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Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca2+ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca2+-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.
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Purpose: To investigate morphological and hemodynamic characteristics of the ophthalmic artery (OA) in patients with white matter hyperintensity (WMH), and the association of the presence and severity of WMH with OA characteristics. Methods: This cross-sectional study included 44 eyes of 25 patients with WMH and 38 eyes of 19 controls. The Fazekas scale was adopted as criteria for evaluating the severity of white matter hyperintensities. The morphological characteristics of the OA were measured on the basis of three-dimensional reconstruction. The hemodynamic parameters of the OA were calculated using computational fluid dynamics simulations. Results: Compared with the control group, the diameter (16.0±0.27 mm vs. 1.71±0.18 mm, P=0.029), median blood flow velocity (0.12 m/s vs. 0.22 m/s, P<0.001), mass flow ratio (2.16% vs. 3.94%, P=0.012) and wall shear stress (2.65 Pa vs. 9.31 Pa, P<0.001) of the OA in patients with WMH were significantly decreased. After adjusting for confounding factors, the diameter, blood flow velocity, wall shear stress, and mass flow ratio of the OA were significantly associated with the presence of WMH. Male sex and high low-density protein level were associated with moderate-to-severe total WMH, and smoking was associated with the moderate-to-severe periventricular WMH. Conclusions: The diameter, blood flow velocity, mass flow ratio, and wall shear stress of the OA were independently associated with the presence of WMH. Atherosclerosis might be involved in the common mechanism of the occurrence of WMH and the OA changes.
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Hemodinâmica , Artéria Oftálmica , Substância Branca , Humanos , Masculino , Feminino , Artéria Oftálmica/diagnóstico por imagem , Artéria Oftálmica/fisiopatologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia , Substância Branca/irrigação sanguínea , Substância Branca/patologia , Estudos Transversais , Hemodinâmica/fisiologia , Pessoa de Meia-Idade , Idoso , Velocidade do Fluxo Sanguíneo , Imageamento por Ressonância Magnética , AdultoRESUMO
Organic acid metabolites exhibit acidic properties. These metabolites serve as intermediates in major carbon metabolic pathways and are involved in several biochemical pathways, including the tricarboxylic acid (TCA) cycle and glycolysis. They also regulate cellular activity and play crucial roles in epigenetics, tumorigenesis, and cellular signal transduction. Knowledge of the binding proteins of organic acid metabolites is crucial for understanding their biological functions. However, identifying the binding proteins of these metabolites has long been a challenging task owing to the transient and weak nature of their interactions. Moreover, traditional methods are unsuitable for the structural modification of the ligands of organic acid metabolites because these metabolites have simple and similar structures. Even minor structural modifications can significantly affect protein interactions. Thermal proteome profiling (TPP) provides a promising avenue for identifying binding proteins without the need for structural modifications. This approach has been successfully applied to the identification of the binding proteins of several metabolites. In this study, we investigated the binding proteins of two TCA cycle intermediates, i.e., succinate and fumarate, and lactate, an end-product of glycolysis, using the matrix thermal shift assay (mTSA) technique. This technique involves combining single-temperature (52 â) TPP and dose-response curve analysis to identify ligand-binding proteins with high levels of confidence and determine the binding affinity between ligands and proteins. To this end, HeLa cells were lysed, followed by protein desalting to remove endogenous metabolites from the cell lysates. The desalted cell lysates were treated with fumarate or succinate at final concentrations of 0.004, 0.04, 0.4, and 2 mmol/L in the experimental groups or 2 mmol/L sodium chloride in the control group. Considering that the cellular concentration of lactate can be as high as 2-30 mmol/L, we then applied lactate at final concentrations of 0.2, 1, 5, 10, and 25 mmol/L in the experimental groups or 25 mmol/L sodium chloride in the control group. Using high-sensitivity mass spectrometry coupled with data-independent acquisition (DIA) quantification, we quantified 5870, 5744, and 5816 proteins in succinate, fumarate, and lactate mTSA experiments, respectively. By setting stringent cut-off values (i.e., significance of changes in protein thermal stability (p-value)<0.001 and quality of the dose-response curve fitting (square of Pearson's correlation coefficient, R2)>0.95), multiple binding proteins for these organic acid metabolites from background proteins were confidently determined. Several known binding proteins were identified, notably fumarate hydratase (FH) as a binding protein for fumarate, and α-ketoglutarate-dependent dioxygenase (FTO) as a binding protein for both fumarate and succinate. Additionally, the affinity data for the interactions between these metabolites and their binding proteins were obtained, which closely matched those reported in the literature. Interestingly, ornithine aminotransferase (OAT), which is involved in amino acid biosynthesis, and 3-mercaptopyruvate sulfurtransferase (MPST), which acts as an antioxidant in cells, were identified as lactate-binding proteins. Subsequently, an orthogonal assay technique developed in our laboratory, the solvent-induced precipitation (SIP) technique, was used to validate the mTSA results. SIP identified OAT as the top target candidate, validating the mTSA-based finding that OAT is a novel lactate-binding protein. Although MPST was not identified as a lactate-binding protein by SIP, statistical analysis of MPST in the mTSA experiments with 10 or 25 mmol/L lactate revealed that MPST is a lactate-binding protein with a high level of confidence. Peptide-level empirical Bayes t-tests combined with Fisher's exact test also supported the conclusion that MPST is a lactate-binding protein. Lactate is structurally similar to pyruvate, the known binding protein of MPST. Therefore, assuming that lactate could potentially occupy the binding site of pyruvate on MPST. Overall, the novel binding proteins identified for lactate suggest their potential involvement in amino acid synthesis and redox balance regulation.
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Ciclo do Ácido Cítrico , Humanos , Células HeLa , Ácido Succínico/metabolismo , Ácido Succínico/química , Fumaratos/metabolismo , Fumaratos/químicaRESUMO
The brain presents age-related structural and functional changes in the human life, with different extends between subjects and groups. Brain age prediction can be used to evaluate the development and aging of human brain, as well as providing valuable information for neurodevelopment and disease diagnosis. Many contributions have been made for this purpose, resorting to different machine learning methods. To solve this task and reduce memory resource consumption, we develop a mini architecture of only 10 layers by modifying the deep residual neural network (ResNet), named ResNet mini architecture. To support the ResNet mini architecture in brain age prediction, the brain age dataset (OpenNeuro #ds000228) that consists of 155 study participants (three classes) and the Alzheimer MRI preprocessed dataset that consists of 6400 images (four classes) are employed. We compared the performance of the ResNet mini architecture with other popular networks using the two considered datasets. Experimental results show that the proposed architecture exhibits generality and robustness with high accuracy and less parameter number.
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Envelhecimento , Encéfalo , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Envelhecimento/fisiologia , Imageamento por Ressonância Magnética/métodos , Aprendizado Profundo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Aprendizado de Máquina , Feminino , Idoso de 80 Anos ou mais , Masculino , Pessoa de Meia-IdadeRESUMO
Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.
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Antineoplásicos , Carcinoma Hepatocelular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas , Fator de Transcrição STAT3 , Sorafenibe , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Nus , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto , Movimento Celular/efeitos dos fármacos , Masculino , Transdução de Sinais/efeitos dos fármacos , Oligonucleotídeos/farmacologiaRESUMO
OBJECTIVE: To evaluate the relationship between CXCL12/CXCR4 and the progress, prognosis of esophageal squamous cell carcinoma (ESCC), providing evidence for potential early diagnosis, clinical treatment, prognosis evaluation, and therapeutic target of ESCC. METHODS: Databases of PubMed, the Cochrane Library, Embase, and Web of Science were searched for the relationship between CXCL12/CXCR4 and clinicopathological characteristics and survival time of ESCC. Stata16.0 software was used to conduct meta-analysis. RESULTS: A total of 10 studies involving 1216 cases of patients with ESCC were included in our study. The results indicated that high-level expression of CXCR4 was significantly correlated with tumor differentiation [ORâ =â 0.69, 95% confidence interval (CI): (0.50, 0.97)], tumor infiltration [ORâ =â 0.39, 95% CI: (0.25, 0.61)], lymph node metastasis [ORâ =â 0.36, 95% CI: (0.21, 0.61)], clinical stage [ORâ =â 0.33, 95% CI: (0.24, 0.45)] of ESCC. The expression of CXCR4 was also significantly correlated with OS [HRâ =â 2.00, 95% CI: (1.63, 2.45)] and disease-free survival [HRâ =â 1.76, 95% CI: (1.44, 2.15)] in patients of ESCC after surgical resection. No significant relationship was observed between the expression of CXCL12 and the clinicopathological characteristics of ESCC. CONCLUSION: CXCR4 might be a potential biomarker for the progress and prognosis evaluation, and therapeutic target for ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Prognóstico , Biomarcadores Tumorais/metabolismo , Receptores CXCR4RESUMO
CASE PRESENTATION: A 38-year-old previously healthy woman was referred to our sleep center for recurrent witnessed breathing arrest during sleep. She had been brought to the ED 3 months earlier because of sudden onset of dizziness with nausea and vomiting, numbness and weakness of the left limb, less clear speech, double vision, dysphagia, and choking cough while drinking water. Brain MRI showed an acute cerebral infarction in the left medulla oblongata (Fig 1). High-resolution MRI showed vertebral artery dissection (Fig 2). Antiplatelet aggregation, lipid reduction, plaque stabilization, and trophic nerve treatments were administered, and the left limb strength, speech, and swallowing function improved. She complained of poor sleep and difficulties with memory.
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Isquemia Encefálica , Apneia do Sono Tipo Central , Acidente Vascular Cerebral , Feminino , Humanos , Adulto , Imageamento por Ressonância Magnética , InfartoRESUMO
BACKGROUND: Colorectal cancer is a major global health challenge that predominantly affects older people. Surgical management, despite advancements, requires careful consideration of preoperative patient status for optimal outcomes. AIM: To summarize existing evidence on the association of frailty with short-term postoperative outcomes in patients undergoing colorectal cancer surgery. METHODS: A literature search was conducted using PubMed, EMBASE and Scopus databases for observational studies in adult patients aged ≥ 18 years undergoing planned or elective colorectal surgery for primary carcinoma and/or secondary metastasis. Only studies that conducted frailty assessment using recognized frailty assessment tools and had a comparator group, comprising nonfrail patients, were included. Pooled effect sizes were reported as weighted mean difference or relative risk (RR) with 95% confidence intervals (CIs). RESULTS: A total of 24 studies were included. Compared with nonfrail patients, frailty was associated with an increased risk of mortality at 30 d (RR: 1.99, 95%CI: 1.47-2.69), at 90 d (RR: 4.76, 95%CI: 1.56-14.6) and at 1 year (RR: 5.73, 95%CI: 2.74-12.0) of follow up. Frail patients had an increased risk of any complications (RR: 1.81, 95%CI: 1.57-2.10) as well as major complications (Clavien-Dindo classification grade ≥ III) (RR: 2.87, 95%CI: 1.65-4.99) compared with the control group. The risk of reoperation (RR: 1.18, 95%CI: 1.07-1.31), readmission (RR: 1.70, 95%CI: 1.36-2.12), need for blood transfusion (RR: 1.67, 95%CI: 1.52-1.85), wound complications (RR: 1.49, 95%CI: 1.11-1.99), delirium (RR: 4.60, 95%CI: 2.31-9.16), risk of prolonged hospitalization (RR: 2.09, 95%CI: 1.22-3.60) and discharge to a skilled nursing facility or rehabilitation center (RR: 3.19, 95%CI: 2.0-5.08) was all higher in frail patients. CONCLUSION: Frailty in colorectal cancer surgery patients was associated with more complications, longer hospital stays, higher reoperation risk, and increased mortality. Integrating frailty assessment appears crucial for tailored surgical management.
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Municipal solid waste incineration fly ash (MSWIFA) can be reused as a positive additive to strengthen soft soil. In this study, MSWIFA was initially used as a supplementary solidification material in combination with ordinary Portland cement to prepare fly ash cement-stabilized soil (FACS) with silty sand and silty clay, respectively. The ratio of MWSIFA to total mass was 5%, 10%, and 15%, and the cement content was set as 10% and 15%. The mechanical properties of FACS were evaluated by unconfined compressive strength test. The heavy metal-leaching test was conducted to estimate the environmental risk of FACS. The scanning electron microscope was used to test the micro-structure of FACS. The X-ray diffraction was performed to analyze material composition of FACS. The result indicates that the collaborative solidification of soft soil with MSWIFA and cement is feasible. Regarding the silty clay, the FA had positive effects on the silty clay in the service age (between 50 and 100% with 15% MSWIFA), as the MSWIFA reformulated the initial silty clay structure, resulting in interconnection and pore fill between particles. It can be founded that C-S-H and ettringite are the main products of MSWIFA and cement hydration, which are formed by the hydration of C3S and C2S. Regarding the silty sand, the MSWIFA decreased the peak strength (between 35 and 48% with 15% MSWIFA) but increased the ductility of the stabilized cement. Under the same mix proportions, the leaching toxicities of Zn and Pb in FACS of silty clay were obviously lower than were those of silty sand. Generally, the leaching concentrations of tested metals under all the mix proportions were well below the limit value set by GB 18598-2019 for hazardous waste landfill. Thus, the reuse of MSWIFA in cement-stabilized soil would be one of the effective methods in soft soil treatment and solid waste reduction.
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Metais Pesados , Eliminação de Resíduos , Cinza de Carvão , Resíduos Sólidos/análise , Argila , Solo , Areia , Incineração , Metais Pesados/análise , Eliminação de Resíduos/métodos , Carbono/química , Material ParticuladoRESUMO
Eph receptor tyrosine kinases participate in a variety of normal and pathogenic processes during development and throughout adulthood. This versatility is likely facilitated by the ability of Eph receptors to signal through diverse cellular signalling pathways: primarily by controlling cytoskeletal dynamics, but also by regulating cellular growth, proliferation, and survival. Despite many proteins linked to these signalling pathways interacting with Eph receptors, the specific mechanisms behind such links and their coordination remain to be elucidated. In a proteomics screen for novel EPHB2 multi-effector proteins, we identified human MYC binding protein 2 (MYCBP2 or PAM or Phr1). MYCBP2 is a large signalling hub involved in diverse processes such as neuronal connectivity, synaptic growth, cell division, neuronal survival, and protein ubiquitination. Our biochemical experiments demonstrate that the formation of a complex containing EPHB2 and MYCBP2 is facilitated by FBXO45, a protein known to select substrates for MYCBP2 ubiquitin ligase activity. Formation of the MYCBP2-EPHB2 complex does not require EPHB2 tyrosine kinase activity and is destabilised by binding of ephrin-B ligands, suggesting that the MYCBP2-EPHB2 association is a prelude to EPHB2 signalling. Paradoxically, the loss of MYCBP2 results in increased ubiquitination of EPHB2 and a decrease of its protein levels suggesting that MYCBP2 stabilises EPHB2. Commensurate with this effect, our cellular experiments reveal that MYCBP2 is essential for efficient EPHB2 signalling responses in cell lines and primary neurons. Finally, our genetic studies in Caenorhabditis elegans provide in vivo evidence that the ephrin receptor VAB-1 displays genetic interactions with known MYCBP2 binding proteins. Together, our results align with the similarity of neurodevelopmental phenotypes caused by MYCBP2 and EPHB2 loss of function, and couple EPHB2 to a signalling effector that controls diverse cellular functions.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas F-Box , Receptor EphB2 , Ubiquitina-Proteína Ligases , Animais , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Caenorhabditis elegans/genética , Receptor EphB2/genética , Transdução de Sinais , Ubiquitina , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
OBJECTIVES: To observe the effect of electroacupuncture (EA) on nuclear transcription factor E2 related factor 2 (Nrf2)/NOD-like receptor family pyrin domain-containing protein 3 (NLRP3)/cysteine aspartic acid specific protease-1 (Caspase-1) pathway in the substantia nigra (SN) of mice with Parkinson's disease (PD), so as to explore the neuroprotective mechanism of EA. METHODS: Forty C57BL/6 male mice were randomly divided into 4 groups, namely, control, PD model, EA and sham-EA groups, with 10 mice in each group. The PD mouse model was established by gavage of rotenone for 4 weeks. Mice in the EA group were given EA stimulation (1 mA, 2 Hz) at "Fengfu" (GV36), bilateral "Taichong" (LR3) and "Zusanli" (ST36) for 30 min, once daily for 2 consecutive weeks. And mice in the sham-EA group were given acupuncture at the subcutaneous areas of the same acupoints without EA stimulation. The open-field test was used for assessment of mouse behavior. The levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in the serum were detected by enzyme-linked immunosorbent assay . The positive expression of tyrosine hydroxylase (TH) in SN was determined by immunohistochemistry. The mRNA expression levels of Nrf2, NLRP3, Caspase-1, gasdermin D(GSDMD), IL-1ß, IL-18 and the protein expression levels of Nrf2, NLRP3, Caspase-1 and GSDMD in the SN were detected by quantitative real-time PCR and Western blot, separately. RESULTS: After modeling, compared with the control group, the behavioral score was increased (P<0.01), the total exercise time, the total distance and the average speed were decreased (P<0.01), and the positive expression of TH and the mRNA and protein expression levels of Nrf2 in the SN were decreased (P<0.01), while the contents of IL-1ß and IL-18 in serum, the mRNA and protein expression levels of NLRP3, Caspase-1 and GSDMD and the mRNA expression levels of IL-1ß and IL-18 in the SN were up-regulated (P<0.01) in the PD model group. Following EA intervention, the behavioral score was decreased(P<0.01), the total exercise time, total distance and average speed were increased (P<0.01), the positive expression of TH and the mRNA and protein expressions of Nrf2 in SN were up-regulated (P<0.01, P<0.05), while the contents of IL-1ß and IL-18 in serum, the mRNA and protein expression levels of NLRP3, Caspase-1 and GSDMD as well as the mRNA expression levels of IL-1ß and IL-18 in the SN were down-regulated (P<0.01, P<0.05) in the EA group relative to the PD model and sham-EA groups. There were no significant differences in the above indicators between the PD model and sham-EA groups. CONCLUSIONS: EA stimulation of GV36, LR3 and ST36 can improve motor deficits, reduce the loss of dopamine neurons in the SN, and inhibit neuroinflammatory responses in mice with PD, which may be related to its effects in regulating the Nrf2/NLRP3/Caspase-1 pathway mediated pyroptosis.
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Eletroacupuntura , Doença de Parkinson , Camundongos , Masculino , Animais , Doença de Parkinson/genética , Doença de Parkinson/terapia , Interleucina-18 , Fator 2 Relacionado a NF-E2/genética , Caspase 1/genética , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Camundongos Endogâmicos C57BL , Interleucina-1beta/genética , RNA MensageiroRESUMO
Due to the sustained proliferative potential of cancer cells, inducing cell death is a potential strategy for cancer therapy. Paraptosis is a mode of cell death characterized by endoplasmic reticulum (ER) and/or mitochondrial swelling and cytoplasmic vacuolization, which is less investigated. Considerable evidence shows that paraptosis can be triggered by various chemical compounds, particularly in cancer cells, thus highlighting the potential application of this non-classical mode of cell death in cancer therapy. Despite these findings, there remain significant gaps in our understanding of the role of paraptosis in cancer. In this review, we summarize the current knowledge on chemical compound-induced paraptosis. The ER and mitochondria are the two major responding organelles in chemical compound-induced paraptosis, which can be triggered by the reduction of protein degradation, disruption of sulfhydryl homeostasis, overload of mitochondrial Ca2+, and increased generation of reactive oxygen species. We also discuss the stumbling blocks to the development of this field and the direction for further research. The rational use of paraptosis might help us develop a new paradigm for cancer therapy.
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Neoplasias , Paraptose , Linhagem Celular Tumoral , Morte Celular , Espécies Reativas de Oxigênio/metabolismo , Retículo Endoplasmático/metabolismo , Apoptose , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer's and Parkinson's. The cytokine interleukin-12 activates signal transducer and activator of transcription 4 (Stat4), and consumption of a high-fat, high-cholesterol diet (HFD-C) and Stat4 activity are associated with inflammation, atherosclerosis, and a diabetic metabolic phenotype. In studies of in vitro hippocampal slices from control Stat4fl/flLdlr-/- mice fed a HFD-C diabetogenic diet, we show that Schaffer collateral-CA1 synapses exhibited larger reductions in activity-dependent, long-term potentiation (LTP) of synaptic transmission, compared to mice fed a standard diet. Glucose tolerance and insulin sensitivity shifts produced by HFD-C diet were reduced in Stat4ΔLysMLdlr-/- mice compared to Stat4fl/flLdlr-/- controls. Stat4ΔLysMLdlr-/- mice, which lack Stat4 under control of the LysMCre promoter, were resistant to HFD-C induced impairments in LTP. In contrast, Schaffer collateral-CA1 synapses in Stat4ΔLysMLdlr-/- mice fed the HFD-C diet showed larger LTP than control Stat4fl/flLdlr-/- mice. Expression of a number of neuroinflammatory and synaptic plasticity genes was reduced by HFD-C diet in control mice, and less affected by HFD-C diet in Stat4ΔLysMLdlr-/- mice. These data suggest that suppression of Stat4 activation may protect against effects of Western diet on cognition, type 2 diabetes, and reduce risk of Alzheimer's disease and other neurodegenerative disorders associated with neuroinflammation.
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Diabetes Mellitus Tipo 2 , Fator de Transcrição STAT4 , Camundongos , Animais , Fator de Transcrição STAT4/metabolismo , Doenças Neuroinflamatórias , Plasticidade Neuronal , Colesterol/metabolismo , Células Mieloides/metabolismoRESUMO
OBJECTIVES: To evaluate the performance of coronary computed tomography angiography (CCTA) derived characteristics including CT derived fractional flow reserve (CT-FFR) with FFR as a reference standard in identifying the lesion-specific ischemia by machine learning (ML) algorithms. METHODS: The retrospective analysis enrolled 596 vessels in 462 patients (mean age, 61 years ± 11 [SD]; 71.4 % men) with suspected coronary artery disease who underwent CCTA and invasive FFR. The data were divided into training cohort, internal validation cohort, external validation cohorts 1 and 2 according to participating centers. All CCTA-derived parameters, which contained 10 qualitative and 33 quantitative plaque parameters, were collected to establish ML model. The Boruta and unsupervised clustering algorithm were implemented to select important and non-redundant parameters. Finally, the eight features with the highest mean importance were included for further ML model establishment and decision tree building. Five models were built to predict lesion-specific ischemia: stenosis degree from CCTA, CT-FFR, ΔCT-FFR, ML model and nested model. RESULTS: Low-attenuation plaque, bend and lesion length were the main predictors of ischemia-specific lesions. Of 5 models, the ML model showed favorable discrimination for ischemia-specific lesions in the training and three validation sets (area under the curve [95 % confidence interval], 0.93 [0.90-0.96], 0.86 [0.79-0.94], 0.88 [0.83-0.94], and 0.90 [0.84-0.96], respectively). The nested model which combined the ML model and CT-FFR showed better diagnostic efficacy (AUC [95 %CI], 0.96 [0.94-0.99], 0.92 [0.86-0.99], 0.92 [0.86-0.99] and 0.94 [0.91-0.98], respectively; all P < 0.05), and net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were significantly higher than CT-FFR alone. CONCLUSIONS: Comprehensive CCTA-derived multiparameter model could better predict the ischemia-specific lesions by ML algorithms compared to stenosis degree from CTA, CT-FFR and ΔCT-FFR. Decision tree can be used to predict myocardial ischemia effectively.
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Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Placa Aterosclerótica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Angiografia por Tomografia Computadorizada/métodos , Constrição Patológica , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , População do Leste Asiático , Isquemia , Aprendizado de Máquina , Valor Preditivo dos Testes , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , IdosoRESUMO
OBJECTIVES: To observe the effects of electroacupuncture (EA) at "Fengfu" (GV16), "Taichong" (LR3) and "Zusanli" (ST36) on α-synuclein (α-syn), Occludin, Claudin-1, thioredoxin interaction protein (TXNIP) and Nod-like receptor 3 (NLRP3) in Parkinson's disease (PD) mice, so as to investigate the mechanisms of EA on intestinal barrier function and inflammation in PD mice. METHODS: Thirty six C57BL/6 mice were randomly divided into control, model and EA groups, with 12 mice in each group. PD mice model was induced by rotenone intragastric administration for 28 days. Mice in the EA group were treated with EA (2 Hz, 1 mA) at GV16, LR3 and ST36 for 30 min, once a day for 14 days. The behavioral scores were observed. The total distance of autonomic movement was measured by open field test. The expression level of α-syn in substantia nigra and colon tissue was determined by immunohistochemistry. The colonic morphology and goblet cell distribution were observed by Alcian blue staining. The expression levels of Occludin, Claudin-1, TXNIP and NLRP3 mRNA in colon tissue were detected by real-time fluorescence quantitative PCR. RESULTS: Compared with the control group, the behavioral scores of rats were increased (P<0.01)ï¼the total distance of autonomous movement was decreased (P<0.01)ï¼the positive expression level of α-syn in the substantia nigra and colon was increased (P<0.01)ï¼the goblet cells and crypts in colon tissue were reduced, and the muscular layer was thinnerï¼the expression levels of Occludin and Claudin-1 mRNAs in colon tissue were decreased (P<0.01) while TXNIP and NLRP3 mRNAs were increased (P<0.01) in the model group. Compared with the model group, the surface villi of colon tissue was more complete, the goblet cells and crypts were increased, and the muscular layer was thickenedï¼the other indexes were reversed (P<0.01, P<0.05) in the EA group. CONCLUSIONS: EA at GV16, LR3 and ST36 can reduce the abnormal accumulation of α-syn in the substania nigra and colon tissue of PD mice, alleviate the damage of intestinal barrier, regulate TXNIP/NLRP3 signaling pathway, so as to delay the occurrence and development of PD.
Assuntos
Eletroacupuntura , Doença de Parkinson , Animais , Camundongos , Ratos , Proteínas de Ciclo Celular/metabolismo , Claudina-1 , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ocludina , Doença de Parkinson/genética , Doença de Parkinson/terapia , Ratos Sprague-Dawley , RNA Mensageiro , Transdução de Sinais , TiorredoxinasRESUMO
PURPOSE: To determine the reliability of dynamic magnetic resonance imaging (MRI) perfusion parameters for the evaluation of blood supply to spinal metastatic tumors. METHODS: A total of 36 patients with spinal metastasis who underwent dynamic contrast-enhanced magnetic resonance spinal perfusion imaging at Tianjin Hospital from December 2018 to December 2020 were reviewed. Subsequently, the patients underwent corresponding preoperative examination using digital subtraction angiography of the spine at the hospital and were divided into 2 groups accordingly. Differences in dynamic MRI perfusion parameters between the 2 groups were analyzed. RESULTS: There were statistically significant differences between the 2 groups in the quantitative dynamic contrast-enhanced MRI perfusion parameters vascular permeability and plasma volume, as well as semi-quantitative peak enhancement and blood flow ratio parameters. CONCLUSIONS: Dynamic MRI perfusion may distinguish spinal metastatic lesions with rich blood supply from those with poor blood supply and may help clinicians identify patients that can benefit from invasive spinal angiography and preoperative embolization. This technique may also provide guidance on decision taking for surgery basing on dynamic MRI perfusion parameters.
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Meios de Contraste , Neoplasias , Humanos , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética/métodos , Angiografia Digital/métodos , PerfusãoRESUMO
OBJECTIVE: The global aim to lower preterm birth rates has been hampered by the insufficient and incomplete understanding of its etiology, classification, and diagnosis. This study was designed to evaluate the association of phenotypically classified preterm syndromes with neonatal outcomes; to what extent would these outcomes be modified after the obstetric interventions, including use of glucocorticoid, magnesium sulfate, and progesterone. METHODS: This was a retrospective cohort study conducted at Tongji Hospital (composed of Main Branch, Optical Valley Branch and Sino-French New City Branch) in Wuhan. A total of 900 pregnant women and 1064 neonates were retrospectively enrolled. The outcomes were the distribution of different phenotypes among parturition signs and pathway to delivery, the association of phenotypically classified clusters with short-term unfavorable neonatal outcomes, and to what extent these outcomes could be modified by obstetric interventions. RESULTS: Eight clusters were identified using two-step cluster analysis, including premature rupture of fetal membranes (PPROM) phenotype, abnormal amniotic fluid (AF) phenotype, placenta previa phenotype, mixed condition phenotype, fetal distress phenotype, preeclampsia-eclampsia & hemolysis, elevated liver enzymes, and low platelets syndrome (PE-E&HELLP) phenotype, multiple fetus phenotype, and no main condition phenotype. Except for no main condition phenotype, the other phenotypes were associated with one or more complications, which conforms to the clinical practice. Compared with no main condition phenotype, some phenotypes were significantly associated with short-term adverse neonatal outcomes. Abnormal AF phenotype, mixed condition phenotype, PE-E&HELLP phenotype, and multiple fetus phenotype were risk factors for neonatal small-for gestation age (SGA); placenta previa phenotype was not associated with adverse outcomes except low APGAR score being 0-7 at one min; mixed condition phenotype was associated with low APGAR scores, SGA, mechanical ventilation, and grade HI-W intraventricular hemorrhage (IVH); fetal distress phenotype was frequently associated with neonatal SGA and mechanical ventilation; PE-E&HELLP phenotype was correlated with low APGAR score being 0-7 at one min, SGA and neonatal intensive care unit (NICU) admission; multiple fetus phenotype was not a risk factor for the outcomes included except for SGA. Not all neonates benefited from obstetric interventions included in this study. CONCLUSION: Our research disclosed the independent risk of different preterm phenotypes for adverse pregnancy outcomes. This study is devoted to putting forward the paradigm of classifying preterm birth phenotypically, with the ultimate purpose of defining preterm phenotypes based on multi-center studies and diving into the underlying mechanisms.
Assuntos
Síndrome HELLP , Placenta Prévia , Complicações na Gravidez , Nascimento Prematuro , Recém-Nascido , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Sofrimento FetalRESUMO
OBJECTIVE: Cardiopulmonary resuscitation (CPR) after cardiac arrest (CA) is one of the main causes of capillary leakage syndrome (CLS). This study aimed to establish a stable CLS model following the CA and cardiopulmonary resuscitation (CA-CPR) model in Sprague-Dawley (SD) rats. METHODS: We conducted a prospective, randomized, animal model study. All adult male SD rats were randomly divided into a normal group (group N), a sham operation group (group S), and a cardiopulmonary resuscitation group (group T). The SD rats of the three groups were all inserted with 24-G needles through their left femoral arteries and right femoral veins. In group S and group T, the endotracheal tube was intubated. In group T, CA induced by asphyxia (AACA) was caused by vecuronium bromide with the endotracheal tube obstructed for 8 min, and the rats were resuscitated with manual chest compression and mechanical ventilation. Preresuscitation and postresuscitation measurements, including basic vital signs (BVS), blood gas analysis (BG), routine complete blood count (CBC), wet-to-dry ratio of tissues (W/D), and the HE staining results after 6 h were evaluated. RESULTS: In group T, the success rate of the CA-CPR model was 60% (18/30), and CLS occurred in 26.6% (8/30) of the rats. There were no significant differences in the baseline characteristics, including BVS, BG, and CBC, among the three groups (P>0.05). Compared with pre-asphyxia, there were significant differences in BVS, CBC, and BG, including temperature, oxygen saturation (SpO2), mean arterial pressure (MAP), central venous pressure (CVP), white blood cell count (WBC), hemoglobin, hematocrit, pH, pCO2, pO2, SO2, lactate (Lac), base excess (BE), and Na+ (P<0.05) after the return of spontaneous circulation (ROSC) in group T. At 6 h after ROSC in group T and at 6 h after surgery in groups N and S, there were significant differences in temperature, heart rate (HR), respiratory rate (RR), SpO2, MAP, CVP, WBC, pH, pCO2, Na+, and K+ among the three groups (P<0.05). Compared with the other two groups, the rats in group T showed a significantly increased W/D weight ratio (P<0.05). The HE-stained sections showed consistent severe lesions in the lung, small intestine, and brain tissues of the rats at 6 h after ROSC following AACA. CONCLUSION: The CA-CPR model in SD rats induced by asphyxia could reproduce CLS with good stability and reproducibility.
Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca , Animais , Masculino , Ratos , Asfixia/complicações , Reanimação Cardiopulmonar/efeitos adversos , Reanimação Cardiopulmonar/métodos , Parada Cardíaca/terapia , Estudos Prospectivos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
Thermal enhanced soil vapour extraction (T-SVE) is a remedial technique involving gas, aqueous, solid and nonaqueous phases along with mass and heat transfer. Interphase mass transfer of contaminants and water evaporation/condensation will cause the redistribution of phase saturation, eventually affecting the performance of T-SVE. In this study, a multiphase, multicompositional and nonisothermal model was developed to simulate the T-SVE treatment of contaminated soil. The model was calibrated using published data from the SVE laboratory and T-SVE field experiments. The temporal and spatial distributions of the contaminant concentrations in the four different phases, the mass transfer rates and the temperatures are presented to reveal the coupling interactions that occur between multiple fields during T-SVE. A series of parametric studies were carried out to investigate the effect of water evaporation and adsorbed/dissolved contaminants on the T-SVE performance. It was found that endothermic evaporation, exothermic condensation and the interaction between different removal paths of a contaminant played critical roles in the thermal enhancement of SVE. Ignoring them can result in significant differences in the removal efficiency values.
Assuntos
Recuperação e Remediação Ambiental , Poluentes do Solo , Temperatura Alta , Solo , Gases , Água , Poluentes do Solo/análiseRESUMO
Background: Non-alcoholic fatty liver disease (NAFLD) represents a severe public health problem. Dysbiosis of gut microbiome has been identified as one of the key environmental factors contributing to NAFLD. As an essential nutrition, Vitamin D (VD) plays an important role in regulating gut microbiota based on its receptor (Vitamin D Receptor, VDR) which is highly expressed in the gastrointestinal tract. Methods: Rats were fed with HFD (high-fat diet) for 12 weeks. And the rats were treated with VD two times a week by intraperitoneal injection for 12 weeks. H&E staining combined with plasma biochemical index was performed to characterize pathological changes and function of the liver. Fecal microbiota 16S rRNA gene sequencing and metabolomics were taken to reveal the altered gut microbiota and metabolites. Result: The VD alleviates the HFD-induced lipid accumulation in the liver as well as decreases the levels of amlodipine besylate (ALT) and amlodipine aspartate (AST). VD supplement decreased the ratio of phylum Firmicutes/Bacteroidetes (F/B) but increased alpha diversity. In addition, the VD treatment improved the HFD-induced gut microbiota by increasing the Prevotella and Porphyromonadaceae and decreasing Mucispirillum, Acetatifactor, Desulfovibrio, and Oscillospira abundance. Furthermore, the capability of tyrosine metabolism, tryptophan metabolism, arginine biosynthesis, and sphingolipid metabolism was enhanced after VD treatment. Consistently, Prevotella positively correlated with tryptophan metabolism and sphingolipid metabolism. Importantly, the Prevotella abundance was positively associated with serotonin, melatonin, tryptamine, L-arginine, and 3-dehydrosphinganine which synthesize from tryptophan, tyrosine, arginosuccinate, and serine, respectively. Conclusion: VD treatment inhibited HFD-induced NAFLD accompany by dysbiosis gut microbiota and metabolites, suggesting that VD supplement could be a potential intervention used for NAFLD treatment by targeting the specific microbiota.