RESUMO
8-oxoguanine (o8G), a prevalent oxidative modification in RNA induced by reactive oxygen species (ROS), plays a pivotal role in regulating RNA functions. Accurate detection and quantification of o8G modifications is critical to understanding their biological significance and potential as disease biomarkers, but effective detection methods remain limited. Here, we have developed a highly specific T3 DNA ligase-dependent qPCR assay that exploits the enzyme's ability to discriminate o8G from guanine (G) with single-nucleotide resolution. This method can detect o8G in RNA at levels as low as 500 fM, with an up to 18-fold higher selectivity for discriminating o8G from G. By simulating oxidative stress conditions in SH-SY5Y and HS683 cell lines treated with rotenone, we successfully identified site-specific o8G modifications in key miRNAs associated with neuroprotective responses, including miR-124, let-7a and miR-29a. The developed assay holds significant promise for the practical identification of o8G, facilitating its potential for detailed studies of o8G dynamics in various biological contexts and diseases.
Assuntos
Guanina , Guanina/análogos & derivados , Guanina/química , Guanina/metabolismo , Humanos , RNA/metabolismo , RNA/análise , MicroRNAs/análise , MicroRNAs/metabolismo , DNA Ligases/metabolismo , Linhagem Celular Tumoral , Estresse Oxidativo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Cigarette smoke (CS), an indoor environmental pollutant, is a prominent risk factor for emphysema, which is a pathological feature of chronic obstructive pulmonary disease (COPD). Emerging function of circRNAs in immune responses and disease progression shed new light to explore the pathogenesis of emphysema. In this research, we demonstrated, by single-cell RNA sequencing (scRNAseq), that the ratio of M2 macrophages were increased in lung tissues of humans and mice with smoking-related emphysema. Further, our data showed that circADAMTS6 was associated with cigarette smoke extract (CSE)-induced M2 macrophage polarization. Mechanistically, in macrophages, circADAMTS6 stabilized CAMK2A mRNA via forming a circADAMTS6/IGF2BP2/CAMK2A RNA-protein ternary complex to activate CREB, which drives M2 macrophage polarization and leads to emphysema. In addition, in macrophages of mouse lung tissues, downregulation of circADAMTS6 reversed M2 macrophage polarization, the proteinase/anti-proteinase imbalance, and the elastin degradation, which protecting against CS-induced emphysema. Moreover, for macrophages and in a model with co-cultured lung organoids, the target of circADAMTS6 restored the growth of lung organoids compared to CSE-treated macrophages. Our results also demonstrated that, for smokers and COPD smokers, elevation of circADAMTS6 negatively correlated with lung function. Overall, this study reveals a novel mechanism for circADAMTS6-driven M2 macrophage polarization in smoking-related emphysema and postulates that circADAMTS6 could serve as a diagnostic and therapeutic marker for smoking-related emphysema.
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Cigarette smoke (CS), the main source of indoor air pollution and the primary risk factor for respiratory diseases, contains chemicals that can perturb microbiota through antibiotic effects. Although smoking induces a disturbance of microbiota in the lower respiratory tract, whether and how it contributes to initiation or promotion of emphysema are not well clarified. Here, we demonstrated an aberrant microbiome in lung tissue of patients with smoking-related COPD. We found that Stenotrophomonas maltophilia (S. maltophilia) was expanded in lung tissue of patients with smoking-related COPD. We revealed that S. maltophilia drives PANoptosis in alveolar epithelial cells and represses formation of alveolar organoids through IRF1 (interferon regulatory factor 1). Mechanistically, IRF1 accelerated transcription of ZBP1 (Z-DNA Binding Protein 1) in S. maltophilia-infected alveolar epithelial cells. Elevated ZBP1 served as a component of the PANoptosome, which triggered PANoptosis in these cells. By using of alveolar organoids infected by S. maltophilia, we found that targeting of IRF1 mitigated S. maltophilia-induced injury of these organoids. Moreover, the expansion of S. maltophilia and the expression of IRF1 negatively correlated with the progression of emphysema. Thus, the present study provides insights into the mechanism of lung dysbiosis in smoking-related COPD, and presents a potential target for mitigation of COPD progression.
Assuntos
Células Epiteliais Alveolares , Fator Regulador 1 de Interferon , Enfisema Pulmonar , Fumar , Stenotrophomonas maltophilia , Animais , Humanos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/microbiologia , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Pulmão/microbiologia , Microbiota , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/microbiologia , Fumar/efeitos adversosRESUMO
Epidemiologic surveys have indicated that cigarette smoking is an important risk factor for diabetes, but its mechanisms remain unclear. Andrographolide, an herb traditionally utilized in medicine, provides anti-inflammatory benefits for various diseases. In the present work, 265 patients with Type 2 diabetes (T2D) were investigated, and male C57BL/6 mice were exposed to cigareete smoke (CS) and/or to intraperitoneally injected andrographolide for 3 months. To elucidate the mechanism of CS-induced hyperglycemia and the protective mechanism of andrographolide, MIN6 cells were exposed to cigarette smoke extract (CSE) and/or to andrographolide. Our data from 265 patients with T2D showed that urinary creatinine and serum inflammatory cytokines (interleukin 6 (IL-6), IL-8, IL-1ß, and tumor necrosis factor α (TNF-α)) increased with smoking pack-years. In a mouse model, CS induced hyperglycemia, decreased insulin secretion, and elevated inflammation and pyroptosis in ß-cells of mice. Treatment of mice with andrographolide preserved pancreatic function by reducing the expression of inflammatory cytokines; the expression of TXNIP, NLRP3, cleaved caspase 1, IL-1ß; and the N-terminal of gasdermin D (GSDMD) protein. For MIN6 cells, CSE caused increasing secretion of the inflammatory cytokines IL-6 and IL-1ß, and the expression of TXNIP and pyroptosis-related proteins; however, andrographolide alleviated these changes. Furthermore, silencing of TXNIP showed that the blocking effect of andrographolide may be mediated by TXNIP. In sum, our results indicate that CS induces hyperglycemia through TXNIP-NLRP3-GSDMD axis-mediated inflammation and pyroptosis of islet ß-cells and that andrographolide is a potential therapeutic agent for CS-induced hyperglycemia.
Assuntos
Fumar Cigarros , Diabetes Mellitus Tipo 2 , Diterpenos , Hiperglicemia , Proteínas de Ligação a Fosfato , Humanos , Masculino , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Citocinas/metabolismo , Proteínas de Transporte , Gasderminas , Produtos do TabacoRESUMO
Cigarettes contain various chemicals that cause damage to nerve cells. Exposure to cigarette smoke (CS) causes insulin resistance (IR) in nerve cells. However, the mechanisms for a disorder in the cigarette-induced insulin signaling pathway and in neurotoxicity remain unclear. Therefore, we evaluated, by a series of pathology analyses and behavioral tests, the neurotoxic effects of chronic exposure to CS on C57BL/6 mice. Mice exposed to CS with more than 200 mg/m3 total particulate matter (TPM) exhibited memory deficits and cognitive impairment. Pathological staining of paraffin sections of mouse brain tissue revealed that CS-exposed mice had, in the brain, neuronal damage characterized by thinner pyramidal and granular cell layers and fewer neurons. Further, the exposure of SH-SY5Y cells to cigarette smoke extract (CSE) resulted in diminished insulin sensitivity and reduced glucose uptake in a dose-dependent fashion. The PI3K/GSK3 insulin signaling pathway is particularly relevant to neurotoxicity. microRNAs are involved in the PI3K/GSK3ß/p-Tau pathway, and we found that cigarette exposure activates miR-153-3p, decreases PI3K regulatory subunits PIK3R1, and induces Tau hyperphosphorylation. Exposure to an miR-153 inhibitor or to a PI3K inhibitor alleviated the reduced insulin sensitivity caused by CS. Therefore, our results indicate that miR-153-3p, via PIK3R1, causes insulin resistance in the brain, and is involved in CS-induced neurotoxicity.
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Silicosis is a severe occupational lung disease caused by inhalation of silica particles. Unfortunately, there are currently limited treatment options available for silicosis. Recent advances have indicated that bone marrow mesenchymal stem cells (BMSCs) have a therapeutic effect on silicosis, but their efficacy and underlying mechanisms remain largely unknown. In this study, we focused on the early phase of silica-induced lung injury to investigate the therapeutic effect of BMSCs. Our findings demonstrated that BMSCs attenuated silica-induced acute pulmonary inflammation by inhibiting NLRP3 inflammasome pathways in lung macrophages. To further understand the mechanisms involved, we utilized RNA sequencing to analyze the transcriptomes of BMSCs co-cultured with silica-stimulated bone marrow-derived macrophages (BMDMs). The results clued tumor necrosis factor-stimulated gene 6 (TSG-6) might be a potentially key paracrine secretion factor released from BMSCs, which exerts a protective effect. Furthermore, the anti-inflammatory and inflammasome pathway inhibition effects of BMSCs were attenuated when TSG-6 expression was silenced, both in vivo and in vitro. Additionally, treatment with exogenous recombinant mouse TSG-6 (rmTSG-6) demonstrated similar effects to BMSCs in attenuating silica-induced inflammation. Overall, our findings suggested that BMSCs can regulate the activation of inflammasome in macrophages by secreting TSG-6, thereby protecting against silica-induced acute pulmonary inflammation both in vivo and in vitro.
Assuntos
Células-Tronco Mesenquimais , Pneumonia , Silicose , Camundongos , Animais , Pulmão , Dióxido de Silício/toxicidade , Dióxido de Silício/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Silicose/terapia , Silicose/metabolismo , Silicose/patologia , Pneumonia/metabolismo , Pneumonia/patologia , Macrófagos , Inflamação/patologia , Anti-Inflamatórios/farmacologiaRESUMO
Melanoma is the most invasive skin cancer, with a high mortality rate. However, existing therapeutic drugs have side effects, low reactivity, and lead to drug resistance. As the power source in cells, mitochondria play an important role in the survival of cancer cells and are an important target for tumor therapy. This study aimed to develop a new anti-melanoma compound that targets mitochondria, evaluate its effect on the proliferation and metastasis of melanoma cells, and explore its mechanism of action. The novel mitochondria-targeting compound, SCZ0148, was synthesized by modifying the structure of cyanine. Then, A375 and B16 cells were incubated with different concentrations of SCZ0148, and different doses of SCZ0148 were administered to A375 and B16 xenograft zebrafish. The results showed that SCZ0148 targeted mitochondria, had dose- and time-dependent effects on the proliferation of melanoma cell lines, and had no obvious side effects on normal cells. In addition, SCZ0148 induced melanoma cell apoptosis through the reactive oxygen species-mediated mitochondrial pathway of apoptosis and promoted autophagy. SCZ0148 significantly inhibited the migration of melanoma cells via a matrix metalloprotein 9-mediated pathway. Similarly, SCZ0148 inhibited melanoma cell proliferation in a concentration-dependent manner in vivo. In summary, SCZ0148 may be a novel anti-melanoma compound that targets mitochondria.
RESUMO
Malignant melanoma is the most fatal form of skin cancer worldwide, and earlier diagnosis and more effective therapies are required to improve prognosis. As a possible solution, near-infrared fluorescent heptamethine cyanine dyes have been shown to be useful for tumor diagnosis and treatment. Here, we synthesized a novel theranostic agent, IR-817, a multifunctional bioactive small-molecule that has near-infrared emission, targets mitochondria in cancer cells, and has selective anti-cancer effects. In in vitro experiments, IR-817 preferentially accumulated in melanoma cells through organic anion transporting polypeptide transporters but also selectively inhibited the growth of tumor cells by inducing mitochondrial-dependent intrinsic apoptosis. Mechanistically, IR-817 caused G0/G1 cell cycle arrest by targeting the E2F/Cyclin/CDK pathway. Finally, IR-817 significantly suppressed the growth of xenograft tumors in zebrafish and mice. Immunohistochemical staining and hematoxylin and eosin staining revealed that IR-817 induced apoptosis and inhibited tumor cell proliferation without notable side effects. Therefore, mitochondrial-targeting theranostic agent IR-817 may be promising for accurate tumor diagnosis, real-time monitoring, and safe anti-cancer treatments.
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It is difficult to treat malignant melanoma because of its high malignancy. New and effective therapies for treating malignant melanoma are urgently needed. Ergosterols are known for specific biological activities and have received widespread attention in cancer therapy. Here, LH-1, a kind of ergosterol from the secondary metabolites of the marine fungus Pestalotiopsis sp., was extracted, isolated, purified, and further investigated the biological activities against melanoma. In vitro experiments, the anti-proliferation effect on tumor cells was detected by MTT and colony formation assay, and the anti-metastatic effect on tumor cells was investigated by wound healing assay and transwell assay. Subcutaneous xenograft models, histopathology, and immunohistochemistry have been used to verify the anti-tumor, toxic, and side effect in vivo. Besides, the anti-tumor mechanism of LH-1 was studied by mRNA sequencing. In vitro, LH-1 could inhibit the proliferation and migration of melanoma cells A375 and B16-F10 in a dose-dependent manner and promote tumor cell apoptosis through the mitochondrial apoptosis pathway. In vivo assays confirmed that LH-1 could suppress melanoma growth by inducing cell apoptosis and reducing cell proliferation, and it did not have any notable toxic effects on normal tissues. LH-1 may play an anti-melanoma role by upregulating OBSCN gene expression. These findings suggest that LH-1 may be a potential for the treatment of melanoma.
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Inflammation is one of the major adverse effects of fine particulate matter (PM2.5) on the lung system; however, its mechanisms remain unclear. Rats were exposed to different concentrations of PM2.5 to investigate the mechanism of short-term exposure-induced lung inflammation. The regulation of PI3K-Akt and DNA methyltransferase 3b (DNMT3b) was assessed by using a PI3K inhibitor and a DNA methyltransferase inhibitor. We found that PM2.5 could decrease interferon-γ (IFN-γ) levels and increase interleukin 4 (IL-4), IL-5 and IL-13 levels in bronchoalveolar lavage fluid (BALF) to promote eosinophil infiltration and eventually lead to allergic pulmonary inflammation. Moreover, the CpG island methylation rate of the IFN-γ promoter and the protein expression of DNMT3b, PI3K and p-Akt were increased in lung tissues after PM2.5 exposure. Both inhibitors reversed the CpG island hypermethylation of IFN-γ. In conclusion, in PM2.5-induced lung injury, the activated PI3K-Akt pathway, via an increase in DNMT3b expression, is involved in CpG hypermethylation of the IFN-γ gene promoter.
Assuntos
Interleucina-4 , Pneumonia , Animais , DNA , DNA (Citosina-5-)-Metiltransferases , Poeira , Interferon gama/genética , Interleucina-13 , Interleucina-5 , Pulmão , Material Particulado/toxicidade , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , DNA Metiltransferase 3BRESUMO
Occupational exposure to trichloroethylene (TCE) causes a systemic skin disorder with hepatitis known as TCE hypersensitivity syndrome (TCE-HS). Human Leukocyte Antigen (HLA)-B*13:01 is its susceptibility factor; however, the immunological pathogenesis of TCE-HS remains unknown. We herein examined the hypothesis that autoantibodies to CYP2E1 are primarily involved in TCE-HS. A case-control study of 80 TCE-HS patients, 186 TCE-tolerant controls (TCE-TC), and 71 TCE-nonexposed controls (TCE-nonEC) was conducted to measure their serum anti-CYP2E1 antibody (IgG) levels. The effects of TCE exposure indices, such as 8-h time-weighted-average (TWA) airborne concentrations, urinary metabolite concentrations, and TCE usage duration; sex; smoking and drinking habits; and alanine aminotransferase (ALT) levels on the antibody levels were also analyzed in the two control groups. There were significant differences in anti-CYP2E1 antibody levels among the three groups: TCE-TC > TCE-HS patients > TCE-nonEC. Antibody levels were not different between HLA-B*13:01 carriers and noncarriers in TCE-HS patients and TCE-TC. The serum CYP2E1 measurement suggested increased immunocomplex levels only in patients with TCE-HS. Multiple regression analysis for the two control groups showed that the antibody levels were significantly higher by the TCE exposure. Women had higher antibody levels than men; however, smoking, drinking, and ALT levels did not affect the anti-CYP2E1 antibody levels. Anti-CYP2E1 antibodies were elevated at concentrations lower than the TWA concentration of 2.5 ppm for TCE exposure. Since HLA-B*13:01 polymorphism was not involved in the autoantibody levels, the possible mechanism underlying the pathogenesis of TCE-HS is that TCE exposure induces anti-CYP2E1 autoantibody production, and HLA-B*13:01 is involved in the development of TCE-HS.
Assuntos
Citocromo P-450 CYP2E1 , Síndrome de Hipersensibilidade a Medicamentos , Exposição Ocupacional , Tricloroetileno , Autoanticorpos/sangue , Autoanticorpos/genética , Autoanticorpos/imunologia , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Citocromo P-450 CYP2E1/sangue , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/imunologia , Síndrome de Hipersensibilidade a Medicamentos/sangue , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/imunologia , Feminino , Antígenos HLA-B/sangue , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Hepatite Autoimune/sangue , Hepatite Autoimune/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Masculino , Exposição Ocupacional/efeitos adversos , Polimorfismo Genético , Tricloroetileno/imunologia , Tricloroetileno/toxicidadeRESUMO
The increased drug resistance and metastasis of melanoma resulted in poor prognosis of patients. Here, we designed and synthesized a novel hemicyanine-based fluorescent probe ZWZ-3, and investigated its application for melanoma imaging and treatment both in vitro and in vivo. ZWZ-3 preferentially accumulated in melanoma cells via a process that depended on the organic anion-transporting polypeptide (OATP), which targeted mitochondria on the hemicyanine cationic nitrogen. In addition, we investigated the effect and molecular mechanism of ZWZ-3 in melanoma. In vitro studies showed that ZWZ-3 promoted the generation of reactive oxygen species and induced mitochondrial-mediated cell apoptosis by upregulating Bax and activating caspase-3, caspase-9, and PARP. Importantly, ZWZ-3 also induced autophagy by upregulating LC-3II and Atg5 and downregulating P62. It significantly suppressed tumor growth of A375 xenograft tumor in mice without notable side effects. Histological and immunohistochemical analyses revealed that ZWZ-3 induced apoptosis and inhibited tumor cell proliferation. Thus, ZWZ-3 represents a novel theranostic agent that can be used to effectively targeting, detecting, and treating melanoma. It could also help monitoring disease progression and response to treatment.
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Occupational trichloroethylene (TCE) exposure can cause hypersensitivity syndrome (TCE-HS). The human leukocyte antigen (HLA)-B*13:01 is reportedly an important allele involved in TCE-HS onset. However, the threshold exposure level causing TCE-HS in relation to HLA-B*13:01 remains unknown. We conducted a case-control study comprising 37 TCE-HS patients and 97 age- and sex-matched TCE-tolerant controls from the Han Chinese population. Urine and blood of patients were collected on the first day of hospitalization, and those of controls were collected at the end of their shifts. Urinary trichloroacetic acid (TCA) was measured as an exposure marker, and end-of-shift levels in the patients were estimated using the biological half-life of 83.7 h. HLA-B genotype was identified using DNA from blood. Crude odds ratios (ORs) for TCE-HS in the groups with urinary TCA concentration >15 mg/L to ≤50 mg/L and of >50 mg/L were 21.9 [95% confidence interval (CI) 4.2-114.1] and 27.6 (6.1-125.8), respectively, when the group with urinary TCA ≤15 mg/L was used as a reference. The frequency of HLA-B*13:01, the most common allele in the patients, was 62.2% (23/37), which was significantly higher than 17.5% (17/97) in the TCE-tolerant controls, with a crude OR of 8.4 (3.1-22.6). The mutually-adjusted ORs for urinary TCA >15 to ≤50 mg/L, >50 mg/L, and for HLA-B*13:01 were 33.4 (4.1-270.8), 34.0 (5.3-217.1), and 11.0 (2.4-50.7), respectively. In conclusion, reduction of TCE exposure to ≤15 mg/L is required for TCE-HS prevention because urinary TCA concentration >15 mg/L showed increased risk of TCE-HS, regardless of whether the patients had the HLA-B*13:01 allele.
Assuntos
Exposição Ocupacional , Tricloroetileno , Alelos , Estudos de Casos e Controles , Antígenos HLA-B/genética , Humanos , Exposição Ocupacional/efeitos adversos , Ácido Tricloroacético , Tricloroetileno/análise , Tricloroetileno/toxicidadeRESUMO
BACKGROUND: Ubiquitously distributed benzene is a known hematotoxin. Increasing evidence has suggested that erythroid-related hematologic parameters may be sensitive to benzene exposure. Fat content, which is also closely associated with erythroid-related hematologic parameters, may affect the distribution and/or metabolism of benzene, and eventually benzene-induced toxicity. METHODS: To explore the influence of benzene exposure, fat content, and their interactions on erythroid-related hematologic parameters, we recruited 1669 petrochemical workers and measured their urinary S-phenylmercapturic acid (SPMA) concentration and erythroid-related hematological parameters. Indices for fat content included body fat percentage (BF%), plasma total cholesterol (TC) and triglycerides (TG), and occurrence of fatty liver. RESULTS: The dose-response curve revealed U-shaped nonlinear relationships of SPMA with hematocrit (HCT) and mean corpuscular hemoglobin concentration (MCHC) (P-overall < 0.001, and P-nonlinear < 0.015), as well as positive linear associations and r-shaped nonlinear relationships of continuous fat content indices with erythroid-related hematological parameters (P-overall ≤0.005). We also observed modification effects of fat content on the associations between benzene exposure and erythroid-related hematological parameters, with workers of lower or higher BF% and TG more sensitive to benzene-induced elevation of MCHC (Pinteraction = 0.021) and benzene-induced decrease of HCT (Pinteraction = 0.050), respectively. We also found that some erythroid-related hematologic parameters differed between subgroups of workers with different SPMA levels and fat content combination. CONCLUSIONS: Our study suggested that benzene exposure, fat content, and their interactions may affect erythroid-related hematological parameters in petrochemical workers in a complex manner that are worthy of further investigation.
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Tecido Adiposo , Benzeno/toxicidade , Composição Corporal , Exposição Ambiental/efeitos adversos , Hematologia , Lipídeos , Ocupações , Acetilcisteína/análogos & derivados , Acetilcisteína/urina , Adulto , Benzeno/metabolismo , Biomarcadores/urina , Indústria Química , Colesterol , Estudos Transversais , Suscetibilidade a Doenças , Exposição Ambiental/análise , Eritrócitos , Feminino , Hematócrito , Hemoglobinas , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/análise , TriglicerídeosRESUMO
Current treatment of advanced-stage nasopharyngeal carcinoma (NPC) is not satisfactory. Here, we developed a folic acid (FA) modified, gefitinib (GEF) and yttrium 90 (Y90) co-loaded, core-shell structured lipid-polymer hybrid nanoparticles (FA-GEF-Y90-LPNP). The size and zeta potential, drug release behavior, and uptake by tumor cells were investigated. The antitumor efficiency and toxicity of LPNP were evaluated in cancer cells and in tumor bearing mice. FA-GEF-Y90-LPNP with a mean size of 150 nm and zeta potential of -40 mV was able to enhance the accumulation in the NPC cells and exhibited the highest cytotoxicity. The AUC and T1/2 of FA-GEF-Y90-LPNP group was 217.62 ± 10.32 mg/L.h and 12.09 ± 0.43 h, respectively. FA-GEF-Y90-LPNP exhibited the best in vivo tumor inhibition ability, leading to a 221.2 ± 13.5 mm3 of tumor volume at day 21. FA-GEF-Y90-LPNP treatment resulted in almost no difference in the body weight. This may be the evidence that the systemic toxicity of FA-GEF-Y90-LPNP is low and may be used as safety system for the treatment of NPC.
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Ácido Fólico/farmacologia , Gefitinibe/farmacologia , Nanopartículas/química , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Polímeros/química , Radioisótopos de Ítrio/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiorradioterapia/métodos , Portadores de Fármacos/química , Humanos , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da PartículaRESUMO
Occupational trichloroethylene (TCE) exposure can induce life-threatening generalized dermatitis accompanied by hepatitis: TCE hypersensitivity syndrome (HS). Since the patients' exposure levels have not been fully clarified, this study estimated end-of-shift urinary concentrations of trichloroacetic acid (TCA) and their lower limit below which the disease occurrence was rare. TCA concentration was measured in 78 TCE HS patients whose urine was collected at admission between 2nd and 14th d after their last shift. Then a linear regression model was used to calculate the mean TCA concentration with 95% confidence interval (95% CI) and 95% prediction interval (95% PI) in the end-of-shift urine. The estimated mean concentration was 83 (95% CI, 49-140)â mg/l with 95% PI 9.6-720â mg/l. TCA concentrations were also measured in the end-of-shift urine of 38 healthy workers involved in the same job as were the patients. The geometric mean and its 95% CI were 127â mg/l and 16-984â mg/l, respectively. The exposure levels in HS patients might have thus overlapped with those in workers without HS. Accordingly, it was suggested that HS occurred in the environment where the workers were exposed to the TCE concentration corresponding to the urinary TCA concentration as low as 10â mg/l.
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Hipersensibilidade , Exposição Ocupacional/análise , Dermatopatias/induzido quimicamente , Tricloroetileno/efeitos adversos , Adolescente , Adulto , China/epidemiologia , Feminino , Hepatite/complicações , Humanos , Masculino , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Ácido Tricloroacético/urina , Tricloroetileno/análiseRESUMO
OBJECTIVES: The aim of this study was to explore the link between autophagy and collagen metabolism in patients with pelvic organ prolapse (POP) by detecting the expressions of autophagy factors, collagen, desmin, cytokeratin, and vimentin. METHODS: Histology of anterior vaginal wall and uterosacral ligament was assessed by hematoxylin-eosin staining in POP and non-POP control patients (n = 50 per group). Expressions of collagen types I and III, LC3II, beclin 1, and p62 were examined by Western blot analysis. Expressions of LC3, vimentin, desmin, and cytokeratin were detected by immunohistochemical staining. A linkage between the mean of LC3 integrated option density summation (IOD SUM) and POP clinicopathologic parameters including Pelvic Organ Prolapse Quantification (POP-Q) staging, age, body mass index, gravidity, and parity was analyzed by χ test, respectively. RESULTS: Compared with the control group, the following differences were found both in the vaginal wall and in the uterosacral ligament of the POP group: hematoxylin-eosin staining showed that collagen was more fragmented and disorganized. Expressions of collagen types I and III, LC3II, and beclin 1 were diminished, whereas the p62 level was elevated in Western blotting. Immunohistochemical staining showed that expression of LC3 was down-regulated, whereas vimentin level was increased. There were no significant differences in the expressions of desmin and cytokeratin in the 2 groups (P > 0.05). Mean of LC3 IOD SUM was highly linked to the POP-Q stage in the POP group (P < 0.05), whereas there was no significant correlation between the mean of LC3 IOD SUM and POP groups in age, body mass index, gravidity, and parity, respectively(P > 0.05). CONCLUSIONS: Autophagic activity is impaired in the POP group, which may relate to collagen deposition.
Assuntos
Autofagia , Colágeno/metabolismo , Ligamentos/metabolismo , Prolapso de Órgão Pélvico/metabolismo , Vagina/metabolismo , Idoso , Western Blotting , Estudos de Casos e Controles , Desmina/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Pessoa de Meia-Idade , Prolapso de Órgão Pélvico/patologia , Vimentina/metabolismoRESUMO
OBJECTIVE: The aims of this study were to investigate the effects of the vasodilator prostaglandin E1 on microvascular permeability, the expression of vascular endothelial growth factor (VEGF), as well as the structural and functional changes of the peripheral nerve in diabetic rats. METHODS: Streptozotocin-induced diabetes mellitus were randomly divided into two groups and intraperitoneally received, once daily, an injection of prostaglandin E1 at 1.6 µg/kg in normal saline or the same volume of normal saline (diabetic control), respectively. Six rats were randomly selected as normal controls. RESULTS: Diabetic controls exhibited a significant increase in the tail flick threshold temperature, water content of the sciatic nerve, serum VEGF level, and VEGF level in the sciatic nerve; in addition, a decrease in the sciatic nerve conduction velocity (NCV) was observed, compared with normal rats (P<0.01). Treatment with prostaglandin E1 resulted in similar changes but at a slower rate than in those without treatment. Diabetic control rats also showed histological and ultrastructural abnormalities of the sciatic nerve, whereas prostaglandin E1-treated rats exhibited similar but less severe injury. The serum VEGF level was negatively correlated with the sciatic NCV (r=-0.932, P<0.01) and positively correlated with the tail flick threshold temperature (r=0.835, P<0.01) as well as the water content of the sciatic nerve (r=0.901, P<0.01). CONCLUSION: Prostaglandin E1 could protect the peripheral nerve by improving sciatic nerve function, reducing the VEGF level, and decreasing the vascular permeability. This study provides an experimental proof that prostaglandin E1 has potential benefits in improving DPN in early stage.
Assuntos
Alprostadil/farmacologia , Permeabilidade Capilar , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas , Fármacos Neuroprotetores/farmacologia , Nervo Isquiático , Fator A de Crescimento do Endotélio Vascular , Vasodilatadores/farmacologia , Alprostadil/administração & dosagem , Animais , Permeabilidade Capilar/efeitos dos fármacos , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/prevenção & controle , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vasodilatadores/administração & dosagemRESUMO
AIMS: The nailfold microcirculation index (MI) is a non-invasive, objective, and highly sensitive blood capillary detection method. This study evaluated the diagnostic efficiency of the nailfold MI relative to the more subjective vibration perception threshold (VPT) examination for early diagnostic screening of diabetic peripheral neuropathy (DPN). METHODS: From February 2015 to February 2016, 227 diabetes mellitus patients and 39 healthy individuals were enrolled. Each subject underwent the MI test and the VPT examination. RESULTS: MI was more closely associated with DPN than age, diabetic duration, smoking, drinking, systolic pressure, serum creatinine, 24-h urinary protein, hypoxia-inducible factor-1α (HIF1A), vascular endothelial growth factor (VEGF), the VEGF receptors Flt-1 and Flt-4, ankle branchial index (ABI), DPN, or DPN stage (OR=11.819). Both the MI and VPT closely correlated with age, diabetic duration, serum creatinine, 24-h urinary protein, HIF1A, VEGF, Flt-1, Flt-4, ABI, DPN, and DPN stage. By the receiver operating characteristic (ROC) curve, the MI diagnostic cutoff point was 2.56, where the corresponding Youden's index was maximum and the area under ROC curve was 0.943. The diagnostic efficiency of MI and VPT were similar. MI and VPT indicated similar percentages of diabetic patients with DPN at the most severe stage, while MI achieved a higher diagnostic rate for the earliest stages. CONCLUSIONS: The nailfold MI is a feasible method for clinical early diagnostic screening of DPN in diabetic patients, and is more objective and reliable than VPT.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/diagnóstico , Dedos/irrigação sanguínea , Microcirculação , Unhas , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Percepção , Curva ROC , VibraçãoRESUMO
As an allotetraploid oilcrop, Brassica napus contains four duplicated Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) genes, which catalyze one of the rate-limiting steps in triacylglycerol (TAG) biosynthesis in plants. While all four BnDGAT1s have been expressed functionally in yeast, their expression patterns in different germplasms and tissues and also consequent contribution to seed oil accumulation in planta remain to be elucidated. In this study, the coding regions of the four BnDGAT1s were expressed in an Arabidopsis dgat1 mutant. All four BnDGAT1s showed similar effects on oil content and fatty acid composition, a result which is different from that observed in previous studies of their expression in yeast. Expression patterns of BnDGAT1s were analyzed in developing seeds of 34 B. napus inbred lines and in different tissues of 14 lines. Different expression patterns were observed for the four BnDGAT1s, which suggests that they express independently or randomly in different germplasm sources. Higher expression of BnDGAT1s was correlated with higher seed oil content lines. Tissue-specific analyses showed that the BnDGAT1s were expressed in a uniform pattern in different tissues. Our results suggest that it is important to maintain expression of the four BnDGAT1s for maximum return on oil content.