Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress

Regulated cell death (RCD) guarantees to preserve organismal homeostasis. Apoptosis and autophagy are two major arms of RCD, while endoplasmic reticulum (ER) as a crucial organelle involved in proteostasis, promotes cells toward autophagy and apoptosis. Alteration in ER stress and autophagy machinery is responsible for a great number of diseases. Therefore, targeting those pathways appears to be beneficial in the treatment of relevant diseases. Meantime, among the traditional herb medicine, kaempferol as a flavonoid seems to be promising to modulate ER stress and autophagy and exhibits protective effects on malfunctioning cells. There are some reports indicating the capability of kaempferol in affecting autophagy and ER stress. In brief, kaempferol modulates autophagy in noncancerous cells to protect cells against malfunction, while it induces cell mortality derived from autophagy through the elevation of p‐AMP‐activated protein kinase, light chain‐3‐II, autophagy‐related geness, and Beclin‐1 in cancer cells. Noteworthy, kaempferol enhances cell survival through C/EBP homologous protein (CHOP) suppression and GRP78 increment in noncancerous cells, while it enhances cell mortality through the induction of unfolding protein response and CHOP increment in cancer cells. In this review, we discuss how kaempferol modulates autophagy and ER stress in noncancer and cancer cells to expand our knowledge of new pharmacological compounds for the treatment of associated diseases.     

心阳片通过抑制心肌细胞自噬改善心力衰竭小鼠心功能的作用研究

目的探讨心阳片调节心肌细胞自噬改善心力衰竭(Heart failure,HF)小鼠心功能的作用机制。方法将48只雄性C57BL/6J小鼠随机分为假手术组,模型组,心阳片低、中、高剂量组(455、910、1820 mg·kg^-1)及3-甲基腺嘌呤组(15 mg·kg^-1,腹腔注射给药),每组8只;采用主动脉弓缩窄术复制HF小鼠模型;按上述剂量灌胃给药,灌胃体积为8 mL·kg^-1,每天给药1次,连续4周。采用心脏彩超检测各组小鼠心功能:小鼠左心室射血分数(LVEF)及左室短轴缩短率(LVFS);采用q PCR法检测小鼠心脏组织HF生物标记物B型钠尿肽(BNP)mRNA的表达;采用Western Blot法检测小鼠心肌细胞自噬相关蛋白Beclin-1及LC3BⅡ/Ⅰ的表达。结果与假手术组比较,模型组小鼠的LVEF、LVFS显著降低(P<0.05),BNP mRNA及Beclin-1、LC3BⅡ/Ⅰ蛋白表达明显上调(P<0.05)。与模型组比较,心阳片低、中、高剂量组及3-甲基腺嘌呤组小鼠的LVEF、LVFS显著升高(P<0.05),BNP mRNA及Beclin-1、LC3BⅡ/Ⅰ蛋白表达明显下调(P<0.05)。结论心阳片可能通过抑制心肌细胞过度自噬改善HF小鼠的心功能。     

lncRNA减轻心肌缺血再灌注损伤的研究进展

长链非编码RNA(lncRNA)是一类长度大于200个核苷酸且无蛋白质编码能力的RNA,但在增殖、凋亡、迁移、侵袭和分化等多种生物过程中起着非常重要的调节作用。研究发现lncRNA与心肌缺血再灌注(I/R)损伤的发生发展密切相关。本综述讨论了lncRNA减少心肌I/R损伤及其可能机制的研究进展。     

华良姜素对PDGF-BB诱导血管平滑肌细胞增殖和迁移的影响

目的]探讨华良姜素对PDGF-BB诱导下血管平滑肌细胞增殖和迁移的影响及可能的机制。 [方法]利用25 μg/L的PDGF-BB处理人主动脉血管平滑肌细胞(HA-VSMC)诱导血管平滑肌细胞增殖和迁移。实验分为正常对照组、PDGF-BB组(模型组)、PDGF-BB+华良姜素(10、20、40 μmol/L)组和DMSO组。采用CCK-8实验检测HA-VSMC增殖活力,Transwell实验检测HA-VSMC迁移能力,Western blot检测自噬效应蛋白p62、LC3、雷帕霉素靶蛋白(mTOR)以及磷酸化mTOR(p-mTOR)蛋白表达水平的变化。 [结果]PDGF-BB处理后,HA-VSMC增殖和迁移能力显著上调(P＜0.01),华良姜素显著抑制PDGF-BB诱导的HA-VSMC的增殖和迁移,且随浓度的上升抑制能力越明显(P＜0.05)。与模型组比较,40 μmol/L华良姜素处理后,LC3Ⅰ以及mTOR蛋白表达水平显著降低(P＜0.05);LC3Ⅱ/LC3Ⅰ、p62与p-mTOR蛋白表达水平显著升高(P＜0.05),同时发现40 μmol/L华良姜素与AMPK抑制剂Compound C,对PDGF-BB诱导的HA-VSMC AMPK/mTOR信号通路的影响一致。 [结论]华良姜素可抑制PDGF-BB诱导的HA-VSMC的增殖和迁移,其作用机制可能是通过上调AMPK/mTOR信号通路,抑制自噬实现。     

Cell death mechanisms induced by synergistic effects of halofuginone and artemisinin in colorectal cancer cells

Our previous study found that the combination of halofuginone (HF) and artemisinin (ATS) synergistically arrest colorectal cancer (CRC) cells at the G1/G0 phase of the cell cycle; however, it remains unclear whether HF-ATS induces cell death. Here we report that HF-ATS synergistically induced caspase-dependent apoptosis in CRC cells. Specifically, both in vitro and in vivo experiments showed that HF or HF-ATS induces apoptosis via activation of caspase-9 and caspase-8 while only caspase-9 is involved in ATS-induced apoptosis. Furthermore, we found HF or HF-ATS induces autophagy; ATS can''t induce autophagy until caspase-9 is blocked. Further analyzing the crosstalk between autophagic and caspase activation in CRC cells, we found autophagy is essential for activation of caspase-8, and ATS switches to activate capase-8 via induction of autophagy when caspase-9 is inhibited. When apoptosis is totally blocked, HF-ATS switches to induce autophagic cell death. This scenario was then confirmed in studies of chemoresistance CRC cells with defective apoptosis. Our results indicate that HF-ATS induces cell death via interaction between apoptosis and autophagy in CRC cells. These results highlight the value of continued investigation into the potential use of this combination in cancer therapy.     

尿石素A激活自噬改善糖尿病小鼠肝脏胰岛素抵抗研究

目的研究尿石素A(UA)对2型糖尿病模型小鼠肝脏胰岛素信号通路的影响及与自噬的关系。方法将C57BL/6小鼠按体质量随机分成4组,即对照组、模型组、尿石素A(50 mg/kg)组、尿石素A(50 mg/kg)联合氯喹(50 mg/kg)组,高脂饲料喂养6周后,ip链脲佐菌素(STZ)建立2型糖尿病模型。各组小鼠ig给药7周,检测小鼠体质量、饮水量、血脂、空腹血糖(FBG)、空腹胰岛素(FINS)水平;计算胰岛素抵抗指数(HOMA-IR)、胰岛素敏感指数(ISI);HE染色观察小鼠肝组织病理变化;蛋白免疫印迹法检测小鼠肝组织磷酸化蛋白激酶B(p-Akt)、葡萄糖转运蛋白2(Glut2)、磷酸化糖原合酶激酶-3β(p-GSK3β)及自噬相关蛋白微管相关蛋白质1轻链3Ⅱ/Ⅰ(LC3 Ⅱ/Ⅰ)、选择性自噬接头蛋白(p62)表达水平。结果与模型组比较,UA能够显著改善糖尿病模型小鼠肝组织脂肪变和水肿;显著降低血浆三酰甘油(TG)、游离脂肪酸(FFA)、低密度脂蛋白-胆固醇(LDL-C)、FBG、FINS水平,升高高密度脂蛋白-胆固醇(HDL-C)水平(P0.01);显著降低HOMA-IR,升高ISI(P0.01);上调肝组织p-Akt、Glut2、p-GSK3β、LC3Ⅱ/Ⅰ蛋白表达,抑制p62蛋白表达(P0.01)。联合氯喹后,小鼠FBG、FINS、HOMA-IR增加,ISI降低(P0.05);肝组织水肿和脂肪病变明显加重;肝组织p-Akt、Glut2、LC3Ⅱ/Ⅰ蛋白表达水平降低,p62蛋白表达水平升高(P0.05),显示自噬抑制剂氯喹明显削弱了UA的作用。结论 UA可能是通过激活肝脏自噬改善糖尿病小鼠肝脏胰岛素抵抗。     

内质网应激对缺血性脑卒中神经元凋亡与自噬的调控及中医药的干预

内质网作为细胞内的一种膜质细胞器,通过参与分泌蛋白和跨膜蛋白的合成、折叠、成熟和翻译后修饰以维持细胞内稳态,与疾病的发生发展密切相关。当内质网环境受到干扰后蛋白质将发生折叠或错误折叠,此时内质网应激被激活,可对神经元的凋亡与自噬进行调控,在缺血性脑卒中中扮演着重要角色。本文从内质网应激的信号通路入手,探讨内质网应激与神经元凋亡和自噬的关系,介绍中医药通过内质网应激途径调控缺血性脑卒中神经元凋亡与自噬的研究概况,为研究中医药在缺血性脑卒中的作用机制提供新的现代医学的理论支持和作用靶点。     

Role and mechanism of action of LAPTM4B in EGFR-mediated autophagy

LAPTM4B is upregulated in the majority of types of cancer and associated with cancer cell proliferation, survival and drug resistance, as well as poor patient prognosis. LAPTM4B knockdown inhibits autophagosome maturation in the context of metabolic stress. Autophagy is a homeostatic process that degrades and recycles intracellular components in response to metabolic stress. The function of autophagy is dual, as this process can either have a tumor suppressor or an oncogenic role. EGFR serves an important role in determining the tumor-suppressive or oncogenic roles of autophagy. EGFR family members regulate autophagy through various signaling pathways, including PI3K/AKT signaling. Notably, LAPTM4B also promotes cancer cell proliferation via the PI3K/AKT signaling pathway. In addition, LAPTM4B can enhance and prolong EGFR signal transduction by blocking active EGFR intraluminal sorting and lysosomal degradation. Thus, LAPTM4B may be associated with autophagy through EGFR signaling. The present review proposed that LAPTM4B participates in regulating autophagy through the EGFR pathway.     

Modulation of autophagy for neuroprotection and functional recovery in traumatic spinal cord injury

Spinal cord injury(SCI) is a serious central nervous system trauma that leads to loss of motor and sensory functions in the SCI patients. One of the cell death mechanisms is autophagy, which is ‘self-eating' of the damaged and misfolded proteins and nucleic acids, damaged mitochondria, and other impaired organelles for recycling of cellular building blocks. Autophagy is different from all other cell death mechanisms in one important aspect that it gives the cells an opportunity to survive or demise depending on the circumstances. Autophagy is a therapeutic target for alleviation of pathogenesis in traumatic SCI. However, functions of autophagy in traumatic SCI remain controversial. Spatial and temporal patterns of activation of autophagy after traumatic SCI have been reported to be contradictory. Formation of autophagosomes following therapeutic activation or inhibition of autophagy flux is ambiguous in traumatic SCI studies. Both beneficial and harmful outcomes due to enhancement autophagy have been reported in traumatic SCI studies in preclinical models. Only further studies will make it clear whether therapeutic activation or inhibition of autophagy is beneficial in overall outcomes in preclinical models of traumatic SCI. Therapeutic enhancement of autophagy flux may digest the damaged components of the central nervous system cells for recycling and thereby facilitating functional recovery. Many studies demonstrated activation of autophagy flux and inhibition of apoptosis for neuroprotective effects in traumatic SCI. Therapeutic induction of autophagy in traumatic SCI promotes axonal regeneration, supporting another beneficial role of autophagy in traumatic SCI. In contrast, some other studies demonstrated that disruption of autophagy flux in traumatic SCI strongly correlated with neuronal death at remote location and impaired functional recovery. This article describes our current understanding of roles of autophagy in acute and chronic traumatic SCI, crosstalk between autophagy and apoptosis, therapeutic activation or inhibition of autophagy for promoting functional recovery, and future of autophagy in traumatic SCI.