Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 43
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Front Cell Dev Biol ; 10: 1069248, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36467418

RESUMO

Orbital and eyelid disorders affect normal visual functions and facial appearance, and precise oculoplastic and reconstructive surgeries are crucial. Artificial intelligence (AI) network models exhibit a remarkable ability to analyze large sets of medical images to locate lesions. Currently, AI-based technology can automatically diagnose and grade orbital and eyelid diseases, such as thyroid-associated ophthalmopathy (TAO), as well as measure eyelid morphological parameters based on external ocular photographs to assist surgical strategies. The various types of imaging data for orbital and eyelid diseases provide a large amount of training data for network models, which might be the next breakthrough in AI-related research. This paper retrospectively summarizes different imaging data aspects addressed in AI-related research on orbital and eyelid diseases, and discusses the advantages and limitations of this research field.

2.
Am J Cancer Res ; 12(10): 4502-4519, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36381328

RESUMO

Tumor metastasis is the major cause of cancer mortality; therefore, it is imperative to discover effective therapeutic drugs for anti-metastasis therapy. In the current study, we investigated whether ivermectin (IVM), an FDA-approved antiparasitic drug, could prevent cancer metastasis. Colorectal and breast cancer cell lines and a cancer cell-derived xenograft tumor metastasis model were used to investigate the anti-metastasis effect of IVM. Our results showed that IVM significantly inhibited the motility of cancer cells in vitro and tumor metastasis in vivo. Mechanistically, IVM suppressed the expressions of the migration-related proteins via inhibiting the activation of Wnt/ß-catenin/integrin ß1/FAK and the downstream signaling cascades. Our findings indicated that IVM was capable of suppressing tumor metastasis, which provided the rationale on exploring the potential clinical application of IVM in the prevention and treatment of cancer metastasis.

3.
BMC Pharmacol Toxicol ; 23(1): 46, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35804463

RESUMO

BACKGROUND: Permethrin is one of the pyrethroid insecticides, which is widely used in agriculture and public health. Although acute toxicity of the insecticide has been studied, the chronic toxicity upon the long-term exposure has not been clear yet. The purpose of the current study is to investigate the organ toxicities of permethrin following its long-term low-dose exposure. METHODS: Male Wistar rats were daily administrated orally with permethrin (75 mg/kg body weight/day, gavage) for 90 days, and then the samples of biofluids (blood and urine) and organs including liver and kidney were collected. The serum and urine samples were measured by biochemical assay and the tissues of kidney and liver were examined and analyzed by histopathological method. RESULTS: The results showed that no change was found in serum and urine biochemical parameters for the toxicity; however, significant changes including hyperchromatic nuclei swollen in the hepatic parenchymal cells and the swelling proximal tubules in the kidneys were observed in the tissue structures of liver and kidneys in the histopathological sections. CONCLUSION: These results indicate that low-dose long-term exposure of permethrin can cause chronic toxicity with slight liver and kidney damage.


Assuntos
Inseticidas , Permetrina , Animais , Inseticidas/toxicidade , Rim/patologia , Fígado/patologia , Masculino , Permetrina/toxicidade , Ratos , Ratos Wistar
4.
BMC Pharmacol Toxicol ; 22(1): 60, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670615

RESUMO

BACKGROUND: This study aims to establish an in vitro monitoring approach to evaluate the pesticide exposures. We studied the in vitro cytotoxicity of three different body fluids of rats to the respective corresponding tissue-derived cells. METHODS: Wistar rats were orally administrated daily with three different doses of chlorpyrifos (1.30, 3.26, and 8.15 mg/kg body weight/day, which is equal to the doses of 1/125, 1/50, and 1/20 LD50, respectively) for consecutive 90 days. Blood samples as well as 24-hour urine and fecal samples were collected and processed. Then, urine, serum, and feces samples were used to treat the correspondent cell lines, i.e., T24 bladder cancer cells, Jurkat lymphocytes, and HT-29 colon cancer cells respectively, which derived from the correspondent tissues that could interact with the respective corresponding body fluids in organism. Cell viability was determined by using MTT or trypan blue staining. RESULTS: The results showed that urine, serum, and feces extract of the rats exposed to chlorpyrifos displayed concentration- and time-dependent cytotoxicity to the cell lines. Furthermore, we found that the cytotoxicity of body fluids from the exposed animals was mainly due to the presence of 3, 4, 5-trichloropyrindinol, the major toxic metabolite of chlorpyrifos. CONCLUSIONS: These findings indicated that urine, serum, and feces extraction, especially urine, combining with the corresponding tissue-derived cell lines as the in vitro cell models could be used to evaluate the animal exposure to pesticides even at the low dose with no apparent toxicological signs in the animals. Thus, this in vitro approach could be served as complementary methodology to the existing toolbox of biological monitoring of long-term and low-dose exposure to environmental pesticide residues in practice.


Assuntos
Clorpirifos/toxicidade , Fezes/química , Inseticidas/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorpirifos/sangue , Clorpirifos/urina , Monitoramento Ambiental/métodos , Humanos , Inseticidas/sangue , Inseticidas/urina , Masculino , Ratos Wistar
5.
Toxicol Ind Health ; 37(5): 270-279, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33856234

RESUMO

The organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) and heavy metal cadmium (Cd) are widespread environmental pollutants. They are persistent in the environment and can accumulate in organisms. Although the individual toxicity of DDT and Cd has been well documented, their combined toxicity is still not clear. Since liver is their common target, in this study, the individual and combined toxicity of DDT and Cd in human liver carcinoma HepG2 and human normal liver THLE-3 cell lines were investigated. The results showed that DDT and Cd inhibited the viability of HepG2 and THLE-3 cells dose-dependently and altered lysosomal morphology and function. Intracellular reactive oxygen species and lipid peroxidation levels were induced by DDT and Cd treatment. The combined cytotoxicity of DDT and Cd was greater than their individual cytotoxicity, and the interaction between Cd and DDT was additive on the inhibition of cell viability and lysosomal function of HepG2 cells. The interaction was antagonistic on the inhibition of cell viability of THLE-3 cells. These results may facilitate the evaluation of the cumulative risk of pesticides and heavy metal residues in the environment.


Assuntos
Cádmio/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/efeitos adversos , DDT/toxicidade , Poluentes Ambientais/toxicidade , Células Hep G2/efeitos dos fármacos , Inseticidas/toxicidade , Metais Pesados/toxicidade , Células Cultivadas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estresse Oxidativo/efeitos dos fármacos
6.
Front Microbiol ; 12: 649390, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33821158

RESUMO

The emergence and dissemination of bacterial infections is paralyzing our public health systems worldwide. Worse still, there are no effective antibiotics against bacterial toxins, which facilitate the infection. Natural herbs that target bacterial toxins may be a better choice for therapy of infectious diseases. However, most natural drugs present unknown compositions and unclear mechanisms. Here we demonstrated that the Chinese herb Paeoniae Radix aqueous extract (PRAE) could suppress alpha-toxin (α-toxin) of Staphylococcus aureus. We observed that the paeoniflorin derivative (PRAE-a) derivative in PRAE significantly abolished the hemolytic activity of S. aureus α-toxin. The analyses of high-performance liquid chromatography (HPLC), mass spectrometer (MS), Fourier transform infrared spectrometer (FTIR), and nuclear magnetic resonance (NMR) showed that PRAE-a was a glycoside compound with a paeoniflorin nucleus. We further found that PRAE-a disrupted the pore-forming ability of α-toxin by prevention of the dimer to heptamer. Therefore, PRAE-a proved to be an effective therapy for S. aureus lung infections in mice by inhibiting α-toxin. Collectively, these results highlighted that PRAE-a can be used as an antibacterial agent to attenuate S. aureus virulence by targeting α-toxin.

7.
Neuropharmacology ; 189: 108535, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33766630

RESUMO

Neuregulin-1 (NRG1), a family of EGF-like factors that activates ErbB receptors, can regulate the proliferation, migration, and myelinating of Schwann cells. We previously reported that NRG1/ErbB signal is responsible for organophosphate (OP)-induced delayed neuropathy (OPIDN) in hens, a susceptive animal model to neuropathic organophosphorous compounds. Our previous study discovered that a neuropathic OP, tri-o-cresyl phosphate (TOCP) activated NRG1/ErbB signaling pathway in both spinal cord and sciatic nerves of hens during the formation of OPIDN and lapatinib, a non-selective antagonist of ErbB1 and ErbB2 receptors, alleviated the toxicity. In this study, we intended to further look into the potential role of NRG1 in the pathogenesis of TOCP-induced axon damage in spinal cord and sciatic nerves and whether lapatinib could also rescue this damage in mice, an OPIDN-resistant animal model. The results revealed that no obvious toxic signs were observed after single TOCP exposure. However, slight histopathological wreck in lumbar spinal cord and sciatic nerves was found following TOCP intoxication, and the damage in sciatic nerves was characterized by axon degeneration of myelin sheath but not the loss of neural skeleton. Only histopathological damage induced by TOCP in spinal cord could be prevented by lapatinib. The translational expression of NRG1/ErbB signaling molecules was analyzed by both in vivo and in vitro studies. In general, NRG1/ErbB pathway was activated by TOCP while combined treatment with lapatinib attenuated TOCP-induced NRG1/ErbB signaling cascade. The results implied that NRG1/ErbB system may predominately play functional role in spinal cord (central nervous system) but not in sciatic nerves (peripheral nervous system) of mouse subjected to neurotoxic OP, which was confirmed by the study in vitro that lapatinib was not able to attenuate TOCP-induced neurotoxicity in rodent Schwann cell line RSC 96 cells.


Assuntos
Axônios/efeitos dos fármacos , Lapatinib/farmacologia , Plastificantes/toxicidade , Medula Espinal/efeitos dos fármacos , Tritolil Fosfatos/toxicidade , Animais , Axônios/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/farmacologia , Nervo Isquiático/citologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Medula Espinal/citologia , Medula Espinal/patologia
8.
Brain Res Bull ; 169: 51-62, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434623

RESUMO

Retinal detachment refers to the separation of the retinal neuroepithelium and pigment epithelium, usually involving the death of photoreceptor cells. Severe detachment may lead to permanent visual impairment if not treated properly and promptly. According to the underlying causes, retinal detachment falls into one of three categories: exudative retinal detachment, traction detachment, and rhegmatogenous retinal detachment. Like many other diseases, it is difficult to study the pathophysiology of retinal detachment directly in humans, because the human retinal tissues are precious, scarce and non-regenerative; thus, establishing experimental models that better mimic the disease is necessary. In this review, we summarize the existing models of the three categories of retinal detachment both in vivo and in vitro, along with an overview of their examination methods and the major strengths and weaknesses of each model.


Assuntos
Retina/fisiopatologia , Descolamento Retiniano/diagnóstico , Animais , Modelos Animais de Doenças , Descolamento Retiniano/etiologia , Descolamento Retiniano/fisiopatologia
9.
Ecotoxicol Environ Saf ; 195: 110467, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182532

RESUMO

Heavy metals and pesticides can be easily enriched in food chains and accumulated in organisms, thus pose significant threat to human health. However, their combined effects for long-term exposure at low dose has not been thoroughly investigated; especially there was no biofluid biomarker available to noninvasively diagnose the toxicosis of the combined exposure of the two chemicals at their low levels. In this study, we investigated the change of urine metabolites of rats with 90-day exposure to heavy metal cadmium (Cd) and/or organophosphorus pesticide chlorpyrifos (CPF) using gas chromatography-mass spectrometry (GC-MS)-based metabolomics approach. Our results showed that the interaction of Cd and CPF mainly displayed an antagonistic effect. We identified the panels of metabolite biomarkers in urine: benzoic acid and mannose were unique biomarkers for Cd exposure; creatinine and N-phenylacetyl glycine were unique biomarkers for CPF exposure; anthranilic acid, ribitol, and glucose were unique biomarkers for Cd plus CPF exposure. Our results suggest that 90-day exposure to Cd and/or CPF could cause a disturbance in energy and amino acid metabolism. And urine metabolomics analysis can help understand the toxicity of low dose exposure to mixed environmental chemicals.


Assuntos
Cádmio/toxicidade , Clorpirifos/toxicidade , Inseticidas/toxicidade , Animais , Ácido Benzoico/urina , Biomarcadores/urina , Creatinina/urina , Interações Medicamentosas , Cromatografia Gasosa-Espectrometria de Massas , Glicina/análogos & derivados , Glicina/urina , Masculino , Manose/urina , Metabolômica , Ratos
10.
Sci Rep ; 10(1): 4999, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193438

RESUMO

Chlorpyrifos (CPF) and cadmium (Cd) are widespread environmental pollutants, which are often present in drinking water and foods. However, the combined effects of CPF and Cd were not entirely clear at present. There was also no biomarker available to diagnose the poisoning of the two chemicals at low dose for long-term exposures. In this study, we investigated the change of serum metabolites of rats with subchronic exposure to CPF, Cd, and CPF plus Cd using gas chromatography-mass spectrometer-based metabolomics approach. We performed a stepwise optimization algorithm based on receiver operating characteristic to identify serum metabolite biomarkers for toxic diagnosis of the chemicals at different doses after 90-day exposure. We found that aminomalonic acid was the biomarker for the toxicity of Cd alone administration, and serine and propanoic acid were unique biomarkers for the toxicities of CPF plus Cd administrations. Our results suggest that subchronic exposure to CPF and Cd alone, or in combination at their low doses, could cause disturbance of energy and amino acid metabolism. Overall, we have shown that analysis of serum metabolomics can make exceptional contributions to the understanding of the toxic effects following long-term low-dose exposure of the organophosphorus pesticide and heavy metal.


Assuntos
Cádmio/toxicidade , Clorpirifos/toxicidade , Reativadores da Colinesterase/toxicidade , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Malonatos/sangue , Propionatos/sangue , Serina/sangue , Testes de Toxicidade Crônica/métodos , Animais , Biomarcadores/sangue , Cádmio/administração & dosagem , Clorpirifos/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Poluentes Ambientais/administração & dosagem , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Ratos Sprague-Dawley , Fatores de Tempo
11.
Biomarkers ; 25(1): 94-99, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31762333

RESUMO

Background: Permethrin is a type of widely used pyrethroid pesticide. Although acute toxicity of permethrin has been well-characterised, the non-acute toxicity of permethrin upon long-term exposure at low dose has been seldom studied yet. The current study investigates the time-course change of the metabolomic profiles of urine following the low level long-term exposure of permethrin and identified biomarkers of the chronic toxicity of permethrin.Methods: Male Wistar rats were administrated orally with permethrin (75 mg/kg body weight/day, 1/20 LD50) daily for consecutive 90 days. The urine samples from day 30, day 60, and day 90 after the first dosing were collected and analysed by 1H NMR spectrometry. Serum biochemical analysis was also carried out.Results: Permethrin caused significant changes in the urine metabolites such as taurine, creatinine, acetate, lactate, dimethylamine, dimethylglycine, and trimethylamine-N-oxide. These biological markers indicated prominent kidney and liver toxicity induced by permethrin. However, there was no change in serum biochemical parameters for the toxicity, indicating that metabolomic approach was much more sensitive in detecting the chronic toxicity.Conclusion: The time-course alteration of metabolomic profiles of the urine based on 1H NMR reflects the progressive development of the chronic toxicity with the long-term low-level exposure of permethrin.


Assuntos
Inseticidas/toxicidade , Metaboloma/efeitos dos fármacos , Permetrina/toxicidade , Animais , Biomarcadores/urina , Masculino , Metabolômica , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar , Medição de Risco , Fatores de Tempo , Testes de Toxicidade Crônica , Urinálise
12.
Sci Rep ; 9(1): 16989, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740703

RESUMO

As a major kind of carbamate insecticide, propoxur plays an important role in agriculture, veterinary medicine, and public health. The acute toxicity of propoxur is mainly neurotoxicity due to the inhibition of cholinesterase. However, little is known regarding the toxicity of propoxur upon long-term exposure at low dose. In this study, Wistar rats were orally administrated with low dose (4.25 mg/kg body weight/day) for consecutive 90 days. And the urine samples in rats treated with propoxur for 30, 60, and 90 days were collected and analyzed by employing 1H NMR-based metabolomics approach. We found that propoxur caused significant changes in the urine metabolites, including taurine, creatinine, citrate, succinate, dimethylamine, and trimethylamine-N-oxide. And the alteration of the metabolites was getting more difference compared with that of the control as the exposure time extending. The present study not only indicated that the changed metabolites could be used as biomarkers of propoxur-induced toxicity but also suggested that the time-course alteration of the urine metabolomic profiles could reflect the progressive development of the toxicity following propoxur exposure.


Assuntos
Biomarcadores/urina , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Propoxur/toxicidade , Administração Oral , Animais , Ácido Cítrico/urina , Creatinina/urina , Dimetilaminas/urina , Inseticidas/administração & dosagem , Inseticidas/toxicidade , Masculino , Metilaminas/urina , Propoxur/administração & dosagem , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar , Ácido Succínico/urina , Taurina/urina , Fatores de Tempo
13.
Front Neurosci ; 13: 586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244597

RESUMO

Hypothermia therapy is an old and important method of neuroprotection. Until now, many neurological diseases such as stroke, traumatic brain injury, intracranial pressure elevation, subarachnoid hemorrhage, spinal cord injury, hepatic encephalopathy, and neonatal peripartum encephalopathy have proven to be suppressed by therapeutic hypothermia. Beneficial effects of therapeutic hypothermia have also been discovered, and progress has been made toward improving the benefits of therapeutic hypothermia further through combination with other neuroprotective treatments and by probing the mechanism of hypothermia neuroprotection. In this review, we compare different hypothermia induction methods and provide a summarized account of the synergistic effect of hypothermia therapy with other neuroprotective treatments, along with an overview of hypothermia neuroprotection mechanisms and cold/hypothermia-induced proteins.

14.
J Exp Clin Cancer Res ; 38(1): 265, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215501

RESUMO

BACKGROUND: Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs. METHODS: We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo. MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro. Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo. Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR. RESULTS: Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo. Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription. CONCLUSIONS: These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers.


Assuntos
Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ivermectina/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Vincristina/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Feminino , Células HCT116 , Humanos , Ivermectina/farmacologia , Células K562 , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , NF-kappa B/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vincristina/farmacologia
15.
Neurochem Int ; 126: 86-95, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30878570

RESUMO

Therapeutic hypothermia as a physical method to lower the brain temperature of patients has been widely used in clinics as an effective and necessary step during the treatment of acute brain injury or edema. However, due to limitations of the ocular structure, the application of hypothermia in retinal neuroprotection still has an obvious barrier. Here, the neuroprotective mechanism produced by hypothermia in the retina was investigated, with the hopes of deciphering the key molecular targets of the signaling pathway to finally realize the ocular neuroprotection by regulating specific molecular targets. In present study, it was first demonstrated that hypothermia produced significant neuroprotection on photoreceptors (661 W cell) against glucose deprivation (GD)-induced injury in vitro and visible light-induced retinal damage in vivo. The results disclosed that hypothermia (32 °C) was able to attenuate the upregulation of heme oxygenase-1, cleaved Caspase-3, cleaved Caspase-9, and B-cell lymphoma-2-associated X caused by GD, and restored the decline of protective factor B-cell lymphoma-2 as well. Moreover, hypothermia suppressed the excessive generation of intracellular reactive oxygen species and depolarization of mitochondrial membrane potential, and showed marked neuroprotection against GD-induced damage in photoreceptors, which significantly reduced cell death percentage in vitro. In in vivo experiments, it was found that hypothermia was able to protect retinal function against light injury, restoring the decline of a-waves and b-waves in electroretinograms and maintaining the thickness of the retinal outer nuclear layer. Furthermore, hypothermia blocked the visible light-induced cell death pathway in the retina, suppressing poly(ADP-ribose) polymerase-1 activation. More importantly, it was demonstrated that cold-inducible RNA-binding protein (Cirbp) as a key molecular target played an important role in hypothermia-induced neuroprotection, which is the first proof of its function in ophthalmology. In in vitro experiments, hypothermia caused marked expression of Cirbp in photoreceptors. And reducing the expression of Cirbp with specific small interfering RNA was able to block the hypothermia-induced neuroprotection. Consistently, overexpressed Cirbp with Cirbp-gene-modified lentivirus mimicked the neuroprotection against GD-induced injury even under normal temperature (37 °C) conditions. Additionally, the overexpression of Cirbp was detected in hypothermia-treated retinas. These results indicate that hypothermia promotes neuroprotection in photoreceptors via activation of the Cirbp pathway. The study presented here suggests that therapeutic hypothermia may promote neuroprotection in the retina by activating Cirbp, and regulating Cirbp may mimic similar protection even under normal temperature conditions, which might be a specific molecular target in retinal neuroprotection.


Assuntos
Hipotermia Induzida , Células Fotorreceptoras/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular , Hipotermia Induzida/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
16.
Chem Res Toxicol ; 32(1): 122-129, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30500169

RESUMO

Cadmium (Cd) and chlorpyrifos (CPF) often coexist in the environment and induce combined toxicity to organisms. Here we studied the combined nephrotoxicity of environmentally relevant low doses of Cd and CPF. We treated the mice for 90 days with different doses of Cd and CPF and their mixtures via oral gavage. Then histopathological evaluation and biochemical analysis for kidney tissues were carried out. The change of metabolites in kidney was detected by using a metabolomics approach using GC-MS. We found that Cd, CPF, and their mixtures caused oxidative damage as well as disturbance of renal amino acid metabolism. We identified potential metabolite biomarkers in kidney, which included acetic acid for CPF treatment, glycerol and carboxylic acid for Cd treatment, and l-ornithine for the mixture of CPF and Cd treatment, respectively. In addition, we found that Cd promoted the metabolism of CPF in kidney. This may contribute to the result that the toxicity of the mixtures was lower than the sum of the toxicities of Cd and CPF alone. In conclusion, our results indicated that CPF and Cd could disrupt the kidney metabolism in rats even when they were exposed to a very low dose of CPF and Cd.


Assuntos
Cloreto de Cádmio/toxicidade , Clorpirifos/toxicidade , Rim/efeitos dos fármacos , Administração Oral , Animais , Cloreto de Cádmio/administração & dosagem , Clorpirifos/administração & dosagem , Relação Dose-Resposta a Droga , Cromatografia Gasosa-Espectrometria de Massas , Rim/metabolismo , Rim/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Free Radic Biol Med ; 129: 569-581, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30342188

RESUMO

Retinal degeneration is a major cause of severe vision loss and irreversible blindness and is characterized by progressive damage to retinal photoreceptor cells. Resveratrol (RSV) serves as an activator of the histone deacetylase, Sirt1, and has been shown to exert anti-oxidative properties. In this study, we mimicked retinal degeneration by subjecting photoreceptors (661 W cells) to glucose deprivation (GD) or light exposure. Under these conditions, we investigated the mechanisms underlying GD- or light exposure-induced cell death and the protective effect of RSV. We found that GD and light exposure resulted in mitochondrial dysfunction, oxidative stress, and cell death. Treatment of injured cells with RSV decreased the production of reactive oxygen species (ROS), improved the ratio of reduced/oxidized glutathione (GSH/GSSG), mitochondrial membrane potential and morphology, and reduced apoptosis. We used the caspase inhibitor, z-VAD-fmk, and a lentiviral-mediated shRNA knockdown of PARP-1 to reveal that GD and light exposure-induced cell death have different underlying mechanisms; GD triggered a caspase-dependent cell death pathway, whereas light exposure triggered a PARP-dependent cell death pathway. The level of caspase-9 and caspase-3, upregulated following GD, were reduced by treatment with RSV. Similarly, the level of PARP-1 and AIF, upregulated following light exposure, were decreased by treatment with RSV. Additionally, treatment with RSV elevated the protein expression and enzymatic activity of Sirt1 and a Sirt1 inhibitor reduced the protective effect of RSV against insult-induced cellular injuries, indicating that RSV's protective effect may involve Sirt1 activation. Finally, we investigated the neuroprotection of RSV in vivo. Administration of RSV to mice under extreme light exposure led to a suppression of the light-induced thinning of the outer nuclear layer (ONL) detected by hematoxylin and eosin (H&E) staining and restored retinal function evaluated by electroretinography (ERG). Taken together, our findings provide evidence that treatment with RSV has neuroprotective effects on both GD and light exposure-induced cell death pathways in photoreceptor cells.


Assuntos
Antioxidantes/farmacologia , Poli(ADP-Ribose) Polimerase-1/genética , Espécies Reativas de Oxigênio/antagonistas & inibidores , Resveratrol/farmacologia , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Inibidores de Caspase/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glucose/deficiência , Glucose/farmacologia , Glutationa/metabolismo , Luz/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Fotorreceptoras Retinianas Cones/citologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Transdução de Sinais/genética , Sirtuína 1/genética , Sirtuína 1/metabolismo
18.
Am J Transl Res ; 10(9): 2868-2876, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323873

RESUMO

Formation of tertiary dentin to maintain pulp vitality is a major odontoblastic response to dental pulp injury. Human bone morphogenetic protein 2 (hBMP2) can promote proliferation and differentiation of odontoblasts. Current study is interested in evaluating if the hBMP2 can promote the regeneration of tertiary dentin and cure dental pulp injury using the adenoviral vector to deliver hBMP2 cDNA into the pulp. Primary culture of dental pulp cells of exfoliated deciduous teeth (hDPCs) was established. Human serotype 5 adenoviral vector, AdCMV-hBMP2, was created. AdCMV-hBMP2 was used to transduce hDPCs in vitro and dental pulp cells in animal model in vivo. Data clearly demonstrated that hBMP2 increased ALP and mineralization. Reverse transcription-real time quantitative PCR (RT-QPCR) data showed that hBMP2 dramatically increased gene expressions of Runx2 (Runt-related transcription factor 2), ALP, Col Iα (Collagen 1a1), SP7 (Osterix), DMP1 (dentin matrix acidic phosphoprotein 1), DSPP (dentin sialophosphoprotein), and BSP (bonesialoprotein), which are normally involved in osteogenesis/odontogenesis. Data from in vivo assays demonstrated that hBMP2 promoted pulp cell proliferation and increased formation of tertiary dentin in dental pulp. Our in vitro and in vivo data suggest that hBMP2 gene can efficiently be delivered into the dental pulp cells by adenovirus, and show potential clinical application for the treatment of dental pulp damage.

19.
Front Mol Neurosci ; 11: 129, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29740279

RESUMO

Organophosphate-induced delayed neuropathy (OPIDN) is characterized by progressive axonal degeneration and demyelination of the spinal cord and sciatic nerves. The neuregulin 1/epidermal growth factor receptor (ErbB) signaling pathway is crucial for axonal myelination. In this study, we investigated whether the neuregulin 1/ErbB signaling pathway mediated the progression of OPIDN. Adult hens were given tri-o-cresyl phosphate (TOCP), a typical neuropathic organophosphorus compound, to induce OPIDN. The ErbB inhibitor lapatinib was administered to hens 4 h prior to and 4 days after TOCP exposure. The neuregulin 1/ErbB signaling pathway was examined for their role in maintaining spinal cord and sciatic nerve fiber integrity. Schwann cell line sNF96.2 was used as the in vitro cell model. The in vivo results showed that TOCP (750 mg/kg body weight, p.o.) induced prominent ataxia and significant axon degeneration in the spinal cord and sciatic nerves. Lapatinib (25 mg/kg body weight, p.o.) treatment attenuated OPIDN clinically and histopathlogically and partially prevented the TOCP-induced activation of neuregulin 1/ErbB signaling pathway. Lapatinib also prevented the TOCP-induced inhibition of neuropathy target esterase (NTE), a key enzyme during the development of OPIDN, and the disturbed metabolism of phosphatidylcholine in sciatic nerves. In addition, lapatinib was shown, in vitro, to protect sNF96.2 cells from TOCP-induced dedifferentiation through neuregulin 1/ErbB signaling. Our results suggest that neuregulin 1/ErbB, through regulation of NTE activity in the peripheral nervous system, mediates the progression of OPIDN. Thus, this signal may serve as a potential target for the treatment of OPIDN.

20.
J Environ Pathol Toxicol Oncol ; 37(4): 305-316, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30806237

RESUMO

Induced pluripotent stem cells (also called iPSCs) are somatic cells reprogrammed by overexpressing four nuclear transcriptional factors containing Sox2, Klf4, c-myc and Oct4 is the one of research hotspots. Its pluripotency, self-renewal capacity and wide accessibility to donor tissues have made possible the means for modified regenerative medicine. They are considered a possible basis of healthy tissue to cure diseases, like ophthalmic diseases, degenerative diseases, age-related macular degeneration (AMD), are primarily because of the weakening capability of photoreceptor cells, retinal ganglion cells (RGCs), retinal pigmented epithelium (RPE) or other retinal cells. And these retinal cells are unable to regenerate and currently there are no effective treatments to restore sight. iPSCs allow for the in vitro development of numerous varieties of retinal cells, and may treat these diseases by retinal transplantation. Although other stem cells could differentiate into retinal cells, iPSCs derived retinal cells might have numerous benefits as compared to other stem cell sources including embryonic stem (ES) cells. Mainly they would be directly obtained from the patient, therefore eradicating every probable chance of adverse immune responses. Second, making iPSCs just needs somatic cells, thus circumventing the valid ethical issues which limited the clinic use of ES cells derived from human. Third, iPSCs are parallel to ES cells in differentiation ability, they can be expanded in vitro and induced to differentiate into retinal cells, providing a renewable source for therapeutic applications and scientific researches. In this current review, we have concise latest progresses.


Assuntos
Células-Tronco Pluripotentes Induzidas/transplante , Doenças Retinianas/terapia , Transplante de Células-Tronco/métodos , Engenharia Tecidual/métodos , Animais , Humanos , Fator 4 Semelhante a Kruppel , Pesquisa Translacional Biomédica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...