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Pig carcass traits are among the most economically significant characteristics and are crucial for genetic selection in breeding and enhancing the economic efficiency. Standardized and automated carcass phenotyping can greatly enhance the measurement efficiency and accuracy, thereby facilitating the selection and breeding of superior pig carcasses. In this study, we utilized phenotypic images and data from 3912 pigs to propose a deep learning-based approach for the automated determination of pig carcass phenotypic traits. Using the YOLOv8 algorithm, our carcass length determination model achieves an average accuracy of 99% on the test set. Additionally, our backfat segmentation model, YOLOV8n-seg, demonstrates robust segmentation performance, with a Mean IoU of 89.10. An analysis of the data distribution comparing manual and model-derived measurements revealed that differences in the carcass straight length are primarily concentrated between -2 cm and 4 cm, while differences in the carcass diagonal length are concentrated between -3 cm and 2 cm. To validate the method, we compared model measurements with manually obtained data, achieving coefficients of determination (R2) of 0.9164 for the carcass straight length, 0.9325 for the carcass diagonal length, and 0.7137 for the backfat thickness, indicating high reliability. Our findings provide valuable insights into automating carcass phenotype determination and grading in pig production.
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Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague-Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.
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Lesiones Traumáticas del Encéfalo , Enfermedades Neuroinflamatorias , Talidomida/análogos & derivados , Ratas , Animales , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Estrés Oxidativo , Citocinas/metabolismo , Corteza Cerebral/metabolismo , Modelos Animales de EnfermedadRESUMEN
The overuse of nitrogen fertilizers has led to environmental pollution, which has prompted the widespread adoption of biochar as a soil conditioner in agricultural production. To date, there has been a lack of research on the effects of biochar and its combination with nitrogen fertilizer on the quality of broomcorn millet (Panicum miliaceum L.) starch. Thus, this study examined the physicochemical characteristics of starch in two types of broomcorn millet (waxy and non-waxy) under four different conditions, including a control group (N0), nitrogen fertilizer treatment alone (N150), biochar treatment alone (N0+B), and a combination of biochar and nitrogen fertilizer treatments (N150+B). The results showed that, in comparison to the control, all the treatments, particularly N150+B, decreased the content of amylose and gelatinization temperature and enhanced the starch transparency gel consistency and swelling power. In addition, biochar can improve the water solubility of starch and the gelatinization enthalpy. Importantly, the combination of biochar and nitrogen fertilizer increased the proportion of A-granules, final viscosity, starch content, and the average degree of amylopectin in polymerization. Thus, this research indicates that the combinations of biochar and nitrogen fertilizer result in the most significant improvement in the quality of starch produced from broomcorn millet.
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Recent evidence shows that small RNAs are transferred from a species to another through cross-species transmission and exhibit biological activities in the receptor. In this study, we focused on tomato-derived sRNAs play a role of defense against Botrytis cinerea. Bioinformatics method was firstly employed to identify tomato-encoded sRNAs as the cross-species antifungal factors targeting B. cinerea genes. Then the expression levels of some identifed sRNAs were checked in B. cinerea-infected plant using qRT-PCR method. Exogenic RNA-induced gene silences analysis were performed to investigate the antifungal roles of the sRNAs, and the target genes in B. cinerea of antifungal sRNAs would be confirmed by using co-expression analysis. Results showed that a total of 21 B.cinerea-induced sRNAs with high abundance were identified as the cross-kingdom regulator candidates. Among them, three sRNAs containing a miRNA (miR396a-5p) and two siRNA (siR3 and siR14) were selected for experimental validation and bioassay analysis. qRT-PCR confirmed that all of these 3 sRNAs were induced in tomato leaves by B. cinerea infection. Correspondingly, 4 virulence genes of B. cinerea respectively targeted by these 3 sRNAs were down-regulated. Bioassay revealed that all of these 3 cross-species sRNAs could inhibit the virulence and spore gemination of B. cinerea. Correspondingly, the coding genes of B. cinerea targeted by these sRNAs were also down-regulated. Moreover, the virulence inhibition by double strand sRNA was more effective than that by single strand sRNA. The inhibition efficiency of sRNA against B. cinerea increased with the increase of its concentration. Our findings provide new evidence into the coevolution of pathogens and host plants, as well as new directions for the use of plant-derived sRNAs to control pathogens.
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Nitrogen is a key factor affecting sorghum growth and grain quality. This experiment was designed to investigate the physicochemical properties of sorghum starch in four sorghum varieties (Liaoza 10, Liaoza 19, Jinza 31, and Jinza 34) under four nitrogen levels: 0 kg/ha urea (N1), 300 kg/ha urea as base fertilizer (N2), 300 kg/ha urea as topdressing at the jointing stage (N3), and 450 kg/ha urea as topdressing at the jointing stage (N4). The results showed that grain size and amylose content increased with increasing nitrogen fertilizer level, peaking at N3. The peak viscosity, final viscosity, gelatinization temperature, initial temperature, final temperature, and enthalpy value increased with the nitrogenous fertilizer level, peaking at N3. The application of nitrogen fertilizer at the jointing period significantly increased the above indicators. However, excess nitrogen at the jointing period (N4) can significantly reduce the above indicators, thus changing the physicochemical properties and structure of sorghum starch. Overall, nitrogen significantly affects the structure and physicochemical properties of sorghum starch.
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Antioxidants are prevalently used during rubber production to improve rubber performance, delay aging, and extend service life. However, recent studies have revealed that their transformation products (TPs) could adversely affect environmental organisms and even lead to environmental events, which led to great public concern about environmental occurrence and potential impacts of rubber antioxidants and their TPs. In this review, we first summarize the category and application of rubber antioxidants in the world, and then demonstrate the formation mechanism of their TPs in the environment, emphasizing their influence on the ozone oxidative degradation. The potential toxic effects of antioxidants and their TPs are further reviewed to improve understanding of their biological health impact and environmental risks. Finally, the environmental occurrences of antioxidants and their TPs are summarized and their environmental impacts are demonstrated based on the recent studies. Due to the currently limited understanding on the toxic and biological effects of these compounds, further studies are required in order to better assess various TPs of these antioxidants and their environmental impact. To our knowledge, this is the first review on antioxidants and their TPs in the environment, which may elevate the environmental risk awareness of rubber products and their TPs in the near future.
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Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Goma/toxicidad , AntioxidantesRESUMEN
BACKGROUND: Intrauterine adhesion (IUA) is a clinical disease characterized by the uterine cavity occlusion caused by the damage of the endometrial basal layer. Bone marrow mesenchymal stem cells (BMSCs) transplantation have the potential to promote endometrial regeneration mainly through paracrine ability. Estrogen is an indispensable and important factor in the repair of endometrial damage, which has been reported as a promising and adjunctive therapeutic application for stem cell transplantation therapy. This study aims to investigate the synergistic effect of BMSCs and estrogen on improving the endometrial regeneration and restoring the endometrium morphology in a dual damage model of IUA in rabbits and the underlying molecular mechanisms. METHODS: BMSCs were isolated and identified by adipogenic and osteogenic differentiation and flow cytometry assays. The rabbit IUA animal model was established by a dual damage method of mechanical curettage and lipopolysaccharide infection. Additionally, we investigated the therapeutic impact of both BMSCs and estrogen either separately or in combination in a rabbit model. The retention of PKH26-labeled BMSCs was observed by vivo fluorescence imaging.The number of endometrial glands and the degree of fibrosis were observed by H&E and Masson staining respectively. Western blotting, Immunohistochemistry and immunofluorescence staining were performed to detect biomarkers related to endometrial epithelium, endometrial fibrosis and EMT. Finally, the protein expression of core molecules of Wnt/ß-catenin pathway was detected by Western blotting. RESULTS: PKH26-labeled fluorescence results revealed that BMSCs appeared and located in the endometrial glands and extracellular matrix area when orthotopic transplanted into the uterine cavity. Histological assays showed that remarkably increasing the number of endometrial glands and decreasing the area of endometrial fibrosis in the BMSCs combined with estrogen treatment group. Moreover, downregulated expression of fibrosis markers (fibronectin, CollagenI, a-SMA) and interstitial markers (ZEB1, Vimentin, N-cadherin), as well as upregulated E-cadherin expression were found in the combined group. Further study of in vivo staining revealed that fluorescence intensity of CK7 was stronger in the combined group than that of direct BMSCs intrauterine transplantation, while vimentin showed the opposite results. Moreover, the protein levels of ß-catenin, Axin2, C-myc, CycinE of Wnt/ß-catenin signaling pathway increased in the BMSCs combined with estrogen group than in the other treatment groups. CONCLUSION: BMSCs combined with estrogen can promote the differentiation of stem cells into endometrial epithelial cells to facilitate the regeneration of damaged endometrium. The potential mechanism of the synergistic effect may inhibit the occurrence of EMT by activating the Wnt/ß-catenin signaling pathway.
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Transición Epitelial-Mesenquimal , Células Madre Mesenquimatosas , Enfermedades Uterinas , Vía de Señalización Wnt , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Cadherinas/metabolismo , Endometrio/metabolismo , Estrógenos/metabolismo , Femenino , Humanos , Osteogénesis , Conejos , Adherencias Tisulares , Enfermedades Uterinas/patología , Enfermedades Uterinas/terapia , Vimentina/metabolismo , beta Catenina/metabolismoRESUMEN
In this study, the organ distribution and exposure risk from dietary intake of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were investigated for lotus collected from Ya-er Lake, a lake in Hubei Province, Central China that was historically polluted by the chlor-alkali industry. The highest concentrations of PCDD/Fs were found in the main and fibrous lotus roots, with mean values of 48.9 ± 90.1 pg/g and 94.6 ± 143 pg/g, respectively. In all the investigated samples, Octa-CDD (OCDD) and Octa-CDF (OCDF) were the predominant congeners, at 26% and 17% of Σ17 PCDD/Fs, respectively, followed by 1,2,3,4,6,7,8-HpCDF (9%). The distribution ratios of PCDD/Fs in adjacent lotus organs indicated that PCDD/Fs accumulated easily in edible organs, such as lotus seeds, membrane and leaves. The WHO-TEQ in the edible lotus organs and the probable daily intake (PDI) of lotus products by residents were calculated: the toxic equivalents in the lotus fruit parts reached a mean of 2 pg WHO-TEQ2005/g dw, and the mean weekly intake of lotus products for adolescents living around Ya-er Lake was 2.3 pg WHO-TEQ/kg bw/week. These results suggested that long-term consumption of lotus products from Ya-er Lake presents a health hazard to residents.
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Benzofuranos , Dioxinas , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Álcalis , China , Dibenzofuranos , Dibenzofuranos Policlorados , Ingestión de Alimentos , LagosRESUMEN
Background: Geese are conventionally considered to be herbivorous, which could also be raised with concentrate feeding diets without green grass because of the similar gastrointestinal tract with other poultry. However, the geese gut microbiota profiles and their interactions with epithelial cells are still of limited study. Flavonoids were well-documented to shape gut microbiota and promote epithelial barrier functions individually or cooperatively with other metabolites. Therefore, in the present study, honeycomb flavonoids (HF) were supplemented to investigate the effects on growth performances, intestinal development, and gut microbiome of geese. Material and Methods: A total of 400 1-day-old male lion-head geese with similar birth weight (82.6 ± 1.4 g) were randomly divided into five treatments: the control treatment (CON) and the HF supplementation treatments, HF was supplemented arithmetically to increase from 0.25 to 1%. Growth performance, carcass performances, and intestines' development parameters were measured to determine the optimum supplement. Junction proteins including ZO-1 and ZO-2 and cecal microbiota were investigated to demonstrate the regulatory effects of HF on both microbiota and intestinal epithelium. Results: Results showed that 0.5% of HF supplement had superior growth performance, carcass performance, and the total parameters of gastrointestinal development to other treatments. Further research showed that tight junction proteins including ZO-1 and ZO-2 significantly up-regulated, while Firmicutes and some probiotics including Clostridiales, Streptococcus, Lachnoclostridium, and Bifidobacterium, remarkably proliferated after HF supplement. In conclusion, HF supplement in concentrate-diet feeding geese effectively increased the growth performances by regulating the gut microbiota to increase the probiotic abundance to promote the nutrient digestibility and fortify the epithelial development and barrier functions to facilitate the nutrient absorption and utilization.
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Purpose: Radiation pneumonitis (RP) frequently occurs during a treatment course of chest radiotherapy, which significantly reduces the clinical outcome and efficacy of radiotherapy. The ability to easily predict RP before radiotherapy would allow this disease to be avoided. Methods and Materials: This study recruited 48 lung cancer patients requiring chest radiotherapy. For each participant, RNA sequencing (RNA-Seq) was performed on a peripheral blood sample before radiotherapy. The RNA-Seq data was then integrated into a genome-scale flux analysis to develop an RP scoring system for predicting the probability of occurrence of RP. Meanwhile, the clinical information and radiation dosimetric parameters of this cohort were collected for analysis of any statistical associations between these parameters and RP. A non-parametric rank sum test showed no significant difference between the predicted results from the RP score system and the clinically observed occurrence of RP in this cohort. Results: The results of the univariant analysis suggested that the tumor stage, exposure dose, and bilateral lung dose of V5 and V20 were significantly associated with the occurrence of RP. The results of the multivariant analysis suggested that the exposure doses of V5 and V20 were independent risk factors associated with RP and a level of RP ≥ 2, respectively. Thus, our results indicate that our RP scoring system could be applied to accurately predict the risk of RP before radiotherapy because the scores were highly consistent with the clinically observed occurrence of RP. Conclusion: Compared with the standard statistical methods, this genome-scale flux-based scoring system is more accurate, straightforward, and economical, and could therefore be of great significance when making clinical decisions for chest radiotherapy.
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Intrauterine adhesion (IUA) is one of the most prevalent reproductive system diseases in females. MicroRNAs (miRNAs) are reported to be master regulators in a variety of diseases, including IUA, but the role of microRNA-543 (miR-543) in IUA remains to be elucidated. In this study, we observed that miR-543 was downregulated in transforming growth factor-beta (TGF-ß)-treated endometrial stromal cells (ESCs). Functionally, we observed that miR-543 suppressed the migration, epithelial-to-mesenchymal transition (EMT), and inhibited expression of extracellular matrix (ECM) proteins in TGF-ß-treated ESCs. Mechanistically, MAPK1 is targeted by miR-543 after prediction and screening. A luciferase reporter assay demonstrated that miR-543 complementarily binds with the 3' untranslated region of mitogen-activated protein kinase 1 (MAPK1), and western blot analysis indicated that miR-543 negatively regulates MAPK1 protein levels. In addition, results from rescue assays showed that miR-543 inhibits the migration and EMT of TGF-ß-treated ESCs by targeting MAPK1. In addition, we observed that miR-543 inactivates the Wnt/ß-catenin signaling pathway through inhibiting the phosphorylation of MAPK1 and ß-catenin. Finally, we confirmed that miR-543 represses migration, EMT and inhibits levels of ECM proteins in TGF-ß-treated ESCs by targeting the Wnt/ß-catenin signaling pathway. Our results demonstrated that miR-543 suppresses migration and EMT of TGF-ß-treated ESCs by targeting the MAPK and Wnt/ß-catenin pathways.
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Tumores Estromáticos Endometriales/patología , Transición Epitelial-Mesenquimal , MicroARNs/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Movimiento Celular , Proliferación Celular , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Tumores Estromáticos Endometriales/genética , Tumores Estromáticos Endometriales/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Quinasas Activadas por Mitógenos/genética , Factor de Crecimiento Transformador beta/genética , Células Tumorales Cultivadas , Proteínas Wnt/genética , beta Catenina/genéticaRESUMEN
Although estrogen has crucial functions for endometrium growth, the specific dose and underlying molecular mechanism in intrauterine adhesion (IUA) remain unclear. In this study, we aimed to investigate the effects of estrogen on epithelial-mesenchymal transition (EMT) in normal and fibrotic endometrium, and the role of estrogen and Wnt/ß-catenin signaling in the formation of endometrial fibrosis. CCK-8 and immunofluorescence assay were performed to access the proliferation of different concentrations of estrogen on normal human endometrial epithelial cells (hEECs). qRT-PCR and western blot assay were utilized to explore the effect of estrogen on EMT in normal and fibrotic endometrium, and main components of Wnt/ß-catenin signaling pathway in vitro. Hematoxylin and eosin and Masson staining were used to evaluate the effect of estrogen on endometrial morphology and fibrosis in vivo. Our results indicated that the proliferation of normal hEECs was inhibited by estrogen at a concentration of 30 nM accompanied by upregulation of mesenchymal markers and downregulation of epithelial markers. Interestingly, in the model of transforming growth factor ß1 (TGF-ß1)-induced endometrial fibrosis, the same concentration of estrogen inhibited the process of EMT, which might be partially mediated by regulation of the Wnt/ß-catenin pathway. In addition, relatively high doses of estrogen efficiently increased the number of endometrial glands and reduced the area of fibrosis as determined by the reduction of EMT in IUA animal models. Taken together, our results demonstrated that an appropriate concentration of estrogen may prevent the occurrence and development of IUA by inhibiting the TGF-ß1-induced EMT and activating the Wnt/ß-catenin pathway.
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Transición Epitelial-Mesenquimal , Factor de Crecimiento Transformador beta1 , Enfermedades Uterinas , Animales , Estrógenos , Femenino , Humanos , Vía de Señalización WntRESUMEN
Although estrogen has crucial functions for endometrium growth, the specific dose and underlying molecular mechanism in intrauterine adhesion (IUA) remain unclear. In this study, we aimed to investigate the effects of estrogen on epithelial-mesenchymal transition (EMT) in normal and fibrotic endometrium, and the role of estrogen and Wnt/β-catenin signaling in the formation of endometrial fibrosis. CCK-8 and immunofluorescence assay were performed to access the proliferation of different concentrations of estrogen on normal human endometrial epithelial cells (hEECs). qRT-PCR and western blot assay were utilized to explore the effect of estrogen on EMT in normal and fibrotic endometrium, and main components of Wnt/β-catenin signaling pathway in vitro. Hematoxylin and eosin and Masson staining were used to evaluate the effect of estrogen on endometrial morphology and fibrosis in vivo. Our results indicated that the proliferation of normal hEECs was inhibited by estrogen at a concentration of 30 nM accompanied by upregulation of mesenchymal markers and downregulation of epithelial markers. Interestingly, in the model of transforming growth factor β1 (TGF-β1)-induced endometrial fibrosis, the same concentration of estrogen inhibited the process of EMT, which might be partially mediated by regulation of the Wnt/β-catenin pathway. In addition, relatively high doses of estrogen efficiently increased the number of endometrial glands and reduced the area of fibrosis as determined by the reduction of EMT in IUA animal models. Taken together, our results demonstrated that an appropriate concentration of estrogen may prevent the occurrence and development of IUA by inhibiting the TGF-β1-induced EMT and activating the Wnt/β-catenin pathway.
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Humanos , Animales , Femenino , Enfermedades Uterinas , Factor de Crecimiento Transformador beta1 , Transición Epitelial-Mesenquimal , Estrógenos , Vía de Señalización WntRESUMEN
Cortical and hippocampal neuronal damages caused by traumatic brain injury (TBI) are associated with motor and cognitive impairments; however, only little attention paid to the striatal damage. It is known that the p53 tumor-suppressor transcription factor participated in TBI-induced secondary brain damage. We investigated how the p53 inactivator pifithrin (PFT)-α affected TBI-induced striatal neuronal damage at 24 h post-injury. Sprague-Dawley rats subjected to a controlled cortical impact were used as TBI models. We observed that p53 mRNA significantly increased, whereas p53 protein expression was distributed predominantly in neurons but not in glia cells in striatum after TBI. PFT-α improved motor deficit following TBI. PFT-α suppressed TBI-induced striatal glial activation and expression of proinflammatory cytokines. PFT-α alleviated TBI-induced oxidative damage TBI induced autophagy was evidenced by increased protein expression of Beclin-1 and shift of microtubule-associated light chain (LC)3-I to LC3-II, and decreased p62. These effects were reduced by PFT-α. Post-injury PFT-α treatment reduced the number of degenerating (FJC-positive) and apoptotic neurons. Our results suggest that PFT-α may provide neuroprotective effects via p53-dependent or -independent mechanisms depending on the cell type and timing after the TBI and can possibly be developed into a novel therapy to ameliorate TBI-induced neuronal damage.
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Benzotiazoles/administración & dosificación , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/prevención & control , Fármacos Neuroprotectores/administración & dosificación , Tolueno/análogos & derivados , Proteína p53 Supresora de Tumor/metabolismo , Estriado Ventral/patología , Animales , Apoptosis , Autofagia , Western Blotting , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Inflamación , Neuroglía/patología , Neuronas/patología , Estrés Oxidativo , Ratas Sprague-Dawley , Tolueno/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Intracerebral hemorrhage (ICH) is one of the most common forms of cerebral hemorrhage, the morbidity and death of ICH is high worldwide. ICH can be spontaneous or caused by hypertension, coagulopathy, angiopathy, head trauma, bleeding disorders, tumors, or drug usage. ICH is the most serious and least treatable form of hemorrhagic stroke, with rapidly increasing hematoma size and often resulting in significant brain injury and long term neurological deficits. Surgical hematoma evacuation remains controversial. The currently therapy is mainly supportive with limited benefit. New therapeutic approaches are desperately needed. METHODS: In this review, we provide an overview of the published literature concerning the pathophysiology leading to the ongoing neurologic damage, Emerging information of the physio-pathologic mechanisms of injury that occur after ICH is available from current animal models. Ideal therapeutic strategies should target on the pathophysiology of ICH. This review summarizes the recent advances in developing pharmaceutical agents in terms of therapeutic targets and effects in pre-clinical and clinical studies. RESULTS: Recent animal and clinical studies have provided important information about the parallel and sequential deleterious mechanisms underlying ICH-induced brain injury and pharmacological agents targeting on these mechanisms. Neuroscientists have paid more attention to novel drug development that target on antioxidants, antiinflammatory, and anti-apoptosis for neuroprotection after ICH. CONCLUSION: Although ICH remains without an approved treatment proven to decrease morbidity and mortality, notable advances in the understanding of ICH pathophysiology and new drug development have been made in the last decade.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/uso terapéutico , Animales , Hemorragia Cerebral/fisiopatología , HumanosRESUMEN
Methamphetamine (METH)-induced cell death contributes to the pathogenesis of neurotoxicity; however, the relative roles of oxidative stress, apoptosis, and autophagy remain unclear. L-Ascorbate, also called vitamin (Vit.) C, confers partial protection against METH neurotoxicity via induction of heme oxygenase-1. We further investigated the role of Vit. C in METH-induced oxidative stress, apoptosis, and autophagy in cortical cells. Exposure to lower concentrations (0.1, 0.5, 1 mM) of METH had insignificant effects on ROS production, whereas cells exposed to 5 mM METH exhibited ROS production in a time-dependent manner. We confirmed METH-induced apoptosis (by nuclear morphology revealed by Hoechst 33258 staining and Western blot showing the protein levels of pro-caspase 3 and cleaved caspase 3) and autophagy (by Western blot showing the protein levels of Belin-1 and conversion of microtubule-associated light chain (LC)3-I to LC3-II and autophagosome staining by monodansylcadaverine). The apoptosis as revealed by cleaved caspase-3 expression marked an increase at 18 h after METH exposure while both autophagic markers, Beclin 1 and LC3-II, marked an increase in cells exposed to METH for 6 and 24 h, respectively. Treating cells with Vit. C 30 min before METH exposure time-dependently attenuated the production of ROS. Vitamin C also attenuated METH-induced Beclin 1 and LC3-II expression and METH toxicity. Treatment of cells with Vit. C before METH exposure attenuated the expression of cleaved caspase-3 and reduced the number of METH-induced apoptotic cells. We suggest that the protective effect of Vit. C against METH toxicity might be through attenuation of ROS production, autophagy, and apoptosis.
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Apoptosis/efectos de los fármacos , Ácido Ascórbico/farmacología , Autofagia/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Metanfetamina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , Animales Recién Nacidos , Antioxidantes/farmacología , Apoptosis/fisiología , Autofagia/fisiología , Células Cultivadas , Estimulantes del Sistema Nervioso Central/toxicidad , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Relación Dosis-Respuesta a Droga , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Neuronal apoptosis in the hippocampus has been detected after TBI. The hippocampal dysfunction may result in cognitive deficits in learning, memory, and spatial information processing. Our previous studies demonstrated that a p53 inhibitor, pifithrin-α oxygen analogue (PFT-α (O)), significantly reduced cortical cell death, which is substantial following controlled cortical impact (CCI) TBI, and improved neurological functional outcomes via anti-apoptotic mechanisms. In the present study, we examined the effect of PFT-α (O) on CCI TBI-induced hippocampal cellular pathophysiology in light of this brain region's role in memory. To investigate whether p53-dependent apoptosis plays a role in hippocampal neuronal loss and associated cognitive deficits and to define underlying mechanisms, SD rats were subjected to experimental CCI TBI followed by the administration of PFT-α or PFT-α (O) (2mg/kg, i.v.) or vehicle at 5h after TBI. Magnetic resonance imaging (MRI) scans were acquired at 24h and 7days post-injury to assess evolving structural hippocampal damage. Fluoro-Jade C was used to stain hippocampal sub-regions, including CA1 and dentate gyrus (DG), for cellular degeneration. Neurological functions, including motor and recognition memory, were assessed by behavioral tests at 7days post injury. p53, p53 upregulated modulator of apoptosis (PUMA), 4-hydroxynonenal (4-HNE), cyclooxygenase-IV (COX IV), annexin V and NeuN were visualized by double immunofluorescence staining with cell-specific markers. Levels of mRNA encoding for caspase-3, p53, PUMA, Bcl-2, Bcl-2-associated X protein (BAX) and superoxide dismutase (SOD) were measured by RT-qPCR. Our results showed that post-injury administration of PFT-α and, particularly, PFT-α (O) at 5h dramatically reduced injury volumes in the ipsilateral hippocampus, improved motor outcomes, and ameliorated cognitive deficits at 7days after TBI, as evaluated by novel object recognition and open-field test. PFT-α and especially PFT-α (O) significantly reduced the number of FJC-positive cells in hippocampus CA1 and DG subregions, versus vehicle treatment, and significantly decreased caspase-3 and PUMA mRNA expression. PFT-α (O), but not PFT-α, treatment significantly lowered p53 and elevated SOD2 mRNA expression. Double immunofluorescence staining demonstrated that PFT-α (O) treatment decreased p53, annexin V and 4-HNE positive neurons in the hippocampal CA1 region. Furthermore, PUMA co-localization with the mitochondrial maker COX IV, and the upregulation of PUMA were inhibited by PFT-α (O) after TBI. Our data suggest that PFT-α and especially PFT-α (O) significantly reduce hippocampal neuronal degeneration, and ameliorate neurological and cognitive deficits in vivo via antiapoptotic and antioxidative properties.
Asunto(s)
Benzotiazoles/uso terapéutico , Lesiones Traumáticas del Encéfalo/complicaciones , Trastornos del Conocimiento , Tolueno/análogos & derivados , Proteína p53 Supresora de Tumor/metabolismo , Aldehídos/metabolismo , Animales , Anexina A5/genética , Anexina A5/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Benzotiazoles/química , Benzotiazoles/farmacología , Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Conducta Exploratoria/efectos de los fármacos , Fluoresceínas/metabolismo , Imagen por Resonancia Magnética , Masculino , Oxígeno , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Factores de Tiempo , Tolueno/química , Tolueno/farmacología , Tolueno/uso terapéutico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI. METHODS: The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). RESULTS: Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α. CONCLUSIONS: Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.