RESUMEN
Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we comprehensively evaluated a novel agent, O6-methyl-2'-deoxyguanosine-5'-triphosphate (O6-methyl-dGTP) for its anti-GBM activity both in vitro and in vivo. Notably, O6-methyl-dGTP exhibited pronounced cytotoxicity against GBM cells, including those resistant to TMZ and overexpressing O6-methylguanine-DNA methyltransferase (MGMT). Mechanistic investigations revealed that O6-methyl-dGTP could be incorporated into genomic DNA, disrupting nucleotide pools balance, and inducing replication stress, resulting in S-phase arrest and DNA damage. The compound exerted its anti-tumor properties through the activation of AIF-mediated apoptosis and the parthanatos pathway. In vivo studies using U251 and Ln229 cell xenografts supported the robust tumor-inhibitory capacity of O6-methyl-dGTP. In an orthotopic transplantation model with U87MG cells, O6-methyl-dGTP showcased marginally superior tumor-suppressive activity compared to TMZ. In summary, our research, for the first time, underscores the potential of O6-methyl-dGTP as an effective candidate against GBM, laying a robust scientific groundwork for its potential clinical adoption in GBM treatment regimens.
Asunto(s)
Glioblastoma , Polifosfatos , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Nucleósidos/farmacología , Nucleósidos/uso terapéutico , Caspasas , Línea Celular Tumoral , Temozolomida/farmacología , Temozolomida/uso terapéutico , Nucleótidos , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/farmacología , O(6)-Metilguanina-ADN Metiltransferasa/uso terapéutico , Desoxiguanosina/farmacología , Desoxiguanosina/uso terapéutico , ADN , Resistencia a AntineoplásicosRESUMEN
OBJECTIVES: To explore the changes in gut microbiota and levels of short-chain fatty acids (SCFA) in infants with cow's milk protein allergy (CMPA), and to clarify their role in CMPA. METHODS: A total of 25 infants diagnosed with CMPA at Children's Hospital Affiliated to Zhengzhou University from August 2019 to August 2020 were enrolled as the CMPA group, and 25 healthy infants were selected as the control group. Fecal samples (200 mg) were collected from both groups and subjected to 16S rDNA high-throughput sequencing technology and liquid chromatography-mass spectrometry to analyze the changes in gut microbial composition and metabolites. Microbial diversity was analyzed in conjunction with metabolites. RESULTS: Compared to the control group, the CMPA group showed altered gut microbial structure and significantly increased α-diversity (P<0.001). The abundance of Firmicutes, Clostridiales and Bacteroidetes was significantly decreased, while the abundance of Sphingomonadaceae, Clostridiaceae_1 and Mycoplasmataceae was significantly increased in the CMPA group compared to the control group (P<0.001). Metabolomic analysis revealed reduced levels of acetic acid, butyric acid, and isovaleric acid in the CMPA group compared to the control group, and the levels of the metabolites were positively correlated with the abundance of SCFA-producing bacteria such as Faecalibacterium and Roseburia (P<0.05). CONCLUSIONS: CMPA infants have alterations in gut microbial structure, increased microbial diversity, and decreased levels of SCFA, which may contribute to increased intestinal inflammation.
Asunto(s)
Microbioma Gastrointestinal , Hipersensibilidad a la Leche , Lactante , Niño , Femenino , Animales , Bovinos , Humanos , Hipersensibilidad a la Leche/diagnóstico , Ácidos Grasos Volátiles , Bacterias/genética , Ácido Butírico , Proteínas de la LecheRESUMEN
Necroptosis is a recently discovered necrotic cell death which is regulated by receptor interacting protein kinase 1 (RIPK1) and RIPK3 under the stimulus of death signal and can be inhibited by necrostatin-1 (Nec-1) specifically. Therefore, the aim was to investigate the role of necroptosis in a rat model of acute respiratory distress syndrome (ARDS) induced by oleic acid (OA) and assess the effect of Nec-1 on lung injury in ARDS. Our results found that RIPK1, RIPK3 and mixed lineage kinase domain-like protein (MLKL) were abundantly expressed in rat lung tissues of OA-induced ARDS. Nec-1 pretreatment improved pulmonary function and attenuated lung edema dramatically in OA-induced ARDS rats. Furthermore, Nec-1 reduced RIPK1-RIPK3 interaction and down-regulated RIPK1-RIPK3-MLKL signal pathway, and inhibited inflammatory response by reducing neutrophil infiltration and protein leakage into lung tissue in OA-induced ARDS. Collectively, our study proves the intervention of necroptosis in OA-induced ARDS. Moreover, our findings imply that Nec-1 plays an important role in the treatment of ARDS via inhibiting necroptosis and inflammation.
Asunto(s)
Imidazoles/uso terapéutico , Indoles/uso terapéutico , Sustancias Protectoras/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/prevención & control , Animales , Apoptosis/efectos de los fármacos , Líquido del Lavado Bronquioalveolar , Agregación Celular/efectos de los fármacos , Recuento de Células , Modelos Animales de Enfermedad , Imidazoles/farmacología , Inmunohistoquímica , Indoles/farmacología , Inflamación/patología , Masculino , Necrosis , Ácido Oléico , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/fisiopatología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The present study was aimed to investigate the role of necroptosis in the pathogenesis of acute respiratory distress syndrome (ARDS). The rat model of ARDS was induced by intravenous injection of oleic acid (OA), and observed for 4 h. The lung injury was evaluated by arterial blood gas, lung wet-dry weight ratio (W/D) and histological analyses. Simultaneously, bronchoalveolar lavage fluid (BALF) was collected for total and differential cell analysis and total protein determination. Tumor necrosis factor alpha (TNF-α) level in BALF was determined with a rat TNF-α ELISA kit. Expressions of receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL) in lung tissue were determined by Western blot and immunohistochemical staining. The interaction between RIPK1 and RIPK3 was explored by immunoprecipitation. The results showed that, compared with those in control group, total white blood cells count (WBC), polymorphonuclear percentage (PMN%), total protein concentration, TNF-α level in BALF, W/D, and the alveolar-arterial oxygen tension difference (P(A-a)O2) in OA group were significantly increased at 4 h after OA injection. Western blot and immunostaining further showed remarkably increased expressions of RIPK1, RIPK3 and MLKL in lung tissue from OA group. Additionally, immunoprecipitation results indicated an enforced interaction between RIPK1 and RIPK3 in OA group. Collectively, the TNF-α level in BALF and the RIPK1-RIPK3-MLKL signaling pathway in lung tissue were found to be upregulated and activated with the process of ARDS. These findings implicate that RIPK1/RIPK3-mediated necroptosis plays a possible role in the pathogenesis of ARDS, which may provide a new idea to develop novel drugs for the therapy of ARDS.
Asunto(s)
Enfermedades Pulmonares , Trastornos Respiratorios , Enfermedad Aguda , Animales , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Necrosis , Ácido Oléico , Ratas , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Transducción de Señal , Factor de Necrosis Tumoral alfaRESUMEN
Akebia saponin D (ASD) is a typical bioactive triterpenoid saponin obtained from the rhizome of Dipsacus asper Wall. Previous studies have found that ASD has a hepatoprotective effect in a mouse model. The purpose of this paper was to explore the molecular mechanism of the hepatoprotective effects of ASD on BRL cells and isolated rat liver mitochondria. We investigated the effects of ASD on rotenone-induced toxicity in BRL cells. The results showed that ASD inhibited the accumulation of reactive oxidant species, ATP deficiency, and mitochondrial membrane potential dissipation; ameliorates mitochondrial respiratory dysfunction, and improved the activity of complex I in a concentration-dependent manner, indicating that ASD likely improved mitochondrial function. ASD suppressed rotenone-induced BRL cell apoptosis and increased Bcl-2/Bax ratio. These results suggest that ASD may exert hepatoprotective effects against rotenone-induced toxicity through mitochondria. This study supports our previous research that ASD possesses hepatoprotective activity in vivo and it is worthy of further study.
Asunto(s)
Antioxidantes/farmacología , Hígado/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Rotenona/toxicidad , Saponinas/farmacología , Adenosina Trifosfato/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Citoprotección , Dipsacaceae , Relación Dosis-Respuesta a Droga , Complejo I de Transporte de Electrón/metabolismo , Metabolismo Energético/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Plantas Medicinales , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Endogámicas BUF , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Rizoma , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Aim: Liquid biopsies analyzing cell-free DNA (cfDNA) methylation in plasma offer a noninvasive diagnostic for diseases, with the potential of aging biomarkers underexplored. Methods: Utilizing enzymatic methyl-seq (EM-seq), this study assessed cfDNA methylation patterns in aging with blood from 35 healthy individuals. Results: It found aging signatures, including higher cfDNA levels and variations in fragment sizes, plus approximately 2000 age-related differentially methylated CpG sites. A biological age predictive model based on 48 CpG sites showed a strong correlation with chronological age, verified by two datasets. Age-specific epigenetic shifts linked to inflammation were revealed through differentially methylated regions profiling and Olink proteomics. Conclusion: These findings suggest cfDNA methylation as a potential aging biomarker and might exacerbate immunoinflammatory reactivity in older individuals.
Our bodies undergo many changes as we age, some of which might affect our health. To better understand these changes, scientists study something called 'cell-free DNA' (cfDNA) in our blood. This cfDNA can give us clues about our health and the risk of diseases like cancer or heart conditions.In our research, we analyzed cfDNA from the blood of 35 people to identify patterns associated with aging. We discovered that approximately 2000 specific spots in our DNA change in a way that's linked to aging. These changes might help us figure out someone's biological age essentially, how old their body seems based on various health factors, which can differ from their actual age.We also found that these DNA changes could indicate how aging might make the body's defense system which fights off diseases react more intensely. Understanding this could be crucial for managing health as we get older.Our study suggests that cfDNA could be a useful marker for aging, offering a new approach to understanding and possibly managing the health effects associated with growing older.
Asunto(s)
Envejecimiento , Ácidos Nucleicos Libres de Células , Islas de CpG , Metilación de ADN , Epigénesis Genética , Inflamación , Humanos , Envejecimiento/genética , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/genética , Femenino , Inflamación/genética , Masculino , Anciano , Persona de Mediana Edad , Adulto , Biomarcadores/sangre , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: To study the mechanism of treating diabetic foot by clearing heat, detoxification, activating blood, and dredging collaterals method. METHODS: Sixty diabetic foot patients were randomly assigned to the treatment group and the control group, 30 cases in each group. On the basis of the same routine treatment, patients in the treatment group were treated by Qingjie Tongluo Recipe (QTR) plus external washing of Chinese herbs plus external dressing by herbs with removing necrosis and promoting granulation actions, while those in the control group were treated with routine aseptic external dressing. Three months was taken as one therapeutic course. The wound area and basic fibroblast growth factor (bFGF) were detected before and after treatment. The content of vascular endothelial growth factor (VEGF), the peripheral vascular and nerve functions were also measured. The therapeutic effects were also observed. RESULTS: After treatment, in the treatment group,15 patients were cured, 12 markedly effective, 2 effective, 1 ineffective, the cure rate was 50.0% and the total effective rate was 96.7%, while in the control group, 9 cases were cured, 6 markedly effective, 8 effective, 7 ineffective, the cure rate was 30.0% and the total effective rate was 76.7%. The total effective rate was better in the treatment group than in the control group (P <0. 01). The contents of bFGF and VEGF were significantly higher in the two groups after treatment (P <0.01). Besides, better results were obtained in the treatment group (P < 0.01). The blood flow speed of the dorsalis pedis artery, the inner diameter of the dorsalis pedis artery, and the common peroneal nerve conduction velocity were somewhat improved (P <0.05, P <0.01). Besides, better results were obtained in the treatment group (P <0.01). CONCLUSIONS: QTR combined external washing plus external dressing by herbs with removing necrosis and promoting granulation actions could promote the healing of diabetic foot induced ulcers, improve the vascular and nerve functions. Its efficacy was superior to that of the control group.
Asunto(s)
Pie Diabético/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Oxidative stress can attack precursor nucleotides, resulting in nucleic acid damage in cells. It remains unclear how 8-oxo-dGTP and 8-oxoGTP, oxidized forms of dGTP and GTP, respectively, could affect DNA or RNA oxidation levels and tumor development. To address this, we intravenously administered 8-oxo-dGTP and 8-oxoGTP to wild-type and MTH1-knockout mice. 8-oxoGTP administration increased frequency of tumor incidence, which is more prominent in MTH1-knockout mice. However, 8-oxo-dGTP treatment rather reduced tumor development regardless of the mouse genotype. The tumor suppressive effects of 8-oxo-dGTP were further confirmed using xenograft and C57/6J-ApcMin/Nju mouse models. Mechanistically, 8-oxo-dGTP increased the 8-oxo-dG contents in DNA and DNA strand breakage, induced cell cycle arrest in S phase and apoptosis mediated by AIF, eventually leading to reduced tumor incidence. These results suggest distinct roles of 8-oxo-dGTP and 8-oxoGTP in tumor development.
Asunto(s)
Neoplasias , Monoéster Fosfórico Hidrolasas , Humanos , Animales , Ratones , Monoéster Fosfórico Hidrolasas/genética , Fase S , Nucleótidos de Desoxiguanina/metabolismo , Neoplasias/genética , ADN/metabolismo , Ratones Noqueados , Apoptosis , Enzimas Reparadoras del ADN/genéticaRESUMEN
AIMS: Glucagon-like peptide 1 (GLP-1) is produced by the L subtype of enteroendocrine cells (EECs). Patients with type 2 diabetes (T2D) exhibit reduced incretin effect, but the pathophysiology and functional change of the L-cells remain unclear. Deciphering the mechanisms of the biological changes in L-cells under T2D conditions may assist in the research of gut-based strategies for T2D therapy. METHODS: We investigated the fasting serum GLP-1 levels and the distribution of colonic L-cells in young and aged participants with and without T2D. Additionally, we established an aged male T2D Wistar rat model subjected to a long-term high-fat and high-fructose (HFHF) diet. Histological investigations and single-cell RNA sequencing (scRNA-seq) analyses were performed to explore the mechanisms underlying functional changes in the colonic EECs. RESULTS: We observed a decline in circulating GLP-1 levels and a reduced number of colonic L-cells in elderly patients with T2D. The mechanisms underlying impaired L-cell formation and disturbed GLP-1 production were revealed using aged T2D rats induced by a long-term HFHF diet. The scRNA-seq results showed that the transcription factors that regulate L-cell commitment, such as Foxa1, were downregulated, and the expression of genes that participate in encoding GLP-1, GLP-1 posttranslational processing, hormone secretion, and nutrient sensing was disturbed. CONCLUSIONS: Taken together, the reduced L-cell lineage commitment and disturbed L-cell functions might be the major cause of the reduced GLP-1 production in aged populations with T2D. Our study provides new insights for identifying novel targets in colonic L-cells for improving endogenous GLP-1 production.
Asunto(s)
Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón , Humanos , Ratones , Anciano , Masculino , Ratas , Animales , Células L , Ratas Wistar , Células Enteroendocrinas/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/farmacologíaRESUMEN
The objective of this study was to research the characteristics of fractions of organic nitrogen and active nitrogen and their relationship under different biochar applications and to provide a basis for the preparation and practical application of biochar from Eucalyptus forest wastes. In a long-term positioning test of biochar application from 2017, six different treatments were selected:0(CK), 0.5%(T1), 1%(T2), 2%(T3), 4%(T4), and 6%(T5). The contents of soil organic nitrogen components, total nitrogen(TN), dissolved organic nitrogen(DON), and microbial biomass nitrogen(MBN) following the different treatments were measured. The results showed that:â compared with that of the control, with the increase in biochar application, the contents of soil TN, acidolysis of total organic nitrogen(AHON), ammonia nitrogen(AN), amino acid nitrogen(AAN), MBN, DON, and nitrogen storage(NS) increased significantly by 45.48%-156.32%, 44.31%-171.31%, 38.06%-223.37%, 39.42%-163.32%, 36.72%-109%, 23.27%-113.51%, and 29.45%-62.37%, respectively. The contents of soil hydrolyzable unknown nitrogen(HUN) and non-hydrolyzable nitrogen(NHN) also increased significantly by 88.41%-158.71% and 50.24%-139.01%, respectively. The contents of soil amino sugar nitrogen(ASN) decreased by 7.72%-32.73%. The contents of different forms of organic nitrogen fractions in all treatments displayed an order of AN > AAN > NHN > HUN > ASN. Compared with the no biochar treatment, each biochar treatment increased the contents and proportion of AHON in the TN. â¡ With the exception of HUN, the contents of other soil organic nitrogen components and active nitrogen content decreased with the increase in soil depth. ⢠There were significantly positive correlations between TN, MBN, and DON and AHON, NHN, and NS contents. The principal component analysis showed that bulk density and ASN and TN and HUN, AAN, DON, and AHON were closely related, respectively. In conclusion, the application of forestry waste biochar for five years could significantly increase the content of soil organic nitrogen component and active nitrogen, thereby improving the capacity of the soil to supply nitrogen. AHON, AN, and AAN were the main factors contributing to soil active nitrogen content.
Asunto(s)
Eucalyptus , Suelo , Suelo/química , Carbono/análisis , Nitrógeno/análisis , China , Carbón Orgánico/químicaRESUMEN
The cumulative evidence suggests that oxytocin is involved in the male sexual behaviors. However, no significant sexual impairments were observed in oxytocin gene knock-out (KO) mice, suggesting that oxytocin is not necessary for sexual behavior in male mice. To better understand the role of oxytocin in male erection, two types of oxytocin gene KO mice were created. In the first type, the oxytocin gene was deleted in the zygote, while in the second type, the oxytocin gene was mutated in adulthood by injecting the CRISPR/Cas9 AAVs. The results showed that disrupting the oxytocin gene at either the embryonic or adult stage did not affect erection, indicating that oxytocin is not necessary for penile erection. Pharmacologically, injecting oxytocin receptor agonist Carbetocin into the VTA of the oxytocin gene KO mice still evoked penile erection. By employing the Oxt-Ires-Cre mice, we found that specifically activating oxytocinergic neurons through chemogenetics strongly induced penile erection, while inhibiting these neurons blocked the erection responses. Furthermore, ablating PVN oxytocinergic neurons abolished the male erection response. In conclusion, although the neuropeptide oxytocin is not essential for male erection, the activity of oxytocinergic neurons is required. Our results might reflect the redundancy in the central nerve system in the sense that many signals contribute to the activation of oxytocinergic neurons to evoke penile erection during sexual behaviors.
Asunto(s)
Neuronas , Oxitocina , Erección Peniana , Animales , Masculino , Ratones , Neuronas/fisiología , Núcleo Hipotalámico Paraventricular , Erección Peniana/fisiología , Receptores de Oxitocina/genética , Oxitocina/metabolismoRESUMEN
To investigate the effects of biochar(BC) addition on soil organic carbon(SOC) contents and its fractions under different biochar applications, Eucalyptus waste twigs in Northern Guangxi were used to produce BC at 500â. Additionally, we sought to clarify and define the carbon sequestration potential of soil and provide a basis for the preparation of biochar from Eucalyptus forest wastes and soil improvement. In a long-term positioning test of biochar application from 1997, six different treatments were selected:0(CK), 0.5%(T1), 1%(T2), 2%(T3), 4%(T4), and 6%(T5). The contents of SOC, light fraction organic carbon(LFOC), heavy fraction organic carbon(HFOC), easily oxidized organic carbon(EOC), dissolved organic carbon(DOC), particulate organic carbon(POC), microbial biomass carbon(MBC), and carbon stock(CS) following the different treatments were measured. The results showed that:â compared to that in the control, biochar application induced an increase in each soil organic carbon fraction with increasing application rate and reached a maximum under the T4 or T5 treatments; with the increase in biochar application, the contents of SOC, DOC, EOC, POC, MBC, and CS increased significantly by 101.62%, 67.46%, 143.03%, 164.78%, 110.88%, and 41.73%, respectively. â¡ The contents of LFOC and HFOC in the 0-10, 10-20, and 20-30 cm soil layers increased significantly by 41.41%-140.63%, 9.26%-87.04%, and -19.54%-106.90% and 15.32%-78.99%, 15.72%-75.25%, and 89.49%-148.64%, respectively, with the increase in biochar application. The average contents of LFOC and HFOC in the 0-30 cm soil layer also increased gradually. The soil carbon pool of the Eucalyptus forest was dominated by a relatively stable heavy fraction organic carbon. ⢠The contents of carbon stock, soil organic carbon, and its fractions decreased with the increase in soil depth. In conclusion, the application of forestry waste biochar for five years could significantly increase the content of SOC and its components, thereby increasing soil organic carbon activity. Therefore, increasing the amount of biochar was an effective measure to enhance the carbon storage, soil stable carbon pool, and soil quality of the Eucalyptus plantation field. This study provides a reference for the resource utilization of forestry waste and improvements in soil fertility of Eucalyptus plantations.
Asunto(s)
Carbono , Eucalyptus , Carbono/análisis , Suelo , ChinaRESUMEN
MTH1 protein can sanitize the damaged (d)NTP pool and MTH1 inhibitors have been developed to impede the growth of rapidly proliferating tumor cells; however, the effect of MTH1 inhibition on breast cancer stemness has not been reported yet. Here, we constructed breast cancer cell lines with the stable depletion of MTH1. MTH1 suppression clearly increased the ratio of CD44+CD24-/low subpopulations and promoted the formation of tumorspheres in MCF7 and T47D cells. RNA expression profiling, RT-qPCR and Western blotting showed the upregulation of master stem cell transcription factors Sox2, Oct4 and Nanog in MTH1 knockdown cells. GSEA suggested and Western blotting verified that MTH1 knockdown increased the expression of phosphorylated STAT3 (Tyr705). Furthermore, we indirectly demonstrated that the increased concentration of 8-oxo-dGTP and 8-oxo-GTP in MTH1-knockdown cells and exogenous 8-oxoGTP, rather than 8-oxo-dGTP, could significantly increase the phosphorylation of STAT3. In conclusion, this work indicates that MTH1 inhibition increased the proportion of breast cancer stem cells (BCSCs) and promoted stemness properties in MCF7 cells.
Asunto(s)
Neoplasias de la Mama , Factor de Transcripción STAT3 , Neoplasias de la Mama/patología , Enzimas Reparadoras del ADN , Femenino , Humanos , Células MCF-7 , Células Madre Neoplásicas/metabolismo , Monoéster Fosfórico Hidrolasas , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Activación Transcripcional , Regulación hacia ArribaRESUMEN
The effects of dietary Selenium (Se) supplementation on muscle superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) activities and haemolymph superoxide anions (O(2)-) of Neocaridina heteropoda exposed to ambient nitrite were investigated. The results showed supplementation of Se in diet could enhance the resistance of shrimp to low concentration ambient nitrite. The results demonstrated that Se might have a potentially useful role as an effective antioxidant and resistance to aqueous nitrite in shrimp and the effect of the organic Se was better than that of the inorganic Se.
Asunto(s)
Antioxidantes/metabolismo , Decápodos/efectos de los fármacos , Nitritos/toxicidad , Selenio/farmacología , Contaminantes del Agua/toxicidad , Animales , Decápodos/enzimología , Decápodos/crecimiento & desarrollo , Pruebas de ToxicidadRESUMEN
BACKGROUND: The oral cavity is a complex environment in which periodontal tissue is constantly stimulated by external microorganisms and mechanical forces. Proper mechanical force helps maintain periodontal tissue homeostasis, and improper inflammatory response can break the balance. Periodontal ligament (PDL) cells play crucial roles in responding to these challenges and maintaining the homeostasis of periodontal tissue. However, the mechanisms underlying PDL cell property changes induced by inflammatory and mechanical force microenvironments are still unclear. Recent studies have shown that exosomes function as a means of cell-cell and cell-matrix communication in biological processes. METHODS: Human periodontal ligament stem cells (HPDLSCs) were tested by the CCK8 assay, EdU, alizarin red, and ALP staining to evaluate the functions of exosomes induced by a mechanical strain. MicroRNA sequencing was used to find the discrepancy miRNA in exosomes. In addition, real-time PCR, FISH, luciferase reporter assay, and western blotting assay were used to investigate the mechanism of miR-181b-5p regulating proliferation and osteogenic differentiation through the PTEN/AKT pathway. RESULTS: In this study, the exosomes secreted by MLO-Y4 cells exposed to mechanical strain (Exosome-MS) contributed to HPDLSC proliferation and osteogenic differentiation. High-throughput miRNA sequencing showed that miR181b-5p was upregulated in Exosome-MS compared to the exosomes derived from MLO-Y4 cells lacking mechanical strain. The luciferase reporter assay demonstrated that miR-181b-5p may target phosphatase tension homolog deletion (PTEN). In addition, PTEN was negatively regulated by overexpressing miR-181b-5p. Real-time PCR and western blotting assay verified that miR-181b-5p enhanced the protein kinase B (PKB, also known as AKT) activity and improved downstream factor transcription. Furthermore, miR-181b-5p effectively ameliorated the inhibition of HPDLSC proliferation and promoted HPDLSC induced by inflammation. CONCLUSIONS: This study concluded that exosomes induced by mechanical strain promote HPDLSC proliferation via the miR-181b-5p/PTEN/AKT signaling pathway and promote HPDLSC osteogenic differentiation by BMP2/Runx2, suggesting a potential mechanism for maintaining periodontal homeostasis.
Asunto(s)
Fenómenos Biológicos , Exosomas , MicroARNs , Diferenciación Celular , Proliferación Celular , Exosomas/genética , Exosomas/metabolismo , Humanos , MicroARNs/genética , Osteocitos/metabolismo , Osteogénesis/genética , Fosfohidrolasa PTEN/genética , Ligamento Periodontal/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
The complete mitochondrial genome (mitogenome) of Sideridis albicosta is described in this study. The circular molecule is 15,320 bp in length and contains 13 protein-coding genes (PCGs), two rRNA genes, 22 tRNA genes, and one AT-rich region. Thirteen PCGs is 11,252 bp in total, encoding 3723 amino acids. All PCGs start with ATN, except for COI gene starting with CGA; 10 of the 13 PCGs use the typical stop codon TAA, whereas COI, COII, and ND4 stop with a single T. The rrnL and rrnS genes are 1377 bp and 783 bp in length, respectively. The 328 bp AT-rich region contains several structures characteristic of the lepidopterans. New phylogenetic analyses upon mitogenomics would provide us further insights on the taxonomy and phylogeny of Noctuoidea.
RESUMEN
The C-reactive protein/albumin ratio (CAR) has been shown to play a significant prognostic role in several cancers. We aimed to comprehensively explore the potential role of the CAR as a prognostic indicator in solid cancers. In this meta-analysis, we collected data from 10 studies that examined the association between serum CAR and overall survival in patients with cancer. This meta-analysis included 4592 tumor patients. The eligible studies were found through the PubMed and Web of Science databases updated on 6 Oct 2016. The pooled hazard ratio (2.01, 95% CI: 1.58-2.56, p < 0.001) indicated that high CAR yielded worse survival in different cancers. Subgroup analyses showed a significant association between CAR and prognosis, regardless of the cutoff value, cutoff value selection, treatment method, country, sample size, stage and cancer type. This meta-analysis suggests that CAR may be a potential prognostic marker in solid cancers. However, further large prospective studies should be conducted to explore the critical role of CAR in survival of cancer patients.
Asunto(s)
Biomarcadores de Tumor/sangre , Proteína C-Reactiva/metabolismo , Neoplasias/sangre , Pronóstico , Humanos , Neoplasias/patología , Albúmina SéricaRESUMEN
BACKGROUND: Arsenic trioxide (As2O3) has been identified as a very potent anti-acute leukemic agent. However its role in apoptosis needs to be elucidated. As2O3 interferes with the proliferation and survival of tumor cells via a variety of mechanisms. Drug-target interactions at the level of nuclear matrix (NM) may be critical events in the induction of cell death by As2O3. This study dealt with As2O3-target interactions at the level of NM in chronic myelogenous leukemia cell line K562 by proteomics. METHODS: K562 cells were cultured in MEM and treated with different concentrations of As2O3. The nuclear matrix proteins were analyzed by high-resolution two-dimensional gel electrophoresis and computer-assisted image analysis. RESULTS: As2O3 significantly inhibited the growth of chronic myelogenous leukemia cell line K562 at low concentrations. While more than 200 protein spots were shared among the nuclear matrices, about 18 distinct spots in the nuclear matrices were found characteristic for As2O3 treated cells. CONCLUSIONS: As2O3 induces apoptosis in K562 cells in a dose and time-dependent manner. Our results demonstrated that for the detection of the onset of apoptosis, the alteration in the composition of nuclear matrix proteins was a more sensitive indicator than nucleosomal DNA fragmentation test. These results indicated that As2O3 might be clinically useful in the treatment of chronic myelogenous leukemia. The changes of nuclear matrix proteins in the treated cells can be used as a useful indicator for this treatment.