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Heterogeneous phase combined flooding (HPCF) has been a promising technology used for enhancing oil recovery in heterogeneous mature reservoirs. However, the injectivity and propagation behavior of preformed particle gel (PPG) in low-medium-permeability reservoir porous media is crucial for HPCF treatment in a low-medium-permeability reservoir. Thus, the injectivity and propagation behavior of preformed particle gel in a low-medium-permeability reservoir were systematically studied by conducting a series of sand pack flooding experiments. The matching factor (δ) was defined as the ratio of the average size of PPG particles to the mean size of pore throats and the pressure difference ratio (ß) was proposed to characterize the injectivity and propagation ability of PPG. The results show that with the increase in particle size and the decrease in permeability, the resistance factor and residual resistance factor increase. With the increase in the matching factor, the resistance factor and residual resistance factor increase. The higher the resistance factor and residual resistance factor are, the worse the injectivity of particles is. By fitting the relationship curve, PPG injection and propagation standards were established: when the matching coefficient is less than 55 and ß is less than 3.4, PPG can be injected; when the matching coefficient is 55-72 and ß is 3.4-6.5, PPG injection is difficult; when the matching coefficient is greater than 72 and ß is greater than 6.5, PPG cannot be injected Thus, the matching relationship between PPG particle size and reservoir permeability was obtained. This research will provide theoretical support for further EOR research and field application of heterogeneous phase combined flooding.
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Alzheimer's disease is a neurodegenerative disorder characterized by the presence of neurodegenerative lesions and cognitive impairment. In this study, a series of novel palmatine derivatives were designed and synthesized through the introduction of a heteroatom using carbodiimide-mediated condensation. The synthesized compounds were then screened for toxicity and potency, leading to the identification of compound 2q, which exhibited low toxicity and high potency. Our findings demonstrated that compound 2q displayed significant neuroprotective activity in vitro, emerging as a promising candidate for Alzheimer's disease treatment.
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Alcaloides de Berberina , Fármacos Neuroprotetores , Alcaloides de Berberina/farmacologia , Alcaloides de Berberina/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Estrutura Molecular , Humanos , Doença de Alzheimer/tratamento farmacológico , Relação Estrutura-Atividade , AnimaisRESUMO
BACKGROUND: Patients with liver cancer complicated by portal hypertension present complex challenges in treatment. AIM: To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this condition. METHODS: Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group (n = 50) and a control group (n = 50) according to the treatment regimen. The research group received radiofrequency ablation (RFA) in combination with sorafenib, and the control group only received RFA. The short-term efficacy of both the research and control groups was observed. Liver function and portal hypertension were compared before and after treatment. Alpha-fetoprotein (AFP), glypican-3 (GPC-3), and AFP-L3 levels were compared between the two groups prior to and after treatment. The occurrence of adverse reactions in both groups was observed. The 3-year survival rate was compared between the two groups. Basic data were compared between the survival and non-surviving groups. To identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension, multivariate logistic regression analysis was employed. RESULTS: When comparing the two groups, the research group's total effective rate (82.00%) was significantly greater than that of the control group (56.00%; P < 0.05). Following treatment, alanine aminotransferase and aspartate aminotransferase levels increased, and portal vein pressure decreased in both groups. The degree of improvement for every index was substantially greater in the research group than in the control group (P < 0.05). Following treatment, the AFP, GPC-3, and AFP-L3 levels in both groups decreased, with the research group having significantly lower levels than the control group (P < 0.05). The incidence of diarrhea, rash, nausea and vomiting, and fatigue in the research group was significantly greater than that in the control group (P < 0.05). The 1-, 2-, and 3-year survival rates of the research group (94.00%, 84.00%, and 72.00%, respectively) were significantly greater than those of the control group (80.00%, 64.00%, and 40.00%, respectively; P < 0.05). Significant differences were observed between the survival group and the non-surviving group in terms of Child-Pugh grade, history of hepatitis, number of tumors, tumor size, use of sorafenib, stage of liver cancer, histological differentiation, history of splenectomy and other basic data (P < 0.05). Logistic regression analysis demonstrated that high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, no use of sorafenib, liver cancer stage IIIC, and previous splenectomy were independent risk factors for poor prognosis in patients with liver cancer complicated with portal hypertension (P < 0.05). CONCLUSION: Patients suffering from liver cancer complicated by portal hypertension benefit from the combination of RFA and sorafenib therapy because it effectively restores liver function and increases survival rates. The prognosis of patients suffering from liver cancer complicated by portal hypertension is strongly associated with factors such as high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, lack of sorafenib use, liver cancer at stage IIIC, and prior splenectomy.
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Hepatite A , Hipertensão Portal , Neoplasias Hepáticas , Humanos , Prognóstico , Sorafenibe/uso terapêutico , alfa-Fetoproteínas , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Hipertensão Portal/complicaçõesRESUMO
The Henan Oilfield's medium-permeability blocks face challenges such as high temperatures and severe heterogeneity, making conventional flooding systems less effective. The starch gel system is an efficient approach for deep profile control in high-temperature reservoirs, while the nano-MoS2 system is a promising enhanced oil recovery (EOR) technology for high-temperature low-permeability reservoirs. Combining these two may achieve the dual effects of profile control and oil displacement, significantly enhancing oil recovery in high-temperature heterogeneous reservoirs. The basic performance evaluation of the combination system was carried out under reservoir temperature. Displacement experiments were conducted in target blocks under different permeabilities and extreme disparity core flooding to evaluate the combination system's oil displacement effect. Additionally, the displacement effects and mechanisms of the starch gel and nano-MoS2 combination system in heterogeneous reservoirs were evaluated by simulating interlayer and intralayer heterogeneity models. The results show that the single nano-MoS2 system's efficiency decreases with increased core permeability, and its effectiveness is limited in triple and quintuple disparity parallel experiments. After injecting the starch gel-nano-MoS2 combination system, the enhanced oil recovery effect was significant. The interlayer and intralayer heterogeneous models demonstrated that the primary water flooding mainly affected the high-permeability layers, while the starch gel effectively blocked the dominant channels, forcing the nano-MoS2 oil displacement system towards unswept areas. This coordination significantly enhanced oil displacement, with the combination system improving recovery by 15.33 and 12.20 percentage points, respectively. This research indicates that the starch gel and nano-MoS2 combination flooding technique holds promise for enhancing oil recovery in high-temperature heterogeneous reservoirs of Henan Oilfield, providing foundational support for field applications.
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BACKGROUND: C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons. However, its function is still not clear. We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain. METHODS: C1ql3 knockout (KO) rats were generated using CRISPR/Cas9. C1ql3 KO was determined by polymerase chain reaction (PCR), DNA sequencing, and western blotting. Microglia morphology and cytokine expression with or without lipopolysaccharide (LPS) stimulus were analyzed using immunohistochemistry and real-time PCR. The brain structure changes in KO rats were examined using magnetic resonance imaging. Neuronal architecture alteration was analyzed by performing Golgi staining. Behavior was evaluated using the open field test, Morris water maze test, and Y maze test. RESULTS: C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia, whereas C1ql3 KO did not influence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10. C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation. The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats. C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density. C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory. CONCLUSIONS: C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation, resulting in hyperactive behavior and impaired short memory in rats, which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.
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BACKGROUND: Tripartite motif (TRIM46) is a relatively novel protein that belongs to tripartite motif family. TRIM46 organizes parallel microtubule arrays on the axons, which are important for neuronal polarity and axonal function. TRIM46 is highly expressed in the brain, but its biological function in adults has not yet been determined. RESULTS: Trim46 knockout (KO) rat line was established using CRISPR/cas9. Trim46 KO rats had smaller hippocampus sizes, fewer neuronal dendritic arbors and dendritic spines, and shorter and more distant axon initial segment. Furthermore, the protein interaction between endogenous TRIM46 and FK506 binding protein 5 (FKBP5) in brain tissues was determined; Trim46 KO increased hippocampal FKBP5 protein levels and decreased hippocampal protein kinase B (Akt) phosphorylation, gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1) protein levels. Trim46 KO rats exhibited hypoactive behavioral changes such as reduced spontaneous activity, social interaction, sucrose preference, impaired prepulse inhibition (PPI), and short-term reference memory. CONCLUSIONS: These results demonstrate the significant impact of Trim46 KO on brain structure and behavioral function. This study revealed a novel potential association of TRIM46 with dendritic development and neuropsychiatric behavior, providing new insights into the role of TRIM46 in the brain.
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Hipocampo , Animais , Ratos , Hipocampo/metabolismo , Neurônios/metabolismo , Comportamento Animal/fisiologia , Masculino , Ratos Sprague-Dawley , Técnicas de Inativação de Genes , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genética , Dendritos/metabolismoRESUMO
T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T-cell development and homeostasis is unknown. Using CD4cre -Trappc1flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number of naive T cells in the periphery, whereas thymic T-cell development in Trappc1 cKO mice was identical as WT mice. In the culture assays and mouse models with adoptive transfer of the sorted WT (CD45.1+ CD45.2+ ) and Trappc1 cKO naive T cells (CD45.2+ ) to CD45.1+ syngeneic mice, Trappc1-deficient naive T cells showed significantly reduced survival ability compared with WT cells. RNA-seq and molecular studies showed that Trappc1 deficiency in naive T cells reduced protein transport from the endoplasmic reticulum to the Golgi apparatus, enhanced unfolded protein responses, increased P53 transcription, intracellular Ca2+ , Atf4-CHOP, oxidative phosphorylation, and lipid peroxide accumulation, and subsequently led to ferroptosis. Trappc1 deficiency in naive T cells increased ferroptosis-related damage-associated molecular pattern molecules like high mobility group box 1 or lipid oxidation products like prostaglandin E2, leukotriene B4, leukotriene C4, and leukotriene D4. Functionally, the culture supernatant of Trappc1 cKO naive T cells significantly promoted neutrophils to express inflammatory cytokines like TNFα and IL-6, which was rescued by lipid peroxidation inhibitor Acetylcysteine. Importantly, Trappc1 cKO mice spontaneously developed severe autoinflammatory disease 4 weeks after birth. Thus, intrinsic expression of Trappc1 in naive T cells plays an integral role in maintaining T-cell homeostasis to avoid proinflammatory naive T-cell death-caused autoinflammatory syndrome in mice. This study highlights the importance of the TRAPPC in T-cell biology.
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Ferroptose , Doenças Hereditárias Autoinflamatórias , Camundongos , Animais , Linfócitos T , Camundongos Knockout , Diferenciação CelularRESUMO
The globe has faced severe challenges recently, and environmental deterioration has become more prominent. Therefore, the world has taken several initiatives to deal with environmental issues while the problem remains intact. Interestingly, the OECD economies are the leading example to understand the accurate picture of sustainability across the near regions. This study makes an effort to introduce the core factors such as economic development, renewable energy, tourism, natural resources, and innovations in OECD economies over the period of 2000-2021. Similarly, to investigate the study's objectives, this study employs the quantile autoregressive distributed lag model (Q-ARDL). The analyzed results show the significant contribution of renewable energy, tourism, and natural resources to environmental sustainability. In contrast, income and innovations contribute to ecological deterioration. Moreover, the quantile causality is being used by this empirical study to investigate the causal association among studied variables. However, using green energy in sustainable tourism is highly recommended for specified economies. In order to deal with environmental pressure, this research proposes green implications to attain the desired sustainability level.
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Desenvolvimento Econômico , Turismo , Pesquisa Empírica , Renda , Energia Renovável , Dióxido de CarbonoRESUMO
Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPß and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a-PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis.
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Citocinas , Sepse , Humanos , Regulação para Cima , Citocinas/metabolismo , PPAR gama/metabolismo , Síndrome da Liberação de Citocina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
Neutrophil extracellular traps (NETs) participate in the rapid inhibition and clearance of pathogens during infection; however, the molecular regulation of NET formation remains poorly understood. In the current study, we found that inhibition of the wild-type p53-induced phosphatase 1 (Wip1) significantly suppressed the activity of Staphylococcus aureus (S. aureus) and accelerated abscess healing in S. aureus-induced abscess model mice by enhancing NET formation. A Wip1 inhibitor significantly enhanced NET formation in mouse and human neutrophils in vitro. High-resolution mass spectrometry and biochemical assays demonstrated that Coro1a is a substrate of Wip1. Further experiments also revealed that Wip1 preferentially and directly interacts with phosphorylated Coro1a than compared to unphosphorylated inactivated Coro1a. The phosphorylated Ser426 site of Coro1a and the 28-90 aa domain of Wip1 are essential for the direct interaction of Coro1a and Wip1 and for Wip1 dephosphorylation of p-Coro1a Ser426. Wip1 deletion or inhibition in neutrophils significantly upregulated the phosphorylation of Coro1a-Ser426, which activated phospholipase C and subsequently the calcium pathway, the latter of which promoted NET formation after infection or lipopolysaccharide stimulation. This study revealed Coro1a to be a novel substrate of Wip1 and showed that Wip1 is a negative regulator of NET formation during infection. These results support the potential application of Wip1 inhibitors to treat bacterial infections.
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Armadilhas Extracelulares , Camundongos , Humanos , Animais , Proteína Fosfatase 2C/metabolismo , Armadilhas Extracelulares/metabolismo , Abscesso , Staphylococcus aureus/metabolismo , Neutrófilos/metabolismo , Proteínas dos MicrofilamentosRESUMO
BACKGROUND: Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron-sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death. METHODS: We generated neuron-specific Isca1 knockout rat (Isca1flox/flox -NeuN-Cre) using CRISPR-Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons. RESULTS: This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis. CONCLUSIONS: This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.
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Proteínas Ferro-Enxofre , Doenças Mitocondriais , Ratos , Humanos , Animais , Síndrome , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteínas Ferro-Enxofre/química , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Trifosfato de Adenosina/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismoRESUMO
Hundreds of pathogenic variants of mitochondrial DNA (mtDNA) have been reported to cause mitochondrial diseases, which still lack effective treatments. It is a huge challenge to install these mutations one by one. We repurposed the DddA-derived cytosine base editor to incorporate a premature stop codon in the mtProtein-coding genes to ablate mitochondrial proteins encoded in the mtDNA (mtProteins) instead of installing pathogenic variants and generated a library of both cell and rat resources with mtProtein depletion. In vitro, we depleted 12 of 13 mtProtein-coding genes with high efficiency and specificity, resulting in decreased mtProtein levels and impaired oxidative phosphorylation. Moreover, we generated six conditional knockout rat strains to ablate mtProteins using Cre/loxP system. Mitochondrially encoded ATP synthase membrane subunit 8 and NADH:ubiquinone oxidoreductase core subunit 1 were specifically depleted in heart cells or neurons, resulting in heart failure or abnormal brain development. Our work provides cell and rat resources for studying the function of mtProtein-coding genes and therapeutic strategies.
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Códon sem Sentido , Mitocôndrias , Ratos , Animais , Sequência de Bases , Mitocôndrias/genética , Mitocôndrias/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , MutaçãoRESUMO
OBJECTIVE: To evaluate the efficacy of drug-eluting beads transarterial chemoembolization (DEB-TACE) in the treatment of hepatocellular carcinoma (HCC) by propensity score matching (PSM) technique. METHODS: The clinical data of HCC patients treated with DEB-TACE in the First Affiliated Hospital of Zhengzhou University from June 2017 to June 2020 as well as their 36-month-follow-up data were retrospectively analyzed. The subjects were matched in pairs based on baseline data and laboratory indicators using the PSM method and divided into a pirarubicin group (n = 34), raltitrexed group (n = 34), and arsenic trioxide group (n = 34). Clinical efficacy was evaluated according to mRECIST criteria. The levels of alpha fetal protein (AFP), carcinoma embryonic antigen (CEA) and carbohydrate antigen-125 (CA125) in serum were detected by enzyme-linked immunosorbent assay (ELISA). The progression-free survival (PFS) and overall survival (OS) were recorded by outpatient, inpatient, and telephone follow-up. Adverse reactions were counted. RESULTS: After PSM, no significant differences were seen in gender, age, tumor burden, Child-Pugh grade, portal vein tumor thrombus or TACE frequency among the three groups (all P>0.05). The ORR rate of the pirarubicin group and arsenic trioxide group at both 3rd and 6th month post-operation was significantly higher than that of the raltitrexed group (all P<0.05). Before and 1 month after treatment, there were no significant differences in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin (TBIL) levels between the three groups (all P>0.05). Before treatment, no significant differences were observed in AFP, CEA, or CA125 levels among the three groups (all P>0.05). After treatment, the levels of AFP in the pirarubicin group and arsenic trioxide group were lower than those in the raltitrexed group (both P<0.05), but there were no significant differences in CEA and CA125 levels (all P>0.05). There were no significant differences in PFS and OS among the three groups (all P>0.05), and the incidence of fever, abdominal pain, and myelosuppression showed no significant differences among the three groups (all P>0.05). CONCLUSION: The efficacies of DEB-TACE loaded with pirarubicin, raltitrexed, or arsenic trioxide in treating HCC were generally comparable, and the survival benefit of patients was similar. The short-term efficacy of the pirarubicin group and arsenic trioxide group was slightly better than that of the raltitrexed group.
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An animal model harboring pathogenic mitochondrial DNA (mtDNA) mutations is important to understand the biological links between mtDNA variation and mitochondrial diseases. DdCBE, a DddA-derived cytosine base editor, has been utilized in zebrafish, mice, and rats for tC sequence-context targeting and human mitochondrial disease modeling. However, human pathogenic mtDNA mutations other than the tC context cannot be manipulated. Here, we screened the combination of different DdCBE pairs at pathogenic mtDNA mutation sites with nC (n for a, g, or c) context and identified that the left-G1333C (L1333C) + right G1333N (R1333N) pair could mediate Câ G-to-Tâ A conversion effectively at aC sites in rat C6 cells. The editing efficiency at disease-associated mtDNA mutation sites within aC context was further confirmed to be up to 67.89% in vivo. Also, the installed disease-associated mtDNA mutations were germline transmittable. Moreover, the edited rats showed impaired cardiac function and mitochondrial function, resembling human mitochondrial disease symptoms. In summary, for the first time, we expanded the DdCBE targeting scope to an aC motif and installed the pathogenic mutation in rats to model human mitochondrial diseases.
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Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma. Immunoglobulin FcγRIIa receptor (FCGR2A) has been implicated in various cancers, however, its role on ccRCC is not well studied. A total of 151 patients with ccRCC were recruited for the study. Cox proportional hazards regression analysis was performed to calculate the hazard radios of FCGR2A expression and tumor characteristics. Pathological changes associated with ccRCC in tumor tissue sections were analyzed by hematoxylin-eosin staining. Immunohistochemical and immunofluorescence staining were used to detect the protein expression of FCGR2A in the tissue sections. Correlation between the expression of FCGR2A and the overall survival (OS) of ccRCC patients was analyzed by biological process neural network and support vector machine. The expression of FCGR2A was significantly correlated with the TNM of tumor, family history of ccRCC and Fuhrman stage of ccRCC. Patients with high FCGR2A expression in the tumor tissue, had poorer OS than the patients with low and moderate FCGR2A expression. The Receiver operating characteristic curve showed that FCGR2A can be used as a sensitive and specific biomarker for the diagnosis of ccRCC. Western blotting revealed that the FCGR2A was expressed at higher levels in the ccRCC tissues. Biological process neural network and support vector machine fitting showed that the R2 between FCGR2A and survival time of ccRCC patients was 0.8429 and 0.7669, respectively. FCGR2A is highly expressed in ccRCC, higher expression of FCGR2A is associated with poorer OS of ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Neoplasias Renais/diagnóstico , Prognóstico , Biomarcadores Tumorais/metabolismo , Receptores de IgGRESUMO
Bisphenol A (BPA) is putatively regarded as an environmental neurotoxicant found in everyday plastic products and materials, however, the possible neurobehavioral adverse consequences and molecular mechanisms in animals have not been clearly characterized. The nematode Caenorhabditis elegans has become a promising animal model for neurotoxicological researches. To investigate the dose-effect relationships of BPA-induced neurotoxicity effects, the locomotion behavior and developmental parameters of the nematode were determined after BPA exposure. The present data demonstrated that BPA caused neurobehavioral toxicities, including head thrashes and body bends inhibition. In addition, when C. elegans was exposed to BPA at a concentration higher than 2 µM, growth and survival rate were decreased. The serotonergic, dopaminergic and GABAergic neurons were damaged by BPA. Furthermore, lower levels of mRNA expression related to dopamine, serotonin and GABA were detected in the worms exposed to 50 µM BPA. Increased SOD-3 expression might be adaptive response to BPA exposure. Moreover, oxidative damage triggered by BPA was manifested by changes in GST-4 expression, accompany with abnormity of ATP synthesis, but not nuclear localization of DAF-16/FOXO. Finally, we showed that epigallocatechin-3-gallate partially rescued BPA-induced reactive oxygen species (ROS) production and neurobehavioral toxicity. Altogether, the neurobehavioral and developmental toxicity of BPA may be induced by neurotransmission abnormity and oxidative damage. The present data imply that oxidative stress is linked to neuronal damage and neurobehavioral harm resulting from developmental BPA exposure.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Estresse Oxidativo , Compostos Benzidrílicos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neurotransmissores/metabolismoRESUMO
OBJECTIVE: Ovarian cancer and renal cancer are malignant tumors; however, the relationship between TTK Protein Kinase (TTK), AKT-mTOR pathway and ovarian cancer, renal cancer remains unclear. METHODS: Download GSE36668 and GSE69428 from Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed. Created protein-protein interaction (PPI) network. Used Gene Ontology analysis (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional enrichment analysis. Gene Set Enrichment Analysis (GSEA) analysis and survival analysis were performed. Created animal model for western blot analysis. Gene Expression Profiling Interactive Analysis (GEPIA) was performed to explore the role of TTK on the overall survival of renal cancer. RESULTS: GO showed that DEGs were enriched in anion and small molecule binding, and DNA methylation. KEGG analysis presented that they mostly enriched in cholesterol metabolism, type 1 diabetes, sphingolipid metabolism, ABC transporters, etc., TTK, mTOR, p-mTOR, AKT, p-AKT, 4EBP1, p-4EBP1 and Bcl-2 are highly expressed in ovarian cancer, Bax, Caspase3 are lowly expressed in ovarian cancer, cell apoptosis is inhibited, leading to deterioration of ovarian cancer. Furthermore, the TTK was not only the hub biomarker of ovarian cancer, but also one significant hub gene of renal cancer, and its expression was up-regulated in the renal cancer. Compared with the renal cancer patients with low expression of TTK, the patients with high expression of TTK have the poor overall survival (P = 0.0021). CONCLUSION: TTK inhibits apoptosis through AKT-mTOR pathway, worsening ovarian cancer. And TTK was also one significant hub biomarker of renal cancer.
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Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Ovarianas , Feminino , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Redes Reguladoras de Genes , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão Gênica , Carcinoma de Células Renais/genética , Serina-Treonina Quinases TOR/genética , Neoplasias Renais/genética , Neoplasias Ovarianas/patologia , Biologia ComputacionalRESUMO
TSPAN7 is related to various neurological disorders including autism spectrum disorder (ASD). However, the underlying synaptic mechanism of TSPAN7 in ASD is still unclear. Here, we showed that Tspan7 knockout rats exhibited ASD-like and ID-like behavioral phenotypes, brain structure alterations including decreased hippocampal and cortical volume, and related pathological changes including reduced hippocampal neurons number, neuronal complexity, dendritic spines, and synapse-associated proteins. Then, we found that TSPAN7 deletion interrupted the integrin ß1/FAK/SRC signal pathway that was followed by the down-regulation of PSD95, SYN, and GluR1/2, which are key synaptic integrity-related proteins. Furthermore, reactivation of SRC restored the expression of synaptic integrity-related proteins in primary neurons of TSPAN7 knockout brains. Taken together, our results suggested that TSPAN7 knockout caused ASD-like and ID-like behaviors in rats and impaired neuronal synapses possibly through the down-regulation of the integrin ß1/FAK/SRC signal pathway, which might be a new mechanism on regulation of synaptic proteins expression and on ASD pathogenesis by mutated TSPAN7. These findings provide novel insights into the role of TSPAN7 in psychiatric diseases and highlight integrin ß1/FAK/SRC as a potential target for ASD therapy.