Preclinical toxicological assessment of a novel monoclonal antibody targeting human platelet-derived growth factor CC (PDGF-CC) in PDGF-CChum mice.

Platelet-derived growth factor CC (PDGF-CC) is important during foetal development but also in pathogenesis of neurologic diseases, cancer and fibrosis. We have previously demonstrated that blocking the PDGF-CC/PDGF receptor alpha (PDGFRα) axis resulted in reduction of stroke volume and cerebrovascular permeability after experimentally induced stroke. Recently, we could translate these findings into the clinic showing that imatinib, a small tyrosine kinase inhibitor targeting PDGF receptors, can significantly improve neurological outcome after ischemic stroke in human. Herein we report preclinical toxicological analyses of our newly generated monoclonal anti-human PDGF-CC antibody 6B3 (mAb 6B3) in PDGF-CC humanized mice. Beside histological organ assessment, we also analysed serum, urine, haematological parameters and the general health status of the treated mice. We could not find any indications that mAb 6B3 is toxic or has other significant side effects neither in short, nor in long treatment regimens. Our results indicate that mAb 6B3 can be further developed for clinical use. This opens up the possibility to assess the therapeutic potential of blocking PDGF-CC in diverse pathological conditions such as neurologic diseases, cancer and fibrosis.

α-Iso-Cubebene Inhibits PDGF-Induced Vascular Smooth Muscle Cell Proliferation by Suppressing Osteopontin Expression.

α-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis (SC), a well-known medicinal herb that ameliorates cardiovascular symptoms. Thus, we examined the effect of ICB on vascular smooth muscle cell (VSMC) proliferation, a key feature of diverse vascular diseases. When VSMCs primary cultured from rat thoracic aorta were stimulated with PDGF (1-10 ng/ml), cell proliferation and osteopontin (OPN) expression were concomitantly up-regulated, but these effects were attenuated when cells were treated with MPIIIB10, a neutralizing monoclonal antibody for OPN. In aortic tissues exposed to PDGF, sprouting VSMC numbers increased, which was attenuated in tissues from OPN-deficient mice. Furthermore, VSMC proliferation and OPN expression induced by PDGF were attenuated dose-dependently by ICB (10 or 30 µg/ml). Reporter assays conducted using OPN promoter-luciferase constructs showed that the promoter region 538-234 bp of the transcription start site was responsible for transcriptional activity enhancement by PDGF, which was significantly inhibited by ICB. Putative binding sites for AP-1 and C/EBPß in the indicated promoter region were suggested by TF Search, and increased binding of AP-1 and C/EBPß in PDGF-treated VSMCs was demonstrated using a ChIP assay. The increased bindings of AP-1 and C/EBPß into OPN promoter were attenuated by ICB. Moreover, the PDGF-induced expression of OPN was markedly attenuated in VSMCs transfected with siRNA for AP-1 and C/EBPß. These results indicate that ICB inhibit VSMC proliferation by inhibiting the AP-1 and C/EBPß signaling pathways and thus downregulating OPN expression.

Targeting pancreatic cancer using a combination of gemcitabine with the omega-3 polyunsaturated fatty acid emulsion, Lipidem™.

SCOPE: Pancreatic cancer remains a disease of poor prognosis, with alternate strategies being sought to improve therapeutic efficacy. Omega-3 fatty acids have shown clinical benefit, and mechanisms of action are under investigation. METHODS AND RESULTS: Proliferation assays, flow cytometry, invasion assays, ELISA and western blotting were used to investigate efficacy of omega-3 fatty acids alone and in combination with gemcitabine. The docosahexanoic acid (DHA)/eicosapentanoic acid (EPA) combination, Lipidem™, in combination with gemcitabine inhibited growth in pancreatic cancer and pancreatic stellate cell (PSC) lines, with PSCs exhibiting greatest sensitivity to this combination. Invasion of pancreatic cancer cells and PSCs in a 3D spheroid model, was inhibited by combination of gemcitabine with Lipidem™. PSCs were required for cancer cell invasion in an organotypic co-culture model, with invasive capacity reduced by Lipidem™ alone. Platelet-derived growth factor (PDGF) is a key cytokine in pro-proliferative and invasion signalling, and thus a critical regulator of interactions between pancreatic cancer cells and adjacent stroma. Platelet-derived growth factor (PDGF-BB) secretion was completely inhibited by the combination of Lipidem™ with gemcitabine in cancer cells and PSCs. CONCLUSION: Lipidem™ in combination with gemcitabine, has anti-proliferative and anti-invasive efficacy in vitro, with pancreatic stellate cells exhibiting the greatest sensitivity to this combination.

Chrysanthemum boreale flower floral water inhibits platelet-derived growth factor-stimulated migration and proliferation in vascular smooth muscle cells.

CONTEXT: Chrysanthemum boreale Makino (Compositae) (CBM) is a traditional medicine that has been used for the prevention or treatment of various disorders; it has various properties including antioxidation, anti-inflammation, and antitumor. OBJECTIVE: The present study was designed to explore the in vitro effect of CBM flower floral water (CBMFF) on atherosclerosis-related responses in rat aortic smooth muscle cells (RASMCs). MATERIALS AND METHODS: CBMFF was extracted from CBM flower by steam distillation and analyzed using gas chromatography-mass spectrometry. The anti-atherosclerosis activity of CBMFF was tested by estimating platelet-derived growth factor (PDGF)-BB (10 ng/mL)-induced proliferation and migration levels and intracellular kinase pathways in RASMCs at CBMFF concentrations of 0.01-100 µM and analyzing ex vivo aortic ring assay. RESULTS: Gas chromatography-mass spectrometry showed that the CBMFF contained a total of seven components. The CBMFF inhibits PDGF-BB-stimulated RASMC migration and proliferation (IC50: 0.010 µg/mL). Treatment of RASMCs with PDGF-BB induced PDGFR-ß phosphorylation and increased the phosphorylations of MAPK p38 and ERK1/2. CBMFF addition prevented PDGF-BB-induced phosphorylation of these kinases (IC50: 008 and 0.018 µg/mL, for p38 MAPK and ERK1/2, respectively), as well as PDGFR-ß (IC50: 0.046 µg/mL). Treatment with inhibitors of PDGFR, P38 MAPK, and ERK1/2 decreased PDGF-BB-increased migration and proliferation in RASMCs. Moreover, the CBMFF suppressed PDGF-BB-increased sprout outgrowth of aortic rings (IC50: 0.047 µg/mL). DISCUSSION AND CONCLUSION: These results demonstrate that CBMFF may inhibit PDGF-BB-induced vascular migration and proliferation, most likely through inhibition of the PDGFR-ß-mediated MAPK pathway; therefore, the CBMFF may be promising candidate for the development of herbal remedies for vascular disorders.

MMP regulation of corneal keratocyte motility and mechanics in 3-D collagen matrices.

Previous studies have shown that platelet derived growth factor (PDGF) can stimulate corneal keratocyte spreading and migration within 3-D collagen matrices, without inducing transformation to a contractile, fibroblastic phenotype. The goal of this study was to investigate the role of matrix metalloproteinases (MMPs) in regulating PDGF-induced changes in keratocyte motility and mechanical differentiation. Rabbit corneal keratocytes were isolated and cultured in serum-free media (S-) to maintain their quiescent phenotype. A nested collagen matrix construct was used to assess 3-D cell migration, and a standard collagen matrix model was used to assess cell morphology and cell-mediated matrix contraction. In both cases constructs were cultured in S- supplemented with PDGF, with or without the broad spectrum MMP inhibitors GM6001 or BB-94. After 4 days, f-actin, nuclei and collagen fibrils were imaged using confocal microscopy. To assess sub-cellular mechanical activity (extension and retraction of cell processes), time-lapse DIC imaging was also performed. MT1-MMP expression and MMP-mediated collagen degradation were also examined. Results demonstrated that neither GM6001 nor BB-94 affected corneal keratocyte viability or proliferation in 3-D culture. PDGF stimulated elongation and migration of corneal keratocytes within type I collagen matrices, without causing a loss of their dendritic morphology or inducing formation of intracellular stress fibers. Treatment with GM6001 and BB-94 inhibited PDGF-induced keratocyte spreading and migration. Relatively low levels of keratocyte-induced matrix contraction were also maintained in PDGF, and the amount of PDGF-induced collagen degradation was similar to that observed in S- controls. The collagen degradation pattern was consistent with membrane-associated MMP activity, and keratocytes showed positive staining for MT1-MMP, albeit weak. Both matrix contraction and collagen degradation were reduced by MMP inhibition. For most outcome measures, the inhibitory effect of BB-94 was significantly greater than that of GM6001. Overall, the data demonstrate for the first time that even under conditions in which low levels of contractility and extracellular matrix proteolysis are maintained, MMPs still play an important role in mediating cell spreading and migration within 3-D collagen matrices. This appears to be mediated at least in part by membrane-tethered MMPs, such as MT1-MMP.

[Vascular morphological and microdensity changes of corneal neovascularization induced by topical bevacizumab and sunitinib in an animal model]. / Cambios en la morfología y la microdensidad neovascular corneal inducidos tras la administración tópica de bevacizumab y sunitinib en un modelo animal.

OBJECTIVE: To evaluate the effects of topical bevacizumab and topical sunitinib on vascular microdensity and morphology of corneal neovascularization (NV). METHODS: A total of 33 rabbits were distributed into 3 groups: group 1 (control; n=11): saline; group 2 (n=11): bevacizumab 5mg/ml; and group 3 (n=11): sunitinib 0.5mg/ml. A corneal NV model was used, based on sutures in the right eye of each rabbit. Each treatment was administered topically 3 times daily for 14 days. Corneas were then processed for the study of vascular microdensity (6 eyes) and vascular morphology analysis (5 eyes) using enzymatic staining histological techniques RESULTS: The vascular response in group 3 was limited to small-sized tree formations with various vascular axes compared with the extensive, lush and directional corneal NV of group 1 and 2. In the histological sections near the limb, there were no differences in vascular microdensity studies between the three groups. However, the mean sectional area of vessels (MSAV) in group 3 was 41.88% lower than in group 1 and 19.19% lower than in group 2. In distal sections, there were no differences between groups 1 and 2. However, group 3 was characterized by absence of vessels. CONCLUSIONS: Bevacizumab produced no changes in the morphology of the vessels or the vascular microdensity. Sunitinib reduced the size of the new vessels and induced changes in the vascular tree.

Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.

BACKGROUND: Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling. OBJECTIVE: To determine whether myofibroblasts contribute to atrial myocyte electromechanical remodeling via direct physical contact and platelet-derived growth factor (PDGF) signaling. METHODS: Myofibroblasts and myocytes from adult sheep atria were co-cultured for 24 hours. Alternatively adult sheep atrial myocytes were exposed to 1 ng/mL recombitant PDGF AB peptide for 24 hours. RESULTS: Myocytes making contact with myofibroblasts demonstrated significant reduction (P ≤ .05) in peak L-type calcium current density, shortening of action potential duration (APD), and reduction in calcium transients. These effects were blocked by pretreatment with a PDGF-AB neutralizing anti-body. Heterocellular contact also severely disturbed the localization of the L-type calcium channel. Myocytes exposed to recombinant PDGF-AB peptide for 24 hours demonstrated reduced APD50, APD80 and Peak L-type calcium current. Pretreatment with a PDGF-AB neutralizing antibody prevented these effects. Finally, while control atrial myocytes did not respond in a 1:1 manner to pacing frequencies of 3 Hz or higher, atrial myocytes from hearts that were tachypaced for 2 months and normal myocytes treated with PDGF-AB for 24 hours could be paced up to 10 Hz. CONCLUSIONS: In addition to leading to fibrosis, atrial myofibroblasts contribute to electromechanical remodeling of myocytes via direct physical contact and release of PDGF-AB, which may be a factor in PAF-induced remodeling.

Regorafenib (BAY 73-4506): stromal and oncogenic multikinase inhibitor with potential activity in renal cell carcinoma.

The introduction of targeted therapies, specifically those that target the VEGF receptor (VEGFR), PDGF receptor (PDGFR) and the mTOR pathways, has significantly changed the approach to patients with unresectable renal cell cancer (RCC). However, drug resistance develops through bypassing of targeted pathways. Regorafenib (BAY 73-4506) is a novel bi-aryl urea compound that has potential anti-tumour activity in RCC, as along with targeting VEGF and PDGF receptors, it targets additional kinases associated with alternative pathways of angiogenesis and resistance to VEGF-targeted drugs. Based on a phase II clinical trial, the efficacy outcome of regorafenib in the first-line setting of unresectable RCC appears comparable that of other targeted first-line drugs. However, testing regorafenib in standard phase III trials seems inappropriate in view of its toxic effects. Further assessment of regorafenib should exploit the drug's ability to inhibit mechanisms of escape from anti-angiogenic treatment through biomarker-driven clinical trials.

Bufalin inhibits platelet-derived growth factor-BB-induced mesangial cell proliferation through mediating cell cycle progression.

Bufalin, a traditional Chinese medicine, has been reported as a protective factor in many tumors. We therefore investigated the effect of bufalin on platelet-derived growth factor (PDGF)-BB-induced proliferation of cultured rat mesangial cells. The effect of bufalin on cell proliferation and its underlying mechanisms were investigated in cultured rat mesangial cells (MCs) by the methylthiazoletetrazolium (MTT) assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and cyclin-dependent kinases (CDK)2 and CDK4 kinase assays. Bufalin inhibited 20 ng/ml PDGF-BB-induced MC proliferation in a dose-dependent manner. Similar results were observed in different concentrations of bufalin, which blocked PDGF-BB-induced progression through G0/G1 to S phase of the cell cycle. Furthermore, bufalin not only inhibited upregulation of cyclin D1 and CDK4, but also downregulation of p21 in both mRNA and protein levels. Although bufalin did not affect p27 and CDK2 mRNA expression, it reversed downregulation of p27 and upregulation of CDK2 in protein level. Activity of CDK2 and CDK4 was also inhibited by bufalin. However, both bufalin and PDGF-BB did not affect cyclin E mRNA or protein expression. These results suggest that bufalin could inhibit MC proliferation by modulating cell cycle progress, indicating that bufalin could be a potential therapeutic agent for the prevention of mesangial proliferative glomerulonephritis.

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms.

With the introduction of targeted drug therapies, a paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards to replace the use of cytokines as standard therapy. Recently, these substances have been complemented by everolimus and pazopanib. An interdisciplinary consensus conference was held to discuss which criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2009 conference provided the basis for the 2010 meeting. The results of the 2010 conference are presented as short theses.

2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-glucoside inhibits platelet-derived growth factor-induced proliferation of vascular smooth muscle cells by regulating the cell cycle.

1. 2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-glucoside (TSG) has been shown to have an anti-atherosclerotic effect. Vascular smooth muscle cell (VSMC) proliferation contributes to the pathobiology of atherosclerosis. The aim of the present study was to investigate the effects of TSG on platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation and to explore the molecular mechanisms underlying the effects. 2. Cultured rat VSMC were pretreated with TSG (l-50 µmol/L) for 1 h, followed by exposure to PDGF-BB (10 ng/mL) for 24 h, after which cell proliferation and cell cycle stages were examined. The expression of protein cell cycle regulators, including retinoblastoma (Rb), cyclin D1/E, cyclin-dependent kinase (CDK) 2/4, CDK inhibitors p21 and p27 and proliferative cell nuclear antigen (PCNA), was examined. Activation of extracellular signal-regulated kinase (ERK) 1/2 was evaluated to elucidate the possible upstream mechanism by which TSG affects cell cycle regulators. 3. The results showed that TSG dose-dependently inhibited PDGF-BB-induced VSMC proliferation, possibly by blocking the progression of the cell cycle from the G(1) to S phase. In addition, TSG significantly inhibited PDGF-BB-induced phosphorylation of Rb and the expression of cyclin D1, CDK4, cyclin E, CDK2 and PCNA. In addition, TSG suppressed PDGF-BB-induced downregulation of p27 and upregulation of p21, as well as PDGF-BB-induced activation of ERK1/2. 4. Together, the findings of the present study provide the first evidence that TSG can inhibit PDGF-BB-stimulated VSMC proliferation via cell cycle arrest in association with modulation of the expression of cell cycle regulators, which may be mediated, at least in part, by suppression of ERK1/2 activation.

Differential inhibitory effects of salvianolic acids on activation of rat hepatic stellate cells by platelet-derived growth factor.

Platelet-derived growth factor (PDGF) induces cell proliferation together with oxidative stress. The present study investigated the effects of salvianolic acid A (Sal A) and B (Sal B) on the PDGF-induced signaling cascades in hepatic stellate cells (HSCs). HSC-T6, a rat hepatic stellate cell line, was stimulated with PDGF (10 ng/mL). The inhibitory effects of Sal A and B on oxidative stress-related signaling pathways were assessed in vitro. The protein levels were measured by Western blotting. FACS analysis was applied to detect the thioredoxin (Trx) level. Sal A and B showed different inhibitory abilities on the PDGF-related pathway. Sal A inhibited 70-kDa ribosomal S6 kinase (p70(s6k)) and associated proteins. Sal B attenuated PDGF-induced c-jun-N-terminal kinase (JNK), p38, and PKC- δ phosphorylations. Both Sal A and B diminished the activation of PKD, Trx, heme-oxygenase (HO)-1, and Nrf2. Taken together, our results showed that Sal A and B attenuated PDGF-induced ROS formation in HSCs, possibly through different signaling pathways.

Signaling pathways in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common cancer, and its mortality rate is the third highest after lung and colon cancer. Its incidence has significantly increased in the last two decades in close relation with the ubiquitous spread of viral hepatitis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Molecular therapies such as sorafenib, a BRAF/ VEGFR/PDGFR tyrosine kinase inhibitor, have shown to improve survival in patients with advanced HCC. This recent success has spurred intensive research aimed at identifying aberrant activation of signaling pathways. This approach will probably aid to define previously unrecognized oncogenic addiction loops in HCC and in developing more effective targeted therapies.

Multitargeted therapy of cancer by lycopene.

Lycopene (psi,psi-carotene) is the most abundant carotenoid in tomatoes and is the red pigment of not only tomatoes but also rosehips, watermelon, papaya, pink grapefruit, and guava. Unlike beta-carotene, lycopene lacks a beta-ionone ring and therefore has no pro-vitamin A activity. However, the 11 conjugated and two non-conjugated double bonds in lycopene make it highly reactive towards oxygen and free radicals, and this anti-oxidant activity probably contributes to its efficacy as a chemoprevention agent. The reactivity of lycopene also explains why it isomerizes rapidly in blood and tissues from the biosynthetic all-trans form to a mixture of cis-isomers. Prospective and retrospective epidemiological studies indicating an inverse relationship between lycopene intake and prostate cancer risk have been supported by in vitro and in vivo experiments showing that oral lycopene is bioavailable, accumulates in prostate tissue and is localized to the nucleus of prostate epithelial cells. In addition to antioxidant activity, in vitro experiments indicate other mechanisms of chemoprevention by lycopene including induction of apoptosis and antiproliferation in cancer cells, anti-metastatic activity, and the upregulation of the antioxidant response element leading to the synthesis of cytoprotective enzymes. Lycopene is a substrate for carotene-9',10'-monooxygenase (CMO2) and can be converted to apo-10'-carotenal. Although Phase I and II studies have been published that establish the safety of lycopene supplementation, carefully designed and adequately powered clinical studies of lycopene are still needed to confirm its efficacy as a chemoprevention agent.

Therapeutic effect of magnesium lithospermate B on neointimal formation after balloon-induced vascular injury.

Vascular smooth muscle cell (VSMC) proliferation and migration in response to platelet-derived growth factor (PDGF) play an important role in the development of atherosclerosis and restenosis. Recent evidence indicates that PDGF increases intracellular levels of reactive oxygen species in VSMCs and that both PDGF-induced VSMC proliferation and migration are reactive oxygen species-dependent. Danshen is a representative oriental medicine used for the treatment of vascular disease. Previously, we reported that magnesium lithospermate B, an active component of Danshen, is a potent antioxidant. Thus we investigated the therapeutic potential of magnesium lithospermate B in neointimal formation after carotid artery injury in rats along with its effects on the PDGF signaling pathway for stimulating VSMC proliferation and migration in vitro. PDGF is dimeric glycoprotein composed of two A or two B chains. In this study, we used PDGF-BB, which is one of the isoforms of PDGF (i.e., PDGF-AA, PDGF-BB, and PDGF-AB). Our results demonstrated that magnesium lithospermate B directly scavenged reactive oxygen species in a xanthine/xanthine oxidase system and reduced PDGF-BB-induced intracellular reactive oxygen species generation in VSMCs. In a rat carotid artery balloon injury model, magnesium lithospermate B treatment (10 mg/kg/day, i.p) showed a significant effect on the prevention of neointimal formation compared with vehicle treatment. In cultured VSMCs, magnesium lithospermate B significantly attenuated PDGF-BB-induced cell proliferation and migration as measured by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide (MTT) assay and transwell migration assays, respectively. Further, magnesium lithospermate B inhibited PDGF-BB-induced phosphorylation of phospatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways by scavenging reactive oxygen species. Together, these data indicated that magnesium lithospermate B, a potent reactive oxygen species scavenger, prevented both injury-induced neointimal formation in vivo and PDGF-BB-induced VSMC proliferation and migration in vitro, suggesting that magnesium lithospermate B may be a promising agent to prevent atherosclerosis and restenosis following angioplasty.

Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis.

OBJECTIVES: Ischaemic complications occur in 15-20% of patients with giant cell arteritis (GCA). The aim of our study was to explore the effect of mesenchymal growth factors expressed in GCA lesions on myointimal cell responses related to the development of intimal hyperplasia and vessel occlusion. METHODS: We developed a method to obtain primary human temporal artery derived myointimal cells (HTAMCs) based on the culture of temporal artery sections on Matrigel. RESULTS: Among the factors tested (platelet-derived growth factor (PDGF)-AB, fibroblast growth factor (FGF)-2, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF)beta, chemokine (C-C motif) ligand (CCL)2, interleukin (IL)6 and IL1beta), PDGF exhibited the strongest activity in inducing HTAMC proliferation and migration. As assessed by protein array, immunoassay and quantitative real-time reverse transcriptase (RT)-PCR, PDGF stimulated matrix proteins (collagen I, collagen III and fibronectin) as well as CCL2 and angiogenin production by HTAMCs. Imatinib mesylate inhibited PDGF-mediated activation of signalling pathways (Src, extracellular signal-regulated kinase (ERK) and Akt phosphorylation) related to cell motility and survival, efficiently resulting in inhibition of PDGF-induced HTAMC responses. Myointimal cell outgrowth from cultured temporal artery sections from patients with GCA, where multiple interactions take place, was also efficiently reduced by imatinib. CONCLUSION: Among several mediators produced in GCA, PDGF has the highest vaso-occlusive potential. PDGF may also contribute to disease perpetuation by stimulating the production of angiogenic factors (angiogenin) and chemoattractants (CCL2). Imatinib mesylate strongly inhibits PDGF-mediated responses, suggesting a therapeutic potential to limit vascular occlusion and ischaemic complications in large vessel vasculitis.

Chinese herb Radix Polygoni Multiflori as a therapeutic drug for liver cirrhosis in mice.

Liver regeneration not only plays a functional role in directing the restoration of liver mass after resection or injury, but also may have participated in effective therapy of liver cirrhosis. Additionally, hepatocyte growth factor (HGF) appears to be a factor of great importance in liver regeneration and attenuated progression of experimental liver cirrhosis. The aim of this study is to use Radix Polygoni Multiflori (POMU) extract, a Chinese herb traditionally used for liver-protective therapy, as a reagent for the evaluation of its potential medicinal use in liver cirrhosis. We used in vitro coculture system to show that POMU could promote the expression of HGF by hepatic nonparenchymal cells, consequently the proliferation of primary liver cells and phagocytic activity of Kupffer cells using fluorescein-labeled Escherichia coli as the target, and inhibit the proliferation of stellate cells. Using dimethylnitrosamine-induced liver cirrhosis animal, POMU even at 20 mg/(kg day) dosage, was illustrated to reverse the pathogenic progression of the disease, decrease the hydroxyproline content and increases the expression of HGF messenger RNA in liver tissue. The survival rate was significantly increased in the POMU-treated animal. In conclusion, our study showed the promise of POMU in the medicinal use for the treatment of liver cirrhosis.

Inhibition of pro-angiogenic factors by a lipid-rich shark extract.

This study aimed to determine whether a shark muscle oil-olive oil mixture influences activators of human angiogenesis. The mixture completely abolished the stimulation induced by vascular endothelial growth factor (VEGF), fibroblast growth factor-2, transforming growth factor-beta, and platelet-derived growth factor. This suggests that it may compete with these growth factors for their binding sites on the endothelial cell surface either by binding to the growth factor or by blocking the actual receptor. The possibility of the oil binding to the VEGF receptor was studied through the use of soluble forms of the receptors (VEGF-R1 and VEGF-R2). It was found that the shark oil-olive oil inhibited the formation of the complexes of VEGF with both of the receptors. This could have been because the oil bound to either the VEGF or the receptor or both. To determine which is possible, the shark oil-olive oil was mixed with the receptors. The molecular size of the receptors increased, and these larger forms of the receptor had reduced capacity for complexing with VEGF. Therefore, one mode of potential anti-angiogenic action of the shark muscle oil-olive oil is the inhibition of the activity of a number of stimulatory molecules, including VEGF. This study demonstrates that the blend of shark and olive oils antagonizes VEGF activity by binding to at least two receptors for the factor, thereby inhibiting the activation by the growth factor.