Artemisinin attenuated ischemic stroke induced cell apoptosis through activation of ERK1/2/CREB/BCL-2 signaling pathway in vitro and in vivo

Ischemic stroke is characterized by the presence of both brain ischemic and reperfusion-induced injuries in the brain, leading to neuronal dysfunction and death. Artemisinin, an FDA-approved antimalarial drug, has been reported to have neuroprotective properties. However, the effect of artemisinin on ischemic stroke is not known. In the present study, we investigated the effect of artemisinin on ischemic stroke using an oxygen-glucose deprivation/reperfusion (OGD/RP) cellular model and a mouse middle cerebral artery occlusion (MCAO) animal model and examined the underlying mechanisms. The obtained results revealed that a subclinical antimalarial concentration of artemisinin increased cell viability and decreased LDH release and cell apoptosis. Artemisinin also attenuated the production of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (Δψm). Importantly, artemisinin attenuated the infarction volume and the brain water content in the MCAO animal model. Artemisinin also improved neurological and behavioural outcomes and restored grasp strength and the recovery of motor function in MCAO animals. Furthermore, artemisinin treatment significantly inhibited the molecular indices of apoptosis, oxidative stress and neuroinflammation and activated the ERK1/2/CREB/BCL-2 signaling pathway. Further validation of the involved signaling pathway by the ERK1/2 inhibitor PD98059 revealed that inhibiting the ERK1/2 signaling pathway or silencing ERK1/2 reversed the neuroprotective effects of artemisinin. These results indicate that artemisinin provides neuroprotection against ischemic stroke via the ERK1/2/CREB/BCL-2 signaling pathway. Our study suggests that artemisinin may play an important role in the prevention and treatment of stroke.     

格列苯脲调节大鼠低氧高二氧化碳性肺血管收缩时ERK1/2信号的作用

目的：探究ATP敏感性钾离子通道在低氧高二氧化碳性肺血管收缩（HHPV）中的作用及与细胞外信号调节激酶1/2（ERl（1/2）信号通路的关系。方法：制备正常SD大鼠离体三级肺动脉环,建立大鼠离体肺动脉环灌流的模型,用格列本脲（Cly）、ely＋U0126（ERK1/2抑制剂）联合孵育三级肺动脉环,按照低氧高二氧化碳反应性测定方法测定所有血管环的张力值。结果：①常氧状态下,三级肺动脉环的张力值无明显变化;②急性低氧高二氧化碳条件下,三级肺动脉环呈现双向性的收缩（与常氧状态下值相比,P〈0．05,P〈0．01）;③经Gly孵育的三级肺动脉环,其Ⅱ期收缩幅度增强（与低氧高二氧化碳状态下值相比,P〈0．05,P〈0．01）;④急性低氧高二氧化碳条件下,U0126能使Gly所致的三级肺动脉环Ⅱ期持续收缩幅度显著降低（与低氧高二氧化碳状态下值相比,P〈0．05,P〈0．01）,I期收缩和I期舒张均没有明显变化（P均〉0．05）。结论：ATP敏感性钾离子通道（KAlP）阻断剂-Gly可能通过活化ERK1/2信号通路介导了大鼠HHPV的发生。     

Recovery of neurological function of ischemic stroke by application of conditioned medium of bone marrow mesenchymal stem cells derived from normal and cerebral ischemia rats

Background

Several lines of evidence have demonstrated that bone marrow-derived mesenchymal stem cells (BM-MSC) release bioactive factors and provide neuroprotection for CNS injury. However, it remains elusive whether BM-MSC derived from healthy donors or stroke patients provides equal therapeutic potential. The present work aims to characterize BM-MSC prepared from normal healthy rats (NormBM-MSC) and cerebral ischemia rats (IschBM-MSC), and examine the effects of their conditioned medium (Cm) on ischemic stroke animal model.

Results

Isolated NormBM-MSC or IschBM-MSC formed fibroblastic like morphology and expressed CD29, CD90 and CD44 but failed to express the hematopoietic marker CD34. The number of colony formation of BM-MSC was more abundant in IschBM-MSC than in NormBM-MSC. This is in contrast to the amount of Ficoll-fractionated mononuclear cells from normal donor and ischemic rats. The effect of cm of BM-MSC was further examined in cultures and in middle cerebral artery occlusion (MCAo) animal model. Both NormBM-MSC Cm and IschBM-MSC Cm effectively increased neuronal connection and survival in mixed neuron-glial cultures. In vivo, intravenous infusion of NormBM-MSC Cm and IschBM-MSC Cm after stroke onset remarkably improved functional recovery. Furthermore, NormBM-MSC Cm and IschBM-MSC Cm increased neurogenesis and attenuated microglia/ macrophage infiltration in MCAo rat brains.

Conclusions

Our data suggest equal effectiveness of BM-MSC Cm derived from ischemic animals or from a normal population. Our results thus revealed the potential of BM-MSC Cm on treatment of ischemic stroke.     

Retracted: MicroRNA-150 contributes to ischemic stroke through its effect on cerebral cortical neuron survival and function by inhibiting ERK1/2 axis via Mal

Ischemic stroke, caused by the blockage of blood supply, is a major cause of death worldwide. For identifying potential candidates, we explored the effects microRNA-150 (miR-150) has on ischemic stroke and its underlying mechanism by developing a stable middle cerebral artery occlusion (MCAO) rat model. Gene expression microarray analysis was performed to screen differentially expressed genes associated with MCAO. We evaluated the expression of miR-150 and Mal and the status of ERK1/2 axis in the brain tissues of MCAO rats. Then the cerebral cortical neurons (CCNs) were obtained and introduced with elevated or suppressed miR-150 or silenced Mal to validate regulatory mechanisms for miR-150 governing Mal in vitro. The relationship between miR-150 and Mal was verified by dual luciferase reporter gene assay. Besides, cell growth and apoptosis of CCNs were detected by means of MTT assay and flow cytometry analyses. We identified Mal as a downregulated gene in MCAO, based on the microarray data of GSE16561. MiR-150 was over-expressed and negatively targeted Mal in the brain tissues obtained from MCAO rats and their CCNs. Increasing miR-150 blocked the ERK1/2 axis, resulting in an inhibited cell growth of CNNs but an enhanced apoptosis. Furthermore, MiR-150 inhibition was observed to have effects on CNNs as opposed to those inhibited by miR-150 promotion. The key findings of this study support the notion that miR-150 under-expression-mediated direct promotion of Mal protects CNN functions through the activation of the ERK1/2 axis, and underscore the concept that miR-150 may represent a novel pharmacological target for ischemic stroke intervention.     

Effect of ganglioside combined with Chip Jiaji electro-acupuncture on Nogo-NgR signal pathway in SCI rats

At present, the effect of ganglioside combined with Jiaji electroacupuncture (Jiaji EA) on SCI still remains unclear. This study explores the effect of ganglioside combined with electroacupuncture on Nogo/NgR signal pathway in spinal cord tissue of spinal cord injury (SCI) rats. Basso Beattie Bresnahan (BBB) score was used to evaluate spinal cord function after modeling and 14 days post ganglioside and electroacupuncture treatment. RT-qPCR and western blot were performed to evaluate the expression levels of targets in spinal cord tissue. After 14 days of treatment, the BBB scores of Jiaji EA group, ganglioside group and combination group were all improved. The expression levels of IL-1β, IL-6 and TNF-α in Jiaji EA group, ganglioside group and combination group were significantly lower than those in model group. Both of mRNA and protein expression levels of Nogo-A, NgR and LINGO-1 in the model group were significantly higher than those in the Jiaji EA group, ganglioside group and combination group. Ganglioside combined with Jiaji EA has a stronger effect on promoting the recovery of nerve function. Its mechanism of action may be related to its inhibition of the expression of proinflammatory cytokines such as IL-1β, IL-6 and TNF-α and Nogo-NgR signal pathway to promote neuronal growth. Our results will provide fundamental information for further SCI studies.     

Neuroprotective effect of PEP-1-peroxiredoxin2 on CA1 regions in the hippocampus against ischemic insult

Background

Oxidative stress is a leading cause of various diseases, including ischemia and inflammation. Peroxiredoxin2 (PRX2) is one of six mammalian isoenzymes (PRX1–6) that can reduce hydrogen peroxide (H₂O₂) and organic hydroperoxides to water and alcohols.

Methods

We produced PEP-1-PRX2 transduction domain (PTD)-fused protein and investigated the effect of PEP-1-PRX2 on oxidative stress-induced neuronal cell death by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Western blot, immunofluorescence microscopy, and immunohistochemical analysis.

Results

Our data showed that PEP-1-PRX2, which can effectively transduce into various types of cells and brain tissues, could be implicated in suppressing generation of reactive oxygen species, preventing depolarization of the mitochondrial membrane, and inhibiting the apoptosis pathway in H₂O₂-stimulated HT22, murine hippocampal neuronal cells, likely resulting in protection of HT22 cells against H₂O₂-induced toxicity. In addition, we found that in a transient forebrain ischemia model, PEP-1-PRX2 inhibited the activation of astrocytes and microglia in the CA1 region of the hippocampus and lipid peroxidation and also prevented neuronal cell death against ischemic damage.

Conclusions

These findings suggest that the transduced PEP-1-PRX2 has neuroprotective functions against oxidative stress-induced cell death in vitro and in vivo.

General significance

PEP-1-PRX2 could be a potential therapeutic agent for oxidative stress-induced brain diseases such as ischemia.     

Neuroprotective effect of ischemic preconditioning via modulating the expression of adropin and oxidative markers against transient cerebral ischemia in diabetic rats

IntroductionIschemic preconditioning (IPreC) can render the brain more tolerant to a subsequent potential lethal ischemic injury. Hyperglycemia has been shown to increase the size of ischemic stroke and worsen the clinical outcome following a stroke, thus exacerbating oxidative stress. Adropin has a significant association with cardiovascular disease, especially with diabetes. In this study, we aimed to evaluate the role of the IPreC due to modulating the expression of adropin and oxidative damage markers against stroke by induced transient middle cerebral artery occlusion (MCAo) in streptozotocin (STZ)-induced diabetic rats.Material-method72 male Spraque Dawley rats were allocated to 8 groups. In order to evaluate alterations of anti/oxidative status and adropin level, we induced transient MCAo seven days after STZ-induced diabetes. Also we performed IPreC 72 h before transient MCAo to assess whether IPreC could have a neuroprotective effect against ischemia-reperfusion injury.ResultsThe general characteristics of STZ-treated rats (STZ) included reduced body weight and elevated blood glucose levels compared to non-diabetic ones. Ischemic preconditioning before cerebral ischemia significantly reduced infarction size compared with the other groups [IPreC + MCAo (27 ± 11 mm³) vs. MCAo (109 ± 17 mm³) p < 0.001; STZ + IPreC + MCAo (38 ± 10 mm³) vs. STZ + MCAo (165 ± 45 mm³) p < 0.001, respectively]. The mean total antioxidant status level in IPreC groups was higher than other groups (p ≤ 0.05). Moreover, IPreC considerably decreased mean adropin levels compared with other groups (p ≤ 0.05).ConclusionThe study results supported the neuroprotective effects of ischemic preconditioning in MCA infarcts correlated with the level of oxidative damage markers and adropin.     

Lentiviral-mediated silencing of mast cell-expressed membrane protein 1 promotes angiogenesis of rats with cerebral ischemic stroke

Cerebral ischemic stroke is a devastating neurological disease with high rates of morbidity, disability, and mortality. Lentiviral-mediated mast cell-expressed membrane protein 1 (MCEMP1) has been shown to function in ischemic stroke. Hence, this study aims to explore the function of MCEMP1 specifically in angiogenesis, neuronal proliferation, and apoptosis in rats with cerebral ischemic stroke. Initially, stroke-related genes were obtained through microarray-based gene expression analysis, followed by the construction of a lentiviral vector for MCEMP1 shRNA and establishment of the middle cerebral artery occlusion model. After rats were transfected with MCEMP1 shRNA lentivirus, microvessel density (MVD), expression of MCEMP1, caspase-3, and vascular endothelial growth factor (VEGF), and neuronal proliferation and apoptosis were measured to explore the role of MCEMP1 in cerebral ischemic stroke. MCEMP1 was found to be highly expressed in rats with cerebral ischemic stroke. Silencing of MCEMP1 led to upregulation of VEGF, while downregulation of caspase-3, and resulted in the promotion of MVD in rats with ischemic stroke. Moreover, MCEMP1 silencing could increase Ki67 positive cells and reduce terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells in the marginal zone of cortical infarction in rats. Our study provides evidence that silenced MCEMP1 could enhance angiogenesis and suppress neuronal apoptosis in rats with cerebral ischemic stroke, highlighting that MCEMP1 silencing could serve as a therapeutic target for cerebral ischemic stroke treatment.     

普伐他汀联合阿司匹林治疗老年缺血性脑卒中的疗效及对血脂和认知功能的影响

目的:探讨普伐他汀联合阿司匹林对老年缺血性脑卒中的治疗疗效及其对患者血脂和认知功能的影响。方法:选择我院80例老年缺血性脑卒中患者,按入院顺序采用随机数字表法平均分为两组各40例,两组患者均给予常规缺血性脑卒中对症治疗,研究组患者在此基础上使用普伐他汀联合阿司匹林治疗,对照组患者仅使用阿司匹林治疗。比较两组患者治疗疗效,同时比较两组患者血清中血脂水平及认知功能改变情况。结果:研究组患者总治疗有效率为92.5%,明显高于对照组65%,比较差异具有统计学意义(P0.05);研究组患者治疗后血脂水平较治疗前明显下降,且下降程度显著高于对照组,比较差异具有统计学意义(P0.05);研究组患者治疗后认知功能评分总分为(93.75±11.45)分,明显高于对照组(84.11±12.04)分,比较差异具有统计学意义(P0.05)。结论:普伐他汀联合阿司匹林对老年缺血性脑卒中的治疗疗效显著,可有效改善患者血脂水平和认知功能,值得推广应用。     

Effects of ERK1/2 signal pathway on cardiomyocyte during glucose lowering

Objective: This study investigated whether the extracellular signal-regulated kinase 1/2 (ERK1/2) signal pathway affects cardiomyocyte apoptosis and the expression of tumor necrosis factor (TNF-α) at different glucose-lowering rates.

Methods: Cardiomyocytes of Wistar neonate rats were maintained in a medium supplemented with 25?mmol/L glucosamine for 72?h. Then the medium was changed to different concentrations of glucosamine, and all cells were divided into five groups. The survival rate of cardiomyocyte was measured using the Cell Counting Kit-8; cardiomyocyte apoptosis was measured using the flow cytometry instrument and laser confocal microscope; TNF-α was measured using the enzyme-linked immunosorbent assay; and ERK1/2 protein and phosphorylation were measured using the Western blot. Cardiomyocyte apoptosis and TNF-α were measured again after adding U0126.

Results: As the glucose-lowering rate increased, the survival rate of cardiomyocytes increased in group B and decreased in groups C, D, and E. The TNF-α concentration increased in groups B, C, and D and decreased in group E. After 24?h, the apoptosis rate decreased in group B and increased in groups C, D, and E. The expression of p-ERK1/2 increased in groups B, D, and E, and was the lowest in group C. After adding U0126, the survival rate of cardiomyocyte in all groups increased and TNF-α concentration decreased.

Conclusions: The influence of glucose-lowering rate on cardiomyocyte apoptosis and TNF-α was caused by the p-ERK1/2 pathway. During the glucose-lowering course, the p-ERK1/2 pathway promoted cardiomyocyte apoptosis, and TNF-α secretion was related to not only osmotic pressure but also ERK1/2 signal pathway activation.     

LEF-1的调控及其与肿瘤的关系研究进展

淋巴细胞增强因子（lymphoid enhancer factor,LEF-1）是Wnt信号通路中的一个重要调控因子。其异常表达对肿瘤细胞增殖和凋亡调控起关键作用。LEF-1作为Wnt信号通路核内的转录因子,还与T细胞受体α（TCRα）的增强子相互作用形成特定的构象,从而与其他因子结合共同调节基因的表达。同时,LEF-1为一多启动子基因,编码产生致瘤的全长形式的LEF-1和对Wnt信号通路起负向调控作用的截短形式的LEF-1。诸多研究结果表明肿瘤的发生发展与LEF／TCF各亚型的比例有关。就Wnt／LEF-1信号通路的调控以及与肿瘤的关系做一综述。     

Role of Keap1-Nrf2/ARE signal transduction pathway in protection of dexmedetomidine preconditioning against myocardial ischemia/reperfusion injury

Objective: To explore the role and mechanism of the Kelch sample related protein-1-nuclear factor erythroid-2 related factor 2/antioxidant response element (Keap1-Nrf2/ARE) signaling pathway in protection of dexmedetomidine (DEX) preconditioning against myocardial ischemia/reperfusion injury (MIRI). Methods: A total of 70 male SD rats were randomly divided into seven equal groups (n=10): blank control (S group), ischemia/reperfusion injury (C group), DEX preconditioning (DEX group), tertiary butylhydroquinone (tBHQ) control (tBHQ group), combined tBHQ and DEX preconditioning (tBHQ+DEX group), all-trans retinoic acid (ATRA) control (ATRA group), and combined ATRA and DEX preconditioning (ATRA+DEX group). Serum creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) concentrations were measured by ELISA kits, and the infarct size (IS) was assessed by Evan’s blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining. Oxidative stress was assessed through Western blotting for expression of Keap1-Nrf2/ARE pathway members and oxidative stress markers. Results: Cardioprotection of DEX, tBHQ, and tBHQ+DEX preconditioning treatments were shown as lower concentrations of serum CK-MB and cTnI and a smaller IS following MIRI in rats compared with those of MIRI rats without pre-treatment. In addition, tBHQ+DEX preconditioning exhibited stronger myocardial protection compared with DEX preconditioning. Mechanistically, the cardioprotection offered by DEX, tBHQ, and tBHQ+DEX preconditioning treatments was mediated via exerting antioxidant stress through activation of the Keap1-Nrf2/ARE signal transduction pathway. Conversely, the protective effects of DEX were diminished by blocking the Keap1-Nrf2/ARE pathway with inhibitor ATRA. Conclusion: DEX preconditioning protects against MIRI by exerting antioxidant stress through activation of the Keap1-Nrf2/ARE signal transduction pathway, while inhibition of the Keap1-Nrf2/ARE signal transduction pathway reverses the protective effect of DEX preconditioning on MIRI.     

Ridaforolimus体外单独或联合氟康唑抗念珠菌作用的研究

由念珠菌感染引起的侵袭性念珠菌病治疗困难、死亡率高,是临床一大难题。氟康唑是目前治疗该病的一线用药,但近年来耐药菌株逐渐增多,治疗困难。因此,开发新的有效抗真菌药物或发现可提高现有抗真菌药物活性的化合物十分必要。通过体外抗真菌药物敏感性试验,我们发现TOR通路抑制剂ridaforolimus具有抗念珠菌作用。随后我们通过纸片法及微量液基稀释法评价该化合物单独或与氟康唑联合对念珠菌的抗菌效果。结果表明ridaforolimus对念珠菌有杀伤作用,在与氟康唑联合时增强了氟康唑的抗念珠菌能力,逆转了白念珠菌对氟康唑的耐药,并将氟康唑由抑菌剂转化为杀菌剂。本研究为ridaforolimus作为新型抗真菌药及氟康唑增敏剂提供了一定理论基础。     

Impacts of COX-1 gene polymorphisms on vascular outcomes in patients with ischemic stroke and treated with aspirin

As the key point of function for aspirin to educe anti-platelet effects, cyclooxygenase-1 (COX-1) gene polymorphisms have long been suspected as a potential cause for aspirin nonresponsiveness. But this hypothesis has not been confirmed by large longitudinal studies. This study prospectively evaluated the impacts of COX-1 gene polymorphisms on stroke recurrence and other vascular events in a large cohort of Chinese patients with ischemic stroke and treated with aspirin. Between December 2009 and October 2012, consecutive patients with ischemic stroke and treated with aspirin were enrolled. Polymorphisms of four alleles (rs1330344, rs10306114, rs3842788 and rs5788) in COX-1 gene were determined at baseline. The primary endpoint was a composite of nonfatal ischemic stroke, myocardial infarction, and death from cardiovascular causes. Impacts of COX-1 gene polymorphisms on vascular outcomes were evaluated with multivariate analysis. A total of 859 patients were included in data analysis. The minor allele frequencies of rs1330344, rs10306114, rs3842788 and rs5788 were 38.53%, 0.12%, 6.64% and 5.53%, respectively. During 14.64 ± 7.44 months of follow-up, primary endpoint was observed in 67 (7.80%) patients. Incidence of primary endpoint was higher in patients with CC genotype of rs1330344 than in patients with CT or TT genotype (HR = 1.916, 95% CI: 1.126–3.260, P = 0.016). After being adjusted for potential confounding factors, rs1330344 CC genotype was still independently associated with incidence of primary endpoint (HR = 1.958, 95% CI: 1.151–3.332, P = 0.013). The impacts of other three tested polymorphisms on primary endpoint were unremarkable. In conclusion, in Chinese patients with ischemic stroke and treated with aspirin, CC genotype of rs1330344 may increase the risk of subsequent vascular events.     

H2S对大鼠心肌肥大与miRNA-133a和Ca2+/CaN/NFATc4信号通路的影响

目的：研究硫化氢（H₂S）对心肌细胞肥大的负性调控作用与miRNA-133a介导Ca²⁺/CaN/NFATc4信号通路的关系。方法：异丙肾上腺素（ISO）诱导体外培养的大鼠心肌细胞肥大模型;Leica图像分析软件测量心肌细胞表面积;qRT-PCR检测脑钠尿肽（BNP）、β-肌球蛋白重链（β-MHC）、H₂S合酶（CSE）、miRNA-133a和钙调神经磷酸酶（CaN） mRNA表达;Western blot检测CaN、活化T细胞核因子c4（NFATc4）蛋白表达;Elisa方法检测心肌细胞H₂S含量;激光共聚焦显微镜检测心肌细胞钙离子浓度;细胞免疫荧光检测NFATc4核转位变化。结果：①心肌细胞肥大时,CSE/H₂S水平、miRNA-133a mRNA表达均显著下降。应用NaHS预处理,能上调心肌细胞CSE/H₂S水平,增加H₂S含量和miRNA-133a mRNA表达,并明显抑制心肌细胞肥大。②心肌细胞肥大时,细胞内钙离子浓度明显增加,CaN表达和NFATc4胞核蛋白表达增加,NFATc4核转位明显增强;应用NaHS预处理能明显抑制ISO诱导的上述效应。③应用antagomir-133a能逆转H₂S抑制心肌细胞肥大的作用,使心肌细胞内钙离子浓度、CaN表达和NFATc4胞核蛋白表达增加,NFATc4核转位增强。结论：H₂S通过负性调控作用抑制心肌细胞肥大,该作用可能与H₂S上调miRNA-133a的表达,抑制其下游的Ca²⁺/CaN/NFATc4信号通路的激活有关。     

Retracted: Upregulated microRNA-31 inhibits oxidative stress-induced neuronal injury through the JAK/STAT3 pathway by binding to PKD1 in mice with ischemic stroke

Ischemic stroke (IS), which is characterized by high morbidity, disability, and mortality, is recognized as a major cerebrovascular disease. MicroRNA-31 (miR-31) was reported to participate in the progression of brain disease. The present study was conducted in order to investigate the effect of miR-31 on oxidative stress-induced neuronal injury in IS mice with the involvement of protein kinase D1 (PKD1) and the JAK/STAT3 pathway. C57BL/6J mice were used to establish the middle cerebral artery occlusion (MCAO) model. Astrocytes were transfected with miR-31 mimic, miR-31 inhibitor, si-PKD1, or JAK-STAT3 pathway inhibitor. Following the establishment of an oxygen–glucose deprivation (OGD) model, the astrocytes were cocultured with neuronal OGD. Lower miR-31, higher PKD1 expressions, and activated JAK/STAT3 pathway were found in both the MCAO and OGD models. miR-31 could negatively target PKD1. In an MCAO model, overexpressing miR-31 and silencing PKD1 reduced neuronal injury, cerebral infarct volume, neuron loss, and oxidative stress injury, inhibited the activation of JAK/STAT3 pathway and the expressions of PKD1, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, malondialdehyde, 4-HNE, 8-HOdG, caspase-3, and Bax, but increased the superoxide dismutase content. In the OGD model, overexpression of miR-31 and silencing of PKD1 attenuated oxidative stress-induced neuronal injury, and diminished the lactate dehydrogenase leakage and reactive oxygen species level, accompanied by elevated neuronal viability. These results indicate that miR-31 alleviates inflammatory response as well as an oxidative stress-induced neuronal injury in IS mice by downregulating PKD1 and JAK/STAT3 pathway.     

Association of RDM1 with osteosarcoma progression via cell cycle and MEK/ERK signalling pathway regulation

RAD52 motif-containing 1 (RDM1), a key regulator of DNA double-strand break repair and recombination, has been reported to play an important role in the development of various human cancers, such as papillary thyroid carcinoma, neuroblastoma and lung cancer. However, the effect of RDM1 on osteosarcoma (OS) progression remains unclear. Here, this study mainly explored the connection between RDM1 and OS progression, as well as the underlying mechanism. It was found that RDM1 was highly expressed in OS cells compared with human osteoblast cells. Knockdown of RDM1 caused OS cell proliferation inhibition, cell apoptosis promotion and cell cycle arrest at G1 stage, whereas RDM1 overexpression resulted in the opposite phenotypes. Furthermore, RDM1 silencing leads to a significant decrease in tumour growth in xenograft mouse model. RDM1 also increased the protein levels of MEK 1/2 and ERK 1/2. All these findings suggest that RDM1 plays an oncogenic role in OS via stimulating cell cycle transition from G1 to S stage, and regulating MEK/ERK signalling pathway, providing a promising therapeutic factor for the treatment of OS.