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1.
Chemosphere ; 286(Pt 1): 131683, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34351278

RESUMO

Butachlor being an important member of chloroacetanilide herbicides, is frequently used in agriculture to control unwanted weeds. Exposure to butachlor can induce cancer, human lymphocyte aberration, and immunotoxic effects in animals. The current experimental trial was executed to determine the potential risks of herbicide butachlor to immunotoxicity and its mechanism of adverse effects on the spleen. For this purpose, mice were exposed to 8 mg/kg butachlor for 28 days, and the toxicity of butachlor on the spleen of mice was evaluated. We found that butachlor exposure led to an increase in serum ALB, GLU, TC, TG, and TP and changes in the morphological structure of the spleen of mice. More importantly, results showed that butachlor significantly increased the expression level of ATG-5, decreased the protein expression of LC3B and M-TOR, and significantly decreased the mRNA content of M-TOR and p62. Results revealed that the mRNA contents of APAF-1, CYTC, and CASP-9 related genes were significantly decreased after butachlor treatment. Subsequently, the mRNA levels of inflammatory cytokines (IL-1ß, TNF-α, IL-10) were reduced in the spleen of treated mice. This study suggested that butachlor induce spleen toxicity and activate the immune response of spleen tissue by targeting the CYTC/BCL2/M-TOR pathway and caspase cascading activation of spleen autophagy and apoptosis pathways which may ultimately lead to immune system disorders.


Assuntos
Herbicidas , Acetanilidas , Animais , Apoptose , Autofagia , Herbicidas/toxicidade , Camundongos , Baço
2.
J Hazard Mater ; 422: 126899, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34418838

RESUMO

Copper (Cu), a hazardous heavy metal, can lead to toxic effects on host physiology. Recently, specific mitochondria-localized miRNAs (mitomiRs) were shown to modulate mitochondrial function, but the underlying mechanisms remain undefined. Here, we identified mitomiR-1285 as an important molecule regulating mitochondrial dysfunction and mitophagy in jejunal epithelial cells under Cu exposure. Mitochondrial dysfunction and mitophagy were the important mechanisms of Cu-induced pathological damage in jejunal epithelial cells, which were accompanied by significant increase of mitomiR-1285 in vivo and in vitro. Knockdown of mitomiR-1285 significantly attenuated Cu-induced mitochondrial respiratory dysfunction, ATP deficiency, mitochondrial membrane potential reduction, mitochondrial reactive oxygen species accumulation, and mitophagy. Subsequently, bioinformatics analysis and luciferase reporter assay demonstrated that IDH2 was a direct target of mitomiR-1285. RNA interference of IDH2 dramatically reversed the effect that mitomiR-1285 knockdown relieved mitochondrial dysfunction and mitophagy induced by Cu, and the opposite effect was shown by overexpression of IDH2. Therefore, our results suggested that mitomiR-1285 aggravated Cu-induced mitochondrial dysfunction and mitophagy via suppressing IDH2 expression. These findings identified the important mechanistic connection between mitomiRs and mitochondrial metabolism under Cu exposure, providing a new insight into Cu toxicology.


Assuntos
MicroRNAs , Mitofagia , Animais , Cobre/toxicidade , Células Epiteliais , Mitocôndrias , Mitofagia/genética , Suínos
3.
Sci Total Environ ; : 152188, 2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34875328

RESUMO

As the primary source of electricity for various devices, batteries are important contributors to the overall electronic waste generated; and are widely considered a source of highly ecotoxic pollutants. Material leakage in battery manufacturing has not been completely solved, and the elucidation of the toxic mechanisms of battery wastewater exposure is needed. We demonstrated that battery waste exposure disrupted the intestinal flora and aggravated hepatotoxicity via the gut-liver axis. Under battery waste exposure, colon epithelium suffered physiological damage, and gene and protein expression levels related to gut barrier function (ZO-1, claudin-1, and Occludin) were significantly downregulated. Meanwhile, battery waste reduced the richness and diversity of the flora, causing metabolites produced by intestinal microbes to enter the gut-liver axis. Gut microbial dysbiosis impaired mitochondrial respiratory function in liver tissue cells, and mitophagy, apoptosis, and the disorder of glycolipids and amino acid metabolism were induced in hosts exposed to battery toxins. Altogether, these results provided novel insights into the underlying mechanisms of battery wastewater-related hepatotoxicity induced by gut microbiota via the gut-liver axis, which has public health implications where humans and animals are exposed to industrial toxins generated by uncontained battery disposal.

4.
Ecotoxicol Environ Saf ; 230: 113117, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34959015

RESUMO

Arsenic is a dangerous metalloid-material which is known to cause liver injury in many animals and humans. However, little is known about the underlying mechanism of arsenic-induced hepatotoxicity in poultry. This study was executed to systematically investigate the potential role of mitochondrial biogenesis, mitophagy and apoptosis in duck hepatotoxicity caused by arsenic. Results showed that the body weight and liver coefficient of duck had distinct changed after arsenic-exposure, and the arsenic content in serum and liver also increased significantly in a dose-dependent manner. Meanwhile, histopathological examination and metabolomics results showed that arsenic-exposure caused severe steatosis and metabolism disorder in liver tissues. Furthermore, arsenic-exposure significantly inhibited AMPK/PGC-1α-mediated mitochondrial biogenesis, determined by the ultrastructure observation and down-regulation of p-AMPKα/AMPKα, PGC-1α, NRF1, NRF2, TFAM, TFB1M, TFB2M and COX-Ⅳ expression levels. Besides, arsenic-treatment obviously increased the levels of mitophagy (PINK1, Parkin, LC3, P62) and pro-apoptotic (Caspase-3, Caspase-9, Cleaved Caspase-3, Cytc, Bax, P53) indexes, and simultaneously resulted in reductions in anti-apoptosis index (Bcl-2). Overall, our findings provided evidences that arsenic-induced duck hepatotoxicity may be caused by a combination of impaired mitochondrial biosynthesis, mitophagy, and mitochondrial-dependent apoptosis. To our knowledge, this is the first report to systematically investigate the potential mechanism of arsenic-induced hepatotoxicity in poultry.

5.
Food Funct ; 12(20): 9642-9657, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34664585

RESUMO

Copper (Cu) is an essential trace mineral, but its excessive intake can lead to potentially toxic effects on host physiology. The mammalian intestine harbors various microorganisms that are associated with intestinal barrier function and inflammation. In this study, the influences of Cu on barrier function, microbiota, and its metabolites were examined in the jejunum and colon of pigs. Here, we identified that the physical and chemical barrier functions were impaired both in the jejunum and colon, as evidenced by the decreased expression of tight junction proteins (ZO-1, Occludin, Claudin-1, and JAM-1) and mucous secretion-related genes, positive rate of Muc2, and secretion of SIgA and SIgG. Additionally, inflammatory cytokines were overexpressed in the jejunum and colon. Furthermore, Cu might increase the abundances of Mycoplasma, Actinobacillus and unidentified_Enterobacteriaceae in the jejunum, which significantly affected pentose and glucoronate interconversions, histidine metabolism, folate biosynthesis, porphyrin metabolism, and purine metabolism. Meanwhile, the abundances of Lactobacillus and Methanobrevibacter were remarkably decreased and Streptococcus, unidentified_Enterobacteriaceae, and unidentified_Muribaculaceae were significantly increased in the colon, with an evident impact on glycerophospholipid metabolism, retinol metabolism, and steroid hormone biosynthesis. These findings revealed that excess Cu had significant effects on the microbiota and metabolites in the jejunum and colon, which were involved in intestinal barrier dysfunction and inflammation.

6.
Ecotoxicol Environ Saf ; 223: 112587, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352579

RESUMO

Cu is a metallic element that widely spread over in the environment, which have raised wide concerns about the potential toxic effects and public health threat. The objective of this study aimed to investigate the impression of copper (Cu)-triggered toxicity on mitochondrial dynamic, oxidative stress, and unfolded protein response (UPRmt) in fundic gland of pigs. Weaned pigs were randomly distributed into three groups, fed with different Cu of 10 mg/kg (control group), 125 mg/kg (group I), and 250 mg/kg (group Ⅱ). The trial persisted for 80 days and the fundic gland tissues were collected for further researches. Moreover, the markers participated to mitochondrial dynamic, UPRmt,and oxidative stress in fundic gland were determined. Results revealed that vacuolar degeneration were observed in the treated groups contrast with control group, and the Cu level was boosted with the increasing intake of Cu. Besides that, the levels of CAT, TRX, H2O2, and G6PDH were reduced in group Ⅰ and group Ⅱ, the mRNA levels of NRF2, HO-1, SOD-1, CAT, SOD-2, GSR, GPX1, GPX4, and TRX in the treated groups were promoted contrast to control group. Furthermore, the protein expression of KEAP1 was dramatically decreased, and the protein expression of NRF2, TRX and HO-1 were markedly enhanced in group Ⅰ and Ⅱ at 80 days. Moreover, the mRNA and protein expression levels of MFN1, MFN2, and OPA1 down-regulated and protein level of DRP1 was increased with the adding levels of Cu. Nevertheless, the UPRmt-related mRNA levels of CLPP, HTRA-2, CHOP, HSP10, and HSP60 were enhanced dramatically in Cu treatment group compared with control group. In general, our current study demonstrated that excessive absorption of Cu in fundic gland were related with stimulating UPRmt, oxidative stress, and the NRF2 interceded antioxidant defense. These results could afford an updated evidence on molecular theory of Cu-invited toxicity.


Assuntos
Cobre , Dinâmica Mitocondrial , Animais , Cobre/toxicidade , Peróxido de Hidrogênio , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Suínos , Resposta a Proteínas não Dobradas
7.
J Inorg Biochem ; 224: 111581, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34419760

RESUMO

Copper (Cu) is one of the ubiquitous environmental pollutants which have raised wide concerns about the potential toxic effects and public health threat. For deeply investigating the nephrotoxicity induced by Cu, the effects of Cu on mitochondria-mediated apoptosis in kidney were first to analyze by combining metabolomics and molecular biology techniques. In this study, broiler chicks were fed with different contents of Cu (11, 110, 220, and 330 mg/kg Cu) for 49 d. The results of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining and transmission electron microscope showed that Cu could induce apoptosis in kidney, characterized by the increasing of TUNEL-positive cells and mitochondrial vacuolation. Additionally, a total of 62 differential metabolites were detected by liquid chromatography-mass spectrometry (LC-MS), and mainly enriched in the metabolic pathways including riboflavin metabolism, glutathione metabolism, sphingolipid metabolism, and glycerophospholipid metabolism, which were closely to mitochondrial metabolism. Meanwhile, the decreased mitochondrial membrane potential (MMP), increased mitochondrial membrane permeability and the change of mRNA and protein expression levels associated with mitochondria-mediated apoptosis and mitochondrial dynamics confirmed that Cu could induce mitochondria-mediated apoptosis. Therefore, our results demonstrated that Cu induced mitochondria-mediated apoptosis in kidney. Moreover, this study highlighted the metabolic characteristics of Cu to kidney, which suggested that mitochondrial metabolism could be considered as an important factor influencing toxicity.

8.
Ecotoxicol Environ Saf ; 220: 112394, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34091186

RESUMO

Arsenic (As) and antimony (Sb) are known as an environmental contaminant with cardiotoxicity properties. The endoplasmic reticulum (ER) is the largest calcium reservoir in the cell, and its calcium homeostasis disorder plays a vital role in endoplasmic reticulum stress (ERS) and apoptosis. The objective of this study was to investigate whether As and Sb induced apoptosis via endoplasmic reticulum stress (ERS) linked to calcium homeostasis disturbance. In this study, thirty-two adult mice were gavage-fed daily with As2O3 (4 mg/kg), SbCl3 (15 mg/kg) and co-treat with SbCl3 (15 mg/kg) and As2O3 (4 mg/kg) daily for 60 days. It was observed that As or/and Sb caused histopathological lesions and ER expansion of the heart. Meanwhile, the gene expression of ER Ca2+ release channels (RyR2 and IP3R) and calmodulin-dependent protein kinase II (CaMKII) increased while the levels of mRNA and protein of ER Ca2+ uptake channel (SERCA2) downregulated significantly compared to the controls. Then, As or/and Sb induced ERS and triggered the ER apoptotic pathway by activating unfolded protein response (UPR)-associated genes ((PERK, ATF6, IRE1, XBP1, JNK, GRP78), and apoptosis-related genes (Caspase12, Caspase3, p53, CHOP). Above indicators in As + Sb group became more severe than that of As group and Sb group. Overall, our results proved that the cardiotoxicity caused by As or/and Sb might be concerning disturbing calcium homeostasis, which induced apoptosis through the ERS pathway.


Assuntos
Antimônio/toxicidade , Arsênio/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Coração/efeitos dos fármacos , Animais , Antimônio/metabolismo , Apoptose , Arsênio/metabolismo , Canais de Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxinas , Caspase 3/metabolismo , Morte Celular , Regulação para Baixo , Retículo Endoplasmático/metabolismo , Poluentes Ambientais/toxicidade , Homeostase/efeitos dos fármacos , Masculino , Metais Pesados/toxicidade , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Resposta a Proteínas não Dobradas
9.
Bioact Mater ; 6(12): 4580-4590, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34095617

RESUMO

CRISPR-Cas12a system has been shown promising for nucleic acid diagnostics due to its rapid, portable and accurate features. However, cleavage of the amplicons and primers by the cis- and trans-activity of Cas12a hinders the attempts to integrate the amplification and detection into a single reaction. Through phosphorothioate modification of primers, we realized onepot detection with high sensitivity using plasmids of SARS-CoV-2, HPV16 and HPV18. We also identified the activated Cas12a has a much higher affinity to C nucleotide-rich reporter than others. By applying such reporters, the reaction time required for a lateral-flow readout was significantly reduced. Furthermore, to improve the specificity of the strip-based assay, we created a novel reporter and, when combined with a customized gold-nanopaticle strip, the readout was greatly enhanced owing to the elimination of the nonspecific signal. This established system, termed Targeting DNA by Cas12a-based Eye Sight Testing in an Onepot Reaction (TESTOR), was validated using clinical cervical scrape samples for human papillomaviruses (HPVs) detection. Our system represents a general approach to integrating the nucleic acid amplification and detection into a single reaction in CRISPR-Cas systems, highlighting its potential as a rapid, portable and accurate detection platform of nucleic acids.

10.
Chemosphere ; 283: 131226, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34146870

RESUMO

Butachlor is a systemic herbicide widely applied on wheat, rice, beans, and different other crops, and is frequently detected in groundwater, surface water, and soil. Therefore, it is necessary to investigate the potential adverse health risks and the underlying mechanisms of hepatotoxicity caused by exposure to butachlor in invertebrates, other nontarget animals, and public health. For this reason, a total of 20 mice were obtained and randomly divided into two groups. The experimental mice in one group were exposed to butachlor (8 mg/kg) and the mice in control group received normal saline. The liver tissues were obtained from each mice at day 21 of the trial. Results indicated that exposure to butachlor induced hepatotoxicity in terms of swelling of hepatocyte, disorders in the arrangement of hepatic cells, increased concentrations of different serum enzymes such as alkaline phosphate (ALP) and aspartate aminotransferase (AST). The results on the mechanisms of liver toxicity indicated that butachlor induced overexpression of Apaf-1, Bax, Caspase-3, Caspase-9, Cyt-c, p53, Beclin-1, ATG-5, and LC3, whereas decreases the expression of Bcl-2 and p62 suggesting abnormal processes of apoptosis and autophagy. Results on different metabolites (61 differential metabolites) revealed upregulation of PE and LysoPC, whereas downregulation of SM caused by butachlor exposure in mice led to the disruption of glycerophospholipids and lipid metabolism in the liver. The results of our experimental research indicated that butachlor induces hepatotoxic effects through disruption of lipid metabolism, abnormal mechanisms of autophagy, and apoptosis that provides new insights into the elucidation of the mechanisms of hepatotoxicity in mice induced by butachlor.


Assuntos
Herbicidas , Acetanilidas/toxicidade , Animais , Herbicidas/toxicidade , Metabolismo dos Lipídeos , Fígado , Camundongos
11.
Ecotoxicol Environ Saf ; 220: 112395, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102394

RESUMO

Copper (Cu), one of the heavy metals, is far beyond the carrying capacity of the environment with Cu mining, industrial wastewater discharging and the use of Cu-containing pesticides. Intaking excess Cu can cause toxic effects on liver, kidney, heart, but few studies report Cu toxicity on brain tissue. It is noteworthy that most toxicity tests are based on rodent models, but large mammals chosen as animal models has no reported. To explore the relationship of the Cu toxicity and mitochondria-mediated apoptosis on hypothalamus in pigs, the content of Cu, histomorphology, mitochondrial related indicators, apoptosis, and AMPK-mTOR signaling pathway were detected. Results showed that Cu could accumulate in hypothalamus and lead to mitochondrial dysfunction, evidenced by the decrease of ATP production, activities of respiratory chain complex I-IV, and mitochondrial respiratory function in Cu-treated groups. Additionally, the genes and proteins expression of Bax, Caspase-3, Cytc in treatment group were higher than control group. Furthermore, the protein level of p-AMPK was enhanced significantly and p-mTOR was declined, which manifested that AMPK-mTOR signaling pathway was activated in Cu-treated groups. In conclusion, this study illuminated that the accumulation of Cu could cause mitochondrial dysfunction, induce mitochondria-mediated apoptosis and activate AMPK-mTOR pathway in hypothalamus.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cobre/toxicidade , Hipotálamo/efeitos dos fármacos , Metais Pesados/toxicidade , Mitocôndrias/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose , Caspase 3/metabolismo , Cobre/metabolismo , Citocromos c/metabolismo , Exposição Ambiental , Hipotálamo/metabolismo , Metais Pesados/metabolismo , Mitocôndrias/metabolismo , Modelos Animais , Transdução de Sinais , Suínos , Proteína X Associada a bcl-2/metabolismo
12.
Sci Total Environ ; 788: 147780, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34022569

RESUMO

Arsenic is an important hazardous metalloid commonly found in polluted soil, rivers and groundwater. However, few studies exist regarding the effect of arsenic trioxide (ATO) on the gut-liver axis and consequent hepatotoxicity in waterfowl. Here, we investigated the influence of ATO on duck intestines and livers, and explored the role of the gut-liver axis in ATO-induced hepatotoxicity and intestinal toxicity. Our results demonstrated that ATO-exposure induced intestinal damage, liver inflammatory cell infiltration and vesicle steatosis. Additionally, the intestinal microbiota community in ATO-exposed ducks displayed significantly decreased α-diversity and an altered bacterial composition. Moreover, ATO-exposure markedly reduced the expression of intestinal barrier-related proteins (Claudin-1, MUC2, ZO-1 and Occludin), resulting in increased intestinal permeability and elevated lipopolysaccharide levels. Simultaneously, ATO-exposure also upregulated pyroptosis-related index levels in the liver and jejunum, and increased pro-inflammatory cytokine production (IFN-γ, TNF-α, IL-18, and IL-1ß). Our further mechanistic studies showed that ATO-induced liver and jejunum inflammation were provoked by the activation of the LPS/TLR4/NF-κB signaling pathway and NLRP3 inflammasome. In summary, these results manifested that ATO exposure can cause liver and jejunal inflammation and pyroptosis, and the indirect gut-liver axis pathway may play an essential role in the potential mechanism of ATO-induced hepatotoxicity.


Assuntos
Arsênio , Patos , Animais , Arsênio/toxicidade , Inflamação/induzido quimicamente , Fígado , Piroptose
13.
Ecotoxicol Environ Saf ; 218: 112284, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33945902

RESUMO

Copper poses huge environmental and public health concerns due to its widespread and persistent use in the past several decades. Although it is well established that at higher levels copper causes nephrotoxicity, the exact mechanisms of its toxicity is not fully understood. Therefore, this experimental study for the first time investigates the potential molecular mechanisms including transcriptomics, metabolomics, serum biochemical, histopathological, cell apoptosis and autophagy in copper-induced renal toxicity in pigs. A total of 14 piglets were randomly assigned to two group (7 piglets per group) and treated with a standard diet (11 mg CuSO4 per kg of feed) and a high copper diet (250 mg CuSO4 per kg of feed). The results of serum biochemical tests and renal histopathology suggested that 250 mg/kg CuSO4 in the diet significantly increased serum creatinine (CREA) and induced renal tubular epithelial cell swelling. Results on transcriptomics and metabolomics showed alteration in 804 genes and 53 metabolites in kidneys of treated pigs, respectively. Combined analysis of transcriptomics and metabolomics indicated that different genes and metabolism pathways in kidneys of treated pigs were involved in glycerophospholipids metabolism and glycosphingolipid metabolism. Furthermore, copper induced mitochondrial apoptosis characterized by increased bax, bak, caspase 3, caspase 8 and caspase 9 expressions while decreased bcl-xl and bcl2/bax expression. Exposure to copper decreased the autophagic flux in terms of increased number of autophagosomes, beclin1 and LC3b/LC3a expression and p62 accumulation. These results indicated that the imbalance of glycosphingolipid metabolism, the impairment of autophagy and increase mitochondrial apoptosis play an important role in copper induced renal damage and are useful mechanisms to understand the mechanisms of copper nephrotoxicity.

14.
Chemosphere ; 277: 130222, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33794430

RESUMO

Fluorine (F) and its compounds produced from industrial production and coal combustion can cause air, water and soil contamination, which can accumulate in animals, plants and humans via food chain threatening public health. Fluoride exposure affects liver, kidney, gastrointestinal and reproductive system in humans and animals. Literature regarding fluoride influence on intestinal structure and microbiota composition in ducks is scarce. This study was designed to investigate these effects by using simple and electron microscopy and 16S rRNA sequencing techniques. Results indicated an impaired structure with reduced relative distribution of goblet cells in the fluoride exposed group. Moreover, the gut microbiota showed a significant decrease in alpha diversity. Proteobacteria, Firmicutes and Bacteroidetes were the most abundant phyla in both control and fluoride-exposed groups. Specifically, fluoride exposure resulted in a significant decrease in the relative abundance of 9 bacterial phyla and 15 bacterial genera. Among them, 4 phyla (Latescibacteria, Dependentiae, Zixibacteria and Fibrobacteres) and 4 genera (Thauera, Hydrogenophaga, Reyranella and Arenimonas) weren't even detectable in the gut microbiota of the ducks. In summary, higher fluoride exposure can significantly damage the intestinal structure and gut microbial composition in ducks.


Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Patos , Fluoretos/toxicidade , Humanos , RNA Ribossômico 16S/genética
15.
Ecotoxicol Environ Saf ; 217: 112225, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33864983

RESUMO

Long-term exposure to excessive fluoride causes chronic damage in the body tissues and could lead to skeletal and dental fluorosis. Cartilage damage caused by excessive fluoride intake has gained wide attention, but how fluoride accumulation blocks the development of chondrocytes is still unclear. Here, we report a negative correlation between the length and growth plate width after NaF treatments via apoptosis and autophagy, with shrinkage of cells, nuclear retraction, dissolution of chondrocytes. Whereas, fluoride exposure had no significant effect on the number and distribution of the osteoclasts which were well aligned. More importantly, fluoride exposure induced apoptosis of tibial bone through CytC/Bcl-2/P53 pathways via targeting Caspase3, Caspase9, Bak1, and Bax expressions. Meanwhile, the Beclin1, mTOR, Pakin, Pink, and p62 were elevated in NaF treatment group, which indicated that long-term excessive fluoride triggered the autophagy in the tibial bone and produced the chondrocyte injury. Altogether, fluoride exposure induced the chondrocyte injury by regulating the autophagy and apoptosis in the tibial bone of ducks, which demonstrates that fluoride exposure is a risk factor for cartilage development. These findings revealed the essential role of CytC/Bcl-2/P53 pathways in long-term exposure to fluoride pollution and block the development of chondrocytes in ducks, and CytC/Bcl-2/P53 can be targeted to prevent fluoride induced chondrocyte injury.


Assuntos
Condrócitos/fisiologia , Patos/fisiologia , Fluoretos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Condrócitos/efeitos dos fármacos , Condrogênese , Fluoretos/metabolismo , Lâmina de Crescimento
16.
Biomed Res Int ; 2021: 8871328, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33532499

RESUMO

Acetyl-L-carnitine (ALC) is an effective substrate for mitochondrial energy metabolism and is known to prevent neurodegeneration and attenuate heavy metal-induced injury. In this study, we investigated the function of ALC in the recovery of mouse spermatogonia cells (GC-1 cells) after heat stress (HS). The cells were randomly divided into three groups: control group, HS group (incubated at 42°C for 90 min), and HS + ALC group (treatment of 150 µM ALC after incubated at 42°C for 90 min). After heat stress, all of the cells were recovered at 37°C for 6 h. In this study, the content of intracellular lactate dehydrogenase (LDH) in the cell supernatant and the malondialdehyde (MDA) levels, catalase (CAT) levels, and total antioxidant capacity (T-AOC) were significantly increased in the HS group compared to the CON group. In addition, the mitochondrial membrane potential (MMP) was markedly decreased, while the apoptosis rate and the expression of apoptosis-related genes (Bcl-2, Bax, and caspase3) were significantly increased in the HS group compared to the CON group. Furthermore, the number of autophagosomes and the expression of autophagy-related genes (Atg5, Beclin1, and LC3II) and protein levels of p62 were increased, but the expression of LAMP1 was decreased in the HS group compared to the CON group. However, treatment with ALC remarkably improved cell survival and decreased cell oxidative stress. It was unexpected that levels of autophagy were markedly increased in the HS + ALC group compared to the HS group. Taken together, our present study evidenced that ALC could alleviate oxidative stress and improve the level of autophagy to accelerate the recovery of GC-1 cells after heat stress.


Assuntos
Acetilcarnitina/farmacologia , Autofagia/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Espermatogônias/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Masculino , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espermatogônias/citologia
17.
Ecotoxicol Environ Saf ; 213: 112040, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33610943

RESUMO

Among different synthetic compounds copper (Cu) is persistently and frequently used as growth promoter, antibacterial, antifungal and antiparasitic agent and has become common environmental pollutant. Therefore, this study explores the cardio-toxic effects of control group (10 mg/kg bw Cu) and treatment group (125 and 250 mg/kg bw Cu), and it association with process of autophagy and metabolomics in myocardium of pigs kept in three different experimental treatments for a period of 80 days. The results of serum biochemical parameters showed a significantly increase in creatinine kinase (CK), creatine kinase-MB (CK-MB), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) and aspartate aminotransferase (AST) in pigs exposed to 125 mg/kg bw and 250 mg/kg bw Cu. Meanwhile, the severe structural abnormalities in cardiomyocytes were found when exposed to 250 mg/kg Cu at day 80. In addition, the mRNA and proteins (Beclin1, ATG5 and LC3II) expression levels were significantly increased and p62 was significantly decreased in cardiomyocytes exposed to 250 mg/kg Cu at day 80 of the trial. Further, UPLC-QTOF/MS technique showed that 7 metabolites were up-regulated and 37 metabolites were down-regulated in cardiomyocytes after 250 mg/kg Cu treatment, with a principal impact on the metabolic pathways including glycerophospholipid metabolism, one carbon pool by folate, fatty acid elongation and fatty acid degradation, which were related to autophagy. Overall, our study identified the autophagy processes and metabolites in metabolic pathways in Cu-induced myocardium injury, which provided useful evidence of myocardium toxicity caused by Cu exposure via metabolomics and multiple bioanalytic methods.


Assuntos
Autofagia/efeitos dos fármacos , Cobre/toxicidade , Poluentes Ambientais/toxicidade , Coração/efeitos dos fármacos , Animais , Poluentes Ambientais/metabolismo , Coração/fisiologia , Redes e Vias Metabólicas , Metabolômica , Miocárdio/metabolismo , Suínos
18.
J Hazard Mater ; 408: 124888, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33360697

RESUMO

Copper (Cu), a transition metal with essential cellular functions, exerts toxic effects when present in excess by inducing oxidative stress. However, the Cu-induced crosstalk between mitophagy and apoptosis and the underlying mechanisms are unknown. Here, the mechanism of Cu-induced hepatotoxicity mediated by mitophagy and apoptosis was explored in vivo and in vitro. In in vivo experiments, chickens were fed a diet with various levels of Cu (11, 110, 220, and 330 mg/kg) for 7 weeks, which led to ultrastructural damage, mitophagy, and apoptosis in liver tissue. In vitro experiments on primary chicken hepatocytes showed that Cu treatment for 24 h increased the numbers of mitophagosomes and upregulated PINK1, parkin, and p62 mRNA levels and parkin and p62 protein levels, inducing mitophagy. Moreover, treatment with 3- methyladenine (3-MA) aggravated Cu-induced S-phase arrest in cell cycle; increased the apoptotic rate; increased p53, Bak1, Bax, Cyt C, and Caspase3/cleaved-caspase3 mRNA and protein levels; and decreased Bcl2 mRNA and protein levels. However, rapamycin (Rapa) had the opposite effects on the above factors. In general, the results reveal that Cu exposure can cause mitophagy through the PINK1/Parkin pathway in chicken livers, and that mitophagy might attenuate Cu-induced mitochondrial apoptosis.


Assuntos
Galinhas , Mitofagia , Animais , Apoptose , Cobre/toxicidade , Fígado , Mitocôndrias , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética
19.
PLoS Biol ; 18(12): e3000978, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33320883

RESUMO

The recent outbreak of betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is responsible for the Coronavirus Disease 2019 (COVID-19) global pandemic, has created great challenges in viral diagnosis. The existing methods for nucleic acid detection are of high sensitivity and specificity, but the need for complex sample manipulation and expensive machinery slow down the disease detection. Thus, there is an urgent demand to develop a rapid, inexpensive, and sensitive diagnostic test to aid point-of-care viral detection for disease monitoring. In this study, we developed a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated proteins (Cas) 12a-based diagnostic method that allows the results to be visualized by the naked eye. We also introduced a rapid sample processing method, and when combined with recombinase polymerase amplification (RPA), the sample to result can be achieved in 50 minutes with high sensitivity (1-10 copies per reaction). This accurate and portable detection method holds a great potential for COVID-19 control, especially in areas where specialized equipment is not available.


Assuntos
Teste para COVID-19/métodos , Sistemas CRISPR-Cas/genética , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Sequência de Bases , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Ecotoxicol Environ Saf ; 206: 111366, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33010598

RESUMO

To explore the effects of copper (Cu) on energy metabolism and AMPK-mTOR pathway-mediated autophagy in kidney, a total of 240 one-day-old broiler chickens were randomized into four equal groups and fed on the diets with different levels of Cu (11, 110, 220, and 330 mg/kg) for 49 d. Results showed that excess Cu could induce vacuolar degeneration and increase the number of autophagosomes in kidney, and the adenosine triphosphate (ATP) level and mRNA levels of energy metabolism-related genes were decreased with the increasing dietary Cu level. Moreover, immunohistochemistry and immunofluorescence showed that the positive expressions of Beclin1 and LC3-II were mainly located in cytoplasm of renal tubular epithelial cells and increased significantly with the increasing levels of Cu. The mRNA levels of Beclin1, Atg5, LC3-I, LC3-II, Dynein and the protein levels of Beclin1, Atg5, LC3-II/LC3-I and p-AMPKα1/AMPKα1 were markedly elevated in treated groups compared with control group (11 mg/kg Cu). However, the mRNA and protein levels of p62 and p-mTOR/mTOR were significantly decreased with the increasing levels of Cu. These results suggest that impaired energy metabolism induced by Cu may lead to autophagy via AMPK-mTOR pathway in kidney of broiler chickens.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Cobre/toxicidade , Metabolismo Energético/efeitos dos fármacos , Rim/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Galinhas , Exposição Dietética/efeitos adversos , Exposição Dietética/análise , Metabolismo Energético/genética , Rim/metabolismo , Rim/patologia , Transdução de Sinais/efeitos dos fármacos
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