EGCG经AKT1-Mdm-2-p53途径抑制卵巢癌HO-8910细胞的增殖

目的：初步探讨EGCG对卵巢癌HO-8910细胞增殖的抑制作用及其机制。方法：通过绘制细胞生长曲线、平皿克隆和软琼脂集落形成实验观察EGCG对HO-8910细胞增殖的抑制作用;Westem—blotting检测AKT1、Mdm-2与p53蛋白的表达。结果：（1）细胞生长曲线、平皿克隆和软琼脂集落形成实验结果显示,EGCG可有效抑制HO-8910细胞的增殖（n=3,P〈0．05）。（2）Western—blotting检测结果显示,EGCG处理后AKT1与Mdm-2蛋白表达均降低,而p53蛋白表达升高（P〈0．05）。结论：EGCG通过抑制HO-8910细胞中AKT1与Mdm-2蛋白表达,促使p53蛋白表达而发挥其对细胞增殖的抑制作用。     

Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor

The PI3K signaling pathway is activated in a broad spectrum of human cancers, either directly by genetic mutation or indirectly via activation of receptor tyrosine kinases or inactivation of the PTEN tumor suppressor. The key nodes of this pathway have emerged as important therapeutic targets for the treatment of cancer. In this study, we show that (−)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is an ATP-competitive inhibitor of both phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with K_i values of 380 and 320 nM respectively. The potency of EGCG against PI3K and mTOR is within physiologically relevant concentrations. In addition, EGCG inhibits cell proliferation and AKT phosphorylation at Ser473 in MDA-MB-231 and A549 cells. Molecular docking studies show that EGCG binds well to the PI3K kinase domain active site, agreeing with the finding that EGCG competes for ATP binding. Our results suggest another important molecular mechanism for the anticancer activities of EGCG.     

EGCG经AKT1-Mdm-2-p53途径抑制卵巢癌HO-891O细胞的增殖

初步探讨EGCG对卵巢癌HO-8910细胞增殖的抑制作用及其机制.方法:通过绘制细胞生长曲线、平皿克隆和软琼脂集落形成实验观察EGCG对HO-8910细胞增殖的抑制作用;Western-blotting检测AKT1、Mdm-2与p53蛋白的表达.结果:(1)细胞生长曲线、平皿克隆和软琼脂集落形成实验结果显示,EGCG可有效抑制HO-8910细胞的增殖(n=3,P＜0.05).(2)Westemblotting检测结果显示,EGCG处理后AKT1与Mdm-2蛋白表达均降低,而p53蛋白表达升高(P＜0.05).结论:EGCG通过抑制HO-8910细胞中AKT1与Mdm-2蛋白表达,促使p53蛋白表达而发挥其对细胞增殖的抑制作用.     

Atractylenolide I inhibits colorectal cancer cell proliferation by affecting metabolism and stemness via AKT/mTOR signaling

BackgroundAtractylenolide I (ATL-1) is a natural herbal compound used in traditional Chinese medicine that has exhibited anti-cancer properties. The anti-tumorigenic activity of ATL-1 against colorectal cancer (CRC) and the underlying signaling pathways involved in its mechanisms are examined here.HypothesisATL-1 exerts therapeutic effect against CRC by disrupting glucose metabolism and cancer stem cell maintenance via AKT/mTOR pathway regulation.Study designIn vitro studies were performed in COLO205 and HCT116 CRC cell lines and in vivo studies were conducted in a mouse xenograft model of CRC tumor.MethodsCRC cells were treated with ATL-1 at various concentrations, with or without inhibitors of AKT or mTOR. Cell proliferation, apoptosis, invasion, stemness maintenance, glucose metabolism, and AKT/mTOR signaling were evaluated. CRC tumor-xenografted mice were treated with an AKT inhibitor and/or ATL-1, and glucose metabolism and stemness maintenance were examined in tumor tissues.ResultsATL-1 significantly inhibited the invasion of CRC cells by inducing their apoptosis, possibly via the excessive production of reactive oxygen species. Glucose metabolism (Warburg effect) was also altered and stem-like traits were suppressed by ATL-1. In addition, ATL-1 effectively acted as an inhibitor or AKT/mTOR by downregulating the phosphorylation of proteins related to the AKT/mTOR pathway. In vivo studies showed that tumor weight and volume were reduced by ATL-1 and that aerobic glycolysis, stemness maintenance, and AKT/mTOR activation were impaired by ATL-1 in colorectal tumors.ConclusionsATL-1 acts as an effective agent to suppress colorectal tumor progression, mainly by inhibiting CRC cell proliferation through altering apoptosis, glucose metabolism, and stem-like behavior. These processes were mediated by the AKT/mTOR signaling pathway both in vitro and in vivo. ATL-1 may be a potential agent to be used in molecular-targeted strategies for cancer treatment.     

Mechanistic action of mesenchymal stem cell injection in the treatment of chemically induced ovarian failure in rabbits

BackgroundNo curative treatment is known for primary ovarian failure; however, mesenchymal stem cells (MSCs), through self-renewal and regeneration, push the trial to evaluate their role in the treatment of ovarian failure. The aim of this study was to explore the impact of MSCs on cyclophosphamide (CTX)-induced ovarian failure in rabbits and to clarify the mechanism(s) by which MSCs exert their action.MethodsThirty-five adult female rabbits were injected with CTX to induce ovarian failure. Five rabbits were euthanized after the last injection of CTX for histological examination. The others (30 rabbits) were further subdivided into two groups: group 1 (ovarian failure group, 15 rabbits) received no treatment; group 2 (ovarian failure and MSC recipient group, 15 rabbits) received MSCs isolated from extracted bone marrow of male rabbits.ResultsA decrease of follicle-stimulating hormone and an increase of estrogen and vascular endothelial growth factor (VEGF) levels in the MSC recipient group versus the ovarian failure group were found. Weak caspase-3 expression and +ve proliferating cell nuclear antigen staining after MSC injection were detected. Cytological and histological examinations showed increased follicle numbers with apparent normal structure of ovarian follicles in the MSC recipient group. Moreover, Y chromosome–containing cells from male donors were present within the ovarian tissues in group 2.ConclusionsThe current study suggests that intravenous injection of MSCs into rabbits with chemotherapy-induced ovarian damage improved ovarian function. MSCs accomplish this function by direct differentiation into specific cellular phenotypes and by secretion of VEGF, which influence the regeneration of the ovary.     

Epigallocatechin gallate induces expression of heme oxygenase-1 in endothelial cells via p38 MAPK and Nrf-2 that suppresses proinflammatory actions of TNF-α

Epigallocatechin gallate (EGCG), the major polyphenol in green tea, acutely stimulates production of nitric oxide (NO) from vascular endothelium to reduce hypertension and improve endothelial dysfunction in spontaneously hypertensive rats. Herein, we explored additional mechanisms whereby EGCG may mediate beneficial cardiovascular actions. When compared with vehicle-treated controls, EGCG treatment (2.5 μM, 8 h) of human aortic endothelial cells (HAEC) caused a ~three-fold increase in heme oxygenase-1 (HO-1) mRNA and protein with comparable increases in HO-1 activity. This was unaffected by pretreatment of cells with wortmannin, LY294002, PD98059 or L-NAME (PI 3-kinase, MEK and NO synthase inhibitors, respectively). Pretreatment of HAEC with SB203580 (p38 MAPK inhibitor) or siRNA knockdown of p38 MAPK completely blocked EGCG-stimulated induction of HO-1. EGCG treatment also inhibited tumor-necrosis-factor-α-stimulated expression of vascular cell adhesion molecule (VCAM)-1 and decreased adhesion of monocytes to HAEC. siRNA knockdown of HO-1, p38 MAPK or Nrf-2 blocked these inhibitory actions of EGCG. In HAEC transiently transfected with a human HO-1 promoter luciferase reporter (or an isolated Nrf-2 responsive region), luciferase activity increased in response to EGCG. This was inhibitable by SB203580 pretreatment. EGCG-stimulated expression of HO-1 and Nrf-2 was blocked by siRNA knockdown of Nrf-2 or p38 MAPK. Finally, liver from mice chronically treated with EGCG had increased HO-1 and decreased VCAM-1 expression. Thus, in vascular endothelium, EGCG requires p38 MAPK to increase expression of Nrf-2 that drives expression of HO-1, resulting in increased HO-1 activity. Increased HO-1 expression may underlie anti-inflammatory actions of EGCG in vascular endothelium that may help mediate beneficial cardiovascular actions of green tea.     

Suppression of FAM83D Inhibits Glioma Proliferation,Invasion and Migration by Regulating the AKT/mTOR Signaling Pathway

ObjectiveTo explore the mechanism by which the family with sequence similarity 83, member D (FAM83D)-mediated AKT/mTOR signaling pathway activation affects the proliferation and metastasis of glioma cells.MethodsFAM83D protein expression in glioma cells and tissues was detected by western blotting. Glioma U87 and U251 cells were selected and divided into the Mock, siNC, siFAM83D, FAM83D, MK2206 and FAM83D + MK2206 groups. Cell proliferation was assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) and clone formation assays, while invasion and migration were evaluated by Transwell assays and wound healing tests. The protein expression of members of the AKT/mTOR pathway was determined via western blotting. Xenograft models were also established in nude mice to observe the in vivo effect of FAM83D on the growth of glioma.ResultsFAM83D was upregulated in glioma patients, especially in those with Stage III-IV. In addition, cells treated with siFAM83D had significant downregulation of p-AKT/AKT and p-mTOR/mTOR, with decreased proliferation and colony numbers, as well as decreased invasion and migration compared to the Mock group. However, FAM83D overexpression could activate the Akt/mTOR pathway and promote the proliferation, invasion and migration of glioma cells. Moreover, treatment with MK2206, an inhibitor of AKT, reversed the promoting effect of FAM83D on the growth of glioma cells. The in vivo experiments demonstrated that silencing FAM83D could inhibit the in vivo growth of glioma cellsConclusionFAM83D was upregulated in glioma and silencing FAM83D suppressed the proliferation, invasion and migration of glioma cells via inhibition of the AKT/mTOR pathway.     

Green tea polyphenol (−)-epigallocatechin gallate reduces matrix metalloproteinase-9 activity following transient focal cerebral ischemia

Green tea polyphenol (?)-epigallocatechin gallate (EGCG) has been reported to reduce neuronal damage after cerebral ischemic insult. EGCG is known to reduce matrix metalloproteinase (MMP) activity. MMP can play an important role in the pathophysiology of neurological disorders including cerebral ischemia. The purpose of the current study was to investigate whether EGCG shows an inhibitory effect on MMP activity and neural tissue damage following transient focal cerebral ischemia. In the present study, C57BL/6 mice were subjected to 80 min of focal ischemia induced by middle cerebral artery occlusion (MCAO). Animals were killed 24 h after ischemia. EGCG (50 mg/kg) was administered intraperitoneally immediately after ischemia. Gelatin gel zymography showed an increase in the active form of MMP-9 after ischemia. EGCG reduced ischemia-induced up-regulation of the active form of MMP-9. In in situ zymography, EGCG reduced up-regulation of gelatinase activity induced by cerebral ischemia. Co-incubation with EGCG reduced gelatinase activity directly in postischemic brain section. In 2,3,5-triphenyltetrazolium chloride (TTC) assay, brain infarction was remarkable in the middle cerebral artery territory after focal cerebral ischemia. In EGCG-treated mice, infarct volume was significantly reduced compared with vehicle-treated mice. These results demonstrate that EGCG, a green tea polyphenol, may reduce up-regulation of MMP-9 activity and neuronal damage following transient focal cerebral ischemia. In addition to its antioxidant effect, MMP-9 inhibition might be a possible mechanism potentially involved in the neuroprotective effect of a green tea polyphenol, EGCG.     

SIRT3 inhibited the formation of calcium oxalate-induced kidney stones through regulating NRF2/HO-1 signaling pathway

Oxidative stress is important for the calcium oxalate (CaOx)-induced kidney stone formation. Sirtuin 3 (SIRT3) plays an essential role in the amelioration of oxidative damages. This study aims to explore the effect of SIRT3 on the formation of CaOx-induced kidney stones and the underlying mechanism. SIRT3 expression in renal tissues was detected by immunohistochemistry. Apoptosis in renal tissues was examined by TUNEL staining. Crystal-cell adherence and cell apoptosis in HK-2 cells were assessed by analyzing Ca²⁺ concentration and by the flow cytometry analysis, respectively. Protein expression of SIRT3, nuclear factor erythroid 2-related factor (NRF2), heme oxygenase-1 (HO-1), and Bax in renal tissues or HK-2 cells was examined by Western blot analysis. Renal pathological changes and the adhesion of CaOx crystals in the kidneys were examined by hematoxylin-eosin and von Kossa staining, respectively. Human kidneys with stones showed enhanced renal apoptosis, downregulated SIRT3 expression, and upregulated NRF2/HO-1 expression, compared with the controls. Furthermore, SIRT3 overexpression inhibited the CaOx-induced promotion of crystal-cell adherence and cell apoptosis in human proximal tubular cell line HK-2 cells, which was reversed by the NRF2 knockdown. Moreover, our in vivo assay further confirmed that SIRT3 overexpression alleviated the glyoxylate administration-induced renal damage, renal apoptosis, and crystals deposition in the kidneys from the stone model mice, which was also associated with its activation of the NRF2/HO-1 pathway. Our findings support the notion that overexpression of SIRT3 may inhibit the formation of CaOx-induced kidney stones, at least in part, through regulating the NRF2/HO-1 signaling pathway.     

SETD2 epidermal deficiency promotes cutaneous wound healing via activation of AKT/mTOR Signalling

ObjectivesCutaneous wound healing is one of the major medical problems worldwide. Epigenetic modifiers have been identified as important players in skin development, homeostasis and wound repair. SET domain–containing 2 (SETD2) is the only known histone H3K36 tri‐methylase; however, its role in skin wound healing remains unclear.Materials and MethodsTo elucidate the biological role of SETD2 in wound healing, conditional gene targeting was used to generate epidermis‐specific Setd2‐deficient mice. Wound‐healing experiments were performed on the backs of mice, and injured skin tissues were collected and analysed by haematoxylin and eosin (H&E) and immunohistochemical staining. In vitro, CCK8 and scratch wound‐healing assays were performed on Setd2‐knockdown and Setd2‐overexpression human immortalized keratinocyte cell line (HaCaT). In addition, RNA‐seq and H3K36me3 ChIP‐seq analyses were performed to identify the dysregulated genes modulated by SETD2. Finally, the results were validated in functional rescue experiments using AKT and mTOR inhibitors (MK2206 and rapamycin).ResultsEpidermis‐specific Setd2‐deficient mice were successfully established, and SETD2 deficiency resulted in accelerated re‐epithelialization during cutaneous wound healing by promoting keratinocyte proliferation and migration. Furthermore, the loss of SETD2 enhanced the scratch closure and proliferation of keratinocytes in vitro. Mechanistically, the deletion of Setd2 resulted in the activation of AKT/mTOR signalling pathway, while the pharmacological inhibition of AKT and mTOR with MK2206 and rapamycin, respectively, delayed wound closure.ConclusionsOur results showed that SETD2 loss promoted cutaneous wound healing via the activation of AKT/mTOR signalling.     

Antimutagenic and anticarcinogenic activity of tea polyphenols

Tea is the most popular beverage, consumed by over two thirds of the world's population. Tea is processed differently in different parts of the world to give green (20%), black (78%) or oolong tea (2%). Green tea is consumed mostly in Japan and China. The antimutagenic and anticarcinogenic activities of green tea are extensively examined. The chemical components of green and black tea are polyphenols, which include EC, ECG, EGC, EGCG and TFs. This article reviews the epidemiological and experimental studies on the antimutagenicity and anticarcinogenicity of tea extracts and tea polyphenols. In Japan, an epidemiological study showed an inverse relationship between habitual green tea drinking and the standardized mortality rates for cancer. Some cohort studies on Chanoyu (Japanese tea ceremony) women teachers also showed that their mortality ratio including deaths caused by malignant neoplasms were surprisingly low. The antimutagenic activity against various mutagens of tea extracts and polyphenols including ECG and EGCG has been demonstrated in microbial systems (Salmonella typhimurium and Escherichia coli), mammalian cell systems and in vivo animal tests. The anticarcinogenic activity of tea phenols has been shown in experimental animals such as rats and mice, in transplantable tumors, carcinogen-induced tumors in digestive organs, mammary glands, hepatocarcinomas, lung cancers, skin tumors, leukemia, tumor promotion and metastasis. The mechanisms of antimutagenesis and anticarcinogenesis of tea polyphenols suggest that the inhibition of tumors may be due to both extracellular and intracellular mechanisms including the modulation of metabolism, blocking or suppression, modulation of DNA replication and repair effects, promotion, inhibition of invasion and metastasis, and induction of novel mechanisms.     

四物汤在卵巢衰老大鼠骨骼肌中的雌激素样作用机制研究

摘要 目的：探讨四物汤通过胰岛素样生长因子-1（Insulin-ike growth factors-1，IGF-1）/磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素靶蛋白（Mammalian target of rapamycin，mTOR）mTOR信号通路发挥对4-乙烯基环己烯二环氧化合物（4-Vinylcyclohexene Diepoxide，VCD）诱导的卵巢衰老大鼠骨骼肌的保护作用及其分子机制。方法：选用28日龄雌性F-344大鼠，随机选取6只作为空白对照组，剩余大鼠连续腹腔注射VCD溶液（160 mg/kg/d）20天，每天阴道涂片检测动情周期，连续观察12 d无角化细胞或仅有少量角化细胞即符合"卵巢衰老"表现，经动情周期筛选出24只造模成功的大鼠，分为模型组（Model）、阳性（戊酸雌二醇，E₂）对照组、四物汤高剂量（SWT-H）组和四物汤低剂量（SWT-L）组，每组6只，灌胃持续3周后取材。取大鼠骨骼肌组织进行HE染色观察病理组织结构；MASSON染色骨骼肌纤维形态变化；RT-PCR检测骨骼肌组织中各基因的mRNA水平。结果：与空白组比较，模型组骨骼肌肌纤维排列疏松，分布不均且有断点，胞浆不均，细胞核增多，出现增生的结缔组织，胶原纤维逐渐增多且肌纤维间距变宽；与模型组相比，E₂组、SWT-H组与SWT-L组肌纤维排列相对整齐，胞浆较为均匀。肌肉形态较规则，纤维间距缩短，胶原纤维减少。RT-PCR结果显示，与空白组相比，模型组IGF-1、PI3K、AKT、mTOR基因的mRNA表达量明显下调，E₂组、SWT-H组与SWT-L组的IGF-1、PI3K、mTOR的表达明显上升，SWT-H组AKT表达无明显变化，无统计学意义，SWT-L组AKT表达相对降低。与模型组相比，E₂组、SWT-H组与SWT-L组的IGF-1、AKT、mTOR的表达明显增加，且具有剂量依赖性，PI3K表达增加，但无明显剂量依赖性。结论：四物汤可以明显改善VCD诱导的卵巢衰老大鼠的肌肉减少情况，其机制可能是通过IGF-1-PI3K-AKT-mTOR信号通路来发挥其抑制肌肉流失的作用。     

KEAP1基因及其突变位点对非小细胞肺癌细胞株作用的实验初步研究

摘要 目的：研究KEAP1基因及KEAP1基因突变位点对肺癌细胞株的作用。方法：通过Western blot 方法,比较携带KEAP1 基因突变的肺癌细胞株（A549,NCI-H460,NCI-H838）与KEAP1 基因野生型的肺癌细胞株（NCI-H292, NCI-H1299, 95D, SPC-A1）之间,NRF2基因与NRF2下游基因HO-1的蛋白表达水平,检测并比较两组细胞的活性氧（ROS）含量;以新发现的非小细胞肺癌（NSCLC）病人的 KEAP1 体细胞突变作为模板构建 KEAP1 突变质粒,对自身存在 KEAP1 突变的肺癌细胞株A549,通过改造的 pMSCV 逆病毒转染体系,分别构建过表达空载,野生型及突变型 KEAP1 的 A549 稳定细胞株,比较过表达不同质粒的细胞间丙二醛（MDA）含量及 NRF2 下游抗氧化等相关基因的表达水平;通过克隆形成实验检测细胞增殖情况。结果：KEAP1基因突变组肺癌细胞株与KEAP1基因无突变的对照组细胞株相比,NRF2和HO-1蛋白表达显著增高,活性氧水平显著降低（P<0.01）;过表达野生型KEAP1 与过表达空载的 A549细胞相比,NRF2 及其下游基因转录水平表达显著下降（P<0.01）,蛋白水平表达下降,细胞内丙二醛水平显著增高（P<0.01）,克隆形成率显著降低（P<0.01）,而过表达突变型 KEAP1 与过表达空载的 A549细胞相比,NRF2 及其下游基因表达、细胞内丙二醛水平、克隆形成率均无显著差异（P>0.05）。结论：KEAP1基因具有抑癌作用,其突变为失活型突变,突变后KEAP1/NRF2通路激活,KEAP1基因突变可能通过改变细胞的氧化应激水平,促进肺癌的发生发展。     

Blood brain barrier permeability of (−)-epigallocatechin gallate,its proliferation-enhancing activity of human neuroblastoma SH-SY5Y cells,and its preventive effect on age-related cognitive dysfunction in mice

BackgroundThe consumption of green tea catechins (GTCs) suppresses age-related cognitive dysfunction in mice. GTCs are composed of several catechins, of which epigallocatechin gallate (EGCG) is the most abundant, followed by epigallocatechin (EGC). Orally ingested EGCG is hydrolyzed by intestinal biota to EGC and gallic acid (GA). To understand the mechanism of action of GTCs on the brain, their permeability of the blood brain barrier (BBB) as well as their effects on cognitive function in mice and on nerve cell proliferation in vitro were examined.MethodsThe BBB permeability of EGCG, EGC and GA was examined using a BBB model kit. SAMP10, a mouse model of brain senescence, was used to test cognitive function in vivo. Human neuroblastoma SH-SY5Y cells were used to test nerve cell proliferation and differentiation.ResultsThe in vitro BBB permeability (%, in 30 min) of EGCG, EGC and GA was 2.8±0.1, 3.4±0.3 and 6.5±0.6, respectively. The permeability of EGCG into the BBB indicates that EGCG reached the brain parenchyma even at a very low concentration. The learning ability of SAMP10 mice that ingested EGCG (20 mg/kg) was significantly higher than of mice that ingested EGC or GA. However, combined ingestion of EGC and GA showed a significant improvement comparable to EGCG. SH-SY5Y cell growth was significantly enhanced by 0.05 µM EGCG, but this effect was reduced at higher concentrations. The effect of EGC and GA was lower than that of EGCG at 0.05 µM. Co-administration of EGC and GA increased neurite length more than EGC or GA alone.ConclusionCognitive dysfunction in mice is suppressed after ingesting GTCs when a low concentration of EGCG is incorporated into the brain parenchyma via the BBB. Nerve cell proliferation/differentiation was enhanced by a low concentration of EGCG. Furthermore, the additive effect of EGC and GA suggests that EGCG sustains a preventive effect after the hydrolysis to EGC and GA.     

Targeting HO-1 by Epigallocatechin-3-Gallate Reduces Contrast-Induced Renal Injury via Anti-Oxidative Stress and Anti-Inflammation Pathways

Both oxidative stress and inflammation are involved in the pathogenesis of contrast-induced nephropathy (CIN). Epigallocatechin-3-gallate (EGCG), a purified catechin from green tea, has antioxidant and anti-inflammatory effects. However, it is unknown whether or not EGCG is effective in treating CIN. Our present study found that intravenous administration of EGCG, either before or just after the establishment of CIN, had a protective effect, determined by normalization of serum creatinine and blood urea nitrogen levels, improvement in renal histopathological scoring and alleviation of apoptosis, accompanied by decreased oxidative stress and inflammation. Because EGCG is a potent inducer of the antioxidant heme oxygenase-1 (HO-1), we studied HO-1 signaling in CIN. HO-1 levels were increased in CIN; treatment with EGCG further increased HO-1 levels, accompanied by an increase in Nrf2, a regulator of antioxidant proteins. Interestingly, blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) prevented the protective effect of EGCG on CIN. ZnPP also blocked the ability of EGCG to increase the activity of an antioxidant (superoxide dismutase), and decrease markers of oxidative stress (myeloperoxidase and malondialdehyde) and inflammation (myeloperoxidase and IL-1β), indicating that HO-1 is the upstream molecule that regulates the EGCG-mediated protection. To determine further the role of HO-1 on the EGCG-mediated inhibition of inflammation, we studied the effect of EGCG on the NLRP3 inflammasome, an upstream signaling of IL-1β. EGCG down-regulated NLRP3 expression, which was blocked by ZnPP, indicating that HO-1 links EGCG with NLRP3. Therefore, EGCG, via up-regulation of HO-1, protects against CIN by amelioration of oxidative stress and inflammation.     

Small Ribosomal Protein Subunit S7 Suppresses Ovarian Tumorigenesis through Regulation of the PI3K/AKT and MAPK Pathways

Small ribosomal protein subunit S7 (RPS7) has been reported to be associated with various malignancies, but the role of RPS7 in ovarian cancer remains unclear. In this study, we found that silencing of RPS7 by a specific shRNA promoted ovarian cancer cell proliferation, accelerated cell cycle progression, and slightly reduced cell apoptosis and response to cisplatin treatment. Knockdown of RPS7 resulted in increased expression of P85α, P110α, and AKT2. Although the basal levels of ERK1/2, MEK1/2, and P38 were inconsistently altered in ovarian cancer cells, the phosphorylated forms of MEK1/2 (Ser217/221), ERK1/2 (Thr202/Tyr204), JNK1/2 (Thr183/Tyr185), and P38 (Thr180/Tyr182) were consistently reduced after RPS7 was silenced. Both the in vitro anchorage-independent colony formation and in vivo animal tumor formation capability of cells were enhanced after RPS7 was depleted. We also showed that silencing of RPS7 enhanced ovarian cancer cell migration and invasion. In sum, our results suggest that RPS7 suppresses ovarian tumorigenesis and metastasis through PI3K/AKT and MAPK signal pathways. Thus, RPS7 may be used as a potential marker for diagnosis and treatment of ovarian cancer.