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Escherichia coli K1 is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli K1 meningitis remains unclear. Blood-brain barrier (BBB) penetration is a crucial step in E. coli meningitis development. Here, we uncovered the crucial role of CsiR, a GntR family regulator, in E. coli K1 virulence. During infection, csiR expression was induced due to the derepression by Fur in the blood and human brain microvascular endothelial cells (HBMECs). CsiR positively regulated ilvB expression, which is associated with branched chain amino acid synthesis. Furthermore, we revealed that IlvB activated the FAK/PI3â K pathway of HBMECs to induce actin cytoskeleton rearrangements, thereby promoting the bacterial invasion and penetration of the BBB. Overall, this study reveals a CsiR-mediated virulence regulation pathway in E. coli K1, which may provide a useful target for the prevention or therapy of E. coli meningitis.
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BACKGROUND: Neuroimaging studies have revealed abnormal functional interaction during the processing of emotional faces in patients with major depressive disorder (MDD), thereby enhancing our comprehension of the pathophysiology of MDD. However, it is unclear whether there is abnormal directional interaction among face-processing systems in patients with MDD. METHODS: A group of patients with MDD and a healthy control group underwent a face-matching task during functional magnetic resonance imaging. Dynamic causal modelling (DCM) analysis was used to investigate effective connectivity between 7 regions in the face-processing systems. We used a Parametric Empirical Bayes model to compare effective connectivity between patients with MDD and controls. RESULTS: We included 48 patients and 44 healthy controls in our analyses. Both groups showed higher accuracy and faster reaction time in the shape-matching condition than in the face-matching condition. However, no significant behavioural or brain activation differences were found between the groups. Using DCM, we found that, compared with controls, patients with MDD showed decreased self-connection in the right dorsolateral prefrontal cortex (DLPFC), amygdala, and fusiform face area (FFA) across task conditions; increased intrinsic connectivity from the right amygdala to the bilateral DLPFC, right FFA, and left amygdala, suggesting an increased intrinsic connectivity centred in the amygdala in the right side of the face-processing systems; both increased and decreased positive intrinsic connectivity in the left side of the face-processing systems; and comparable task modulation effect on connectivity. LIMITATIONS: Our study did not include longitudinal neuroimaging data, and there was limited region of interest selection in the DCM analysis. CONCLUSION: Our findings provide evidence for a complex pattern of alterations in the face-processing systems in patients with MDD, potentially involving the right amygdala to a greater extent. The results confirm some previous findings and highlight the crucial role of the regions on both sides of face-processing systems in the pathophysiology of MDD.
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Amígdala del Cerebelo , Trastorno Depresivo Mayor , Reconocimiento Facial , Imagen por Resonancia Magnética , Humanos , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/diagnóstico por imagen , Masculino , Femenino , Adulto , Reconocimiento Facial/fisiología , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Vías Nerviosas/fisiopatología , Vías Nerviosas/diagnóstico por imagen , Teorema de Bayes , Adulto Joven , Mapeo Encefálico , Expresión Facial , Persona de Mediana Edad , Tiempo de Reacción/fisiologíaRESUMEN
Diquat dibromide (DQ) is a globally used herbicide in agriculture, and its overuse poses an important public health issue, including male reproductive toxicity in mammals. However, the effects and molecular mechanisms of DQ on testes are limited. In vivo experiments, mice were intraperitoneally injected with 8 or 10â¯mg/kg/ day of DQ for 28 days. It has been found that heme oxygenase-1 (HO-1) mediates DQ-induced ferroptosis in mouse spermatogonia, thereby damaging testicular development and spermatogenesis. Histopathologically, we found that DQ exposure caused seminiferous tubule disorders, reduced germ cells, and increased sperm malformation, in mice. Reactive oxygen species (ROS) staining of frozen section and transmission electron microscopy (TEM) displayed DQ promoted ROS generation and mitochondrial morphology alterations in mouse testes, suggesting that DQ treatment induced testicular oxidative stress. Subsequent RNA-sequencing further showed that DQ treatment might trigger ferroptosis pathway, attributed to disturbed glutathione metabolism and iron homeostasis in spermatogonia cells in vitro. Consistently, results of western blotting, measurements of MDA and ferrous iron, and ROS staining confirmed that DQ increased oxidative stress and lipid peroxidation, and accelerated ferrous iron accumulation both in vitro and in vivo. Moreover, inhibition of ferroptosis by deferoxamine (DFO) markedly ameliorated DQ-induced cell death and dysfunction. By RNA-sequencing, we found that the expression of HO-1 was significantly upregulated in DQ-treated spermatogonia, while ZnPP (a specific inhibitor of HO-1) blocked spermatogonia ferroptosis by balancing intracellular iron homeostasis. In mice, administration of the ferroptosis inhibitor ferrostatin-1 effectively restored the increase of HO-1 levels in the spermatogonia, prevented spermatogonia death, and alleviated the spermatogenesis disorders induced by DQ. Overall, these findings suggest that HO-1 mediates DQ-induced spermatogonia ferroptosis in mouse testes, and targeting HO-1 may be an effective protective strategy against male reproductive disorders induced by pesticides in agriculture.
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Diquat , Ferroptosis , Hemo-Oxigenasa 1 , Herbicidas , Especies Reactivas de Oxígeno , Espermatogonias , Testículo , Animales , Masculino , Ferroptosis/efectos de los fármacos , Ratones , Espermatogonias/efectos de los fármacos , Espermatogonias/patología , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Testículo/efectos de los fármacos , Testículo/patología , Diquat/toxicidad , Herbicidas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Proteínas de la MembranaRESUMEN
The thermally regenerative electrochemical cycle (TREC) is a reliable and efficient approach to converting low-grade heat into electricity. A high temperature coefficient (α) is the key to maximize the energy conversion efficiency of the TREC system. In this study, we present significant improvement of α of a Prussian blue analogue (PBA)-based electrochemical cell by adding poly(4-styrenesulfonic acid) (PSS) to the electrolyte. Raman spectra showed that water-soluble charged polymers strongly affect the ion hydration structure and increase the entropy change (ΔS) during ion intercalation in PBA. A large α of -2.01 mV K-1 and high absolute heat-to-electricity conversion efficiency up to 1.83% was achieved with a TREC cell in the temperature range 10-40 °C. This study provides a fundamental understanding of the origin of α and a facile method to boosting the temperature coefficient for building a highly efficient low-grade heat harvesting system.
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AIM: To determine the level of knowledge about skin tears among geriatric ward nurses and identify associated factors. METHODS: In this cross-sectional study in Southwest China, 1172 geriatric ward nurses from 10 hospitals participated. Data were collected using Sojump, a Chinese web-based platform, and the Skin Tear Knowledge Assessment Instrument was used to assess their knowledge. The analysis involved descriptive statistics, correlation analysis, and multiple linear regression. RESULTS: The study involved participants with an average age of 36.73 (SD = 6.54) years. More than half of the participants had less than 10 years of experience in geriatric wards. 27 % specialized in wound care, and 68.1 % lacked specific training in skin tear (ST) knowledge. Additionally, 82.7 % of geriatric nurses had never been exposed to guidelines on ST prevention and management. In the geriatric ward, 36.6 % of nurses received training in ST prevention. The average knowledge score about Skin Tears (STs) was 9.52 (SD = 2.39) out of 18. 'Treatment' had the lowest mean score, while 'Specific patient groups' had the highest. The multiple linear regression analysis found that nurses' knowledge of STs was influenced by sex(ß = 0.096, P < 0.001), educational level(ß = 0.062, P < 0.001), participation in ST (ß = -0.193, P < 0.001 and wound care training(ß = -0.120, P = 0.004), and specialization as a wound care nurse(ß = -0.350, P = 0.001). These factors explained 61.3 % of the variance in knowledge about STs among the participants. CONCLUSION: The geriatric ward had limited knowledge of STs. To improve their skills in dealing with STs, managers should provide tailored training to nurses and establish a standardized, evidence-based nursing process.
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Following peripheral nerve injury (PNI), Wallerian degeneration (WD) in the distal stump can generate a microenvironment favorable for nerve regeneration. Brief low-frequency electrical stimulation (ES) is an effective treatment for PNI, but the mechanism underlying its effect on WD remains unclear. Therefore, we hypothesized that ES could enhance nerve regeneration by accelerating WD. To verify this hypothesis, we used a rat model of sciatic nerve transection and provided ES at the distal stump of the injured nerve. The injured nerve was then evaluated after 1, 4, 7, 14 and 21 days post injury (dpi). The results showed that ES significantly promoted the degeneration and clearance of axons and myelin, and the dedifferentiation of Schwann cells. It upregulated the expression of BDNF and NGF and increased the number of monocytes and macrophages. Through transcriptome sequencing, we systematically investigated the effect of ES on the molecular processes involved in WD at 4 dpi. Evaluation of nerves bridged using silicone tubing after transection showed that ES accelerated early axonal and vascular regeneration while delaying gastrocnemius atrophy. These results demonstrate that ES promotes nerve regeneration by accelerating WD and upregulating the expression of neurotrophic factors.
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Traumatismos de los Nervios Periféricos , Neuropatía Ciática , Ratas , Animales , Traumatismos de los Nervios Periféricos/metabolismo , Degeneración Walleriana/terapia , Degeneración Walleriana/patología , Neuropatía Ciática/patología , Nervio Ciático/metabolismo , Células de Schwann/metabolismo , Axones/metabolismo , Regeneración Nerviosa/fisiología , Estimulación EléctricaRESUMEN
BACKGROUND: Podocyte apoptosis is one of the important pathological mechanisms of diabetic kidney disease (DKD). Acteoside (Act), a major active component of Rehmannia glutinosa leaves total glycoside, has a strong renoprotective action. Our study aims to demonstrate Act's renoprotective actions in db/db mice. METHODS: We adopted C57BLKS/J db/db mice as DKD animal models. After 8 weeks of Act administration, the 24-hour urine albumin, renal function index, and blood lipid levels were quantified using matching kits. Renal pathology was evaluated by HE and PAS staining. The podocyte damage and apoptosis-related signaling pathway were observed by using immunohistochemistry, western blot, and TUNEL staining. RESULTS: The albuminuria of db/db mice was reduced from 391 ug/24 h to 152 ug/24 h, and renal pathology changes were alleviated after Act administration. The western blot and immunohistochemistry showed that Act treatment upregulated the synaptopodin and podocin expression compared with db/db mice, while the TUNEL staining indicated podocyte apoptosis was inhibited. The B-cell lymphoma-2 (Bcl-2) level was upregulated in the Act group, but cleaved caspase-3 and Bcl-2 associated X protein (Bax) expression declined, while the protein kinase B/glycogen synthase kinase-3ß (AKT/GSK-3ß) signaling pathway was repressed. CONCLUSIONS: By inhibiting the AKT/GSK-3ß signaling pathway, Act protected podocytes from apoptosis, decreasing the urine albumin of db/db mice and delaying the course of DKD.
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Nefropatías Diabéticas , Podocitos , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Podocitos/metabolismo , Podocitos/patología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Transducción de Señal , Apoptosis , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Nefropatías Diabéticas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Albúminas/metabolismoRESUMEN
The widespread applications of silver nanoparticles (AgNPs) throughout our daily lives have raised concerns regarding their environmental health and safety (EHS). Despite an increasing number of studies focused on the EHS impacts of AgNPs, there remain significant knowledge gaps with respect to their potential health impacts on susceptible populations, such as lactating mothers and infants. Herein, we aimed to investigate the deleterious effects of AgNPs with different sizes (20 and 40 nm) and surface coatings (PVP and BPEI) on maternal mice and their offspring following lactation exposure at doses of 20, 100 and 400 µg/kg body weight. We discovered that AgNPs could accumulate in the maternal mammary glands and disrupt the epithelial barrier in a dose-dependent manner. Notably, BPEI-coated AgNPs caused more damage to the mammary glands than PVP-coated particles. Importantly, we observed that, while AgNPs were distributed throughout the blood and main tissues, they were particularly enriched in the brains of breastfed offspring after maternal exposure during lactation, exhibiting exposure dosage- and particle coating-dependent patterns. Compared to PVP-coated nanoparticles, BPEI-coated AgNPs were more readily transferred to the offspring, possibly due to their enhanced deposition in maternal mammary glands. Moreover, we observed reduced body weight, blood cell toxicity, and tissue injuries in breastfed offspring whose dams received AgNPs. As a whole, these results reveal that maternal exposure to AgNPs results in the translocation of AgNPs into offspring via breastfeeding, inducing developmental impairments in these breastfed offspring. This study provides important new insights into the EHS impacts of AgNP consumption during lactation.
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Lactancia , Nanopartículas del Metal , Femenino , Animales , Ratones , Plata/toxicidad , Nanopartículas del Metal/toxicidad , Tamaño de la Partícula , Peso CorporalRESUMEN
As a fundamental physical parameter, viscosity influences the diffusion in biological processes. The changes in intracellular viscosity led to the occurrence of relevant diseases. Monitoring changes in cellular viscosity is important for distinguishing abnormal cells in cell biology and oncologic pathology. Here, we devised and synthesized a viscosity-sensitive fluorescent probe LBX-1. LBX-1 showed high sensitivity, providing a large Stokes shift as well as an enhancement in fluorescent intensity (16.1-fold) from methanol solution to glycerol solution. Furthermore, the probe LBX-1 could localize in mitochondria because of the ability of the probe to penetrate the cell membrane and accumulate in mitochondria. These results suggested that the probe could be utilized in monitoring the changes in mitochondrial viscosity in complex biological systems.
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Colorantes Fluorescentes , Mitocondrias , Humanos , Colorantes Fluorescentes/metabolismo , Células HeLa , Viscosidad , Mitocondrias/metabolismo , Membrana Celular/metabolismoRESUMEN
Bacterial meningitis is a devastating disease occurring worldwide, with up to half of survivors left with permanent neurological sequelae. Neonatal meningitis-causing Escherichia coli (NMEC) is the most common Gram-negative bacillary organism that causes meningitis, particularly during the neonatal period. Here, RNA-seq transcriptional profiles of microglia in response to NMEC infection show that microglia are activated to produce inflammatory factors. In addition, we found that the secretion of inflammatory factors is a double-edged sword that promotes polymorphonuclear neutrophil (PMN) recruitment to the brain to clear the pathogens but, at the same time, induces neuronal damage, which may be related to the neurological sequelae. New neuroprotective therapeutic strategies must be developed for the treatment of acute bacterial meningitis. We found that transforming growth factor-ß (TGF-ß) may be a strong candidate in the treatment of acute bacterial meningitis, as it shows a therapeutic effect on bacterial-meningitis-induced brain damage. Prevention of disease and early initiation of the appropriate treatment in patients with suspected or proven bacterial meningitis are the key factors in reducing morbidity and mortality. Novel antibiotic and adjuvant treatment strategies must be developed, and the main goal for new therapies will be dampening the inflammatory response. Based on this view, our findings may help develop novel strategies for bacterial meningitis treatment.
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Infecciones por Escherichia coli , Meningitis Bacterianas , Meningitis por Escherichia coli , Recién Nacido , Humanos , Microglía , Meningitis por Escherichia coli/microbiología , Meningitis Bacterianas/microbiología , Infecciones por Escherichia coli/microbiología , Escherichia coliRESUMEN
This research aims to investigate nonionic hyperbranched polyesters (HBPs) derived from indole and lignin resources as new nontoxic antimicrobial coatings. Three nonionic HBPs with zero to two methoxy ether substituents on each benzene ring in the polymer backbones were synthesized by melt-polycondensation of three corresponding AB2 monomers. The molecular structures and thermal properties of the obtained HBPs were characterized by gel permeation chromatography, nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry analyses. These HBPs were conveniently spin-coated on a silicon substrate, which exhibited significant antibacterial effect against Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis). The presence of methoxy substituents enhanced the antimicrobial effect, and the resulting polymers showed negligible leakage in water. Finally, the polymers with the methoxy functionality exhibited excellent biocompatibility according to the results of hemolysis and MTT assay, which may facilitate their biomedical applications.
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Antiinfecciosos , Poliésteres , Aldehídos , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Indoles/farmacología , Lignina/farmacología , Poliésteres/química , Poliésteres/farmacología , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Atherosclerosis (AS) is chronic pathological process based on the inflammatory reaction associated with factors including vascular endothelial dysfunction, inflammation, and autoimmunity. Inflammasomes are known to be at the core of the inflammatory response. As a pattern recognition receptor of innate immunity, the NLRP3 inflammasome mediates the secretion of inflammatory factors by activating the Caspase-1, which is important for maintaining the immune system and regulating the gut microbiome, and participates in the occurrence and development of AS. The intestinal microecology is composed of a large number of complex structures of gut microbiota and its metabolites, which play an important role in AS. The gut microbiota and its metabolites regulate the activation of the NLRP3 inflammasome. Targeting the NLRP3 inflammasome and regulating intestinal microecology represent a new direction for the treatment of AS. This paper systematically reviews the interaction between the NLRP3 inflammasome and gut microbiome in AS, strategies for targeting the NLRP3 inflammasome and gut microbiome for the treatment of AS, and provides new ideas for the research and development of drugs for the treatment of AS.
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Aterosclerosis , Microbioma Gastrointestinal , Microbioma Gastrointestinal/fisiología , Humanos , Inflamasomas , Inflamación/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
BACKGROUND: Helicobacter pylori (H. pylori) infection is the main factor leading to some gastric diseases. Currently, H. pylori infection is primarily treated with antibiotics. However, with the widespread application of antibiotics, H. pylori resistance to antibiotics has also gradually increased year by year. Vaccines may be an alternative solution to clear H. pylori. AIMS: By reviewing the recent progress on H. pylori vaccines, we expected it to lead to more research efforts to accelerate breakthroughs in this field. MATERIALS & METHODS: We searched the research on H. pylori vaccine in recent years through PubMed®, and then classified and summarized these studies. RESULTS: The study of the pathogenic mechanism of H. pylori has led to the development of vaccines using some antigens, such as urease, catalase, and heat shock protein (Hsp). Based on these antigens, whole-cell, subunit, nucleic acid, vector, and H. pylori exosome vaccines have been tested. DISCUSSION: At present, researchers have developed many types of vaccines, such as whole cell vaccines, subunit vaccines, vector vaccines, etc. However, although some of these vaccines induced protective immunity in mouse models, only a few were able to move into human trials. We propose that mRNA vaccine may play an important role in preventing or treating H. pylori infection. The current study shows that we have developed various types of vaccines based on the virulence factors of H. pylori. However, only a few vaccines have entered human clinical trials. In order to improve the efficacy of vaccines, it is necessary to enhance T-cell immunity. CONCLUSION: We should fully understand the pathogenic mechanism of H. pylori and find its core antigen as a vaccine target.
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Infecciones por Helicobacter , Helicobacter pylori , Ratones , Animales , Humanos , Helicobacter pylori/genética , Infecciones por Helicobacter/prevención & control , Vacunas Bacterianas , Ureasa , Antibacterianos , Vacunas de ARNmRESUMEN
To further improve the anti-tumor activity of Harmine (HM), we took the hybridization approach and synthesized harmine derivatives-furoxan hybrids containing nitric oxide (NO) releasing parts by connecting NO donors with anti-tumor active fragments to harmine. Then, the synthesized compounds were evaluated for their in vitro cytotoxicity against five human cancer cell lines. Among them, compound 10 was found to have the strongest antiproliferative activity against HepG2 (IC50 = 1.79 µM). In addition, compound 10 produced high levels of NO in vitro, verifying that the release of NO was closely correlated to the antiproliferative activity. In addition, Compound 10 also showed good plasma stability. Finally, we also preliminarily investigated the acute toxicity of compound 10 in mice and assessed the absorption of compound 10 by Caco-2 cell permeability assay. In brief, the remarkable biological characteristics of the new harmine derivatives-furoxan hybrids may make them promising candidates for human cancer intervention.
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Antineoplásicos , Harmina , Animales , Antineoplásicos/farmacología , Apoptosis , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Harmina/farmacología , Humanos , Ratones , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Relación Estructura-ActividadRESUMEN
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) are global epidemic public health problems with pathogenesis incompletely understood. Hepatocyte excessive apoptosis is a significant symbol for NAFLD/NASH patients, and therefore anti-apoptosis therapy could be used for NAFLD/NASH treatment. Up-regulation of BCL-2 has been found to be closely related with anti-apoptosis. BCL-2 gene promoter region has a C-rich sequence, which can form i-motif structure and play important role in regulating gene transcription. In this study, after extensive screening and evaluation, we found that acridone derivative A22 could up-regulate BCL-2 transcription and translation in vitro and in cells through selective binding to and stabilizing BCL-2 gene promoter i-motif. Our further experiments showed that A22 could reduce hepatocyte apoptosis in NAFLD/NASH model possibly through up-regulating BCL-2 expression. A22 could reduce inflammation, endoplasmic reticulum stress and cirrhosis in high-fat diet-fed mice liver model. Our findings provide a potentially new approach of anti-apoptosis for NAFLD/NASH treatment, and A22 could be further developed as a lead compound for NAFLD/NASH therapy. Our present study first demonstrated that gene promoter i-motif could be targeted for gene up-regulation for extended treatment of other important diseases besides cancer.
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Acridonas/uso terapéutico , Genes bcl-2 , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Regulación hacia Arriba/efectos de los fármacos , Animales , Apoptosis , Línea Celular Tumoral , Dieta Alta en Grasa , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/patología , Regiones Promotoras Genéticas/efectos de los fármacosRESUMEN
A substantial fraction of transcripts are known as long noncoding RNAs (lncRNAs), and these transcripts play pivotal roles in the development of cancer. However, little information has been published regarding the functions of lncRNAs in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. In our previous studies, we demonstrated that small nucleolar RNA host gene 5 (SNHG5), a known lncRNA, is dysregulated in gastric cancer (GC). In this study, we explored the expression and function of SNHG5 in development of ESCC. SNHG5 was found to be downregulated in human ESCC tissues and cell lines, and this downregulation was associated with cancer progression, clinical outcomes and survival rates of ESCC patients. Furthermore, we also found that overexpression of SNHG5 significantly inhibited the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Notably, we found that metastasis-associated protein 2 (MTA2) was pulled down by SNHG5 in ESCC cells using RNA pulldown assay. We also found that SNHG5 reversed the epithelial-mesenchymal transition by interacting with MTA2. In addition, overexpression of SNHG5 downregulated the transcription of MTA2 and caused its ubiquitin-mediated degradation. Thus, overexpression of MTA2 partially abrogated the effect of SNHG5 in ESCC cell lines. Furthermore, we found that MTA2 mRNA expression was significantly elevated in ESCC specimens, and a negative correlation between SNHG5 and MTA2 expression was detected. Overall, this study demonstrated, for the first time, that SNHG5-regulated MTA2 functions as an important player in the progression of ESCC and provide a new potential therapeutic strategy for ESCC.
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Transición Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Histona Desacetilasas/metabolismo , ARN Largo no Codificante/metabolismo , Proteínas Represoras/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Conjuntos de Datos como Asunto , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Esófago/patología , Esófago/cirugía , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Persona de Mediana Edad , Invasividad Neoplásica/genética , Proteolisis , RNA-Seq , Ubiquitina/metabolismo , Ubiquitinación/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Metastasis-associated protein 2 (MTA2) is frequently amplified in many types of cancers; however, the role and underlying molecular mechanism of MTA2 in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we reported that MTA2 is highly expressed in ESCC tissue and cells, and is closely related to the malignant characteristics and poor prognosis of patients with ESCC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promoted ESCC growth, metastasis, and epithelial-mesenchymal transition (EMT) progression. This integrative analysis combined with expression microarray showed that MTA2 could interact with eukaryotic initiation factor 4E (EIF4E), which positively regulates the expression of Twist, known as a master regulator of EMT. Moreover, the results of chromatin immunoprecipitation revealed that MTA2 was recruited to the E-cadherin promoter by Twist, which reduced the acetylation level of the promoter region and thus inhibited expression of E-cadherin, and subsequently promoted the aggressive progression of ESCC. Collectively, our study provided novel evidence that MTA2 plays an aggressive role in ESCC metastasis by a novel EIF4E-Twist positive feedback loop, which may provide a potential therapeutic target for the management of ESCC.
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Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Histona Desacetilasas/metabolismo , Proteínas Nucleares/genética , Proteínas Represoras/metabolismo , Proteína 1 Relacionada con Twist/genética , Animales , Antígenos CD/genética , Cadherinas/genética , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/secundario , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Esófago/patología , Esófago/cirugía , Factor 4E Eucariótico de Iniciación/genética , Retroalimentación Fisiológica , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histona Desacetilasas/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteína 1 Relacionada con Twist/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Most macromolecular antimicrobials are ionic and thus lack miscibility/compatibility with nonionic substrate materials. In this context, nonionic hyperbranched polyesters (HBPs) with indole or isatin functionality were rationally designed, synthesized, and characterized. Antimicrobial disk diffusion assay indicated that these HBPs showed significant antibacterial activity against 8 human pathogenic bacteria compared to small molecules with indole or isatin groups. According to DSC measurements, up to 20% indole-based HBP is miscible with biodegradable polyesters (polyhydroxybutyrate or polycaprolactone), which can be attributed to the favorable hydrogen bonding between the N-H moiety of indole and the CâO of polyesters. HBPs with isatin or methylindole were completely immiscible with the same matrices. None of the HBPs leaked out from plastic matrix after being immersed in water for 5 days. The incorporation of indole into HBPs as well as small molecules facilitated their enzymatic degradation with PETase from Ideonella sakaiensis, while isatin had a complex impact. Molecular docking simulations of monomeric molecules with PETase revealed different orientations of the molecules at the active site due to the presence of indole or isatin groups, which could be related to the observed different enzymatic degradation behavior. Finally, biocompatibility analysis with a mammalian cell line showed the negligible cytotoxic effect of the fabricated HBPs.
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Isatina , Animales , Antibacterianos , Burkholderiales , Humanos , Indoles , Isatina/farmacología , Simulación del Acoplamiento Molecular , Poliésteres , PolímerosRESUMEN
BACKGROUND: Helicobacter pylori-associated gastritis (HPAG) is a common digestive system disease that its therapeutic goal is to eradicate Helicobacter pylori. However, due to the widespread use of antibiotics, problems for example, antibiotic resistance, reinfection, and gastrointestinal side effects have emerged. The solution of above problems provides a broad space for traditional Chinese medicine (TCM) to exert its remarkable advantages on the treatment of HPAG. METHODS: Extensive database retrieval using platforms not limited to but including Web of Science, SpringerLink, ScienceDirect, Google Scholar, China National Knowledge Infrastructure, Wanfang, and VIP database was performed using keywords such as "Helicobacter pylori-associated gastritis" or "HPAG" or "Helicobacter pylori" or "H. pylori" or "gastritis" and "traditional Chinese medicine" or "TCM" or "herbs" or "Chinese herbal medicine". In addition, related books, PhD, and master's dissertations were also researched to provide a comprehensive review. RESULTS: This review mainly introduces the clinical efficacy of TCM formulas for HPAG, as well as active ingredient and pharmacological mechanisms of herbs. What's more, this review puts forward potential prospects for future research. CONCLUSION: These research works have shown the therapeutic benefits of TCM in the treatment of HPAG. The development of TCM with more specific functions and practical data will not only become a significant trend in the world market but also have an irreplaceable role in the future treatment of HPAG. More continued researches should be undertaken in the future.
Asunto(s)
Medicamentos Herbarios Chinos , Gastritis , Infecciones por Helicobacter , Medicina Tradicional China , China , Medicamentos Herbarios Chinos/uso terapéutico , Gastritis/tratamiento farmacológico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , HumanosRESUMEN
Telomere is a specialized DNA-protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different proteins, with telomeric repeat factors 1 (TRF1) and 2 (TRF2) binding to double-strand telomeric DNA. Telomeric DNA consists of complementary G-rich and C-rich repeats, which could form G-quadruplex and intercalated motif (i-motif), respectively, during cell cycle. Its G-rich transcription product, telomeric repeat-containing RNA (TERRA), is essential for telomere stability and heterochromatin formation. After extensive screening, we found that acridine derivative 2c and acridine dimer DI26 could selectively interact with TRF1 and telomeric i-motif, respectively. Compound 2c blocked the binding of TRF1 with telomeric duplex DNA, resulting in up-regulation of TERRA. Accumulated TERRA could bind with TRF1 at its allosteric site and further destabilize its binding with telomeric DNA. In contrast, DI26 could destabilize telomeric i-motif, resulting in down-regulation of TERRA. Both compounds exhibited anti-tumour activity for A549 cells, but induced different DNA damage pathways. Compound 2c significantly suppressed tumour growth in A549 xenograft mouse model. The function of telomeric i-motif structure was first studied with a selective binding ligand, which could play an important role in regulating TERRA transcription. Our results showed that appropriate level of TERRA transcript could be important for stability of telomere, and acridine derivatives could be further developed as anti-cancer agents targeting telomere. This research increased understanding for biological roles of telomeric i-motif, TRF1 and TERRA, as potential anti-cancer drug targets.