RESUMEN
BACKGROUND: Owing to the widespread use of chemical pesticides to control agricultural pests, pesticide tolerance has become a serious problem. In recent years, it has been found that symbiotic bacteria are related to pesticides tolerance. To investigate the potential role of microorganisms in the pesticide tolerance of Chilo suppressalis, this study was conducted. RESULTS: The insect was fed with tetracycline and cefixime as the treatment group (TET and CFM, respectively), and did not add antibiotics in the control groups (CK). The 16S rDNA sequencing results showed that antibiotics reduced the diversity of C. suppressalis symbiotic microorganisms but did not affect their growth and development. In bioassays of the three C. suppressalis groups (TET, CFM, and CK), a 72 h LC50 fitting curve was calculated to determine whether long-term antibiotic feeding leads to a decrease in pesticide resistance. The CK group of C. suppressalis was used to determine the direct effect of antibiotics on pesticide tolerance using a mixture of antibiotics and pesticides. Indirect evidence suggests that antibiotics themselves did not affect the pesticide tolerance of C. suppressalis. The results confirmed that feeding C. suppressalis cefixime led to a decrease in the expression of potential tolerance genes to chlorantraniliprole. CONCLUSIONS: This study reveals the impact of antibiotic induced changes in symbiotic microorganisms on the pesticide tolerance of C. suppressalis, laying the foundation for studying the interaction between C. suppressalis and microorganisms, and also providing new ideas for the prevention and control of C. suppressalis and the creation of new pesticides.
Asunto(s)
Antibacterianos , Bacterias , Antibacterianos/farmacología , Animales , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Plaguicidas/farmacología , Mariposas Nocturnas/microbiología , Mariposas Nocturnas/efectos de los fármacos , Simbiosis , ARN Ribosómico 16S/genética , Microbiota/efectos de los fármacos , Tetraciclina/farmacologíaRESUMEN
Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.
Asunto(s)
Linfocitos T CD8-positivos , Células Asesinas Naturales , Neoplasias Pulmonares , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Células Asesinas Naturales/inmunología , Microambiente Tumoral/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Linfocitos T CD8-positivos/inmunología , Ratones , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Linfocitos Infiltrantes de Tumor/inmunología , Fenotipo , Receptor de Muerte Celular Programada 1 , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
OBJECTIVE: This study explored the relationship between the activation of the jak/stat3 signaling pathway and the CSN5 gene transcript and protein expression levels in the hematopoietic stem cells of patients with myelodysplastic syndromes (MDSs). This study also aimed to investigate the correlation between the expression level of CSN5 and the deubiquitination of HSF1, as well as the transcript level of the spi1/pu.1 genes to explore the pathogenesis of MDS. MATERIALS AND METHODS: We isolated cells from normal individuals and MDS patients, and the mRNA and protein expression levels of spi1/pu.1 in cd34+ cells (hematopoietic stem cells) were measured by PCR and western blotting, respectively. A ChIP assay was used to detect the binding of HSF1 to the spi1/pu.1 promoter in cd34+ cells. The ubiquitination of HSF1 in cd34+ cells was detected by CO-IP. The binding of HSF1 and Fbxw7α was detected in in cd34+ cells by CO-IP. The binding of HSF1 and CSN5 was evaluated. A luciferase reporter assay was used to detect the effect of STAT3 on CSN5 promoter activation in cd34+ cells. Western blotting was used to detect the phosphorylation of STAT3 in cd34+ cells of MDS patients. The binding of STAT3 and C/EBP beta in cd34+ cells was detected by CO-IP. RESULTS: Inhibition of SPI1/PU.1 expression was observed in MDS samples with low proliferation ability. Further experiments proved that phosphorylation of STAT3 affected CSN5 function and mediated the ubiquitination of HSF, the upstream regulator of SPI1/PU.1 transcription, which led to the inhibition of SPI1/PU.1 expression. Restoration of CSN5 rescued the inhibition of HSF1 ubiquitination, causing SPI1/PU.1 transcription to resume and increasing SPI1/PU.1 expression, promoting the recovery of cell proliferation in hypocellular MDS. CONCLUSIONS: Our research revealed the regulatory role of the CSN5/HSF/SPI1/PU.1 axis in hypocellular MDS, providing a probable target for clinical intervention.
RESUMEN
Seafood consumption provides essential elements to humans while also posing risks to human health. A total of 2610 individuals of five edible marine bivalve species (Ruditapes philippinarum, Paphia undulata, Meretrix meretrix, Sinonovacula constricta and Meretrix lyrata) were randomly sampled from six farmer markets in three cities (Beihai, Qinzhou and Fangchenggang) in the southernmost coastal region of China. The concentrations of heavy metals (Cu, Pb, Zn, Cd, Cr, Hg and As) were determined by inductively coupled plasma mass spectrometry (ICP-MS). The estimated daily intake (EDI), target hazard quotient (THQ), total hazard index (HI), and target cancer risk (TR) were calculated to evaluate potential human health risks from bivalve consumption. The mean concentrations of metals in the tissues of bivalves descended in the order Zn > Cu > As > Cd > Cr >Pb > Hg in descending order, and the concentrations varied substantially among the five bivalves. Heavy metal concentrations in edible tissues of most bivalve samples were below the safety limits set by national and international regulations, and there were significant correlations between certain metal concentrations. The EDI values for each metal in each bivalve were significantly lower than the corresponding PTDI (provisional tolerable daily intake) values. Health risk assessment showed that although there is no noncarcinogenic health risk for local residents exposed to individual or combined metals from these bivalves, there is a carcinogenic risk from Cd and Cr exposure. Thus, in the long term, monitoring and controlling bivalve consumption will be important. Although current accumulation levels of bivalves are safe, continued and excessive lifetime consumption over 70 years may pose a target cancer risk.
Asunto(s)
Bivalvos , Metales Pesados , Animales , China , Ciudades , Monitoreo del Ambiente , Contaminación de Alimentos/análisis , Humanos , Metales Pesados/análisis , Metales Pesados/toxicidad , Medición de RiesgoRESUMEN
BACKGROUND/AIMS: Platelet microvesicles (PMVs) contribute to angiogenesis and vasculogenesis, but the mechanisms underlying these contributions have not been fully elucidated. In the present study, we investigated whether PMVs regulate the angiogenic properties of endothelial cells (ECs) via mechanisms extending beyond the transport of angiogenic regulators from platelets. METHODS: In vitro Matrigel tube formation assay and in vivo Matrigel plug assay were used to evaluate the pro-angiogenic activity of PMVs. The effects of PMVs on the migration of human umbilical vein endothelial cells (HUVECs) were detected by transwell assay and wound-healing assay. Real-time PCR and western blot were conducted to examine mRNA and protein expression of pro-angiogenic factors in HUVECs. Matrix metalloproteinase (MMP) activity was assayed by gelatin zymography. Moreover, the effects of specific MMP inhibitors were tested. RESULTS: PMVs promoted HUVEC capillary-like network formation in a dose-dependent manner. Meanwhile, PMVs dose-dependently facilitated HUVEC migration. Levels of MMP-2 and MMP-9 expression and activity were up-regulated in HUVECs stimulated with PMVs. Inhibition of MMPs decreased their pro-angiogenic and pro-migratory effects on HUVECs. Moreover, we confirmed the pro-angiogenic activity of PMVs in vivo in mice with subcutaneous implantation of Matrigel, and demonstrated that blockade of MMPs attenuated PMV-induced angiogenesis. CONCLUSION: The findings of our study indicate that PMVs promote angiogenesis by up-regulating MMP expression in ECs via mechanism extending beyond the direct delivery of angiogenic factors.
Asunto(s)
Células Endoteliales de la Vena Umbilical Humana/enzimología , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Fisiológica/fisiología , Regulación hacia Arriba/fisiología , Inhibidores de la Angiogénesis/farmacología , Plaquetas/metabolismo , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Dipéptidos/farmacología , Humanos , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 9 de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Nickel compounds are well-established human carcinogens with weak mutagenic activity. Histone methylation has been proposed to play an important role in nickel-induced carcinogenesis. Nicotinamide N-methyltransferase (NNMT) decreases histone methylation in several cancer cells by altering the cellular ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). However, the role of NNMT in nickel-induced histone methylation remains unclear. METHODS: BEAS-2B cells were exposed to different concentrations of nickel chloride (NiCl2) for 72 h or 200 µM NiCl2 for different time periods. Histone H3 on lysine 9 (H3K9) mono-, di-, and trimethylation and NNMT protein levels were measured by western blot analysis. Expressions of NNMT mRNA and the H3k9me2-associated genes, mitogen-activated protein kinase 3 (MAP2K3) and dickkopf1 (DKK1), were determined by qPCR analysis. The cellular ratio of nicotinamide adenine dinucleotide (NAD+) to reduced NAD (NADH) and SAM/SAH ratio were determined. RESULTS: Exposure of BEAS-2B cells to nickel increased H3K9 dimethylation (H3K9me2), suppressed the expressions of H3K9me2-associated genes (MAP2K3 and DKK1), and induced NNMT repression at both the protein and mRNA levels. Furthermore, over-expression of NNMT inhibited nickel-induced H3K9me2 and altered the cellular SAM/SAH ratio. Additionally, the NADH oxidant phenazine methosulfate (PMS) not only reversed the nickel-induced reduction in NAD+/NADH but also inhibited the increase in H3K9me2. CONCLUSIONS: These findings indicate that the repression of NNMT may underlie nickel-induced H3K9 dimethylation by altering the cellular SAM/SAH ratio.
Asunto(s)
Histonas/metabolismo , Níquel/farmacología , Nicotinamida N-Metiltransferasa/metabolismo , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Línea Celular , Histonas/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , MAP Quinasa Quinasa 3/genética , MAP Quinasa Quinasa 3/metabolismo , Metilación/efectos de los fármacos , Nicotinamida N-Metiltransferasa/genéticaRESUMEN
BACKGROUND: Both cadmium (Cd) and bisphenol A (BPA) are commonly encountered in humans' daily activities, but their combined genotoxic effects remain unclear. METHODS: In the present study, we exposed a mouse embryonic fibroblast cell line (NIH3T3) to Cd for 24 h, followed by a 24 h BPA exposure to evaluate toxicity. The cytotoxicity was evaluated by viability with CCK-8 assay and lactate dehydrogenase (LDH) release. Reactive oxygen species (ROS) production was measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA). And DNA damage was measured by 8-hydroxydeoxyguanosine (8-OHdG), phosphorylated H2AX (γH2AX) and the comet assay. The flow cytometry was used to detect cell cycle distribution, and apoptosis was determined by TUNEL assay and western blot against poly-ADP-ribose polymerase (PARP). RESULTS: The results showed that Cd or BPA treatments alone (with the exception of BPA exposure at 50 µM) did not alter cell viability. However, pre-treatment with Cd aggravated the BPA-induced reduction in cell viability; increased BPA-induced LDH release, ROS production, DNA damage and G2 phase arrest; and elevated BPA-induced TUNEL-positive cells and the expression levels of cleaved PARP. Cd exposure concurrently decreased the expression of 8-oxoguanine-DNA glycosylase-1 (OGG1), whereas OGG1 over-expression abolished the enhancement of Cd on BPA-induced genotoxicity and cytotoxicity. CONCLUSION: These findings indicate that Cd exposure aggravates BPA-induced genotoxicity and cytotoxicity through OGG1 inhibition.
Asunto(s)
Contaminantes Ocupacionales del Aire/farmacología , Compuestos de Bencidrilo/farmacología , Cloruro de Cadmio/farmacología , Daño del ADN , ADN Glicosilasas/antagonistas & inhibidores , Estrógenos no Esteroides/farmacología , Fenoles/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , ADN Glicosilasas/genética , ADN Glicosilasas/metabolismo , Combinación de Medicamentos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación de la Expresión Génica , Histonas/genética , Histonas/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Ratones , Células 3T3 NIH , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Cadmium is a widespread environmental and occupational pollutant that accumulates in human body with a biological half-life exceeding 10 years. Cadmium exposure has been demonstrated to increase rates of cardiovascular diseases. Whether occupational cadmium exposure is associated with the increase in the prevalence of dyslipidemia and hence contributes to the risk of cardiovascular diseases is still equivocal. To test the hypothesis that exposure to cadmium is related to the prevalence of dyslipidemia, we examined the associations between blood cadmium concentration and the prevalence of dyslipidemia in workers occupationally exposed to cadmium in China. METHODS: A cross-sectional survey on demographic data, blood cadmium level and lipid profile in cadmium exposed workers from seven cadmium smelting factories in central and southwestern China was conducted. We measured blood cadmium concentration and lipid components of 1489 cadmium exposed workers. The prevalence of dyslipidemia was compared across blood cadmium quartiles. Associations between the blood cadmium concentrations and the prevalence of dyslipidemia were assessed using confounder adjusted linear and logistic regressions. RESULTS: The blood cadmium concentration was 3.61±0.84µg/L ( mean ±SD). The prevalence of dyslipidemia in this occupational population was 66.3%. Mean blood cadmium concentration of workers with dyslipedemia was significantly higher than that of workers without dyslipidemia (p <0.01). The prevalence of dyslipidemia increased dose-dependently with elevations in blood cadmium concentrations (p for trend <0.001). Elevated levels of blood cadmium were associated with BMI, education attainment, income, smoking status and duration of exposure (all p <0.01). Furthermore, the profile of blood lipid was obviously changed in this occupational population. The prevalence of high TC, high TG, Low HDL-C and high LDL-C rose with increases in blood cadmium levels dose-dependently (p for trend <0.001). The odds ratios (95% confidence interval) for dyslipidemia across the increasing blood cadmium quartiles were 1.21(1.16-1.55), 1.56(1.11-1.87), 1.79(1.26-2.25) respectively (referencing to 1.00; p for trend <0.001), after multivariate adjustment for BMI, education attainment, income, lifestyle factors and duration of exposure, the association between blood cadmium concentrations and the prevalence of dyslipidemia remained unchanged (all p for trend <0.001). CONCLUSION: Elevated blood cadmium concentration is associated with prevalence of dyslipidemia. Cadmium exposure could alter lipid metabolism in humans. It is imperative to control cadmium exposure of occupational population in cadmium related industries and reduce adverse health effects.
Asunto(s)
Cadmio/sangre , Dislipidemias/sangre , Dislipidemias/epidemiología , Exposición Profesional/estadística & datos numéricos , Adulto , Femenino , Humanos , Lípidos/sangre , Masculino , Análisis Multivariante , Oportunidad Relativa , PrevalenciaRESUMEN
With application of nano-sized nickel-containing particles (Nano-Ni) expanding, the health concerns about their adverse effects on the pulmonary system are increasing. However, the mechanisms for the pulmonary toxicity of these materials remain unclear. In the present study, we focused on the impacts of NiO nanoparticles (NiONPs) on sirtuin1 (SIRT1), a NAD-dependent deacetylase, and investigated whether SIRT1 was involved in NiONPs-induced apoptosis. Although the NiONPs tended to agglomerate in fluid medium, they still entered into the human bronchial epithelial cells (BEAS-2B) and released Ni(2+) inside the cells. NiONPs at doses of 5, 10, and 20µg/cm(2) inhibited the cell viability. NiONPs' produced cytotoxicity was demonstrated through an apoptotic process, indicated by increased numbers of Annexin V positive cells and caspase-3 activation. The expression of SIRT1 was markedly down-regulated by the NiONPs, accompanied by the hyperacetylation of p53 (tumor protein 53) and overexpression of Bax (Bcl-2-associated X protein). However, overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs-induced apoptosis and activation of p53 and Bax. Our results suggest that the repression of SIRT1 may underlie the NiONPs-induced apoptosis via p53 hyperacetylation and subsequent Bax activation. Because SIRT1 participates in multiple biologic processes by deacetylation of dozens of substrates, this knowledge of the impact of NiONPs on SIRT1 may lead to an improved understanding of the toxic mechanisms of Nano-Ni and provide a molecular target to antagonize Nano-Ni toxicity.
Asunto(s)
Apoptosis/efectos de los fármacos , Bronquios/metabolismo , Células Epiteliales/metabolismo , Nanopartículas/toxicidad , Níquel/toxicidad , Sirtuina 1/antagonistas & inhibidores , Bronquios/citología , Bronquios/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Humanos , Nanopartículas/metabolismo , Níquel/metabolismo , Sirtuina 1/genéticaRESUMEN
BACKGROUND: Insufficient clearance by microglial cells, prevalent in several neurological conditions and diseases, is intricately intertwined with MFG-E8 expression and inflammatory responses. Electromagnetic field (EMF) exposure can elicit the pro-inflammatory activation and may also trigger an alteration of the clearance function in microglial cells. Curcumin has important roles in the anti-inflammatory and phagocytic process. Here, we evaluated the ability of curcumin to ameliorate the phagocytic ability of EMF-exposed microglial cells (N9 cells) and documented relative pathways. METHODS: N9 cells were pretreated with or without recombinant murine MFG-E8 (rmMFG-E8), curcumin and an antibody of toll-like receptor 4 (anti-TLR4), and subsequently treated with EMF or a sham exposure. Their phagocytic ability was evaluated using phosphatidylserine-containing fluorescent bioparticles. The pro-inflammatory activation of microglia was assessed via CD11b immunoreactivity and the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and nitric oxide (NO) via the enzyme-linked immunosorbent assay or the Griess test. We evaluated the ability of curcumin to ameliorate the phagocytic ability of EMF-exposed N9 cells, including checking the expression of MFG-E8, αvß3 integrin, TLR4, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) using Western blotting. RESULTS: EMF exposure dramatically enhanced the expression of CD11b and depressed the phagocytic ability of N9 cells. rmMFG-E8 could clearly ameliorate the phagocytic ability of N9 cells after EMF exposure. We also found that EMF exposure significantly increased the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) and the production of NO; however, these increases were efficiently chilled by the addition of curcumin to the culture medium. This reduction led to the amelioration of the phagocytic ability of EMF-exposed N9 cells. Western blot analysis revealed that curcumin and naloxone restored the expression of MFG-E8 but had no effect on TLR4 and cytosolic STAT3. Moreover, curcumin significantly reduced the expression of NF-κB p65 in nuclei and phospho-STAT3 (p-STAT3) in cytosols and nuclei. CONCLUSIONS: This study indicates that curcumin ameliorates the depressed MFG-E8 expression and the attenuated phagocytic ability of EMF-exposed N9 cells, which is attributable to the inhibition of the pro-inflammatory response through the NF-κB and STAT3 pathways.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Curcumina/farmacología , Campos Electromagnéticos/efectos adversos , Inflamación/etiología , Microglía , Fagocitos/fisiología , Animales , Antígeno CD11b/metabolismo , Línea Celular Transformada , Citocinas/metabolismo , Relación Dosis-Respuesta en la Radiación , Regulación hacia Abajo/efectos de los fármacos , Citometría de Flujo , Ratones , Microglía/efectos de los fármacos , Microglía/patología , Microglía/efectos de la radiación , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Fagocitos/efectos de los fármacos , Fagocitosis , Factor de Transcripción STAT3/metabolismo , Factores de TiempoRESUMEN
OBJECTIVES: This study aimed to investigate the protective effect of rutin against trimethyltin-induced spatial learning and memory impairment in mice. This study focused on the role of synaptophysin, growth-associated protein 43 and the action of the dopaminergic system in mechanisms associated with rutin protection and trimethyltin-induced spatial learning and memory impairment. METHODS: Cognitive learning and memory was measured by Morris Water Maze. The expression of synaptophysin and growth-associated protein 43 in hippocampus was analyzed by western blot. The concentrations of dopamine, homovanillic acid, and dihyroxyphenylacetic acid in hippocampus were detected using reversed phase high-performance liquid chromatography with electrochemical detection. RESULTS: Trimethyltin-induced spatial learning impairment showed a dose-dependent mode. Synaptophysin but not growth-associated protein 43 was decreased in the hippocampus after trimethyltin administration. The concentration of dopamine decreased, while homovanillic acid increased in the hippocampus after trimethyltin administration. Mice pretreated with 20 mg/kg of rutin for 7 consecutive days exhibited improved water maze performance. Moreover, rutin pretreatment reversed the decrease of synaptophysin expression and dopamine alteration. DISCUSSION: These results suggest that rutin may protect against spatial memory impairment induced by trimethyltin. Synaptophysin and the dopaminergic system may be involved in trimethyltin-induced neuronal damage in hippocampus.
Asunto(s)
Dopamina/metabolismo , Hipocampo/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Rutina/farmacología , Sinaptofisina/metabolismo , Animales , Proteína GAP-43/genética , Proteína GAP-43/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Ratones , Ratones Endogámicos BALB C , Sustancias Protectoras/farmacología , Sinaptofisina/genética , Compuestos de Trimetilestaño/toxicidadRESUMEN
Pancreatic cancer usually has a poor prognosis, and no gene therapy has yet been developed that is effective to treat it. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting pancreatic cancer. First, we successfully extracted MSCs from SD rats. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF) which comprising the N-terminal and the subsequent four kringle domains of HGF, by an adenoviral vector. Then, we confirmed that rat MSCs preferentially migrate to pancreatic cancer cells. Last, MSCs expressing NK4 (NK4-MSCs) strongly inhibited proliferation and migration of the pancreatic cancer cell line SW1990 after co-culture. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting pancreatic cancer.
Asunto(s)
Movimiento Celular , Proliferación Celular , Factor de Crecimiento de Hepatocito/metabolismo , Células Madre Mesenquimatosas/metabolismo , Adenoviridae/genética , Animales , Apoptosis , Western Blotting , Línea Celular Tumoral , Células Cultivadas , Técnicas de Cocultivo , Expresión Génica , Vectores Genéticos/genética , Células HEK293 , Factor de Crecimiento de Hepatocito/genética , Humanos , Neoplasias Pancreáticas/patología , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción GenéticaRESUMEN
Bisphenol A (BPA) is a well-known endocrine-disrupting chemical (EDC) that has received particular attention because of its widespread distribution in humans. Due to its chemical similarity to diethylstilbestrol, which is carcinogenic to mammals, the possible genotoxicity of BPA has already largely been evaluated. However, the results are still inconclusive and controversial. To investigate the genotoxic effects of BPA in rat germ cells and the potential protective action of melatonin against these effects, adult male Sprague-Dawley rats were orally administered BPA at a dose of 200mg/kg body weight per day for ten consecutive days with or without melatonin pretreatment. The thiobarbituric acid reactive substances (TBARS) level and superoxide dismutase (SOD) activity in the testes were evaluated. Subsequently, their spermatocytes were isolated, and DNA damage was assessed using an alkaline comet assay and the meiotic spread method. BPA administration did not significantly affect the weights of rats and their reproductive organs, and no alteration in sperm count was found. However, we demonstrated that BPA administration induced a significant increase in TBARS levels and a decrease in SOD activity that were concomitant with an increase in DNA migration within male germ cells and γH2AX foci formation on the autosomes of pachytene spermatocytes. Furthermore, a decrease in the proportion of 4C-cells was observed. These BPA effects were significantly alleviated by melatonin pretreatment. Nevertheless, the genotoxic effects of BPA were not accompanied by apoptosis in germ cells and morphological changes in the testes. These results indicate that BPA exposure may induce DNA damage accumulation in germ cells via oxidative stress. Moreover, melatonin may be a promising pharmacological candidate for preventing the potential genotoxicity of BPA following occupational or environmental exposure.
Asunto(s)
Antioxidantes/farmacología , Compuestos de Bencidrilo/toxicidad , Daño del ADN/efectos de los fármacos , Melatonina/farmacología , Mutágenos/toxicidad , Fenoles/toxicidad , Espermatozoides/efectos de los fármacos , Animales , Compuestos de Bencidrilo/antagonistas & inhibidores , Masculino , Estrés Oxidativo , Fenoles/antagonistas & inhibidores , Ratas , Ratas Sprague-DawleyRESUMEN
Objective: To compare the diagnostic value of cytobrush, ERCP-guided biopsy, SpyGlass direct visual impression and SpyGlass-guided biospy (SpyBite) in the differential diagnosis of benign and malignant bile duct strictures. Methods: The data of 1,008 patients who were clinically diagnosed with indeterminate biliary strictures and underwent ERCP-guided biopsy, cytobrush, SpyGlass direct visual impression or SpyBite at the First Affiliated Hospital of Nanchang University between January 2010 and December 2019 were collected and analyzed retrospectively. The final diagnose was determined by surgical pathological specimen or follow-up (Malignant stricture can be identified if the stricture showed malignant progression during one year of follow-up). The differential diagnostic value of the above endoscopic diagnostic methods was evaluated by means of sensitivity, specificity, accuracy, positive predictive value, negative predictive value, etc. and safety was evaluated by the incidence rate of adverse events. Results: In terms of sensitivity, standard biopsy group (48.6%) and SpyBite group (61.5%) were significantly higher than cytobrush group (32.0%), and visual impression group (100%) was significantly higher than any other group. As far as specificity was concerned, cytobrush group (99.0%), standard biopsy group (99.3%) and the SpyBite group (100%) were significantly higher than visual impression (55.6%), but there was no statistical difference among the three groups above. As far as accuracy was concerned, standard biopsy group (65.3%), and SpyBite group (80.0%) were significantly higher than cytobrush group (44.4%), and SpyBite group (80.0%) was significantly higher than visual impression group (54.8%). In terms of safety, visual impression group and SpyBite group were significantly higher than cytobrush group and standard biopsy group in post-ERCP cholangitis. Conclusion: SpyBite combined with SpyGlass-guided visual impression was better for differential diagnosis of benign and malignant bile duct strictures in terms of sensitivity and accuracy compared with conventional endoscopic diagnostic methods such as cytobrush and standard biopsy. Furthmore, the incidence rates of adverse events after SpyGlass examination was similar to those after conventional endoscopic diagnostic methods except for higher cholangitis, which could be controlled by antibiotics and might be avoided by adequate biliary drainage.
RESUMEN
The utility of graft-versus-host disease (GVHD) prophylaxis with cyclosporine (CSA), methotrexate (MTX), and antihuman thymocyte globulin (ATG) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) exists in the literature; however, up to now, it has not yet been fully described. This study was to observe the influence of adding ATG on GVHD prophylaxis and the quality of life (QoL) of 96 hemopathic patients after allo-HSCT. We retrospectively analyzed the outcomes of 96 consecutive patients undergoing allo-HSCT, including 54 patients who received ATG regimen without in vitro T cell depletion (TCD) (ATG group) and 42 patients who received neither ATG regimen nor TCD (control group). All patients were followed up, and the factors, including age, sex, HLA and ABO compatibility, related and unrelated donors, and disease status, were undertaken to analysis. All patients in the study achieved trilineage engraftment with full-donor chimerism. The cumulative incidence of acute GVHD (aGVHD) was lower in the ATG group than that in the control group (29.6% versus 57.1%, P = .006), and the cumulative incidence of chronic GVHD (cGVHD) was 35.2% for patients with ATG and 66.7% for patients without ATG (P < .01). Notably, the proportion of patients with Karnofsky scores of >90 was 70.4% in the patients with ATG, and 28.6% in the patients without ATG (P < .001). Furthermore, the cumulative incidence of patients with opportunistic infection was significantly different in both groups posttransplantation, with 44.4% and 19.1% in recipient patients with or without ATG respectively (P < .05). Additional usage of ATG not only decreases the occurrence of aGVHD and cGVHD, but also improves QoL of patients after allo-HSCT without affecting stem cell engraftment or overall survival.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Leucemia/terapia , Acondicionamiento Pretrasplante , Adolescente , Adulto , Suero Antilinfocítico/administración & dosificación , Niño , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/inmunología , Histocompatibilidad/inmunología , Humanos , Inmunosupresores/administración & dosificación , Leucemia/inmunología , Leucemia/mortalidad , Depleción Linfocítica , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Persona de Mediana Edad , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/prevención & control , Calidad de Vida , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
BACKGROUND: Immunological arguments and historical examples have shown that treatment with cord blood for non-hematopoietic activities, such as growth factor production and stimulation of angiogenesis, may not require matching or immune suppression. METHODS: To study the benefit of blood mononuclear cell therapy, 8 patients with idiopathic osteoporosis were given intermittent treatments with non-matched allogeneic cord blood mononuclear cells for 3 months. Morning fasting samples were collected for measuring urine N telopeptide of type-1 collagen, serum bone-specific alkaline phosphatase, and insulin-like growth factor 1 during one-year study. RESULTS: Clinical response was striking. Serum insulin-like growth factor 1 significantly increased in all patients at 3 months compared with baseline values, from 264.1 ± 107.0 to 384.4 ± 63.1 ng/mL (P = 0.002), with a tendency to return to baseline values at 12 months (312.9 ± 75.5 ng/mL, P = 0.083). In contrast, differences in serum bone-specific alkaline phosphatase and urine N telopeptide of type-1 collagen were not significant at 3 (P = 0.765, P = 0.057) or 12 months (P = 0.889, P = 0.122). A beneficial effect on bone density was observed in all patients at the lumbar spine. The mean bone mineral density calculated during therapy (0.6811 ± 0.1442 g/cm(2)) tended higher than baseline values (0.6239 ± 0.1362 g/cm(2), P < 0), and percentage change (median) varied from 8.85% at 3 months to 7.85% at one year. All patients are now well after one year. CONCLUSIONS: The findings indicate that for these patients with idiopathic osteoporosis, treatment with cord blood mononuclear cells led to a significant increase in insulin-like growth factor 1 levels, which favors the increase in bone mineral density.
Asunto(s)
Sangre Fetal/citología , Prueba de Histocompatibilidad , Leucocitos Mononucleares/trasplante , Osteoporosis/terapia , Adulto , Pueblo Asiatico , Densidad Ósea/fisiología , Etnicidad , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Vértebras Lumbares/fisiopatología , Masculino , Persona de Mediana Edad , Trasplante HomólogoRESUMEN
OBJECTIVE: To investigate the injury effects of microwave on the visual performance and the apoptosis of retinal ganglion cells (RGCs) in rats and the relationship between the impaired visual performance and RGCs apoptosis induced by microwave. METHODS: The visual performance of rats was observed by Electroretinogram (ERG) and Flash visual evoked potentials (F-VEP). The apoptosis of RGCs in vivo and in vitro was detected by TUNEL assay and Hoechst staining. RESULTS: Microwave exposure had no influence on ERG-a wave. The amplitude of ERG-b wave decreased significantly on the 3rd day and 7th day after microwave exposure (P < 0.01).The latency of ERG-b wave shortened significantly only at 3rd day after microwave exposure (P < 0.01). The latency of F-VEP extended markedly on the 3rd day after exposure (P < 0.05) and recovered on the 7th day after microwave exposure. The amplitude of F-VEP decreased significantly in exposure group, as compared with sham-exposure group, on the 3rd day and 7th day after microwave exposure (P < 0.05). After microwave exposure for 12 h, the apoptotic rate of RGCs in rat increased from 2.85% to 6.73%, and on the 7th day after exposure, the apoptotic rate of RGCs remained 8.93% (P < 0.05). The apoptotic rate of cultured RGCs increased from 8.42% to 13.91% at 6 hour (P < 0.05) and to 24.14% at 24 hour (P < 0.01) after microwave exposure (P < 0.05 or P < 0.01). CONCLUSION: Microwave exposure can injure the visual performance of rats, and the apoptosis of RGCs induced microwave may be one of the main pathological mechanisms.
Asunto(s)
Microondas/efectos adversos , Retina/efectos de la radiación , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/efectos de la radiación , Animales , Apoptosis/efectos de la radiación , Células Cultivadas , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Mitochondrial dysfunction is thought to be a part of the mechanism underlying nickel-induced neurotoxicity. L-carnitine (LC), a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine in all mammalian species, manifests its neuroprotective effects by improving mitochondrial energetics and function. The purpose of this study was to investigate whether LC could efficiently protect against nickel-induced neurotoxicity. Here, we exposed a mouse neuroblastoma cell line (Neuro-2a) to different concentrations of nickel chloride (NiCl2) (0.25, 0.5, 1, and 2 mM) for 24 h, or to 0.5 mM and 1 mM NiCl2 for various periods (0, 3, 6, 12, or 24 h). We found that nickel significantly increased the cell viability loss and lactate dehydrogenase (LDH) release in Neuro-2a cells. In addition, nickel exposure significantly elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, disrupted the mitochondrial membrane potential (ΔΨ(m)), reduced adenosine-5'-triphosphate (ATP) concentrations and decreased mitochondrial DNA (mtDNA) copy numbers and mtRNA transcript levels. However, all of the cytotoxicities and mitochondrial dysfunctions that were triggered by nickel were efficiently attenuated by pretreatment with LC. These protective effects of LC may be attributable to its role in maintaining mitochondrial function in nickel-treated cells. Our results suggest that LC may have great pharmacological potential in protecting against the adverse effects of nickel in the nervous system.
Asunto(s)
Carnitina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Níquel/toxicidad , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Ratones , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/prevención & control , Níquel/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Recent studies suggest that oxidative stress and mitochondrial dysfunction play important roles in the neurotoxicity of nickel. Because mitochondrial DNA (mtDNA) is highly vulnerable to oxidative stress and melatonin can efficiently protect mtDNA against oxidative damage in various pathological conditions, the aims of this study were to determine whether mtDNA oxidative damage was involved in the neurotoxicity of nickel and to assay the neuroprotective effects of melatonin in mtDNA. In this study, we exposed mouse neuroblastoma cell lines (Neuro2a) to different concentrations of nickel chloride (NiCl(2), 0.125, 0.25, and 0.5 mm) for 24 hr. We found that nickel significantly increased reactive oxygen species (ROS) production and mitochondrial superoxide levels. In addition, nickel exposure increased mitochondrial 8-hydroxyguanine (8-OHdG) content and reduced mtDNA content and mtDNA transcript levels. Consistent with this finding, nickel was found to destroy mtDNA nucleoid structure and decrease protein levels of Tfam, a key protein component for nucleoid organization. However, all the oxidative damage to mtDNA induced by nickel was efficiently attenuated by melatonin pretreatment. Our results suggest that oxidative damage to mtDNA may account for the neurotoxicity of nickel. Melatonin has great pharmacological potential in protecting mtDNA against the adverse effects of nickel in the nervous system.
Asunto(s)
ADN Mitocondrial/efectos de los fármacos , Melatonina/farmacología , Níquel/toxicidad , Estrés Oxidativo/efectos de los fármacos , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Línea Celular Tumoral , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , Superóxidos/metabolismoRESUMEN
OBJECTIVE: To explore the risk factors for relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the measures of prophylaxis and treatment. METHODS: We summarized the clinical data of 82 patients with hematologic malignancies who were treated in our hospital from August 2003 to December 2008. Factors including age, sex, ABO blood group disparity of donor and recipient as well as the type of donor, status of disease, HLA-match, conditioning regimen, whether or not having developed acute GVHD and chronic GVHD, infusion number of CD34(+) cells, relationship between CMV infection and relapse post-transplantation were considered and analyzed. RESULTS: Single factor analysis indicated that there were five independent risk factors related with the disease relapse (P < 0.05), including status of disease, time of diagnosis to transplantation, acute graft versus host disease (aGVHD), conditioning regimen, and chronic graft versus host disease (cGVHD). Simultaneously, the type of donor was a substantial factor (P < 0.01), determined by multi-factor Cox regression analysis. Cox regression analysis determined that disease status (OR = 2.58, 95%CI 1.26 - 5.01, P = 0.01), time from diagnosis to treatment (OR = 1.98, 95%CI 1.11 - 3.63, P = 0.025) and cGVHD (OR = 3.74, 95%CI 1.96 - 7.97, P < 0.001) were major factors for relapse of the patients who had undergone transplantation. CONCLUSIONS: Relapse remains the primary cause of failure after allo-HSCT. Status of disease, time from diagnosis to treatment and not cGVHD are the major risk factors. Effective prevention and treatment of relapse after engraftment can improve the efficacy of HSCT.