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1.
Diabetes ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968428

RESUMO

Retinal fibrosis is one of the major features of Diabetic retinopathy. Our recent research has shown that Poldip2 can affect early DR through oxidative stress, but whether or not Poldip2 would regulate retinal fibrosis during DR development is still enigmatic. Here, Diabetic Sprague-Dawley (SD) rats were induced with STZ and treated with AAV9-Poldip2shRNA, while human retinal pigment epithelial cells (ARPE-19) were treated with high glucose (HG) or Poldip2 siRNA. We identified that in STZ-induced DR rats and ARPE-19 treated with high glucose, the expression of Poldip2, TGFß1, P-SMAD3/SMAD3, MMP9, COL-1, FN, and CTGF increased while the expression of Cadherin decreased. However, deleting Poldip2 inhibited the TGF-ß1/SMAD3 signaling pathway and attenuated the above protein expression in vivo and in vitro. Mechanistically, we found that Poldip2 promotes the activation of SMAD3, and facilitates its nuclear translocation through interacting with it, and significantly enhances the expression of fibrosis makers. Collectively, it was identified that Poldip2 is a novel regulator of DR fibrosis and it is expected to become a therapeutic target for PDR.

2.
J Neuroimmunol ; 393: 578401, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38996718

RESUMO

BACKGROUND: We previously reported that the HMGB1/TLR4 axis promoted inflammation during the acute phase of intracerebral hemorrhage. Given that this phase is known to involve neuronal pyroptosis and neuroinflammation, here we explore whether HMGB1/TLR signaling activate inflammasome and pyroptosis after intracerebral hemorrhage. METHODS: Autologous blood was injected into Sprague-Dawley rats to induce intracerebral hemorrhage. Neurological deficits were assessed using a modified neurological severity score. These expression and localization of NLRP1 and NLRP3 inflammasomes, as well as the levels of pyroptosis and pyroptosis-associated proteins were assessed using Western blot or immunocytochemistry. These experiments were repeated in animals that received treatment with short interfering RNAs against NLRP1 or NLRP3, with HMGB1 inhibitor ethyl pyruvate or TLR4 inhibitor TAK-242. RESULTS: Intracerebral hemorrhage upregulated NLRP1 and NLRP3 in the ipsilateral striatum and increased the proportions of these cells that were pyroptosis-positive. Additionally, the levels of caspase protein family (e.g., pro-caspase-1 and caspase-1), apoptosis-associated speck-like protein (ASC), pro-interleukin-1ß (IL-1ß), and IL-1ß were also elevated. These effects on pyroptosis and associated neurological deficit, were partially reversed by knockdown of NLRP1 or NLRP3, or by inhibition of HMGB1 or TLR4. Inhibition of HMGB1 or TLR4 resulted in the downregulation NLRP3 but not NLRP1. CONCLUSIONS: The HMGB1/TLR4 signaling may activate the NLRP3 inflammasome during the acute phase of intracerebral hemorrhage, resulting in the inflammatory process known as pyroptosis. These insights suggest potential therapeutic targets for the mitigation tissue injury and associated neurological deficits following hemorrhagic stroke.

3.
Clin Neurol Neurosurg ; 244: 108440, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38996800

RESUMO

BACKGROUND AND PURPOSE: Toll-like receptors (TLRs) are involved in innate immunity and inflammatory responses in various diseases. Our study aimed to investigate the association between the levels of soluble TLR4 (sTLR4) and soluble TLR2 (sTLR2) and clinical outcomes following intracerebral hemorrhage (ICH). METHODS: Patients admitted to department of Neurology with acute ICH were included. Plasma levels of sTLR4 and sTLR2 after ICH were measured by enzyme-linked immunosorbent assay. Poor clinical outcome was defined as a modified Rankin score (mRS) of 3-6 at 3-month and 12-month after onset. RESULTS: All 207 patients with ICH and 100 non-stroke controls were included in our analysis. The mean sTLR4 level was 4.53±1.51 ng/ml and mean sTLR2 level was 3.65±0.72 ng/ml. There was significant trend towards worse clinical outcomes with increasing sTLR4 and sTLR2 terciles at 3 and 12 months. According to receiver operating curve (ROC), the sTLR4 was reliable predictor for poor clinical outcome at 3 months (ROC=0.75) and 12 months (ROC=0.74). The sTLR2 was less reliable predictor for poor clinical outcome at 3 months (ROC=0.64) and 12 months (ROC=0.65). The level of sTLR4 was an independent predictor of poor clinical outcome at 12-month (OR 1.24, 95 % CI 1.16-1.80; P=0.019). CONCLUSIONS: The sTLR4 quantification may provide accurate prognostic information after ICH.

4.
Int J Ophthalmol ; 17(5): 883-895, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38766339

RESUMO

AIM: To explore the correlation of gut microbiota and the metabolites with the progression of diabetic retinopathy (DR) and provide a novel strategy to elucidate the pathological mechanism of DR. METHODS: The fecal samples from 32 type 2 diabetes patients with proliferative retinopathy (PDR), 23 with non-proliferative retinopathy (NPDR), 27 without retinopathy (DM), and 29 from the sex-, age- and BMI- matched healthy controls (29 HC) were analyzed by 16S rDNA gene sequencing. Sixty fecal samples from PDR, DM, and HC groups were assayed by untargeted metabolomics. Fecal metabolites were measured using liquid chromatography-mass spectrometry (LC-MS) analysis. Associations between gut microbiota and fecal metabolites were analyzed. RESULTS: A cluster of 2 microbiome and 12 metabolites accompanied with the severity of DR, and the close correlation of the disease progression with PDR-related microbiome and metabolites were found. To be specific, the structure of gut microbiota differed in four groups. Diversity and richness of gut microbiota were significantly lower in PDR and NPDR groups, than those in DM and HC groups. A cluster of microbiome enriched in PDR group, including Pseudomonas, Ruminococcaceae-UCG-002, Ruminococcaceae-UCG-005, Christensenellaceae-R-7, was observed. Functional analysis showed that the glucose and nicotinate degradations were significantly higher in PDR group than those in HC group. Arginine, serine, ornithine, and arachidonic acid were significantly enriched in PDR group, while proline was enriched in HC group. Functional analysis illustrated that arginine biosynthesis, lysine degradation, histidine catabolism, central carbon catabolism in cancer, D-arginine and D-ornithine catabolism were elevated in PDR group. Correlation analysis revealed that Ruminococcaceae-UCG-002 and Christensenellaceae-R-7 were positively associated with L-arginine, ornithine levels in fecal samples. CONCLUSION: This study elaborates the different microbiota structure in the gut from four groups. The relative abundance of Ruminococcaceae-UCG-002 and Parabacteroides are associated with the severity of DR. Amino acid and fatty acid catabolism is especially disordered in PDR group. This may help provide a novel diagnostic parameter for DR, especially PDR.

5.
Int Immunopharmacol ; 131: 111858, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38492336

RESUMO

BACKGROUND: Diabetes is a global health problem whose common complication is diabetic cardiomyopathy, characterized by chronic inflammation of the heart muscle. Macrophages are the main white blood cells found in the resting heart. Therefore, we investigated the underling mechanism of macrophage on myocardial fibrosis in diabetes. METHODS: Here, echocardiography was utilized to evaluate cardiac function, and the degree of myocardial fibrosis was assessed using Masson's trichrome staining, followed by single-cell RNA sequencing (scRNA-seq) to analyze the phenotype, function, developmental trajectory, and interactions between immune cells, endothelial cells (ECs), and fibroblasts (FBs) in the hearts of db/db mice at different stages of diabetes. Macrophages and cardiac fibroblasts were also co-cultured in order to study the signaling between macrophages and fibroblasts. RESULTS: We found that with the development of diabetes mellitus, myocardial hypertrophy and fibrosis occurred that was accompanied by cardiac dysfunction. A significant proportion of immune cells, endothelial cells, and fibroblasts were identified by RNA sequencing. The most significant changes observed were in macrophages, which undergo M1 polarization and are critical for oxidative stress and extracellular matrix (ECM) formation. We further found that M1 macrophages secreted interleukin-1ß (IL-1ß), which interacted with the receptor on the surface of fibroblasts, to cause myocardial fibrosis. In addition, crosstalk between M1 macrophages and endothelial cells also plays a key role in fibrosis and immune response regulation through IL-1ß and corresponding receptors. CONCLUSIONS: M1 macrophages mediate diabetic myocardial fibrosis through interleukin-1ß interaction with fibroblasts.


Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Camundongos , Animais , Interleucina-1beta , Células Endoteliais , Macrófagos , Fibrose
6.
Eur J Pharmacol ; 971: 176521, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38522639

RESUMO

Maintaining blood-brain barrier (BBB) integrity is critical components of therapeutic approach for ischemic stroke. Fibroblast growth factor 17 (FGF17), a member of FGF8 superfamily, exhibits the strongest expression throughout the wall of all major arteries during development. However, its molecular action and potential protective role on brain endothelial cells after stroke remains unclear. Here, we observed reduced levels of FGF17 in the serum of patients with ischemic stroke, as well as in the brains of mice subjected to middle cerebral artery occlusion (MCAO) injury and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cells (bEnd.3) cells. Moreover, treatment with exogenous recombinant human FGF17 (rhFGF17) decreased infarct volume, improved neurological deficits, reduced Evans Blue leakage and upregulated the expression of tight junctions in MCAO-injured mice. Meanwhile, rhFGF17 increased cell viability, enhanced trans-endothelial electrical resistance, reduced sodium fluorescein leakage, and alleviated reactive oxygen species (ROS) generation in OGD/R-induced bEnd.3 cells. Mechanistically, the treatment with rhFGF17 resulted in nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and upregulation of heme oxygenase-1 (HO-1) expression. Additionally, based on in-vivo and in-vitro research, rhFGF17 exerted protective effects against ischemia/reperfusion (I/R) -induced BBB disruption and endothelial cell apoptosis through the activation of the FGF receptor 3/PI3K/AKT signaling pathway. Overall, our findings indicated that FGF17 may hold promise as a novel therapeutic strategy for ischemic stroke patients.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Traumatismo por Reperfusão , Ratos , Humanos , Camundongos , Animais , Barreira Hematoencefálica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Endoteliais , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Reperfusão , Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/uso terapêutico , Fatores de Crescimento de Fibroblastos/metabolismo
7.
Int Immunopharmacol ; 130: 111700, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38382262

RESUMO

Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells. Edaravone dexborneol (EDB) is a combination of edaravone and borneol that has been identified as a clinical protectant for stroke management. In this study, we verified the anti-inflammatory effect of EDB in the mouse model of ischemia and investigated its modulatory action on inflammation-related cells. C57BL/6 male mice, which had the transient middle cerebral artery occlusion (tMCAO), were treated (i.p.) with EDB (15 mg/kg). EDB administration significantly reduced the brain infarction and improved the sensorimotor function after stroke. And EDB alleviated the neuroinflammation by restraining the polarization of microglia/macrophages and astrocyte toward proinflammatory phenotype and inhibiting the production of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) and chemokines (including MCP-1 and CXCL1). Furthermore, EDB ameliorated the MCAO-induced impairment of Blood-brain barrier (BBB) by suppressing the degradation of tight junction protein and attenuated the accumulation of peripheral leukocytes in the ischemic brain. Additionally, systemic EDB administration inhibited the macrophage phenotypic shift toward the M1 phenotype and the macrophage-dependent inflammatory response in the spleen and blood. Collectively, EDB protects against ischemic stroke injury by inhibiting the proinflammatory activation of microglia/macrophages and astrocytes and through reduction by invasion of circulating immune cells, which reduces central and peripheral inflammation following stroke.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Camundongos , Masculino , Microglia , Edaravone/uso terapêutico , Astrócitos/metabolismo , Isquemia Encefálica/metabolismo , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Leucócitos/metabolismo
8.
J Alzheimers Dis ; 96(1): 135-148, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37742652

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a protein synthesized in the brain and widely expressed in the nervous system. Previous studies have demonstrated a controversial role of BDNF in neurological diseases. OBJECTIVE: In this study, we aimed to assess the association between BDNF levels and the risk of neurological diseases by Mendelian randomization analysis. METHODS: From a genome-wide association analysis of plasma proteins comprising 3,301 European participants, we isolated 25 genetic variations as instrumental variables for BDNF levels. Summary statistics data on six common neurological diseases as outcome variables. Two-sample Mendelian randomization (MR) analysis was used to assess whether plasma BDNF is causally related to neurological diseases. We also performed sensitivity analysis to ensure the robustness of the results and reverse MR to exclude potential reverse causality. RESULTS: We confirmed the significant causal relationship between BDNF levels and the risk of Alzheimer's disease (AD) (OR, 0.92; 95% CI, 0.85, 0.98; p = 0.013). Other methods have also shown similar results. We infer that BDNF also reduces the risk of epilepsy (OR, 0.94; 95% CI, 0.90, 0.98; p = 0.004). In reverse MR analysis, we also found that AD can affect the level of BDNF. CONCLUSIONS: Our study suggests higher plasma BDNF was associated with the reduced risk of AD. Moreover, higher plasma BDNF is a protective factor on AD and focal epilepsy. The results provide credence to the idea that BDNF may play a significant role in the development of focal epilepsy and AD.


Assuntos
Doença de Alzheimer , Epilepsias Parciais , Doenças do Sistema Nervoso , Humanos , Fator Neurotrófico Derivado do Encéfalo/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doenças do Sistema Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética
9.
Brain Behav ; 13(8): e3164, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37461166

RESUMO

OBJECTIVE: To observe the clinical effect of botulinum toxin type A (BTA) injection into the salivary glands of the severe neurological patients with tracheotomy METHODS: Seven patients with severe neurological disorders after tracheotomy and obvious drooling symptoms were enrolled. BTA was injected into bilateral parotid glands and submandibular glands under the guidance of ultrasound. Unstimulated salivary flow rate (uSFR) and Drooling Severity and Frequency Scale (DSFS) were used to evaluate drooling before injection, 1 week, and 4 weeks after injection. We compared the extubation time, time of changing from balloon cannula to metal cannula, hospitalization time and incidence of recurrent pulmonary infection between these patients and other patients accepted conventional curation. RESULTS: (1) The drooling severity scale (DSFS-S), the drooling frequency scale (DSFS-F), the drooling frequency and severity scale total score (DSFS-T) were significantly lower at 4 weeks after BTA injection compared to prior-treatment (p < .001). (2) uSFR of 1 week and 4 weeks were both statistically decreased than the untreated condition (p < .001). (3) Compared with the conventional group, the time of changing from balloon cannula to metal cannula was shortened obviously (p < .05) and incidence of recurrent pulmonary infection was clearly decreased (p < .05) after BTA treatment CONCLUSION: Ultrasound-guided BTA injection into salivary glands can effectively reduce saliva secretion. We also found that the time of changing cannula was shortened obviously and the incidence of recurrent pneumonia infection was reduced. BTA injection of salivary glands to cure drooling could advance to the clinical therapy in severe neurological patients after tracheotomy.


Assuntos
Toxinas Botulínicas Tipo A , Doenças do Sistema Nervoso , Sialorreia , Humanos , Sialorreia/tratamento farmacológico , Sialorreia/etiologia , Traqueotomia/efeitos adversos , Salivação , Resultado do Tratamento
10.
Genome Biol ; 24(1): 155, 2023 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-37381036

RESUMO

BACKGROUND: The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation. RESULTS: We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes. CONCLUSIONS: Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.


Assuntos
Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Humanos , Células HeLa , Proteínas de Ciclo Celular/genética , Cromatina , Proteínas de Ligação a DNA , Coesinas
11.
Front Neurosci ; 17: 1117057, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37214383

RESUMO

Introduction: Intracerebral hemorrhage (ICH) is the most prevalent cause of death. We sought to explore whether serum Fibroblast growth factor 21 (FGF21) is of substantial benefit in predicting poor prognosis in ICH patient. Methods: A prospective, multicenter cohort analysis of serum FGF21 levels in 418 ICH patients was carried out. At three months following ICH start, the primary endpoint was death or major disability, whereas the secondary endpoint was death. We investigated the association between serum FGF21 and clinical outcomes. We added FGF21 to the existing rating scale to assess whether it enhanced the prediction ability of the original model. Effectiveness was determined by calculating the C-statistic, net reclassification index (NRI), absolute integrated discrimination improvement (IDI) index. Results: Among 418 enrolled patients, 217 (51.9%) of the all subjects had death or significant disability. Compared with patients in the lowest quartile group, those in the first quartile group had higher risk of the primary outcome (Odds ratio, 2.73 [95%CI,1.42-5.26, p < 0.05]) and second outcome (Hazard ratio, 4.28 [95%CI,1.61-11.42, p < 0.001]). The integration of FGF21 into many current ICH scales improved the discrimination and calibration quality for the integrated discrimination index's prediction of main and secondary findings (all p < 0.05). Conclusion: Elevated serum FGF21 is associated with increased risks of adverse clinical outcomes at 3 months in ICH patients, suggesting FGF21 may be a valuable prognostic factor.

12.
Bioorg Chem ; 136: 106543, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37119784

RESUMO

Curcumin is identified that it has the potential to treat Parkinson's disease (PD), but its instability limits its further application in clinic. The mono-carbonyl analogs of curcumin (MACs) with diketene structure can effectively improve its stability, but it is highly toxic. In the present study, a less cytotoxic and more stable monoketene MACs skeleton S2 was obtained, and a series of monoketene MACs were synthesized by combining 4-hydroxy-3­methoxy groups of curcumin. In the 6-OHDA-induced PD's model in-vitro, some compounds exhibited significant neurotherapeutic effect. The quantitative structure-activity relationship (QSAR) model established by the random forest algorithm (RF) for the cell viability rate of above compounds showed that the statistical results are good (R2 = 0.883507), with strong reliability. Among all compounds, the most active compound A4 played an important role in neuroprotection in the PD models both in vitro and in vivo by activating AKT pathway, and then inhibiting the apoptosis of cells caused by endoplasmic reticulum (ER) stress. In the PD model in-vivo, compound A4 significantly improved survival of dopaminergic neurons and the contents of neurotransmitters. It also enhanced the retention of nigrostriatal function which was better than the effect in the mice treated by Madopar, a classical clinical drug for PD. In summary, we screened out the compound A4 with high stability, less cytotoxic monoketene compounds. And these founding provide evidence that the compound A4 can protect dopaminergic neurons via activating AKT and subsequently suppressing ER stress in PD.


Assuntos
Curcumina , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Camundongos , Apoptose , Curcumina/farmacologia , Curcumina/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reprodutibilidade dos Testes
13.
J Cell Mol Med ; 27(10): 1410-1422, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37060584

RESUMO

The role of pescadillo1 (PES1) in regulating vascular permeability has been unknown. This study probes the role of PES1 and its mediated molecular mechanism in modulating vascular hyperpermeability in diabetic mice. Male C57BL/6J and db/db mice were fed a standard diet and a ketogenic diet (KD). Meanwhile, mouse vascular endothelial cells (MVECs) were treated with ß-hydroxybutyric acid (ß-HB), Pes1 siRNA or a Pes1 overexpression plasmid. Additionally, knockout (KO) of Pes1 in mice was applied. After 12 weeks of feedings, enhanced vascular PES1 expression in diabetic mice was inhibited by the KD. The suppression of PES1 was also observed in ß-HB-treated MVECs. In mice with Pes1 KO, the levels of vascular VEGF and PES1 were attenuated, while the levels of vascular VE-cadherin, Ang-1 and Occludin were upregulated. Similar outcomes also occurred after the knockdown of Pes1 in cultured MVECs, which were opposite to the effects induced by PES1 overexpression in MVECs. In vitro and in vivo experiments showed that high glucose concentration-induced increases in vascular paracellular permeability declined after MVECs were treated by ß-HB or by knockdown of Pes1. In contrast, increases in vascular permeability were induced by overexpression of Pes1, which were suppressed by coadministration of ß-HB in cultured endothelial cells. Similarly declines in vascular permeability were found by Pes1 knockdown in diabetic mice. Mechanistically, ß-HB decreased PES1-facilitated ubiquitination of VE-cadherin. The KD suppressed the diabetes-induced increase in PES1, which may result in vascular hyperpermeability through ubiquitination of VE-cadherin in type 2 diabetic mice.


Assuntos
Permeabilidade Capilar , Diabetes Mellitus Tipo 2 , Dieta Cetogênica , Animais , Camundongos , Permeabilidade Capilar/fisiologia , Diabetes Mellitus Tipo 2/dietoterapia , Regulação para Baixo , Camundongos Endogâmicos C57BL , Hiperglicemia/prevenção & controle , Técnicas de Silenciamento de Genes , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Camundongos Knockout , Células Cultivadas , Masculino
14.
Clin J Pain ; 39(4): 175-179, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36943161

RESUMO

OBJECTIVES: The periaqueductal gray (PAG) is a key region in the descending pain modulatory system. We applied a Granger causality analysis-based approach to examine resting-state effective connectivity of the bilateral PAG regions in migraine patients without aura (MwoA). MATERIALS AND METHODS: Resting-state functional magnetic resonance imaging data were obtained from 28 MwoA patients and 17 healthy controls. The effective connectivity of the bilateral PAG was characterized using a voxel-wised Granger causality analysis method. The resulting effective connectivity measurements were assessed for correlations with other clinical features. RESULTS: Compared with the healthy controls, MwoA patients showed increased effective connectivity from the left PAG to the left anterior cingulate gyrus and right postcentral gyrus. Meanwhile, MwoA patients also showed increased effective connectivity from the right PAG to the left precentral gyrus and increased effective connectivity from the left caudate and right middle occipital gyrus to the right PAG. DISCUSSION: Abnormally increased effective connectivity between PAG and limbic system, primary sensorimotor cortex, and visual cortex may play a key role in neuropathological features, perception, and affection of MwoA. The current study provides further insights into the complex scenario of MwoA mechanisms.


Assuntos
Epilepsia , Enxaqueca sem Aura , Humanos , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Enxaqueca sem Aura/diagnóstico por imagem , Dor , Giro do Cíngulo , Imageamento por Ressonância Magnética/métodos , Encéfalo
15.
Plants (Basel) ; 12(5)2023 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-36903849

RESUMO

Light, as an energy source, has been proven to strongly affect photosynthesis and, thus, can regulate the yield and quality of tea leaves (Camellia sinensis L.). However, few comprehensive studies have investigated the synergistic effects of light wavelengths on tea growth and development in green and albino varieties. Thus, the objective of this study was to investigate different ratios of red, blue and yellow light and their effects on tea plants' growth and quality. In this study, Zhongcha108 (green variety) and Zhongbai4 (albino variety) were exposed to lights of different wavelengths for a photoperiod of 5 months under the following seven treatments: white light simulated from the solar spectrum, which served as the control, and L1 (red 75%, blue 15% and yellow 10%), L2 (red 60%, blue 30% and yellow 10%), L3 (red 45%, far-red light 15%, blue 30% and yellow 10%), L4 (red 55%, blue 25% and yellow 20%), L5 (red 45%, blue 45% and yellow 10%) and L6 (red 30%, blue 60% and yellow 10%), respectively. We examined how different ratios of red light, blue light and yellow light affected tea growth by investigating the photosynthesis response curve, chlorophyll content, leaf structure, growth parameters and quality. Our results showed that far-red light interacted with red, blue and yellow light (L3 treatments) and significantly promoted leaf photosynthesis by 48.51% in the green variety, Zhongcha108, compared with the control treatments, and the length of the new shoots, number of new leaves, internode length, new leaf area, new shoots biomass and leaf thickness increased by 70.43%, 32.64%, 25.97%, 15.61%, 76.39% and 13.30%, respectively. Additionally, the polyphenol in the green variety, Zhongcha108, was significantly increased by 15.6% compared to that of the plants subjected to the control treatment. In addition, for the albino variety Zhongbai4, the highest ratio of red light (L1 treatment) remarkably enhanced leaf photosynthesis by 50.48% compared with the plants under the control treatment, resulting in the greatest new shoot length, number of new leaves, internode length, new leaf area, new shoot biomass, leaf thickness and polyphenol in the albino variety, Zhongbai4, compared to those of the control treatments, which increased by 50.48%, 26.11%, 69.29%, 31.61%, 42.86% and 10.09%, respectively. Our study provided these new light modes to serve as a new agricultural method for the production of green and albino varieties.

16.
Comput Biol Med ; 157: 106692, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36924734

RESUMO

Few researches have looked at the relationship between nonalcoholic fatty liver disease (NAFLD) at the time of admission and the long-term outcomes of patients suffering from acute ischemic stroke (AIS). We aimed to probe the relationship between NAFLD risk evaluated by NAFLD indices and long-term endpoints, along with the prognostic value of merging NAFLD indices with established risk markers for the prognosis of AIS patients. The fatty liver index (FLI) and the Hepatic steatosis index (HSI) were used to evaluate NAFLD risk in the Third China National Stroke Registry (CNSR-III), a large, prospective, national, multicenter cohort registry study. NAFLD was defined as FLI ≥35 for males and FLI ≥ 20 for females, as well as HSI>36. Death or major disability (modified Rankin Scale score ≥3) were the primary outcomes following the beginning of a stroke. On patient outcomes, the prognostic performance of two objective NAFLD parameters was evaluated. NAFLD was detected in 32.10-51.90% of AIS patients. After 1-year, 14.5% of the participants had died or suffered a severe outcome. After controlling for known risk factors, NAFLD was associated with a modest probability of adverse outcome (odds ratio,0.72[95% CI, 0.61-0.86] for FLI; odds ratio,0.68[95% CI, 0.55-0.85] for HSI). The inclusion of the two NAFLD indicators in the conventional prediction model was justified by the integrated discrimination index, continuing to increase the model's overall predictive value for long-term adverse outcomes. NAFLD risk was linked to a lower risk of long-term death or major disability in people with AIS. The predictive value of objective NAFLD after AIS was demonstrated in our study.


Assuntos
AVC Isquêmico , Hepatopatia Gordurosa não Alcoólica , Acidente Vascular Cerebral , Masculino , Feminino , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/complicações
17.
Transl Res ; 258: 1-15, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36775058

RESUMO

Previous studies indicated that increased hepatic pescadillo 1 (PES1) in type II diabetic mice was associated with lipid dysregulation. However, the role of PES1 in obesity-associated lipid dysregulation is still unknown. This study investigates the effects and underlying mechanism. Livers from obese and healthy humans and mice were collected, and C57BL/6J mice were either fed on standard diet or high fat diet (HFD). McArdle 7777 rat hepatoma cells were treated with phosphate-buffered saline and oleic acid (OA)+ palmitic acid (PA), respectively. In vitro Pes1 knockdown or overexpression and in vivo Pes1 knockdown or liver-specific ablation or supplementation of Pes1 were used to explore the modulating role of PES1. We found that obesity in humans enhanced hepatic PES1 protein, accompanied by increased plasma TG. These data are consistent with those from OA+PA-treated cells and from HFD- or Pes1 overexpression-treated C57BL/6J mice. In vitro and in vivo Pes1 knockdown in cultured cells and in ob/ob mice promoted the expression of autophagy markers (TFEB, Beclin1 and LC3B-Ⅱ) while decreasing p62 and TG, contrary to Pes1 overexpression in cells and in normal mice. Moreover, liver-specific knockout of Pes1 protected the mice fed on HFD from increased TG levels, facilitating the TFEB, Beclin1 and LC3B-Ⅱ and curbing p62. Mechanistically, OA+PA increased C/EBPß binding to the Pes1 promoter, leading to the elevation of PES1, and subsequently enhancing PES1-facilitated ubiquitination of TFEB. Our findings reveal that overexpression of hepatic PES1 in obesity may induce TG dysregulation by inhibiting autophagy.


Assuntos
Diabetes Mellitus Experimental , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Autofagia , Proteína Beclina-1 , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Lipídeos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Proteínas de Ligação a RNA/metabolismo
18.
Phys Rev Lett ; 129(9): 090502, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36083655

RESUMO

We study the problem of generating independent samples from the output distribution of Google's Sycamore quantum circuits with a target fidelity, which is believed to be beyond the reach of classical supercomputers and has been used to demonstrate quantum supremacy. We propose a method to classically solve this problem by contracting the corresponding tensor network just once, and is massively more efficient than existing methods in generating a large number of uncorrelated samples with a target fidelity. For the Sycamore quantum supremacy circuit with 53 qubits and 20 cycles, we have generated 1×10^{6} uncorrelated bitstrings s which are sampled from a distribution P[over ^](s)=|ψ[over ^](s)|^{2}, where the approximate state ψ[over ^] has fidelity F≈0.0037. The whole computation has cost about 15 h on a computational cluster with 512 GPUs. The obtained 1×10^{6} samples, the contraction code and contraction order are made public. If our algorithm could be implemented with high efficiency on a modern supercomputer with ExaFLOPS performance, we estimate that ideally, the simulation would cost a few dozens of seconds, which is faster than Google's quantum hardware.

19.
Analyst ; 147(19): 4326-4336, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36040713

RESUMO

As an indispensable genetically encoded optical method for detecting and visualizing protein-protein interactions (PPIs) directly in live cells, bimolecular fluorescence complementation (BiFC) assay has gained popularity over the past decade mainly because of its high sensitivity and easy usage. However, most existing fluorescent protein-based BiFC (FP-BiFC) assays still suffer from relatively low specificity or imaging signal-to-noise (S/N) ratios. Thus, developing high S/N ratio BiFC probes, especially in the widely used bright green-yellow region of the spectrum is very meaningful. In addition, synthetic engineering of BiFC probes which can be readily used for multiplexing imaging is also highly valuable for uncovering more or new layers of information on PPIs. In this report, we developed a bright stable green fluorescent protein Springgreen-M based on our previously evolved fast reversible photoswitching fluorescent protein (RSFP) GMars-T. We then established a novel BiFC assay based on Springgreen-M for imaging PPIs in live cells with high specificity. Combined with the same lineage, BiFC assays readily developed from photoconvertible fluorescent protein mMaple3 or reversibly photoswitchable fluorescent protein GMars-T, high specificity multiplexing imaging of PPIs could also be realized in the same live cell. Thus, our newly developed Springgreen-M and Springgreen-M-based BiFC probes will meet the urgent need for high-specificity BiFC detection, flexible visualization and screening of PPIs in live cells.


Assuntos
Corantes Fluorescentes , Sondas Moleculares , Proteínas de Fluorescência Verde/genética , Proteínas Luminescentes/metabolismo , Microscopia de Fluorescência/métodos
20.
Oxid Med Cell Longev ; 2022: 6482363, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35602097

RESUMO

Background: Endothelial dysfunction and cardiomyopathy are considered to be important vascular complications associated with diabetes. This study was designed to investigate whether capsaicin (CAP), a selective TRPV1 agonist, could prevent diabetes-induced endothelial dysfunction and cardiomyopathy. Methods: Male Sprague Dawley rats aged 8 weeks were injected intraperitoneally with streptozotocin (STZ, 50 mg/kg) to establish the diabetes model. The diabetic rats were randomly divided into the untreated diabetes group (DM, 10/group) and diabetes plus CAP treatment group (DM+CAP, 10/group); meanwhile, the nondiabetic healthy rats were used as normal controls (10/group). DM+CAP group were treated with CAP by gavage for 8 weeks. The cultured mouse vascular endothelial cells were exposed to different concentrations of glucose in the presence or absence of CAP treatment. The TRPV1 inhibitor capsazepine (CPZ) and eNOS inhibitor L-NAME were used in vivo and in vitro experiment. Results: CAP treatment significantly decreased the serum total cholesterol (TC) and total triglyceride (TG) and ameliorated the pathogenesis and fibrosis in the heart, while did not significantly improve plasma glucose level and the body weights of diabetic rats. In addition, CAP enhanced the expression of TRPV1 and eNOS in the heart and normalized the vascular permeability under diabetic state. Similarly, CAP treatment also increased nitric oxide and reduced reactive oxygen species. The same results were observed in cultured mouse vascular endothelial cells by CAP treatment. These beneficial effects of CAP were abolished by either CPZ or L-NAME. Conclusions: CAP might protect against hyperglycemia-induced endothelial dysfunction and diabetic cardiomyopathy through TRPV1/eNOS pathway.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Doenças Vasculares , Animais , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia , Canais de Cátion TRPV/metabolismo , Doenças Vasculares/patologia
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