Tetrahydrocurcumin is more effective than curcumin in preventing azoxymethane-induced colon carcinogenesis

Scope : Tetrahydrocurcumin (THC), a major metabolite of curcumin (CUR), has been demonstrated to be anti‐cancerogenic and anti‐angiogenic and prevents type II diabetes. In this present study, we investigated the chemopreventive effects and underlying molecular mechanisms of dietary administration of CUR and THC in azoxymethane (AOM)‐induced colon carcinogenesis in mice. Methods and results : All mice were sacrificed at 6 and 23 wk, and colonic tissue was collected and examined. We found that dietary administration of both CUR and THC could reduce aberrant crypt foci and polyps formation, while THC showed a better inhibitory effect than CUR. At the molecular level, results from Western blot analysis and immunohistochemistry staining showed that dietary CUR and THC exhibited anti‐inflammatory activity by decreasing the levels of inducible NOS and COX‐2 through downregulation of ERK1/2 activation. In addition, both dietary CUR and THC significantly decreased AOM‐induced Wnt‐1 and β‐catenin protein expression, as well as the phosphorylation of GSK‐3β in colonic tissue. Moreover, dietary feeding with CUR and THC markedly reduced the protein level of connexin‐43, an important molecule of gap junctions, indicating that both CUR and THC might interfer with the intercellular communication of crypt cells. Conclusion : Taken together, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary THC against AOM‐induced colonic tumorigenesis.     

Hibiscus sabdariffa Leaf Polyphenolic Extract Induces Human Melanoma Cell Death,Apoptosis, and Autophagy

Melanoma is the least common but most fatal form of skin cancer. Previous studies have indicated that an aqueous extract of Hibiscus sabdariffa leaves possess hypoglycemic, hypolipidemic, and antioxidant effects. In this study, we want to investigate the anticancer activity of Hibiscus leaf polyphenolic (HLP) extract in melanoma cells. First, HLP was exhibited to be rich in epicatechin gallate (ECG) and other polyphenols. Apoptotic and autophagic activities of HLP and ECG were further evaluated by DAPI stain, cell‐cycle analysis, and acidic vascular organelle (AVO) stain. Our results revealed that both HLP and ECG induced the caspases cleavages, Bcl‐2 family proteins regulation, and Fas/FasL activation in A375 cells. In addition, we also revealed that the cells presented AVO‐positive after HLP treatments. HLP could increase the expressions of autophagy‐related proteins autophagy‐related gene 5 (ATG5), Beclin1, and light chain 3‐II (LC3‐II), and induce autophagic cell death in A375 cells. These data indicated that the anticancer effect of HLP, partly contributed by ECG, in A375 cells. HLP potentially could be developed as an antimelanoma agent.     

Pterostilbene induces autophagy and apoptosis in sensitive and chemoresistant human bladder cancer cells

Scope: Bladder cancer is one of the most common malignancies in the world. The majority of bladder cancer deaths are due to unresectable lesions that are resistant to chemotherapy. Pterostilbene (PT), a naturally occurring phytoalexin, possesses a variety of pharmacologic activities, including antioxidant, cancer prevention activity and cytotoxicity to many cancers. We found that PT effectively inhibits the growth of sensitive and chemoresistant human bladder cancer cells by inducing cell cycle arrest, autophagy and apoptosis. Down‐regulations of Cyclin A, B and D1 and pRB are the results of PT‐induced cell cycle arrest. Methods and results: Autophagy occurred at an early stage and was observed through the formation of acidic vesicular organelles (the marker for autophagy) and microtubule‐associated protein 1 light chain 3‐II production. Apoptosis occurred at a later stage and was detected by Annexin V and 4′,6‐diamidino‐2‐phenylindole staining. PT‐induced autophagy was triggered by the inhibition of active human protein kinase/the mammalian TOR/p70S6K pathway and activation of extracellular signal‐regulated kinase pathway. Inhibition of autophagy by pretreatment with 3‐methyladenine, bafilomycin A1, Beclin 1 or extracellular signal‐regulated kinase short hairpin RNA enhanced PT‐triggered apoptosis. Conclusion: This is the first study to demonstrate that PT causes autophagy in cancer cells and suggests that PT could serve as a new and promising agent for the treatment of sensitive and chemoresistant bladder cancer cells.     

Curcumin provides potential protection against the activation of hypoxia and prolyl 4-hydroxylase inhibitors on prostate-specific antigen expression in human prostate carcinoma cells

Scope: Prostate‐specific antigen (PSA) is a well‐known marker for diagnosing and monitoring prostate cancer. Curcumin, a yellow curry pigment, has been reported to enhance androgen receptor (AR) degradation. We examined the effects of curcumin on increasing PSA expression by hypoxia and prolyl hydroxylase inhibitors, L ‐mimosine and dimethyloxalylglycine (DMOG), in human prostate carcinoma LNCaP cells. Methods and results: The ³H‐thymidine incorporation assay revealed that either L ‐mimosine or DMOG treatments attenuated cell proliferation. Immunoblot and enzyme‐linked immunosorbent assays (ELISA) indicated that both L ‐mimosine and DMOG have an effect similar to hypoxia, which stabilized hypoxia‐inducible factor‐1α (HIF‐1α) and induced PSA gene expression. The results of the immunoblot and transient gene expression assays indicated that induction of the PSA expression by hypoxia is both HIF‐1α‐ and AR‐dependent. Immunoblot assays revealed that a curcumin treatment (10 μM) decreased the protein abundance of AR but did not significantly affect the protein levels of HIF‐1α and vascular endothelial growth factor, which were induced by hypoxia. ELISA and transient gene expression assays indicated that curcumin blocked the activation of L ‐mimosine or DMOG treatment on PSA expression. Conclusions: These results indicate that curcumin blocked the enhanced effect of PSA expression by L ‐mimosine and DMOG that induce hypoxia condition.     

Cover Picture: Mol. Nutr. Food Res. 11'2011

Regular issues provide a wide range of research, review and food & function articles covering all aspects of Molecular Nutrition & Food Research. Selected topics of issue 11 are: GABA (γ‐amino butyric acid), a non‐protein amino acid counters the beta‐adrenergic cascade‐activated oncogenic signaling in pancreatic cancer: A review of experimental evidence Mechanisms of weight maintenance under high‐ and low‐protein, low‐glycaemic index diets Tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death through coordinative modulation of PI3K/Akt‐mTOR and MAPKs signaling pathways in human leukemia HL‐60 cells Maternal folate supply and sex influence gene‐specific DNA methylation in the fetal gut Bilberries and their anthocyanins ameliorate experimental colitis     

The flavonoid tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562

We explored the mechanism of cell death of the polymethoxyflavone tangeretin (TAN) in K562 breakpoint cluster region‐abelson murine leukemia (Bcr‐Abl+) cells. Flow cytometric analysis showed that TAN arrested the cells in the G₂/M phase and stimulated an accumulation of the cells in the sub‐G₀ phase. TAN‐induced cell death was evidenced by poly(ADP)‐ribose polymerase cleavage, DNA laddering fragmentation, activation of the caspase cascade and downregulation of the antiapoptotic proteins Mcl‐1 and Bcl‐x_L. Pretreatment with the pancaspase inhibitor Z‐VAD‐FMK_blocked caspase activation and cell cycle arrest but did not inhibit apoptosis which suggest that other cell killing mechanisms like endoplasmic reticulum (ER)‐associated cell death pathways could be involved. We demonstrated that TAN‐induced apoptosis was preceded by a rapid activation of the proapoptotic arm of the unfolded protein response, namely PKR‐like ER kinase. This was accompanied by enhanced levels of glucose‐regulated protein of 78 kDa and of spliced X‐box binding protein 1. Furthermore, TAN sensitized K562 cells to the cell killing effects of imatinib via an apoptotic mechanism. In conclusion, our results suggest that TAN is able to induce apoptosis in Bcr‐Abl+ cells via cell cycle arrest and the induction of the unfolded protein response, and has synergistic cytotoxicity with imatinib.     

Suppression of EGF-induced tumor cell migration and matrix metalloproteinase-9 expression by capsaicin via the inhibition of EGFR-mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP-1 signaling

Scope: Capsaicin is a cancer‐suppressing agent. The aim of our study was to determine the effect of capsaicin on tumor invasion and migration; the possible mechanisms involved in this inhibition were investigated in human fibrosarcoma cells. Methods and results: We employed invasion, migration and gelatin zymography assays to characterize the effect of capsaicin on HT‐1080 cells. Transient transfection assays and immunoblot analysis were performed to study its molecular mechanisms of action. Capsaicin inhibited the epidermal growth factor (EGF)‐induced activation of matrix metalloproteinase (MMP)‐9 and MMP‐2, and further inhibited cell invasion and migration. Capsaicin decreased the EGF‐induced expression of MMP‐9, MMP‐2, and MT1‐MMP, but did not alter TIMP‐1 and TIMP‐2 levels. Capsaicin suppressed EGF‐induced c‐Jun and c‐Fos nuclear translocation, and also abrogated the EGF‐induced phosphorylation of EGF receptor (EGFR), focal adhesion kinase (FAK), protein kinase C (PKC), phosphatidylinositol 3‐Kinase (PI3K)/Akt, extracellular regulated kinase (ERK)1/2, and JNK1/2, an upstream modulator of AP‐1. Furthermore, the EGFR inhibitor inhibited EGF‐induced MMP‐9 expression, as well as AP‐1 activity and cell migration. Conclusion: Capsaicin inhibited the EGF‐induced invasion and migration of human fibrosarcoma cells via EGFR‐dependent FAK/Akt, PKC/Raf/ERK, p38 mitogen‐activated protein kinase (MAPK), and AP‐1 signaling, leading to the down‐regulation of MMP‐9 expression. These results indicate the role of capsaicin as a potent anti‐metastatic agent, which can markedly inhibit the metastatic and invasive capacity of fibrosarcoma cells.     

Anti-proliferative effect of curcumin on melanoma cells is mediated by PDE1A inhibition that regulates the epigenetic integrator UHRF1

Scope: Curcumin inhibits proliferation of many cancer cells. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic adenosine‐3′,5′‐monophosphate (cAMP) and/or cyclic guanosine‐3′,5′‐monophosphate (cGMP), play a pivotal role in signalling pathways involved in cell proliferation. Therefore, this study investigated PDE1–5 participations in the anti‐proliferative properties of curcumin in B16F10 murine melanoma cells. Methods and results: We report that curcumin inhibits PDE1–5 activities (IC₅₀?10^?5 M), indicating that curcumin acts as a non‐selective PDE inhibitor. In melanoma cells, PDE4 and PDE1 represent the major cAMP‐PDEs and cGMP‐PDEs activities, respectively. Curcumin treatment decreased PDE1 and PDE4 activities and dose dependently increased intracellular cGMP levels, whereas cAMP levels were unchanged. Curcumin inhibited cell proliferation and cell cycle progression by accumulating cells in the S‐ and G2/M‐phases with enhanced expressions of cyclin‐dependent kinase inhibitors. In contrast, expressions of PDE1A, cyclin A and the epigenetic integrator ubiquitin‐like containing PHD and Ring Finger domains 1 (UHRF1) and DNA methyltransferase 1 (DNMT1) were decreased by curcumin. Interestingly, PDE1A overexpression increased UHRF1 and DNMT1 expressions and rescued the B16F10 cells from curcumin anti‐proliferative effects. Nimodipine, a PDE1 inhibitor, mimicked the curcumin effects. Conclusion : Curcumin exerts its anti‐cancer property by targeting PDE1 that inhibits melanoma cell proliferation via UHRF1, DNMT1, cyclin A, p21 and p27 regulations. This suggests that natural PDE1 inhibitors present in food might be effective in preventing cancer.     

Antiproliferative activity of fucoidan was associated with the induction of apoptosis and autophagy in AGS human gastric cancer cells

Fucoidan, a sulfated polysaccharide purified from brown algae, possesses a variety of pharmacologic effects, including antiinflammatory, antioxidant, and anticancer properties; however, the underlying action mechanisms are not completely understood. This study investigated the possible mechanisms through which fucoidan exerts its antiproliferative action in cultured AGS human gastric adenocarcinoma cells. We found that fucoidan effectively inhibits the growth of AGS cells by inducing autophagy, as well as apoptosis. Apoptosis by fucoidan treatment was associated with the downregulation of antiapoptotic Bcl-2 and Bcl-xL expression, loss of mitochondrial membrane potential, activation of caspases, and concomitant degradation of poly-(ADP-ribose) polymerase protein. In addition, the morphological study indicated a characteristic finding of autophagy, such as the formation of autophagosomes in fucoidan-treated AGS cells. Furthermore, markers of autophagy, namely, the conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II and increased beclin-1 accumulation, were observed. Overall, the present data suggest that fucoidan induces apoptotic and autophagic cell death, and both apoptotic and autophagic mechanisms contribute to the fucoidan-induced AGS cell death.     

Curcumin induces heme oxygenase-1 in normal human skin fibroblasts through redox signaling: relevance for anti-aging intervention

Scope: Curcumin, a component of the spice turmeric, was tested for its potential hormetic anti‐aging effects as an inducer of mild stress. Methods and results: Early passage young human skin fibroblasts treated with low doses of curcumin (below 20 μM) showed a time‐ and concentration‐dependent induction of heme oxygenase‐1 (HO‐1), followed by compensatory increase in glutathione‐S‐transferase activity, GSH levels and GSH/GSSG ratio. These effects were preceded by induction of oxidative stress (increased levels of reactive oxygen species and DNA damage) and impairment of cells' GSH redox state. Curcumin also induced nuclear factor‐erythroid‐2‐related factor 2 accumulation in the nuclei. The use of the antioxidant N‐acetyl cysteine prevented the induction of HO‐1 by curcumin. Pharmacological inhibition of phosphatidylinositol 3‐kinase, but not other kinases, significantly prevented curcumin‐induced HO‐1 levels, which was corroborated by the induction of phospho‐Akt levels by curcumin. Late passage senescent cells already had higher HO‐1 levels, and further induction of HO‐1 by curcumin was considerably impaired. The induction of stress responses by curcumin in human cells led to protective hormetic effects to further oxidant challenge. Conclusion: Curcumin induces cellular stress responses in normal human skin fibroblasts through phosphatidylinositol 3‐kinase/Akt pathway and redox signaling, supporting the view that curcumin‐induced hormetic stimulation of cellular antioxidant defenses can be a useful approach toward anti‐aging intervention.     

Oleuropein and hydroxytyrosol inhibit MCF‐7 breast cancer cell proliferation interfering with ERK1/2 activation

The growth of many breast tumors is stimulated by estradiol (E2), which activates a classic mechanism of regulation of gene expression and signal transduction pathways inducing cell proliferation. Polyphenols of natural origin with chemical similarity to estrogen have been shown to interfere with tumor cell proliferation. The aim of this study was to investigate whether hydroxytyrosol (HT) and oleuropein (OL), two polyphenols contained in extra‐virgin olive oil, can affect breast cancer cell proliferation interfering with E2‐induced molecular mechanisms. Both HT and OL inhibited proliferation of MCF‐7 breast cancer cells. Luciferase gene reporter experiments, using a construct containing estrogen responsive elements able to bind estrogen receptor alpha (ERα) and the study of the effects of HT or OL on ERα expression, demonstrated that HT and OL are not involved in ERα‐mediated regulation of gene expression. However, further experiments pointed out that both OL and HT determined a clear inhibition of E2‐dependent activation of extracellular regulated kinase1/2 belonging to the mitogen activating protein kinase family. Our study demonstrated that HT and OL can have a chemo‐preventive role in breast cancer cell proliferation through the inhibition of estrogen‐dependent rapid signals involved in uncontrolled tumor cell growth.     

Involvement of MAPK, Bcl-2 family, cytochrome c, and caspases in induction of apoptosis by 1,6-O,O-diacetylbritannilactone in human leukemia cells

1,6-O,O-diacetylbritannilactone (OODBL) isolated from Inula britannica, exhibits potent antitumor activity against several human cancer cell lines. However, the molecular mechanism of OODBL in the induction of anticancer activity is still unclear. In the present study, we demonstrated that OODBL induced the occurrence of apoptosis in human leukemic (HL-60) cells and cell arrest at the S phase. On the other hand, activation of caspase-8, -9, and -3, phosphorylation of Bcl-2 and Bid, and increased release of cytochrome c from mitochondria into cytosolic fraction were detected in OODBL-treated HL-60 cells. We further demonstrated that production of reactive oxygen species (ROS), activation of mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways may play an important role in OODBL-induced apoptosis. The results from the present study highlight the molecular mechanisms underlying OODBL-induced anticancer activity.     

AMPK-endoplasmic reticulum stress axis contributes to lipopolysaccharide-caused mitochondrial dysfunction by regulating mitochondria-associated membrane function in bovine hepatocytes

Mitochondrial homeostasis is closely associated with cellular homeostasis process, whereas mitochondrial dysfunction contributes to apoptosis and mitophagy. Hence, analyzing the mechanism of lipopolysaccharide (LPS)-caused mitochondrial damage is necessary to understand how cellular homeostasis is maintained in bovine hepatocytes. Mitochondria-associated membranes (MAM), a connection between endoplasmic reticulum (ER) and mitochondria, is important to control mitochondrial function. To investigate the underlying mechanisms of the LPS-caused mitochondrial dysfunction, hepatocytes isolated from dairy cows at ∼160 d in milk (DIM) were pretreated with the specific inhibitors of adenosine 5′-monophosphate-activated protein kinase (AMPK), ER stress, RNA-activated protein kinase-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), c-Jun N-terminal kinase, and autophagy followed by a 12 I1/4g/mL LPS treatment. The results showed that inhibiting ER stress with 4-phenylbutyric acid decreased the levels of autophagy and mitochondrial damage with AMPK inactivation in LPS-treated hepatocytes. The AMPK inhibitor compound C pretreatment alleviated LPS-induced ER stress, autophagy and mitochondrial dysfunction by regulating the expression of MAM-related genes, such as mitofusin 2 (MFN2), PERK, and IRE1α. Moreover, inhibiting PERK and IRE1α mitigated autophagy and mitochondrial dynamic disruption by regulating the MAM function. Additionally, blocking c-Jun N-terminal kinase, the downstream sensor of IRE1α, could reduce the levels of autophagy and apoptosis and restore the balance of mitochondrial fusion and fission by modulating the B cell leukemia 2 (BCL-2)/BCL-2 interacting protein 1 (BECLIN1) complex in the LPS-treated bovine hepatocytes. Furthermore, autophagy blockage with chloroquine could intervene in LPS-caused apoptosis to restore mitochondrial function. Collectively, these findings suggest that the AMPK-ER stress axis is involved in the LPS-caused mitochondrial dysfunction by mediating the MAM activity in bovine hepatocytes.     

Dimethoxycurcumin, a synthetic curcumin analogue with higher metabolic stability, inhibits NO production, inducible NO synthase expression and NF-kappaB activation in RAW264.7 macrophages activated with LPS

Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) in activated macrophages is linked to acute and chronic inflammation. Thus, it would be valuable to develop inhibitors of NO and/or iNOS for potential therapeutic use. We investigated whether dimethoxycurcumin (DiMC), a synthetic curcumin analogue with higher metabolic stability over curcumin, could inhibit NO production and iNOS expression in activated macrophages. RAW264.7 macrophages were activated with lipopolysaccharide (LPS) in the absence or presence of DiMC, which contains four methoxy groups at two aromatic rings, curcumin containing two, bis-demethoxycurcumin (BDMC) containing none, or tetrahydrocurcumin (THC) containing two but lacking conjugated double bonds in the central seven-carbon chain. NO production, iNOS expression and NF-kappaB activity were examined. DiMC, curcumin and BDMC inhibited NO production, iNOS expression and NF-kappaB activation, with DiMC being the most effective, followed by curcumin and BDMC. THC failed to inhibit NO production, iNOS expression and NF-kappaB activation. Our results suggest that DiMC inhibits NO production, iNOS expression and NF-kappaB activation in LPS-activated macrophages, which may be due not only to the conjugated double bonds but also the increased number of methoxy groups.     

食源性黄酮类化合物调控自噬干预疾病的研究进展

黄酮类化合物是植物源食品中最重要的一类活性成分,具有抗炎、抗癌、预防心血管疾病等生物学功能。自噬通过降解细胞内受损的线粒体、折叠的蛋白体、病毒等物质维持细胞内的稳态。它分为巨自噬、微自噬和分子伴侣介导的自噬,其中巨自噬是主要类型。黄酮类物质能够通过不同的信号通路调控自噬进而干预疾病,其中磷脂酰肌醇3激酶/蛋白激酶B/雷帕霉素的哺乳动物靶标(Phosphatidylinosittide 3-kinase/Protein kinaseB/mammalian target of Rapamycin,PI3K/AKT/mTOR)是主要的调控自噬的信号通路。本文针对植物源食品中几种常见的黄酮类化合物,综述了其通过自噬干预炎症、癌症、肝病以及心血管疾病等发生的分子机制和研究进展。     

Riboflavin at High Doses Enhances Lung Cancer Cell Proliferation,Invasion, and Migration

The influence of riboflavin (vitamin B₂) upon growth, invasion, and migration in non‐small cell lung cancer cell lines was evaluated. Riboflavin at 1, 10, 25, 50, 100, 200, or 400 μmol/L was added into A549, H3255, or Calu‐6 cells. The effects of this compound upon level and/or expression of reactive oxygen species (ROS), inflammatory cytokines, intercellular adhesion molecule (ICAM)‐1, fibronectin, matrix metalloproteinase (MMP)‐9, MMP‐2, focal adhesion kinase (FAK), nuclear factor kappa B (NF‐κB), and mitogen‐activated protein kinase (MAPK) were examined. Results showed that riboflavin at test doses did not affect the level of ROS and glutathione. Riboflavin at 200 and 400 μmol/L significantly enhanced cell growth in test lung cancer cell lines, and at 400 μmol/L significantly increased the release of interleukin‐6, tumor necrosis factor‐alpha, and vascular endothelial growth factor. This agent at 200 and 400 μmol/L also upregulated protein production of ICAM‐1, fibronectin, MMP‐9, MMP‐2, NF‐κB p50, p‐p38 MAPK, and FAK; and at 400 μmol/L enhanced invasion and migration in test cell lines. These findings suggested that riboflavin at high doses might promote lung cancer progression.     

EGCG inhibits protein synthesis,lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells

In the previous studies, (–)‐epigallocatechin‐3‐gallate (EGCG) has been shown to have anticarcinogenic effects via modulation in protein expression of p53. Using p53 positive Hep G2 and p53 negative Hep 3B cells, we found that treatment of EGCG resulted in dose‐dependent inhibition of cellular proliferation, which suggests that the interaction of EGCG with p53 may not fully explain its inhibitory effect on proliferation. Caloric restriction (CR) reduces the incidence and progression of spontaneous and induced tumors in laboratory rodents. EGCG has multiple beneficial activities similar to those associated with CR. One key enzyme thought to be activated during CR is AMP‐activated kinase (AMPK), a sensor of cellular energy levels. Here, we showed that EGCG activated AMPK in both p53 positive and negative human hepatoma cells. The activation of AMPK suppressed downstream substrates, such as mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E‐binding protein‐1 (4E‐BP1) and a general decrease in mRNA translation. Moreover, EGCG activated AMPK decreases the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl‐CoA carboxylase (ACC). Interestingly, the decision between apoptosis and growth arrest following AMPK activation is greatly influenced by p53 status. In p53 positive Hep G2 cells, EGCG blocked the progression of cell cycle at G1 phase by inducing p53 expression and further up‐regulating p21 expression. However, EGCG inducted apoptosis in p53 negative Hep 3B cells. Based on these results, we have demonstrated that EGCG has a potential to be a chemoprevention and anti‐lipogenesis agent for human hepatoma cells.     

姜黄素调节Na/K-ATPase/Src信号通路保护LLC-PK1细胞缺氧复氧损伤

目的：阐明姜黄素作为Na/K-ATPase（NKA）不完全促进剂,通过影响NKA/类固醇受体辅助活化因子（steroid receptor coactivator,Src）受体复合物的活化保护细胞免于缺氧复氧损伤。方法：通过酶筛选实验明确姜黄素对NKA活性和构型的影响,利用缺氧复氧模型模拟细胞氧化应激损伤。姜黄素预保护猪肾上皮LLC-PK1细胞1 h后进行缺氧1 h复氧3 h处理,检测胞外乳酸脱氢酶（lactate dehydrogenase,LDH）活力、细胞活力以及Src、p-Src、细胞外调节蛋白激酶（extracellular signal-regulated protein kinases,Erk）、p-Erk蛋白表达情况。结果：姜黄素能够抑制NKA活性,通过促进Src和Erk1/2磷酸化激活NKA/Src信号通路,但乌本苷存在时姜黄素会增加NKA活性,抑制NKA/Src信号通路过度激活。姜黄素预保护能减轻LLC-PK1细胞氧化应激损伤,降低LDH活力,增加细胞活力,并减少Src、Erk磷酸化蛋白表达。结论：姜黄素对NKA/Src信号通路具有双向调节作用,姜黄素可以通过对NKA/Src信号通路的调节保护细胞免于缺氧复氧损伤。