RESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a global pandemic which may compromise the management of vascular emergencies. An uncompromised treatment for ruptured abdominal aortic aneurysm (rAAA) during such a health crisis represents a challenge. This study aimed to demonstrate the treatment outcomes of rAAA and the perioperative prevention of cross-infection under the COVID-19 pandemic. METHODS: In cases of rAAA during the pandemic, a perioperative workflow was applied to expedite coronavirus testing and avoid pre-operative delay, combined with a strategy for preventing cross-infection. Data of rAAA treated in 11 vascular centers between January-March 2020 collected retrospectively were compared to the corresponding period in 2018 and 2019. RESULTS: Eight, 12, and 14 rAAA patients were treated in 11 centers in January-March 2018, 2019, and 2020, respectively. An increased portion were treated at local hospitals with a comparable outcome compared with large centers in Guangzhou. With EVAR-first strategy, 85.7% patients with rAAA in 2020 underwent endovascular repair, similar to that in 2018 and 2019. The surgical outcomes during the pandemic were not inferior to that in 2018 and 2019. The average length of ICU stay was 1.8 ± 3.4 days in 2020, tending to be shorter than that in 2018 and 2019, whereas the length of hospital stay was similar among 3 years. The in-hospital mortality of 2018, 2019, and 2020 was 37.5%, 25.0%, and 14.3%, respectively. Three patients undergoing emergent surgeries were suspected of COVID-19, though turned out to be negative after surgery. CONCLUSIONS: Our experience for emergency management of rAAA and infection prevention for healthcare providers is effective in optimizing emergent surgical outcomes during the COVID-19 pandemic.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/cirurgia , COVID-19/prevenção & controle , Infecção Hospitalar/prevenção & controle , Controle de Infecções , Procedimentos Cirúrgicos Vasculares , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico , Ruptura Aórtica/diagnóstico , COVID-19/diagnóstico , COVID-19/transmissão , COVID-19/virologia , Teste para COVID-19 , China , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/transmissão , Infecção Hospitalar/virologia , Emergências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Fluxo de TrabalhoRESUMO
Vascular metabolic dysfunction presents in various diseases, such as atherosclerosis, hypertension, and diabetes mellitus. Due to the high prevalence of these diseases, it is important to explore treatment strategies to protect vascular function. Resveratrol (RSV), a natural polyphenolic phytochemical, is regarded as an agent to regulate metabolic pathways. Many studies have proven that RSV has beneficial effects on improving metabolism in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), which provide new directions to treat vascular metabolic diseases. Herein, we overviewed that RSV could regulate cell metabolism activity by inhibiting glucose uptake, suppressing glycolysis, preventing cells from fatty acid-related damages, reducing lipogenesis, increasing fatty acid oxidation, enhancing lipolysis, elevating uptake and synthesis of glutamine, and increasing NO release. Furthermore, in clinical trials, although the results from different studies remain controversial, we proposed that RSV had better therapeutic effects at high concentrations and for patients with metabolic disorders.
Assuntos
Doenças Metabólicas , Estilbenos , Doenças Vasculares , Humanos , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Células Endoteliais/metabolismo , Doenças Metabólicas/tratamento farmacológico , Metabolismo dos Lipídeos , Ácidos Graxos/metabolismo , Estilbenos/farmacologiaRESUMO
OBJECTIVE: The development of in-stent restenosis (ISR) hinders the long-term patency of carotid artery stenting (CAS), yet no optimal treatment has been established. In the present study, we compared the outcomes of redo CAS (rCAS) and carotid endarterectomy (CEA) for ISR. METHODS: A systematic search using the terms "in-stent restenosis," "carotid endarterectomy," and "carotid artery stenting" was conducted in the PubMed, Embase, and Cochrane databases. Studies reporting perioperative stroke, death, and other important complications of rCAS or CEA for ISR after previous CAS with four or more patients were included. Pooled and sensitivity analyses were conducted to synthesize and compare estimates of the outcomes. RESULTS: A total of 11 studies with 1057 patients who had undergone rCAS (n = 894) or CEA (n = 163) met the inclusion criteria. The CEA group had a significantly greater proportion of symptomatic patients (rCAS vs CEA, 30.4% vs 42.1%; P < .01). The duration from primary CAS to reintervention was relatively longer in the CEA group (rCAS vs CEA, median, 8.8 months [range, 3-26 months] vs 19.9 months [range, 0-54 months]). In the rCAS group, a greater proportion of patients had hypertension, hypercholesterolemia, and coronary artery disease and had received antiplatelet therapy before reintervention. Because of insufficient data or a low incidence, the only complications feasible for further analysis were restenosis, myocardial infarction, cranial nerve injury, and neck hematoma. No significant differences were found in the primary end point of mortality/stroke event-free rate (rCAS vs CEA, 99% vs 98%; P > .05) or other secondary end points (event-free restenosis, 100% vs 100%; event-free myocardial infarction, 100% vs 98%; event-free cranial nerve injury, 100% vs 98%; event-free neck hematoma, 100% vs 100% for rCAS vs CEA; P > .05 for all). CONCLUSIONS: rCAS is commonly used to treat patients with severe and/or symptomatic ISR after primary CAS. Although the endovascular approach is less invasive, both rCAS and CEA can be performed safely with similar short- and midterm outcomes of stroke, death, and surgery-related complications.
Assuntos
Estenose das Carótidas/terapia , Endarterectomia das Carótidas , Procedimentos Endovasculares/instrumentação , Stents , Idoso , Estenose das Carótidas/mortalidade , Estenose das Carótidas/fisiopatologia , Estenose das Carótidas/cirurgia , Endarterectomia das Carótidas/efeitos adversos , Endarterectomia das Carótidas/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Retratamento , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
Critical limb ischemia (CLI) is a severe form of peripheral artery diseases (PAD) and seriously endangers the health of people. Therapeutic angiogenesis represents an important treatment strategy for CLI; various methods have been applied to enhance collateral circulation. However, the current development drug therapy to promote angiogenesis is limited. Resveratrol (RSV), a polyphenol compound extracted from plants, has various properties such as anti-oxidative, anti-inflammatory and anti-cancer effects. Whether RSV exerts protective effects on CLI remains elusive. In the current study, we demonstrated that oral intake of RSV significantly improved hind limb ischemia in mice, and increased the expression of phosphorylated Forkhead box class-O1 (FoxO1). RSV treatment in human umbilical vein endothelial cells (HUVECs) could increase the phosphorylation of FoxO1 and its cytoplasmic re-localization to promote angiogenesis. Then we manipulated FoxO1 in HUVECs to further verify that the effect of RSV on angiogenesis is in a FoxO1-dependent manner. Furthermore, we performed metabolomics to screen the metabolic pathways altered upon RSV intervention. We found that the pathways of pyrimidine metabolism, purine metabolism, as well as alanine, aspartate and glutamate metabolism, were highly correlated with the beneficial effects of RSV on the ischemic muscle. This study provides a novel direction for the medical therapy to CLI.
Assuntos
Isquemia Crônica Crítica de Membro/tratamento farmacológico , Proteína Forkhead Box O1/metabolismo , Neovascularização Patológica/tratamento farmacológico , Resveratrol/farmacologia , Animais , Isquemia Crônica Crítica de Membro/metabolismo , Proteína Forkhead Box O1/genética , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/metabolismo , Fosforilação/efeitos dos fármacosRESUMO
The positioning and movement of the nucleus has recently emerged as an important aspect of cell migration. Understanding of nuclear positioning and movement has reached an apogee in studies of fibroblast migration. Specific nuclear positioning and movements have been described in the polarization of fibroblast for cell migration and in active migration in 2D and 3D environments. Here, we review recent studies that have uncovered novel molecular mechanisms that contribute to these events in fibroblasts. Many of these involve a connection between the nucleus and the cytoskeleton through the LINC complex composed of outer nuclear membrane nesprins and inner nuclear membrane SUN proteins. We consider evidence that appropriate nuclear positioning contributes to efficient fibroblast polarization and migration and the possible mechanism through which the nucleus affects cell migration.
Assuntos
Núcleo Celular/metabolismo , Fibroblastos/metabolismo , Transporte Biológico , Movimento CelularRESUMO
In the city that never sleeps, great science never takes a break. On 15 January 2016, the 'New York Symposium on Quantitative Biology of the Cell', a one-day local meeting of the American Society for Cell Biology (ASCB), took place at Columbia University Medical Center in upper Manhattan. Focusing on the quantitative understanding of cellular and multicellular systems, this meeting created an otherwise rare opportunity for interaction among scientists at various career levels with differing but complementary backgrounds. Highlighting cutting-edge experimental measurements and theoretical modeling, the symposium broke the barrier between disciplines and ignited a hopefully continuing regional dialogue on the emergent topic of quantitative biology of the cell.
Assuntos
Biologia Celular , Citoesqueleto/metabolismo , Humanos , Imageamento Tridimensional , Engenharia Metabólica , Modelos TeóricosRESUMO
PURPOSE: To report the use of the octopus endograft technique to treat a patient with a ruptured thoracoabdominal aortic aneurysm (TAAA). CASE REPORT: A 46-year-old man was diagnosed with a contained rupture of a 9-cm type V TAAA. The presence of an occluded superior mesenteric artery (SMA), a stenotic celiac trunk, an enlarged inferior mesenteric artery (IMA), and rich collaterals with the SMA and celiac trunk made endovascular repair with the octopus endograft technique appear feasible. Two stent-grafts were overlapped in the thoracic aorta with the short limb of the distal bifurcated stent-graft about 3 cm above the celiac trunk and the long limb at the level of the renal arteries. A limb graft was introduced into the long limb of the bifurcated stent-graft and deployed with the lower end just above the orifice of the IMA. The celiac trunk was embolized. Viabahn stent-grafts were deployed through the bifurcated stent-graft limbs to revascularize the renal arteries. Completion angiography suggested free flow in the renal arteries, though the gutters around the Viabahn stent-grafts generated a moderate endoleak that persisted at 4-month follow-up. The gutters were then sealed with coil embolization, which eliminated the endoleak and induced complete thrombosis in the aneurysm sac at the 6-month follow-up. One-year computed tomography revealed significant sac shrinkage. CONCLUSION: The octopus endograft technique may serve as a feasible, effective, and safe treatment alternative for highly selected patients with ruptured TAAA.
Assuntos
Aneurisma da Aorta Torácica/cirurgia , Ruptura Aórtica/cirurgia , Implante de Prótese Vascular/métodos , Procedimentos Endovasculares/métodos , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/fisiopatologia , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/fisiopatologia , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Endoleak/etiologia , Endoleak/terapia , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Stents , Resultado do TratamentoRESUMO
The recognition of bird species through the analysis of their vocalizations is a crucial aspect of wildlife conservation and biodiversity monitoring. In this study, the acoustic features of Certhia americana, Certhia brachydactyla, and Certhia familiaris were calculated including the Acoustic complexity index (ACI), Acoustic diversity index (ADI), Acoustic evenness index (AEI), Bioacoustic index (BI), Median of the amplitude envelop (MA), and Normalized Difference Soundscape Index (NDSI). Three machine learning models, Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost), were constructed. The results showed that the XGBoost model had the best performance among the three models, with the highest accuracy (0.8365) and the highest AUC (0.8871). This suggests that XGBoost is an effective tool for bird species recognition based on acoustic indices. The study provides a new approach to bird species recognition that utilizes sound data and acoustic characteristics.
Assuntos
Acústica , Aves , Animais , Animais Selvagens , Biodiversidade , Aprendizado de MáquinaRESUMO
Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.
Assuntos
COVID-19 , Microbioma Gastrointestinal , Trombose , Humanos , Camundongos , Animais , Integrina alfa2beta1/genética , Integrina alfa2beta1/metabolismo , Colágeno/metabolismo , Plaquetas/metabolismo , COVID-19/metabolismoRESUMO
BACKGROUND: Head and neck squamous cell carcinomas are the sixth most common malignant tumors worldwide. Tongue squamous cell carcinoma is a common malignant tumor of this type, and it is associated with poor prognosis, a high rate of recurrence and a low survival rate. Plumbagin is derived from Plumbago zeylanica L, several studies report that plumbagin could inhibit cell, tumor metastasis, induce apoptosis in various cancer cells. Patient-derived xenograft (PDX) model can maintain the heterogeneity and microenvironment of human tumors, is a powerful research tool for developing potentially effective therapies for TSCC. METHODS: Tumor tissues obtained from TSCC patients were implanted into immunodeficient mice to establish TSCC PDX models. Subsequently, the PDX models were used to evaluate the anti-tumor effects of plumbagin on TSCC. Furthermore, we conducted next-generation sequencing (NGS) and explored the mRNA expression profiles between the treatment and control groups. We selected eight mRNAs related to the characteristics and prognosis of TSCC patients for further analysis. RESULTS: Plumbagin could inhibit the growth of TSCC PDX models and inhibit expression of Akt/mTOR pathway. In addition, plumbagin was shown to increase drug sensitivity to cisplatin. The eight mRNAs selected for further analysis, AXL, SCG5, VOPP1, DCBLD2 and DRAM1 are cancer-promoting genes, DUSP1, AQP5 and BLNK are cancer suppressor genes. And they were related to the diagnosis, growth, prognosis, and immune cell infiltration in TSCC patients. CONCLUSION: Plumbagin exhibits an inhibitory effect on the growth of the PDX model of TSCC. Moreover, plumbagin enhances the inhibitory effects of cisplatin.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias da Língua , Humanos , Animais , Camundongos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinoma de Células Escamosas/genética , Neoplasias da Língua/genética , Proliferação de Células , Linhagem Celular Tumoral , Microambiente Tumoral , Fatores de TranscriçãoRESUMO
Interactions between chromosomes and LINC (linker of nucleoskeleton and cytoskeleton) complexes in the nuclear envelope (NE) promote homolog pairing and synapsis during meiosis. By tethering chromosomes to cytoskeletal motors, these connections lead to processive chromosome movements along the NE. This activity is usually mediated by telomeres, but in the nematode Caenorhabditis elegans, special chromosome regions called "pairing centers" (PCs) have acquired this meiotic function. Here, we identify a previously uncharacterized meiosis-specific NE protein, MJL-1 (MAJIN-Like-1), that is essential for interactions between PCs and LINC complexes in C. elegans. Mutations in MJL-1 eliminate active chromosome movements during meiosis, resulting in nonhomologous synapsis and impaired homolog pairing. Fission yeast and mice also require NE proteins to connect chromosomes to LINC complexes. Extensive similarities in the molecular architecture of meiotic chromosome-NE attachments across eukaryotes suggest a common origin and/or functions of this architecture during meiosis.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Camundongos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Membrana Nuclear/genética , Membrana Nuclear/metabolismo , Meiose/genética , Telômero/genética , Telômero/metabolismo , Pareamento Cromossômico , Proteínas de Membrana/metabolismoRESUMO
Meiotic chromosome segregation relies on synapsis and crossover (CO) recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in 'homolog engagement' is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans, recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break (DSB) induction. Inactivation of CHK-2 terminates DSB formation and enables CO designation and cell cycle progression. These findings illuminate how meiotic cells ensure CO formation and accurate chromosome segregation.
Most animals, plants, and fungi reproduce sexually, meaning that the genetic information from two parents combines during fertilization to produce offspring. This parental genetic information is carried within the reproductive cells in the form of chromosomes. Reproductive cells in the ovaries or testes first multiply through normal cell division, but then go through a unique type of cell division called meiosis. During meiosis, pairs of chromosomes the two copies inherited from each parent must find each other and physically line up from one end to the other. As they align side-by-side with their partners, chromosomes also go through a mixing process called recombination, during which regions of one chromosome cross over to the paired chromosome to exchange information. Scientists are still working to understand how this process of chromosome alignment and crossing-over is controlled. If chromosomes fail to line up or cross over during meiosis, eggs or sperm can end up with too many or too few chromosomes. If these faulty reproductive cells combine during fertilization this can lead to birth defects and developmental problems. To minimize this problem, reproductive cells have a quality control mechanism during meiosis called "crossover assurance", which limits how often mistakes occur. Zhang et al. have investigated how cells can tell if their chromosomes have accomplished this as they undergo meiosis. They looked at egg cells of the roundworm C. elegans, whose meiotic processes are similar to those in humans. In C. elegans, a protein called CHK-2 regulates many of the early events during meiosis. During successful meiosis, CHK-2 is active for only a short amount of time. But if there are problems during recombination, CHK-2 stays active for longer and prevents the cell division from proceeding. Zhang et al. uncovered another protein that affects for how long CHK-2 stays switched on. When chromosomes align with their partners, a protein called PLK-2 sticks to other proteins at the interface between the aligned chromosomes. A combination of microscopy and test tube experiments showed that when PLK-2 is bound to this specific location, it can turn off CHK-2. However, if the chromosome alignment fails, PLK-2 is not activated to switch off CHK-2. Therefore, CHK-2 is only switched off when the chromosomes are properly aligned and move on to the next step in crossing-over, which then allows meiosis to proceed. Thus, PLK-2 and CHK-2 work together to detect errors and to slow down meiosis if necessary. Further experiments in mammalian reproductive cells will reveal how similar the crossover assurance mechanism is in different organisms. In the future, improved understanding of quality control during meiosis may eventually lead to improvements in assisted reproduction.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Quinase do Ponto de Checagem 2/genética , Quinase do Ponto de Checagem 2/metabolismo , Pareamento Cromossômico , Meiose , Complexo Sinaptonêmico/metabolismoRESUMO
Obesity is one of the most prevalent chronic metabolic diseases, and induction of apoptosis in preadipocytes and adipocytes is a potential strategy to treat obesity. Celastrol represents one of the most robust anti-obesity phytochemicals so far, yet its direct binding target remains elusive. Here, we determined that celastrol could induce apoptosis in preadipocytes via mitochondrial mediated pathway. Further study clarified that celastrol inhibited the fusion of autophagosome and lysosome to prohibit autophagy, leading to cell apoptosis. By conducting virtual screening and genetic manipulation, we verified that overexpression of VAMP7 and RAB7 could block the effects of celastrol on inhibiting autophagy and inducing apoptosis. The Surface Plasmon Resonance study confirmed the direct binding of celastrol with VAMP7 and RAB7. The functional study illustrated the inhibition of RAB7 GTPase activity after celastrol treatment. Moreover, celastrol induced comparable apoptosis in murine epididymal adipose tissue, human preadipocytes and adipocytes, but not in human hepatocytes. An inhibitory effect on differentiation of human primary visceral preadipocytes was also observed. In conclusion, celastrol exhibited inhibitory effect of autophagy via direct binding with VAMP7 and RAB7, leading to an increase in preadipocytes apoptosis. These results advance our understanding in the potential application of celastrol in treating obesity.
RESUMO
Oogenesis involves transduction of mechanical forces from the cytoskeleton to the nuclear envelope (NE). In Caenorhabditis elegans, oocyte nuclei lacking the single lamin protein LMN-1 are vulnerable to collapse under forces mediated through LINC (linker of nucleoskeleton and cytoskeleton) complexes. Here, we use cytological analysis and in vivo imaging to investigate the balance of forces that drive this collapse and protect oocyte nuclei. We also use a mechano-node-pore sensing device to directly measure the effect of genetic mutations on oocyte nuclear stiffness. We find that nuclear collapse is not a consequence of apoptosis. It is promoted by dynein, which induces polarization of a LINC complex composed of Sad1 and UNC-84 homology 1 (SUN-1) and ZYGote defective 12 (ZYG-12). Lamins contribute to oocyte nuclear stiffness and cooperate with other inner nuclear membrane proteins to distribute LINC complexes and protect nuclei from collapse. We speculate that a similar network may protect oocyte integrity during extended oocyte arrest in mammals.
Assuntos
Proteínas de Caenorhabditis elegans , Membrana Nuclear , Animais , Caenorhabditis elegans/genética , Oogênese/genética , Oócitos , Núcleo Celular , Mamíferos , Laminina , Proteínas de Caenorhabditis elegans/genéticaRESUMO
Background: Aortic dissection (AD) is a serious aortic disease. Although current imaging methods can provide accurate diagnosis for AD, they do not include essential biological information. The aim of this study is to identify plasma metabolites for the risk and severity of type B AD (TBAD). Methods: In this cross-sectional study, we enrolled 16 hypertensive patients with TBAD and 7 hypertensive patients without TBAD in Jieyang People's Hospital between December 2021 and April 2022. After plasma metabolomics analysis, a metabolites risk score (MRS) model was conducted through logistic regression and least absolute shrinkage and selection operator (LASSO) regression to predict the risk of TBAD. Subsequently, TBAD group was divided into uncomplicated and complicated TBAD subgroups for further screening for metabolites related to the severity of TBAD. Results: Three metabolites, including 1,5-anhydro-D-glucitol, D-(+)-sucrose and PC(O-16:0/0:0) were related to the risk of TBAD. Compared to hypertensive patients without TBAD, the abundance of 1,5-anhydro-D-glucitol and D-(+)-sucrose were significantly increased while PC(O-16:0/0:0) was significantly reduced in hypertensive patients with TBAD (P<0.001). We subsequently built an MRS model based on these three metabolites. Furthermore, we found that hydrocinnamic acid (r=0.741, P<0.001) was independently correlated with the TBAD severity, while glycine deoxycholic acid (r=-0.538, P=0.008) and glycochenodeoxycholic acid (r=-0.538, P=0.008) were inversely correlated with the TBAD severity independently. Conclusions: The present study screened out three plasma metabolites associated with the risk of TBAD, constructed an MRS model, and identified three metabolites that were independently associated with the severity of TBAD. These findings may serve to identify more TBAD-related biomarkers and shed light on exploring potential mechanisms of TBAD.
RESUMO
Heteroepitaxial growth of high Al-content AlGaN often results in a high density of threading dislocations and surface hexagonal hillocks, which degrade the performance and reliability of AlGaN-based UVC light emitting diodes (LEDs). In this study, the degradation mechanism and impurity/defect behavior of UVC LEDs in relation to the hexagonal hillocks have been studied in detail. It was found that the early degradation of UVC LEDs is primarily caused by electron leakage. The prominent contribution of the hillock edges to the electron leakage is unambiguously evidenced by the transmission electron microscopy measurements, time-of-flight secondary ion mass spectrometry, and conductive atomic force microscopy. Dislocations bunching and segregation of impurities, including C, O, and Si, at the hillock edges are clearly observed, which facilitate the trap-assisted carrier tunneling in the multiple quantum wells and subsequent recombination in the p-AlGaN. This work sheds light on one possible degradation mechanism of AlGaN-based UVC LEDs.
RESUMO
During the early meiotic prophase, connections are established between chromosomes and cytoplasmic motors via a nuclear envelope bridge, known as a LINC (linker of nucleoskeleton and cytoskeleton) complex. These widely conserved links can promote both chromosome and nuclear motions. Studies in diverse organisms have illuminated the molecular architecture of these connections, but important questions remain regarding how they contribute to meiotic processes. Here, we summarize the current knowledge in the field, outline the challenges in studying these chromosome dynamics, and highlight distinctive features that have been characterized in major model systems.
Assuntos
Meiose , Microtúbulos , Cromossomos/genética , Citoesqueleto/genética , Meiose/genética , Microtúbulos/genética , Membrana Nuclear/genéticaRESUMO
Drug repositioning represents a cost- and time-efficient strategy for drug development. Here, we present a workflow of in silico screening of ACE2 enzymatic activators to treat COVID-19-induced metabolic complications. By using structure-based virtual screening and signature-based off-target effect identification via the Connectivity Map database, we provide a ranked list of the repositioning candidates as potential ACE2 enzymatic activators to ameliorate COVID-19-induced metabolic complications. The workflow can also be applied to other diseases with ACE2 as a potential target. For complete details on the use and execution of this protocol, please refer to Li et al. (2022).
Assuntos
COVID-19 , Enzima de Conversão de Angiotensina 2 , Ativadores de Enzimas , Ensaios de Triagem em Larga Escala , Humanos , SARS-CoV-2RESUMO
Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.
Assuntos
Tratamento Farmacológico da COVID-19 , Mesilato de Imatinib/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Metazolamida/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/complicações , COVID-19/metabolismo , COVID-19/virologia , Células Cultivadas , Chlorocebus aethiops , Regulação para Baixo/efeitos dos fármacos , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/virologia , Metazolamida/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , SARS-CoV-2/fisiologia , Células Vero , Internalização do Vírus/efeitos dos fármacosRESUMO
Background Although glycoursodeoxycholic acid (GUDCA) has been associated with the improvement of metabolic disorders, its effect on atherosclerosis remains elusive. This study aimed to investigate the role of GUDCA in the development of atherosclerosis and its potential mechanisms. Methods and Results Human THP-1 macrophages were used to investigate the effect of GUDCA on oxidized low-density lipoprotein-induced foam cell formation in vitro. We found that GUDCA downregulated scavenger receptor A1 mRNA expression, reduced oxidized low-density lipoprotein uptake, and inhibited macrophage foam cell formation. In an in vivo study, apolipoprotein E-deficient mice were fed a Western diet for 10 weeks to induce atherosclerosis, and then were gavaged once daily with or without GUDCA for 18 weeks. Parameters of systemic metabolism and atherosclerosis were detected. We found that GUDCA improved cholesterol homeostasis and protected against atherosclerosis progression as evidenced by reduced plaque area along with lipid deposition, ameliorated local chronic inflammation, and elevated plaque stability. In addition, 16S rDNA sequencing showed that GUDCA administration partially normalized the Western diet-associated gut microbiota dysbiosis. Interestingly, the changes of bacterial genera (Alloprevotella, Parabacteroides, Turicibacter, and Alistipes) modulated by GUDCA were correlated with the plaque area in mice aortas. Conclusions Our study for the first time indicates that GUDCA attenuates the development of atherosclerosis, probably attributable to the inhibition of foam cell formation, maintenance of cholesterol homeostasis, and modulation of gut microbiota.