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BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of three receptors commonly targeted in breast cancer treatment. In this study, the research focused on investigating the role of centrosomal protein 55 (CEP55) in TNBC progression and its interaction with the transcription factor Spi-1 proto-oncogene (SPI1). METHODS: Various techniques including qRT-PCR, western blotting, and immunohistochemistry assays were utilized to examine gene expression patterns. Functional assays such as wound-healing assay, transwell invasion assay, 5-Ethynyl-2'-deoxyuridine assay, and metabolic assays were conducted to assess the impact of CEP55 on the behaviors of TNBC cells. CD163-positive macrophages were quantified by flow cytometry. The chromatin immunoprecipitation assay and dual-luciferase reporter assay were performed to assess the association of SPI1 with CEP55. A xenograft mouse model experiment was used to analyze the impact of SPI1 on tumor development in vivo. RESULTS: CEP55 and SPI1 expression levels were significantly upregulated in TNBC tissues and cells. The depletion of CEP55 led to decreased TNBC cell migration, invasion, proliferation, glucose metabolism, and M2 macrophage polarization, indicating its crucial role in promoting TNBC progression. Moreover, SPI1 transcriptionally activated CEP55 in TNBC cells, and its overexpression was associated with accelerated tumor growth in vivo. Further, CEP55 overexpression relieved SPI1 silencing-induced inhibitory effects on TNBC cell migration, invasion, proliferation, glucose metabolism, and M2 macrophage polarization. CONCLUSION: SPI1-mediated transcriptional activation of CEP55 plays a key role in enhancing TNBC cell migration, invasion, proliferation, glucose metabolism, and M2 macrophage polarization. These insights provide valuable information for potential targeted therapies to combat TNBC progression by modulating the SPI1-CEP55 axis.
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Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.
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Neural stem cells play a crucial role in maintaining brain homeostasis. Neural stem cells senescence can lead to the decline of nerve repair and regeneration, causing brain aging and neurodegenerative diseases. However, the mechanism underlying neural stem cells senescence remains poorly understood. In this study, we report a novel HO-1/PARP1 non-canonical pathway highlighting how oxidative stress triggers the DNA damage response, ultimately leading to premature cellular senescence in neural stem cells. HO-1 acts as a sensor for oxidative stress, while PARP1 functions as a sensor for DNA damage. The simultaneous expression and molecular interaction of these two sensors can initiate a crosstalk of oxidative stress and DNA damage response processes, leading to the vicious cycle. The persistent activation of this pathway contributes to the senescence of neural stem cells, which in turn plays a crucial role in the progression of neurodegenerative diseases. Consequently, targeting this novel signaling pathway holds promise for the development of innovative therapeutic strategies and targets aimed at mitigating neural stem cells senescence-related disorders.
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Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.
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OBJECTIVE: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. METHODS: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. RESULTS: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. CONCLUSION: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.
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Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Luteolina , Neurogénesis , Neuronas , Ratas Sprague-Dawley , Animales , Luteolina/farmacología , Ratas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Neurogénesis/efectos de los fármacos , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Humanos , Estrés Psicológico/fisiopatología , Estrés Psicológico/tratamiento farmacológico , Femenino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/fisiopatología , Antidepresivos/farmacología , Neurotrofina 3/metabolismo , Neurotrofina 3/genéticaRESUMEN
Sterigmatocystins and aflatoxins are a group of mycotoxins mainly isolated from fungi of the genera Aspergillus. Since the discovery of sterigmatocystins in 1954 and aflatoxins in 1961, many scholars have conducted a series of studies on their structural identification, synthesis and biological activities. Studies have shown that sterigmatocystins and aflatoxins have a wide range of biological activities such as antitumour, antibacterial, anti-inflammatory, antiplasmodial, etc. The sterigmatocystins and aflatoxins had been shown to be hepatotoxic and nephrotoxic in animals. This review attempts to give a comprehensive summary of progress on the chemical structural features, synthesis, and bioactivity of sterigmatocystins and aflatoxins reported from 1954 to April 2024. A total of 72 sterigmatocystins and 20 aflatoxins are presented in this review. This paper reviews the chemical diversity and potential activity and toxicity of sterigmatocystins and aflatoxins, enhances the understanding of sterigmatocystins and aflatoxins that adversely affect humans and animals, and provides ideas for their prevention, research and development.
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OBJECTIVES: To explore how the circular non-coding RNA circ_0072088 influences the progression of breast carcinoma (BC) by affecting cell behavior. METHODS: We measured the levels of circ_0072088, microRNA-607 (miR-607), and ring finger protein 2 (RNF2) mRNA levels in BC tissues and cell lines using quantitative real-time PCR. We also conducted cell counting kit-8 (CCK-8), BrdU incorporation, and flow cytometry assays to assess cell viability, cell cycle, and apoptosis, respectively. RESULTS: We observed increased levels of circ_0072088 and RNF2, and decreased levels of miR-607 in BC tissues. Overexpressing circ_0072088 promoted BC cell proliferation and cell cycle progression while inhibiting apoptosis. Conversely, silencing circ_0072088 had the opposite effects. Our data suggest that circ_0072088 directly targets and downregulates miR-607, which in turn upregulates RNF2, a target of miR-607. Moreover, miR-607 overexpression could mitigate the pro-proliferative and anti-apoptotic effects of circ_0072088 on BC cells. CONCLUSION: Circ_0072088 drives BC progression by downregulating miR-607 and upregulating RNF2, thereby promoting cell proliferation and cycle progression while reducing apoptosis.
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BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. RESULTS: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. CONCLUSION: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.
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Enfermedad de Alzheimer , Humanos , Masculino , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones Transgénicos , Proteómica , Hipocampo/metabolismo , Hipocampo/patología , Trastornos de la Memoria/metabolismoRESUMEN
Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.
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This research establishes an emergency evacuation time model specifically designed for subway stations with complex structures. The model takes into account multiple factors, including passenger flow rate, subway facility parameters, and crowd density, to accurately assess evacuation times. It considers the impact of horizontal walking distance, flow rate, subway train size, and stair parameters on the overall evacuation process. By identifying bottleneck points such as gates, car doors, and stairs, the model facilitates the evaluation of evacuation capacity and the formulation of effective evacuation plans, particularly in multiline subway transfer stations. The good consistency is achieved between the calculated evacuation time and simulated results using the Pathfinder software (with the relative error of 5.4%). To address urban traffic congestion and enhance subway station safety, the study recommends implemented measures for emergency diversion and passenger flow control. Additionally, the research presents characteristic mathematical models for various evacuation routes by considering the structural and temporal characteristics of metro systems. These models provide valuable guidance for conducting large-scale passenger evacuation simulations in complex environments. Future research can further enhance the model by incorporating psychological factors, evacuation signage, and strategies for vulnerable populations. Overall, this study contributes to a better understanding of evacuation dynamics and provides practical insights to improve safety and efficiency in subway systems.
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Modelos Teóricos , Vías Férreas , Simulación por Computador , Programas Informáticos , AglomeraciónRESUMEN
Sestrins are metabolic regulators that respond to stress by reducing the levels of reactive oxygen species (ROS) and inhibiting the activity of target of rapamycin complex 1 (mTORC1). Previous research has demonstrated that Sestrin2 mitigates ischemia-reperfusion (IR) injury in the heart, liver, and kidneys. However, its specific role in intestinal ischemia-reperfusion (IIR) injury remains unclear. To elucidate the role of Sestrin2 in IIR injury, we conducted an experimental study using a C57BL/6J mouse model of IIR. We noticed an increase in the levels of Sestrin2 expression and indicators associated with ferroptosis. Our study revealed that manipulating Sestrin2 expression in Caco-2 cells through overexpression or knockdown resulted in a corresponding decrease or increase, respectively, in ferroptosis levels. Furthermore, our investigation revealed that Sestrin2 alleviated ferroptosis caused by IIR injury through the activation of the Keap1/Nrf2 signal pathway. This finding highlights the potential of Sestrin2 as a therapeutic target for alleviating IIR injury. These findings indicated that the modulation of Sestrin2 could be a promising strategy for managing prolonged IIR injury.
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Ferroptosis , Isquemia Mesentérica , Daño por Reperfusión , Animales , Humanos , Ratones , Células CACO-2 , Ferroptosis/genética , Isquemia , Proteína 1 Asociada A ECH Tipo Kelch/genética , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Reperfusión , Daño por Reperfusión/genética , Transducción de SeñalRESUMEN
Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives (3-18) were synthesized using epimers 1 and 2 as parent molecules, isolated from Sphagneticola trilobata, and evaluated for their anti-HCC activity. Furthermore, the structures of 4, 6, and 14 were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of 3-18 on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound 10 exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that 10 induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that 10 may possess the properties to be a drug candidate. Thus, 10 may be a promising lead compound for the treatment of HCC.
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Butiratos , Carcinoma Hepatocelular , Furanos , Neoplasias Hepáticas , Sesquiterpenos , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Isobutiratos , Neoplasias Hepáticas/tratamiento farmacológico , Sesquiterpenos/farmacología , Lactonas/farmacologíaRESUMEN
PURPOSE: Hirschsprung's disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype-phenotype relationship. METHODS: We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance. RESULTS: Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33-50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance. CONCLUSION: We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases.
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Enfermedad de Hirschsprung , Obstrucción Intestinal , Receptor de Endotelina B , Humanos , Recién Nacido , China/epidemiología , Enfermedad de Hirschsprung/genética , Incidencia , Mutación , Receptor de Endotelina B/genéticaRESUMEN
Two new sesquiterpene glycosides, 8α,12,15ß-trihydroxycopacamphan-15-O-ß-D-glucopyranoside (1) and dendrobiumane C-11-O-ß-D-glucopyranoside (2), along with three known terpenoids (3-5) were isolated from the aerial stems of Dendrobium henanense. Their structures were elucidated based on NMR-spectroscopic and HR-MS analyses. All compounds could reduce the levels of NO, TNF-α and IL-1ß in LPS-induced RAW264.7 cells with IC50 values ranging from 10.37 to 34.55 µΜ.
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AIM:To investigate the mechanism of Piezo1 channel activation promoting the increase in intra-cellular Ca2+ concentration([Ca2+]i)of rat coronary artery smooth muscle cells(CASMCs).METHODS:The primary CASMCs of SD rats were cultured,and the expression and subcellular localization of Piezo1 in the cells were observed by immunofluorescence staining.The Piezo1 and stromal interaction molecule 1(STIM1)in CASMCs were knocked down by siRNA transfection,and the expression levels of the proteins were detected by Western blot.Utilizing laser confocal mi-croscopy,the change of[Ca2+]i in CASMCs was detected by Fluo-4 AM fluorescent probes.RESULTS:It was confirmed by immunofluorescence staining that the expression of Piezo1 existed in primary rat CASMCs.Immunofluorescence staining also showed that Piezo1 was co-located with sarco-/endoplasmic reticulum Ca2+-ATPase 2(SERCA2),mitochondrial outer membrane protein TOM20 and nuclear membrane protein lamin B1.Western blot results showed that the protein expres-sion levels of STIM1 and Piezo1 were significantly down-regulated by siRNA transfection(P<0.05).Compared with con-trol group,Yoda1,the agonist of Piezo1,could increase the extracellular Ca2+ influx of CASMCs(P<0.01).However,the Ca2+ influx mediated by Yoda1 was not affected by the inhibition of L-type calcium channels.Treatment with Yoda1 in-creased the intracellular Ca2+ release of CASMCs(P<0.01).However,inhibition of calcium channels on endoplasmic re-ticulum,ryanodine receptor and inositol 1,4,5-triphosphate receptor,did not affect intracellular Ca2+ release mediated by Yoda1.After the Ca2+ in endoplasmic reticulum was emptied using thapsigargin(TG),Yoda1 also mediated the Ca2+ re-lease of other organelles in CASMCs(P<0.01).After inhibition of L-type calcium channels,treatment with store-operated calcium channel(SOCC)inhibitor BTP2 or knockdown of STIM1 led to the decrease in extracellular Ca2+ influx of CASMCs mediated by Yoda1(P<0.01).Treatment with TG increased the release of Ca2+ from the endoplasmic reticulum of CASMCs after knockdown of Piezo1(P<0.05),but the extracellular Ca2+ influx mediated by TG was not affected.After inhibition of L-type calcium channels and SOCC,knockdown of Piezo1 led to the decreases in intracellular Ca2+ release and extracellular Ca2+ influx induced by Yoda1(P<0.01).CONCLUSION:The Piezo1 agonist orchestrates the influx of extracellular Ca2+ by activating Piezo1 channels on the cell membrane and inducing the indirect activation of SOCC.More-over,it facilitates the release of Ca2+ from organelles.Consequently,these pathways synergistically elevate the[Ca2+]i of rat CASMCs.
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AIM:To investigate the influence of fat mass and obesity-associated(Fto)gene on the aberrant contraction of aortic smooth muscle in diabetes mellitus(DM)mice,and to explore the mechanism of Fto gene underlying the calcium regulation.METHODS:Smooth muscle-specific Fto gene knockout(FtoSMKO)mice were generated using Cre-loxP technology.The experiment involved 3 groups of mice:wild-type(WT)group,DM model group and FtoSMKO-DM group,with 15 mice in each group.In DM group and FtoSMKO-DM group,type 1 DM was induced by intraperitoneal injec-tion of streptozotocin.The mice in WT group were injected with equal volume of citric acid-sodium citrate buffer solution.The influences of different drugs on the contraction responses of aortic smooth muscle in mice were analyzed using a multi-myograph system.The expression level of FTO protein in the aortic tissues was detected by Western blot.RESULTS:(1)Compared with WT mice,the expression levels of FTO protein in the aortic tissues of DM mice were significantly in-creased(P<0.01).(2)The expression level of FTO protein in smooth muscle was significantly decreased after knockout of Fto gene(P<0.01).Compared with WT group,the mice in DM group exhibited a significant decrease in body weight and a marked increase in fasting blood glucose level(P<0.05).There were no noticeable differences in body weight or fasting blood glucose level between FtoSMKO-DM group and DM group(P>0.05).(3)The contraction responses of aortic smooth muscle in DM group were substantially increased by phenylephrine compared with WT group.Specifically,vaso-constriction responses mediated by non-L-type calcium channels and store-operated calcium channels(SOCC)were signifi-cantly enhanced in DM group.In addition,the responses mediated by inositol 1,4,5-trisphosphate receptors(IP3R),which facilitate calcium release from the sarcoplasmic reticulum,were significantly enhanced.However,the responses mediated by caffeine-activated ryanodine receptors(RyR),which also facilitate calcium release from the sarcoplasmic re-ticulum,were significantly inhibited(P<0.05).(4)Compared with DM group,the phenylephrine-induced contraction re-sponses of aortic smooth muscle in FtoSMKO-DM group were greatly weakened(P<0.05).In particular,the vasoconstriction responses mediated by non-L-type calcium channels and SOCC in FtoSMKO-DM group were greatly suppressed(P<0.05),while those mediated by caffeine-activated RyR were dramatically boosted(P<0.05).However,IP3R-mediated responses were not affected(P>0.05).CONCLUSION:Smooth muscle-specific Fto gene knockout suppresses contractile hyperre-sponsiveness in the aortic smooth muscle of DM mice,which may be attributed to involvement of FTO protein in calcium regulation in the vascular smooth muscle.
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Different from accounting supervision and audit supervision,financial supervision pays more attention to the standardization of economic behavior from the management and governance level,financial supervision has the characteristics of comprehensiveness,foresightedness and guidance,which is very important for the healthy development of public hospital.By analyzing the main problems and challenges faced by the internal financial supervision in public hospitals,it discusses the construction of supervision system,the perfection of working mechanism,the optimization of supervision means and the construction of supervision environment,to explore the concrete ways and suggestions of improving the efficiency of internal financial supervision in public hospitals.
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Objective To construct a clinical prediction model for the risk of Alzheimer's disease based on ApoE,combined with risk factors and common clinical indicators.Methods There were 61 cases of Alzheimer's disease patients and 111 cases of fuzzy matching healthy physical examination from Nanjing Hospital of Chinese Medicine data platform from January 2019 to January 2021.Using LASSO regression screening of risk factors,constructing logistic regression forecasting model,10 fold cross verifies the degree of differentiation,validation the calibration of the bootstrap method.The clinical guidance of the prediction model was evaluated by the clinical decision curve,and finally,the clinical prediction model was visualized by nomogram.Results 12 variables were screened out and four risk factors were included,which are age,free triiodothyroxine(FT3),gender and ApoE.The AUC of ROC of the whole sample was 0.879,and the average AUC of ROC after 10 folded and 9 crossed training sets verification was 0.864.Bootstrap method and Hosmer-Lemeshow were used to test the calibration degree.Results χ2 =6.496,P=0.592>0.05.The threshold probability of clinical decision curve ranged from 1%to 88.6%.Conclusion Individualized evaluation of patients using clinical prediction models constructed by age,FT3,gender and ApoE can provide early warning of Alzheimer's disease,carry out early prevention intervention and slow down the development of the disease.
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Objective To explore the effects and mechanism of Baishile Capsules regulating SHH/Gli1 signaling pathway on hippocampal neurogenesis of depression model rats.Methods Totally 32 SD rats were randomly divided into control group,model group,fluoxetine(5.4 mg/kg)group and Baishile Capsules(2.88 g/kg)group,with 8 rats in each group.A depression rat model was established using chronic unpredictable mild stress and single cage feeding method.The model was established and administered simultaneously for 21 consecutive days.Depression-like behavior in rats were evaluated by sucrose preference experiment and open field experiment,ELISA was used to detect brain derived neurotrophic factor(BDNF)contents in rat serum and hippocampal tissue,the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus was observed by immunofluorescence,immunofluorescence and Western blot were used to detect the fluorescence intensity and protein expression of SHH,Gli1,Smo,Ptch in hippocampal tissue.Results Compared with the control group,the degree of sucrose preference significantly decreased in the model group(P<0.01),the number of horizontal and vertical movements significantly decreased(P<0.01),the contents of BDNF in serum and hippocampal tissue significantly decreased(P<0.05),the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus significantly decreased(P<0.01),and the fluorescence intensity and protein expression of SHH,Gli1,Smo,Ptch in hippocampal tissue significantly decreased(P<0.01,P<0.05).Compared with the model group,the degree of sucrose preference and the number of horizontal and vertical movements in fluoxetine group and Baishile Capsule group increased significantly(P<0.05,P<0.01),the contents of BDNF in serum and hippocampal tissue significantly increased(P<0.05,P<0.01),and the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus significantly increased(P<0.01,P<0.05),the fluorescence intensity and protein expressions of SHH,Gli1,Smo,Ptch in hippocampal tissue significantly increased(P<0.01,P<0.05).Conclusion Baishile Capsule can promote the hippocampus neurogenesis in depression model rats by regulating SHH/Gli1 signaling pathway,and play an antidepressant role.
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Objective:To investigate the effect of preoperative old muscular calf vein thrombosis on the safety and efficacy of total knee arthroplasty (TKA).Methods:A total of 411 patients with end-stage knee osteoarthritis who underwent primary TKA in the First Affiliated Hospital of Nanjing Medical University from September 2021 to March 2023 were retrospectively analyzed. There were 89 males and 322 females, aged 68.05±5.91 years (range, 50-82 years). The body mass index was 26.8±3.7 kg/m 2 (range, 17.4-39.8 kg/m 2). The group was divided into a preoperative thrombosis group (47 cases) and a preoperative none-thrombosis group (364 cases) according to whether or not there was a combination of old muscular calf vein thrombosis before TKA. The clinical characteristics (location and size) and lower limb swelling were observed, and the American Knee Society (AKS) score, visual analogue scale (VAS) and Villalta score were recorded to compare the differences between the two groups. Results:All patients successfully completed the operation and were followed up for 7.4±1.1 months (range, 6-9 months). Postoperative deep venous thrombosis (DVT) occurred in 96% (45/47) of the patients in the preoperative thrombus group, which was greater than the 38.5% (140/364) in the preoperative none-thrombus group, and the difference was statistically significant (χ 2=55.184, P<0.001). 29% (13/45) of the patients who developed DVT postoperatively in the preoperative thrombus group had DVT located in the main vein, which was greater than the 9% (12/140) in the preoperative none-thrombus group, and the difference was statistically significant (χ 2=12.028, P<0.001). 51% (23/45) of patients with DVT after operation had thrombosis ≥6 mm, which was higher than 34% (47/140) of patients in the preoperative none-thrombus group, and the difference was statistically significant (χ 2=4.454, P=0.035). The rate of thigh swelling on postoperative day 3 was 8.42%±3.50% in the group with preoperative thrombus and 7.80%±4.12% in the preoperative none-thrombus group, and the differences were not statistically significant ( t=-0.995, P=0.320). The rate of calf swelling on postoperative day 3 was 8.14%±3.40% in the preoperative thrombus group, which was greater than the 5.51%±3.45% in the preoperative none-thrombus group, and the difference was statistically significant ( t=-4.923, P<0.001). Postoperative AKS scores were elevated in both groups and were greater than preoperative scores at 3 and 6 months postoperatively, with statistically significant differences ( P<0.05). There was no significant difference in AKS score between the two groups before operation ( P>0.05), and the AKS scores in the preoperative thrombus group were smaller than those in the preoperative none-thrombus group at 3 and 6 months postoperatively, with a statistically significant difference ( P<0.05). Postoperative VAS scores were reduced in both groups and were smaller than preoperative scores at 3 and 6 months postoperatively, with statistically significant differences ( P<0.05). There was no significant difference in preoperative VAS scores between the two groups ( P<0.05), and the VAS scores in the preoperative thrombus group were greater than those in the preoperative none-thrombus group at 3 and 6 months postoperatively, with a statistically significant difference ( P<0.05). The Villalta score of patients with DVT after operation in the preoperative thrombus group was 4.47±2.47 at the last follow-up, which was greater than that of the preoperative none-thrombus group, which was 2.90±1.92, and the difference was statistically significant ( t=-4.395, P<0.001). Conclusion:Preoperative combined old muscular calf vein thrombosis increases the incidence of postoperative DVT and the dangerousness of DVT is higher.