RESUMO
Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear. We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity. In mice navigating a virtual-reality environment, targeted optogenetic activation of individual CA1 cells at specific places induced stable representations of these places in the targeted cells. Optical elicitation, recording, and modulation of synaptic transmission in behaving mice revealed that activity in presynaptic CA2/3 cells was required for the induction of plasticity in CA1 and, furthermore, that during induction of these place fields in single CA1 cells, synaptic input from CA2/3 onto these same cells was potentiated. These results reveal synaptic implementation of hippocampal behavioral timescale plasticity and define a methodology to resolve synaptic plasticity during learning and memory in behaving mammals.
Assuntos
Região CA1 Hipocampal , Hipocampo , Camundongos , Animais , Região CA1 Hipocampal/fisiologia , Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Aprendizagem/fisiologia , Neurônios , Transmissão Sináptica/fisiologia , MamíferosRESUMO
Animals in the natural world constantly encounter geometrically complex landscapes. Successful navigation requires that they understand geometric features of these landscapes, including boundaries, landmarks, corners and curved areas, all of which collectively define the geometry of the environment1-12. Crucial to the reconstruction of the geometric layout of natural environments are concave and convex features, such as corners and protrusions. However, the neural substrates that could underlie the perception of concavity and convexity in the environment remain elusive. Here we show that the dorsal subiculum contains neurons that encode corners across environmental geometries in an allocentric reference frame. Using longitudinal calcium imaging in freely behaving mice, we find that corner cells tune their activity to reflect the geometric properties of corners, including corner angles, wall height and the degree of wall intersection. A separate population of subicular neurons encode convex corners of both larger environments and discrete objects. Both corner cells are non-overlapping with the population of subicular neurons that encode environmental boundaries. Furthermore, corner cells that encode concave or convex corners generalize their activity such that they respond, respectively, to concave or convex curvatures within an environment. Together, our findings suggest that the subiculum contains the geometric information needed to reconstruct the shape and layout of naturalistic spatial environments.
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Meio Ambiente , Percepção de Forma , Hipocampo , Neurônios , Animais , Feminino , Masculino , Camundongos , Cálcio/análise , Cálcio/metabolismo , Percepção de Forma/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Propriedades de SuperfícieRESUMO
Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50-70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)-high expression of which is a signature specific to the S-III subtype-alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Terapia de Alvo Molecular/tendências , Proteômica , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Processos de Crescimento Celular , Movimento Celular , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estadiamento de Neoplasias , Prognóstico , Esterol O-Aciltransferase/genéticaRESUMO
Varicella-zoster virus (VZV), a common pathogen with humans as the sole host, causes primary infection and undergoes a latent period in sensory ganglia. The recurrence of VZV is often accompanied by severe neuralgia in skin tissue, which has a serious impact on the life of patients. During the acute infection of VZV, there are few related studies on the pathophysiological mechanism of skin tissue. In this study, transcriptome sequencing data from the acute response period within 2 days of VZV antigen stimulation of the skin were used to explore a model of the trajectory of skin tissue changes during VZV infection. It was found that early VZV antigen stimulation caused activation of mainly natural immune-related signaling pathways, while in the late phase activation of mainly active immune-related signaling pathways. JAK-STAT, NFκB, and TNFα signaling pathways are gradually activated with the progression of infection, while Hypoxia is progressively inhibited. In addition, we found that dendritic cell-mediated immune responses play a dominant role in the lesion damage caused by VZV antigen stimulation of the skin. This study provides a theoretical basis for the study of the molecular mechanisms of skin lesions during acute VZV infection.
Assuntos
Herpesvirus Humano 3 , Transdução de Sinais , Pele , Infecção pelo Vírus da Varicela-Zoster , Herpesvirus Humano 3/genética , Pele/patologia , Pele/virologia , Pele/imunologia , Animais , Infecção pelo Vírus da Varicela-Zoster/virologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Infecção pelo Vírus da Varicela-Zoster/genética , Infecção pelo Vírus da Varicela-Zoster/patologia , Humanos , Camundongos , Células Dendríticas/imunologia , Herpes Zoster/virologia , Herpes Zoster/patologia , Herpes Zoster/genética , Herpes Zoster/imunologia , Transcriptoma , Modelos Animais de Doenças , Antígenos Virais/imunologia , Antígenos Virais/genética , NF-kappa B/metabolismo , NF-kappa B/genéticaRESUMO
Inhibitory interneurons are crucial to brain function and their dysfunction is implicated in neuropsychiatric conditions. Emerging evidence indicates that cholecystokinin (CCK)-expressing interneurons (CCK+) are highly heterogenous. We find that a large subset of parvalbumin-expressing (PV+) interneurons express CCK strongly; between 40 and 56% of PV+ interneurons in mouse hippocampal CA1 express CCK. Primate interneurons also exhibit substantial PV/CCK co-expression. Mouse PV+/CCK+ and PV+/CCK- cells show distinguishable electrophysiological and molecular characteristics. Analysis of single nuclei RNA-seq and ATAC-seq data shows that PV+/CCK+ cells are a subset of PV+ cells, not of synuclein gamma positive (SNCG+) cells, and that they strongly express oxidative phosphorylation (OXPHOS) genes. We find that mitochondrial complex I and IV-associated OXPHOS gene expression is strongly correlated with CCK expression in PV+ interneurons at both the transcriptomic and protein levels. Both PV+ interneurons and dysregulation of OXPHOS processes are implicated in neuropsychiatric conditions, including autism spectrum (ASD) disorder and schizophrenia (SCZ). Analysis of human brain samples from patients with these conditions shows alterations in OXPHOS gene expression. Together these data reveal important molecular characteristics of PV-CCK co-expressing interneurons and support their implication in neuropsychiatric conditions.
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BACKGROUND: This study investigated the clinical application of the indocyanine green (ICG) fluorescence navigation technique in bile duct identification during laparoscopic common bile duct exploration (LCBDE) for complex hepatolithiasis. METHODS: Eighty patients with complex hepatolithiasis were admitted to our department between January 2022 and June 2023 and randomly divided into control and observation groups. The control group underwent conventional LCBDE, while the observation group underwent LCBDE guided by ICG fluorescence. RESULTS: Intraoperatively, the observation group had shorter operation and search times for the common bile duct (CBD), as well as reduced intraoperative blood loss and fewer complications, such as conversion to laparotomy and various injuries (gastroduodenal, colon, pancreatic, and vascular) than the control group, with statistical significance (P < 0.05). Postoperatively, the observation group had lower rates of postoperative bile leakage, abdominal infection, postoperative hemorrhage, and residual stone than the control group. Additionally, the observation group demonstrated significantly shorter times for resuming flatus, removal of the abdominal drainage tube, and hospitalization than the control group, with statistical significance (P < 0.05). CONCLUSION: ICG fluorescence navigation technology effectively visualizes the bile duct, improves its identification rate, shortens the operation time, prevents biliary tract injury, and reduces the occurrence of complications.
Assuntos
Coledocolitíase , Laparoscopia , Litíase , Hepatopatias , Humanos , Coledocolitíase/cirurgia , Ducto Colédoco/cirurgia , Verde de Indocianina , Laparoscopia/métodos , Tempo de Internação , Litíase/cirurgia , Hepatopatias/cirurgia , Estudos RetrospectivosRESUMO
Psoriasis, an immune-mediated inflammatory skin disorder, seriously affects the quality of life of nearly four percent of the world population. Euphorbia helioscopia L. is the monarch constituent of Chinese ZeQi powder preparation for psoriasis, so it is necessary to illustrate its active ingredients. Thus, twenty-three diterpenoids, including seven new ones, were isolated from the whole herb of E. helioscopia L. Compounds 1 and 2, each featuring a 2,3-dicarboxylic functionality, are the first examples in the ent-2,3-sceo-atisane or the ent-2,3-sceo-abietane family. Extensive spectroscopic analysis (1D, 2D NMR, and HRMS data) and computational methods were used to confirm their structures and absolute configurations. According to the previous study and NMR data from the jatropha diterpenes obtained in this study, some efficient 1H NMR spectroscopic rules for assigning the relative configurations of 3α-benzyloxy-jatroph-11E-ene and 7,8-seco-3α-benzyloxy-jatropha-11E-ene were summarized. Moreover, the hyperproliferation of T cells and keratinocytes is considered a key pathophysiology of psoriasis. Anti-proliferative activities against induced T/B lymphocytes and HaCaT cells were tested, and IC50 values of some compounds ranged from 6.7 to 31.5 µM. Compounds 7 and 11 reduced the secretions of IFN-γ and IL-2 significantly. Further immunofluorescence experiments and a docking study with NF-κB P65 showed that compound 13 interfered with the proliferation of HaCaT cells by inhibiting the NF-κB P65 phosphorylation at the protein level.
Assuntos
Diterpenos , Euphorbia , Psoríase , Euphorbia/química , Humanos , Psoríase/tratamento farmacológico , Psoríase/patologia , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Queratinócitos/efeitos dos fármacosRESUMO
This work reports that a low-temperature thermal calcination strategy was adopted to modulate the electronic structure and attain an abundance of surface-active sites while maintaining the crystal morphology. All the experiments demonstrate that the new photocatalyst nano MIL-125(Ti)-250 obtained by thermal calcination strategy has abundant Ti3+ induced by oxygen vacancies and high specific surface area. This facilitates the adsorption and activation of N2 molecules on the active sites in the photocatalytic nitrogen fixation. The photocatalytic NH3 yield over MIL-125(Ti)-250 is enhanced to 156.9â µmol g-1 h-1 , over twice higher than that of the parent MIL-125(Ti) (76.2â µmol g-1 h-1 ). Combined with density function theory (DFT), it shows that the N2 adsorption pattern on the active sites tends to be from "end-on" to "side-on" mode, which is thermodynamically favourable. Moreover, the electrochemical tests demonstrate that the high atomic ratio of Ti3+ /Ti4+ can enhance carrier separation, which also promotes the efficiency of photocatalytic N2 fixation. This work may offer new insights into the design of innovative photocatalysts for various chemical reduction reactions.
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Mass spectrometry (MS)-based metabolic profiling of the endophytic fungus Chaetomium nigricolor F5 guided the isolation of five novel cytochalasans, chamisides B-F (1-5), and two known ones, chaetoconvosins C and D (6 and 7). Their structures including stereochemistry were unambiguously determined by MS, nuclear magnetic resonance, and single-crystal X-ray diffraction analyses. Compounds 1-3 share a new 5/6/5/5/7-fused pentacyclic skeleton in cytochalasans and are appropriately proposed to be the key biosynthetic precursors of co-isolated cytochalasans with a 6/6/5/7/5, 6/6/5/5/7, or 6/6/5 ring system. Remarkably, compound 5 with a relatively flexible side chain showed promising inhibition activity against the cholesterol transporter protein Niemann-Pick C1-like 1 (NPC1L1), expanding the function of cytochalasans.
Assuntos
Sordariales , Estrutura Molecular , Fungos , Citocalasinas/farmacologia , Citocalasinas/químicaRESUMO
In the field of embodied AI, vision-and-language navigation (VLN) is a crucial and challenging multi-modal task. Specifically, outdoor VLN involves an agent navigating within a graph-based environment, while simultaneously interpreting information from real-world urban environments and natural language instructions. Existing outdoor VLN models predict actions using a combination of panorama and instruction features. However, these methods may cause the agent to struggle to understand complicated outdoor environments and ignore the details in the environments to fail to navigate. Human navigation often involves the use of specific objects as reference landmarks when navigating to unfamiliar places, providing a more rational and efficient approach to navigation. Inspired by this natural human behavior, we propose an object-level alignment module (OAlM), which guides the agent to focus more on object tokens mentioned in the instructions and recognize these landmarks during navigation. By treating these landmarks as sub-goals, our method effectively decomposes a long-range path into a series of shorter paths, ultimately improving the agent's overall performance. In addition to enabling better object recognition and alignment, our proposed OAlM also fosters a more robust and adaptable agent capable of navigating complex environments. This adaptability is particularly crucial for real-world applications where environmental conditions can be unpredictable and varied. Experimental results show our OAlM is a more object-focused model, and our approach outperforms all metrics on a challenging outdoor VLN Touchdown dataset, exceeding the baseline by 3.19% on task completion (TC). These results highlight the potential of leveraging object-level information in the form of sub-goals to improve navigation performance in embodied AI systems, paving the way for more advanced and efficient outdoor navigation.
Assuntos
Visão Ocular , Percepção Visual , HumanosRESUMO
Two previously undescribed flavonoid thioglucosides lepidiumflavonosides A and B (1-2) and two known megastigmane compounds (7E,9S)-9-hydroxy-5,7-megastigmadien-4-one 9-O-ß-D-glucopyranoside (3) and (9S)-4-oxo-ß-inol ß-D-glucopyranoside (4) were isolated from the water extract of the seeds of Lepidium apetalum Willd. The structural elucidation of isolated compounds was unambiguously determined based on extensive 1D and 2D NMR spectroscopic analyses. All compounds were evaluated for their estrogen-like effects on MCF-7 cells in vitro. The results showed that compounds 1-4 significantly promoted the proliferation of MCF-7 cells, and the proliferation was antagonized by the specific ER antagonist ICI182,780, suggesting that compounds 1-4 might have the estrogen-like effect in vitro potentially.
Assuntos
Flavonoides , Lepidium , Flavonoides/farmacologia , Flavonoides/química , Tioglucosídeos/análise , Lepidium/química , Estrogênios/farmacologia , Sementes/químicaRESUMO
One new 6a,11a-dehydropterocarpan derivative, 6-O-methyl-anhydrotuberosin (1), one new 6a-hydroxypterocarpan, (6aR,11aR,11bR)-hydroxytuberosone (7), and seven known compounds including two 6a,11a-dehydropterocarpans (2 and 4), two coumestans (3 and 5), one isoflavonoid (6) and two other phenolic compounds (8 and 9) were isolated from the roots of Pueraria lobata. The structures of the isolated compounds were elucidated with spectroscopic and spectrometric methods (1 D and 2DNMR, HRESIMS). Compounds 1, 2, 4-5 showed potent LSD1 inhibitory activities with IC50 values ranging from 1.73 to 4.99 µM. Furthermore, compound 2 showed potent cytotoxicity against gastric cancer cell lines MGC-803 and BGC-823, and lung cancer cell lines H1299 and H460.
Assuntos
Isoflavonas , Pueraria , Pueraria/química , Linhagem Celular , Fenóis , Histona Desmetilases/análise , Raízes de Plantas/química , Isoflavonas/farmacologia , Isoflavonas/químicaRESUMO
One new dibenzyltyrolactone lignan dysoslignan A (1), three new arylnaphthalide lignans dysoslignan B-C (2-4), along with fourteen known metabolites (5-18), were isolated from the roots and rhizomes of Dysosma versipellis. Their structures and stereochemistry were determined from analysis of NMR spectroscopic and circular dichroism (CD) data. Compound 2 represents the first report of naturally occurring arylnaphthalide lignan triglycoside. The cytotoxic activities of all isolated compounds were evaluated against A-549 and SMMC-7721 cell lines. Compounds 7-10 and 14-16 were more toxic than cisplatin in two tumor cell lines. This investigation clarifies the potential effective substance basis of D. versipellis in tumor treatment.
Assuntos
Berberidaceae , Lignanas , Raízes de Plantas , Rizoma , Células A549 , Antineoplásicos/efeitos adversos , Antineoplásicos/toxicidade , Berberidaceae/química , Berberidaceae/metabolismo , Dicroísmo Circular , Cisplatino/efeitos adversos , Cisplatino/toxicidade , Lignanas/química , Lignanas/isolamento & purificação , Lignanas/metabolismo , Lignanas/toxicidade , Espectroscopia de Ressonância Magnética , Neoplasias/tratamento farmacológico , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Rizoma/química , Rizoma/metabolismo , Linhagem Celular TumoralRESUMO
Ten alkaloids(1-10) were isolated from the ethyl acetate extract of the fruit of Lycium chinense var. potaninii by silica gel, ODS, and preparative high performance liquid chromatography(HPLC), and identified by NMR and MS as methyl(2S)-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl]-3-(phenyl)propanoate(1), methyl(2R)-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]-3-(phenyl)propanoate(2), 3-hydroxy-4-ethyl ketone pyridine(3), indolyl-3-carbaldehyde(4),(R)-4-isobutyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde(5),(R)-4-isopropyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-car-baldehyde(6), methyl(2R)-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]-3-(4-hydroxyphenyl)propanoate(7), dimethyl(2R)-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]butanedioate(8), 4-[formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]butanoate(9), 4-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]butanoic acid(10). All the compounds were isolated from the plant for the first time. Among them, compounds 1-3 were new compounds. Compounds 1-9 were evaluated for hypoglycemic activity in vitro with the palmitic acid-induced insulin resistance in HepG2 cells. At 10 µmol·L~(-1), compounds 4, 6, 7, and 9 can promote the glucose consumption of HepG2 cells with insulin resistance.
Assuntos
Alcaloides , Resistência à Insulina , Lycium , Lycium/química , Frutas/química , Propionatos , Alcaloides/farmacologiaRESUMO
BACKGROUND: For patients with congenital aortic valve stenosis (AVS), comprehensive analysis of surgical aortic valvuloplasty (SAV) or balloon dilation (BD) is scarce and remains controversial. METHODS: This study reviewed AVS data (aortic peak gradient, aortic insufficiency, and survival and reoperation) for patients who were suitable for biventricular repair at our center in 2008 to 2018. Patients were categorized into two subgroups based on age (≤3 or >3 months). RESULTS: A total of 194 patients were treated, including 124 with SAV and 70 with BD. Resulting data revealed that residual aortic gradient at discharge was worse for BD (p = 0.001). While for patients younger than 3 months, the relief of AVS was comparable between the two groups (p = 0.624). There was no significant difference in time-related survival between the two groups (log-rank p = 0.644). Multivariate analysis demonstrated that preoperative left ventricular end-diastolic dimension predicted early death (p = 0.045). Survival in the two groups after 10 years was 96.8% in SAV and 95.7% in BD (p = 0.644). Freedom from reoperation after 10 years was 58.1% in SAV and 41.8% in BD patients (p = 0.01). There was no significant difference in freedom from reoperation between SAV and BD in patients younger than 3 months (p = 0.84). Multivariate analysis indicated that residual aortic peak gradient was predictive of reoperation (p = 0.038). CONCLUSION: Both methods achieved excellent survival outcomes at our center. SAV achieved superior gradient reduction and minimized the necessity for reoperation. For patients younger than 3 months, BD rivaled SAV both in aortic stenosis relief and freedom from reoperation.
Assuntos
Insuficiência da Valva Aórtica , Estenose da Valva Aórtica , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Cateterismo , Criança , Humanos , Lactente , Reoperação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Three new polyhydroxylated oleanane triterpenoids, cissatriterpenoid A-C (1-3), along with one known analogue (4), were isolated from the whole plant of Cissampelos pareira var. hirsuta. Their chemical structures were elucidated by extensive spectroscopic data (IR, HR-ESI-MS, 1H-NMR, 13C-NMR, DEPT, 1H-1H COSY, HSQC, HMBC, NOESY) and the microhydrolysis method. The isolation of compounds 1-4 represents the first report of polyhydroxylated oleanane triterpenoids from the family Menispermaceae. All isolated compounds were evaluated for their cytotoxicity against five human cancer cell lines, and the inhibitory activity against NO release in LPS-induced RAW 264.7 cells. Compound 3 showed the most potent cytotoxic activities against the A549, SMMC-7721, MCF-7, and SW480 cell lines, with IC50 values of 17.55, 34.74, 19.77, and 30.39 µM, respectively, whereas three remaining ones were found to be inactive. The preliminary structure-activity relationship analysis indicated that the γ-lactone ring at C-22 and C-29, and the olefinic bond at C-12 and C-13 were structurally required for the cytotoxicity of polyhydroxylated oleanane triterpenoids against these four cell lines. Based on lipid-water partition coefficients, compound 3 is less lipophilic than 1 and 4, which agrees with their cytotoxic activities. This confirms the potential of C. pareira var. hirsuta in the tumor treatment.
Assuntos
Antineoplásicos Fitogênicos , Cissampelos/química , Citotoxinas , Neoplasias/tratamento farmacológico , Ácido Oleanólico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Humanos , Células MCF-7 , Camundongos , Neoplasias/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Células RAW 264.7RESUMO
BACKGROUND: Inositol polyphosphate 4-phosphatase type II (INPP4B) is a negative regulator of the PI3K-Akt signalling pathway and plays a contradictory role in different types of cancers. However, the its biological role played by INPP4B in human gallbladder cancer (GBC) has not been elucidated. In this study, we investigated the expression, clinical significance and biological function of INPP4B in GBC patients and cell lines. METHODS: The INPP4B protein expression levels in gallbladder cancer tissues and normal gallbladder tissues were detected by immunohistochemistry, and the clinical significance of INPP4B was analysed. Knockdown and overexpression of INPP4B in GBC-SD and SGC-996 cells followed by cell proliferation, clonogenic, apoptosis detection, scratch wound-healing and transwell assays were used to identify INPP4B function in vitro. RESULTS: INPP4B was up-regulated in human GBC tissues compared with normal gallbladder tissues and was related to histopathological differentiation (p = 0.026). Here, we observed that INPP4B was highly expressed in high-moderately differentiated tumours compared with low-undifferentiated tumours (p = 0.022). Additionally, we found that INPP4B expression was not associated with overall survival of GBC patients (p = 0.071) and was not an independent prognostic factor. Furthermore, when we stratified the relationship between INPP4B expression and the prognosis of GBC based on histopathological differentiation, we found that INPP4B played a contradictory role in GBC progression depending on the degree of differentiation. In addition, INPP4B knockdown inhibited the proliferation, colony formation, migration and invasion in GBC cells, while INPP4B overexpression had the opposite effects in vitro, which indicates its role as an oncoprotein. CONCLUSIONS: These findings suggested that INPP4B may play a dual role in the prognosis of GBC depending on the degree of differentiation and that INPP4B might act as an oncogene in gallbladder cancer cells.
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Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Monoéster Fosfórico Hidrolases/genética , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Monoéster Fosfórico Hidrolases/metabolismo , Carga TumoralRESUMO
ABSTACTA chemical investigation of the whole plant of traditional Chinese medicine, Chrysanthemum indicum L., led to the discovery of six guaianolide-type sesquiterpenoids 1-6 with a 1,10-splited skeleton. The structure of the new compound 1 was established by extensive analysis of UV, IR, MS, NMR and ECD data. Compounds 3-6 are mutually stereoisomers with four chiral centers and their absolute configurations were determined by comparison of ECD spectra. The anti-inflammatory effects of these isolates on lipopolysaccharide (LPS)-induced nitric oxide (NO) were investigated in RAW 264.7 cells. Results showed that most of the compounds displayed NO production inhibitory activities with IC50 values ranged from 3.54 to 8.17 µM.
Assuntos
Chrysanthemum , Sesquiterpenos , Animais , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico , Células RAW 264.7 , Sesquiterpenos/farmacologiaRESUMO
BACKGROUND: The desirable distance, defined as offset, between the central line of the superior vena cava (SVC) and the intra-atrial conduit after an intra-atrial conduit (IAC) Fontan's procedure remained unclear. We compared the hemodynamic features using virtual surgery with different offset designs in our study. METHODS: Three-dimensional models of IAC Fontan's procedure were reconstructed according to the magnetic resonance imagings (MRIs) of three patients, then four models for each patient with different offsets equaling 100, 67, 33, and 0% of the diameter of the IVC were reconstructed. Computational fluid dynamics (CFD) were performed in each model to predict the best hemodynamic features, including streamlines of blood flow, wall shear stress (WSS), energy loss (EL), and the hepatic flow distribution (HFD) ratio. RESULTS: Comprehensive evaluation of WSS, EL, and HFD revealed than an offset of 33% presents the best hemodynamic performance among the three patients modeled. In patient A, an offset of 33% resulted in the best HFD (left pulmonary artery/right pulmonary artery [LPA/RPA] = 35/65%). In patient B, the best trade-off between HFD (35/65%), and WSS was achieved with an offset of 33%. In patient C, EL peaked at an offset of 0% and significantly dropped at an offset of 33% with a desirable HFD (60/40%). CONCLUSIONS: We verified that the offset distance influences hemodynamic performance in IAC Fontan's procedure. Considering several hemodynamic parameters, the best trade-offs between hemorheology, pulmonary perfusion, and energy efficiency were achieved at an offset of 33%. This distance should be taken into consideration and optimized during the surgical planning for the IAC Fontan's procedure.
Assuntos
Técnica de Fontan , Cardiopatias Congênitas/cirurgia , Hemodinâmica , Artéria Pulmonar/cirurgia , Circulação Pulmonar , Veia Cava Inferior/cirurgia , Veia Cava Superior/cirurgia , Adolescente , Velocidade do Fluxo Sanguíneo , Feminino , Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Artéria Pulmonar/anormalidades , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Resultado do Tratamento , Veia Cava Inferior/anormalidades , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/fisiopatologia , Veia Cava Superior/anormalidades , Veia Cava Superior/diagnóstico por imagem , Veia Cava Superior/fisiopatologiaRESUMO
Lung biopsy is the gold standard for evaluating pathological changes in the pulmonary vascular bed. Knowing the distribution characteristics of pulmonary vascular lesions can improve the accuracy of lung biopsy. To investigate the distribution characteristics of pulmonary vascular remodeling, a reliable porcine model of shunt-associated pulmonary arterial hypertension (PAH) was established. Twenty piglets were randomly divided into the experimental group (n = 10) and the control group (n = 10). A modified Blalock-Taussig shunt (MBTS, left innominate artery to main pulmonary artery) was created surgically in the experimental group. Three months later, an invasive catheter was used to obtain hemodynamic parameters, and lung biopsy was performed to assess the remodeling of pulmonary vascular bed. MBTS was successfully implemented in six piglets. There's no significant difference in hemodynamic parameters of the two groups before the shunt. However, these parameters and right ventricular hypertrophy index of the experimental group were significantly increased after three months shunting. Pathological changes in the experimental group, including thickening of pulmonary artery media, intimal fibrosis, and right ventricular hypertrophy, were observed. Furthermore, the percentage of media thickness and medial area of the experimental group were significantly higher than control group. Histopathology showed that vascular remodeling of the lung was inhomogeneous and that the lateral lesion was more severe than other segments. These results indicated that MBTS could be used to establish a reliable porcine model of shunt-associated PAH and that multisite detection with different segments should be applied to assess the severity of pulmonary vascular remodeling.