Luteolin, a bioactive compound from Celastrus orbiculatus stem, inhibits cervical cancer via CA2 suppression: A translational study bridging basic research and clinical application.

Spasmolytic polypeptide-expressing metaplasia (SPEM) is a gastric precancerous lesion (GPL) with high malignant potential. The ethyl acetate extract of Celastrus orbiculatus Thunb. effectively ameliorates GPL and gastric cancer progression. Meanwhile, the primary active constituent of this plant, pristimerin, also demonstrates notable antitumor activity. To investigate the therapeutic effects of pristimerin on SPEM and its underlying mechanisms. Pristimerin was administered to high-dose tamoxifen-induced SPEM mice to assess its effects on pathological progression, glycolytic reprogramming, and Cdkn1c (p57) expression. Human gastric epithelial (GES-1) cells were treated with tamoxifen and then with pristimerin or 2-deoxy-D-glucose to demonstrate that pristimerin ameliorates SPEM by regulating glycolytic reprogramming. Furthermore, gastric organoids were treated with N-methyl-N'-nitro-N-nitrosoguanidine/Helicobacter pylori, followed by Cdkn1c overexpression or knockdown and then pristimerin, to confirm p57 as the key target through which pristimerin regulates glycolytic reprogramming and reverses SPEM. Pristimerin effectively ameliorated gastric mucosal damage and oxyntic atrophy induced by high-dose tamoxifen, suppressed the aberrant upregulation of key glycolytic regulators, SPEM-specific markers, and stem cell markers, and upregulated p57 expression. In tamoxifen-induced GES-1 cells, pristimerin exhibited comparable therapeutic effects. Crucially, glycolysis inhibition in GES-1 cells effectively ameliorated tamoxifen-induced SPEM-associated phenotypes. In gastric organoids, Cdkn1c overexpression suppressed glycolytic reprogramming and SPEM phenotype activation, whereas Cdkn1c knockdown attenuated pristimerin-mediated inhibition of glycolysis and amelioration of SPEM. Pristimerin effectively ameliorates gastric mucosal pathological damage and oxyntic atrophy in high-dose tamoxifen-induced SPEM mice, and improves SPEM progression by modulating Cdkn1c (p57)-mediated glycolytic reprogramming.

Introduction: Cancer Stem Cells (CSCs) drive tumor initiation, progression, and recurrence due to their self-renewal and differentiation capacities. Herbal medicines offer potential for targeting CSCs by disrupting key pathways, inducing apoptosis, and enhancing the efficacy of conventional therapy. This review evaluates the effectiveness of plant-based compounds in suppressing CSCs across various cancers. Methods: A systematic search was conducted across databases (ISI Web of Science, PubMed, ScienceDirect, Scopus, Biological Abstracts, Chemical Abstracts) up to March 2025, using keywords such as "cancer stem cells and plant extracts." Inclusion criteria were English-language original articles or reviews on plant-based compounds targeting CSCs (in vitro, in vivo, or clinical studies) with full-text availability. Duplicates, non-relevant, non-English, or abstract-only studies were excluded, yielding 43 studies. Results: Herbal medicines derived from plants such as Pao Pereira, Rauwolfia vomitoria, and Celastrus orbiculatus inhibit CSC proliferation, self-renewal, and chemoresistance across breast, colon, pancreatic, gastric, ovarian, prostate, glioblastoma, hepatic, and lung cancers. Mechanisms include disruption of the TGF-β/Smad pathway, induction of apoptosis via caspase activation, and ROS-mediated oxidative stress, with compounds such as curcumin and resveratrol targeting Wnt, Notch, and Hedgehog pathways. Discussion: Plant-derived compounds show promise in targeting CSCs, enhancing chemotherapy sensitivity, and reducing tumor recurrence. However, inconsistent potency, limited clinical data, and bioavailability challenges limit translation. Standardized extracts and rigorous clinical trials are needed to validate efficacy and safety. Conclusion: Herbal medicines offer a promising complementary approach to CSC-targeted cancer therapy, but further research is essential to overcome current limitations and enable clinical integration.

Age-related macular degeneration (AMD) is a leading cause of blindness in people over 65 years old. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for neovascular AMD (nAMD); however, fibrosis remains an unmet medical need due to the lack of effective medications. This study evaluated eight natural products from Celastrus orbiculatus, which has been reported to have anti-inflammatory effects, for their effects on the fibrotic pathological process as well as choroidal neovascularization (CNV). We investigated the half-maximal inhibitory concentration (IC50) values of these compounds on VEGF and alphasmooth muscle actin (α-SMA, a fibrosis marker) expression-induced by human acute monocytic cell (THP-1) conditioned media in retinal pigment epithelium cells (ARPE-19). Four compounds reduced both VEGF and α-SMA at 10 μM, with three-Celafolin A-1, COFH5645, and COFH543435-showing the highest potency. Intravitreal injections of the compound in a mouse model of CNV induced by laser photocoagulation confirmed its efficacy. Celafolin A-1 significantly reduced α-SMA and VEGF expression and decreased hyper-reflective lesions and CNV areas. Binding affinity measurements using biolayer interferometry identified an interaction between Celafolin A-1 and crystallin alpha B (Cryab), a protein involved in stress responses and fibrosis. Celafolin A-1 reduced the expression levels of Cryab as well as its phosphorylated form at Ser45, indicating that its mechanism involves the regulation of Cryab phosphorylation. Taken together, Celafolin A-1 exhibits dual inhibitory effects on VEGF and fibrosis, suggesting it as a candidate for the treatment of nAMD.

Celastrus orbiculatus fruits as Beihehuan (BHH) in Chinese are used as an alternative to Albizia julibrissin flowers (Hehuanhua) for insomnia treatment in North of China. Both of them perhaps contain similar material foundations with common components, making them highly worthy of systematic analysis of the ingredients and related pharmacological mechanisms. In this study, the components in BHH were comprehensively analyzed by LC-MS/MS-based molecular networking technology combined with literature reports, and important targets and core active ingredients in BHH that can treat insomnia were screened through network pharmacology and molecular docking analysis. Finally, a total of 136 components were annotated and summarized. BHH had flavonoids, fatty acids, and volatile oil as similar or the same component categories and structures as Hehuanhua, especially different categories of dihydro-β-agarofuran-type sesquiterpenoids with similar functions. The screened top 10 KEGG pathways involved signal transduction related to neurotransmitters, hormones, and addictive substances, and the selected effective ingredients could play synergistic roles in inflammation regulation and neuroprotection. These results provide that BHH may be able to replace Hehuanhua in treating insomnia and other neurological disorders; modern research can provide the scientific connotation and basis for the proposed forward-thinking TCM theory of "effect-oriented source unification" and "heteroagent possessing homofunction."

Kaempferitrin (KAE) is a natural flavonol dirhamnopyranoside with various pharmacological activities, isolated from the antithrombotic fraction of Celastrus orbiculatus Thunb. This study aimed to investigate the antithrombotic activity and “effective forms” of KAE. The results showed that KAE significantly prolonged rabbit plasma recalcification time in vitro. In the FeCl3-induced rat arterial thrombosis model, KAE demonstrated antithrombotic effects by inhibiting coagulation, platelet aggregation, and fibrinolysis, with a lesser risk of bleeding compared to aspirin. KAE was orally administered to rats, and a total of 192 metabolites were characterized. These included 25 phase I metabolites, 8 hydroxylated and methylated metabolites, 57 sulfated metabolites, 74 glucuronidated metabolites, 26 sulfated and glucuronidated metabolites, and 2 glycosylated metabolites. Twenty-eight compounds were considered the in vivo “effective forms” of KAE for their antithrombotic activity. Network pharmacology, molecular docking, and molecular dynamics simulations collectively predict that these “effective forms” may exert antithrombotic effects by suppressing the SRC/PI3K/AKT pathway. This study provides a foundation for a better understanding of the in vivo “effective forms” and mechanisms underlying KAE’s antithrombotic activity, which is essential for understanding of “hexue” traditional efficacy of C. orbiculatus.

The present study focuses on the green synthesis of silver nanoparticles (AgNPs) using the ethanolic extract of Celastrus orbiculatus and their incorporation into hydrogel formulations for enhanced topical antimicrobial activity. Various nanoparticle formulations (F1–F9) were evaluated for percentage yield, entrapment efficiency, and particle size, with formulation F2 identified as the optimized batch. Characterization using FTIR, UV–Vis spectroscopy, and SEM confirmed successful nanoparticle synthesis and morphology. The optimized AgNPs were incorporated into hydrogel formulations (G1–G6), with G3 selected as the optimal gel based on its physicochemical properties, including high drug content (4.05 ± 0.25 mg/100 mg), appropriate pH, viscosity, spreadability, and extrudability. In-vitro drug release from G3 followed a diffusion-controlled mechanism (Higuchi model, r² = 0.9779). Antimicrobial studies revealed that the AgNP-loaded gel (G3) showed significantly greater zones of inhibition against Staphylococcus aureus and Klebsiella pneumoniae compared to the crude extract. These results highlight the potential of green-synthesized AgNP hydrogels as effective topical antimicrobial agents.

Phytochemical investigation of the ethyl acetate extract of the stems of Celastrus orbiculatus Thunb. led to the isolation of a new neolignan, celastorbiol A (1), and two new homoisoflavones, celastrones A and B (2 and 3), along with five known 3-benzylchroman derivatives, including 7,4'-dihydrohomoisoflavanone (4), 3-deoxysappanone B (5), 3'-deoxysappanone A (6), bonducelin (7), and sappanone A (8). Their structures were determined based on extensive spectroscopic and spectrometric data analyses, and computational studies. Compounds 1, 6, and 8 exhibited cytotoxic activities against human gastric cancer AGS and HGC-27 cell lines with IC50 values that ranged from 42.82 ±0.98 to 98.04 ±1.33 µM.

The genus Celastrus L. includes about 35 species of deciduous or evergreen climbing shrubs, most often large lianas with alternate leaf arrangement. Bittersweets grow in Australia, Madagascar, America, as well as East and Southeast Asia, including the Russian Far East. Celastrus orbiculatus Thunb. – one of the most popular types of bittersweets, widely used in Russia, including the Moscow Region, for vertical gardening. In addition to being decorative, some parts of the plant are edible and potentially medicinal. The currently available data on the leaf productivity of C. orbiculatus plants is not enough for a comprehensive assessment of the correspondding plant material, as well as its implementation in practice, primarily due to the lack of information on the size and weight characteristics of shoots and leaves. The purpose of the study is to evaluate the productivity of the leaf mass of Celastrus orbiculatus Thunb. in the conditions of the Moscow Region. The objects of study are 20 one-year-old highly elongated shoots of the liana C. orbiculatus from the arboretum of Tsitsin Main Botanical Garden, Russian Academy of Sciences. Weighing and measuring the length and width of leaves from each shoot (17–46 leaves, 32 on average) were carried out, starting from the top leaf. It was established that C. orbiculatus has highly variable sizes (5.27±0.14 × 3.52±0.11 cm) and weight (0.19±0.01 g, up to 0.30±0.02 g ) leaves of typical shape. Despite the fact that the leaves do not reach their maximum length, as in natural conditions, C. orbiculatus successfully grows in the conditions of the Moscow Region, being distinguished by high leaf productivity.

Retraction Note: Research on the efficacy of Celastrus Orbiculatus in suppressing TGF-β1-induced epithelial-mesenchymal transition by inhibiting HSP27 and TNF-α-induced NF-κB/Snail signaling pathway in human gastric adenocarcinoma

Abstract Tree-afflicting pests, such as insects and pathogens, could change forests in ways promoting invasions by non-native plants. After tree death associated with the fungal pathogen oak wilt (Bretziella fagacearum) and its attempted containment (severing root connectivity and sanitation removal of infected trees), we examined change in cover of the non-native liana Oriental bittersweet (Celastrus orbiculatus Thunb.; hereafter Celastrus) at 28 sites in temperate black oak (Quercus velutina Lam.) forests, Ohio, USA. During our 5-yr study spanning 2020 to 2024, Celastrus cover increased significantly (P < 0.05) through time at oak wilt sites but not in untreated reference forest sites without evidence of oak wilt. Celastrus cover increased by an order of magnitude, up to an average of 32 times among oak wilt treatments up to 10 yr old. By 2024, Celastrus cover ranged from 6% to 22% on average in 5- to 10-yr-old oak wilt treatments, compared with 1% cover in reference forest. Results indicate that non-native plant invasion accelerated following disturbance associated with a fungal pathogen and its attempted containment and, more generally, suggest that tree-afflicting pests can promote invasive plants in forests. Co-management of tree-afflicting pests and non-native plants may become increasingly important to ensure forests recovering from tree mortality are dominated by native plants.

The increasingly negative impact of invasive alien species on ecosystem structure and function, biodiversity, health, and the economy has led to an intensification of efforts to control or eradicate these species.The growing threats from invasive alien species are well illustrated by the expansion of the List of invasive alien species of Union concern (EU Regulation 1143/2014), which has been updated three times since the initial list was adopted in 2016.The number of species included has risen from 37 in 2016 to 88 today.The most recent data from Romania indicate the presence of 10 of the 41 invasive alien plant species (IAPS) of Union concern in Romania.Among them, three species (i.e., Baccharis halimifolia, Celastrus orbiculatus, and Heracleum mantegazzianum) are records submitted through citizen science apps and not confirmed through peer-reviewed publications.To provide distribution data for IAPS of Union concern in an environmentally sensitive area, between 2022 and 2023, we sampled 166 terrestrial, aquatic and riparian plots from the Lower Siret Floodplain (Eastern Romania).We identified two IAPS Union concerns, namely Ailanthus altissima in 8 (5.63%) sample areas located predominantly on the left bank of the Siret River, in the sector between Movileni and Poiana (Galati), having the primary pathways of introduction Unaided (n = 4), Release in nature (n = 2) and Transport -Stowaway (n = 2), and Elodea nuttallii in one sample area near Movileni (Galati).We recommend further monitoring, focusing on areas already invaded or likely to be invaded, as well as the removal and replacement of IAPS species.Additionally, we suggest raising public awareness through educational campaigns, increasing the use of open data repositories by scientists, as well as advocacy for a more intense use of citizen science platforms for monitoring.

abstract: A newly discovered naturalised specimen of Celastrus orbiculatus in Newry, Northern Ireland, was identified using DNA barcoding of nuclear ribosomal ITS and plastid trn L–F region sequences, phylogenetic tree reconstruction of closely related species and morphological trait comparisons. It represents the first report of this potentially invasive alien species on the island of Ireland. Historical archival records and dendrochronological examination were utilised to estimate when and how this exotic liana was introduced and to determine the age of the current specimens. The oldest aboveground living stem was estimated to be 24 years old from ring counts and it is likely that the specimen is a nursery escape given its proximity to the abandoned Daisy Hill Nursery. We provide initial evidence on habitat interactions of the Newry C. orbiculatus specimens and found that it exerts dominance over the community during the reproductive period from May to November (total coverage = 50–60%). Our findings suggest that the climate in Ireland and Northern Ireland (Köppen's Cfb zone) is favourable for the growth and reproduction of C. orbiculatus . In addition, the edaphic conditions in Daisy Hill Wood (pH = 5.6 ± 0.1; average soil organic matter = 14.3 %) matched the preferences of this introduced neophyte. We therefore anticipate that, without human control, the Newry C. orbiculatus specimens will persist and potentially expand in distribution.

Celastrus orbiculatus Thunb. extract inhibits inflammatory metabolic adaptation in macrophages and regulates polarization via modulating PKM2

Celastrus orbiculatus extract contains various biologically active components which have extensive medicinal value.The present work investigated the inhibitory mechanism of Celastrus orbiculatus extract on the invasion and metastasis of gastric cancer (GC) cells (GCCs), with particular emphasis on the function of the ras-related C3 botulinum toxin substrate 1 (Rac1)/LIM domain kinase 1 (LIMK1)/cofilin1 signalling pathway (SPW) in this process.First, celastrin was extracted from Celastrus orbiculatus using an ultrasonic extraction (ULE) method and detected by high-performance liquid chromatography (HPLC).The human GCC line MGC-803 was then used in the study.The prepared Celastrus orbiculatus samples showed the same chromatographic peak as the celastrol standard.In contrast to the Ctrl group, the cell proliferation rates (CPRs) and cell invasion rates (CIRs) in groups A, B and C were greatly reduced, while the cell apoptosis rates (CARs) and cell migration rates (CMRs) were greatly increased (p < 0.05).In addition, the Rac1/LIMK1/cofilin1 SPW-associated proteins in the Celastrus orbiculatus treatment groups were strongly downshifted compared to the Ctrl group (p < 0.05).Meanwhile, there was a continuous downward trend with increased DC and time.Celastrus orbiculatus extract, by regulating the Rac1/LIMK1/cofilin1 SPW, suppressed proliferation, invasion and migration of GCCs while facilitating their apoptosis.This discovery provided important evidence for the potential use of Celastrus orbiculatus extract in treating GC. RezumatExtractul de Celastrus orbiculatus conine multiple componente biologic active cu efecte terapeutice.Studiul a investigat mecanismul inhibitor al extractului de Celastrus orbiculatus asupra invaziei i metastazelor celulelor canceroase gastrice (GCC), cu accent deosebit pe funcia substratului 1 (Rac1)/LIM al toxinei botulinice C3 legat de ras 1 (LIMK1)/calea de semnalizare cofilin1 (SPW) n acest proces.n primul rnd, celastrin a fost extras din Celastrus Orbiculatus folosind o metod de extracie cu ultrasunete (ULE) i identificat prin cromatografie lichid de nalt performan (HPLC).Linia GCC uman MGC-803 a fost utilizat n studiu.Probele au prezentat acelai vrf cromatografic ca standardul de celastrol.Spre deosebire de grupul Ctrl, ratele de proliferare celular (CPR) i ratele de invazie celular (CIR) din grupurile A, B i C au fost mult reduse, n timp ce ratele de apoptoz celular (CAR) i ratele de migrare celular (CMR) au fost mult crescute (p < 0,05).n plus, proteinele asociate cu Rac1/LIMK1/cofilin1 SPW din grupurile de tratament cu Celastrus orbiculatus au fost puternic reduse n comparaie cu grupul Ctrl (p < 0,05).Extractul de Celastrus orbiculatus, prin reglarea SPW Rac1/LIMK1/cofilin1, a suprimat proliferarea, invazia i migrarea GCC facilitnd, n acelai timp, apoptoza acestora.

Molecular networking-guided isolation of melanogenesis inhibitory dihydro-β-agarofuran sesquiterpenoids from Celastrus orbiculatus

Celastrus orbiculatus Thunb. is a vine used as a traditional Chinese medicinal herb. In this study, we focused on the anticancer cytotoxicity and underlying mechanism of previously unreported 3-oxygen-substituted isoflavone analogue (3-benzyloxychromone, 3-Boc) from the herb. Initially, we established cell line-derived xenograft mouse model using H1299 non-small cell lung cancer (NSCLC) cells and found that the ethanol crude extracts of the stem part of C. orbiculatus (200 mg/kg) could substantially suppress the growth of xenograft tumors in athymic nu/nu mice. We compared 3-Boc with three other flavonoid analogues isolated from the stem part of C. orbiculatus. Among these, 3-Boc showed the most potent cytotoxicity against H1299 and H1975 NSCLC cells. Colony formation, EdU incorporation and Annexin V-FITC/PI apoptosis assays demonstrated that 3-Boc induced growth inhibition primarily by inhibiting DNA replication and inducing apoptotic death of NSCLC cells. Structure-based target prediction and MD simulation suggested that 3-Boc potentially suppressed the activity of glycogen synthase kinase-3β (GSK-3β) by interacting with the ATP-binding site. Western blot analysis indicated that 3-Boc triggered the phosphorylation of Serine 21 of GSK-3α or Serine 9 of GSK-3β in a time- and dose-dependent manner. To investigate the dependency of GSK-3β, we established GSK-3β knockout in H1299 cells. Depletion of GSK-3β enhanced 3-Boc-induced cytotoxicity compared with wild-type counterparts through activated c-Jun/ATF2 signaling pathway. Altogether, our study highlights the anticancer potential of C. orbiculatus and the discovery of novel 3-oxygen-substituted chromone from the herb, which may have important implications for screening promising modulators of GSK-3β and related signaling pathways in the treatment of cancer.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease globally, characterized by the accumulation of lipids, oxidative stress, and mitochondrial dysfunction in the liver. Celastrus orbiculatus Thunb. (COT) and its active compound celastrol (CEL) have demonstrated antioxidant and anti-inflammatory properties. Our prior research has shown the beneficial effects of COT in mitigating NAFLD induced by a high-fat diet (HFD) in guinea pigs by reducing hepatic lipid levels and inhibiting oxidative stress. This study further assessed the effects of COT on NAFLD and explored its underlying mitochondria-related mechanisms. COT extract or CEL was administered as an intervention in C57BL/6J mice fed a HFD or in HepG2 cells treated with sodium oleate. Oral glucose tolerance test, biochemical parameters including liver enzymes, blood lipid, and pro-inflammatory factors, and steatosis were evaluated. Meanwhile, mitochondrial ultrastructure and indicators related to oxidative stress were tested. Furthermore, regulators of mitochondrial function were measured using RT-qPCR and Western blot. The findings demonstrated significant reductions in hepatic steatosis, oxidative stress, and inflammation associated with NAFLD in both experimental models following treatment with COT extract or CEL. Additionally, improvements were observed in mitochondrial structure, ATP content, and ATPase activity. This improvement can be attributed to the significant upregulation of mRNA and protein expression levels of key regulators including FGF21, AMPK, PGC-1α, PPARγ, and SIRT3. These findings suggest that COT may enhance mitochondrial function by activating the FGF21/AMPK/PGC-1α signaling pathway to mitigate NAFLD, which indicated that COT has the potential to target mitochondria and serve as a novel therapeutic option for NAFLD.

Asian bittersweet (Celastrus orbiculatus) is a widespread, invasive, twining vine in eastern North American forests. Factors associated with its local occurrence are well known but seldom reported at geographic scales coarser than research locations. We evaluated its occurrence across a hierarchy of land units ranging from coarse (provinces), intermediate (landscapes), and fine (site) scales in North Carolina and Virginia. Chi-square tests indicated a significant difference in the proportion of plots with C. orbiculatus in mountain (5.5%) compared to piedmont (9.9%) provinces. Using groups of forest types (e.g., Acer-Betula, Quercus-Pinus) to represent landscape-scale land units, C. orbiculatus occurred in a greater proportion of plots classified as Quercus-Carya. At the fine scale of sample sites within landscapes, in plots where C. orbiculatus was present the soil moisture regime was classified as mesic significantly more often than xeric in both provinces. Foliage cover differed between mountain (9.6%) and piedmont provinces (5.1%), and among several forest type groups at the landscape scale but responded weakly to moisture regime. Our results show that the proportional occurrence of C. orbiculatus varied significantly among land units at each hierarchical level. We suggest that our land units, defined by physiography, tree communities and soil moisture regime, represent tentative ecosystems that can be included as spatial variables in models to improve predictions of the presence of C. orbiculatus, for example in response to a changing climate.

Vasculogenic Mimicry (VM) can reduce the efficacy of anti-angiogenesis and promote distant metastasis in hepatocellular carcinoma (HCC). Our previous studies have found that Celastrus orbiculatus extract (COE) can inhibit the VM formation in HCC by reducing EphA2 expression. However the underlying mechanism related to EphA2 in VM formation is unclear. This study aimed to confirm that EphA2 is one of the potential targets of COE, and to explore the effect of EphA2 in VM formation in hypoxia context in HCC. TCM Systems Pharmacology database and proteomics analysis were used to explore the key targets of COE in HCC treatment. CD31-PAS double staining and VE-CAD staining were used to indicate vasculogenic mimicry. The localization of EphA2 and VE-CAD was examined through fluorescent microscopy. CCK8 assay, cell invasion assay, and tube formation assay were used to indicate the formation of VM under hypoxic conditions. The regulatory relationship of EphA2 upstream and downstream molecules were evaluated through COIP and Western Blot. The nude mouse xenograft tumor models were used to observe the VM formation after knocking down or overexpressing EphA2. EphA2 is identified to the target of COE, and the driving gene of HCC. In HCC surgical specimens, EphA2 expression is closely associated with the VM formation of HCC. COE-regulated EphA2 is involved in hypoxia-induced VM formation in HCC cells in vitro. EphA2 is regulated by HIF directly or indirectly by C-MYC. Overexpression of EphA2 can promote the VM formation of HCC in nude mice, while knocking down EphA2 can inhibit the VM formation. EphA2, as a target of COE, plays a crucial regulatory role in the formation of vasculogenic mimicry in HCC, involving upstream HIF/MYC transcriptional promotion and downstream PI3K/FAK/VE-CAD expression regulation.