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  • 1.

    【2hr】Towards feedback-controlled nanomedicines for smart, adaptive delivery

    包量

    机译 致力于反馈控制的纳米药物，以实现智能，自适应的递送
    摘要：Nanomedicines for controlled drug release provide temporal and spatial regulation of drug bioavailability in the body. The timing of drug release is usually engineered either for slow gradual release over an extended period of time or for rapid release triggered by a specific change in its physicochemical environment. However, between these two extremes, there is the desirable possibility of adaptive nanomedicines that dynamically modulate drug release in tune with its changing environment. Adaptation and response through communication with its environment is a fundamental trait of living systems; therefore, the design of biomimetic nanomedicines through the approaches of bottom-up synthetic biology provides a viable route to this goal. This could enable drug delivery systems to optimize release in synchronicity with the body’s natural biological rhythms and the personalized physiological characteristics of the patient, e.g. their metabolic rate. Living systems achieve this responsiveness through feedback-controlled biochemical processes that regulate their functional outputs. Towards this goal of adaptive drug delivery systems, we review the general benefits of nanomedicine formulations, provide existing examples of experimental nanomedicines that encapsulate the metabolic function of enzymes, and give relevant examples of feedback-controlled chemical systems. These are the underpinning concepts that hold promise to be combined to form novel adaptive release systems. Furthermore, we motivate the advantages of adaptive release through chronobiological examples. By providing a brief review of these topics and an assessment of the state of the art, we aim to provide a useful resource to accelerate developments in this field.Impact statementThe timing and rate of release of pharmaceuticals from advanced drug delivery systems is an important property that has received considerable attention in the scientific literature. Broadly, these mostly fall into two classes: controlled release with a prolonged release rate or triggered release where the drug is rapidly released in response to an environmental stimulus. This review aims to highlight the potential for developing adaptive release systems that more subtlety modulate the drug release profile through continuous communication with its environment facilitated through feedback control. By reviewing the key elements of this approach in one place (fundamental principles of nanomedicine, enzymatic nanoreactors for medical therapies and feedback-controlled chemical systems) and providing additional motivating case studies in the context of chronobiology, we hope to inspire innovative development of novel “chrononanomedicines.”
  • 2.

    【2hr】Plant synthetic biology could drive a revolution in biofuels and medicine

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    机译 植物合成生物学可以推动生物燃料和医学的革命
    • 作者：Jenny C Mortimer
    • 刊名：Experimental Biology and Medicine
    • 2019年第4期
    摘要：Population growth, climate change, and dwindling finite resources are amongst the major challenges which are facing the planet. Requirements for food, materials, water, and energy will soon exceed capacity. Green biotechnology, fueled by recent plant synthetic biology breakthroughs, may offer solutions. This review summarizes current progress towards robust and predictable engineering of plants. I then discuss applications from the lab and field, with a focus on bioenergy, biomaterials, and medicine.Impact statementThe plant synthetic biology field has exploded in the last five years, in part driven by techniques such as CRISPR and cheap DNA synthesis. This review summarizes the current state of research in plant synthetic biology, and how it is being applied to two topics: renewable fuels and chemicals, and medicine.
  • 3.

    【2hr】Inhibition of Mastermind-like 1 alleviates liver fibrosis induced by carbon tetrachloride in rats

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    机译 抑制Mastermind-like 1减轻大鼠四氯化碳引起的肝纤维化
    摘要：Mastermind-like 1 (MAML1) functions in critical transcriptional coactivation in Notch and Wnt/β-catenin signal pathways, which participate in hepatic fibrosis. This study is aimed to reveal the potential role of MAML1 in liver fibrosis and identify its underlying mechanism. In present research, the enhanced expression of MAML1 was found in the fibrotic liver tissues in carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats, and MAML1 expression increased gradually during the activation of hepatic stellate cells (HSCs) isolated from the normal rat. Further studies showed that blocking MAML1 expression efficiently decreased the expression of α-SMA and collagen I (Col1a1) in HSCs. Interestingly, MAML1 may modulate HSCs activation via interrupting both Notch and Wnt/β-catenin signal transductions, and the inhibition of MAML1 by a recombinant adeno-associated virus type 1 vector carrying shRNA targeting MAML1 alleviated CCl4-induced hepatic fibrosis in rats. These findings suggest that the selective regulation of MAML1 expression may be a feasible therapeutic approach to reverse liver fibrosis.Impact statementLiver fibrosis is a common wound-healing response to all kinds of liver injuries. Hepatic stellate cells (HSCs) activation is the key event during liver fibrogenesis. Thus, the elucidation of mechanisms for regulating HSCs activation is helpful for identifying novel anti-fibrotic targets and strategies. MAML1, an important component of Notch signal, functions in critical transcriptional coactivation in the Notch and Wnt/β-catenin signal pathways. In the present study, we investigated the potential function of MAML1 during hepatic fibrogenesis in rats. Our results demonstrated that MAML1 participates in liver fibrosis through modulating HSCs activation via interrupting both the Notch and Wnt/β-catenin signal transductions. Additionally, the inhibition of MAML1 markedly attenuated CCl4-induced hepatic fibrogenesis in rats. Our results shed a light for the exploitation of a new therapeutic strategy for hepatic fibrosis via targeting MAML1.
  • 4.

    【2hr】The profile analysis of circular RNAs in human placenta of preeclampsia

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    机译 子痫前期人胎盘中环状RNA的谱分析
    摘要：A total of 70 pregnant women were recruited for this study, including 35 early onset preeclampsia (PE) and 35 normal pregnant women. By RNA sequencing, the circular RNA (circRNAs) in placenta were identified. Differentially expressed circRNAs were bioinformatics analyzed with gene ontology, Kyoto Encyclopedia of Genes and Genomes, and circRNA–miRNA interaction prediction. Quantitative real time polymerase chain reaction(qRT-PCR) assay was used to verify the results. Compared with the normal pregnant women, there were 49 circRNAs differentially expressed in the placental tissue of PE women, including two circRNAs were up-regulated and 47 were down-regulated. Ten differentially expressed circRNAs were selected for validation by qRT-PCR, among which results of three circRNAs, circRNA_3286, circRNA_5593, and circRNA_3800, were consistent with the sequencing. According to the bioinformatic prediction, we speculate that these circRNAs may be involved in some cellular regulatory functions in PE through their targeted miRNAs. We also evaluated the expression of circRNA_3286 in plasma to be used as a potential biomarker for PE; in vitro Transwell assay shown transfected with si-circ-3286 significantly reduced invasion in HTR8/Svneo cells. In conclusion, we displayed a preliminary landscape of circRNA differential expression in PE and discussed their possible regulatory mechanisms. This study revealed a new insight into the molecular mechanism of PE.Impact statementThe abnormal expression of many regulatory factors may be involved in the development of PE. circRNAs are proved to have a series of important biological functions; however, reports about circRNA and PE are rare. In this work, we evaluated the profile analysis of circRNAs in human placenta of PE by RNA-seq and found some newly differentially expressed circRNAs which might be involved in PE. Combined with bioinformatics analysis, their possible functions were preliminarily discussed.
  • 5.

    【2hr】Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats

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    机译 瘦素诱导雄性Sprague-Dawley大鼠胃黏膜中致癌基因的表达
    摘要：Leptin promotes the growth of gastric cancer cells in vitro. It is, however, unknown if leptin induces gastric cancer in vivo. This study therefore investigated the effect of leptin on the histology and expression of tumorigenic genes in the stomach of rats following 40 weeks of leptin treatment. Male Sprague-Dawley rats, aged 6 weeks, were randomized into control and experimental groups (n = 8 per group). The experimental group was given intraperitoneal injections of leptin (60 µg/kg/day) once daily for 40 weeks, whereas the control group received intraperitoneal injection of an equal volume of normal saline daily. Rats were housed in polypropylene cages for the duration of the study. Body weight was measured weekly. Upon completion of treatment, rats were euthanized and their stomachs were collected for histopathological examination, microarray, and RT-qPCR. Data were analyzed using one-way ANOVA and Fisher’s exact test. On histology, one rat (12.5%) in the leptin-treated group had a large red-colored tumor nodule at the pyloric antrum of the stomach. Microscopically, stomachs of two leptin-treated rats (25%) showed hyperplasia or dysplasia. Microarray analysis revealed significant upregulation of a number of genes in the stomachs of leptin-treated rats that have been shown to be associated with tumorigenesis in other tissues, including Furin (protein maturation), Eef1a1 and Eif4g2 (translation factors), Tmed2 (vesicular trafficking), Rab7a (plasma membrane trafficking), Rfwd2 (protein degradation), Fth1 and Ftl1 (oxygen transport), Tspan8, Tspan1, Fxyd3, and Rack1 (cell migration), Pde4d (signal transduction), Nupr1 and Ybx1 (transcription factors), Ptma and Tmem134 (oncogenes), Srsf2 (mRNA maturation), and Reep5 (cell proliferation). None of the known oncogenes were, however, significantly up-regulated. In conclusion, although the overall effect of leptin on gastric carcinogenesis seems inconclusive, the findings of dysplasia and the up-regulation of some of the cancer-related genes nevertheless warrant further scrutiny on the role of leptin in gastric cancer.Impact statementGastric cancer is the third most common cause of death due to cancer in the world. Obese individuals are at risk of developing gastric cancer, and the reason for this is unknown. Serum leptin levels are high in obese individuals and leptin is known to induce proliferation of gastric cancer cells in vitro. However, to date, no reports exist on the tumorigenic effects of leptin on the stomach in vivo. This study therefore determines if chronic leptin administration induces gastric carcinogenesis in non-obese rats, which might serve as a useful animal model for future studies. Although the findings are somewhat inconclusive, to our knowledge, however, this is the first study to show the up-regulation of numerous potential driver genes that highlight the potential role of leptin in the higher prevalence of gastric cancer among obese individuals. The findings certainly necessitate further scrutiny of leptin gastric cancer.
  • 6.

    【2hr】A scientist engineer’s contribution to therapeutic discovery and development

    包量

    机译 科学家工程师对治疗发现和开发的贡献
    • 作者：Jennifer L Wilson
    • 刊名：Experimental Biology and Medicine
    • 2018年第14期
    摘要：An engineering perspective views cells as complex circuits that process inputs – drugs, environmental cues – to create complex outcomes – disease, growth, death – and this perspective has immense potential for drug development. Logical rules can describe the features of cells and reductionist approaches have exploited these rules for drug development. In contrast, the reductionist approach serially characterizes cellular components and develops a deep understanding of each component’s specific role. This approach underutilizes the full system of biomolecules relevant to disease pathology and drug effects. An engineering perspective provides the tools to understand and leverage the full extent of biological systems; applying both reverse and forward engineering, a strength of the engineering approach has demonstrated progress in advancing understanding of disease and drug mechanisms. Drug development lacks sufficient engineering specifications, or empirical models, of drug pharmacodynamic effects and future efforts to derive empirical models of drug effects will streamline this development. At this stage of progress, the scientist engineer is uniquely poised to solve problems in therapeutics related to modulating multiple diseases with a single or multiple therapeutic agents and identifying pharmacodynamics biomarkers with knowledge of drug pathways. This article underscores the value of these principles in an age where drug development costs are soaring and finding efficacious therapies is challenging.Impact statementMany untreated diseases are not monogenic and are instead caused by multiple genetic defects. Because of this complexity, computational, logical, and systems understanding will be essential to discovering novel therapies. The scientist engineer is uniquely disposed to use this type of understanding to advance therapeutic discovery. This work highlights benefits of the scientist engineer perspective and underscores the potential impact of these approaches for future therapeutic development. By framing the scientist engineer’s tool set and increasing awareness about this approach, this article stands to impact future therapeutic development efforts in an age of rising development costs and high drug attrition.
  • 7.

    【2hr】Buformin increases radiosensitivity in cervical cancer cells via cell-cycle arrest and delayed DNA-damage repair

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    机译 Buformin通过细胞周期停滞和延迟的DNA损伤修复来提高子宫颈癌细胞的放射敏感性
    摘要：Buformin is a commonly used hypoglycemic agent, and numerous studies have shown that buformin has potent antitumor effects in several malignancies. In this study, we aimed to assess the cytotoxic effect of buformin combined with ionizing radiation (IR) on two human cervical cancer cell lines (Hela and Siha). Cytotoxicity was detected by colony formation assays; impacts on the cell cycle and apoptosis were detected by flow cytometric analyses. Changes in histone H2AX (γ-H2AX) phosphorylation and impacts on the AMPK/S6 pathway were also explored. Our data show that the combination of buformin and IR had a much stronger antiproliferative effect and resulted in more apoptosis than did buformin or IR alone. Combination treatment with a low dose of buformin (10 µM) and IR (4 Gy) caused G2/M-phase cell cycle arrest. Consistent with these findings, Western blotting showed that the combination of buformin and IR activated AMPK and suppressed S6. In addition, delayed disappearance of γ-H2AX was detected by immunofluorescence in cervical cancer cells treated with buformin plus IR. Taken together, the data indicate that the combination of a low concentration of buformin and IR increases the radiosensitivity of cervical cancer cells via cell cycle arrest and inhibition of DNA repair. Based on these results, we strongly support the use of buformin as an effective agent for improving IR treatment efficiency in the context of cervical cancer.Impact statementOur idea originated in the thought of discovering new effects of old drugs. Although this study is a basic research, it is very close to clinical treatment. Flow cytometry and immunofluorescence were used to verify that buformin increases radiosensitivity. We aimed to address one of the thorniest problems in treatment process. Based on discovering new effects of old drugs, it is feasible to use buformin as an anticancer drug in clinical application. This will provide new ideas for clinical treatment.
  • 8.

    【2hr】Feature Article: Trientine selectively delivers copper to the heart and suppresses pressure overload-induced cardiac hypertrophy in rats

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    机译 专题文章：Trientine选择性地将铜输送到心脏并抑制压力超负荷引起的大鼠心脏肥大
    摘要：Dietary copper supplementation reverses pressure overload-induced cardiac hypertrophy by copper replenishment in the heart. A copper-selective chelator, trientine (triethylenetetramine [TETA]), reverses left ventricular hypertrophy associated with diabetes also by copper replenishment in the heart. The present study was undertaken to address the critical issue how TETA delivers copper to the heart. Adult male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Eight weeks after the TAC surgery, cardiac hypertrophy was developed and copper content in the heart was reduced. TETA was then administrated by gavage in two different dosages (21.9 or 87.6 mg/kg day) for six weeks. The results showed that in the lower dosage, TETA replenished copper contents in the heart, along with a decrease in the copper concentration in the blood and kidney, and an increase in the urine. In the higher dosage, TETA did not replenish copper contents in the heart, but markedly increased copper concentrations in the urine and decreased those in the blood and kidney. Neither lower nor higher TETA dosage altered copper concentrations in other organs. Corresponding to myocardial copper replenishment, the lower dose TETA suppresses cardiac hypertrophy, as judged by a reduction in the left ventricle wall thickness and a decrease in the heart size, and diminished cardiac fibrosis, as reflected by a decrease in collagen I content. TETA in the higher dose not only did not suppress cardiac hypertrophy, but also caused cardiac hypertrophy in sham-operated rats. TETA-mediated myocardial copper restoration is independent of copper transporter-1 or -2 but related to an energy-dependent transportation. This study demonstrates that low-dose TETA functions as a copper chaperone, selectively delivering copper to the copper-deprived heart through an active transportation; in higher doses, TETA simply retains its chelator function, removing copper from the body by urinary excretion.Impact statementOur study reveals that TETA, traditionally regarded as a copper chelator, in lower doses delivers copper selectively to the heart through a mechanism independent of copper transporter-1 or -2. Copper supplementation by a lower dose of TETA suppresses pressure overload-induced cardiac hypertrophy. Since ischemic heart disease and hypertrophic cardiomyopathy are accompanied by myocardial copper loss, this approach of using a lower dose of TETA to supplement copper to the heart would help treat the disease condition of patients with such cardiac events.
  • 9.

    【2hr】Acute high-intensity interval exercise induces greater levels of serum brain-derived neurotrophic factor in obese individuals

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    机译 急性高强度间歇运动在肥胖个体中诱导更高水平的血清脑源性神经营养因子
    摘要：Obesity may attenuate the expression of brain-derived neurotrophic factor (BDNF), thereby increasing the risk of cognitive dysfunction. High-intensity interval exercise (HIIE) has been shown to be as or more effective than continuous moderate-intensity exercise (CME) in promoting the expression of BDNF in normal-weight individuals. Therefore, the primary purpose of this study was to examine whether or not acute HIIE could be utilized as a practical model to explore the BDNF response in obese versus normal-weight subjects when compared to acute CME. The potential relationship of exercise-induced BDNF with blood lactate and cortisol was also examined. Twelve male subjects (six obese and six normal-weight) participated in a counterbalanced and caloric equated experiment: HIIE (30 min, 4 intervals of 4 min at 80%–90% of VO2max with 3 min of active recovery at 50–60% VO2max) and CME (38 min at 50%–60% VO2max). Blood samples were collected prior to, immediately following exercise, and 1 h into recovery for measurements of serum BDNF, blood lactate, and plasma cortisol. Our results showed that the BDNF response to acute HIIE was greater than CME in obese subjects when compared to normal-weight subjects. Similarly, although acute HIIE induced greater blood lactate and plasma cortisol levels than CME, obese subjects produced less blood lactate, but no difference in cortisol than normal-weight subjects. These findings suggest that acute HIIE may be a more effective protocol to upregulate BDNF expression in an obese population, independent of increased lactate and cortisol levels.Impact statementHigh-intensity interval exercise (HIIE) has been shown to be a time-efficient exercise strategy that provides similar or superior physiological benefits as traditional continuous moderate-intensity exercise (CME). Our previous study demonstrated an equivalent elevation on the BDNF response in both obese and normal-weight individuals following 30 min of acute CME. To discover a time-efficient exercise strategy to improve brain health in an obese population, the present study found that obese individuals elicit a greater level of BDNF following acute HIIE versus CME than normal-weight individuals. These findings indicate that acute HIIE may be an effective strategy to upregulate BDNF expression in obese individuals.
  • 10.

    【2hr】Identification of miR-708-5p in peripheral blood monocytes: Potential marker for postmenopausal osteoporosis in Mexican-Mestizo population

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    机译 外周血单核细胞中miR-708-5p的鉴定：墨西哥混血儿绝经后骨质疏松的潜在标志
    摘要：Osteoporosis is the most frequent disorder of bone metabolism, owing to an alteration between osteoclast and osteoblast activity, which results from the interaction of genetic, environmental, and epigenetic factors. microRNAs, small non-coding RNAs of around 22 nucleotides with important regulatory roles in gene regulation, that target mRNAs for post-transcriptional destabilization have been suggested as biomarkers in several disorders. In this work, we used small RNA sequencing to identify microRNAs from peripheral blood monocytes that were differentially expressed between non-osteoporotic and osteoporotic Mexican postmenopausal women, to elucidate the potential role of microRNAs as non-invasive marker candidates in osteoporosis. We identified six candidate microRNAs: four were up-regulated (miR-708-5p, miR-34b-5p, miR-3161, miR-328-5p), while two were down-regulated (miR-4422 and miR-939-3p) in osteoporotic women. Differential expression was validated by quantitative RT-PCR and only the upregulation of miR-708-5p was found to be statistically significant. Bioinformatic analysis of target genes for miR-708-5p showed 15 signaling pathways related to bone metabolism. Since monocytes are osteoclast precursors, 10 potential target genes present in these pathways and related to osteoclastogenesis were identified (AKT1, AKT2, CCND1, PARP1, SMAD3, CXCL5, FKBP5, MAP2K3, MMP2, and IKBKG). Five of them were found to be down-regulated according to microarray expression data. This is the first time that miR-708-5p has been identified in peripheral blood monocytes and associated with postmenopausal osteoporosis. Our results suggest that miR-708-5p reduces the expression of AKT1, AKT2, PARP1 FKBP5, and MP2K3 in peripheral blood monocytes contributing to an osteoporotic phenotype and could be a candidate marker for postmenopausal osteoporosis in Mexican population.Impact statementThis is the first study in which hsa-miR-708-5p has been identified in peripheral blood monocytes (osteoclast precursors) and associated with postmenopausal osteoporosis through small RNA-Sequencing, in an Admixed Mexican Mestizo population. By conducting in silico and bioinformatic analyzes, we identified target genes and important signaling pathways involved in bone metabolism pointing hsa-miR-708-5p as a candidate marker for osteoporosis in Mexican population. These approaches provide a landscape of the post-transcriptional regulation, which can be useful for the management of postmenopausal osteoporosis along with the potential use of microRNAs as markers for its early detection.
  • 11.

    【2hr】Drug discovery and development: Biomarkers of neurotoxicity and neurodegeneration

    包量

    机译 药物发现与开发：神经毒性和神经变性的生物标志物
    摘要：The discovery and development of new drugs are vital if we are to improve and expand treatment options available to improve outcomes for patients. Overall, therapeutic strategies fall into two broad categories: small molecules and biologics, although more recently there has been a growth in novel platforms such as miRNAs and oligonucleotides. On average, the development of a small molecule drug takes around 12 years and costs around $50m. Despite this huge investment of time and money, attrition remains a major challenge and very few molecules actually make it through to the market. Here, we look at reasons for attrition in the small molecule field with a focus on neurotoxicology and efforts being made to improve success via the development of imaging and fluidic biomarkers. We also look at learnings from other models of CNS damage and degeneration such as Parkinson’s disease, traumatic brain injury, and multiple sclerosis since these may offer the opportunity to improve tools available to nonclinical toxicologists in the early detection of potential neurotoxicity. Reciprocally, learnings from studies of animal neurotoxicity may offer better ways to potentially monitor patients during clinical development of new drugs for neurodegeneration.Impact statementAttrition in drug discovery and development remains a major challenge. Safety/toxicity is the most prevalent reason for failure with cardiovascular and CNS toxicities predominating. Non-invasive biomarkers of neurotoxicity would provide significant advantage by allowing earlier prediction of likely neurotoxicity in preclinical studies as well as facilitating clinical trials of new therapies for neurodegenerative conditions such as Parkinson’s disease (PD) and multiple sclerosis (MS).
  • 12.

    【2hr】Feature Article: Selective modulation of tonically active GABAA receptor functional subgroups by G-proteins and protein kinase C

    包量

    机译 专题文章：G蛋白和蛋白激酶C对音调活跃的GABAA受体功能亚组的选择性调节
    摘要：Ionotropic receptors of γ-aminobutyric acid (GABAARs) produce two forms of inhibitory signaling: phasic inhibition triggered by activation of synaptic GABAARs at GABAergic synapses, and tonic inhibition generated in large part through persistent activation of extrasynaptic GABAARs. It has recently been demonstrated that tonic inhibition may also involve spontaneously opening GABAARs (s-GABAARs) whose activation does not require binding of γ-aminobutyric acid (GABA). Here, we examine intracellular mechanisms modulating GABAARs’ tonic effects in rat dentate gyrus granule cells (DGCs). Cellular control of s-GABAARs-delivered tonic current appears to involve signaling inputs from G-protein-dependent and -independent molecular cascades, whereas tonic GABA-dependent current in DGCs is regulated by protein kinase C. The intracellular agents that modulate s-GABAAR-generated inhibition could thus represent a generic mechanism controlling signal integration in central neural circuits.Impact statementHere we study intracellular mechanisms which regulate inhibitory signaling delivered through continuously (tonically) open ionotropic receptors of γ-aminobutyric acid (GABA) of dentate gyrus granule cells (DGCs). We found that, apart of classical GABA-A receptors (GABAARs) which can be activated by GABA binding, a significant part of tonic inhibitory current is delivered by newly discovered spontaneously opening GABAARs (s-GABAARs), which enter active state without binding of GABA. We have also found that conventional GABAARs and s-GABAARs are regulated by different intracellular mechanisms, which may overlap and thus induce various signaling repercussions. Our results demonstrate that s-GABAARs play a key role in the mechanism that implements DGCs functional role in the brain. On top of that, since regulatory mechanisms under study are affected in a number of pathological states, our results may have broad implications for treatment of neurological disorders.
  • 13.

    【2hr】Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100

    包量

    机译 溶血磷脂酸类似物Rx100预防和治疗分泌性腹泻
    摘要：Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea causes 2.5 million deaths annually among children under the age of five in the developing world. A critical barrier in treating diarrheal disease is lack of easy-to-use effective treatments. While antibiotics may shorten the length and severity of diarrhea, oral rehydration remains the primary approach in managing secretory diarrhea. Existing treatments mostly depend on reconstituting medicines with water that is often contaminated which can be an unresolved problem in the developing world. Standard treatments for secretory diarrhea also include drugs that decrease intestinal motility. This approach is less than ideal because in cases where infection is the cause, this can increase the incidence of bacterial translocation and the potential for sepsis. Our goal is to develop a safe, effective, easy-to-use, and inexpensive treatment to reduce fluid loss in secretory diarrhea. We have developed Rx100, which is a metabolically stable analog of lysophosphatidic acid. We tested the hypothesis that Rx100, similarly to lysophosphatidic acid, inhibits the activation of the cystic fibrosis transmembrane regulator Cl− channel and also reduces barrier permeability resulting in the decrease of fluid loss in multiple etiologies of secretory diarrhea. Here we have established the bioavailability and efficacy of Rx100 in cholera toxin-induced secretory diarrhea models. We have demonstrated the feasibility of Rx100 as an effective treatment for Citrobacter rodentium infection-induced secretory diarrhea. Using both the open- and closed-loop mouse models, we have optimized the dosing regimen and time line of delivery for Rx100 via oral and parenteral delivery.Impact statementA critical barrier in treating diarrheal disease is easy-to-use effective treatments. Rx100 is a first in class, novel small molecule that has shown efficacy after both subcutaneous and oral administration in a mouse cholera-toxin- and Citrobacter rodentium infection-induced diarrhea models. Our findings indicate that Rx100 a metabolically stable analog of the lipid mediator lysophosphatidic acid blocks activation of CFTR-mediated secretion responsible for fluid discharge in secretory diarrhea. Rx100 represents a new treatment modality which does not directly block CFTR but attenuates its activation by bacterial toxins. Our results provide proof-of-principle that Rx100 can be developed for use as an effective oral or injectable easy-to-use drug for secretory diarrhea which could significantly improve care by eliminating the need for severely ill patients to regularly consume large quantities of oral rehydration therapies and offering options for pediatric patients.
  • 14.

    【2hr】The downregulation of WWOX induces epithelial–mesenchymaltransition and enhances stemness and chemoresistance in breastcancer

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    机译 WWOX的下调诱导上皮-间质过渡并增强乳房的干性和化学抗性癌症
    摘要：WW domain-containing oxidoreductase (WWOX), an important tumor suppressor, is essential for regulating cell proliferation and apoptosis. Our study demonstrates that low level of WWOX is associated with the triple-negative subtype of breast cancer (TNBC), which has higher stem cell phenotype and chemoresistance. We evaluated the role of WWOX in regulation of breast cancer stem cells (BCSC) phenotype and chemoresistance. Our results showed that knockdown of WWOX increases the stemness of breast cancer cells. Meanwhile, downregulation of WWOX induces the epithelial–mesenchymal transition (EMT) and chemoresistance of breast cancer cell lines. Our findings revealed the role of the WWOX in the regulation of the BCSC population and chemotherapeutic sensitivity and may provide insights for the development of more effective therapies targeting cancer stem cells in breast cancer.Impact statementOvercoming resistance to chemotherapy is one of the fundamental issues of clinical treatment and CSCs are responsible for the poor therapeutic effects of chemotherapy. WW domain-containing oxidoreductase (WWOX), an important tumor suppressor, regulatescancer cells’ response to chemotherapy. The major finding of ourstudy is the novel role of WWOX in the chemoresistance of breastcancer through the regulation of cell stemness and EMT. Theplasticity may play a crucial role in tumor metastasis,treatment resistance and tumor recurrence. Our findings may shednew light on the alterations of BCSCs and pave the way for thediscovery of novel and more effective therapies to treat breastcancer by targeting WWOX.
  • 15.

    【2hr】Long non-coding RNA HULC affects the proliferation, apoptosis, migration, and invasion of mesenchymal stem cells

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    机译 长期的非编码RNA HULC影响间充质干细胞的增殖，凋亡，迁移和侵袭
    摘要：Further studies on the molecular mechanisms of mesenchymal stem cells in the maintenance of growth and function are essential for their clinical application. Growing evidence has shown that long non-coding RNAs (lncRNAs) play an important role in the regulation of mesenchymal stem cells. Recently, it is reported that highly upregulated in liver cancer (HULC), with another lncRNA MALAT-1, accelerated liver cancer stem cell growth. The regulating role of MALAT-1 in mesenchymal stem cells has been investigated. However, the effects of HULC on the mesenchymal stem cells are unknown. In this study, we overexpressed HULC in mesenchymal stem cells derived from umbilical cord and analyzed the cell phenotypes, proliferation, apoptosis, migration, invasion and differentiation of mesenchymal stem cells. We found that overexpression of HULC significantly promotes cell proliferation through promoting cell division and inhibits cell apoptosis. HULC-overexpressed mesenchymal stem cells migrate and invade faster than control mesenchymal stem cells. HULC has no effect on phenotypes and differentiation of mesenchymal stem cells. Furthermore, we found that the expression of HULC in mesenchymal stem cells could be reduced by several inflammatory factors, including TNF-α, TGF-β1, and R848. Taken together, our data demonstrated that HULC has a vital role in the growth and function maintenance of mesenchymal stem cells without affecting differentiation.Impact statementExploring the molecular mechanisms of growth and function in MSCs is the key to improve their clinical therapeutic effects. Currently, more and more evidence show that the long non-coding RNA (lncRNA) plays an important role in the growth, stemness and function of MSCs.Both HULC and MALAT1 are the earliest discovered LNCRNAs, which are closely related to tumor growth. All of them can promote the growth of liver cancer stem cells. Previously, we have studied the effects of MALAT1 on the growth and function of MSCs. In this study, we focused on the effects of HULC on MSCs. We elucidated the effects of HULC on the growth and differentiation of MSCs, and explored the relationship between inflammatory stimuli and HULC expression in MSCs. Our findings provide a new molecular target for the growth and clinical application of MSCs.
  • 16.

    【2hr】Association between IL1A and IL1B polymorphisms and primary open angle glaucoma in a Brazilian population

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    机译 IL1A和IL1B多态性与巴西人群原发性开角型青光眼之间的关联
    摘要：The aim of this study was to investigate the association of five polymorphisms in the IL1A and IL1B genes in Brazilian patients with primary open angle glaucoma (POAG). A case–control study, including 214 unrelated POAG patients and 187 healthy individuals, was conducted to evaluate the frequency of polymorphisms in the IL1A and IL1B genes. Ophthalmic evaluation was performed and genomic DNA was obtained from all participants. Five single nucleotide polymorphisms (SNPs): IL1A (–889C/T: rs1800587:C > T, +4845G/T:rs17561G>T) and IL1B (–31C/T:rs1143627:T > C, –511C/T:rs16944C>T and +3954C/T:rs1143634:C > T) were genotyped through direct sequencing. The association of individual SNPs was tested using logistic regression. There was an association between the –31C/T and –511 C/T polymorphisms in the IL1B gene with POAG (p = 0.002 and p = 0.009, respectively). High linkage disequilibrium was observed between the –31C/T and –511C/T polymorphisms. The statistical analysis showed that the T/C haplotype (–31/–511) in the IL1B gene is more frequent in controls (p = 0.011) and the C/T haplotype (–31/–511) is more common in POAG patients (p = 0.018). Among POAG cases, the genotypic distribution of the –31C/T and –511 C/T SNPs was significantly different in patients who underwent anti-glaucomatous surgery compared to patients without surgery (p = 0.016 and 0.023, respectively). There was no statistically significant difference for the remaining SNPs between POAG patients and controls. In conclusion, the C allele of the –31C/T and the T allele of the –511C/T polymorphisms in the IL1B gene may represent a “risk haplotype” for the development of POAG in Brazilian individuals. Further studies with larger cohorts of patients are necessary to substantiate these findings.Impact statementThis study is the first, according to our knowledge, to show the association between glaucoma and the functional –31C/T single nucleotide polymorphism. We provide evidence indicating that homozygotes CC at –31C/T and TT at –511 C/T of IL1B are at risk for glaucoma. We also demonstrated that these polymorphisms are in strong linkage disequilibrium (LD). Increasing evidence support the role of inflammation in glaucoma and this study is an important result that reinforces these findings. How IL-1 signaling influences the triggering and pathogenesis of glaucoma remains to be investigated. Greater understanding of the mechanisms leading to glaucoma will provide the development of new management strategies that target the primary disease lesion and maybe the discovery of new treatments.
  • 17.

    【2hr】The expression of somatostatin receptor 2 decreases during cystgrowth in mice with polycystic kidney disease

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    机译 囊肿过程中生长抑素受体2的表达降低多囊肾疾病小鼠体内的生长
    摘要：Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal cyst formation and expansion. Several clinical trials show that somatostatin analogs halt cyst growth and progression of ADPKD by inhibiting adenosine 3′,5′-cyclic monophosphate (cAMP) signaling. However, two studies suggest that the effect of the somatostatin analog octreotide on kidney growth during the first year of treatment is reduced in the subsequent follow-ups and the kidney enlargement resumes. We hypothesize that this biphasic change in kidney growth during octreotide treatment may be due to changes in somatostatin receptor 2 (SSTR2) expression. Here we analyzed the expression of renal SSTR2 in various polycystic kidney disease (PKD) mouse models in which PKD1 gene expression was disrupted on postnatal day 10 or 18 by tamoxifen. Using immunohistochemical analysis, we showed that the distribution of SSTR2 in murine kidneys is mainly in distal tubules and collecting ducts. In addition, in both PKD models, we observed a significant decrease in SSTR2 expression in epithelia of dilated tubules and cystic epithelia in mice with end stage of PKD compared to wild-type mice. These findings were further confirmed by quantitative PCR (qPCR) on mRNA levels ofSSTR2. In conclusion, our data show that SSTR2 expression levels are reducedduring kidney cyst growth, which may suggest reduced efficacy in long-termtreatment with somatostatin analogs.Impact statementSomatostatin (SST) analogs have been shown to halt cyst growth andprogression of autosomal dominant polycystic kidney disease by severalclinical trials. However, two studies suggest that the effect of the SSTanalog octreotide on kidney growth during the first year of treatment isreduced in the subsequent follow-ups and the kidney enlargement resumes.This biphasic change in kidney growth during octreotide treatment may bepartially explained by alterations in SSTR2 expression. Here, we found thatSSTR2 is mainly expressed in distal tubules and collecting ducts in murinekidneys, and the expression of SSTR2 decreases during cyst growth in two PKDmouse models. Our data may thus provide possible explanations for the lackof efficacy in long-term treatment with SST analogs.
  • 18.

    【2hr】Corrigendum

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    机译 更正
    • 作者：
    • 刊名：Experimental Biology and Medicine
    • 2018年第13期
    摘要：
  • 19.

    【2hr】Expression of mitofusin 2 in human sperm and its relationship tosperm motility and cryoprotective potentials

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    机译 mitofusin 2在人精子中的表达及其与精子的关系精子活力和防冻潜能
    摘要：Mitofusin 2 is a kind of mitochondria membrane protein that has been implicated in maintenance of mitochondrial morphology and function. However, the expression and function of mitofusin 2 in human sperm are not well described at present. The aim of this study was to explore the location of mitofusin 2 in human sperm and to discover its relationship to human sperm functions like motility and cryoprotective potentials. Our result showed that mitofusin 2 is specifically localized in the 5–7 μm midpiece between the neck and main part of human sperm tail. The expression level of mitofusin 2 in human sperm was significantly different between the normozoospermia and asthenozoospermia groups (P < 0.05); meanwhile, the sperm of the asthenozoospermia group had a lower mitochondrial membrane potential (P < 0.05), but the results of TUNEL assay did not show significant difference between the two groups. Furthermore, we found that the expression level of mitofusin 2 in the freeze-resistant group (cryo-survival rate >40%) was significantly higher than that of the freeze-intolerant group (cryo-survival rate ≤40%) (P < 0.05). These results demonstrate that the expression level of mitofusin 2 is related to motility andcryoprotective potentials of human sperm. Mitofusin 2 may play a crucial role inthe function of human sperm, which needs further research to discover themechanism.Impact statementThe exact function of mitochondria in human sperm before and duringfertilization process remains controversial. MFN2 is a kind of mitochondriamembrane protein and participates in the regulation of mitochondrialmorphology and function. In this study, we discover the relationship of MFN2expression to human sperm motility and cryoprotective potentials. Ourresults suggest that MFN2 could be a new target for the mechanism researchof asthenozoospermia. MFN2 may also serve as a protein marker predicting theability of human sperm to sustain cryopreservation.
  • 20.

    【2hr】Analysis of the risk factors for contrast-induced nephropathy in over-aged patients receiving coronary intervention

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    机译 接受冠脉介入治疗的超龄患者造影剂诱发肾病的危险因素分析
    摘要：Contrast-induced nephropathy has been the common cause of hospital-acquired acute kidney injury in the elderly patients. This study aimed to analyze the risk factors for contrast-induced nephropathy in over-aged patients undergoing coronary angiography or percutaneous coronary intervention. A total of 470 over-aged patients (≥80 years old) were judged as the contrast-induced nephropathy group (n = 46) and non-contrast-induced nephropathy group (n = 424) according to the postoperative 48-h serum creatinine levels. The patients’ clinical information such as hypertension grade, number and degree of coronary artery stenosis, and death rate was compared. The risk factors for contrast-induced nephropathy were also analyzed. The hypertension grade in the contrast-induced nephropathy group was significantly higher than that in the non-contrast-induced nephropathy group (P = 0.004). The degree of coronary artery stenosis was significantly more in the contrast-induced nephropathy group compared with the non-contrast-induced nephropathy group (P = 0.003). The death rate of the contrast-induced nephropathy group (15.8%) was significantly higher than that of the non-contrast-induced nephropathy group (0.6%; P = 0.000). The percentage of patients with abnormal urine microalbumin was significantly bigger in the contrast-induced nephropathy group (62.5%) when comparing to the non-contrast-induced nephropathy group (23.6%; P = 0.00). Besides, there was also significant difference in the emergency/selective operation between the contrast-induced nephropathy group and non-contrast-induced nephropathy group (P = 0.001). Further, hypertension grade (P = 0.019), emergency/selective operation (P = 0.025), degree of coronary artery stenosis (P = 0.038), eGFR (P = 0.034), and urine microalbumin (P = 0.005) were the risk factors for contrast-induced nephropathy. Hypertension grade, emergency/selective operation, degree of coronary artery stenosis, eGFR, and urine microalbumin were the risk factors for contrast-induced nephropathy in over-aged patients receiving coronary angiography and percutaneous coronary intervention, providing guidance for the clinical prevention of contrast-induced nephropathy.Impact statementIn this work, we evaluated the risk factors for contrast-induced nephropathy (CIN) in over-aged patients receiving coronary angiography (CAG) and percutaneous coronary intervention (PCI). We found that hypertension grade, emergency/selective operation, degree of coronary artery stenosis, eGFR, and urine microalbumin were the risk factors for CIN in over-aged patients receiving CAG and PCI. This study provides guidance for the clinical prevention of CIN in over-aged patients undergoing coronary intervention, highlighting that a perioperative comprehensive management strategy is needed to improve the prognosis.
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