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Neurexin-2 is a potential regulator of inflammatory pain in the spinal dorsal horn of rats. Neurexin-2是大鼠脊髓背角炎症性疼痛的潜在调节因子。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-12-01 Epub Date: 2020-11-08 DOI: 10.1111/jcmm.15707
Longsheng Xu, Qingli Feng, Housheng Deng, Xiaoping Zhang, Huadong Ni, Ming Yao

Chronic pain is one of the serious conditions that affect human health and remains cure still remains a serious challenge as the molecular mechanism remains largely unclear. Here, we used label-free proteomics to identify potential target proteins that regulate peripheral inflammatory pain and reveal its mechanism of action. Inflammation in peripheral tissue was induced by injecting complete Freund's adjuvant (CFA) into rat hind paw. A proteomic method was adopted to compare the spinal dorsal horn (SDH) in peripheral inflammatory pain (PIP) model rats with controls. Differential proteins were identified in SDH proteome by label-free quantification. The role of screened target proteins in the PIP was verified by small interfering RNA (siRNA). A total of 3072 and 3049 proteins were identified in CFA and normal saline (NS) groups, respectively, and 13 proteins were identified as differentially expressed in the CFA group. One of them, neurexin-2, was validated for its role in the inflammatory pain. Neurexin-2 was up-regulated in the CFA group, which was confirmed by quantitative PCR. Besides, intrathecal siRNA-mediated knock-down of neurexin-2 attenuated CFA-induced mechanical and thermal hyperalgesia and reduced the expression of SDH membrane glutamate receptors (eg mGlu receptor 1, AMPA receptor) and postsynaptic density (eg PSD-95, DLG2). These findings increased the understanding of the role of neurexin-2 in the inflammatory pain, implicating that neurexin-2 acts as a potential regulatory protein of inflammatory pain through affecting synaptic plasticity in the SDH of rats.

慢性疼痛是影响人类健康的严重疾病之一,由于其分子机制尚不清楚,其治疗仍是一个严峻的挑战。在这里,我们使用无标记蛋白质组学来鉴定调节外周炎性疼痛的潜在靶蛋白并揭示其作用机制。采用大鼠后爪注射完全弗氏佐剂(CFA)诱导外周组织炎症反应。采用蛋白质组学方法对外周炎性疼痛(PIP)模型大鼠脊髓背角(SDH)与对照组进行比较。通过无标记定量鉴定SDH蛋白质组中的差异蛋白。筛选的靶蛋白在PIP中的作用通过小干扰RNA (siRNA)得到验证。CFA组和生理盐水(NS)组分别鉴定出3072和3049个蛋白,CFA组鉴定出13个蛋白差异表达。其中一种是神经素-2,它在炎症性疼痛中的作用得到了证实。经定量PCR证实,CFA组Neurexin-2表达上调。此外,鞘内sirna介导的神经素-2敲除可减轻cfa诱导的机械痛敏和热痛敏,降低SDH膜谷氨酸受体(如mGlu受体1、AMPA受体)的表达和突触后密度(如PSD-95、DLG2)。这些发现增加了对neurexin-2在炎症性疼痛中的作用的理解,暗示neurexin-2通过影响大鼠SDH突触可塑性作为炎症性疼痛的潜在调节蛋白。
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引用次数: 2
Aldosterone enhances high phosphate-induced vascular calcification through inhibition of AMPK-mediated autophagy. 醛固酮通过抑制ampk介导的自噬增强高磷酸盐诱导的血管钙化。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-12-01 Epub Date: 2020-11-04 DOI: 10.1111/jcmm.15813
Jing-Wei Gao, Wan-Bing He, Chang-Ming Xie, Ming Gao, Lei-Yu Feng, Zhao-Yu Liu, Jing-Feng Wang, Hui Huang, Pin-Ming Liu

It remains unclear whether the necessity of calcified mellitus induced by high inorganic phosphate (Pi) is required and the roles of autophagy plays in aldosterone (Aldo)-enhanced vascular calcification (VC) and vascular smooth muscle cell (VSMC) osteogenic differentiation. In the present study, we found that Aldo enhanced VC both in vivo and in vitro only in the presence of high Pi, alongside with increased expression of VSMC osteogenic proteins (BMP2, Runx2 and OCN) and decreased expression of VSMC contractile proteins (α-SMA, SM22α and smoothelin). However, these effects were blocked by mineralocorticoid receptor inhibitor, spironolactone. In addition, the stimulatory effects of Aldo on VSMC calcification were further accelerated by the autophagy inhibitor, 3-MA, and were counteracted by the autophagy inducer, rapamycin. Moreover, inhibiting adenosine monophosphate-activated protein kinase (AMPK) by Compound C attenuated Aldo/MR-enhanced VC. These results suggested that Aldo facilitates high Pi-induced VSMC osteogenic phenotypic switch and calcification through MR-mediated signalling pathways that involve AMPK-dependent autophagy, which provided new insights into Aldo excess-associated VC in various settings.

目前尚不清楚是否需要高无机磷酸盐(Pi)诱导的钙化性糖尿病,以及自噬在醛固酮(Aldo)增强血管钙化(VC)和血管平滑肌细胞(VSMC)成骨分化中的作用。在本研究中,我们发现Aldo仅在高Pi存在的情况下,体内和体外都能增强VC,同时VSMC成骨蛋白(BMP2、Runx2和OCN)的表达增加,VSMC收缩蛋白(α-SMA、SM22α和smoothelin)的表达降低。然而,这些作用被矿化皮质激素受体抑制剂螺内酯阻断。此外,Aldo对VSMC钙化的刺激作用被自噬抑制剂3-MA进一步加速,并被自噬诱导剂雷帕霉素抵消。此外,化合物C抑制单磷酸腺苷活化蛋白激酶(AMPK)可减弱Aldo/ mr增强VC。这些结果表明,Aldo通过mr介导的信号通路促进高pi诱导的VSMC成骨表型转换和钙化,这些信号通路涉及ampk依赖性自噬,这为各种情况下Aldo过量相关VC提供了新的见解。
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引用次数: 17
Overview of the molecular determinants contributing to the expression of Psoriasis and Psoriatic Arthritis phenotypes. 银屑病和银屑病关节炎表型表达的分子决定因素综述。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-12-01 Epub Date: 2020-10-31 DOI: 10.1111/jcmm.15742
Valerio Caputo, Claudia Strafella, Andrea Termine, Annunziata Dattola, Sara Mazzilli, Caterina Lanna, Terenzio Cosio, Elena Campione, Giuseppe Novelli, Emiliano Giardina, Raffaella Cascella

Psoriasis and psoriatic arthritis are multifactorial chronic disorders whose etiopathogenesis essentially derives from the alteration of several signalling pathways and the co-occurrence of genetic, epigenetic and non-genetic susceptibility factors that altogether affect the functional and structural property of the skin. Although shared and differential susceptibility genes and molecular pathways are known to contribute to the onset of pathological phenotypes, further research is needed to dissect the molecular causes of psoriatic disease and its progression towards Psoriatic Arthritis. This review will therefore be addressed to explore differences and similarities in the etiopathogenesis and progression of both disorders, with a particular focus on genes involved in the maintenance of the skin structure and integrity (keratins and collagens), modulation of patterns of recognition (through Toll-like receptors and dectin-1) and immuno-inflammatory response (by NLRP3-dependent inflammasome) to microbial pathogens. In addition, special emphasis will be given to the contribution of epigenetic elements (methylation pattern, non-coding RNAs, chromatin modifiers and 3D genome organization) to the etiopathogenesis and progression of psoriasis and psoriatic arthritis. The evidence discussed in this review highlights how the knowledge of patients' clinical and (epi)genomic make-up could be helpful for improving the available therapeutic strategies for psoriasis and psoriatic arthritis treatment.

银屑病和银屑病关节炎是一种多因素慢性疾病,其发病机制主要源于几种信号通路的改变以及遗传、表观遗传和非遗传易感性因素的共同发生,这些因素共同影响皮肤的功能和结构特性。虽然已知共有的和不同的易感基因和分子途径有助于病理表型的发生,但需要进一步的研究来解剖银屑病的分子原因及其向银屑病关节炎的进展。因此,本综述将探讨这两种疾病的发病机制和进展的差异和相似之处,特别关注参与维持皮肤结构和完整性的基因(角蛋白和胶原蛋白),识别模式的调节(通过toll样受体和dectin-1)和对微生物病原体的免疫炎症反应(通过nlrp3依赖性炎症体)。此外,将特别强调表观遗传元件(甲基化模式,非编码rna,染色质修饰剂和3D基因组组织)对银屑病和银屑病关节炎的发病和进展的贡献。本综述中讨论的证据强调了患者临床和(epi)基因组组成的知识如何有助于改善银屑病和银屑病关节炎治疗的现有治疗策略。
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引用次数: 38
Hydrogen sulphide ameliorates dopamine-induced astrocytic inflammation and neurodegeneration in minimal hepatic encephalopathy. 硫化氢改善多巴胺诱导的星形细胞炎症和最小肝性脑病的神经变性。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-12-01 Epub Date: 2020-10-28 DOI: 10.1111/jcmm.15728
Weishan Zhuge, Qichuan Zhuge, Weikan Wang, Xiaoai Lu, Ruimin You, Leping Liu, He Yu, Jian Wang, Xuebao Wang, Yiru Ye, Saidan Ding

It has been demonstrated that the action of dopamine (DA) could enhance the production of tumour necrosis factor-α (TNF-α) by astrocytes and potentiate neuronal apoptosis in minimal hepatic encephalopathy (MHE). Recently, sodium hydrosulfide (NaHS) has been found to have neuroprotective properties. Our study addressed whether NaHS could rescue DA-challenged inflammation and apoptosis in neurons to ameliorate memory impairment in MHE rats and in the neuron and astrocyte coculture system. We found that NaHS suppressed DA-induced p65 acetylation, resulting in reduced TNF-α production in astrocytes both in vitro and in vivo. Furthermore, decreased apoptosis was observed in neurons exposed to conditioned medium from DA + NaHS-challenged astrocytes, which was similar to the results obtained in the neurons exposed to TNF-α + NaHS, suggesting a therapeutic effect of NaHS on the suppression of neuronal apoptosis via the reduction of TNF-α level. DA triggered the inactivation of p70 S6 ribosomal kinase (S6K1) and dephosphorylation of Bad, resulting in the disaggregation of Bclxl and Bak and the release of cytochrome c (Cyt. c), and this process could be reversed by NaHS administration. Our work demonstrated that NaHS attenuated DA-induced astrocytic TNF-α release and ameliorated inflammation-induced neuronal apoptosis in MHE. Further research into this approach may uncover future potential therapeutic strategies for MHE.

研究表明,多巴胺(DA)的作用可促进星形胶质细胞产生肿瘤坏死因子-α (TNF-α),并促进极小性肝性脑病(MHE)的神经元凋亡。最近,人们发现氢硫化钠(NaHS)具有神经保护作用。我们的研究探讨了NaHS是否可以挽救da挑战的神经元炎症和凋亡,从而改善MHE大鼠和神经元和星形胶质细胞共培养系统中的记忆障碍。我们发现NaHS抑制da诱导的p65乙酰化,导致体外和体内星形胶质细胞中TNF-α的产生减少。此外,DA + NaHS刺激的星形胶质细胞暴露于条件培养基中,神经元凋亡减少,这与暴露于TNF-α + NaHS的神经元的结果相似,表明NaHS通过降低TNF-α水平来抑制神经元凋亡。DA触发p70 S6核糖体激酶(S6K1)的失活和Bad的去磷酸化,导致Bclxl和Bak的分解和细胞色素c (Cyt)的释放。c),这一过程可以通过NaHS管理来逆转。我们的研究表明,NaHS可减弱da诱导的星形细胞TNF-α释放,并改善炎症诱导的MHE神经元凋亡。对这种方法的进一步研究可能会发现MHE未来潜在的治疗策略。
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引用次数: 2
Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction. Tris-DBA通过SIRT1和SIRT3介导的自噬诱导减弱NLRP3炎症小体的激活信号来改善IgA肾病。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-12-01 Epub Date: 2020-11-01 DOI: 10.1111/jcmm.15663
Chung-Yao Wu, Kuo-Feng Hua, Shin-Ruen Yang, Yi-Shan Tsai, Shun-Min Yang, Chih-Yu Hsieh, Chia-Chao Wu, Jia-Feng Chang, Jack L Arbiser, Chiz-Tzung Chang, Ann Chen, Shuk-Man Ka

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B-cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)-mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechanism of action were examined in a mouse model of IgAN. Treatment of IgAN mice with Tris DBA resulted in markedly improved renal function, albuminuria and renal pathology, including glomerular cell proliferation, neutrophil infiltration, sclerosis and periglomerular inflammation in the renal interstitium, together with (Clin J Am Soc Nephrol. 2011, 6, 1301-1307) reduced mitochondrial ROS generation; (Am J Physiol-Renal Physiol. 2011. 301, F1218-F1230) differentially regulated autophagy and NLRP3 inflammasome; (Clin J Am Soc Nephrol. 2012, 7, 427-436) inhibited phosphorylation of JNK, ERK and p38 MAPK signalling pathways, and priming signal of the NLRP3 inflammasome; and (Free Radic Biol Med. 2013, 61, 285-297) blunted NLRP3 inflammasome activation through SIRT1- and SIRT3-mediated autophagy induction, in renal tissues or cultured macrophages. In conclusion, Tris DBA effectively ameliorated the mouse IgAN model and targeted signalling pathways downstream of ICs-mediated interaction, which is a novel immunomodulatory strategy. Further development of Tris DBA as a therapeutic candidate for IgAN is warranted.

Tris (dibenzylideneacetone) dipalladium (Tris DBA)是一种小分子钯络合物,可以抑制胰腺癌、淋巴细胞白血病和多发性骨髓瘤细胞的生长和增殖。鉴于这种化合物对b细胞恶性肿瘤特别有效,我们已经提出它可以缓解免疫复合物(ic)介导的疾病,特别是IgA肾病(IgAN)。采用IgAN小鼠模型,探讨了Tris DBA对肾小球细胞增殖和肾脏炎症的治疗作用及作用机制。用Tris DBA治疗IgAN小鼠可显著改善肾功能、蛋白尿和肾脏病理,包括肾小球细胞增殖、中性粒细胞浸润、硬化和肾间质肾小球周围炎症,同时减少线粒体ROS生成(clinj Am Soc Nephrol. 2011, 6, 1301-1307);[J] .中国医学杂志。2011。301, F1218-F1230)差异调节自噬和NLRP3炎性体;[J] .中华临床医学杂志。2012,7,427-436]抑制JNK, ERK和p38 MAPK信号通路的磷酸化,以及NLRP3炎性体的启动信号;和(Free radical Biol Med. 2013, 61, 285-297)通过SIRT1-和sirt3介导的自噬诱导,在肾组织或培养的巨噬细胞中减弱NLRP3炎性体的激活。综上所述,Tris DBA有效改善了小鼠IgAN模型,并靶向了ics介导的相互作用下游的信号通路,这是一种新的免疫调节策略。值得进一步开发Tris DBA作为IgAN的候选治疗药物。
{"title":"Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction.","authors":"Chung-Yao Wu,&nbsp;Kuo-Feng Hua,&nbsp;Shin-Ruen Yang,&nbsp;Yi-Shan Tsai,&nbsp;Shun-Min Yang,&nbsp;Chih-Yu Hsieh,&nbsp;Chia-Chao Wu,&nbsp;Jia-Feng Chang,&nbsp;Jack L Arbiser,&nbsp;Chiz-Tzung Chang,&nbsp;Ann Chen,&nbsp;Shuk-Man Ka","doi":"10.1111/jcmm.15663","DOIUrl":"https://doi.org/10.1111/jcmm.15663","url":null,"abstract":"<p><p>Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B-cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)-mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechanism of action were examined in a mouse model of IgAN. Treatment of IgAN mice with Tris DBA resulted in markedly improved renal function, albuminuria and renal pathology, including glomerular cell proliferation, neutrophil infiltration, sclerosis and periglomerular inflammation in the renal interstitium, together with (Clin J Am Soc Nephrol. 2011, 6, 1301-1307) reduced mitochondrial ROS generation; (Am J Physiol-Renal Physiol. 2011. 301, F1218-F1230) differentially regulated autophagy and NLRP3 inflammasome; (Clin J Am Soc Nephrol. 2012, 7, 427-436) inhibited phosphorylation of JNK, ERK and p38 MAPK signalling pathways, and priming signal of the NLRP3 inflammasome; and (Free Radic Biol Med. 2013, 61, 285-297) blunted NLRP3 inflammasome activation through SIRT1- and SIRT3-mediated autophagy induction, in renal tissues or cultured macrophages. In conclusion, Tris DBA effectively ameliorated the mouse IgAN model and targeted signalling pathways downstream of ICs-mediated interaction, which is a novel immunomodulatory strategy. Further development of Tris DBA as a therapeutic candidate for IgAN is warranted.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38562123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 13
Asprin-loaded strontium-containing α-calcium sulphate hemihydrate/nano-hydroxyapatite composite promotes regeneration of critical bone defects. 阿司匹林负载的含锶α-半水合硫酸钙/纳米羟基磷灰石复合材料促进严重骨缺损的再生。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-12-01 Epub Date: 2020-11-07 DOI: 10.1111/jcmm.15918
Yi Jiang, Hanjun Qin, Haoyang Wan, Jun Yang, Qi Yu, Mo Jiang, Bin Yu

Our laboratory originally synthesized strontium(Sr)-containing α-calcium sulphate hemihydrate/nano-hydroxyapatite composite (Sr-α-CSH/n-HA) and demonstrated its ability to repair critical bone defects. This study attempted to incorporate aspirin into it to produce a better bone graft material for critical bone defects. After 5% Sr-α-CSH was prepared by coprecipitation and hydrothermal methods, it was mixed with aspirin solution of different concentrations (50 μg/ml, 200 μg/ml, 800 μg/ml and 3200 μg/ml) at a fixed liquid-solid ratio (0.54 v/w) to obtain aspirin-loaded Sr-α-CSH/n-HA composite. In vitro experiments were performed on the composite extracts. The tibial defects (3 mm*5 mm) in SD rat model were filled with the composite for 4 weeks and 12 weeks to evaluate its osteogenic capacity in vivo. Our results showed its capability of proliferation, migration and osteogenesis of BMSCs in vitro got improved. In vivo treatment with 800 μg/ml aspirin-loaded Sr-α-CSH/n-HA composite led to significantly more new bone formation in the defects compared with Sr-α-CSH/n-HA composite and significantly promoted the expression of osteogenic-related genes and inhibited osteoclast activity. In general, our research suggests that aspirin-loaded Sr-α-CSH/n-HA composite may have a greater capacity of repairing tibial defects in SD rats than simple Sr-α-CSH/n-HA composite.

我们的实验室最初合成了含锶(Sr)的α-半水合硫酸钙/纳米羟基磷灰石复合材料(Sr-α-CSH/n-HA),并证明了其修复严重骨缺损的能力。本研究试图将阿司匹林掺入其中,为严重骨缺损提供更好的骨移植材料。用共沉淀法和水热法制备5% Sr-α-CSH后,与不同浓度的阿司匹林溶液(50 μg/ml、200 μg/ml、800 μg/ml、3200 μg/ml)按固定液固比(0.54 v/w)混合,得到负载阿司匹林的Sr-α-CSH/n-HA复合物。对复合提取物进行体外实验。在SD大鼠胫骨缺损(3 mm*5 mm)内填充该复合材料4周和12周,观察其体内成骨能力。结果表明,体外培养的骨髓间充质干细胞的增殖、迁移和成骨能力明显增强。体内加载800 μg/ml阿司匹林的Sr-α-CSH/n-HA复合材料与Sr-α-CSH/n-HA复合材料相比,可显著增加缺损中新生骨的形成,显著促进成骨相关基因的表达,抑制破骨细胞活性。总的来说,我们的研究表明,加载阿司匹林的Sr-α-CSH/n-HA复合物可能比单纯的Sr-α-CSH/n-HA复合物具有更大的修复SD大鼠胫骨缺损的能力。
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引用次数: 10
MicroRNAs are critical in regulating smooth muscle cell mineralization and apoptosis during vascular calcification. 在血管钙化过程中,microrna在调节平滑肌细胞矿化和凋亡中起关键作用。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-12-01 Epub Date: 2020-10-22 DOI: 10.1111/jcmm.16005
Shan-Shan Wang, Chen Wang, Han Chen

Vascular calcification refers to the pathological deposition of calcium and phosphate minerals into the vasculature. It is prevalent in atherosclerosis, ageing, type 2 diabetes mellitus and chronic kidney disease, thus, increasing morbidity and mortality from these conditions. Vascular calcification shares similar mechanisms with bone mineralization, with smooth muscle cells playing a critical role in both processes. In the last decade, a variety of microRNAs have been identified as key regulators for the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition in vascular smooth muscle cells during vascular calcification. Therefore, this review mainly discusses the roles of microRNAs in the pathophysiological mechanisms of vascular calcification in smooth muscle cells and describes several interventions against vascular calcification by regulating microRNAs. As the exact mechanisms of calcification remain not fully elucidated, having a better understanding of microRNA involvement in vascular calcification may give impetus to development of novel therapeutics for the control and treatment of vascular calcification.

血管钙化是指钙和磷酸盐矿物质在血管内的病理沉积。它在动脉粥样硬化、衰老、2型糖尿病和慢性肾脏疾病中普遍存在,因此,这些疾病的发病率和死亡率都在增加。血管钙化与骨矿化机制相似,平滑肌细胞在这两个过程中都起着关键作用。在过去的十年中,多种microrna已被确定为血管钙化过程中血管平滑肌细胞分化、表型转换、增殖、凋亡、细胞因子产生和基质沉积的关键调节因子。因此,本文主要讨论了microrna在平滑肌细胞血管钙化的病理生理机制中的作用,并介绍了几种通过调节microrna来干预血管钙化的方法。由于钙化的确切机制尚未完全阐明,更好地了解microRNA参与血管钙化可能会推动开发新的治疗方法来控制和治疗血管钙化。
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引用次数: 22
Celastrol attenuates arterial and valvular calcification via inhibiting BMP2/Smad1/5 signalling. Celastrol通过抑制BMP2/Smad1/5信号传导来减缓动脉和瓣膜钙化。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-20 DOI: 10.1111/jcmm.15779
Zhongping Su, Pengyu Zong, Ji Chen, Shuo Yang, Yihui Shen, Yan Lu, Chuanxi Yang, Xiangqing Kong, Yanhui Sheng, Wei Sun

Vascular calcification is an important risk factor for the mortality and morbidity in chronic kidney disease (CKD). Unfortunately, until now there is no certain medication targeting vascular calcification in CKD. In this study, we explored the inhibitory effect of celastrol on high calcium-induced vascular calcification and the underlying molecular mechanisms. Cell proliferation assay showed that celastrol inhibited aortic valve interstitial cell (VIC) and vascular smooth muscle cell (VSMC) proliferation when its concentration was higher than 0.6 μmol/L. 0.8 μmol/L celastrol inhibited the expression of osteogenic genes and calcium deposition induced by high-calcium medium in both AVICs and VSMCs. In mouse vascular calcification model induced by adenine combined with vitamin D, alizarin red and immunostaining showed that celastrol inhibited pro-calcification gene expression and calcium deposition in aortic wall and aortic valve tissues. At the molecular level, celastrol inhibited the increase of BMP2, phosphorylated Smad1/5 (p-Smad1/5) and non-phosphorylated β-catenin (n-p-β-catenin) induced by high-calcium medium both in vitro and in vivo. Also, BMP2 overexpression reversed the anti-calcification effects of celastrol by recovering the decrease of p-Smad1/5 and n-p-β-catenin. Furthermore, celastrol prevented the up-regulation of BMPRII and down-regulation of Smad6 induced by high calcium, and this protectory effect can be abolished by BMP2 overexpression. In conclusion, our data for the first time demonstrate that celastrol attenuates high calcium-induced arterial and valvular calcification by inhibiting BMP2/Smad1/5 signalling, which may provide a novel therapeutic strategy for arterial and valvular calcification in patients with CKD.

血管钙化是慢性肾脏疾病(CKD)死亡率和发病率的重要危险因素。不幸的是,到目前为止,还没有针对CKD血管钙化的特定药物。在本研究中,我们探讨了celastrol对高钙诱导的血管钙化的抑制作用及其分子机制。细胞增殖实验表明,当其浓度大于0.6 μmol/L时,雷公藤红素可抑制主动脉瓣间质细胞(VIC)和血管平滑肌细胞(VSMC)的增殖。0.8 μmol/L雷公藤红素对AVICs和VSMCs成骨基因表达和高钙诱导的钙沉积均有抑制作用。在腺嘌呤联合维生素D诱导的小鼠血管钙化模型中,茜素红和免疫染色显示,celastrol抑制了促钙化基因的表达和主动脉壁和主动脉瓣组织中的钙沉积。在分子水平上,在体外和体内均可抑制高钙培养基诱导的BMP2、磷酸化Smad1/5 (p-Smad1/5)和非磷酸化β-catenin (n-p-β-catenin)的升高。此外,BMP2过表达通过恢复p-Smad1/5和n-p-β-catenin的减少,逆转了celastrol的抗钙化作用。此外,celastrol还能抑制高钙诱导的BMPRII上调和Smad6下调,这种保护作用可被BMP2过表达所消除。总之,我们的数据首次证明了celastrol通过抑制BMP2/Smad1/5信号传导来减弱高钙诱导的动脉和瓣膜钙化,这可能为CKD患者动脉和瓣膜钙化提供一种新的治疗策略。
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引用次数: 14
Pterostilbene enhances sorafenib's anticancer effects on gastric adenocarcinoma. 紫檀芪增强索拉非尼对胃腺癌的抗癌作用。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-10-13 DOI: 10.1111/jcmm.15795
Tingting Zhao, Chun Wang, Xinying Huo, Ming-Liang He, Jinfei Chen

Sorafenib has been approved for the treatment of certain cancers in clinic. However, the effects of sorafenib on gastric adenocarcinoma (GAC) were still limited. This study aimed to evaluate both in vitro and in vivo efficacy of sorafenib in combination with pterostilbene (PTE) on the treatment of GAC. Here, the morphological changes and cell viability were recorded in both N87 and MKN45 cells. The cell cycle profile and apoptosis were assessed by flow cytometry. Subcutaneous tumour xenografts were constructed in nude mice, and IHC staining of the dissected tumour tissues was conducted. Our results showed that PTE enhanced sorafenib's inhibitory effects on cell viability. The obvious down-regulation of cyclin D1, Cdk-2, Cdk-4, Cdk-6 and p62 and the up-regulation of LC3II, caspase-9, caspase-3 and PARP cleavages were observed for the combination treatment with PTE and sorafenib than monotherapy. The combination treatment resulted in a higher level of cell cycle arrest at G1 phase and apoptosis than either drug. Besides, drug combination significantly enhanced the inhibition of tumour growth than sorafenib or PET alone in nude mice. The percentage of Ki-67- and PCNA-positive cells was distinctly reduced, and the apoptotic cells was obviously increased when compared with single drug therapy. Altogether, PET obviously enhanced sorafenib's antitumour effects against GAC through inhibiting cell proliferation, inducing autophagy and promoting apoptosis. The combination therapy with PET and sorafenib may serve as a novel therapeutic strategy for treating GAC and deserve further clinical trials.

索拉非尼已被批准用于临床治疗某些癌症。然而,索拉非尼对胃腺癌(GAC)的作用仍然有限。本研究旨在评价索拉非尼联合紫檀芪(PTE)治疗GAC的体内外疗效。在这里,我们记录了N87和MKN45细胞的形态变化和细胞活力。流式细胞术检测细胞周期及凋亡情况。在裸鼠体内构建皮下肿瘤异种移植物,并对解剖肿瘤组织进行免疫组化染色。我们的研究结果表明PTE增强了索拉非尼对细胞活力的抑制作用。PTE与索拉非尼联合治疗较单药治疗明显下调细胞周期蛋白D1、Cdk-2、Cdk-4、Cdk-6和p62,上调LC3II、caspase-9、caspase-3和PARP切割。联合治疗导致细胞周期阻滞在G1期和凋亡水平高于任何一种药物。此外,联合用药对裸鼠肿瘤生长的抑制作用明显强于单用索拉非尼或PET。与单药治疗相比,Ki-67、pcna阳性细胞比例明显降低,凋亡细胞明显增多。综上所述,PET通过抑制细胞增殖、诱导自噬和促进细胞凋亡,明显增强sorafenib对GAC的抗肿瘤作用。PET联合索拉非尼治疗GAC可能是一种新的治疗策略,值得进一步的临床试验。
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引用次数: 2
Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. 恩格列净在糖尿病小鼠模型中减少心脏基质细胞的衰老并改善心脏功能。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2020-11-01 Epub Date: 2020-09-17 DOI: 10.1111/jcmm.15699
Rosalinda Madonna, Vanessa Doria, Ilaria Minnucci, Angela Pucci, Donato Sante Pierdomenico, Raffaele De Caterina

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin reduces heart failure in diabetes, but underlying mechanisms remain elusive. We hypothesized that empagliflozin could counteract the senescence of cardiac stromal cells (CSC), the action of which limits cardiac damage and cardiac fibrosis in diabetic-like conditions in vitro and in vivo. CSC were isolated from murine heart biopsies (n = 5) through cardiosphere (CSp) formation and incubated for 3 or 48 hours with 5.5 mmol/L normal glucose (NG), high glucose (12-5 and 30.5 mmol/L, HG) or a hyperosmolar control of mannitol (HM) in the presence or absence of empagliflozin 100 nmol/L. The senescent CSC status was verified by β-gal staining and expression of the pro-survival marker Akt (pAkt) and the pro-inflammatory marker p38 (p-P38). The cardiac effects of empagliflozin were also studied in vivo by echocardiography and by histology in a murine model of streptozotocin (STZ)-induced diabetes. Compared to NG, incubations with HG and HM significantly reduced the number of CSps, increased the β-gal-positive CSC and P-p38, while decreasing pAkt, all reversed by empagliflozin (P < .01). Empagliflozin also reversed cardiac dysfunction, cardiac fibrosis and cell senescence in mice with (STZ)-induced diabetes (P < .01). Empagliflozin counteracts the pro-senescence effect of HG and of hyperosmolar stress on CSC, and improves cardiac function via decreasing cardiac fibrosis and senescence in diabetic mice, possibly through SGLT2 off-target effects. These effects may explain empagliflozin unexpected benefits on cardiac function in diabetic patients.

钠-葡萄糖共转运蛋白2 (SGLT2)抑制剂恩格列净可减少糖尿病患者的心力衰竭,但其潜在机制尚不清楚。我们假设恩格列净可以抵消心脏基质细胞(CSC)的衰老,其作用限制了体外和体内糖尿病样条件下的心脏损伤和心脏纤维化。通过心肌球(CSp)形成从小鼠心脏活检组织(n = 5)中分离出CSC,并与5.5 mmol/L正常葡萄糖(NG)、高葡萄糖(12-5和30.5 mmol/L, HG)或高渗控制甘露醇(HM)在100 nmol/L恩格列净存在或不存在的情况下孵育3或48小时。通过β-gal染色和促生存标志物Akt (pAkt)和促炎标志物p38 (p-P38)的表达证实了衰老的CSC状态。通过超声心动图和链脲佐菌素(STZ)诱导的糖尿病小鼠模型的组织学研究了恩格列净对心脏的影响。与NG相比,HG和HM显著减少了csp的数量,增加了β-gal阳性CSC和P-p38,同时降低了pAkt,这些都被恩格列净逆转(P
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引用次数: 20
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