajos , Hemípteros , Animales , Agentes de Control Biológico , Escarabajos/genética , Genómica , InsectosRESUMEN
Heteronemin (Haimian jing) is a sesterterpenoid-type natural marine product that is isolated from sponges and has anticancer properties. It inhibits cancer cell proliferation via different mechanisms, such as reactive oxygen species (ROS) production, cell cycle arrest, apoptosis as well as proliferative gene changes in various types of cancers. Recently, the novel structure and bioactivity evaluation of heteronemin has received extensive attention. Hormones control physiological activities regularly, however, they may also affect several abnormalities such as cancer. L-Thyroxine (T4), steroid hormones, and epidermal growth factor (EGF) up-regulate the accumulation of checkpoint programmed death-ligand 1 (PD-L1) and promote inflammation in cancer cells. Heteronemin suppresses PD-L1 expression and reduces the PD-L1-induced proliferative effect. In the current review, we evaluated research and evidence regarding the antitumor effects of heteronemin and the antagonizing effects of non-peptide hormones and growth factors on heteronemin-induced anti-cancer properties and utilized computational molecular modeling to explain how these ligands interacted with the integrin αvß3 receptors. On the other hand, thyroid hormone deaminated analogue, tetraiodothyroacetic acid (tetrac), modulates signal pathways and inhibits cancer growth and metastasis. The combination of heteronemin and tetrac derivatives has been demonstrated to compensate for anti-proliferation in cancer cells under different circumstances. Overall, this review outlines the potential of heteronemin in managing different types of cancers that may lead to its clinical development as an anticancer agent.
Asunto(s)
Antígeno B7-H1 , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Terpenos/química , Terpenos/farmacología , Hormonas TiroideasRESUMEN
Thyroid hormone analogues-particularly, L-thyroxine (T4) has been shown to be relevant to the functions of a variety of cancers. Integrin αvß3 is a plasma membrane structural protein linked to signal transduction pathways that are critical to cancer cell proliferation and metastasis. Thyroid hormones, T4 and to a less extend T3 bind cell surface integrin αvß3, to stimulate the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway to stimulate cancer cell growth. Thyroid hormone analogues also engage in crosstalk with the epidermal growth factor receptor (EGFR)-Ras pathway. EGFR signal generation and, downstream, transduction of Ras/Raf pathway signals contribute importantly to tumor cell progression. Mutated Ras oncogenes contribute to chemoresistance in colorectal carcinoma (CRC); chemoresistance may depend in part on the activity of ERK1/2 pathway. In this review, we evaluate the contribution of thyroxine interacting with integrin αvß3 and crosstalking with EGFR/Ras signaling pathway non-genomically in CRC proliferation. Tetraiodothyroacetic acid (tetrac), the deaminated analogue of T4, and its nano-derivative, NDAT, have anticancer functions, with effectiveness against CRC and other tumors. In Ras-mutant CRC cells, tetrac derivatives may overcome chemoresistance to other drugs via actions initiated at integrin αvß3 and involving, downstream, the EGFR-Ras signaling pathways.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/prevención & control , Integrina alfaVbeta3/uso terapéutico , Transducción de Señal , Tiroxina/uso terapéutico , Genes erbB-1 , Genes ras , HumanosRESUMEN
BACKGROUND: Perinatal antibiotic treatment alters intestinal microbiota and augments hyperoxia-induced lung injury in mice offspring. The effect of maternal antibiotic treatment (MAT) during pregnancy on the lung microbiota and its relationship with lung injury remains unknown. METHODS: We fed timed-pregnant C57BL/6N mice sterile drinking water containing antibiotics from gestational day 15 to delivery. Neonatal mice were reared in either room air (RA) or hyperoxia (85% O2) from postnatal days 1 to 7. Four study groups were obtained: control + RA, control + O2, MAT + RA, and MAT + O2. On postnatal day 7, lung and intestinal microbiota were sampled from the left lung and lower gastrointestinal tract. The right lung was harvested for histology and cytokine analysis. RESULTS: MAT during pregnancy significantly reduced the total number of commensal bacteria in the intestine and birth body weight of newborn mice compared with control newborn mice. Neonatal hyperoxia exposure impaired alveolarization and angiogenesis, which was exacerbated by MAT. Neonatal hyperoxia altered the composition and diversity of intestinal and lung microbiota and MAT further exacerbated neonatal hyperoxia-induced intestinal and lung dysbiosis. CONCLUSIONS: MAT during pregnancy exacerbates hyperoxia-induced lung injury probably through the modulation of intestinal and lung microbiota in neonatal mice. IMPACT: MAT during pregnancy reduced the total number of commensal bacteria in the intestine. Neonatal hyperoxia altered the composition and diversity of intestinal and lung microbiota. MAT exacerbated neonatal hyperoxia-induced intestinal and lung dysbiosis. Neonatal hyperoxia exposure impaired alveolarization and angiogenesis, which was exacerbated by MAT. Avoiding and carefully using antibiotics during pregnancy is a potential therapeutic target for preventing lung injury in hyperoxia-exposed infants.
Asunto(s)
Hiperoxia/fisiopatología , Lesión Pulmonar/etiología , Pulmón/microbiología , Exposición Materna , Microbiota/efectos de los fármacos , Animales , Animales Recién Nacidos , Peso al Nacer , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Hiperoxia/complicaciones , Ratones , Ratones Endogámicos C57BL , Tasa de SupervivenciaRESUMEN
Prenatal opioid exposure might disturb epigenetic programming in the brain of neonatal offspring with various consequences for gene expressions and behaviors. This study determined whether altered trimethylation of histone 3 at lysine 4 (H3K4me3) in the promoter of the tumor necrosis factor-α (tnf-α) gene with neural cell apoptosis was involved in the ventral-medial striatum, an important brain region for withdrawal symptoms, of neonatal rat offspring from morphine-addicted mothers. Female adult rats were injected with morphine before gestation and until 14 days after giving birth. On postnatal day 14 (P14), rat offspring from morphine-addicted mothers were subjected to an opioid-withdrawal protocol and were analyzed 2 or 8 h after administration of that protocol. Expressions of the TNF-α protein, H3K4me3 in the tnf-α promoter gene, and neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring were evaluated. In the absence of significant opioid withdrawal (2 h after initiation of the opioid-withdrawal protocol on P14), prenatal morphine exposure led to increased levels of H3K4me3 in the tnf-α promoter gene, of the TNF-α protein, and of neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring. Following opioid withdrawal (8 h after initiation of the opioid-withdrawal protocol on P14), differential expression of H3K4me3 in the tnf-α promoter gene locus and upregulation of the level of TNF-α protein expression were further enhanced in these offspring. In addition, increased levels of caspase-3 and neural cell apoptosis were also observed. Taken together, this study revealed that prenatal opioid exposure can activate an epigenetic histone mechanism which regulates proinflammatory factor generation, which hence, led to cell apoptotic damage within the ventral-medial striatum of neonatal rat offspring from morphine-addicted mothers. More importantly, the opioid-withdrawal episode may provide augmented effects for the abovementioned alterations and could lead to deleterious effects in the neonatal brain of such offspring.
Asunto(s)
Apoptosis , Histonas/metabolismo , Dependencia de Morfina/metabolismo , Morfina , Preñez , Regiones Promotoras Genéticas , Factor de Necrosis Tumoral alfa/genética , Analgésicos Opioides , Animales , Animales Recién Nacidos , Encéfalo/patología , Caspasa 3/metabolismo , Cuerpo Estriado , Epigénesis Genética , Femenino , Exposición Materna , Metilación , Embarazo , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/patologíaRESUMEN
Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC50 values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 µM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 µg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.
Asunto(s)
Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/metabolismo , Quinonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The activation of microglial cells plays an important role in the cascade of events leading to inflammation-mediated neurodegenerative disorders. Precision therapeutics require that adjunctively feasible drugs be found to prevent microglial cell activation and prevent inflammation-mediated neuronal injury. Dextromethorphan (DM) has been reported to possess neuroprotective effects in lipopolysaccharide- (LPS-) stimulated animals; however, it remains unclear whether epigenetic regulatory mechanisms in microglial cells are involved in such DM-mediated neuroprotective effects. In this study, DM simultaneously suppressed LPS-induced activation of tumor necrosis factor- (TNF-) α expression and subsequent caspase-3 signaling in primary microglial cells associated with notable morphological changes. Furthermore, therapeutic action sites of DM involved differential enhanced trimethylation of H3K4 modifications in the promoter region of tnf-α gene locus in primary microglial cells. In summary, DM may exert neuroprotective and anti-inflammatory effects through differential epigenetic histone modifications of TNF-α expression in microglial cells and might therefore raise the possibility of providing an adjunctively beneficial role for a tentative therapeutic strategy in neurodegenerative diseases resulting from inflammation.
Asunto(s)
Antiinflamatorios/farmacología , Dextrometorfano/farmacología , Epigénesis Genética/efectos de los fármacos , Histonas/metabolismo , Microglía/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Animales , Caspasa 3/fisiología , Células Cultivadas , Lipopolisacáridos/farmacología , Microglía/fisiología , Regiones Promotoras Genéticas , Ratas , Ratas Sprague-DawleyRESUMEN
Lung cancer is a common cancer in human and has presented significant genetic predisposition. Previous genome-wide association study observed that rs401681 within CLPTM1L (CLPTM1 like) was significantly associated with lung cancer. By analyzing 1000 genomes data for East Asian, we identified only one SNP in nearby region, rs402710, in high linkage disequilibrium with rs401681, which was also associated with lung cancer. However, the real causal SNP and mechanism for the association were still not clear. The following plasmid construction, mutagenesis, transient transfection and luciferase reading indicated that both SNPs could regulate gene expression in lung/bronchial epithelium Beas-2B cell line. By chromosome conformation capture, it was identified that the segment containing these two SNPs could interact with TERT (telomerase reverse transcriptase) promoter, thus indicating that these SNPs confer lung cancer risk by regulating TERT expression instead of CLPTM1L. Through chromatin immunoprecipitation, the transcript factors HNF4A (hepatocyte nuclear factor 4 alpha) and MAF1 (MAF1 homolog, negative regulator of RNA polymerase III) were recognized for the regions spanning rs401681 and rs402710, respectively. Our results uncovered a complete link between these two SNPs and lung cancer.
Asunto(s)
Pueblo Asiatico/genética , Neoplasias Pulmonares/genética , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Telomerasa/genética , Línea Celular Tumoral , Inmunoprecipitación de Cromatina/métodos , Regulación Neoplásica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/etnología , Polimorfismo de Nucleótido SimpleRESUMEN
The aim of this study was to investigate the value of a platelet count (PLT) in the early diagnosis of nosocomial invasive fungal infections in premature infants. Based on clinical diagnosis combined with blood culture results, 72 premature infants of 5354 pediatric patients who were hospitalized in the neonatal ward of our hospital between September 2009 and February 2013 were diagnosed with nosocomial invasive fungal infections (fungal infection group). There were 58 premature infants diagnosed with bacterial infections during the same period (bacterial infection group). The control group included 74 premature infants without nosocomial infections who were hospitalized during the same period. Receiver operating characteristic (ROC) curves were used to analyze the sensitivity, specificity, and diagnostic efficacy of the PLT and white blood cell (WBC) counts and C-reactive protein (CRP) level in the diagnosis of fungal infections in premature infants. The risk factors for invasive fungal infections included birth weight < 2000 g, gestational age < 32 weeks, peripherally inserted central catheter (PICC), oxygen inhalation therapy, intravenous nutrition, and administration of antibiotics (p < 0.05). Compared with the control group, the WBC and PLT counts in the fungal infection group decreased in the early and acute stages of infection (p < 0.01), while the CRP level increased (p < 0.01). The PLT count in the bacterial infection group decreased in the early and acute stages of infection (p < 0.01) and the CRP level increased (p < 0.05). Moreover, the decrease in the PLT count in the fungal infection group was more significant than the bacterial infection group (p < 0.01) and the CRP level increased more in the fungal infection group in the early stage of infection (p < 0.01); however, there were no significant differences in the PLT count and CRP level between the fungal and bacterial infection groups in the acute stage of infection (p > 0.05). ROC curve analysis of the WBC and PLT counts and the CRP level in the early diagnosis of fungal infections showed that the area under the curve of the PLT count was 0.912 (95% confidence interval:0.863-0.961), thus indicating a high accuracy with a cutoff PLT count of 157.0 × 109/L. The corresponding sensitivity and specificity were 77.8% and 94.6%, respectively. We conclude that the PLT count is a convenient, economical, and effective predictor of invasive fungal infections in premature infants and has potential in the early diagnosis of fungal infections.
Asunto(s)
Infección Hospitalaria , Recien Nacido Prematuro , Infecciones Fúngicas Invasoras/sangre , Infecciones Fúngicas Invasoras/diagnóstico , Recuento de Plaquetas , Proteína C-Reactiva , Biología Computacional/métodos , Diagnóstico Precoz , Femenino , Humanos , Lactante , Recién Nacido , Infecciones Fúngicas Invasoras/epidemiología , Infecciones Fúngicas Invasoras/microbiología , Recuento de Leucocitos , Masculino , Curva ROCRESUMEN
UGT2B10 is an important metabolism enzyme in human body and its substrates include multiple amine-containing compounds, especially nicotine, tamoxifen and multiple antidepressants. Multiple common SNPs have been observed in its promoter region, but their role in expression regulation has never been investigated. In this preliminary study, we identified a novel cis-regulatory SNP, rs294775, for UGT2B10 by plasmid construction, mutagenesis, and luciferase assay, whose mechanism was also investigated. Our work provides a basis for further pharmacogenetics study.
Asunto(s)
Glucuronosiltransferasa/genética , Polimorfismo de Nucleótido Simple , Glucuronosiltransferasa/metabolismo , Células Hep G2 , Humanos , MutagénesisRESUMEN
A marine sesterterpenoid-type natural product, heteronemin, retains anticancer effects. In the current study, we investigate the antitumor mechanism of heteronemin in cholangiocarcinoma cells and further explore its molecular targets. Initially, heteronemin exhibited potent cytotoxic effects against cholangiocarcinoma HuccT1 and SSP-25 cells. In vitro, heteronemin altered the abilities of cell adhesion and cell migration in HuccT1 and SSP-25 cell lines. It repressed messenger ribonucleic acid (mRNA) expression levels of transforming growth factor (TGF)-ß, mothers against decapentaplegic homolog (SMAD) and Myc, whose protein products play important roles in regulating cell growth, angiogenesis, and metastasis. In addition, heteronemin altered several signaling pathways. The results indicate that heteronemin was able to modulate cell adhesion, the expression of extracellular matrix (ECM) receptors, the TGF-ß pathway, cell motility, the membrane integration, metastasis response, matrix metalloproteinase (MMP) remodeling, the regulation of metabolism, sprouting angiogenesis, transcription factors, and vasculogenesis in cholangiocarcinoma cell lines. The results also suggest that it activated multiple signal transduction pathways to induce an anti-proliferation effect and anti-metastasis in cholangiocarcinoma. In conclusion, heteronemin may be used as a potential medicine for anticancer therapy.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Terpenos/farmacología , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Poríferos/química , ARN Mensajero/metabolismo , Terpenos/uso terapéutico , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Bronchopulmonary dysplasia (BPD) is the most common long-term complication in surviving extremely preterm infants. This may lead to pulmonary hypertension, increase late neonatal mortality, and cause abnormal neural development. There is still controversy over the efficacy, as well as advantages and disadvantages, of drug therapy for BPD in preterm infants. This article reviews the research progress in the drug therapy for BPD.
Asunto(s)
Displasia Broncopulmonar/tratamiento farmacológico , Humanos , Recién Nacido , Recien Nacido PrematuroRESUMEN
BACKGROUND: Obesity and its comorbidities constitute a serious health burden worldwide. Leptin plays an important role in diet control; however, it has a stimulatory potential on cancer cell proliferation. The OB3 peptide, a synthetic peptide, was shown to be more active than leptin in regulating metabolism but with no mitogenic effects in cancer cells. METHODS: In this study, we investigated the proliferative effects, gene expressions and signaling pathways modulated by leptin and OB3 in human ovarian cancer cells. In addition, an animal study was performed. RESULTS: Leptin, but not OB3, induced the proliferation of ovarian cancer cells. Interestingly, OB3 blocked the leptin-induced proliferative effect when it was co-applied with leptin. Both leptin and OB3 activated the phosphatidylinositol-3-kinase (PI3K) signal transduction pathway. In addition, leptin stimulated the phosphorylation of signal transducer and activator of transcription-3 (STAT3) Tyr-705 as well as estrogen receptor (ER)α, and the expression of ERα-responsive genes. Interestingly, all leptin-induced signal activation and gene expressions were blocked by the co-incubation with OB3 and the inhibition of extracellular signal-regulated kinase (ERK)1/2. Coincidently, leptin, but not OB3, increased circulating levels of follicle-stimulating hormone (FSH) which is known to play important roles in the initiation and proliferation of ovarian cancer cells. CONCLUSIONS: In summary, our findings suggest that the OB3 peptide may prevent leptin-induced ovarian cancer initiation and progression by disrupting leptin-induced proliferative signals via STAT3 phosphorylation and ERα activation. Therefore, the OB3 peptide is a potential anticancer agent that might be employed to prevent leptin-induced cancers in obese people.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Leptina/genética , Leptina/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/fisiopatología , Fragmentos de Péptidos/metabolismo , Transducción de Señal/genética , Animales , Proliferación Celular/genética , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
Bispecific antibodies (bsAbs) are second generation antibodies for therapeutic application in immunotherapy. One of the major strategies of the bsAb platform is the recruitment of immune effector T cells by incorporating an anti-CD3 domain. A bispecific T-cell engager (BiTE), with one end having an affinity for CD3 and the other end with affinity for CD19, has been approved in the US and Europe for the treatment of acute lymphoblastic leukemia. However, due to their small size and lack of Fc region, these single-chain variable fragment (scFv) bsAbs have short half-lives in vivo. Additionally, poor solubility, structural instability, and low production yields have also become major challenges in the bulk production process. To overcome these challenges, we have engineered a tetravalent bsAb with bivalent binding specificity for the CD20 and CD3 antigen in an immunoglobulin G (IgG) format. The fusion of the anti-CD3 scFvs to the CD20 antibody via a linker-hinge domain (LHD) results in improved antibody stabilization and properties. Here we demonstrate this antibody's highly efficient cancer cell elimination in a dose-dependent manner in a CD20-expressing B lymphoblastoid cell line in vitro. Our data suggest the potential clinical application of this bsAb for the treatment of CD20-expressing B cell malignancies.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antígenos CD20/inmunología , Complejo CD3/inmunología , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Células Jurkat , Linfoma de Células B/patología , Ingeniería de Proteínas , Resultado del TratamientoRESUMEN
Periodontitis, a chronic infection by periodontopathic bacteria, induces uncontrolled inflammation, which leads to periodontal tissue destruction. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-glucoside (THSG), a polyphenol extracted from Polygoni Multiflori, reportedly has anti-inflammatory properties. In this study, we investigated the mechanisms of THSG on the Porphyromonas gingivalis-induced inflammatory responses in human gingival fibroblasts and animal modeling of ligature-induced periodontitis. Human gingival fibroblast cells were treated with lipopolysaccharide (LPS) extracted from P. gingivalis in the presence of resveratrol or THSG to analyze the expression of TNF-α, IL-1ß, and IL-6 genes. Increased AMP-activated protein kinase (AMPK) activation and SirT1 expression were induced by THSG. Treatment of THSG decreased the expression of LPS-induced inflammatory cytokines, enhanced AMPK activation, and increased the expression of SirT1. In addition, it suppressed the activation of NF-κB when cells were stimulated with P. gingivalis LPS. The anti-inflammatory effect of THSG and P. Multiflori crude extracts was reproduced in ligature-induced periodontitis animal modeling. In conclusion, THSG inhibited the inflammatory responses of P. gingivalis-stimulated human gingival fibroblasts and ameliorated ligature-induced periodontitis in animal model.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Encía/citología , Glucósidos/farmacología , Glucósidos/uso terapéutico , Periodontitis/tratamiento farmacológico , Polygonaceae/química , Estilbenos/farmacología , Estilbenos/uso terapéutico , Adulto , Animales , Células Cultivadas , Medicamentos Herbarios Chinos/química , Femenino , Fibroblastos/efectos de los fármacos , Encía/efectos de los fármacos , Encía/patología , Glucósidos/química , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Estilbenos/química , Adulto JovenRESUMEN
Chiral spiro-polycyclic oxindoles are valuable heterocyclic ring systems that are widely distributed in natural alkaloids and biologically active compounds. Herein, we reported an asymmetric tandem Michael addition/interrupted Nef reaction of nitromethane with oxindole-derived alkenes catalyzed by a chiral 2-aminobenzimidazole bifunctional organocatalyst. A series of novel enantiomerically enriched spiro-polycyclic oxindole derivatives bearing an oxime group were synthesized in moderate to excellent isolated yields (up to 99%) with an excellent level of enantioselectivities (up to 99% ee). Furthermore, the antiproliferation activity of the resulting oxindoles derivatives were evaluated, and compound 2d demonstrated promising anticancer properties against HCT116 (IC50 = 14.08 µM) and HT29 (IC50 = 15.46 µM) cell lines.