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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 567-573, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812432

RESUMO

OBJECTIVE: To investigate the damaging of human umbilical vein endothelial cells (HUVEC) induced by antiplatelet integrin ß3 antibodies in vitro. METHODS: The serum from 36 chronic ITP patients were collected, flow cytometry and monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay were used to collect antiplatelet integrin ß3 antibodies from the serum of the patients. After HUVEC were treated by ITP patient serum (PS) containing anti-integrin ß3 antibodies, the cell damage was detected by Lactate dehydrogenase (LDH) assay, cell apoptosis was detected by flow cytometry, the expression of apoptosis-related gene Bax was detected by Reverse transcription-Quantitative real-time PCR (RT-qPCR), and expression of Apoptosis-related signaling pathway protein Akt and related protein Bax were detected by Western blot. HUVEC were treated by PS combined with Akt activator SC79, the cells damage were detected by LDH assay, apoptosis of the cells were detected by flow cytometry, the expression of apoptosis-related gene Bax was detected by RT-qPCR. RESULTS: Among 36 cases of serum from the chronic ITP patients, 5 patients' serum containing anti-integrin ß3 antibodies were collected. After HUVEC was treated by PS, the viability of LDH was significant increased(P<0.05), so as for the apoptosis of the cells(P<0.05), the expression of gene and protein of Bax was increased up-regulated(P<0.05), the protein expression of pAkt was down-regulated(P<0.05). Comparing with HUVEC cultured with PS alone, the viability of LDH of HUVEC treated by PS combined with SC79 was significantly reduced(P<0.05), so as for the apoptosis of the cells(P<0.05), and gene expression of Bax was significantly decreased(P<0.05). CONCLUSION: Anti-integrin ß3 serum can cause the damage and apoptosis of HUVEC through Akt signaling pathway,the apoptotic effects of anti-integrin ß3 antibodies to HUVEC was effectively reversed by SC79.


Assuntos
Apoptose , Integrina beta3 , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Transdução de Sinais
2.
Mediators Inflamm ; 2021: 6635925, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833618

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in China and currently worldwide dispersed, resulting in the coronavirus disease 2019 (COVID-19) pandemic. Notably, COVID-19 is characterized by systemic inflammation. However, the potential mechanisms of the "cytokine storm" of COVID-19 are still limited. In this study, fourteen peripheral blood samples from COVID-19 patients (n = 10) and healthy donors (n = 4) were collected to perform the whole-transcriptome sequencing. Lung tissues of COVID-19 patients (70%) presenting with ground-glass opacity. Also, the leukocytes and lymphocytes were significantly decreased in COVID-19 compared with the control group (p < 0.05). In total, 25,482 differentially expressed messenger RNAs (DE mRNA), 23 differentially expressed microRNAs (DE miRNA), and 410 differentially expressed long noncoding RNAs (DE lncRNAs) were identified in the COVID-19 samples compared to the healthy controls. Gene Ontology (GO) analysis showed that the upregulated DE mRNAs were mainly involved in antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, and positive regulation of gamma-delta T cell activation. The downregulated DE mRNAs were mainly concentrated in the glycogen biosynthetic process. We also established the protein-protein interaction (PPI) networks of up/downregulated DE mRNAs and identified 4 modules. Functional enrichment analyses indicated that these module targets were associated with positive regulation of cytokine production, cytokine-mediated signaling pathway, leukocyte differentiation, and migration. A total of 6 hub genes were selected in the PPI module networks including AKT1, TNFRSF1B, FCGR2A, CXCL8, STAT3, and TLR2. Moreover, a competing endogenous RNA network showed the interactions between lncRNAs, mRNAs, and miRNAs. Our results highlight the potential pathogenesis of excessive cytokine production such as MSTRG.119845.30/hsa-miR-20a-5p/TNFRSF1B, MSTRG.119845.30/hsa-miR-29b-2-5p/FCGR2A, and MSTRG.106112.2/hsa-miR-6501-5p/STAT3 axis, which may also play an important role in the development of ground-glass opacity in COVID-19 patients. This study gives new insights into inflammation regulatory mechanisms of coding and noncoding RNAs in COVID-19, which may provide novel diagnostic biomarkers and therapeutic avenues for COVID-19 patients.

3.
Chemosphere ; 278: 130508, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33839383

RESUMO

The large scale lignocellulosic biomass wastes could also be regarded as abundantly-available renewable resources, and how to convert them into value-added products via sustainable approaches is still a big challenge. In this work, we demonstrated a facile pyrolysis method to construct N, P-dually doped biochar materials from the lignocellulosic biomass wastes. The as-synthesized N, P-dually doped biochar samples could act as electrocatalysts for oxygen reduction and evolution reactions (ORR/OER), showing excellent catalytic performance and long-term durability, as well as robust tolerance to CO and methanol. The unique hierarchical porous structure, favorable electronic structure modified by the N and P doping, as well as a variety of defect sites induced by the N and P doping into the carbon framework were identified as the main contributions to the prominent catalytic activity of the as-synthesized N, P-dually doped biochar materials. We expect this work would spur more efforts into developing advanced materials from the large scale lignocellulosic biomass wastes.

4.
Acta Neurochir Suppl ; 131: 59-62, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33839819

RESUMO

OBJECTIVE: This study aimed to examine whether changes in intracranial pressure (ICP) waveform morphologies can be used as a biomarker for early detection of ventriculitis. METHODS: Consecutive patients (N = 1653) were prospectively enrolled in a hemorrhage outcomes study from 2006 to 2018. Of these, 435 patients (26%) required external ventricular drains (EVDs) and 76 (17.5% of those with EVDs) had ventriculitis treated with antibiotics. Nineteen patients (25% of those with ventriculitis) showed culture-positive cerebrospinal fluid (CSF) and were included in the present analysis. CSF was routinely cultured three times per week and additionally if infection was suspected. EVDs were left open for drainage, with ICP assessed hourly by clamping. Using wavelet analysis, we extracted uninterrupted segments of ICP waveforms. We extracted dominant pulses from continuous high-resolution data, using morphological clustering analysis of intracranial pressure (MOCAIP). Then we applied k-means clustering, using the dynamic time warping distance to obtain morphologically similar groupings. Finally, metaclusters and further-split clusters (when equipoise existed) were categorized for broad comparison by clinician consensus. RESULTS: We extracted 275,911 dominant pulses from 459.9 h of EVD data. Of these, 112,898 pulses (40.9%) occurred before culture positivity, 41,300 pulses (15.0%) occurred during culture positivity, and 121,713 pulses (44.1%) occurred after it. K-means identified 20 clusters, which were further grouped into metaclusters: tri-/biphasic, single-peak, and artifactual waveforms. Prior to ventriculitis, 61.8% of dominant pulses were tri-/biphasic; this percentage reduced to 22.6% during ventriculitis and 28.4% after it (p < 0.0001). One day before the first positive cultures were collected, the distribution of metaclusters changed to include more single-peak and artifactual ICP waveforms (p < 0.0001). CONCLUSION: The distribution of ICP waveform morphology changes significantly prior to clinical diagnosis of ventriculitis and may be a potential biomarker.

5.
Medicine (Baltimore) ; 100(15): e25509, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847668

RESUMO

BACKGROUND: Fasting and caloric restriction have a potential means of anti-inflammatory, as they can decrease the level of systemic inflammation. Although encouraging results have been obtained in animal experiments, there is no consensus on whether these results are applicable to human. The objective of this systematic review and meta-analysis is to analyze the influence of fasting and caloric restriction on inflammation levels in humans. METHODS: The systematic review and meta-analysis will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The following eight databases will be searched:(The retrieval time is from the establishment of each database to December 2020): PubMed, the Cochrane Library, Embase, Web of Science, China National Knowledge infrastructure (CNKI), China Biology Medicine (CBM), Wan Fang Data, the Chinese Science and Technology Periodical Database (VIP). Relevant data will be performed by Revman 5.3 software provided (Cochrane Collaboration) and Stata 14.0 statistical software. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSIONS: This systematic review will provide evidence to judge the effectiveness of fasting and calorie restriction in human subjects, so as to provide a sound basis for future research and lifestyle promotion. INPLASY REGISTRATION NUMBER: INPLASY202130026.

6.
Theranostics ; 11(8): 3796-3812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664862

RESUMO

Rationale: Mechanisms underlying the compromised bone formation in type 1 diabetes mellitus (T1DM), which causes bone fragility and frequent fractures, remain poorly understood. Recent advances in organ-specific vascular endothelial cells (ECs) identify type H blood vessel injury in the bone, which actively direct osteogenesis, as a possible player. Methods: T1DM was induced in mice by streptozotocin (STZ) injection in two severity degrees. Bony endothelium, the coupling of angiogenesis and osteogenesis, and bone mass quality were evaluated. Insulin, antioxidants, and NADPH oxidase (NOX) inhibitors were administered to diabetic animals to investigate possible mechanisms and design therapeutic strategies. Results: T1DM in mice led to the holistic abnormality of the vascular system in the bone, especially type H vessels, resulting in the uncoupling of angiogenesis and osteogenesis and inhibition of bone formation. The severity of osteopathy was positively related to glycemic levels. These pathological changes were attenuated by early-started, but not late-started, insulin therapy. ECs in diabetic bones showed significantly higher levels of reactive oxygen species (ROS) and NOX 1 and 2. Impairments of bone vessels and bone mass were effectively ameliorated by treatment with anti-oxidants or NOX2 inhibitors, but not by a NOX1/4 inhibitor. GSK2795039 (GSK), a NOX2 inhibitor, significantly supplemented the insulin effect on the diabetic bone. Conclusions: Diabetic osteopathy could be a chronic microvascular complication of T1DM. The impairment of type H vessels by NOX2-mediated endothelial oxidative stress might be an important contributor that can serve as a therapeutic target for T1DM-induced osteopathy.

7.
Chem Commun (Camb) ; 57(27): 3375-3378, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33683223

RESUMO

Low viscosity photo-curable benzoxazines (BZs) are designed and synthesized for use in stereolithography 3D printing. An initial investigation shows that the thermally polymerized polybenzoxazines (PBZs) have remarkably high Tg (264 °C) and flexural modulus (4.91 GPa) values. Subsequently, the formulated photoprintable resins are employed for use in high-resolution projection micro-stereolithography (PµSL) printing. Complex PBZ 3D structures can be achieved from the as-printed objects after they are thermally treated. These findings advance the design of BZ monomers for photopolymerization-based 3D printing and offer a method for the efficient fabrication of high-performance thermosets for various demanding engineering applications.

8.
Cell Biol Int ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33760350

RESUMO

Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.

9.
Huan Jing Ke Xue ; 42(2): 749-760, 2021 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742869

RESUMO

Emerging contaminants including antibiotics and antibiotic resistance genes (ARGs) have been frequently detected in drinking water resources. In this study, the occurrence of antibiotics and ARGs in various environmental matrices in representative drinking water sources in Jiangsu Province and their influencing factors were explored. Five representative drinking water sources in northern, central, and southern Jiangsu were selected. Water, surface sediment, and epilithic biofilm samples were harvested near the water intakes of each water resource in December 2018 and June 2019. The concentrations and abundances of ten antibiotics, one integrase gene intl1, and seven common ARGs were measured. The results suggest that the concentrations of the target antibiotics and ARGs are relatively low compared to previously reported data in China and elsewhere in the world. The target antibiotics were detected in all of the water sources. The concentrations of sulfonamides in the water, surface sediment, and epilithic biofilm ranged from not found (NF) to 37.4 ng·L-1, NF to 47.3 ng·g-1, and NF to 3759.1 ng·g-1, respectively; the concentrations of quinolones in three matrices were NF-5.3 ng·L-1, 0.4-32.5 ng·g-1, and NF-4220.9 ng·g-1, respectively. The detection rates of the ARGs including sul 1, sul2, tetW, and tetQ were 100%, among which the sulfonamides sul1 and sul2 showed the highest abundance. The absolute abundances of sul1 in the three matrices were 2.48×106 copies·L-1, 3.54×107 copies·g-1, and 1.44×109 copies·g-1, respectively. The abundances of ARGs in the sediments and epilithic biofilms were comparable, and were much higher than in the water body. The phyla Bacteroidetes, Proteobacteris, Firmicutes, Verrucobacteria, and Actinomycetes have proven potential hosts for ARGs and might play an important role in the transmission and diffusion of resistance genes. This study offers baseline information on the presence of antibiotics and ARGs in the drinking water sources of Jiangsu Province, providing a significant theoretical basis for ARGs pollution control and safety guidelines for drinking water resources.


Assuntos
Antibacterianos , Água Potável , Antibacterianos/análise , China , Água Potável/análise , Resistência Microbiana a Medicamentos/genética , Genes Bacterianos/genética , Recursos Hídricos
11.
Phytomedicine ; 85: 153541, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33773190

RESUMO

BACKGROUND: Acute kidney injury (AKI), characterised by excessive inflammatory cell recruitment and programmed cell death, has a high morbidity and mortality; however, effective and specific therapies for AKI are still lacking. OBJECTIVE: This study aimed to evaluate the renoprotective effects of gypenoside XLIX (Gyp XLIX) in AKI. METHODS: The protective effects of Gyp XLIX were tested in two AKI mouse models established using male C57BL/6 mice (aged 6-8 weeks) by a single intraperitoneal injection of cisplatin (20 mg/kg) or renal ischemia-reperfusion for 40 min. Gyp XLIX was administered intraperitoneally before cisplatin administration or renal ischemia-reperfusion. Renal function, tubular injury, renal inflammation and programmed cell death were evaluated. In addition, the renoprotective effects of Gyp XLIX were also evaluated in cisplatin- or hypoxia-treated tubular epithelial cells. The mechanisms underlying these effects were then explored using RNA sequencing. RESULTS: In vivo, Gyp XLIX substantially suppressed the increase in serum creatinine and blood urea nitrogen levels. Moreover, tubular damage was alleviated by Gyp XLIX as shown by periodic acid-Schiff staining, electron microscopy and molecular analysis of KIM-1. Consistently, we found that Gyp XLIX suppressed renal necroptosis though the RIPK1/RIPK3/MLKL pathway. The anti-inflammatory and antinecroptotic effects were further confirmed in vitro. Mechanistically, RNA sequencing showed that Gyp XLIX markedly suppressed the levels of IGF binding protein 7 (IGFBP7). Co-immunoprecipitation and western blot analysis further showed that Gyp XLIX reduced the binding of IGFBP7 to IGF1 receptor (IGF1R). Additionally, picropodophyllin, an inhibitor of IGF1R, abrogated the therapeutic effects of Gyp XLIX on cisplatin-induced renal cell injury; this finding indicated that Gyp XLIX may function by activating IGF1R-mediated downstream signalling Additionally, we also detected the metabolic distribution of Gyp XLIX after injection; Gyp XLIX had a high concentration in the kidney and exhibited a long retention time. These findings may shed light on the application of Gyp XLIX for AKI treatment clinically. CONCLUSION: Gyp XLIX may serve as a potential therapeutic agent for AKI treatment via IGFBP7/ IGF1R-dependent mechanisms.

12.
Clin Transl Med ; 11(3): e321, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33784014

RESUMO

BACKGROUND: The contributions of various types of cell populations in dialysis-related peritoneal fibrosis are poorly understood. Single-cell RNA sequencing brings single-cell level resolution to the analysis of cellular transcriptomics, which provides a new way to further characterize the distinct roles and functional states of each cell population during peritoneal fibrosis. METHODS: Single-cell transcriptomics from normal peritoneal tissues of six patients, from effluent of patients with short-term peritoneal dialysis (less than 2 weeks, n = 6), and from long-term peritoneal dialysis patients (more than 6 years, n = 4) were analyzed. RESULTS: We identified a distinct cell component between samples among different groups. Functional analysis of the differentially expressed genes identified cell type specific biological processes relevant to different fibrosis stages. Well-known key molecular mechanisms participating in the pathophysiology of peritoneal fibrosis were vitrified, and some of them were found to be restricted to specific cell types. Gradually growing enrichment of PI3K/AKT/mTOR pathway and impairment of oxidative phosphorylation in mesothelial cells and fibroblasts were found from healthy control, short-term dialysis, to long-term dialysis, respectively. The fibroblasts' population obtained from the patients, who received peritoneal dialysis, showed a functional characteristic of immune-chemotaxis and immune response, which was characterized by broadly significant increase in the expression of interleukins, chemokines, cytokines, and human leukocyte antigens. Furthermore, we described the intercellular crosstalk networks based on receptor-ligand interactions, and highlighted a central role of fibroblasts in regulating the key mechanisms of peritoneal fibrosis through crosstalk with other cells. CONCLUSIONS: In summary, despite describing information for fibrogenic molecular mechanisms in the resolution level of individual cell populations, this work identifies the significant functional evolution of fibroblasts during peritoneal fibrosis. This study also reveals the intercellular receptor-ligand interactions in which the fibroblasts serve as a major node, eventually providing new insights into the role of fibroblasts during disease pathogenesis.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33674986

RESUMO

OBJECTIVE: Chemoradiotherapy (CRT) is the standard treatment for limited-stage small cell lung cancer (LS-SCLC), which can exert anti-tumor effects by regulating immune cells. Different immune cell subsets are associated with a specific sensitivity to CRT. The purpose of this study was to characterize the proportion or composition of peripheral lymphocytes in patients with LS-SCLC before and after CRT, and evaluate their prognostic value. METHODS: A total of 98 patients with LS-SCLC were enrolled. The expression of CD3, CD4, CD8, CD45RA, CD45RO, CD38, CD56, and CD19 on the surface of peripheral blood cells was detected by flow cytometry and retrospectively analyzed. The relationship between the proportion of lymphocyte subsets, progression-free survival (PFS), and overall survival (OS) was evaluated using a log-rank test and Cox regression model. RESULTS: The median PFS was 12.3 months and the median OS was 21.7 months. Compared with the pre-treatment specimens, post-treatment lymphocytes had increased proportions of CD3+, CD3+CD8+, CD8+CD38+ T cells, and NKT cells, and a decreased proportion of CD3+CD4+ T cells, CD4+CD45RA+ T cells, B cells, NK cells, and CD4/CD8 ratio. Univariate and multivariate analyses showed that prophylactic cranial irradiation, high percentages of CD4+CD45RA+, CD8+CD38+ T cells after CRT independently predicted superior PFS. Male patients with a high baseline CD4+CD45RO+ T cell ratio predicted a poor OS. CONCLUSIONS: CRT induced changes in the proportion of circulating lymphocyte subsets in LS-SCLC, which is helpful for designing a regimen of immune drugs to be combined with CRT. The prognostic value of the proportion of lymphocytes aids in understanding the role of peripheral immune profiles in LS-SCLC.

14.
AMB Express ; 11(1): 35, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33646441

RESUMO

Aflatoxin B1 (AFB1) is one of the most dangerous mycotoxins for humans and animals. This study aimed to investigate the effects of compound probiotics (CP), CP supernatant (CPS), AFB1-degradation enzyme (ADE) on chicken embryo primary intestinal epithelium, liver and kidney cell viabilities, and to determine the functions of CP + ADE (CPADE) or CPS + ADE (CPSADE) for alleviating cytotoxicity induced by AFB1. The results showed that AFB1 decreased cell viabilities in dose-dependent and time-dependent manners. The optimal AFB1 concentrations and reactive time for establishing cell damage models were 200 µg/L AFB1 and 12 h for intestinal epithelium cells, 40 µg/L and 12 h for liver and kidney cells. Cell viabilities reached 231.58% (p < 0.05) for intestinal epithelium cells with CP addition, 105.29% and 115.84% (p < 0.05) for kidney and liver cells with CPS additions. The further results showed that intestinal epithelium, liver and kidney cell viabilities were significantly decreased to 87.12%, 88.7% and 84.19% (p < 0.05) when the cells were exposed to AFB1; however, they were increased to 93.49% by CPADE addition, 102.33% and 94.71% by CPSADE additions (p < 0.05). The relative mRNA abundances of IL-6, IL-8, TNF-α, iNOS, NF-κB, NOD1 (except liver cell) and TLR2 in three kinds of primary cells were significantly down-regulated by CPADE or CPSADE addition, compared with single AFB1 group (p < 0.05), indicating that CPADE or CPSADE addition could alleviate cell cytotoxicity and inflammation induced by AFB1 exposure through suppressing the activations of NF-κB, iNOS, NOD1 and TLR2 pathways.

15.
Aging (Albany NY) ; 132021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33714957

RESUMO

Vascular dementia (VD) is a common disease that occurs during human aging. Gastrodin (GAS) has potential benefits for the prevention and treatment of VD. In the present study, we investigated the effects of GAS on cognitive dysfunction in rats with VD induced by permanent middle cerebral artery occlusion (pMCAO) and explored the underlying mechanism. Immunohistochemical and western blot analyses revealed that GAS attenuated hippocampal levels of LC3 (microtubule-associated protein 1 light chain 3), p62, and phosphorylated CaMKII (Ca2+-calmodulin stimulated protein kinase II) in VD rats. Additionally, our results revealed that cobalt chloride blocked autophagic flux in HT22 cells, which was confirmed by increased levels of LC3 and p62 when combined with chloroquine. Notably, GAS ameliorated the impaired autophagic flux. Furthermore, we confirmed that GAS combined with KN93 (a CaMKII inhibitor) or CaMKII knockdown did not impact the reduced p62 levels when compared with GAS treatment alone. Furthermore, a co-immunoprecipitation assay demonstrated that endogenous p62 bound to CaMKII, as confirmed by mass spectrometric analysis after the immunoprecipitation of p62 from HT22 cells. These findings revealed that GAS attenuated autophagic flux dysfunction by inhibiting the Ca2+/CaMKII signaling pathway to ameliorate cognitive impairment in VD.

16.
Front Immunol ; 12: 637335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767704

RESUMO

Renal ischemia-reperfusion injury (IRI) contributes to acute kidney injury (AKI), increases morbidity and mortality, and is a significant risk factor for chronic kidney disease (CKD). Macrophage infiltration is a common feature after renal IRI, and infiltrating macrophages can be polarized into the following two distinct types: M1 macrophages, i.e., classically activated macrophages, which can not only inhibit infection but also accelerate renal injury, and M2 macrophages, i.e., alternatively activated macrophages, which have a repair phenotype that can promote wound healing and subsequent fibrosis. The role of TSC1, which is a negative regulator of mTOR signaling that regulates macrophage polarization in inflammation-linked diseases, has been well documented, but whether TSC1 contributes to macrophage polarization in the process of IRI is still unknown. Here, by using a mouse model of renal ischemia-reperfusion, we found that myeloid cell-specific TSC1 knockout mice (termed Lyz-TSC1 cKO mice) had higher serum creatinine levels, more severe histological damage, and greater proinflammatory cytokine production than wild-type (WT) mice during the early phase after renal ischemia-reperfusion. Furthermore, the Lyz-TSC1 cKO mice showed attenuated renal fibrosis during the repair phase of IRI with decreased levels of M2 markers on macrophages in the operated kidneys, which was further confirmed in a cell model of hypoxia-reoxygenation (H/R) in vitro. Mechanistically, by using RNA sequencing of sorted renal macrophages, we found that the expression of most M1-related genes was upregulated in the Lyz-TSC1 cKO group (Supplemental Table 1) during the early phase. However, C/EBPß and CD206 expression was decreased during the repair phase compared to in the WT group. Overall, our findings demonstrate that the expression of TSC1 in macrophages contributes to the whole process of IRI but serves as an inflammation suppressor during the early phase and a fibrosis promoter during the repair phase.

17.
Brain Imaging Behav ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33770371

RESUMO

The insula, consisting of functionally diverse subdivisions, plays a significant role in Parkinson's disease (PD)-related cognitive disorders. However, the functional connectivity (FC) patterns of insular subdivisions in PD remain unclear. Our aim is to investigate the changes in FC patterns of insular subdivisions and their relationships with cognitive domains. Three groups of participants were recruited in this study, including PD patients with mild cognitive impairment (PD-MCI, n = 25), PD patients with normal cognition (PD-NC, n = 13), and healthy controls (HCs, n = 17). Resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate the FC in insular subdivisions of the three groups. Moreover, all participants underwent a neuropsychological battery to assess cognition so that the relationship between altered FC and cognitive performance could be elucidated. Compared with the PD-NC group, the PD-MCI group exhibited increased FC between the left dorsal anterior insular (dAI) and the right superior parietal gyrus (SPG), and altered FC was negatively correlated with memory and executive function. Compared with the HC group, the PD-MCI group showed significantly increased FC between the right dAI and the right median cingulate and paracingulate gyri (DCG), and altered FC was positively related to attention/working memory, visuospatial function, and language. Our findings highlighted the different abnormal FC patterns of insular subdivisions in PD patients with different cognitive abilities. Furthermore, dysfunction of the dAI may partly contribute to the decline in executive function and memory in early drug-naïve PD patients.

18.
Eur J Pharmacol ; 899: 174034, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33727056

RESUMO

Glycine receptor is one of the chloride-permeable ion channels composed of combinations of four α subunits and one ß subunit. In adult spinal cord, the glycine receptor α1 subunit is crucial for the generation of inhibitory neurotransmission. The reduced glycinergic inhibition is regarded as one of the key spinal mechanisms underlying pathological pain symptoms. However, the expression and function of glycine receptors in the peripheral system are largely unknown as yet. Here we found that glycine receptor α1 subunit was prevalent in the dorsal root ganglia (DRG) neurons as well as in the sciatic nerves of adult mice. Intraganglionar or intraplantar injection of glycine receptor antagonist strychnine caused the hypersensitivity to mechanical, thermal and cold stimuli, suggesting the functional importance of peripheral glycine receptors in the control of nociceptive signal transmission. Our data showed that peripheral inflammation induced by formalin decreased the expression of glycine receptor α1 subunit on the plasma membrane of DRG neurons, which was attributed to the activation of protein kinase C signaling. Intraplantar application of glycine receptor agonist glycine or positive modulator divalent zinc ion alleviated the first-phase painful behaviors induced by formalin. These data suggested that peripheral glycine receptor might serve as an effective target for pain therapy.

19.
BMC Anesthesiol ; 21(1): 96, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33784963

RESUMO

BACKGROUND: The cumbersome program and the shortage of commercial solution hindered the regular application of regional citrate anticoagulation (RCA). It is urgent to simplify the protocol using only commercial preparations. The aim of this study was to explore the feasibility and efficacy of the modified protocol for continuous veno-venous hemofiltration (CVVH) in unselected critically ill patients. METHODS: A prospective cohort study was conducted in 66 patients who received a new protocol combining fixed citrate concentration with modified algorithm for supplements (i.e., fixed protocol), and compared the efficacy, safety and convenience for this group to a historical control group with a traditional protocol (n = 64), where citrate was titrated according to the circuit ionized calcium concentration (i.e., titrated protocol). The convenience was defined as the demand for monitoring test and dose adjustment of any supplement. RESULTS: The filter lifespan was 63.2 ± 16.1 h in the fixed group and 51.9 ± 17.7 h in the titrated group, respectively. Kaplan-Meier survival analysis demonstrated longer circuit lifetime for fixed group (log-rank, p = 0.026). The incidence of circuit clotting was lower in the fixed protocol (15.2% vs. 29.7% in the titrated protocol, p = 0.047). Moreover, compared with the titrated group, patients with fixed protocol had less demand for monitoring test and dose adjustment of any supplement (the number of times per person per day) (3.3 [IQR 2.3-4.5] vs. 5.7 [IQR 3.3-6.9], p = 0.001 and 1.9 [IQR 0.5-2.7] vs. 6.3 [IQR 4.2-7.9], p < 0.001; respectively). No new onset bleeding complications occurred in all patients. The overall incidence of suspected citrate accumulation was 4.6% and there was no difference between the two groups (p = 0.969), yet a lower rate of metabolic alkalosis was found in the fixed group (3.0% vs. 14.1%, p = 0.024). CONCLUSIONS: Our modified fixed citrate concentration protocol is feasible, safe and effective to enhance the circuit lifespan and the convenience of implementation while maintaining a similar safety when compared to the traditional protocol. Using only commercial preparations may be helpful for widespread application of RCA. TRIAL REGISTRATION: Clinicaltrials.gov. NCT02663960 . Registered 26 January 2016.

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