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1.
Transl Psychiatry ; 14(1): 99, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374212

RESUMO

RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the contribution of rbfox1 to behaviour, we used rbfox1sa15940, a zebrafish mutant line with TL background. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 mutant line with a different genetic background (TU), rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that mutations in rbfox1 lead to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study, thus, highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.


Assuntos
Proteínas de Ligação a RNA , Peixe-Zebra , Humanos , Adulto , Animais , Camundongos , Proteínas de Ligação a RNA/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Peixe-Zebra/metabolismo , Encéfalo/metabolismo , Fenótipo
2.
Food Funct ; 15(4): 2170-2180, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38312068

RESUMO

Vitamin K isoforms are known as co-factors for the synthesis of blood-clotting proteins, but several other bioactivities were reported. In this work, we isolated a vitamin K1-analogue (OH-PhQ) from the cyanobacterium Tychonema sp. LEGE 07196 with lipid reducing activity. OH-PhQ reduced neutral lipid reservoirs with an EC50 value of 31 µM after 48 h exposure in zebrafish larvae, while other vitamin K isoforms had EC50 values of 21.1 µM (K2) and 1.2 µM (K3). No lipid reducing activity was observed for K1 up to 50 µM. The presence of vitamin K isoforms was studied in zebrafish after exposure (OH-PhQ, K1, K2 and K3), and a clear preference for bioconversion was observed to retain K1 and OH-PhQ. Untargeted metabolomics revealed different biological effects for vitamin K isoforms on the subclass and metabolite level, but similarities were present on the compound class level, particularly on the regulation of glycerophospholipids. Our data showed for the first time a lipid reducing activity of OH-PhQ and performed a comparative analysis of vitamin K isoforms, which could be important for the development of future nutraceuticals or food supplements.


Assuntos
Vitamina K , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Metabolismo dos Lipídeos , Vitamina K 1/metabolismo , Isoformas de Proteínas/metabolismo , Lipídeos , Vitamina K 2 , Vitamina K 3
3.
Sci Rep ; 14(1): 3823, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360784

RESUMO

Zebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.


Assuntos
Diabetes Mellitus , Hiperglicemia , Animais , Feminino , Masculino , Hipoglicemiantes/farmacologia , Limoneno , Peixe-Zebra/metabolismo , Glicemia/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Obesidade/metabolismo , Dieta Hiperlipídica , Hiperglicemia/complicações
4.
Bull Environ Contam Toxicol ; 112(2): 34, 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38342962

RESUMO

To understand the underlying molecular mechanisms, mouse bone marrow mesenchymal stem cells (BMSCs) and zebrafish embryos were exposed to the control group and Tributyltin (TBT) group (10 ng/L, environmental concentration) for 48 h, respectively. The expression profiles of RNAs were investigated using whole-transcriptome analysis in mouse BMSCs or zebrafish embryos after TBT exposure. For mouse BMSCs, the results showed 2,449 differentially expressed (DE) mRNAs, 59 DE miRNAs, 317 DE lncRNAs, and 15 circRNAs. Similarly, for zebrafish embryos, the results showed 1,511 DE mRNAs, 4 DE miRNAs, 272 DE lncRNAs, and 28 circRNAs. According to KEGG pathway analysis showed that DE RNAs were mainly associated with immune responses, signaling, and cellular interactions. Competing endogenous RNA (ceRNA) network analysis revealed that the regulatory network of miRNA-circRNA constructed in zebrafish embryos was more complex compared to that of mouse BMSCs.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , RNA Longo não Codificante , Compostos de Trialquitina , Animais , Camundongos , Peixe-Zebra/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Perfilação da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Células-Tronco Mesenquimais/metabolismo
5.
Transl Psychiatry ; 14(1): 82, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38331943

RESUMO

Genetic variants in ZNF536 contribute to the risk for neuropsychiatric disorders such as schizophrenia, autism, and others. The role of this putative transcriptional repressor in brain development and function is, however, largely unknown. We generated znf536 knockout (KO) zebrafish and studied their behavior, brain anatomy, and brain function. Larval KO zebrafish showed a reduced ability to compete for food, resulting in decreased total body length and size. This phenotype can be rescued by segregating the homozygous KO larvae from their wild-type and heterozygous siblings, enabling studies of adult homozygous KO animals. In adult KO zebrafish, we observed significant reductions in anxiety-like behavior and social interaction. These znf536 KO zebrafish have decreased cerebellar volume, corresponding to decreased populations of specific neuronal cells, especially in the valvular cerebelli (Va). Finally, using a Tg[mbp:mgfp] line, we identified a previously undetected myelin structure located bilaterally within the Va, which also displayed a reduction in volume and disorganization in KO zebrafish. These findings indicate an important role for ZNF536 in brain development and implicate the cerebellum in the pathophysiology of neuropsychiatric disorders.


Assuntos
Cerebelo , Peixe-Zebra , Animais , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Animais Geneticamente Modificados/metabolismo , Cerebelo/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Encéfalo/metabolismo
6.
Sci Rep ; 14(1): 3395, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336823

RESUMO

Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysregulation implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed in the early nervous system, yet their contribution to neurogenesis is poorly understood. Notably, a variety of mutations in genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders. To rigorously define the role of NMDA receptors in developmental neurogenesis, we used a mutant zebrafish line (grin1-/-) that lacks all NMDA receptors yet survives to 10 days post-fertilization, offering the opportunity to study post-embryonic neurodevelopment in the absence of NMDA receptors. Focusing on the forebrain, we find that these fish have a progressive supernumerary neuron phenotype confined to the telencephalon at the end of embryonic neurogenesis, but which extends to all forebrain regions during postembryonic neurogenesis. This enhanced neuron population does not arise directly from increased numbers or mitotic activity of radial glia cells, the principal neural stem cells. Rather, it stems from a lack of timely maturation of transit-amplifying neuroblasts into post-mitotic neurons, as indicated by a decrease in expression of the ontogenetically-expressed chloride transporter, KCC2. Pharmacological blockade with MK-801 recapitulates the grin1-/- supernumerary neuron phenotype, indicating a requirement for ionotropic signaling. Thus, NMDA receptors are required for suppression of indirect, transit amplifying cell-driven neurogenesis by promoting maturational termination of mitosis. Loss of suppression results in neuronal overpopulation that can fundamentally change brain circuitry and may be a key factor in pathogenesis of neurodevelopmental disorders caused by NMDA receptor dysfunction.


Assuntos
Células-Tronco Neurais , Receptores de N-Metil-D-Aspartato , Animais , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Neurônios/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Telencéfalo/metabolismo
7.
J Toxicol Environ Health A ; 87(8): 357-370, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38305282

RESUMO

Sodium dodecylbenzene sulfonate (SDBS) is an important surfactant used as a cleaning agent and industrial additive to remove unwanted chemicals which have been detected in the aquatic environment. The aim of this study was to examine the toxicological potential of SDBS on the gills of adult male zebrafish (Danio rerio) exposed to this chemical. For the 96 hr acute exposure, fish were divided into three groups: control, 0.25 mg/L, and 0.5 mg/L of SDBS. After the experiment, morphophysiological analyses (gill histopathology and histochemistry), oxidative stress (determination of gill activities of superoxide dismutase (SOD) and catalase (CAT)), and hematological analyses (leukocyte differentiation) were conducted. Data demonstrated that SDBS at both tested concentrations altered the histopathological index and initiated circulatory disturbances, as well as adverse, progressive, and immunological changes in the gills. In the 0.5 mg/L group, SOD activity decreased significantly, but CAT activity was not altered. Prominent blood changes observed in this group were neutrophilia and lymphocytosis. The number of mucous and chloride cells increased significantly in both groups. Taken together, our findings demonstrated that exposure of D. rerio to SDBS, even for 96 hr, produced adverse morphological and hematological effects associated with a reduction in SOD activity. Our findings indicate that exposure of aquatic species to the anionic surfactant SDBS may lead to adverse consequences associated with oxidative stress. Therefore, this study highlights the risks that this substance may pose to aquatic ecosystems and emphasizes the need for further investigations and strict regulations on its disposal.


Assuntos
Derivados de Benzeno , Poluentes Químicos da Água , Peixe-Zebra , Animais , Masculino , Peixe-Zebra/metabolismo , Brânquias , Ecossistema , Poluentes Químicos da Água/metabolismo , Catalase/metabolismo , Catalase/farmacologia , Estresse Oxidativo , Tensoativos/metabolismo , Tensoativos/farmacologia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Sódio/metabolismo , Sódio/farmacologia
8.
BMC Cancer ; 24(1): 175, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317072

RESUMO

BACKGROUND: Targeted drugs are the main methods of RCC treatment. However, drug resistance is common in RCC patients, in-depth study of the drug-resistant mechanism is essential. METHODS: We constructed sunitinib resistant and Twist overexpressed A498 cells, and studied its mechanisms in vitro and in vivo. RESULTS: In cell research, we found that either sunitinib resistance or Twist overexpression can activate Wnt/ß-catenin and EMT signaling pathway, and the sunitinib resistance may work through ß-catenin/TWIST/TCF4 trimer. In zebrafish research, we confirmed the similarity of Twist overexpression and sunitinib resistance, and the promoting effect of Twist overexpression on drug resistance. CONCLUSIONS: Sunitinib resistance and Twist overexpression can activate Wnt/ß-catenin signaling pathway and EMT to promote the growth and metastasis of RCC cells.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Humanos , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo , Peixe-Zebra/metabolismo , Linhagem Celular Tumoral , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Transição Epitelial-Mesenquimal/genética , Movimento Celular , Proliferação de Células
9.
Int J Biol Macromol ; 259(Pt 1): 129163, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38181906

RESUMO

The inefficient and improper use of conventional pesticides has prompted the development of targeted and cost-effective pesticide delivery systems, which aim to optimize the efficient utilization of pesticides while minimizing environmental pollution in surrounding areas. In this paper, a dual-stimuli-responsive pesticide slow-release nanopesticide system (NES@DMONs@LGN) was designed in this study, utilizing mesoporous silica (DMONs) as a nanocarrier and lignin (LGN) as a capping agent to encapsulate the pesticide molecules within DMONs. This system enables intelligent release of pesticide molecules while preventing environmental pollution caused by leakage. Additionally, NES@DMONs@LGN exhibit excellent specific loading efficiency. The abundant hydrophilic functional groups in the lignin layer on the surface of NES@DMONs@LGN can establish hydrogen bonds with advanced fatty acids and fatty alcohols present in the waxy epidermis of plants, thereby significantly enhancing carrier wettability and adhesion. Typically, phytophagous lepidopteran pests have an alkaline midgut and possess lignin-degrading enzymes. The NES@DMONs@LGN developed in this study are capable of rapid release under high temperature and alkaline conditions. Therefore, the precise release of pesticide molecules in the target pests can be achieved, thus increasing the actual utilization rate of pesticides. The experimental results demonstrated that NES@DMONs@LGN effectively prevented photodegradation of the active ingredient after 48 h of UV irradiation, resulting in a 3.7-fold improvement in photostability and providing robust UV protection. By encapsulating pesticide molecules with nanocarriers, the release of pesticides in non-targeted environments can be prevented, thereby significantly reducing toxicity to zebrafish. Thus, this study provides a promising solution for sustainable greening of agriculture.


Assuntos
Nanopartículas , Praguicidas , Animais , Praguicidas/química , Portadores de Fármacos/química , Lignina , Peixe-Zebra/metabolismo , Nanopartículas/química
10.
Int J Biol Macromol ; 259(Pt 2): 129250, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199551

RESUMO

This study delves into the potential of chito-oligosaccharides (COS) to promote osteoblast differentiation and prevent osteoporosis, utilizing experiments with mouse MSCs and the zebrafish model. The preliminary biocompatibility study affirms the non-toxic nature of COS across various concentrations. In the osteoblast differentiation study, COS enhances ALP activity and calcium deposition at the cellular level. Moreover, COS induces the upregulation of molecular markers, including Runx2, Type I collagen, ALP, osteocalcin, and osteonectin in mouse MSCs. Zebrafish studies further demonstrate COS's anti-osteoporotic effects, showcasing its ability to expedite fin fracture repair, vertebral mineralization, and bone mineralization in dexamethasone-induced osteoporosis models. The scale regenerative study reveals that COS mitigates the detrimental effects of dexamethasone induced osteoclastic activity, reducing TRAP and hydroxyproline levels while elevating the expression of Runx2a MASNA isoform, collagen2α, OC, and ON mRNAs. Additionally, COS enhances calcium and phosphorus levels in regenerated scales, impacting the bone-healthy calcium-to­phosphorus ratio. The study also suggests that COS modulates the MMP3-Osteopontin-MAPK signaling pathway. Overall, this comprehensive investigation underscores the potential of COS to prevent and treat osteoporosis. Its multifaceted cellular and molecular effects, combined with in vivo bone regeneration and repair, propose that COS may be effective in addressing osteoporosis and related bone disorders. Nonetheless, further research is imperative to unravel underlying mechanisms and optimize clinical applications.


Assuntos
Quitosana , Osteoporose , Camundongos , Animais , Peixe-Zebra/metabolismo , Quitosana/metabolismo , Cálcio/metabolismo , Osteogênese , Osteoporose/metabolismo , Diferenciação Celular , Dexametasona/farmacologia , Osteoblastos , Fósforo/metabolismo
11.
Sci Total Environ ; 918: 170436, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38281650

RESUMO

Widespread application of the typical phthalate plasticizers, di (2-ethylhexyl) phthalate (DEHP), poses a serious potential threat to the health of animals and even humans. Previous studies have confirmed the mechanism of DEHP-induced cardiac developmental defects in zebrafish larvae. However, the mechanism of cardiac dysfunction is still unclear. Thus, this work aimed to comprehensively investigate the mechanisms involved in DEHP-induced cardiac dysfunction through computational simulations, in vivo assays in zebrafish, and in vitro assays in cardiomyocytes. Firstly, molecular docking and western blot initially investigated the activating effect of DEHP on Pparg in zebrafish. Although GW9662 (PPARG antagonist) effectively alleviated DEHP-induced cardiac dysfunction and lipid metabolism disorders, it did not restore significant decreases in mitochondrial membrane potential and ATP levels. In vitro assays in cardiomyocytes, DEHP caused overexpression of PPARG and proteins involved in the regulation of Ca2+ homeostasis, and the above abnormalities were effectively alleviated by GW9662, suggesting that the Ca2+ homeostatic imbalance caused by activation of PPARG by DEHP seems to be the main cause of DEHP-induced cardiac dysfunction. To sum up, this work not only refines the mechanism of toxic effects of cardiotoxicity induced by DEHP, but provides an important theoretical basis for enriching the toxicological effects of DEHP.


Assuntos
Anilidas , Dietilexilftalato , Cardiopatias , Ácidos Ftálicos , Humanos , Animais , Dietilexilftalato/toxicidade , Dietilexilftalato/metabolismo , Peixe-Zebra/metabolismo , PPAR gama/metabolismo , Simulação de Acoplamento Molecular , Plastificantes/toxicidade , Plastificantes/metabolismo
12.
Sci Total Environ ; 917: 170521, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38290676

RESUMO

Benzodiazepines (BZDs) have been widely detected in aquatic environments, but their neurotoxic effects and potential mechanisms are still unclear. This study focuses on flunitrazepam (FLZ) and its metabolite, 7-aminoflunitrazepam (7-FLZ), as representative psychotropic BZD. We investigated their neurotoxic effects on adult zebrafish following a 30-day exposure to environmentally relevant concentrations. The findings reveal that exposure to these drugs induces anxiety-like and aggressive behaviors in zebrafish. Additionally, notable morphological damage to brain tissue and mitochondrial structures was observed. Through TUNEL staining, an increase in apoptotic cells was detected in the brain tissue of the exposed group, accompanied by marked elevations in ROS and caspase-3/9 levels. The upregulation of apoptosis-related genes Bax, p53, and Bcl-2 confirmed the occurrence of apoptosis. Furthermore, exposure to the drugs resulted in decreased acetylation levels of brain histones H3 and H4. The upregulation of histone deacetylation enzyme genes (HDAC1, HDAC3, HDAC4, and HDAC6) supported this result. Molecular docking results suggest that compared to 7-FLZ, FLZ has a higher binding affinity with HDAC3 and HDAC4, explaining why it causes lower histone acetylation levels. This study in zebrafish elucidates the neurotoxicity and molecular mechanisms induced by FLZ and 7-FLZ, which is significant for further understanding the impact of BZDs on human health and assessing their ecological risks.


Assuntos
Histonas , Peixe-Zebra , Animais , Humanos , Histonas/metabolismo , Peixe-Zebra/metabolismo , Flunitrazepam/farmacologia , Simulação de Acoplamento Molecular , Apoptose , Estresse Oxidativo , Acetilação
13.
Chemosphere ; 351: 141133, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38199495

RESUMO

Microplastics and nanoplastics are found in marine biota across a wide range of trophic levels and environments. While a large portion of the information about plastic exposure comes from gastrointestinal (GI) data, the relevance of particle accumulation from an oral exposure compared with other types of exposure (e.g. dermal, respiratory) is unknown. To address this gap in knowledge, larval zebrafish (7 days post fertilization) were exposed to two different sizes of nanoplastics through either oral gavage or a waterborne exposure. Larvae were tracked for 48 h post exposure (hpe) to assess the migration and elimination of plastics. Larvae eliminated orally gavaged nanoplastics within 48 hpe. Oral gavage showed limited particle movement from the GI tract into other tissues. In contrast, waterborne nanoplastic-exposed larvae displayed notable fluorescence in tissues outside of the GI tract. The 50 nm waterborne-exposed larvae retained the particles past 48 hpe, and showed accumulation with neuromasts. For both sizes of plastic particles, the nanoplastics were eliminated from non-GI tract tissues by 24 hpe. Our results suggest that waterborne exposure leads to greater accumulation of plastic in comparison to oral exposure, suggesting that plastic accumulation in certain tissues is greater via routes of exposure other than oral consumption.


Assuntos
Plásticos , Poluentes Químicos da Água , Animais , Microplásticos/toxicidade , Microplásticos/metabolismo , Peixe-Zebra/metabolismo , Bioacumulação , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , Larva/metabolismo
14.
Chemosphere ; 351: 141155, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38211790

RESUMO

The paraben family of endocrine disruptors exhibit persistent behaviours in aquatic matrices, having bio-accumulative effects and necessitating toxicity analysis and safe use, as well as prevention of food web penetration. In this study, the toxicity effects of 9 different parabens (Methyl, Ethyl, Propyl, Butyl, Heptyl, Isopropyl, Isobutyl, benzyl parabens and p-hydroxybenzoic acid) were studied against 17 neuronal proteins (Neurog1, Ascl1a, DLA, Syn2a, Ntn1a, Pitx2, and SoxB1, Her/Hes, Zic family) expressed during the early embryonic developmental stage of Danio rerio. The neuronal genes were selected as a biomarker to study the inhibitory effects on the cascade of genes expressed in the early developmental stage. The study uses trRossetta software to predict protein structures of neuronal genes, followed by structural refinement, energy minimisation, and active site prediction, evaluated using energy value, RC plot and ERRAT scores of PROCHECK and ERRAT programs. Compared to raw structures, highly confident predicted structures and quality scores were observed for refined protein with few exceptions. Based on the polarity and charge of the aminoacids, the probable pockets were identified using active site prediction, which were then used for molecular docking analysis. Further, the ADMET analysis, ligand likeliness and toxicological test revealed the paraben family of compounds as one of the most susceptible toxic and mutagenic compounds. The molecular docking results showed an interesting pattern of increasing binding affinity with increase in the carbon chains of paraben molecules. Benzyl Paraben showed higher binding affinities across all 17 neuronal proteins. Finally, gene co-occurrence/co-expression and protein-protein interaction studies using the STRING database depict that all proteins are functionally related and play essential roles in standard biological processes or pathways, conserved and expressed in diverse organisms. The interaction between paraben compounds and neuronal genes indicates high risks of inhibiting reactions in embryonic stages, emphasising the need for effective treatment measures and strict regulations.


Assuntos
Rotas de Resultados Adversos , Poluentes Ambientais , Animais , Feminino , Parabenos/análise , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Simulação de Acoplamento Molecular
15.
Toxicol Appl Pharmacol ; 483: 116809, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38211931

RESUMO

Xanthohumol (XN) is a prominent prenylated flavonoid present in the hop plant (Humulus lupulus L.). Despite undoubted pro-healing properties of hop plant, there is still a need for clinical investigations confirming these effects as well as the underlying molecular mechanisms. The present study was designed to (1) establish the role of XN in non-invasive inflammation induced by chemical damage to zebrafish hair cells, (2) clarify if it influences cell injury severity, neutrophil migration, macrophage activation, cell regeneration, and (3) find out whether it modulates the gene expression profile of chosen immune and stress response markers. All experiments were performed on 3 dpf zebrafish larvae. After fertilization the embryos were transferred to appropriate XN solutions (0.1 µM, 0.3 µM and 0.5 µM). The 40 min 10 µM CuSO4 exposure evoked severe damage to posterior lateral line hair cells triggering a robust acute inflammatory response. Four readouts were selected as the indicators of XN role in the process of inflammation: 1) hair cell death, 2) neutrophil migration towards damaged hair cells, 3) macrophage activation and recruitment to damaged hair cells, 4) hair cell regeneration. The assessments involved in vivo confocal microscopy imaging and qPCR based molecular analysis. It was demonstrated that XN (1) influences death pathway of damaged hair cells by redirecting their severe necrotic phenotype into apoptotic one, (2) impacts the immune response via regulating neutrophil migration, macrophage recruitment and activation (3) modulates gene expression of immune system markers and (4) accelerates hair cell regeneration.


Assuntos
Humulus , Propiofenonas , Animais , Humulus/química , Humulus/metabolismo , Peixe-Zebra/metabolismo , Flavonoides/química , Propiofenonas/toxicidade , Propiofenonas/química , Propiofenonas/metabolismo , Imunidade Inata , Inflamação/induzido quimicamente , Cabelo/metabolismo
16.
Toxicol Appl Pharmacol ; 483: 116817, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38215995

RESUMO

d-Tetramethrin is one of the main components of mosquito control products, and is widely used for the control of dengue fever and insecticide production. Due to its widespread use, d-tetramethrin is a ubiquitous environmental pollutant and poses potential risks to human health. However, the effects of d-tetramethrin on liver morphology and function are not clearly established. In this study, we used zebrafish as an animal model to analyze the acute and chronic effects of d-tetramethrin exposure on the liver. We exposed zebrafish larvae and adults to different concentrations of d-tetramethrin and examined the impact of d-tetramethrin on lipid and glycogen metabolism, cellular properties, oxidative stress, cell proliferation, and apoptosis in the liver. We also analyzed transcriptional changes in genes related to apoptosis, inflammation, and cell proliferation using qPCR. Zebrafish exposed to d-tetramethrin exhibited severe liver damage, as evidenced by the presence of vacuoles and nuclear distortion in liver cells. The liver area in zebrafish larvae of the treatment group was significantly smaller than that of the control group. Significant lipid accumulation and decreased glycogen levels were observed in the livers of both zebrafish larvae and adults exposed to d-tetramethrin. Furthermore, d-tetramethrin exposure induced apoptosis and inflammation in zebrafish embryos. Additionally, d-tetramethrin caused liver damage, metabolic dysfunction, and impaired liver function. These results suggest that d-tetramethrin induces liver toxicity in zebrafish, by inducing oxidative stress and inhibiting cell proliferation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Piretrinas , Peixe-Zebra , Animais , Humanos , Peixe-Zebra/metabolismo , Estresse Oxidativo , Inflamação , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Proliferação de Células , Glicogênio/metabolismo , Glicogênio/farmacologia , Lipídeos , Larva
17.
Inflamm Res ; 73(2): 289-304, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38184500

RESUMO

OBJECTIVE: Intestinal fibrosis, a common and serious complication of inflammatory bowel disease (IBD), results from chronic inflammation. A high-cholesterol diet may be a risk factor for IBD and 27-hydroxylcholesterol (27HC) is the main human cholesterol metabolite. This study investigated whether 27HC can induce intestinal fibrosis. METHODS: The effects of cholesterol and 27HC on intestinal fibrosis were assessed in zebrafish and human intestinal epithelial Caco-2 cells. RESULTS: Cholesterol and 27HC induced intestinal inflammation and collagen deposition, inhibited E-cadherin (E-ca) expression in the intestinal epithelium, and promoted nuclear translocation of ß-catenin in zebrafish. Cholesterol and 27HC up-regulated expression of COL-1, α-SMA, CTGF, TIMP1, N-cadherin, vimentin, glycogen synthesis kinase-3ß (GSK-3ß) and ß-catenin, but inhibited E-ca, in Caco-2 cells. The expression of these proteins was inhibited by CYP27A1 knockdown and ß-catenin knockdown. 27HC-induced nuclear translocation of ß-catenin occurs in Caco-2 cells. p38, ERK, and AKT activate ß-catenin and thereby participate in 27HC-induced epithelia-mesenchymal transition (EMT) and fibrosis. 27HC-increased oxidative stress and the fibrosis and EMT markers, the nuclear translocation of ß-catenin, and the up-regulation of p-cell kinase proteins promoted by 27HC were inhibited by N-acetyl-L-cysteine (NAC). Folic acid (FA), resveratrol (RES), and NAC all ameliorated the 27HC-induced effects in Caco-2 cells and zebrafish. CONCLUSION: A high-cholesterol diet caused intestinal fibrosis in zebrafish, mediated by a major cholesterol metabolite, 27HC. 27HC increased oxidative stress and activated p38, ERK, AKT, and ß-catenin, leading to EMT of epithelial cells and intestinal fibrosis. FA and RES both ameliorated intestinal fibrosis by restraining 27HC-induced ß-catenin activation.


Assuntos
Glicogênio Sintase Quinase 3 beta , Doenças Inflamatórias Intestinais , Estresse Oxidativo , beta Catenina , Animais , Humanos , beta Catenina/metabolismo , Células CACO-2 , Transição Epitelial-Mesenquimal , Fibrose , Glicogênio Sintase Quinase 3 beta/metabolismo , Hidroxicolesteróis/farmacologia , Inflamação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Peixe-Zebra/metabolismo
18.
Dev Growth Differ ; 66(2): 145-160, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38263801

RESUMO

Nuclear receptor subfamily 2 group F (Nr2f) proteins are essential for brain development in mice, but little is known about their precise roles and their evolutionary diversification. In the present study, the expression patterns of major nr2f genes (nr2f1a, nr2f1b, and nr2f2) during early brain development were investigated in zebrafish. Comparisons of their expression patterns revealed similar but temporally and spatially distinct patterns after early somite stages in the brain. Frameshift mutations in the three nr2f genes, achieved using the CRISPR/Cas9 method, resulted in a smaller telencephalon and smaller eyes in the nr2f1a mutants; milder forms of those defects were present in the nr2f1b and nr2f2 mutants. Acridine orange staining revealed enhanced cell death in the brain and/or eyes in all nr2f homozygous mutants. The expression of regional markers in the brain did not suggest global defects in brain regionalization; however, shha expression in the preoptic area and hypothalamus, as well as fgf8a expression in the anterior telencephalon, was disturbed in nr2f1a and nr2f1b mutants, potentially leading to a defective telencephalon. Specification of the retina and optic stalk was also significantly affected. The overexpression of nr2f1b by injection of mRNA disrupted the anterior brain at a high dose, and the expression of pax6a in the eyes and fgf8a in the telencephalon at a low dose. The results of these loss- and gain-of-function approaches showed that nr2f genes regulate the development of the telencephalon and eyes in zebrafish embryos.


Assuntos
Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Camundongos , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Encéfalo/metabolismo , Telencéfalo/metabolismo , Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento
19.
Biochem Biophys Res Commun ; 699: 149551, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38277730

RESUMO

V-ATPase is an ATP hydrolysis-driven proton pump involved in the acidification of intracellular organelles and systemic acid-base homeostasis through H+ secretion in the renal collecting ducts. V-ATPase dysfunction is associated with hereditary distal renal tubular acidosis (dRTA). ATP6V1B1 encodes the B1 subunit of V-ATPase that is integral to ATP hydrolysis and subsequent H+ transport. Patients with pathogenic ATP6V1B1 mutations often exhibit an early onset of sensorineural hearing loss. However, the mechanisms underlying this association remain unclear. We employed morpholino oligonucleotide-mediated knockdown and CRISPR/Cas9 gene editing to generate Atp6v1ba-deficient (atp6v1ba-/-) zebrafish as an ortholog model for ATP6V1B1. The atp6v1ba-/- zebrafish exhibited systemic acidosis and significantly smaller otoliths compared to wild-type siblings. Moreover, deficiency in Atp6v1ba led to degeneration of inner ear hair cells, with ultrastructural changes indicative of autophagy. Our findings indicate a critical role of ATP6V1B1 in regulating lysosomal pH and autophagy in hair cells, and the results provide insights into the pathophysiology of sensorineural hearing loss in dRTA. Furthermore, this study demonstrates that the atp6v1ba-/- zebrafish model is a valuable tool for further investigation into disease mechanisms and potential therapies for acidosis-related hearing impairment.


Assuntos
Acidose Tubular Renal , Acidose , Perda Auditiva Neurossensorial , Compostos Organometálicos , ATPases Vacuolares Próton-Translocadoras , Animais , Humanos , Peixe-Zebra/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/metabolismo , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Mutação , Acidose Tubular Renal/genética , Células Ciliadas Auditivas/patologia , Concentração de Íons de Hidrogênio , Cabelo/metabolismo , Trifosfato de Adenosina
20.
Fish Shellfish Immunol ; 146: 109402, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38281613

RESUMO

Type II interferons (IFNs) are a key class of molecules regulating innate and adaptive immunity in vertebrates. In the present study, two members of the type II IFNs, IFN-γ and IFNγ-rel, were identified in the blunt snout bream (Megalobrama amblycephala). The open reading frame (ORF) of IFN-γ and IFNγ-rel was found to have 564 bp and 492 bp, encoding 187 and 163 amino acids, with the first 26 and 24 amino acids being the signal peptide, respectively. IFN-γ and IFNγ-rel genes showed a high degree of similarity to their zebrafish homologues, being 76.9 % and 58.9 %, respectively. In the phylogenetic tree, IFN-γ and IFNγ-rel were clustered with homologous genes in cyprinids. In blunt snout bream, IFN-γ and IFNγ-rel were constitutively expressed in trunk kidney, head kidney, spleen, liver, heart, muscle, gill, intestine and brain and were significantly up-regulated by poly (I:C) induction in head kidney, spleen, liver, gill and intestine. Using recombinant proteins of IFN-γ and IFNγ-rel, the surface plasmon resonance (SPR) results showed that IFN-γ was bound to CRFB6, CRFB13 and CRFB17, but mainly to CRFB6 and CRFB13, whereas IFN-γrel bound mainly to CRFB17 and had no affinity with CRFB6. These results contribute to a better understanding on type II IFNs and their receptor usage in teleost fish.


Assuntos
Cyprinidae , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Filogenia , Interferon gama/genética , Interferon gama/metabolismo , Sequência de Aminoácidos , Proteínas de Peixes/química , Proteínas Recombinantes/genética , Aminoácidos/genética
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