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1.
Emerg Microbes Infect ; : 1-29, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33576325

RESUMEN

Coccidioidomycosis is endemic to California, Arizona, and Mexico. In recent years, the reported cases of coccidioidomycosis have increased in nonendemic regions. Here, we reported a case of imported pulmonary coccidioidomycosis in a Chinese patient. A 63-year-old man presented with dry cough and fatigue for 6 months, and a computed tomography scan revealed a solitary nodule in the right lower lung and small nodules in both lungs. The diagnosis of coccidioidomycosis was initially confirmed by histopathologic examination. The pathogen Coccidioides spp. was identified by laser capture microdissection (LCM) combined with subsequent molecular techniques based on the positive histopathologic features. Additionally, we reviewed 47 reported cases of coccidioidomycosis in China. The number of reported cases is increasing, and the incidence of disseminated infection has exhibited a trend of shifting towards healthy young adults in China. Since clinical presentations and imaging findings lack specificity, a majority of domestic cases of coccidioidomycosis were initially misdiagnosed as tumors or tuberculosis. Moreover, the diagnosis of endemic mycoses may be challenging because of their rarity and the limited availability of diagnostic tests. The diagnosis was mainly confirmed by histopathological examination. The species involved were identified based on positive cultures in only 4 cases. To our knowledge, this is the first study to use LCM and molecular techniques to identify Coccidioides spp. in the histopathologically positive but uncultivable specimen. Comparing with previous reported studies, LCM combined with nucleic acid amplification techniques improve the ability of species identification for the timely diagnosis of coccidioidomycosis.

2.
Immunity ; 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33561388

RESUMEN

Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.

3.
Artículo en Inglés | MEDLINE | ID: mdl-33616619

RESUMEN

OBJECTIVE: In this study, we explored the effect of semaphorin5A (SEMA5A) on rheumatoid arthritis (RA) pathogenesis and its specific TSP1 domain on pannus formation. METHODS: The expression of SEMA5A was detected in synovium, fibroblast-like synoviocytes (FLS) and synovial fluid of RA patients and healthy controls (HCs) by q-PCR, IHC, WB and ELISA. SEMA5A-mAb intervention was performed to appraise the severity of joints in CIA model. Transcriptome sequencing and bioinformatics analysis in SEMA5A transfected FLS from HCs were performed to screen differentially expressed genes after SEMA5A overexpression. MTT assay in RA-FLS, chicken embryo allantoic membrane experiment and tube formation experiment were used to clarify the influence of SEMA5A on cell proliferation and angiogenesis. Furthermore, rescue experiment verified the function of TSP1 domain of SEMA5A in the progress of RA with Sema5a-/- CIA mice. RESULTS: The expression of SEMA5A increased in RA compared with HCs. Simultaneously, SEMA5A-mAb significantly attenuated joint injury and inflammatory response in CIA models. Besides, transcriptome sequencing and angiogenesis-related experiments verified the ability of SEMA5A to promote FLS proliferation and angiogenesis. Moreover, TSP1 was proved as an essential domain in SEMA5A-inducing angiogenesis in vitro. Additionally, rescue of TSP1-deleted SEMA5A failed to deteriorate the severity of arthritis in CIA model constructed with Sema5a -/- mice. CONCLUSIONS: In summary, up-regulation of SEMA5A was firstly confirmed in pathological lesion of RA patients. Furthermore, the treatment of SEMA5A-mAb attenuated the progress of RA in CIA model. Moreover, TSP1 was indicated as the key domain of SEMA5A to promote pannus formation in RA.

4.
Anim Reprod Sci ; 225: 106685, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33388612

RESUMEN

The present study was conducted to evaluate the effects in vitro on oocyte mitochondrial function of C-type natriuretic peptide (CNP) when treatments were imposed before in vitro maturation (IVM). Immature oocytes were either directly matured in vitro for 24 h (Control, no pre-IVM), or cultured in basic medium not supplemented or supplemented with CNP (100 nM) (Control pre-IVM and CNP pre-IVM, respectively) for 6 h, followed by IVM for 24 h. The results indicated treatment with CNP before IVM affected patterns of distribution of mitochondria, increased the mitochondrial content, membrane potential, and decreased the ROS content in cattle oocytes before and after IVM. Furthermore, treatment of immature cattle oocytes with CNP before IVM induced marked increases in the relative abundance of mRNA transcripts and proteins related to mitochondria development and antioxidative defense mechanisms. Treatment with CNP before oocyte IVM also resulted in an enhanced relative abundance of sirtuin-1 (SIRT1) mRNA transcript in cattle oocytes. Taken together, these results provide evidence that treatment of cattle oocytes with CNP before IVM improved mitochondrial function and antioxidant defense mechanisms in cattle oocytes. Findings in the present study provide insights into the potential mechanisms by which CNP has positive effects on oocyte cytoplasmic organelles, specifically mitochondria.

5.
J Med Virol ; 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33470428

RESUMEN

Evidence in the literature suggests that air pollution exposure affects outcomes of patients with COVID-19. However, the extent of this effect requires further investigation. This study was designed to investigate the relationship between long-term exposure to air pollution and the case fatality rate (CFR) of patients with COVID-19. The data on air quality index (AQI), PM2.5, PM10, SO2 , NO2 , and O3 from 14 major cities in China in the past 5 years (2015-2020) were collected, and the CRF of COVID-19 patients in these cities was calculated. First, we investigated the correlation between CFR and long-term air quality indicators. Second, we examined the air pollutants affecting CFR and evaluated their predictive values. We found a positive correlation between the CFR and AQI (1, 3, and 5 years), PM2.5 (1, 3, and 5 years), and PM10 (1, 3, and 5 years). Further analysis indicated the more significant correlation for both AQI (3 and 5 years) and PM2.5 (1, 3, and 5 years) with CFR, and moderate predictive values for air pollution indicators such as AQI (1, 3, and 5 years) and PM2.5 (1, 3, and 5 years) for CFR. Our results indicate that long-term exposure to severe air pollution is associated with higher CFR of COVID-19 patients. Air pollutants such as PM2.5 may assist with the prediction of CFR for COVID-19 patients.

6.
Brain Res Bull ; 169: 196-204, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33515654

RESUMEN

Orexin-A/B modulates multiple physical functions by activating their receptors (OX1R and OX2R), but its effects in the spinal cord motor control remain unknown. Using acute separation (by digestive enzyme) of cells and patch-clamp recordings, we aimed to investigate the effect and mechanisms of orexin-A on the glycine receptors in the spinal cord ventral horn neurons. Orexin-A potentiated the glycine currents by activating OX1R. In Ca2+-free extracellular solution, orexin-A still increased the glycine currents. While, the orexin-A-induced potentiation was blocked when Ca2+ was chelated by internal infusion of BAPTA, and the orexin-A effect was abolished by the IP3 receptor antagonists heparin and Xe-C. The PKC inhibitor Bis-IV nullified the orexin-A effect. In addition, orexin-A did not cause a further enhancement of the glycine currents after bath application of the PKC activator PMA. In conclusion, after OX1R is activated, a distinct IP3/Ca2+-dependent PKC signaling pathway, is likely responsible for the orexin-A potentiation on glycine currents in the spinal cord ventral horn neurons.

7.
Theranostics ; 11(3): 1446-1457, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33391544

RESUMEN

Objective: Tofacitinib (TOF) is a Janus kinase (JAK) inhibitor used in the treatment of rheumatoid arthritis (RA), but the mechanism of its action remains unclear. In this study, we investigated the influence of TOF on gamma delta regulatory T-cell (γδTreg)/γδT17 cell balance in RA and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in this process. Methods: We detected levels of inflammatory factors in the serum of RA patients before and after administration of TOF using an enzyme-linked immunosorbent assay (ELISA). A collagen-induced arthritis (CIA) model was constructed to investigate the effect of TOF on arthritis symptoms, γδTreg/γδT17 cell balance and the NLRP3 inflammasome. We used bone marrow-derived macrophages (BMDMs) to study the effect of TOF on NLRP3 inflammasome activation. Nlrp3-/- mice were introduced to assess the influence of NLRP3 on γδT17 cell activation in RA. Results: TOF treatment decreased levels of γδT17 cell-related cytokine interleukin-17 (IL-17) in RA patients. In addition, TOF intervention in the CIA model reduced joint inflammation and damage, rebalanced the γδTreg/γδT17 cell ratio and inhibited excessive NLRP3 inflammasome activation in draining lymph nodes and arthritic joints. BMDM intervention experiments demonstrated that TOF decreased the level of secreted IL-1ß via downregulation of NLRP3. Furthermore, experiments using Nlrp3 -/- mice verified that the NLRP3 inflammasome mediated the effect of TOF on γδT17 cell activation. Conclusions: Recovery of γδTreg/γδT17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated γδT17 cell activation.

8.
J Int Med Res ; 49(1): 300060520984932, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33461383

RESUMEN

OBJECTIVE: This study analyzed drug resistance and mutations profiles in Mycobacterium tuberculosis isolates in a surveillance site in Huairou District, Beijing, China. METHODS: The proportion method was used to assess drug resistance profiles for four first-line and seven second-line anti-tuberculosis (TB) drugs. Molecular line probe assays were used for the rapid detection of resistance to rifampicin (RIF) and isoniazid (INH). RESULTS: Among 235 strains of M. tuberculosis, 79 (33.6%) isolates were resistant to one or more drugs. The isolates included 18 monoresistant (7.7%), 19 polyresistant (8.1%), 28 RIF-resistant (11.9%), 24 multidrug-resistant (MDR) (10.2%), 7 pre-extensively drug-resistant (XDR, 3.0%), and 2 XDR strains (0.9%). A higher rate of MDR-TB was detected among previously treated patients than among patients with newly diagnosed TB (34.5% vs. 6.8%). The majority (62.5%) of RIF-resistant isolates exhibited a mutation at S531L in the DNA-dependent RNA polymerase gene. Meanwhile, 62.9% of INH-resistant isolates carried a mutation at S315T1 in the katG gene. CONCLUSION: Our results confirmed the high rate of drug-resistant TB, especially MDR-TB, in Huairou District, Beijing, China. Therefore, detailed drug testing is crucial in the evaluation of MDR-TB treatment.

9.
Cell Death Dis ; 12(1): 102, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33473125

RESUMEN

In inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

10.
Biomark Res ; 8(1): 61, 2020 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-33292652

RESUMEN

Non-coding RNAs are the main component of the extensive transcription results of the mammalian genome. They are not transcribed into proteins but play critical roles in regulating multiple biological processes and affecting cancer progression. m6A modification is one of the most abundant internal RNA modification of mammalian cells, and it involves almost all aspects of RNA metabolism. Recent research revealed tight correlations between m6A modification and ncRNAs and indicated the interaction between m6A and ncRNAs act a pivotal part in the development of cancer. The correlation between m6A modification and ncRNAs provides a new perspective for exploring the potential regulatory mechanism of tumor gene expression, and suggest that m6A modification and ncRNAs may be important prognostic markers and therapeutic targets for multiple cancers. In this review, we summarize the potential regulatory mechanisms between m6A methylation and ncRNAs, highlighting how their relationship affects biological functions in cancer.

11.
Sensors (Basel) ; 20(24)2020 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-33302517

RESUMEN

Collecting and analyzing massive data generated from smart devices have become increasingly pervasive in crowdsensing, which are the building blocks for data-driven decision-making. However, extensive statistics and analysis of such data will seriously threaten the privacy of participating users. Local differential privacy (LDP) was proposed as an excellent and prevalent privacy model with distributed architecture, which can provide strong privacy guarantees for each user while collecting and analyzing data. LDP ensures that each user's data is locally perturbed first in the client-side and then sent to the server-side, thereby protecting data from privacy leaks on both the client-side and server-side. This survey presents a comprehensive and systematic overview of LDP with respect to privacy models, research tasks, enabling mechanisms, and various applications. Specifically, we first provide a theoretical summarization of LDP, including the LDP model, the variants of LDP, and the basic framework of LDP algorithms. Then, we investigate and compare the diverse LDP mechanisms for various data statistics and analysis tasks from the perspectives of frequency estimation, mean estimation, and machine learning. Furthermore, we also summarize practical LDP-based application scenarios. Finally, we outline several future research directions under LDP.

12.
Toxicon ; 189: 39-44, 2020 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-33197481

RESUMEN

The study aimed to examine the effects of zearalenone on genital organ development, serum immunoglobulin, antioxidant capacity, sex hormones and liver function of prepubertal gilts. Forty-eight prepubertal gilts (Landrace × Yorkshire) were randomly divided into three treatment (T1, T2 and T3) groups and a control group (12 replicates per group, 1 gilt per replicate). Prepubertal gilts in the control group were fed with basal diet, and those in T1, T2 and T3 groups were fed with basal diets supplemented with 200 µg/kg, 800 µg/kg and 1600 µg/kg zearalenone during the experiment period, which lasted for 14 d. Feed intake was counted and vulvar area was measured. The blood samples were collected from the anterior vena cava of 6 prepubertal gilts in each group, and immunoglobulins, antioxidant indexes, inflammatory cytokines, genital hormones, and biochemical indexes were analyzed by enzyme-linked immunosorbent assay. The results showed that the average daily feed intake of prepubertal gilts in each group had no significant change (p > 0.05). On 14 d, compared with the control group, the vulva area of prepubertal gilts in each treatment group was significantly increased (p < 0.05). Compared with the control group, the serum immunoglobulin G content in the T3 group was significantly reduced (p < 0.05). The activities of total antioxidant capacity and the superoxide dismutase of serum in the T3 group were significantly reduced (p < 0.05). Compared with the control group, the serum interleukin-4 content in each test group were extremely significantly increased (p < 0.01). The serum contents of luteinizing hormone in the T2 and T3 groups and estradiol in the T3 group were significantly reduced (p < 0.05) than that of control group. Compared with the control group, the activity of aspartate aminotransferase in T3 group was significantly increased (p < 0.05). In conclusion, zearalenone has no significantly effect on the feed intake of prepubertal gilts, but it can reduce its serum immunoglobulin contents and antioxidant properties, disrupt the secretion of sex hormones, increase the vulva area, produce reproductive toxicity and cause liver damage. Therefore, in pig production, the use of antimould reagent together with products of immunity-boosting, antioxidant, anti-inflammatory and hepatoprotective may enhance protection.

13.
Oncol Rep ; 44(6): 2621-2633, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33125106

RESUMEN

Considering the high metastatic potential of osteosarcoma, not only pro­apoptosis, but also anti­metastasis is important for anti­osteosarcoma therapy. Previously, the authors reported the pro­apoptotic and tumor­inhibitory effects of theabrownin (TB) on osteosarcoma cells; however, its effects on the metastasis­related migration and invasion of osteosarcoma cells remain unknown. The present study conducted RNA sequencing (RNA­seq) on xenograft zebrafish samples and performed in vitro experiments, including RT­qPCR, cell viability analysis, clone formation assay, cell cycle analysis, immunofluorescence, cell migration assay, cell invasion assay, wound healing assay and western blot (WB) analysis to evaluate the anti­metastatic effects and mechanism of TB against osteosarcoma cells. The RNA­seq data revealed that TB significantly downregulated the expression of genes involved in the microtubule bundle formation of U2OS cells, which was verified by RT­qPCR. The cell viability and clone formation data indicated that TB significantly inhibited U2OS cell viability and colony numbers. The results of cell cycle analysis revealed the blocked cell cycle progression of U2OS by TB. The immunofluorescent data revealed an evident cytoskeleton­inhibitory effect of TB against the microfilament and microtubule formation of U2OS cells. The results of cell migration and invasion demonstrated that TB significantly inhibited U2OS cell migration and invasion. The results of WB analysis revealed that TB significantly regulated key molecules of epithelial­mesenchymal transition [EMT; e.g., E­cadherin, vimentin, Snail­1, Slug and zinc finger E­box­binding homeobox 1 (ZEB­1)] and those of the nuclear factor (NF)­κB pathway (e.g., NF­κB, phospho­IKKα and phospho­IKKß), indicating that NF­κB pathway­related EMT suppression may mediate the mechanisms underlying the anti­migratory and anti­invasive effects of TB against osteosarcoma. To the best of our knowledge, this is the first study on the inhibitory effects and mechanisms of TB on the cytoskeleton­dependent cell cycle, migration and invasion of human osteosarcoma cells. The findings presented herein suggest that TB may be a promising anti­metastatic candidate for anti­osteosarcoma therapy.

14.
Oxid Med Cell Longev ; 2020: 4894625, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33110473

RESUMEN

Recent therapeutic advances have significantly improved the short- and long-term survival rates in patients with heart disease and cancer. Survival in cancer patients may, however, be accompanied by disadvantages, namely, increased rates of cardiovascular events. Chemotherapy-related cardiac dysfunction is an important side effect of anticancer therapy. While advances in cancer treatment have increased patient survival, treatments are associated with cardiovascular complications, including heart failure (HF), arrhythmias, cardiac ischemia, valve disease, pericarditis, and fibrosis of the pericardium and myocardium. The molecular mechanisms of cardiotoxicity caused by cancer treatment have not yet been elucidated, and they may be both varied and complex. By identifying the functional genetic variations responsible for this toxicity, we may be able to improve our understanding of the potential mechanisms and pathways of treatment, paving the way for the development of new therapies to target these toxicities. Data from studies on genetic defects and pharmacological interventions have suggested that many molecules, primarily those regulating oxidative stress, inflammation, autophagy, apoptosis, and metabolism, contribute to the pathogenesis of cardiotoxicity induced by cancer treatment. Here, we review the progress of genetic research in illuminating the molecular mechanisms of cancer treatment-mediated cardiotoxicity and provide insights for the research and development of new therapies to treat or even prevent cardiotoxicity in patients undergoing cancer treatment. The current evidence is not clear about the role of pharmacogenomic screening of susceptible genes. Further studies need to done in chemotherapy-induced cardiotoxicity.

15.
Biosci Rep ; 40(10)2020 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-33006362

RESUMEN

Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related mortality globally. However, the mechanism underlying NSCLC is not fully understood. Here, we investigated the role of cancer-related regulator of actin dynamics (CRAD) in NSCLC. We showed that CRAD was up-regulated in human NSCLC tissues and lung cancer cell lines. Lentivirus-mediated knockdown of CRAD repressed the proliferation and colony growth of A549 and H1299 cells. Apoptosis was enhanced by CRAD silencing in both cells, implicating that CRAD might maintain the survival of lung cancer cells. Microarray and bioinformatic assay revealed that CRAD directly or indirectly regulated diverse genes, including those involved in cell cycle and DNA damage repair. qRT-PCR and Western blot results confirmed the dysregulated genes as shown in microarray analysis. Claudin 4 was up-regulated in CRAD silenced A549 cells. The knockdown of Claudin 4 blocked the effects of CRAD on the expression of cell cycle and apoptosis effectors and enhanced the viability of A549 cells with CRAD down-regulation. Taken together, our findings demonstrate that CRAD acts as an oncogene in NSCLC at least partly through repressing Claudin 4.

16.
Artículo en Inglés | MEDLINE | ID: mdl-33006934

RESUMEN

With the development of medical artificial intelligence, automatic magnetic resonance image (MRI) segmentation method is quite desirable. Inspired by the power of deep neural networks, a novel deep adversarial network, dilated block adversarial network (DBAN), is proposed to perform left ventricle, right ventricle and myocardium segmentation in short-axis cardiac MRI. DBAN contains a segmentor along with a discriminator. In the segmentor, the dilated block (DB) is proposed to capture and aggregate multi-scale features. The segmentor can produce segmentation probability maps while the discriminator can differentiate the segmentation probability map and the ground truth at the pixel level. In addition, confidence probability maps generated by the discriminator can guide the segmentor to modify segmentation probability maps. Extensive experiments demonstrate that DBAN has achieved the state-of-the-art performance on the ACDC dataset. Quantitative analyses indicate that cardiac function indices from DBAN are similar to those from clinical experts. Therefore, DBAN can be a potential candidate for short-axis cardiac MRI segmentation in clinical applications.

17.
Clin Neurol Neurosurg ; 198: 106172, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32942133

RESUMEN

BACKGROUND: Although several risk factors of the multiple intracranial aneurysms (MIAs) formation has been reported, the results are controversial. We aimed to find out the risk factors of MIAs formation by analyzing our clinic data combined with a meta-analysis. MATERIAL AND METHODS: A retrospective review work of medical records for the patients with aneurysms was undertaken. Univariate analysis was used to examine all mentioned variables. Binary logistic regression analysis was used to identify the risk factors of MIAs formation. RESULTS: In the retrospective review work, a total of 565 patients with aneurysm were included in this study. Of these 565 participants, 449 patients suffered SIAs and 116 patients suffered MIAs. Univariate analysis showed a significant difference in terms of female, cigarette smoking, family history of hypertension, and primary hypertension between the SIAs and MIAs group. The binary logistic regression analysis showed that the female (OR = 1.624), primary hypertension (OR = 1.563), and family history of hypertension (OR = 2.496) were independent risk factors of the formation of MIAs (for each P < 0.05). With regard to the meta-analysis results, it revealed that there was significant difference in the rates of female (P < 0.001), cigarette smoking (P < 0.001), primary hypertension (P = 0.001), and higher age (P = 0.011) among the MIAs patients. CONCLUSIONS: A higher rate of the formation of MIAs is closely associated with the elder and female. Patients with hypertension history, cigarette smoking, and family primary hypertension history also affected the formation of MIAs, these risk factors should be a guard against.

18.
Thromb Res ; 196: 159-166, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32882448

RESUMEN

BACKGROUND: Disseminated intravascular coagulation (DIC), a severe complication of sepsis, promotes multiple organ dysfunctions and lethality. Bacterial infection is the most common cause of sepsis. We previously show an important role of bacteria-released outer membrane vesicles (OMVs) in bacterial infection-induced DIC. In the light of recent advance that activation of caspase-11 and its enzymatic substrate gasdermin D (GSDMD) is able to trigger coagulation, we postulate that OMVs might induce DIC through the caspase-11-GSDMD pathway. METHODS: Caspase-11- or GSDMD-deficient mice and their wild-type (WT) controls were injected with purified Escherichia coli-derived OMVs. Blood samples were then collected. The development of DIC was assessed in terms of the occurrence of coagulopathy, the organ injuries and the lethality. Peritoneal macrophages derived from WT, Caspase-11- or GSDMD-deficient mice were stimulated with OMVs. Then the cell surface tissue factor (TF) activity and thrombin generation were assessed. RESULTS: Genetic deletion of Caspase-11 or GSDMD or pharmacological inhibition of caspase-11 markedly attenuated OMVs-induced coagulopathy, multiple organ injuries and mortality. Caspase-11- or GSDMD-deficient macrophages exhibited markedly reduced TF activity after OMVs stimulation. CONCLUSION: OMVs induce DIC through the caspase-11-GSDMD pathway. These findings might open a new avenue to prevent or treat bacterial infection-induced DIC.

19.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(5): 676-682, 2020 May 30.
Artículo en Chino | MEDLINE | ID: mdl-32897202

RESUMEN

OBJECTIVE: To investigate the effects of etomidate on electrophysiological properties and nicotinic acetylcholine receptors (nAChRs) of ventral horn neurons in the spinal cord. METHODS: The spinal cord containing lumbosacral enlargement was isolated from 19 neonatal SD rats aged 7-12 days. The spinal cord were sliced and digested with papain (0.18 g/30 mL artificial cerebrospinal fluid) and incubated for 40 min. At the ventral horn, acute mechanical separation of neurons was performed with fire-polished Pasteur pipettes, and perforated patch-clamp recordings combined with pharmacological methods were employed on the adherent healthy neurons. In current-clamp mode, the spontaneous action potential (AP) of the ventral horn neurons in the spinal cord was recorded. The effects of pretreatment with different concentrations of etomidate on AP recorded in the ventral horn neurons were examined. In the voltage-clamp mode, nicotine was applied to induce inward currents in the ventral horn neurons, and the effect of pretreatment with etomidate on the inward currents induced by nicotine were examined with different etomidate concentrations, different holding potentials and different use time. RESULTS: The isolated ventral horn neurons were in good condition with large diverse somata and intact processes. The isolated spinal ventral horn neurons (n=21) had spontaneous action potentials, and were continuously perfused for 2 min with 0.3, 3.0 and 30.0 µmol/L etomidate. Compared with those before administration, the AP amplitude, spike potential amplitude and overshoot were concentration-dependently suppressed (P < 0.01), and spontaneous discharge frequency was obviously reduced (P < 0.01, n=12). The APs of the other 9 neurons were completely abolished by etomidate at 3.0 or 30 µmol/L. At the same holding potential (VH=-70 mV), pretreatment with 0.3, 3.0 or 30.0 µmol/L etomidate for 2 min concentration-dependently suppressed the current amplitude induced by 0.4 mmol/L nicotine (P < 0.01, n=7). At the holding potentials of - 30, - 50, and - 70 mV, pretreatment with 30.0 µmol/L etomidate for 2 min voltage-dependently suppressed the current amplitude induced by 0.4 mmol/L nicotine (P < 0.01, n=6 for each holding potential). During the 6 min of 30.0 µmol/L etomidate pretreatment, the clamped cells were exposed to 0.4 mmol/L nicotine for 4 times at 0, 2, 4, and 6 min (each exposure time was 2 s), and the nicotinic current amplitude decreased gradually as the number of exposures increased. But at the same concentration, two nicotine exposures (one at the beginning and the other at the end of the 6 min pretreatment) resulted in a significantly lower inhibition rate compared with 4 nicotine exposures (P < 0.01, n=6). CONCLUSIONS: etomidate reduces the excitability of the spinal ventral neurons in a concentration-dependent manner and suppresses the function of nAChR in a concentration-, voltage-, and use-dependent manner.


Asunto(s)
Neuronas , Animales , Animales Recién Nacidos , Etomidato , Técnicas de Placa-Clamp , Ratas , Médula Espinal
20.
Protein Cell ; 2020 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-32737864

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis due to limited therapeutic options. This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets. We have identified HNF4G gene whose silencing most effectively repressed PDAC cell invasiveness. HNF4G overexpression is induced by the deficiency of transcriptional factor and tumor suppressor SMAD4. Increased HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC (log-rank P = 0.036; HR = 1.60, 95% CI = 1.03-2.47). We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 deficiency. Furthermore, Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC (log-rank P = 0.022; HR = 0.31, 95% CI = 0.14-0.68) but not in patients with SMAD4-normal PDAC. Pathway analysis shows that HNF4G may act in PDAC through the cell-cell junction pathway. These results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.

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