Celastrol promotes apoptosis of breast cancer MDA-MB-231 cells by targeting HSDL2

Objective:Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicinal herb,Tripterygium wilfordii.This study aims to provide a scientific basis for the rational development and use of celastrol in breast cancer.Method:A quantitative chemical biology approach was used to investigate the protein targets and molecular mechanisms of celastrol in breast cancer cells.Results:Low-concentration celastrol exerted an anti-tumor effect by directly binding to hydroxysteroid dehydrogenase-like 2(HSDL2)and inhibiting its expression.Moreover,the expression of the pro-apoptotic protein,Bcl-2-associated X(BaX),increased,the level of the anti-apoptotic protein,B-cell lymphoma-2(Bcl-2),decreased,and the rate of apoptosis increased.After the transfection of cells with si-HSDL2,the apoptosis rate was similar to that observed after the administration of celastrol.However,apoptosis was reversed by the overexpression of HSDL2.Furthermore,our mass spectrometry(MS)data indicated a relationship between HSDL2 and the mitogen-activated protein kinase(MAPK)signaling pathway.We also found that the expression of HSDL2 was directly related to the degree of extracellular signal-regulated kinase(ERK)phosphorylation.Conclusion:Celastrol may promote apoptosis by suppressing the HSDL2/MAPK/ERK signaling pathway.

Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: Possible role in tumor promotion and angiogenesis

AIM： To investigate the association of cyclooxygenase-2 （COX-2） expression with angiogenesis and the number and type of inflammatory cells （macrophages/Kupffer cells; mast cells） within primary hepatocellular carcinoma （HCC） tissues and adjacent non-tumorous （NT） tissues. METHODS： Immunohistochemistry for COX-2, CD34, CD68 and mast cell tryptase （MCT） was performed on 14 well-characterized series of liver-cirrhosis-associated HCC patients. COX-2 expression and the number of inflammatory cells in tumor lesions and surrounding liver tissues of each specimen were compared. Moreover, COX-2, CD34 staining and the number of inflammatory cells in areas with different histological degrees within each tumor sample were comparatively analyzed. RESULTS： The percentage of COX-2 positive cells was significantly higher in NT tissues than in tumors. COX-2 expression was higher in well-differentiated HCC than in poorly-differentiated tissues. Few mast cells were observed within the tumor mass, whereas a higher number was observed in the surrounding tissue, especially in peri-portal spaces of NT tissues. Abundant macrophages/ Kupffer cells were observed in NT tissues, whereas the number of cells was significantly lower in the tumor mass. However, a higher cell number was observed in the welldifferentiated tumor and progressively decreased in relation to the differentiation grade. Within the tumor, a positive correlation was found between COX-2 expression and the number of macrophages/Kupffer cells and mastcells. Moreover, there was a positive correlation between CD34 and COX-2 expression in tumor tissues. Comparison between well- and poorly-differentiated HCC showed that the number of CD34-positive cells decreased with dedifferentiation. However, COX-2 was the only independent variable showing a positive correlation with CD34 in a multivariate analysis. CONCLUSION： The presence of inflammatory cells and COX-2 expression in liver tumor suggests a possible relationship with tumor angiogenesis. COX-2 expressing cells and the number of macrophages/Kupffer cells and mast cells decrease with progression of the disease.

Multifactorial nature of hepatocellular carcinoma drug resistance: Could plant polyphenols be helpful?

Primary hepatocellular carcinoma （HCC） is a quite frequent tumor which results in high mortality and most often exhibits a poor response to present drug therapies. Clearly, a thorough understanding of the biological bases of this malignancy might suggest new strategies for its treatment. Here we examine the evidences that both ＂pharmacological＂ mechanisms （e.g. drug transporter or detoxification enzyme over-expression） and alterations in other critical factors, including the IAPs （Inhibitory of Apoptosis Proteins）, involved in enhancement of cell survival and proliferation may determine the therapeutic resistance of HCC; we also underline the possible role in the process of the activation of transcription factors, like NF-κB, capable of contemporaneously up-regulating the mechanisms discussed. On this basis, we finally comment on the possible use of natural multi-targeted antitumoral agents like plant polyphenols to achieve sensitization to treatments in HCC.

Combination of XianGui capsule and LCZ696 inhibits doxorubicin- induced heart failure in mice

Objective:We used doxorubicin(DOX)-induced heart failure mouse model to investigate the therapeutic effect and involved mechanism of XianGui capsule(XG)combined with Sacubitril Valsartan Sodium tablets(LCZ696)on heart failure.Methods:C57BL/6 mice were divided into control(Ctrl)group,DOX group,XG group,LCZ696 group and combination(XL)group.After the administration,mice heart functions,blood pressure,and serum cardiac injury markers were detected.Heart sections were conducted with HE,Sirius Red and immunohistochemical staining.The heart tissues were collected for the determination of protein or mRNA expression of anti oxidative,fibrosis,inflammation and apoptosis-related genes by Western Blot and qRT-PCR.Results:XG,LCZ696 or XG plus LCZ696 can significantly improve the heart functions of mice,reduce the expression of cardiac injury markers,and inhibit myocardial fibrosis.Mechanically,XG,LCZ696 or their co treatment antagonized myocardial apoptosis,increase forkhead box O3a,superoxide dismutase 2(SOD2)protein,SOD1,catalase mRNA expressions and inhibited the protein and mRNA levels of toll-like 4,nuclear factorkB,and inflammatory cytokines.Conclusion:XG,LCZ696 or XG plus LCZ696 decreases DOX-induced cardiomyocytes apoptosis by reducing inflammatory factors and enhancing expression of antioxidant enzymes,thereby alleviating the development of heart failure.

慢性心理社会应激触发小胶质细胞/巨噬细胞诱导的炎症反应,导致神经元功能障碍和抑郁相关行为

慢性环境压力和创伤性社会经历会导致不良行为变化,是主要抑郁症(MDD)和各种焦虑相关精神障碍的危险因素。临床研究和慢性压力的动物模型研究结果显示,症状严重程度与先天免疫反应和情绪调节相关脑区(mPFC:内侧前额叶皮质)中神经炎症细胞因子信号上调有关。尽管越来越多的证据表明神经可塑性受损和突触信号传导缺陷是与应激相关精神障碍的病理生理学的一部分,但小胶质细胞如何调节神经元稳态以应对慢性压力尚未明确。本研究使用反复社交挫败应激(RSDS)小鼠模型证明小胶质细胞诱导的炎症反应可以调节与心理社会压力相关的神经元可塑性。具体来说,我们发现慢性压力会迅速激活并增殖mPFC中的小胶质细胞以及巨噬细胞浸润,并且这些过程与神经元激活的空间位置相关。此外,我们研究还发现小胶质细胞炎症反应与对慢性压力的敏感性或抗性之间存在显著关联;暴露于慢性压力会加剧突触成分的吞噬作用和神经元可塑性的缺陷。通过使用2种不同的CSF1R抑制剂(脑渗透性的PLX5622和非渗透性的PLX73086),我们证实了小胶质细胞(其次为巨噬细胞)在催化mPFC中与心理社会压力相关的病理表现以及在与抑郁症相关的常见行为缺陷方面的关键作用。

High density lipoproteins and atherosclerosis: emerging aspects

High density lipoproteins (HDL) promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion. This ability is responsible for the most relevant anti-atherogenic effect of HDL. The ability of HDL to promote cholesterol efflux results also in the modulation of a series of responses in the immune cells involved in atherosclerosis,includingmonocyte-macrophages, B and T lymphocytes.Furthermore, during inflammation, the composition of this class of lipoproteins varies to a large extent, thus promoting the formation of dysfunctional HDL. The aim of this review is to discuss the emerging role of HDL in modulating the activity of immune cells and immune-inflammatory mediators during atherogenesis.

ADAM10 facilitates rapid neural stem cell cycling and proper positioning within the subventricular zone niche via JAMC/RAP1Gap signaling

The mechanisms that regulate neural stem cell(NSC)lineage progression and maintain NSCs within diffe rent domains of the adult neural stem cell niche,the subventricular zone are not well defined.Quiescent NSCs are arranged at the apical ventricular wall,while mitotically activated NSCs are found in the basal,vascular region of the subventricular zone.Here,we found that ADAM 10(a disintegrin and metalloproteinase 10)is essential in NSC association with the ventricular wall,and via this adhesion to the apical domain,ADAM10 regulates the switch from quiescent and undiffe rentiated NSC to an actively prolife rative and differentiating cell state.Processing of JAMC(junctional adhesion molecule C)by ADAM 10 increases Rap1 GAP activity.This molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage progression.Understanding the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative prope rties of neural tissue.

Dendrobium huoshanense improves doxorubicin-induced heart failure in C57BL/6 mice

Objective:To investigate the therapeutic effect of Shihu(Dendrobium huoshanense,DH)on doxorubicin(DOX)-induced heart failure in mice and the involved mechanisms.Methods:Male C57BL/6 mice were randomly divided into 3 groups:Control(Ctrl)group,DOX group and DH group.Chronic heart failure was induced by intraperitoneal injection of doxorubicin solution.Mice in DH group were fed normal chow containing DH powder for 4 weeks.After 4-week treatment,electrocardiograms were measured.At the end of experiment,serum and heart sample were collected for determination of indicators for heart failure indicators.The heart tissues were conducted HE,Masson,Sirius red staining and TUNEL staining to determine cardiac tissue morphology,fibrosis,collagen content and apoptosis,respectively.mRNA and protein expression were determined by qRT-PCR and Western blot,respectively.Results:DH reduced the DOX-induced serum biomarkers(creatine kinase,aspartate aminotransferase and lactate dehydrogenase)of heart damage and reduced heart fibrosis.Mechanically,DH inhibited myocardial apoptosis,decreased interleukin 6 and tumor necrosis factoralevels,but increased superoxide dismutase 2 expression.Conclusion:DH alleviates DOX-induced chronic heart failure by inhibiting inflammatory pathway and enhancing anti-oxidative enzymes.Our study provides the potential of DH for heart failure treatment.

Microglial contributions to aberrant neurogenesis and pathophysiology of epilepsy

Microglia are dynamic cells that constitute the brain's innate immune system.Recently,research has demonstrated microglial roles beyond immunity,which include homeostatic roles in the central nervous system.The function of microglia is an active area of study,with insights into changes in neurogenesis and synaptic pruning being discovered in both health and disease.In epilepsy,activated microglia contribute to several changes that occur during epileptogenesis.In this review,we focus on the effects of microglia on neurogenesis and synaptic pruning,and discuss the current state of anti-seizure drugs and how they affect microglia during these processes.Our understanding of the role of microglia post-seizure is still limited and may be pivotal in recognizing new therapeutic targets for seizure intervention.

Kidney Tubular-Cell Secretion of Osteoblast Growth Factor Is Increased by Kaempferol:A Scientific Basis for "The Kidney Controlling the Bone" Theory of Chinese Medicine

Objective： To study, at the cytological level, the basic concept of Chinese medicine that “the Kidney （Shen） controls the bone”. Methods： Kaempferol was isolated form Rhizoma Drynariae （Gu Sui Bu, GSB） and at several concentrations was incubated with opossum kidney （OK） cells, osteoblasts （MC3T3 El） and human fibroblasts （HF） at cell concentrations of 2 x 104/mL. Opossum kidney cell-conditioned culture media with kaempferol at 70 nmol/L （70kaθOKM） and without kaempferol （oOKM） were used to stimulate MC3T3 E1 and HF proliferation. The bone morphological protein receptors I and Ⅱ （BMPR I and Ⅱ） in OK cells were identified by immune-fluorescence staining and Western blot analysis. Results： Kaempferol was found to increase OK cell growth （P〈0.05）, but alone did not promote MC3T3 E1 or HF cell proliferation. However, although OKM by itself increased MC3T3 E1 growth by 198% （P〈0.01）, the 70kaθOKM further increased the growth of these cells by an additional 127% （P〈0.01）. It indicates that the kidney cell generates a previously unknown osteoblast growth factor （OGF） and kaempferol increases kidney cell secretion of OGF. Neither of these media had any significant effect on HF growth. Kaempferol also was found to increase the level of the BMPR Ⅱ in OK cells. Conclusions： This lends strong support to the original idea that the Kidney has a significant influence over bone-formation, as suggested by some long-standing Chinese medical beliefs, kaempferol may also serve to stimulate kidney repair and indirectly stimulate bone formation.

用于精准蛋白降解和癌症治疗的刺激响应型PROTAC进展

刺激响应型蛋白质降解靶向嵌合体(PROTAC)前药可在特定刺激条件下激活PROTAC分子,实现特定区域和细胞的靶蛋白降解,从而克服不可控蛋白降解导致的毒副作用,是改善PROTAC疗效和成药性的有效策略.本文系统总结了目前用于特异性降解病灶组织目标蛋白从而精准治疗肿瘤的各种刺激响应型PROTAC前药策略.首先,本文介绍了PROTAC的发展历程和作用原理,以及目前进入临床试验阶段的PROTAC分子;然后,介绍了细胞内原位生成PROTAC的前药策略,以及各种刺激手段激活的PROTAC前药,包括外源性的光、X-射线以及内源性的肿瘤微环境的乏氧、活性氧和酶等;接着,概括了配体修饰型的主动靶向PROTAC前药,包括抗体、叶酸、适配体等修饰策略.本文重点强调了基于纳米递药系统的PROTAC前药策略,其可实现特异性肿瘤组织药物递送和精准蛋白降解.最后,本文对PROTAC的未来发展进行了探讨和展望.

Breast-to-brain metastasis: a focus on the premetastatic niche

Metastatic disease is the cause for 90%of breast cancer mortalities.For those 10%-20%of patients whose breast cancer metastasizes to the central nervous system,the one-year survival rate is just 20%.Both histology and molecular subtype have a correlation with the site of tumor metastasis,indicating an inherent preferential aspect to metastatic colony formation.The molecular differences between breast cancers may determine the site of metastasis through priming of the premetastatic niche in that site:cell surface molecules,exosomes released from the primary tumor,and soluble factors secreted from both the primary tumor and resident cells within the premetastatic niche all contribute to altering the premetastatic niche to be more favorable for the circulating tumor cells,allowing for cell invasion and growth.Here,we review breast to brain metastasis with a focus on the premetastatic niche.We discuss the secreted factors and exosomes that prime the premetastatic niche within the brain by instigating crosstalk between the resident cells of the brain microenvironment.We report on the individual roles that microglia,astrocytes,pericytes,neurons,and endothelial cells may have in the formation and maintenance of the premetastatic niche.