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1.
Cancer Lett ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32145343

RESUMO

To demonstrate multifaceted contribution of aspartate ß-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's ß-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps<0.001; Cox proportional hazards regression, P<0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

2.
BMC Gastroenterol ; 20(1): 59, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143645

RESUMO

BACKGROUND: The gut microbiota participates in the metabolism of substances and energy, promotes the development and maturation of the immune system, forms the mucosal barrier, and protects the host from pathogen attacks. Although the pathogenesis of cholesterol gallstones is still not clear, studies have suggested that gut microbiota dysbiosis plays an important role in their formation. METHODS: Microbial DNA from faeces of normal control patients and those of patients with calculi was subjected to 16S rRNA gene sequencing to detect gene expression changes in intestinal microbes. ELISA kits were used to measure free bile acids, secondary bile acids and coprostanol according to the manufacturer's instructions. The relationship between flora and their metabolites was then analysed. RESULTS: In the gallstone group, the diversity of intestinal bacteria and the abundances of certain phylogroups were significantly decreased (p < 0.05), especially Firmicutes (p < 0.05), the largest phylum represented by the gut microbiota. This study found an increase in free bile acids (p < 0.001) and secondary bile acids (p < 0.01) in the enterohepatic circulation. Bile salt hydrolase activity was not related to the abundances of BSH-active bacteria. 7a-dehydroxylating gut bacteria were significantly increased (p < 0.01), whereas cholesterol-lowering bacteria were significantly reduced (p < 0.05). The Ruminococcus gnavus group could be used as a biomarker to distinguish the gallstone group from the control group. CONCLUSION: We conclude that intestinal flora imbalance affects bile acid and cholesterol metabolism and is associated with gallstone formation.

3.
Cell Death Dis ; 11(2): 88, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015325

RESUMO

Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.

4.
Int J Biol Sci ; 16(3): 529-542, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32015688

RESUMO

Hyperuricemia (HUA) is a metabolic disease characterized by elevated serum uric acid (SUA). Empagliflozin, a kind of sodium-glucose cotransporter 2 inhibitors, has recently emerged as a new antidiabetic agent by facilitating glucose excretion in urine. Moreover, there was evidence of SUA reduction following treatment with empagliflozin in addition to glycaemic control, while the molecular mechanisms remain unknown. To investigate the potential mechanisms, the model of type 2 diabetes (T2DM) with HUA was established by combination of peritoneal injection of potassium oxonate and intragastric administration of hypoxanthine in KK-Ay mice. A series of method such as RT-PCR, western blot, immunochemistry, immunofluorescence were conducted to explore the mechanism. Our results showed that empagliflozin significantly ameliorated the levels of SUA and blood glucose in T2DM mice with HUA. Furthermore, in both kidney and ileum, empagliflozin obviously promoted protein expression of uric acid (UA) transporter ABCG2, p-AMPK, p-AKT and p-CREB. The same trend was observed in human tubular epithelial (HK-2) cells. Additionally, through application of an AMPK inhibitor (Compound C), it was further confirmed empagliflozin exerted its anti-hyperuricemic effects in an AMPK dependent manner. Meanwhile, with the help of ChIP assay and luciferase reporter gene assay, we found that CREB further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Taken together, our study demonstrated that empagliflozin treatment played an essential role in attenuating HUA by upregulation of ABCG2 via AMPK/AKT/CREB signaling pathway.

5.
Pancreas ; 49(2): 290-299, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32011537

RESUMO

OBJECTIVES: To study the role of kinase inhibitor PD98059 on autophagy flow in the process of trypsinogen activation in pancreatic acinar cell and its related mechanism. METHODS: In the present study, bioinformatics analysis was used to predict kinases and their most relevant inhibitor (PD98059) which participates in autophagy of acute pancreatitis (AP). The rat pancreatic acini AR42J cells were divided into 4 groups: control group, sodium taurocholate hydrate (TLC) group, PD98059 group, and TLC + PD group. Twenty-seven Sprague-Dawley rats were divided into 3 groups (n = 9), including control group, severe AP (SAP) group, and SAP + PD group. We detected trypsinogen activation, autophagic activation, lysosome pH, and cathepsin-L activity in vivo and in vitro. RESULTS: Results revealed trypsinogen activation was significantly inhibited in mitogen-activated protein kinase 1, JAK2, LYN, and their common inhibitor was PD98059. The trypsinogen activation, Beclin1, and light chain 3 II expressions were reduced, whereas the expressions of lysosomal-associated membrane protein 2, cathepsin L1, and cathepsin-L activity is upregulated after the PD98059 pretreatment, both in vivo and in vitro. CONCLUSIONS: Lysosomal dysfunction blocked autophagy flux, accompanied by increasing pancreatic acinar cell autophagy in the process of trypsinogen activation. PD98059 inhibited AP occurrence and pancreatic injury via improving the blocked autophagic pathway and reducing trypsinogen activation.

6.
Medicine (Baltimore) ; 99(6): e19033, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028417

RESUMO

BACKGROUND: Zaoren Anshen capsules (ZRAS) have been widely used to treat patients with insomnia. However, the efficacy and safety of ZRAS for insomnia treatment is not entirely clear. Therefore, it is necessary to clarify the effect of ZRAS for the treatment of insomnia by a systematic meta-analysis. METHODS: We searched PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and WanFang databases and performed a manual search to retrieve relevant articles (available through January 2019) describing randomized controlled trials (RCTs) of ZRAS for the treatment of insomnia. The quality of the selected articles was assessed with the Cochrane risk-of-bias tool. A meta-analysis of the selected articles was performed with RevMan 5.3 software. RESULTS: A total of 13 articles including 1175 patients were included in the study. Overall, our results showed that ZRAS was slightly higher than that of the conventional Western medicine for insomnia in terms of clinical efficacy rate; but there was no statistical difference between the 2 groups (relative risk [RR] = 1.03, 95% confidence interval [CI] = [0.97, 1.09], P = .34). However, it should be noted that ZRAS treatment causes far fewer adverse reaction than treatment with conventional Western medicine (RR = 0.20, 95% CI = [0.14, 0.28], P < .00001). CONCLUSION: Our results suggested that ZRAS is an effective and safe treatment for insomnia, especially in adverse reaction. However, multi-regional and well-designed RCTs studies are needed in the future to validate the results.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Cápsulas , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
FASEB J ; 34(2): 2524-2540, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31908026

RESUMO

The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.

8.
Ying Yong Sheng Tai Xue Bao ; 30(12): 4249-4258, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31840471

RESUMO

According to the fishery resources investigation data in the east of the Nanji Islands during autumn in 2017 and spring in 2018, the inter-specific relationships and ecological relationships between major nekton were analyzed via the index of relative importance, niche breadth, cluster analysis, niche overlap, χ2-test, variance ratio test, association coefficient, percentage of co-occurrence, and point correlation coefficients. The results showed that there were 30 major nekton species in this area. The dominant species were Harpadon nehereus, Portunus trituberculatus, and Oratosquilla oratoria. The niche width of these dominant species was relatively wide. Based on the cluster analysis of niche breadth, the 30 major nekton species could be divided into three categories, wide niche breadth species, moderate niche breath species, and narrow niche breath species. The distribution range of niche overlap value was [0, 0.98], indicating that there were differences in the similarity of species to resource utilization and that the niche was differentiated and accompanied by inter-specific competition. The values of VR and W showed that there was a significant positive correlation among the major nekton species. The χ2-test results indicated significantly interspecific association for 76 species pair (χ2≥3.841), which was related to community stability and species coexistence. Results of association coefficient, percentage of co-occurrence and point correlation coefficients test suggested that the interspecific association was strong and tended to be positive.


Assuntos
Ecossistema , Pesqueiros , Animais , Peixes , Ilhas , Estações do Ano
9.
Zhongguo Zhong Yao Za Zhi ; 44(22): 4912-4917, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31872600

RESUMO

The aim of this paper was to observe the effect of triptolide( TP) on cardiovascular function and its possible mechanism by intraperitoneal injection of bacterial lipopolysaccharide in rats with endotoxemia. Sixty male Sprague-Dawley rats were randomly divided intonormal group( NC group),endotoxemia model group( LPS group),TP low concentration intervention group( LPS + TP-L group,25 µg·kg~(-1)),TP middle concentration intervention group( LPS+TP-M group,50 µg·kg~(-1)),TP high concentration intervention group( LPS+TP-H group,100 µg·kg~(-1)) and polymyxin B group( LPS+PMX-B group,0. 2 mg·kg~(-1)). 10 mg·kg~(-1) LPS was injected intraperitoneally for 6 h to replicate the endotoxemia rat model. The rats in TP intervention groups were pre-treated 15 min before intraperitoneal injection of LPS. Rats in each group underwent total arterial intubation to measure hemodynamic parameters: heart rate( HR),left ventricular diastolic pressure( LVDP),the maximum rate of the increase/decrease of left ventricular pressure( ±dp/dtmax). The levels of BNP,CK-MB and c Tn-Ⅰ in serum and levels of TNF-α and IL-6 in plasma were detected by ELISA. The contents of p65 protein in myocardium and contents of p65,TLR4,i NOS and e NOS protein in thoracic aorta were detected by Western blot. As compared with NC group,the hemodynamic indexes in LPS group were significantly decreased; the contents of BNP,CK-MB and c Tn-Ⅰ in serum,TNF-α and IL-6 in plasma,p65 in myocardium,i NOS,e NOS,TLR4 and p65 in vascular tissues were significantly increased. As compared with LPS group,the hemodynamic indexes were significantly improved in LPS+TP-M group,LPS+TP-H group and LPS+PMX-B group; the contents of BNP,CK-MB and c Tn-Ⅰ in serum,TNF-α and IL-6 in plasma,p65 in myocardium,i NOS,e NOS,TLR4 and p65 in vascular tissues were significantly decreased in each treatment group. Triptolide has a protective effect on cardiovascular damage in a dose-dependent manner in endotoxemia rats,probably through TLR4/NF-κB p65 signaling pathway to improve endothelial function.


Assuntos
Diterpenos/farmacologia , Endotoxemia , Fenantrenos/farmacologia , Substâncias Protetoras/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Endotélio , Compostos de Epóxi/farmacologia , Lipopolissacarídeos , Masculino , NF-kappa B , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Necrose Tumoral alfa
10.
Mol Cancer ; 18(1): 156, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31694640

RESUMO

BACKGROUND: Aspartate ß-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. METHODS: Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. RESULTS: Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH's ß-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. CONCLUSIONS: ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH's pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.

11.
Life Sci ; 239: 117020, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678553

RESUMO

AIMS: Obstructive sleep apnea (OSA) combined with type 2 diabetes (T2DM) may lead to cognitive dysfunction. We previously reported that cognitive impairment is exacerbated in KKAy mice exposed to intermittent hypoxia (IH), during which the DNA binding protein HMGB1 mediates hippocampal neuronal apoptosis by maintaining microglia-associated neuroinflammation, but the underlying mechanism remains largely unknown. MATERIALS AND METHODS: We performed immunofluorescence, Western blotting, and immunohistochemistry experiments in mouse hippocampal tissues and HT22 cells. KKAy type 2 diabetes model mice and normal C57BL/6J mice were exposed to IH or intermittent normoxia. HT22 cells were cultured in high glucose medium and exposed to IH or intermittent normoxia. We transfected HMGB1 siRNA into HT22 cells and then treated them with high glucose combined with intermittent hypoxia. KEY FINDINGS: In conclusion, IH aggravated apoptosis and autophagy defects in T2DM mice, and increased the protein expression of HMGB1 and TLR4. This was also confirmed in HG + IH-treated hippocampal HT22 cells. HMGB1 siRNA can significantly reduce the protein expression of HMGB1 and TLR4, reverse neuronal apoptosis and enhance autophagy. SIGNIFICANCE: We believe that HMGB1 is a key factor in the regulation of hippocampal neuronal apoptosis and autophagy defects in T2DM combined with OSA. Targeting HMGB1/TLR4 signaling as a novel approach may delay or prevent the increased apoptosis and decreased autophagy induced by T2DM combined with OSA, and may ultimately improve cognitive dysfunction.


Assuntos
Apoptose/genética , Autofagia/genética , Diabetes Mellitus Tipo 2/patologia , Proteína HMGB1/genética , Hipocampo/patologia , Neurônios/patologia , Apneia Obstrutiva do Sono/patologia , Receptor 4 Toll-Like/genética , Animais , Hipóxia Celular , Diabetes Mellitus Tipo 2/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/genética , Apneia Obstrutiva do Sono/complicações
12.
Antioxidants (Basel) ; 8(11)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766125

RESUMO

Current research has identified S-nitrosoglutathione reductase (GSNOR) as the central enzyme for regulating protein S-nitrosylation. In addition, the dysregulation of GSNOR expression is implicated in several organ system pathologies including respiratory, cardiovascular, hematologic, and neurologic, making GSNOR a primary target for pharmacological intervention. This study demonstrates the kinetic activation of GSNOR by its substrate S-nitrosoglutathione (GSNO). GSNOR kinetic analysis data resulted in nonhyperbolic behavior that was successfully accommodated by the Hill-Langmuir equation with a Hill coefficient of +1.75, indicating that the substrate, GSNO, was acting as a positive allosteric affector. Docking and molecular dynamics simulations were used to predict the location of the GSNO allosteric domain comprising the residues Asn185, Lys188, Gly321, and Lys323 in the vicinity of the structural Zn2+-binding site. GSNO binding to Lys188, Gly321, and Lys323 was further supported by hydrogen-deuterium exchange mass spectroscopy (HDXMS), as deuterium exchange significantly decreased at these residues in the presence of GSNO. The site-directed mutagenesis of Lys188Ala and Lys323Ala resulted in the loss of allosteric behavior. Ultimately, this work unambiguously demonstrates that GSNO at large concentrations activates GSNOR by binding to an allosteric site comprised of the residues Asn185, Lys188, Gly321, and Lys323. The identification of an allosteric GSNO-binding domain on GSNOR is significant, as it provides a platform for pharmacological intervention to modulate the activity of this essential enzyme.

13.
J Clin Lab Anal ; : e23097, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31774228

RESUMO

BACKGROUND: This study aimed to explore the potential of soluble urokinase plasminogen activator receptor (suPAR) as a biomarker for severe acute pancreatitis (SAP) risk prediction and disease management in SAP patients. METHODS: Totally 225 acute pancreatitis (AP) patients (including 75 SAP, 75 moderate-severe acute pancreatitis [MSAP], and 75 mild acute pancreatitis [MAP] patients) were recruited based on the Atlanta classification, and their serum samples were obtained within 24 hours after admission. Meanwhile, 75 health controls (HCs) were recruited with their serum samples collected at the enrollment. The serum suPAR was then detected using enzyme-linked immunosorbent assay. RESULTS: The suPAR level was increased in SAP patients compared with MSAP patients (P = .023), MAP patients (P < .001), and HCs (P < .001). Receiver operating characteristic (ROC) curve presented that suPAR could not only differentiate SAP patients from HCs (AUC: 0.920, 95%CI: 0.875-0.965) but also differentiate SAP patients from MSAP (AUC: 0.684, 95%CI: 0.600-0.769) and MAP patients (AUC: 0.855, 95%CI: 0.797-0.912). In SAP patients, suPAR was positively correlated with Ranson score (P < .001), acute physiology and chronic healthcare evaluation II score (P = .001), sequential organ failure assessment score (P < .001), and C-reaction protein (P = .002). Further ROC curve exhibited that suPAR (AUC: 0.806, 95%CI: 0.663-0.949) was of good value in predicting increased inhospital mortality of SAP patients. CONCLUSION: Soluble urokinase plasminogen activator receptor is of good predictive value for SAP risk and may serve as a potential biomarker for disease severity, inflammation, and inhospital mortality in SAP patients.

14.
Med Sci Monit ; 25: 9019-9027, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31774737

RESUMO

BACKGROUND Acute pancreatitis (AP) is a common digestive disorder. Its management depends on the severity; therefore, it is essential to stratify AP patients early. D-dimer, a coagulation indicator, appears to be associated with the pathogenesis of AP. The aim of this study was to evaluate D-dimer as an early predictor of the severity of AP. MATERIAL AND METHODS This was a single-center retrospective study of 1260 patients diagnosed based on the revised Atlanta classification. Only patients hospitalized within 24 h of onset were included, and 334 patients were enrolled. Blood was collected at admission and 3 times within 48 h of admission. Values at admission and average of the 3 blood samples were evaluated by univariate and multivariate analyses. Furthermore, the area under the receiver-operating characteristic curve (AUC) was used to estimate the validity of the predictor and to define optimal cut-off points for prediction. RESULTS We found that 53.3% of the patients had mild AP (MAP), 24.3% had moderately severe AP (MSAP), and 22.4% had severe AP (SAP). D-dimer at admission and the average D-dimer could distinguish MAP patients from MSAP and SAP patients, with cut-off values of 3.355 mg/L and 4.868 mg/L, respectively. No difference in the parameters at admission was observed in multivariate analysis in distinguishing SAP from MSAP, but the average D-dimer level was significantly different with a cut-off value of 7.268 mg/L by comparing Ranson score, APACHE II score, and D-dimer level. CONCLUSIONS The average value of D-dimer levels could be used as a predictor of severity of AP. In general, patients with an average D-dimer level <4.868 could be diagnosed with MAP, >7.268 would develop into SAP, and between 4.868 and 7.268 would be MSAP.

15.
Curr Dev Nutr ; 3(9): nzz091, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31528838

RESUMO

Background: The Dietary Approaches to Stop Hypertension (DASH) diet is widely recommended to lower blood pressure, but its mechanisms of action are unclear. Lines of evidence suggest an interaction with the renin-angiotensin-aldosterone system (RAAS). Objective: We conducted a randomized, controlled, cross-over feeding trial to test RAAS-related mechanisms underlying the DASH diet in patients with isolated systolic hypertension. Methods: Participants entered a 1-wk run-in period on a control (CON) diet and then consumed the DASH or CON diets for 4 wk each in randomized sequence. Calorie content was controlled to maintain weight, and sodium intake was set at 3 g daily. After each diet, participants had hormonal and hemodynamic assessments obtained at baseline, in response to RAAS inhibition with captopril (CAP) 25 mg, and to graded angiotensin II (AngII) infusions (1 ng/kg and 3 ng/kg × 45 min). Primary outcomes were mean arterial pressure (MAP) and renal blood flow (RBF), and secondary outcomes were diastolic function, pulse wave velocity (PWV), plasma renin activity (PRA), and aldosterone (ALDO) responses by diet. Results: In total, 44 (19 female) participants completed the study. DASH + CAP significantly lowered MAP compared with CON + CAP (83 ± 11 mmHg compared with 88 ± 14 mmHg, P <0.01). RBF was increased with DASH + CAP compared with CON + CAP (486 ± 149 cc/min compared with 451 ± 171 cc/min, P <0.001). Study diet did not change PWV but CAP reduced diastolic function on the DASH diet (P <0.05). DASH + CAP significantly increased PRA compared with CON + CAP (1.52 ± 1.78 ng/mL/min compared with 0.89 ± 1.17 ng/mL/min; P <0.001). ALDO sensitivity to AngII infusion was greater with DASH when compared to CON (17.4 ± 7.7 ng/mL compared with 13.8 ± 6.2 ng/dL, P <0.05) as was DASH + CAP compared with CON + CAP (15.1 ± 5.3 ng/dL compared with 13.1 ± 5.9 ng/mL, P <0.05). Conclusions: The DASH diet interacts with the RAAS resulting in vascular and hormonal responses similar to a natriuretic effect, which appears to augment the hypotensive effect of angiotensin-converting enzyme (ACE) inhibition in individuals with isolated systolic hypertension. This trial was registered at clinicaltrials.gov as NCT00123006.

16.
Pain Physician ; 22(5): E407-E416, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31561650

RESUMO

BACKGROUND: Percutaneous endoscopic cervical discectomy has evolved as an efficient, minimally invasive spine surgery for radiculopathy caused by soft and/or osseous foraminal stenosis. Although interlaminar access can be used to resect lateral herniated lesions or osteophytes located in the foramina, with limited operative space, nerve retraction may be unavoidable. This procedure may injure the nerve root and cause postoperative arm pain, numbness, and muscle weakness, especially when the herniation is located in the ventral nerve root or when there is a massive osteophyte in the foramina. However, posterior partial cervical pediculectomy under endoscopy provides a new approach to effectively reduce or even avoid nerve retraction and reduce the potential risk of nerve injury. OBJECTIVES: This report presents a partial pediculectomy approach and compares the clinical outcomes of different surgical methods, including posterior percutaneous endoscopic cervical discectomy (P-PECD) and P-PECD combined with partial pediculectomySTUDY DESIGN: This study used a retrospective comparative study design. SETTING: This study took place at the Second Affiliated Hospital of Chongqing Medical University. METHODS: From February 2015 to March 2017, 84 patients with single-level and unilateral soft and/or osseous cervical foraminal stenosis were recruited. Patients were treated with P-PECD (40 patients) and P-PECD combined with partial pediculectomy (44 patients). Postoperative clinical outcomes were assessed using the modified MacNab grading criteria and the Visual Analog Scale (VAS) at different times after surgery. The surgery duration, dosage of postoperative analgesic medication, duration of hospital stay, and postoperative complications were recorded. RESULTS: The mean duration of the conventional P-PECD surgery was 74.48 ± 7.08 minutes, which was significantly longer (P = 0.002) than that observed for the P-PECD with partial pediculectomy (66.00 ± 9.62 minutes). The analgesic dosage in the conventional P-PECD group was significantly higher than that in the partial pediculectomy group (9.14 ± 3.07 units vs. 5.71 ± 3.41 units; P = 0.001). The hospital stay in the conventional P-PECD group was significantly longer than that in the partial pediculectomy group (3.86 ± 0.85 days vs. 3.24 ± 0.83 days; P = 0.022). The VAS scores at 1 day, 3 days, and 7 days after surgery in the conventional P-PECD group were significantly higher than those in the partial pediculectomy group (all P < 0.001). The modified MacNab grading criteria showed no significant difference at each follow-up (P = 1). The incidence of complications in the P-PECD with partial pediculectomy group (2/44, 4.55%) was significantly lower than that in the conventional P-PECD group (4/40, 10.0%), including complications of increased pain, increased numbness, and worsening of muscle weakness. LIMITATIONS: This study is limited by being a retrospective study, and by having a small sample size and a short follow-up period. CONCLUSIONS: As an alternative to the P-PECD surgical technique, P-PECD with partial pediculectomy effectively reduced the postoperative complications and may be preferable when considering the surgery duration, postoperative hospital stay, analgesic dosage, and postoperative VAS score. KEY WORDS: Cervical disc herniation, foraminal stenosis, percutaneous endoscopic cervical discectomy, PECD, P-PECD, partial pediculectomy.

17.
Metabolites ; 9(9)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491957

RESUMO

Flavor is one of the most important sensory characteristics of meat. The development of taste and aroma can be attributed to thousands of flavor molecules and precursors that are present in meat tissues. As a result, the identification of these flavor compounds and an improved understanding of their roles are necessary for improving the sensory quality and customer appeal of meat products. In the current study, we compared the metabolic profiles of meat specimens from the Lubei white goats (LBB), Boer goats (BE) and Jining grey goats (JNQ) by untargeted liquid chromatography-mass spectrometry. Our metabolomic data revealed that the three types of goat meat showed significantly different profiles of fatty acids, aldehydes, ketones, lactones, alkaloids, flavonoids, phenolics and drug residues, which could underpin the nuances of their flavors. Taken together, our results provided insights into the molecular basis for sensory variations between different goat meat products.

18.
Int J Biol Sci ; 15(9): 1846-1860, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523187

RESUMO

Pancreatic disease, including pathologies such as acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC), is a complicated and dangerous clinical condition involving the disruption of exocrine or endocrine function. PC has one of the highest mortality rates among cancers due to insufficient diagnosis in early stages. Furthermore, efficient treatment options for the disease etiologies of AP and CP are lacking. Thus, the identification of new therapeutic targets and reliable biomarkers is required. As essential couriers in intercellular communication, exosomes have recently been confirmed to play an important role in pancreatic disease, but the specific underlying mechanisms are unknown. Herein, we summarize the current knowledge of exosomes in pancreatic disease with respect to diagnosis, molecular mechanisms, and treatment, proposing new ideas for the study of pancreatic disease.

19.
Front Pharmacol ; 10: 886, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447680

RESUMO

Objective: Calcium dobesilate (CaD), an effective drug for the treatment of diabetic microvascular complications, especially diabetic retinopathy, is widely used in the clinic. Interestingly, several studies have indicated that CaD is therapeutic for diabetic kidney disease (DKD). Recently, evidence has indicated that altered vascular endothelial growth factor (VEGF) expression and decreased autophagy are the main pathological mechanisms of proteinuria. Thus, this study was conducted to explore the effect of CaD on restoring autophagy in DKD and the possible signaling pathway between VEGF and autophagy. Methods: Obese mice with spontaneous diabetes (KK-Ay) and high-fat diet- and streptozotocin-induced diabetic mice (HFD/STZ) were used in this study. Biochemical staining, western blotting, and immunohistochemistry were conducted to determine the angioprotective effect of CaD and the underlying mechanism between autophagy and VEGF/VEGFR. Results: Our results showed that CaD was capable of reducing albuminuria and restoring renal histological changes in KK-Ay and HFD/STZ-induced diabetic mice. CaD restored autophagy by decreasing the protein expression of LC3 II, Atg5, and beclin 1 and increasing the expression of P62. Moreover, CaD reduced the activation of the autophagy-related PI3K/AKT/mTOR pathway possibly via decreasing VEGF and downregulating VEGF receptor 2. Conclusion: Overall, CaD, as a novel potential therapeutic drug for DKD, plays a key role in protecting renal function and restoring autophagy by blocking VEGF/VEGFR2 and inhibiting the PI3K/AKT/mTOR signaling pathway.

20.
Exp Mol Med ; 51(8): 90, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375658

RESUMO

Currently, preliminary results have confirmed the existence of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis of pancreatic acinar cells during early acute pancreatitis (AP), which might be a potential target for the effective regulation of necroinflammatory injury. However, the exact effect of receptor-interacting protein kinase 1 (RIPK1)-dependent regulated acinar cell necrosis on AP is still uncertain. In our study, we first explored the changes in the degree of local and systemic inflammation in AP rats when the activation of acinar cell RIPK1 was inhibited. The RIPK1 inhibitor Nec-1 was used to treat rats, and the levels of related inflammatory markers, necrosis indicators and apoptotic indicators were measured. Changes in pancreatic nuclear factor κB (NF-κB) and aquaporin 8 (AQP8) expression were noted. Next, the expression of AQP8 in AR42J cells was inhibited, and the degree of cell necrosis and inflammatory damage was found to be significantly reduced. Most importantly, we demonstrated that the RIPK1/NF-ĸB/AQP8 axis might be a potential regulatory pathway mediating RIPK1-dependent regulated acinar cell necrosis in early AP. Finally, we used the NF-κB inhibitor PDTC and Nec-1 to treat rats in different groups and measured the degree of pathological pancreatic injury, the activation of RIPK1, and the expression of NF-κB and AQP8. In summary, we hypothesized that there might be a RIPK1/NF-ĸB/AQP8 pathway controlling RIPK1-dependent regulated necrosis of acinar cells in AP, which might be a promising therapeutic target against AP-related injury.

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