ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. RECENT FINDINGS: ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. SUMMARY: Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

Angiopoietin inhibitors: A review on targeting tumor angiogenesis.

Angiogenesis is the process of formation of new blood vessels from existing ones. Vessels serve the purpose of providing oxygen, nutrients and removal of waste from the cells. The physiological angiogenesis is a normal process and is required in the embryonic development, wound healing, menstrual cycle. For homeostasis, balance of pro angiogenic factors and anti angiogenic factors like is important. Their imbalance causes a process known as "angiogenic switch" which leads to various pathological conditions like inflammation, tumor and restenosis. Like normal cells, tumor cells also require oxygen and nutrients to grow which is provided by tumor angiogenesis. Hence angiogenic process can be inhibited to prevent tumor growth. This gives rise to study of anti angiogenic drugs. Currently approved anti angiogenic drugs are mostly VEGF inhibitors, but VEGF inhibitors have certain limitations like toxicity, low progression free survival (PFS), and resistance to anti VEGF therapy. This article focuses on angiopoietins as alternative and potential targets for anti angiogenic therapy. Angiopoietins are ligands of Tie receptor and play a crucial role in angiogenesis, their inhibition can prevent many tumor growths even on later stages of development. We present current clinical and preclinical stages of angiopoietin inhibitors. Drugs studied in the article are selective as well as non-selective inhibitors of angiopoietin 2 like Trebananib (AMG 386), AMG 780, REGN 910, CVX 060, MEDI 3617 and dual inhibitors of angiopoietin 2 and VEGF like Vanucizumab and RG7716. The angiopoietin inhibitors show promising results alone and in combination with VEGF inhibitors in various malignancies.

Diabetic Macular Edema: Current Understanding, Pharmacologic Treatment Options, and Developing Therapies.

Diabetic retinopathy and diabetic macular edema comprise a major source of visual disability throughout the developed world. The etiology and pathogenesis of macular edema is intricate and multifactorial, in which the hyperglycemic state in diabetes induces a microangiopathy. Through several inflammatory and vasogenic mediators, including vascular endothelial growth factor (VEGF) upregulation and inflammatory cytokines and chemokines, pathologic changes are induced in the vascular endothelium triggering breakdown of the blood retinal barrier, causing extravasation of fluid into the extracellular space and manifesting clinically as macular edema, resulting in visual loss. The advent of medications targeting the VEGF pathway has led to great clinical improvements compared with the previous standard of care of laser therapy alone, as shown in studies such as RISE, RIDE, VIVID, VISTA, and DRCR. However, analyses have shown that many patients have inadequate response or are nonresponders to anti-VEGF therapy, demonstrating the need for additional therapies to more comprehensively treat this disease. Although corticosteroid treatments and implants have demonstrated some efficacy in adjunctive and supplemental treatment, the need to more adequately treat macular edema remains. Our knowledge of diabetic macular edema continues to grow, leading to new currently available and emerging pharmacotherapies to further enhance our treatment and restore vision in those affected by diabetic macular edema. This review will discuss the pathogenesis of diabetic macular edema and the pharmacologic therapies available for its treatment, including anti-VEGF, steroids, and newer therapies still in development, such as angiopoietin antagonists, Tie2 agonists, kallikrein inhibitors, interleukin inhibitors, and others.

Phase 2 and biomarker study of trebananib, an angiopoietin-blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma.

BACKGROUND: Angiopoietins contribute to tumor angiogenesis and may be upregulated as a compensatory factor after vascular endothelial growth factor (VEGF) blockade. The authors performed a phase 2 and biomarker study to evaluate trebananib, an angiopoietin 1 and angiopoietin 2 blocking peptibody, with and without bevacizumab in patients with recurrent glioblastoma. METHODS: Forty-eight patients who had bevacizumab-naive, recurrent glioblastoma were treated with trebananib (30 mg/kg weekly) as single agent (n = 11) or combined with bevacizumab (n = 37). The primary endpoint was 6-month progression-free survival rate as determined by investigator review. Circulating biomarker levels were assessed before and after study therapy. RESULTS: Trebananib was well tolerated as monotherapy and did not enhance bevacizumab-associated toxicity. Trebananib had no single-agent activity, and all treated patients exhibited progressive disease within 2 months. The 6-month progression-free survival rate for trebananib plus bevacizumab was 24.3% (95% confidence interval [CI], 12.1%-38.8%); whereas the median overall survival was 9.5 months (95% CI, 7.5-4.7 months), and the 12-month overall survival rate was 37.8% (95% CI, 22.6%-53.0%). Baseline and post-treatment changes in circulating vascular VEGF and interleukin-8 levels were correlated with survival among patients who received trebananib plus bevacizumab. CONCLUSIONS: Angiopoietin 1 and angiopoietin 2 inhibition with trebananib was ineffective as monotherapy and did not enhance the ability of VEGF blockade with bevacizumab to improve the outcomes of patients with recurrent glioblastoma. Cancer 2018;124:1438-48. © 2017 American Cancer Society.

Angiopoietin-like protein 2 regulates Porphyromonas gingivalis lipopolysaccharide-induced inflammatory response in human gingival epithelial cells.

Angiopoietin-like protein 2 (ANGPTL2) maintains tissue homeostasis by inducing inflammation and angiogenesis. It is produced in infiltrating immune cells or resident cells, such as adipocytes, vascular endothelial cells, and tumor cells. We hypothesized that ANGPTL2 might play an important role as a unique mediator in both systemic and periodontal disease. We demonstrated an increased ANGPTL2 concentration in gingival crevicular fluid from chronic periodontitis patients. Porphyromonas gingivalis lipopolysaccharide (LPS) treatment strongly induced ANGPTL2 mRNA and protein levels in Ca9-22 human gingival epithelial cells. Recombinant human ANGPTL2 increased interleukin 1ß (IL-1ß), IL-8, and tumor necrosis factor-α (TNF-α) mRNA and protein levels in Ca9-22 cells. Small-interfering (si)RNA-mediated ANGPTL2 knockdown in Ca9-22 cells reduced IL-1ß, IL-8 and TNF-α mRNA and protein levels compared with control siRNA (p<0.01) in P. gingivalis LPS-stimulated Ca9-22 cells. Antibodies against integrin α5ß1, an ANGPTL receptor, blocked induction of these inflammatory cytokines in P. gingivalis LPS-treated Ca9-22 cells, suggesting that secreted ANGPTL induces inflammatory cytokines in gingival epithelial cells via an autocrine loop. The classic sequential cascade of P. gingivalis LPS → inflammatory cytokine induction is well established. However, in the current study, we reveal a novel cascade comprising sequential P. gingivalis LPS → ANGPTL2 → integrin α5ß1 → inflammatory cytokine induction, which might be responsible for inducing potent periodontal disorganization activity in gingival epithelial cells. Via this pathway, ANGPTL2 functions in the pathogenesis of periodontitis and contributes to prolonging chronic inflammation in patients with systemic disease.

The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors.

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486-501. ©2017 AACR.

Therapeutic targeting of the angiopoietin-TIE pathway.

The endothelial angiopoietin (ANG)-TIE growth factor receptor pathway regulates vascular permeability and pathological vascular remodelling during inflammation, tumour angiogenesis and metastasis. Drugs that target the ANG-TIE pathway are in clinical development for oncological and ophthalmological applications. The aim is to complement current vascular endothelial growth factor (VEGF)-based anti-angiogenic therapies in cancer, wet age-related macular degeneration and macular oedema. The unique function of the ANG-TIE pathway in vascular stabilization also renders this pathway an attractive target in sepsis, organ transplantation, atherosclerosis and vascular complications of diabetes. This Review covers key aspects of the function of the ANG-TIE pathway in vascular disease and describes the recent development of novel therapeutics that target this pathway.

Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.

BACKGROUND: Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. METHODS: We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins. RESULTS: The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events. CONCLUSIONS: Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice.

Angiopoietin-like protein (ANGPTL)8 is a negative regulator of lipoprotein lipase-mediated plasma triglyceride (TG) clearance. In this study, we describe a fully human monoclonal antibody (REGN3776) that binds monkey and human ANGPTL8 with high affinity. Inhibition of ANGPTL8 with REGN3776 in humanized ANGPTL8 mice decreased plasma TGs and increased lipoprotein lipase activity. Additionally, REGN3776 reduced body weight and fat content. The reduction in body weight was secondary to increased energy expenditure. Finally, single administration of REGN3776 normalized plasma TGs in dyslipidemic cynomolgus monkeys. In conclusion, we show that blockade of ANGPTL8 with monoclonal antibody strongly reduced plasma TGs in mice and monkeys. These data suggest that inhibition of ANGPTL8 may provide a new therapeutic avenue for the treatment of dyslipidemia with beneficial effects on body weight.

Angiogenesis in Dermatology - Insights of Molecular Mechanisms and Latest Developments.

Angiogenesis is the growth of new blood vessels from pre-existing vessels. It is a biological process essential in physiological wound healing or pathological inflammation and tumor growth, which underlies a complex interplay of stimulating and inhibiting signals. Extracellular matrix, cells of innate and adaptive immunity and endothelial cells itself are a major source of angiogenic factors that activate or inhibit specific receptors and consequently influence intracellular signaling pathways. Most inflammatory and neoplastic diseases in dermatology are characterized by excessive angiogenesis, such as psoriasis, atopic dermatitis, as well as melanoma, non-melanoma skin cancer, but also benign vascular neoplasia. In this article we describe current knowledge of angiogenesis and its most relevant mechanisms in different dermatological disorders with particular emphasis on the angiogenic factors (vascular endothelial growth factor) and angiopoietins as a target of current and future directions of anti-angiogenic therapy.

Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease.

BACKGROUND: Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides. METHODS: We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys. RESULTS: We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels. CONCLUSIONS: Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).

Nonbiological pharmacotherapies for the treatment of diabetic macular edema.

INTRODUCTION: During the past decade, there have been significant advances in the pharmacotherapies for the treatment of diabetic macular edema (DME). Among the presently available treatment options, anti-vascular endothelial growth factors (anti-VEGF) agents are the most favored agents due to their efficacy and safety. The index review focuses on nonbiological therapies that have entered in phase 3 clinical trials for DME. AREAS COVERED: An extensive review of the literature was performed to identify various nonbiological immunotherapies i.e., drugs other than '-mAbs' (monoclonal antibodies including anti-VEGF agents), '-mibs' (proteasome inhibitors), '-NAbs' (nanoparticle albumin-bound), and '-nibs' (small molecule inhibitor/tyrosine kinase inhibitors), among others. Extended-release low-dose corticosteroid devices have been recently approved for the treatment of DME. Other compounds such as non-steroidal anti-inflammatory drugs, antibody mimetic proteins, nonbiological growth factor inhibitors, and inhibitors of protein kinase C have been described. EXPERT OPINION: A number of therapies are under development for the pharmacological management of DME. Due to the rising healthcare costs associated with anti-VEGF agents, a number of alternate treatment options have been explored recently. Some of these agents have reached phase 3 in clinical trials and appear to have a promising role in the management of DME. As further research is conducted, the role of each individual agent will become more defined, alone or in combination therapy.

ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling.

Bone metastasis of breast cancer cells is a major concern, as it causes increased morbidity and mortality in patients. Bone tissue-derived CXCL12 preferentially recruits breast cancer cells expressing CXCR4 to bone metastatic sites. Thus, understanding how CXCR4 expression is regulated in breast cancer cells could suggest approaches to decrease bone metastasis of breast tumor cells. Here, we show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) increases responsiveness of breast cancer cells to CXCL12 by promoting up-regulation of CXCR4 in those cells. In addition, we used a xenograft mouse model established by intracardiac injection of tumor cells to show that ANGPTL2 knockdown in breast cancer cells attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression in those cells, thereby decreasing bone metastasis. Finally, we found that ANGPTL2 and CXCR4 expression levels within primary tumor tissues from breast cancer patients are positively correlated. We conclude that tumor cell-derived ANGPTL2 may increase bone metastasis by enhancing breast tumor cell responsiveness to CXCL12 signaling through up-regulation of tumor cell CXCR4 expression. These findings may suggest novel therapeutic approaches to treat metastatic breast cancer.

Antibodies to human angiopoietin-like protein 3: a patent evaluation of WO2012174178.

The patent WO2012174178 claims the effect of a fully human antibody or antigen-binding fragment of a human antibody which specifically binds and neutralizes, inhibits, blocks, abrogates, reduces or interferes with the activity of human angiopoietin-like protein 3 (hANGPTL3). The effects of human anti-hANGPTL3 mainly inhibit lipoprotein lipase activity and decrease triglyceride levels. In addition, it reduces plasma TC and high-density lipoprotein cholesterol in normal mice and mice with hyperlipoidemia and mimics the plasma profile of human familial combined hypolipidemia. The antibodies are useful in treating diseases or disorders associated with ANGPTL3, such as hyperlipidemia, hyperlipoproteinemia and other dyslipidemias. Furthermore, the anti-hANGPTL3 antibodies can be administered to a subject to prevent or treat abnormal lipid metabolism which causes or enhances the induction of cardiovascular diseases.

Double-antiangiogenic protein DAAP targeting vascular endothelial growth factor A and angiopoietins attenuates collagen-induced arthritis.

INTRODUCTION: Angiogenesis plays a critical role in synovial inflammation and joint destruction in rheumatoid arthritis (RA). Vascular endothelial growth factor A (VEGF-A) and angiopoietins are two important mediators of synovial angiogenesis. We have previously developed a novel chimeric decoy receptor, namely, double-antiangiogenic protein (DAAP), which can both bind VEGF-A and angiopoietins and block their actions. This study was performed to evaluate the antiarthritic effect of DAAP and the combination effect with the tumor necrosis factor α (TNF-α) inhibitor in collagen-induced arthritis (CIA). METHODS: Recombinant DAAP, VEGF-Trap, Tie2-Fc and dimeric Fc proteins were produced and purified from CHO cells in large-scale bioreactors. CIA was induced in DBA/1 mice with type II collagen. The preventive effect of DAAP was determined and compared with other decoy receptors such as VEGF-Trap or Tie2-Fc, which block VEGF-A or angiopoietins, respectively. The clinical, radiographic, pathologic and immunohistochemical analyses were performed in CIA mice. The levels of matrix metalloprotease 3 (MMP-3) and interleukin 1ß (IL-1ß) were quantified by enzyme-linked immunosorbent assay, and receptor activator of nuclear factor κB ligand (RANKL) mRNA levels were measured by polymerase chain reaction. Finally, we investigated the combination effects of DAAP with a low dose of TNF-α decoy receptor (etanercept 10 mg/kg). RESULTS: On the basis of clinical and radiographic evaluation, DAAP had a much greater inhibitory effect than VEGF-Trap or Tie2-Fc on arthritis severity and bone destruction. These inhibitory effects were accompanied by significantly diminishing pathologic abnormalities, CD31-positive vasculature and synovial infiltration by F4/80-positive macrophages. The levels of MMP-3, IL-1ß and RANKL were much lower in the DAAP-injected group than those of the control. Furthermore, DAAP showed a therapeutic effect and a combination effect with etanercept when injected after arthritis onset in established CIA. CONCLUSIONS: DAAP has not only potent prophylactic effects on both inflammation and bone destruction but also therapeutic effects, alone and in combination with a TNF-α inhibitor in CIA mice. These results suggest that DAAP could be used as an effective new therapeutic agent for RA.

Undaria pinnatifida soluble fiber regulates Angptl3-LPL pathway to lessen hyperlipidemia in mice.

Angiopoietin-like protein 3 (Angptl3)-lipoprotein lipase (LPL) pathway may be a useful pharmacologic target for hyperlipidemia. The present study was conducted to test the effect of soluble fiber extracted from Undaria pinnatifida (UP), on hyperlipidemia in apolipoprotein E-deficient (ApoE(-/-)) mice. Forty mice were divided into four groups (n = 10): control group (C57BL/6J mice), ApoE(-/-) mice group, and two groups of ApoE(-/-) mice treated with UP fiber (5 or 10 % per day). UP soluble fiber treatment significantly decreased plasma and hepatic total cholesterol, triglycerides levels, plasma low-density lipoprotein cholesterol, and malondialdehyde concentrations and increased plasma high-density lipoprotein cholesterol level and downregulated protein expression of Angptl3 concomitantly with upregulated protein expression of LPL. In addition, T0901317 caused elevated expression of hepatic Angptl3 protein, and the effect of T0901317 was also abrogated by UP soluble fiber in C57BL/6J mice. The present results suggest that the UP soluble fiber regulates Angptl3-LPL pathway to lessen hyperlipidemia in mice.

Targeted anti-vascular therapies for ovarian cancer: current evidence.

Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis.