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ETHNOPHARMACOLOGICAL RELEVANCE: Microcirculatory dysfunction is one of the main characteristics of sepsis. Shenfu Injection (SFI) as a traditional Chinese medicine is widely applied in clinical severe conditions. Recent studies have shown that SFI has the ability to ameliorate sepsis-induced inflammation and to improve microcirculation perfusion. AIM OF THE STUDY: This study aims to investigate the underlying mechanism of SFI for ameliorating sepsis-associated endothelial dysfunction and organ injury. MATERIALS AND METHODS: Side-stream dark-field (SDF) imaging was used to monitor the sublingual microcirculation of septic patients treated with or without SFI. Septic mouse model was used to evaluate the effects of SFI in vivo. Metabolomics and transcriptomics were performed on endothelial cells to identify the underlying mechanism for SFI-related protective effect on endothelial cells. RESULTS: SFI effectively abolished the disturbance and loss of sublingual microcirculation in septic patients. Twenty septic shock patients with or without SFI administration were enrolled and the data showed that SFI significantly improved the levels of total vessel density (TVD), perfused vessel density (PVD), microvascular flow index (MFI), and the proportion of perfused vessels (PPV). The administration of SFI significantly decreased the elevated plasma levels of Angiopoietin-2 (Ang2) and Syndecan-1, which are biomarkers indicative of endothelial damage in sepsis patients. In the mouse septic model in vivo, SFI inhibited the upregulation of endothelial adhesion molecules and Ly6G + neutrophil infiltration while restored the expression of VE-Cadherin in the vasculature of the lung, kidney, and liver tissue. Additionally, SFI reduced the plasma levels of Ang2, Monocyte Chemoattractant Protein-1(MCP1), and Interleukin-6 (IL6), and alleviated liver and kidney injury in septic mice. Moreover, SFI significantly inhibited the inflammatory activation and increased permeability of endothelial cells induced by endotoxins in vitro. By performing metabolomics and transcriptomics, we identified the activation of PI3K/Akt-mediated glycolysis as the underlying mechanism for SFI-related protective effect on endothelial cells. CONCLUSIONS: Our findings revealed that SFI may improve microcirculation perfusion and endothelial function in sepsis via inhibiting PI3K/Akt-mediated glycolysis, providing theoretical evidence for the clinical application of SFI.

Asunto(s)

Medicamentos Herbarios Chinos , Glucólisis , Proteínas Proto-Oncogénicas c-akt , Animales , Medicamentos Herbarios Chinos/farmacología , Humanos , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Glucólisis/efectos de los fármacos , Microcirculación/efectos de los fármacos , Endotoxemia/tratamiento farmacológico , Ratones Endogámicos C57BL , Femenino , Fosfatidilinositol 3-Quinasas/metabolismo , Persona de Mediana Edad , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Anciano , Transducción de Señal/efectos de los fármacos

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INTRODUCTION: Cetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated. OBJECTIVE: Our study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity. METHODS: Through mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo. RESULTS: Stat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo. CONCLUSION: Our study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.

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We aimed to explore the association between epidural-related maternal fever (ERMF) and prognosis of parturients. 159 parturients who underwent vaginal delivery under labor epidural analgesia (LEA) received noninvasive continuous core body temperature monitoring. 122 of them completed the 42-day postpartum follow-up. Parturients with body temperature ≥38°C during labor were categorized as the Fever group, while the others were categorized as the No-Fever group. Compared to No-Fever group, Fever group had a greater proportion of primiparas, greater gestational age of parturients, and longer third stage of labor. The cesarean section and forceps delivery rates, and the amount of intrapartum hemorrhage in Fever group were significantly higher. There were no significant between-group differences with respect to puerperal infection, and amniotic fluid turbidity degree, neither significant between-group difference at 42-days postpartum. We found that ERMF was associated with some short-term outcomes. However, it showed no relation with long-term prognosis of the parturients at 42-days postpartum.

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Unsupervised image hashing has recently gained significant momentum due to the scarcity of reliable supervision knowledge, such as class labels and pairwise relationship. Previous unsupervised methods heavily rely on constructing sufficiently large affinity matrix for exploring the geometric structure of data. Nevertheless, due to lack of adequately preserving the intrinsic information of original visual data, satisfactory performance can hardly be achieved. In this article, we propose a novel approach, called bidirectional discrete matrix factorization hashing (BDMFH), which alternates two mutually promoted processes of 1) learning binary codes from data and 2) recovering data from the binary codes. In particular, we design the inverse factorization model, which enforces the learned binary codes inheriting intrinsic structure from the original visual data. Moreover, we develop an efficient discrete optimization algorithm for the proposed BDMFH. Comprehensive experimental results on three large-scale benchmark datasets show that the proposed BDMFH not only significantly outperforms the state-of-the-arts but also provides the satisfactory computational efficiency.