BACKGROUND & AIMS: :Although the involvement of Rho proteins in the pathogenesis of vascular diseases is well studied, little is known about the role of their upstream regulators, the Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular wall remodeling. We found that, among the RhoGEFs tested, MCP1 induced tyrosine phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or leukemia-associated RhoGEF in human aortic smooth muscle cells (HASMCs). Moreover, p115 RhoGEF inhibition suppressed MCP1-induced HASMC migration and proliferation. Consistent with these observations, balloon injury (BI) induced p115 RhoGEF tyrosine phosphorylation in rat common carotid arteries, and siRNA-mediated down-regulation of its levels substantially attenuated BI-induced smooth muscle cell migration and proliferation, resulting in reduced neointima formation. Furthermore, depletion of p115 RhoGEF levels also abrogated MCP1- or BI-induced Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling, which, as we reported previously, is involved in vascular wall remodeling. Our findings also show that protein kinase N1 (PKN1) downstream of Rac1-cyclin D1/CDK6 and upstream of CDK4-PAK1 in the p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling axis is involved in the modulation of vascular wall remodeling. Of note, we also observed that CCR2-Gi/o-Fyn signaling mediates MCP1-induced p115 RhoGEF and Rac1 GTPase activation. These findings suggest that p115 RhoGEF is critical for MCP1-induced HASMC migration and proliferation in vitro and for injury-induced neointima formation in vivo by modulating Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling.

背景与目标： : 尽管对Rho蛋白参与血管疾病的发病机理进行了很好的研究，但对其上游调节剂Rho鸟嘌呤核苷酸交换因子 (rhoiefs) 的作用知之甚少。在这里，我们试图鉴定参与单核细胞趋化蛋白1 (MCP1) 诱导的血管壁重塑的RhoGEFs。我们发现，在测试的RhoGEFs中，MCP1诱导人主动脉平滑肌细胞 (HASMCs) 中p115 RhoGEF的酪氨酸磷酸化，但不诱导PDZ RhoGEF或与白血病相关的RhoGEF的酪氨酸磷酸化。此外，p115 rhoge抑制抑制了MCP1-induced HASMC的迁移和增殖。与这些观察结果一致，球囊损伤 (BI) 在大鼠颈总动脉中诱导了p115 RhoGEF酪氨酸磷酸化，而siRNA介导的其水平下调大大减弱了BI诱导的平滑肌细胞迁移和增殖，从而减少了新内膜的形成。此外，p115 RhoGEF水平的耗竭也消除了MCP1或BI诱导的Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号传导，正如我们先前报道的那样，这与血管壁重塑有关。我们的发现还表明，Rac1-cyclin D1/CDK6下游和p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号轴CDK4-PAK1上游的蛋白激酶N1 (PKN1) 参与了血管壁重塑的调节。值得注意的是，我们还观察到CCR2-Gi/o-Fyn信号介导MCP1-induced p115 rhoge和rac1gtpase激活。这些发现表明，p115 RhoGEF对于MCP1-induced HASMC在体外迁移和增殖以及通过调节Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号传导在体内损伤诱导的新内膜形成至关重要。

BACKGROUND & AIMS: OBJECTIVE:To investigate the antifibrotic role of rosmarinic acid (RA), a natural polyphenolic compound, on HSCs activation/proliferation and apoptosis in vitro and in vivo. METHODS:The impact of RA on stellate cell line (HSC-T6) proliferation, activation and apoptosis was assessed along with its safety on primary hepatocytes. In vivo, rats were divided into: (i) normal; (ii) thioacetamide (TAA)-intoxicated rats for 12 weeks; (iii) TAA + silymarin or (iv) TAA + RA. At the end of experiment, liver functions, oxidative stress, inflammatory and profibrogenic markers, tissue inhibitor metalloproteinases type-1 (TIMP-1) and hydroxyproline (HP) levels were evaluated. Additionally, liver histopathology and immunohistochemical examinations of alpha-smooth muscle actin (α-SMA), caspase-3 and proliferation cellular nuclear antigen (PCNA) were determined. RESULTS:RA exhibited anti-proliferative effects on cultured HSCs in a time and concentration dependent manner showing an IC50 of 276 μg/mL and 171 μg/mL for 24 h and 48 h, respectively, with morphological reversion of activated stellate cell morphology to quiescent form. It significantly improved ALT, AST, oxidative stress markers and reduced TIMP-1, HP levels, inflammatory markers and fibrosis score (S1 vs S4). Furthermore, reduction in α-SMA plus elevation in caspase-3 expressions of HSCs in vitro and in vivo associated with an inhibition in proliferation of damaged hepatocytes were recorded. CONCLUSIONS:RA impeded the progression of liver fibrosis through inhibition of HSCs activation/proliferation and induction of apoptosis with preservation of hepatic architecture.

背景与目标：

BACKGROUND & AIMS: :The diffusible messenger, nitric oxide plays multiple roles in neuroprotection, neurodegeneration and brain plasticity. Its involvement in neurogenesis has been disputed, on the basis of results on models in vivo and in culture. We report here that pharmacological blockade of nitric oxide production in rat pups resulted, during a restricted time window of the first three postnatal days, in increased cerebellar proliferation rate, as assessed through tritiated thymidine or BrdU incorporation into DNA. This was accompanied by increased expression of Myc, a transcription factor essential for cerebellar development, and of the cell cycle regulating gene, cyclin D1. These effects were mediated downstream by the nitric oxide-dependent second messenger, cGMP. Schedules of pharmacological NO deprivation targeted to later developmental stages (from postnatal day 3 to 7), no longer increased proliferation, probably because of partial escape of the cGMP level from nitric oxide control. Though limited to a brief temporal window, the proliferative effect of neonatal nitric oxide deprivation could be traced into adulthood. Indeed, the number of BrdU-labeled surviving cells, most of which were of neuronal phenotype, was larger in the cerebellum of 60-day-old rats that had been subjected to NO deprivation during the first three postnatal days than in control rats. Experiments on cell cultures from neonatal cerebellum confirmed that nitric oxide deprivation stimulated proliferation of cerebellar precursor cells and that this effect was not additive with the proliferative action of sonic hedgehog peptide. The finding that nitric oxide deprivation during early cerebellar neurogenesis, stimulates a brief increase in cell proliferation may contribute to a better understanding of the controversial role of nitric oxide in brain development.

背景与目标： 一氧化氮是可扩散的信使，在神经保护，神经变性和大脑可塑性中起着多种作用。根据体内和培养模型的结果，它在神经发生中的参与存在争议。我们在这里报告说，通过trisitation胸苷或BrdU掺入DNA来评估，在出生后的前三天的有限时间窗口内，大鼠幼崽中一氧化氮产生的药理学阻断导致小脑增殖率增加。伴随着Myc (小脑发育必不可少的转录因子) 和细胞周期调节基因cyclin d1的表达增加。这些作用是由一氧化氮依赖性第二信使cGMP介导的。针对后期发育阶段 (从出生后第3天到第7天) 的药理学无剥夺时间表，不再增加增殖，这可能是由于cGMP水平从一氧化氮控制中部分逸出所致。尽管仅限于短暂的颞窗，但新生儿一氧化氮剥夺的增殖作用可以追溯到成年。实际上，在60天大的大鼠的小脑中，BrdU标记的存活细胞的数量 (其中大多数是神经元表型) 在出生后的前三天没有遭受剥夺的大鼠比在对照组中更大。对新生儿小脑细胞培养物的实验证实，一氧化氮的剥夺刺激了小脑前体细胞的增殖，并且这种作用与sonic hedgehog肽的增殖作用无关。发现小脑早期神经发生过程中一氧化氮剥夺会刺激细胞增殖的短暂增加，这可能有助于更好地理解一氧化氮在大脑发育中的有争议作用。

BACKGROUND & AIMS: :Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.

背景与目标： : 尽管许多多发性骨髓瘤 (MM) 患者最初对细胞毒性治疗有反应，但大多数最终复发。采用化疗与靶向生物制剂相结合的新型治疗策略可能会显着增强肿瘤细胞对治疗的反应。我们测试了针对MM的全人抗igf-ir抗体 (A12)，并在体外显示了对MM细胞中igf-i或血清诱导的igf-ir信号的特异性抑制。在各种皮下异种移植MM模型中，A12作为单一药物被证明对体内肿瘤生长具有适度至显着的抑制作用。还在播散性异种移植MM.1S NOD/SCID模型中评估了A12，作为单一疗法或与目前临床使用的其他药物 (硼替佐米，美法仑) 联合使用。通过荧光素酶生物成像确定的肿瘤负荷急剧降低，并且当联合治疗时，总生存期显着延长。免疫组织化学分析表明，与对照肿瘤相比，A12治疗的肿瘤血管形成明显减少。此外，大多数MM系组成型分泌了大量的VEGF，并且在igf-i治疗后这种情况得到了增强。体外A12抑制igf-ir抑制了组成型和igf-i诱导的VEGF分泌，表明与A12治疗相关的推定抗血管生成机制可能有助于其抗肿瘤作用。

BACKGROUND & AIMS: AIM:To investigate the effects of inositol hexaphosphate (IP(6)) on proliferation of HT-29 human colon carcinoma cell line. METHODS:Cells were exposed to various concentrations (0, 1.8, 3.3, 5.0, 8.0, 13.0 mmol/L) of IP(6) for a certain period of time. Its effect on growth of HT-29 cells was measured by MTT assay. The expressions of cell cycle regulators treated with IP(6) for 2 d were detected by immunocytochemistry. RESULTS:IP(6) inhibited the HT-29 cell growth in a dose- and time-dependent manner. Analysis of cell cycle regulator expression revealed that IP(6) reduced the abnormal expression of P53 and PCNA and induced the expression of P21. CONCLUSION:IP(6) has potent inhibitory effect on proliferation of HT-29 cells by modulating the expression of special cell cycle regulators.

背景与目标：

BACKGROUND & AIMS: :The individual roles of the two TNFRs on dendritic cells (DC) are poorly understood. Investigating bone marrow-derived DC from TNFR-deficient mice, we found that cultures from TNFR1(-/-) mice continue to form proliferating clusters for 6-9 mo. In contrast, DC derived from wild-type, TNFR2(-/-), or TNFR1/2(-/-) mice survived for only 3-4 wk. DC obtained from these TNFR1(-/-) long term cultures (LTC) mice show an unusual mixed immature/mature phenotype. The continuous proliferation of the LTC is GM-CSF dependent and correlates with decreased protein levels of the cyclin-dependent kinase inhibitors p27(KIP1) and p21(CIP1). Prolonged survival of TNFR1(-/-) DC appears to be independent from NF-kappaB and Bcl-2 pathways and is rather enabled by the down-regulation of CD95, resulting in the resistance to CD95 ligand-induced apoptosis. These data point to proapoptotic signals mediated via TNFR1 and antiapoptotic signals mediated via TNFR2 in DC.

背景与目标： : 两种tnfr对树突状细胞 (DC) 的个体作用知之甚少。研究来自TNFR缺陷型小鼠的骨髓来源的DC，我们发现来自TNFR1(-/-) 小鼠的培养物在6-9个月内继续形成增殖簇。相反，来自野生型，TNFR2(-/-) 或TNFR1/2(-/-) 小鼠的DC仅存活3-4周。从这些TNFR1(-/-) 长期培养 (LTC) 小鼠获得的DC显示出异常的混合未成熟/成熟表型。LTC的持续增殖是gm-csf依赖性的，并且与细胞周期蛋白依赖性激酶抑制剂p27(KIP1) 和p21(CIP1) 的蛋白水平降低相关。TNFR1(-/-) DC的长期存活似乎独立于NF-κ b和Bcl-2途径，并且由于CD95的下调而导致对CD95配体诱导的凋亡的抗性。这些数据指向DC中通过TNFR1介导的促凋亡信号和通过TNFR2介导的抗凋亡信号。

BACKGROUND & AIMS: :Nanomaterials hold great promise in the manipulation and treatments of mesenchymal stem cells, since they allow the modulation of their properties and differentiation. However, systematic studies have to be carried out in order to assess their potential toxicological effects. The present study reports on biocompatibility evaluation of glycol-chitosan coated barium titanate nanoparticles (BTNPs) on rat mesenchymal stem cells (MSCs). BTNPs are a class of ceramic systems which possess interesting features for biological applications thanks to their peculiar dielectric and piezoelectric properties. Viability was evaluated up to 5 days of incubation (concentrations in the range 0-100 μg/ml) both quantitatively and qualitatively with specific assays. Interactions cells/nanoparticles were further investigated with analysis of the cytoskeleton conformation, with SEM and TEM imaging, and with AFM analysis. Finally, differentiation in adipocytes and osteocytes was achieved in the presence of high doses of BTNPs, thus highlighting the safety of these nanostructures towards mesenchymal stem cells.

背景与目标： : 纳米材料在间充质干细胞的操作和治疗中具有广阔的前景，因为它们可以调节其特性和分化。但是，必须进行系统的研究以评估其潜在的毒理学作用。本研究报道了乙二醇-壳聚糖包被的钛酸钡纳米颗粒 (BTNPs) 对大鼠间充质干细胞 (MSCs) 的生物相容性评价。BTNPs是一类陶瓷系统，由于其独特的介电和压电特性，具有用于生物应用的有趣功能。通过特定测定定量和定性地评估孵育5天 (浓度在0-100 μ g/ml范围内) 的活力。通过分析细胞骨架构象，SEM和TEM成像以及AFM分析进一步研究了细胞/纳米颗粒的相互作用。最后，在高剂量BTNPs的存在下实现了脂肪细胞和骨细胞的分化，从而突出了这些纳米结构对间充质干细胞的安全性。

BACKGROUND & AIMS: :Aberrant metabolism is a hallmark of cancer, but whole metabolomic flux measurements remain scarce. To bridge this gap, we developed a novel metabolic phenotypic analysis (MPA) method that infers metabolic phenotypes based on the integration of transcriptomics or proteomics data within a human genome-scale metabolic model. MPA was applied to conduct the first genome-scale study of breast cancer metabolism based on the gene expression of a large cohort of clinical samples. The modeling correctly predicted cell lines' growth rates, tumor lipid levels, and amino acid biomarkers, outperforming extant metabolic modeling methods. Experimental validation was obtained in vitro. The analysis revealed a subtype-independent "go or grow" dichotomy in breast cancer, where proliferation rates decrease as tumors evolve metastatic capability. MPA also identified a stoichiometric tradeoff that links the observed reduction in proliferation rates to the growing need to detoxify reactive oxygen species. Finally, a fundamental stoichiometric tradeoff between serine and glutamine metabolism was found, presenting a novel hallmark of estrogen receptor (ER)(+) versus ER(-) tumor metabolism. Together, our findings greatly extend insights into core metabolic aberrations and their impact in breast cancer.

背景与目标： : 异常代谢是癌症的标志，但整个代谢组通量测量仍然很少。为了弥合这一差距，我们开发了一种新颖的代谢表型分析 (MPA) 方法，该方法基于人类基因组规模代谢模型中转录组学或蛋白质组学数据的整合来推断代谢表型。根据大量临床样本的基因表达，将MPA应用于乳腺癌代谢的首次基因组规模研究。该模型正确预测了细胞系的生长速率，肿瘤脂质水平和氨基酸生物标志物，优于现有的代谢建模方法。在体外获得了实验验证。分析揭示了乳腺癌中独立于亚型的 “去或生长” 二分法，随着肿瘤发展转移能力，增殖率降低。MPA还确定了化学计量的权衡，该权衡将观察到的增殖速率降低与对活性氧的解毒需求的增长联系起来。最后，发现丝氨酸和谷氨酰胺代谢之间的基本化学计量权衡，呈现了雌激素受体 (ER)() 与ER(-) 肿瘤代谢的新标志。总之，我们的发现极大地扩展了对核心代谢异常及其对乳腺癌影响的见解。

BACKGROUND & AIMS: Melatonin (MLT) treatment in vivo has been shown to have immunomodulatory and anti-immunosenescent effects in the mouse model. In the present report, the in vitro effect of MLT on mitogen-induced lymphocyte proliferation and cytokine expression was evaluated in a rat model. Splenic lymphocytes were isolated from young (6 months) and old (24 months) F344 rats and were incubated with MLT in the presence or absence of mitogens. The proliferative response to concanavalin A (ConA) or PMA plus ionomycin was measured in splenocytes or T cells isolated from young and old rats. In addition, the induction of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production was measured in MLT-treated and untreated lymphocytes isolated from young and old rats. The ConA-induced lymphocyte proliferation and IL-2 expression were significantly lower and induction of IFN-gamma production was significantly higher in splenocytes and purified T cells isolated from old rats compared to splenocytes and T cells isolated from young rats. Treatment of lymphocytes with MLT did not significantly alter ConA-induced lymphocyte proliferation or IL-2 or IFN-gamma expression in lymphocytes isolated from either young or old rats. On the basis of these data, we conclude that in vitro MLT treatment had no immunomodulatory effect on lymphocytes from rats.

背景与目标： 体内褪黑激素 (MLT) 治疗已显示在小鼠模型中具有免疫调节和抗免疫衰老作用。在本报告中，在大鼠模型中评估了MLT对丝裂原诱导的淋巴细胞增殖和细胞因子表达的体外作用。从年轻 (6个月) 和老年 (24个月) F344大鼠中分离脾淋巴细胞，并在存在或不存在有丝分裂原的情况下与MLT一起孵育。在从年轻和老年大鼠分离的脾细胞或T细胞中测量了对伴刀豆球蛋白A (ConA) 或PMA加离子霉素的增殖反应。此外，在从年轻和老年大鼠分离的MLT处理和未处理的淋巴细胞中测量了interleukin-2 (IL-2) 和干扰素-γ (IFN-γ) 产生的诱导。与从年轻大鼠分离的脾细胞和T细胞相比，从老年大鼠分离的脾细胞和纯化的T细胞中，ConA诱导的淋巴细胞增殖和IL-2表达显着降低，而IFN-γ 产生的诱导显着更高。用MLT处理淋巴细胞不会显着改变从年轻或老年大鼠分离的淋巴细胞中ConA诱导的淋巴细胞增殖或IL-2或IFN-γ 表达。根据这些数据，我们得出结论，体外MLT治疗对大鼠淋巴细胞没有免疫调节作用。

BACKGROUND & AIMS: OBJECTIVE:This study aimed to investigate the effect of circular RNA itchy E3 ubiquitin protein ligase on cell proliferation and apoptosis and to explore its target micro-RNAs in prostate cancer cells. METHODS:Circular RNA itchy E3 ubiquitin protein ligase expression in human prostate cancer cells and normal prostate epithelial cells was determined by real time-quantitative polymerase chain reaction assay. Circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids (circular RNA itchy E3 ubiquitin protein ligase(+) group and control overexpression plasmids group were transfected with PC-3 cells. Rescue experiment was performed by transfection of circular RNA itchy E3 ubiquitin protein ligase overexpression and micro-197 overexpression plasmids (circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids/micro RNA (+) group) into PC-3 cells. Cell Counting Kit-8 and annexin V/propidium iodide assays were conducted to evaluate cell proliferation and apoptosis, respectively. Western blot was performed to determine the expressions of apoptotic-related markers. RESULTS:Circular RNA itchy E3 ubiquitin protein ligase expression was decreased in DU 145, 22RV1, VCaP, and PC-3 cells compared to RWPE cells. In PC-3 cells, cell proliferation rate was reduced in circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids group compared to control overexpression plasmids group at 48 hours and 72 hours. Cell apoptosis rate was elevated in circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids group compared to control overexpression plasmids group at 48 hours, and Western blot showed the similar results. Micro RNA-197 but not micro RNA-31 or micro RNA-432 was the target micro-RNA of circular RNA itchy E3 ubiquitin protein ligase. In rescue experiments, cell proliferation rate was elevated, but apoptosis rate was reduced in circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids/micro RNA (+) group compared to circular RNA itchy E3 ubiquitin protein ligase overexpression plasmids group, indicating that circular RNA itchy E3 ubiquitin protein ligase upregulation inhibited cell proliferation but promoted apoptosis through downregulating micro RNA-197. CONCLUSION:Circular RNA itchy E3 ubiquitin protein ligase upregulation suppresses cell proliferation but promotes apoptosis through targeting micro RNA-197 in prostate cancer. Our study may provide a new insight for the treatment of prostate cancer.

背景与目标：

BACKGROUND & AIMS: :Exosomes are key mediators of intercellular communication and play a role in the pathogenesis and progression of cancer. Exosomes in circulating body fluids serve as molecular markers for cancer diagnosis. This study aimed to investigate the role of exosomal microRNA (miR)-1910-3p in breast cancer and determine its clinical diagnostic value. MiR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo. In vitro, exosomes enriched in miR-1910-3p transferred miR-1910-3p to mammary epithelial cells and breast cancer cells, promoting proliferation and migration, inhibiting apoptosis, and inducing autophagy. In vivo, exosomes enriched in miR-1910-3p promoted the proliferation and migration of breast cancer cells. MiR-1910-3p downregulated myotubularin-related protein 3, activated the NF-κB and wnt/β-catenin signaling pathway, and promoted breast cancer progression. Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis when used in combination with the traditional tumor marker CA153. In conclusion, breast cancer cell-derived exosomes promoted the growth, metastasis, and autophagy of breast cancer cells by transferring miR-1910-3p. MiR-1910-3p in serum exosomes may serve as a novel molecular marker for breast cancer diagnosis.

背景与目标： : 外泌体是细胞间通讯的关键介质，在癌症的发病机理和进展中起作用。循环体液中的外泌体可作为癌症诊断的分子标记。本研究旨在探讨外体microRNA (miR)-1910-3p在乳腺癌中的作用，并确定其临床诊断价值。MiR-1910-3p在体外和体内促进了乳腺癌细胞的增殖和迁移。在体外，富含miR-1910-3p的外泌体miR-1910-3p转移至乳腺上皮细胞和乳腺癌细胞，促进增殖和迁移，抑制细胞凋亡，诱导自噬。在体内，富含miR-1910-3p的外泌体促进了乳腺癌细胞的增殖和迁移。MiR-1910-3p下调肌管蛋白相关蛋白3，激活NF-κ b和wnt/β-catenin信号通路，促进乳腺癌进展。外泌体中的血清miR-1910-3p是与传统肿瘤标志物ca153联合使用时提高乳腺癌诊断敏感性的有效诊断标志物。总之，乳腺癌细胞来源的外泌体通过转移miR-1910-3p促进乳腺癌细胞的生长，转移和自噬。血清外泌体中的MiR-1910-3p可作为乳腺癌诊断的新型分子标志物。

BACKGROUND & AIMS: :Consumption of a plant-based diet can prevent the development and progression of chronic diseases associated with extensive neovascularization, including solid malignant tumors. In previous studies, we have shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell proliferation and in vitro angiogenesis. In the present study, we report that certain structurally related flavonoids are more potent inhibitors than genistein. Indeed, 3-hydroxyflavone, 3',4'-dihydroxyflavone, 2',3'-dihydroxyflavone, fisetin, apigenin, and luteolin inhibited the proliferation of normal and tumor cells, as well as in vitro angiogenesis, at half-maximal concentrations in the low micromolar range. We have previously demonstrated that genistein concentrations in the urine of subjects consuming a plant-based diet is 30-fold higher than in subjects consuming a traditional Western diet. The wider distribution and the more abundant presence of flavonoids in the plant kingdom, together with the present results, suggest that flavonoids may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumors.

背景与目标： : 食用以植物为基础的饮食可以防止与广泛的新血管形成 (包括实体恶性肿瘤) 相关的慢性疾病的发展和进展。在先前的研究中，我们已经表明植物来源的异黄酮染料木素是细胞增殖和体外血管生成的有效抑制剂。在本研究中，我们报告某些结构相关的类黄酮比染料木黄酮更有效。实际上，3-羟基黄酮，3 '，4'-二羟基黄酮，2 '，3'-二羟基黄酮，fisetin，芹菜素和木犀草素抑制了正常细胞和肿瘤细胞的增殖，以及体外血管生成在低微摩尔范围内的最大浓度。我们以前已经证明，食用植物性饮食的受试者尿液中的染料木黄酮浓度比食用传统西方饮食的受试者高30倍。类黄酮在植物界的更广泛分布和更丰富的存在，以及目前的结果，表明类黄酮可能有助于植物性饮食对慢性疾病 (包括实体瘤) 的预防作用。

BACKGROUND & AIMS: :Many of new chemical discovered in pharmaceutical industry are hydrophobic compounds. Various techniques have been used to overcome solubility problems of hydrophobic drugs in aqueous media. In the meantime, dendrimers have been considered for sustainability, nanoscale size, high carry capacity, tunable terminal functional groups in terms of drug delivery and solubility. In this work, we have synthesized poly(propylene imine) (PPI) dendrimer up to fifth generation using reduction of nitrile groups after Michael addition and also, polyamidoamine (PAMAM) dendrimer up to fourth generation using Michael addition and amidation reactions. fourth and fifth generations of PPI dendrimer and fourth and third generations of PAMAM dendrimer in different concentrations were used to evaluate the solubility of two hydrophobic drugs (tetracycline and dexamethasone). Furthermore, cytotoxicity of dendrimers and dendrimers/drugs hybrids was studied. The results showed that with increasing concentrations and also the generation of dendrimers, the solubility of these two hydrophobic drugs was increased. Cytotoxicity study through MTT assay against Osteoblast-like cell line (MG-63 cells) showed that dendrimers were relatively cytotoxic where adding dexamethasone caused higher cytotoxicity. However, tetracycline showed no significant effect on cytotoxicity whereas prevented cell proliferation.

背景与目标： : 制药工业中发现的许多新化学物质都是疏水性化合物。已使用各种技术来克服疏水性药物在水性介质中的溶解度问题。同时，已经考虑了树枝状聚合物的可持续性，纳米级尺寸，高承载能力，在药物传递和溶解度方面可调的末端官能团。在这项工作中，我们使用迈克尔加成和酰胺化反应后的腈基还原合成了直到第五代的聚 (丙烯亚胺) (PPI) 树枝状大分子，以及使用迈克尔加成和酰胺化反应直到第四代的聚酰胺胺 (PAMAM) 树枝状大分子。使用不同浓度的第四代和第五代PPI树状聚合物以及第四代和第三代PAMAM树状聚合物来评估两种疏水药物 (四环素和地塞米松) 的溶解度。此外，还研究了树状大分子和树状大分子/药物杂种的细胞毒性。结果表明，随着浓度的增加和树枝状聚合物的产生，这两种疏水性药物的溶解度都增加了。通过MTT分析对成骨细胞样细胞系 (MG-63细胞) 的细胞毒性研究表明，在添加地塞米松引起较高细胞毒性的情况下，树枝状聚合物具有相对的细胞毒性。然而，四环素对细胞毒性没有显着影响，而阻止了细胞增殖。

BACKGROUND & AIMS: Background:Skull diversity in the neotropical leaf-nosed bats (Phyllostomidae) evolved through a heterochronic process called peramorphosis, with underlying causes varying by subfamily. The nectar-eating (subfamily Glossophaginae) and blood-eating (subfamily Desmondontinae) groups originate from insect-eating ancestors and generate their uniquely shaped faces and skulls by extending the ancestral ontogenetic program, appending new developmental stages and demonstrating peramorphosis by hypermorphosis. However, the fruit-eating phyllostomids (subfamilies Carollinae and Stenodermatinae) adjust their craniofacial development by speeding up certain developmental processes, displaying peramorphosis by acceleration. We hypothesized that these two forms of peramorphosis detected by our morphometric studies could be explained by differential growth and investigated cell proliferation during craniofacial morphogenesis. Results:We obtained cranial tissues from four wild-caught bat species representing a range of facial diversity and labeled mitotic cells using immunohistochemistry. During craniofacial development, all bats display a conserved spatiotemporal distribution of proliferative cells with distinguishable zones of elevated mitosis. These areas were identified as modules by the spatial distribution analysis. Ancestral state reconstruction of proliferation rates and patterns in the facial module between species provided support, and a degree of explanation, for the developmental mechanisms underlying the two models of peramorphosis. In the long-faced species, Glossophaga soricina, whose facial shape evolved by hypermorphosis, cell proliferation rate is maintained at lower levels and for a longer period of time compared to the outgroup species Miniopterus natalensis. In both species of studied short-faced fruit bats, Carollia perspicillata and Artibeus jamaicensis, which evolved under the acceleration model, cell proliferation rate is increased compared to the outgroup. Conclusions:This is the first study which links differential cellular proliferation and developmental modularity with heterochronic developmental changes, leading to the evolution of adaptive cranial diversity in an important group of mammals.

背景与目标：

BACKGROUND & AIMS: :At present, the functional recovery after nerve injury is not satisfactory in clinical practice. The aim of this study was to explore the molecular mechanism of miR-21 promoting Schwann cells (SC) proliferation and axon regeneration after peripheral nerve injury, providing a theoretical basis for injured nerve repair. Nerve injury models were constructed to determine the expression of miR-21 in the injured nerve by Quantitative Real-Time PCR (qRT-PCR). After miR-21 over-expression SC (mimic-miR-21) group, control SC (control-miR-21) group and blank SC (RSC96) group were constructed, SC proliferation was determined by CCK-8, cell cycle was analysed by flow cytometry, dorsal root ganglion neuron (DRGn) axon regeneration was observed after DRGn was cultured with SCs for 7 days, the expressions of TGFβI, TIMP3, EPHA4 as well as apoptosis-related proteins caspase-3 and caspase-9 were detected by qRT-PCR and Western blot in the three groups, respectively. Target genes were confirmed by dual-luciferase reporter gene assay. The expressions of TGFβI, TIMP3 and EPHA4 were assessed by immunofluorescence in vivo. qRT-PCR indicated that miR-21 expression was significantly higher in the model group than in the sham operation and blank groups. SC proliferation index (PI) was significantly higher, the apoptosis rate was significantly lower, the axon was significantly longer, and mRNA and protein expressions of TGFβI, TIMP3, EPHA4 as well as apoptosis-related proteins caspase-3 and caspase-9 were significantly lower in the mimic-miR-21 group than in the control-miR-21 and RSC96 groups. The double luciferase assay confirmed that TGFβI, TIMP3 and EPHA4 were potential target genes of miR-21. In vivo immunofluorescence also indicated that expressions of TGFβI, TIMP3, EPHA4 were lower in the mimic-miR-21 group than in the control-miR-21 and RSC96 groups. We conclude that during injured peripheral nerve repair, miRNA-21 plays an important role in promoting SC proliferation and axon regeneration by regulating TGFβI, TIMP3 and EPHA4 target genes.

背景与目标： : 目前，神经损伤后的功能恢复在临床上并不令人满意。本研究旨在探讨周围神经损伤后miR-21促进雪旺细胞 (SC) 增殖和轴突再生的分子机制，为损伤神经修复提供理论依据。构建神经损伤模型，通过定量实时PCR (qRT-PCR) 测定损伤神经中miR-21的表达。构建miR-21过表达SC (mimic-miR-21) 组，对照组SC (control-miR-21) 组和空白SC (RSC96) 组，用CCK-8测定SC的增殖，用流式细胞术分析细胞周期，用SCs培养DRGn 7 d后观察背根神经节神经元 (DRGn) 轴突再生，qRT-PCR和Western blot分别检测三组中TGFβI，TIMP3，EPHA4以及凋亡相关蛋白caspase-3和caspase-9的表达。通过双荧光素酶报告基因分析证实了靶基因。通过体内免疫荧光评估tgfβ i，TIMP3和EPHA4的表达。qRT-PCR显示模型组miR-21表达明显高于假手术组和空白组。mimic-miR-21组的SC增殖指数 (PI) 明显升高，凋亡率明显降低，轴突明显延长，TGFβI，TIMP3，EPHA4以及凋亡相关蛋白caspase-3和caspase-9的mRNA和蛋白表达明显低于control-miR-21和RSC96组。双荧光素酶检测证实tgf β i、TIMP3和EPHA4是miR-21的潜在靶基因。体内免疫荧光还表明，mimic-miR-21组tgfβ i，TIMP3，EPHA4的表达低于control-miR-21和RSC96组。我们得出结论，在受损的周围神经修复过程中，miRNA-21通过调节tgfβ i，TIMP3和EPHA4靶基因在促进SC增殖和轴突再生中起重要作用。