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OBJECTIVE: Aortic dissection (AD) is a prevalent and acute clinical catastrophe characterized by abrupt manifestation, swift progression, and elevated fatality rates. Despite smoking being a significant risk factor for AD, the precise pathological process remains elusive. This investigation endeavors to explore the mechanisms by which smoking accelerates AD through ferroptosis induction. METHODOLOGY: In this novel study, we detected considerable endothelial cell death by ferroptosis within the aortic inner lining of both human AD patients with a smoking history and murine AD models induced by ß-aminopropionitrile, angiotensin II, and nicotine. Utilizing bioinformatic approaches, we identified microRNAs regulating the expression of the ferroptosis inhibitor Glutathione peroxidase 4 (GPX4). Nicotine's impact on ferroptosis was further assessed in human umbilical vein endothelial cells (HUVECs) through modulation of miR-1909-5p. Additionally, the therapeutic potential of miR-1909-5p antagomir was evaluated in vivo in nicotine-exposed AD mice. FINDINGS: Our results indicate a predominance of ferroptosis over apoptosis, pyroptosis, and necroptosis in the aortas of AD patients who smoke. Nicotine exposure instigated ferroptosis in HUVECs, where the miR-1909-5p/GPX4 axis was implicated. Modulation of miR-1909-5p in these cells revealed its regulatory role over GPX4 levels and subsequent endothelial ferroptosis. In vivo, miR-1909-5p suppression reduced ferroptosis and mitigated AD progression in the murine model. CONCLUSIONS: Our data underscore the involvement of the miR-1909-5p/GPX4 axis in the pathogenesis of nicotine-induced endothelial ferroptosis in AD.
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Disección Aórtica , Ferroptosis , Células Endoteliales de la Vena Umbilical Humana , MicroARNs , Nicotina , Fosfolípido Hidroperóxido Glutatión Peroxidasa , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Animales , Ferroptosis/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ratones , Nicotina/farmacología , Nicotina/toxicidad , Disección Aórtica/inducido químicamente , Disección Aórtica/metabolismo , Disección Aórtica/genética , Masculino , Ratones Endogámicos C57BL , Femenino , Progresión de la EnfermedadRESUMEN
The identification of interaction between protein and ligand including binding positions and strength plays a critical role in drug discovery. Molecular docking and molecular dynamics (MD) techniques have been widely applied to predict binding positions and binding affinity. However, there are few works that describe the systematic exploration of the MD trajectory evolution in this context, potentially leaving out important information. To address the problem, we build a framework, Moira (molecular dynamics trajectory analysis), which enables automating the whole process ranging from docking, MD simulations and various analyses as well as visualizations. We utilized Moira to analyze 400 MD simulations in terms of their geometric features (root mean square deviation and protein-ligand interaction profiler) and energetics (molecular mechanics Poisson-Boltzmann surface area) for these trajectories. Finally, we demonstrate the performance of different analysis techniques in distinguishing native poses among four poses.
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Simulación de Dinámica Molecular , Proteínas , Ligandos , Simulación del Acoplamiento Molecular , Proteínas/química , Descubrimiento de Drogas , Unión ProteicaRESUMEN
Open abdomen (OA) is an effective method for treating critical abdominal conditions such as severe abdominal infections. The temporary abdominal closure (TAC) technique is often used to temporarily restore the physiological environment of the abdominal cavity and maintain the homeostatic balance of the abdominal cavity. However, most of the common TAC materials available today lack bio-responsiveness, tend to abrade the intestinal canal, and lead to delayed tissue healing of the wound. Hydrogels could mimic the extracellular matrix and have shown significant potential in life science fields such as tissue regeneration, wound repair, and controlled drug release. In this study, a composite hydrogel scaffold was constructed by the Schiff base reaction of oxidized pullulan polysaccharide with carboxymethyl chitosan. The hydrogel exhibited excellent self-healing, cellular biocompatibility, and antibacterial and anti-inflammatory abilities, and in experiments it reduced secondary damage caused by friction between tissue and patch, thereby preventing serious complications such as intestinal fistula, promoted M1-M2 polarization of macrophages, reduced the inflammatory response, regulated the inflammatory microenvironment in vivo, promoted angiogenesis and granulation tissue regeneration, and accelerated wound healing. Therefore, our hydrogel provides a new strategy for material-assisted wound protection during OA and has potential clinical applications.
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It is hard to directly deploy deep learning models on today's smartphones due to the substantial computational costs introduced by millions of parameters. To compress the model, we develop an â0-based sparse group lasso model called MobilePrune which can generate extremely compact neural network models for both desktop and mobile platforms. We adopt group lasso penalty to enforce sparsity at the group level to benefit General Matrix Multiply (GEMM) and develop the very first algorithm that can optimize the â0 norm in an exact manner and achieve the global convergence guarantee in the deep learning context. MobilePrune also allows complicated group structures to be applied on the group penalty (i.e., trees and overlapping groups) to suit DNN models with more complex architectures. Empirically, we observe the substantial reduction of compression ratio and computational costs for various popular deep learning models on multiple benchmark datasets compared to the state-of-the-art methods. More importantly, the compression models are deployed on the android system to confirm that our approach is able to achieve less response delay and battery consumption on mobile phones.
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Compresión de Datos , Redes Neurales de la Computación , Algoritmos , Fenómenos FísicosRESUMEN
Emerging evidence suggests that majority of the transfer RNA (tRNA)-derived small RNA, including tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), play a significant role in the molecular mechanisms underlying some human diseases. However, expression of tRFs/tiRNAs and their potential roles in aortic dissection (AD) remain unclear. This study examined the expression characteristics and explored the functional roles of tRFs/tiRNAs in AD using RNA-sequencing, bioinformatics, real-time quantitative reverse transcription polymerase chain reaction, and loss- and gain-of-function analysis. Results revealed that a total of 41 tRFs/tiRNAs were dysregulated in the AD group compared to the control group. Among them, 12 were upregulated and 29 were downregulated (fold change≥1.5 and p < 0.05). RT-qPCR results revealed that expressions of tRF-1:30-chrM.Met-CAT was significantly upregulated, while that of tRF-54:71-chrM.Trp-TCA and tRF-1:32-chrM.Cys-GCA were notably downregulated; expression patterns were consistent with the RNA sequencing data. Bioinformatic analysis showed that a variety of related pathways might be involved in the pathogenesis of AD. Functionally, tRF-1:30-chrM.Met-CAT could facilitate proliferation, migration, and phenotype switching in vascular smooth muscle cells (VSMCs), which might serve as a significant regulator in the progression of AD. In summary, the study illustrated that tRFs/tiRNAs expressed in AD tissues have potential biological functions and may act as promising biomarkers or therapeutic targets for AD.
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Disección Aórtica , ARN de Transferencia , Disección Aórtica/genética , Biomarcadores , Biología Computacional , Humanos , ARN de Transferencia/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
There is still a lack of relevant studies on surgical site infection (SSI) after emergency abdominal surgery (EAS) in China. This study aims to understand the incidence of SSI after EAS in China and discuss its risk factors. All adult patients who underwent EAS in 47 hospitals in China from May 1 to 31, 2018, and from May 1 to June 7, 2019, were enrolled in this study. The basic information, perioperative data, and microbial culture results of infected incision were prospectively collected. The primary outcome measure was the incidence of SSI after EAS, and the secondary outcome variables were postoperative length of stay, ICU admission rate, ICU length of stay, 30-day postoperative mortality, and hospitalization cost. Univariate and multivariate logistic regression were used to analyze the risk factors. The results were expressed as the odds ratio and 95% confidence interval. A total of 953 patients [age 48.8 (SD: 17.9), male 51.9%] with EAS were included in this study: 71 patients (7.5%) developed SSI after surgery. The main pathogen of SSI was Escherichia coli (culture positive rate 29.6%). Patients with SSI had significantly longer overall hospital (p < 0.001) and ICU stays (p < 0.001), significantly higher ICU admissions (p < 0.001), and medical costs (p < 0.001) than patients without SSI. Multivariate logistic regression analysis showed that male (P = 0.010), high blood glucose level (P < 0.001), colorectal surgery (P < 0.001), intestinal obstruction (P = 0.045) and surgical duration (P = 0.007) were risk factors for SSI, whereas laparoscopic surgery (P < 0.001) was a protective factor. This study found a high incidence of SSI after EAS in China. The occurrence of SSI prolongs the patient's hospital stay and increases the medical burden. The study also revealed predictors of SSI after EAS and provides a basis for the development of norms for the prevention of surgical site infection after emergency abdominal surgery.
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Abdomen/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Laparoscopía/métodos , Adulto , Anciano , China/epidemiología , Femenino , Humanos , Incidencia , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Long intergenic noncoding RNAs (lincRNAs) regulate a series of biological processes, and their anomalous expression plays critical roles in the progression of multiple malignancies, including colorectal cancer (CRC). Although many studies have reported the oncogenic function of LINC00665 in multiple cancers, few studies have explored its role in CRC. The aim of this study was to assess the effect of LINC00665 on the malignant behaviors of CRC and explore the underlying regulatory mechanism of LINC00665. LINC00665 was significantly upregulated in CRC. A loss-of-function assay revealed that LINC00665 downregulation inhibited the proliferation and promoted the apoptosis of CRC cells, which was mediated by cyclin D1, CDK4, caspase-9 and caspase-3. Through mechanistic exploration, we found that miR-126-5p directly bound to LINC00665. Moreover, LINC00665 and miR-126-5p both regulated PAK2 and FZD3 expression. Mechanistically, miR-126-5p was predicted and further verified as a target of both PAK2 and FZD3. These findings demonstrate that LINC00665 might play an important pro-proliferative and antiapoptotic role in CRC and might be a potential biomarker and a new therapeutic target for CRC.
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Apoptosis/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Unión Proteica , Regulación hacia Arriba/genética , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismoRESUMEN
Inflammation and endothelial dysfunction are important participants and drivers in atherosclerosis. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation and the resulting pyroptosis are involved in the initiation and vicious circle of chronic inflammation, thus playing an indispensable role in atherosclerosis. Accordingly, blocking the activation of NLRP3 inflammasome may be a promising treatment strategy to blunt the progression of atherosclerosis. In this study, it was demonstrated that miR-302c-3p exerted anti-pyroptosis effects by directly targeting NLRP3 in vivo and in vitro. In brief, the expression of miR-302c-3p was down-regulated whereas the expression of NLRP3 was up-regulated in human plaques and in vitro pyroptosis model of endothelial cells. Overexpression of miR-302c-3p suppressed endothelial cell pyroptosis by targeting specific sites of NLRP3. By comparison, down-regulation of endogenous miR-302c-3p led to the opposite results, which were reversed by silencing the expression of NLRP3. Finally, the up-regulation of miR-302c-3p inhibited the inflammation and pyroptosis of atherosclerosis mouse model. In conclusion, miR-302c-3p may be a powerful and attractive target for suppressing endothelial inflammation and pyroptosis, providing a novel strategy for preventing or alleviating the progression of atherosclerosis.
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Células Endoteliales/patología , Regulación de la Expresión Génica , Inflamasomas , MicroARNs/genética , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Piroptosis , Animales , Apoptosis , Movimiento Celular , Proliferación Celular , Células Cultivadas , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
Prosthetic materials are widely used for temporary abdominal closure after open abdomen (OA), but local adhesion, erosion and fistula formation caused by current materials seriously affect the quality of life of patients. Recently, a three-dimensional porous network structure hydrogel has been used to simulate cell extracellular matrix that can support cell growth and tissue regeneration. In this study, we prepared an interpenetrating double-network hydrogel by photoinitiating glycidyl methacrylate-conjugated xanthan (XG) and 4-arm polyethylene glycol thiol (TPEG). This double-network hydrogel combined stiffness and deformation ability as well as in situ forming property, which could coat polypropylene (PP) mesh to reduce friction to wound tissues. Moreover, this double-network hydrogel exhibited a denser porous structure that controlled drug release without initial outburst. When testing the hydrogel-coated growth factor-loaded PP mesh on a rat model of OA, it was found that this composite material could reduce inflammation and promote granulation tissue growth. Therefore, our design provides a new strategy of material-assisted wound protection of OA and shows potential clinical applications.
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Gastric cancer is an aggressive disease and a common cause of cancerassociated mortality worldwide. Recent studies have indicated that follistatinlike protein 1 (FSTL1) is expressed and serves essential roles in tumorigenesis; however, the specific functional mechanism of FSTL1 in gastric cancer progression remains ambiguous. CellTiterGlo Luminescent Cell Viability and lactate dehydrogenase assays were used to measure cell survival and cell cytotoxicity, respectively. Cell apoptosis was ascertained using the Cell Death Detection ELISA assay and caspase3/9 activity kits. Reverse transcriptionquantitative polymerase chain reaction and western blotting were used to detect the expression levels of FSTL1. The present study confirmed that FSTL1 was highly expressed in gastric cancer cells compared with in control cells. Subsequently, FSTL1 inhibition by small interfering RNA significantly reduced cancer cell survival and induced cytotoxic effects. In addition, knockdown of FSTL1 in gastric cancer cells promoted apoptosis by increasing caspase3 and caspase9 expression. A decrease in signal transducer and activator of transcription 6 (STAT6) phosphorylation was observed in FSTL1 knockdown cells, and the results confirmed that STAT6 phosphorylation was essential for FSTL1 knockdowninduced cell apoptosis of cancer cells. Taken together, these results demonstrated that FSTL1 knockdown may promote cell apoptosis via the STAT6 signaling pathway; therefore, FSTL1 may be considered a novel diagnostic and therapeutic target for gastric cancer.
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Apoptosis/genética , Proteínas Relacionadas con la Folistatina/genética , Factor de Transcripción STAT6/genética , Neoplasias Gástricas/genética , Carcinogénesis/genética , Caspasa 3/genética , Caspasa 9/genética , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Ensayo de Inmunoadsorción Enzimática , Proteínas Relacionadas con la Folistatina/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Humanos , ARN Interferente Pequeño/genética , Transducción de Señal/genética , Neoplasias Gástricas/patologíaRESUMEN
Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients' poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A), or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat.
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Carcinoma Hepatocelular/patología , Ácidos Hidroxámicos/farmacología , Neoplasias Hepáticas/patología , Morfolinas/farmacología , Sulfonamidas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Benzamidas , Sinergismo Farmacológico , Silenciador del Gen , Células Hep G2 , Humanos , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Poro de Transición de la Permeabilidad Mitocondrial , Mutación , Pirimidinas , Serina-Treonina Quinasas TOR/genéticaRESUMEN
BACKGROUND: The aim of this randomized controlled study was to determine whether octreotide (OCT) or scopolamine butylbromide (SB) was the more effective antisecretive drug controlling gastrointestinal (GI) symptoms due to malignant bowel obstruction (MBO) caused by advanced ovarian cancer. METHODS: Ninety-seven advanced ovarian cancer patients with inoperable MBO were randomized to OCT 0.3 mg/day (OCT group, n = 48) or SB 60 mg/day (SB group, n = 49) for 3 days through a continuous subcutaneous infusion. The following parameters were measured: episodes of vomiting, nausea, dry mouth, drowsiness, and continuous and colicky pain, using a Likert scale corresponding to a numerical value (none 0, slight 1, moderate 2, severe 3) recorded before starting the treatment (T0) and 24 h (T1), 48 h (T2), and 72 h after (T3) and the daily quantity of GI secretions through the Nasogastric tube (NGT) during the period of study. One patient in the SB group is not included in any assessments since she withdrew consent prior to receiving any treatment because of rapidly progressing cancer. RESULTS: OCT significantly reduced the amount of GI secretions at T1, T2, and T3 (P < 0.05) compared with SB. NGT secretions significantly reduced at T1, T2, and T3 compared with T0 (P < 0.05) in the OCT group, while in the SB group, only at T3, NGT secretions significantly reduced compared with T0. OCT treatment induced a significantly rapid reduction in the number of daily episodes of vomiting and intensity of nausea compared with SB treatment. No significant changes were observed in dry mouth, drowsiness, and colicky pain after either drug. Continuous pain values were significantly lower in the OCT group than in the SB group at T2 and T3 (P < 0.05). CONCLUSIONS: At the doses used in this study, OCT was more effective than SB in controlling gastrointestinal symptoms of bowel obstruction. Further studies are necessary to understand the role of hydration more clearly in such a clinical situation.
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Bromuro de Butilescopolamonio/uso terapéutico , Obstrucción Intestinal/tratamiento farmacológico , Neoplasias Hepáticas/complicaciones , Octreótido/uso terapéutico , Neoplasias Ováricas/complicaciones , Neoplasias Peritoneales/complicaciones , Neoplasias Pleurales/complicaciones , Femenino , Estudios de Seguimiento , Fármacos Gastrointestinales/uso terapéutico , Humanos , Obstrucción Intestinal/etiología , Neoplasias Hepáticas/secundario , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Parasimpatolíticos/uso terapéutico , Neoplasias Peritoneales/secundario , Neoplasias Pleurales/secundario , Pronóstico , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To explore the diagnostic value of combined modified Alvarado scores (MAS) and computed tomography imaging in the pathological types of acute appendicitis in adults. METHODS: Clinical data of a total of 396 adult patients with acute appendicitis confirmed by surgery and pathology were analyzed retrospectively from June 2007 to July 2010. Case-control study was used to investigate the MAS. CT signs were studied in 115 patients who underwent preoperative CT scan. Univariable analysis was performed using each indicator among different pathological types. Discriminant classification was formed by applying significant variables identified from univariable analysis and a Fisher discriminant function was created. RESULTS: Twenty three variables were statistically significant among different pathological types after univariable analysis(P<0.05) and were selected for discriminant analysis. Six variables including temperature(X1), leucocyte count(X2), the proportion of neutrophil(X3), MAS points(X4), periappendiceal fat stranding(X5), and extraluminal air(X6) were enrolled. The discriminant function equation was Y1=0.012X1+0.041X2+0.069X3-0.039X4+2.653X5+1.418X6, Y2=0.327X1+0.041X2-0.034X3-0.140X4-1.114X5+2.982X6. The accuracy was 76.5%(88/115) in retrospective assessment and 77.8%(21/27) in prospective assessment. CONCLUSION: The combined use of MAS and CT imaging signs is useful in identifying the pathological types of acute appendicitis in adults, so it is helpful in choosing reasonable therapeutic option for surgeons.
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Apendicitis/diagnóstico , Enfermedad Aguda , Estudios de Casos y Controles , Humanos , Estudios Retrospectivos , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Acute pancreatitis, especially acute necrotizing pancreatitis (ANP), is a serious disease with a high morbidity because of multiorgan dysfunction. Recent studies have indicated that during the pathogenesis of ANP, changes of the microcirculation play an important role in the worsening of the disease. This study based on a model of acute pancreatitis in Wistar rats was to determine the effect of treatment with low-dose dopamine on acute pancreatitis by the dynamic measurement of serum levels of inflammatory factors IL-6 and TNF-alpha. METHODS: Fifty Wistar rats were randomly divided into two groups, and a model of ANP was set up by injecting sodium taurocholate into the pancreatic duct. Rats in the dopamine group (treatment group) were given dopamine by vein and those in the acute pancreatitis group (control group) were given normal saline. To assess the effect of low-dose dopamine (5 mug.kg-1.min-1) on induced acute pancreatitis, the antibody sandwich ELISA method was used to measure the serum levels of IL-6 and TNF-alpha at different times before and after the induction of ANP. RESULTS: The serum levels of IL-6 and TNF-alpha in the treatment and control groups before and after ANP induction were significantly different. There was a markedly significant difference in the comparison of the two groups after ANP induction (P<0.01), but no significant difference in the comparison before the induction (P>0.05). Postoperative pancreatic histopathologic changes in the treatment group were more marked than those in the control group. CONCLUSIONS: Low-dose dopamine is effective in treating ANP by alleviating inflammatory reactions. This effect may be related to the fact that low-dose dopamine not only can increase the blood flow of the pancreatic microcirculation but also reduce its permeability.