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Intestinal Epithelial Axin1 Deficiency Protects Against Colitis via Altered Gut Microbiota

Shari Garrett,Yongguo Zhang,Yinglin Xia,Jun Sun,

《工程（英文）》 doi: 10.1016/j.eng.2023.06.007

摘要： Intestinal homeostasis is maintained by specialized host cells and the gut microbiota. Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis, and its dysregulation has been implicated in inflammation and colorectal cancer. Axin1 negatively regulates activated Wnt/β-catenin signaling, but little is known regarding its role in regulating host–microbial interactions in health and disease. Here, we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation. Axin1 expression was analyzed in human inflammatory bowel disease datasets. To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis, we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell (IEC; Axin1^Δ^IEC) and Paneth cell (PC; Axin1^Δ^PC) to compare with control (Axin1^LoxP; LoxP: locus of X-over, P1) mice. We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease (IBD). Axin1^Δ^IEC mice exhibited altered goblet cell spatial distribution, PC morphology, reduced lysozyme expression, and enriched Akkermansia muciniphila (A. muciniphila). The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium-induced colitis in vivo. Axin1^Δ^IEC and Axin1^Δ^PC mice became more susceptible to dextran sulfate sodium (DSS)-colitis after cohousing with control mice. Treatment with A. muciniphila reduced DSS-colitis severity. Antibiotic treatment did not change the IEC proliferation in the Axin1^Loxp mice. However, the intestinal proliferative cells in Axin1^Δ^IEC mice with antibiotic treatment were reduced compared with those in Axin1^Δ^IEC mice without treatment. These data suggest non-colitogenic effects driven by the gut microbiome. In conclusion, we found that the loss of intestinal Axin1 protects against colitis, likely driven by epithelial Axin1 and Axin1-associated A. muciniphila. Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota. Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.

关键词： Axin1 Bacteria Microbiome inflammation Inflammatory bowel disease Immunity Microbiome Paneth cells Akkermansia muciniphila Wnt

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A ruptured recurrent small bowel gastrointestinal stromal tumour causing hemoperitoneum

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《医学前沿（英文）》 2015年第9卷第1期页码 108-111 doi: 10.1007/s11684-014-0344-0

摘要：

Hemoperitoneum is a rare and potentially life-threatening complication of GIST. We reported a 54-year-old man who developed disseminated intra-abdominal recurrence from a previously resected gastrointestinal stromal tumour (GIST) of the small bowel, and the patient presented with hemoperitoneum. Emergent debulking surgery was performed. A high dose imatinib was prescribed. Despite the presence of residual disease, the patient was well clinically 8 months after the operation. Even though, there is no evidence to support the routine use of debulking surgery in the management of GIST. In our patient, disease progression after second line targeted therapy and the absence of alternative treatment options for spontaneous rupture and hemoperitoneum prompted us to treat the patient aggressively. Resection of the ruptured GIST was carried out for control of bleeding and to prevent recurrent bleeding in this patient with good surgical risks. During the treatment decision-making, the patient’s general condition, the risk of surgery and the extent of dissemination were taken into consideration. In this patient who presented with spontaneous rupture of a small intestinal GIST, the novel use of targeted therapy and aggressive surgical treatment produced reasonably good survival outcome.

关键词： gastrointestinal stromal tumour hemoperitoneum small bowel GIST small bowel neoplasm imatinib

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左炔诺孕酮宫内释放系统对胰岛素样生长因子-1的影响与预防盆腔炎的相关性研究

吴晓杰,刘霞,陶跃平,王洁

《中国工程科学》 2015年第17卷第6期页码 4-7

摘要：

目的：研究左炔诺孕酮宫内释放系统对子宫内膜组织胰岛素样生长因子-1（IGF-1）的影响及预防盆腔炎疗效分析。方法：选取2010―2013年在嘉兴市妇幼保健院行宫腔镜下子宫内膜息肉切除术患者450例进行随机分组，研究组术后子宫内即时放置左炔诺孕酮宫内释放系统，而对照组不予放置。分别对术前及术后6个月子宫内膜组织IGF-1的表达情况进行对比，且随访2年，了解患者盆腔炎发生情况。结果：所有手术均成功，研究组子宫内膜组织IGF-1表达术后明显低于术前，对照组术前及术后子宫内膜组织IGF-1表达变化无差异，二组相比，术后IGF-1表达差异有显著性。随访2年对照组224例患者中39例发生盆腔炎，复发率为10.89 %，而研究组184例发生盆腔炎12例，差异有显著性；研究组子宫内膜厚度术后明显小于术前，差异有显著性，对照组子宫内膜厚度术后与术前变化无差异性。结论：左炔诺孕酮宫内释放系统对子宫内膜的IGF-1表达存在抑制作用，可能是其抑制子宫内膜增生并减少盆腔炎发生的机制之一。

关键词：左炔诺孕酮宫内系统；胰岛素样生长因子；盆腔炎

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Severe adhesive small bowel obstruction

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《医学前沿（英文）》 2012年第6卷第4期页码 436-439 doi: 10.1007/s11684-012-0221-7

摘要：

Adhesive small bowel obstruction is a frequent cause of hospital admission. Water soluble contrast studies may have diagnostic and therapeutic value and avoid challenging demanding surgical operations, but if bowel ischemia is suspected, prompt surgical intervention is mandatory. A 58-year-old patient was operated for extensive adhesive small bowel obstruction after having had two previous laparotomies for colorectal surgery, and had a complex clinical course with multiple operations and several complications. Different strategies of management have been adopted, including non-operative management with the use of hyperosmolar water soluble contrast medium, multiple surgical procedures, total parenteral nutrition (TPN) support, and finally use of anti-adherences icodextrin solution. After 2 years follow-up the patient was doing well without presenting recurrent episodes of adhesive small bowel obstruction. For patients admitted several times for adhesive small bowel obstruction, the relative risk of recurring obstruction increases in relation to the number of prior episodes. Several strategies for non-operative conservative management of adhesive small bowel obstruction have already addressed diagnostic and therapeutic value of hyperosmolar water soluble contrast. According to the most recent evidence-based guidelines, open surgery is the preferred method for surgical treatment of strangulating adhesive small bowel obstruction as well as after failed conservative management. Research interest and clinical evidence are increasing in adhesions prevention. Hyaluronic acid-carboxycellulose membrane and icodextrin may reduce incidence of adhesions.

关键词： post-operative intraperitoneal adhesions adhesive small bowel obstruction adhesiolysis antiadhesion treatments hyperosmolar water soluble contrast medium

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ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis

《医学前沿（英文）》页码 972-992 doi: 10.1007/s11684-023-0990-1

摘要： Owing to the increasing incidence and prevalence of inflammatory bowel disease (IBD) worldwide, effective and safe treatments for IBD are urgently needed. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter and plays an important role in inflammation. To date, H₂S-releasing agents are viewed as potential anti-inflammatory drugs. The slow-releasing H₂S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), known as a potent therapeutic with chemopreventive and cytoprotective properties, has received attention recently. Here, we reported its anti-inflammatory effects on dextran sodium sulfate (DSS)-induced acute (7 days) and chronic (30 days) colitis. We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length. Moreover, ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway. In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels. In addition, ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter, Mucispirillum, Parasutterella, and Desulfovibrio. Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines. Collectively, ADT-OH is safe without any short-term (5 days) or long-term (30 days) toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.

关键词： inflammatory bowel disease ADT-OH intestinal permeability gut microbiota

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Improved dissolution and anti-inflammatory effect of ibuprofen by solid dispersion

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《医学前沿（英文）》 2012年第6卷第2期页码 195-203 doi: 10.1007/s11684-012-0189-3

摘要：

The purpose of this study was to improve the dissolution rate and anti-inflammatory effect of ibuprofen by a solid dispersion (SD) method. Initial screening was developed based on drug solubility in carriers in the liquid state to select a suitable water-soluble carrier system for the preparation of SDs. The dissolution of ibuprofen in urea was higher than in PEG4000 or mannitol. Thus, urea was selected as the carrier for the preparation of SDs. SDs were characterized in terms of dissolution, differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared (FTIR) spectroscopy. Solid dispersion-based (SDBT) and conventional (CT) tablets were prepared by the wet granulation method. The anti-inflammatory effect of SDBT was evaluated using the mouse ear edema test with xylene. In vitro release results indicated that the ibuprofen dissolution rate was improved by the SD. SD characterization results suggested that ibuprofen partly precipitates in crystalline and amorphous forms after SD preparation and that ibuprofen and urea do not interact. SDBT displayed more significant anti-inflammatory effects than CT. The dissolution rate and anti-inflammatory effect of ibuprofen were significantly enhanced by the ibuprofen-urea SD.

关键词： ibuprofen solid dispersion physical mixture dissolution anti-inflammatory effect

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Gut microbiota and its implications in small bowel transplantation

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《医学前沿（英文）》 2018年第12卷第3期页码 239-248 doi: 10.1007/s11684-018-0617-0

摘要：

The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBT and the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host–microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice.

关键词： gut microbiota small bowel transplantation acute rejection chronic rejection mucosal immunity biomarker microbiota-targeted therapy

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Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

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《医学前沿（英文）》 2015年第9卷第2期页码 139-145 doi: 10.1007/s11684-015-0377-z

摘要：

In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the pro-inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

关键词： inflammation obesity cytokine energy expenditure insulin resistance

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宫内节育器表面的细菌生物膜研究

张向卉,曲雯雯,黄薇,方婕,吴凡子,周辛璇

《中国工程科学》 2015年第17卷第6期页码 21-27

摘要：

目的：宫内节育器（IUD）是目前常用的长效避孕措施之一，然而众多研究认为IUD的应用增加了盆腔炎性疾病（PID）的发生率。近年研究发现细菌生物膜（BF）与感染性疾病的发生息息相关，本研究拟探究无盆腔炎疾病妇女的不同类型宫内节育器表面是否存在BF，了解IUD是否为BF形成提供平台，是否增加盆腔炎性疾病的易感性。方法：不同类型IUD标本，根据表面清洁程度分别进行单独电子扫描电镜（SEM）观察，单独需氧、厌氧细菌培养，以及SEM观察+培养了解IUD表面是否存在BF。结果：共纳入IUD标本86例，85例非PID女性的IUD，同期1例盆腔感染性疾病患者的IUD。25例进行单独SEM观察，阳性1例，其余标本未见典型BF结构。单独细菌培养47例，需氧细菌培养阳性1例，见大面积菌苔覆盖，考虑污染可能性大，其余标本未见细菌生长。SEM联合培养14例，细菌培养阳性，电镜无阳性发现。其余培养及SEM观察阴性。结论：不论IUD的类型如何，非PID女性体内的IUD表面无BF存在，不同与其他体内医疗装置，BF的形成不能成为限制IUD应用的理由。

关键词：宫内节育器；盆腔炎性疾病；细菌生物膜；SEM

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Bioactive hyaluronic acid fragments inhibit lipopolysaccharide-induced inflammatory responses via the

Na You, Sasa Chu, Binggang Cai, Youfang Gao, Mizhou Hui, Jin Zhu, Maorong Wang

《医学前沿（英文）》 2021年第15卷第2期页码 292-301 doi: 10.1007/s11684-020-0806-5

摘要： The high- and the low-molecular weight hyaluronic acids (HMW-HA and LMW-HA, respectively) showed different biological activities in inflammation. However, the role of LMW-HA in inflammatory response is controversial. In this study, we aimed to investigate the effect of bioactive hyaluronan (B-HA) on lipopolysaccharide (LPS)-induced inflammatory responses in human macrophages and mice. B-HA was produced from HA treated with glycosylated recombinant human hyaluronidase PH20. Human THP-1 cells were induced to differentiate into macrophages. THP-1-derived macrophages were treated with B-HA, LPS, or B-HA+LPS. The mRNA expression and the production of inflammatory cytokines were determined using quantitative real-time PCR and enzyme-linked immunosorbent assay. The phosphorylation levels of proteins in the nuclear factor- B (NF- B), mitogen-activated protein kinase (MAPK), and IRF-3 signaling pathways were measured using Western blot. The efficacy of B-HA was assessed in a mouse model of LPS-induced inflammation. Results showed that B-HA inhibited the expression of TNF-α, IL-6, IL-1, and IFN-β, and enhanced the expression of the anti-inflammatory cytokine IL-10 in LPS-induced inflammatory responses in THP-1-derived macrophages and . B-HA significantly suppressed the phosphorylation of the TLR4 signaling pathway proteins p65, IKKα/β, I Bα, JNK1/2, ERK1/2, p38, and IRF-3. In conclusion, our results demonstrated that the B-HA attenuated the LPS-stimulated inflammatory response by inhibiting the activation of the TLR4 signaling pathway. B-HA could be a potential anti-inflammatory drug in the treatment of inflammatory disease.

关键词： bioactive hyaluronan lipopolysaccharide inflammatory cytokines TLR4 human macrophages

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Non-genetic mechanisms of diabetic nephropathy

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《医学前沿（英文）》 2017年第11卷第3期页码 319-332 doi: 10.1007/s11684-017-0569-9

摘要：

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes mellitus patients and is characterized by thickened glomerular basement membrane, increased extracellular matrix formation, and podocyte loss. These phenomena lead to proteinuria and altered glomerular filtration rate, that is, the rate initially increases but progressively decreases. DN has become the leading cause of end-stage renal disease. Its prevalence shows a rapid growth trend and causes heavy social and economic burden in many countries. However, this disease is multifactorial, and its mechanism is poorly understood due to the complex pathogenesis of DN. In this review, we highlight the new molecular insights about the pathogenesis of DN from the aspects of immune inflammation response, epithelial–mesenchymal transition, apoptosis and mitochondrial damage, epigenetics, and podocyte–endothelial communication. This work offers groundwork for understanding the initiation and progression of DN, as well as provides ideas for developing new prevention and treatment measures.

关键词： diabetic nephropathy immune inflammatory response epithelial–mesenchymal transition apoptosis mitochondrial damage epigenetics podocyte–endothelial communication

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et’s disease in a Chinese population

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《医学前沿（英文）》 2012年第6卷第4期页码 354-359 doi: 10.1007/s11684-012-0234-2

摘要：

Beh?et’s disease is defined as a multisystemic inflammatory disease. Although the precise pathogenesis and etiology is still a mystery, accumulating evidence shows that genetic variants of immune-related genes have a profound influence on the development of Beh?et’s disease. To explore the genetic factors for Beh?et’s disease, our group investigated the association of Beh?et’s disease with multiple immune response genes and has identified multiple Beh?et’s disease-related immunoregulatory pathways in the Chinese Han population. A large number of gene polymorphisms were studied including STAT4, IL23R, CD40, CCR1/CCR3, STAT3, OPN, IL17, JAK2, MCP-1, CTLA4, PD-1, PD-L1, PD-L2, TGRBR3, CCR6, PTPN22, FCRL3, IRF5, SUMO4 and UBAC2. Significant associations were found between Beh?et’s disease and STAT4, IL23R, CD40, CCR1/CCR3, STAT3, MCP-1, TGFBR3, FCRL3, SUMO4, UBAC2. These genetic predisposition studies support an important role for both lymphocyte differentiation as well as ubiquitination pathways. These findings are helpful in elucidating the pathogenesis of Beh?et’s disease and hopefully will allow the development of novel treatment regimes.

关键词： Beh?et’s disease SNPs immune gene genetic study

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Metformin and metabolic diseases: a focus on hepatic aspects

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《医学前沿（英文）》 2015年第9卷第2期页码 173-186 doi: 10.1007/s11684-015-0384-0

摘要：

Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases.

关键词： metformin diabetes hepatic steatosis inflammatory response insulin resistance

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Heterogeneity of chronic obstructive pulmonary disease: from phenotype to genotype

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《医学前沿（英文）》 2013年第7卷第4期页码 425-432 doi: 10.1007/s11684-013-0295-x

摘要：

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality throughout the world and is mainly characterized by persistent airflow limitation. Given that multiple systems other than the lung can be impaired in COPD patients, the traditional FEV₁/FVC ratio shows many limitations in COPD diagnosis and assessment. Certain heterogeneities are found in terms of clinical manifestations, physiology, imaging findings, and inflammatory reactions in COPD patients; thus, phenotyping can provide effective information for the prognosis and treatment. However, phenotypes are often based on symptoms or pathophysiological impairments in late-stage COPD, and the role of phenotypes in COPD prevention and early diagnosis remains unclear. This shortcoming may be overcome by the potential genotypes defined by the heterogeneities in certain genes. This review briefly describes the heterogeneity of COPD, with focus on recent advances in the correlations between genotypes and phenotypes. The potential roles of these genotypes and phenotypes in the molecular mechanisms and management of COPD are also elucidated.

关键词： chronic obstructive pulmonary disease heterogeneity phenotype genotype prediction

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Acupuncture for the management of dry eye disease

《医学前沿（英文）》 2022年第16卷第6期页码 975-983 doi: 10.1007/s11684-022-0923-4

摘要： The effectiveness of using acupuncture for dry eye disease (DED) is controversial. Thus, this systematic review investigated the effectiveness and feasibility of using acupuncture for DED in accordance with the 2020 PRISMA statement. The outcomes of interests were (1) to evaluate the efficacy of acupuncture in improving the ocular surface disease index (OSDI), Schirmer I test score, and tear breakup time from baseline to the last follow-up; (2) to determine possible complications of using acupuncture; and (3) to investigate the superiority of acupuncture over other commonly used treatments for DED. Data from 394 patients were collected. Results showed that acupuncture significantly prolonged the tear breakup time (P < 0.0001), significantly increased the Schirmer I test score ( P < 0.0001), and significantly reduced the OSDI ( P < 0.0001) from baseline to the last follow-up. Compared with the control group, the acupuncture group had significantly greater Schirmer I test score ( P < 0.0001), significantly longer tear breakup time ( P = 0.0004), and significantly lower OSDI (P = 0.002). These results suggest that acupuncture is effective and feasible in improving symptoms and signs of DED. No severe adverse effects of acupuncture were observed.

关键词： dry eye disease xerophthalmus acupuncture