PEGylated lactoferrin enhances its hepatoprotective effects on acute liver injury induced by D-galactosamine and lipopolysaccharide in rats.

Polyethylene glycol (PEG) is attached to proteins in order to increase their half-life in circulation and reduce their immunogenicity in vivo. The present study was conducted to examine whether two different sizes of PEGylated bovine lactoferrin (40k- and 20k-PEG-bLf) would enhance the protective effect of native bLf on liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in rats. The treatment of PEGylated bLf more remarkably prevented the elevation of serum levels of hepatic enzyme markers and inhibited inflammatory and hemorrhagic changes and hepatic apoptosis induced by GalN/LPS than native bLf.

Relationship between peroxisome proliferator-activated receptor-gamma activation and the ameliorative effects of ascochlorin derivatives on type II diabetes.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a crucial factor in the development of insulin resistance associated with type II diabetes. We previously found that 4-O-carboxymethyl ascochlorin, a derivative of ascochlorin, ameliorates diabetes and activates PPAR-gamma. Here, we compared the relationship between the amelioration of type II diabetes in db/db mice lacking leptin receptor, and PPAR-gamma activation by 4-O-carboxymethyl-ascochlorin, as well as by 4-O-methyl-ascochlorin, a derivative that does not activate PPAR-gamma.

Trans-endothelial and trans-epithelial transfer of lactoferrin into the brain through BBB and BCSFB in adult rats.

The transportation of intravenously administered bovine lactoferrin (bLF) into the cerebrospinal fluid (CSF) was immunohistochemically investigated in adult rats. Administered bLF was detected in the vesicular membranes of endothelial cells in cerebral blood vessels 10 min after the infusion. Numerous immunoreactive small vesicles were also detected at the ependymal cells in the choroid plexus.

Proteome analysis of responses to ascochlorin in a human osteosarcoma cell line by 2-D gel electrophoresis and MALDI-TOF MS.

Ascochlorin is a prenyl-phenol compound that was isolated from the fungus Ascochyta viciae. Ascochlorin reduces serum cholesterol and triglyceride levels, suppresses hypertension and tumor development, and ameliorates type I and II diabetes. Here, to better understand the mechanisms by which ascochlorin regulates physiological or pathological events and induces responses in the pharmacological treatment of cancer, we performed differential analysis of the proteome of the human osteosarcoma cells U2OS in response to ascochlorin.

The ascochlorin derivative, AS-6, inhibits TNF-alpha-induced adhesion molecule and chemokine expression in rat vascular smooth muscle cells.

Vascular inflammation induced by the proinflammatory cytokine/NF-kappaB pathway is one of the key mechanisms in the development of atherosclerosis. Peroxisome proliferators-activated receptor-gamma (PPARgamma) plays an important role in the prevention of arterial inflammation and formation of atherogenesis. Herein we examine the effects of a newly identified synthetic PPARgamma ligand, ascochlorin-6 (AS-6), on TNF-alpha-stimulated NF-kappaB activity and inflammatory molecule expression in vascular smooth muscle cells (VSMCs).

Enteric-formulated lactoferrin was more effectively transported into blood circulation from gastrointestinal tract in adult rats.

We have previously demonstrated that intestinally infused bovine lactoferrin (bLF) is transported into the blood circulation via the lymphatic pathway, not via the portal circulation. Therefore, in the present study, we further investigated whether intragastrically infused enteric-formulated bLF (EF-bLF) was more efficiently absorbed than bLF from the intestine in adult rats. The rats were randomly divided into three groups: 30 and 300 mg kg(-1) non-enteric-formulated bLF (non-EF-bLF) groups and a 30 mg kg(-1) EF-bLF group.

Milk-derived lactoferrin may block tolerance to morphine analgesia.

Lactoferrin (LF) is a multifunctional protein that is widely found in milk, blood, and other biological fluids. In the present study, we investigated the possibility that LF may block a tolerance to morphine-induced analgesia in the mouse. The nociceptive effect of bovine milk-derived LF (bLF) was estimated in the mouse tail-flick test.

Ascochlorin inhibits matrix metalloproteinase-9 expression by suppressing activator protein-1-mediated gene expression through the ERK1/2 signaling pathway: inhibitory effects of ascochlorin on the invasion of renal carcinoma cells.

The expression of matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. Here we examined the effect of ascochlorin, a prenyl-phenol anti-tumor compound from the fungus Ascochyta viciae, on the regulation of signaling pathways that control MMP-9 expression in human renal carcinoma (Caki-1) cells. Ascochlorin reduced the invasive activity of Caki-1 cells and inhibited phorbol 12-myristate 13-acetate-induced increases in MMP-9 expression and activity in a dose-dependent manner.

Selective cytotoxicity of ascochlorin in ER-negative human breast cancer cell lines.

While agents targeting estrogen receptors are most effective in adjuvant therapy for human breast cancers expressing estrogen receptors after surgery, breast cancers lacking estrogen receptor are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including estrogen receptor-antagonists and DNA breaking agents. Here, we found that MX-1, a human breast cancer cell line lacking estrogen receptors, exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos, and Fra-1 when compared with conventional estrogen receptor-positive human breast cancer cell lines. The prenylphenol antibiotic ascochlorin suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells, partly due to induction of apoptosis.

Bovine lactoferrin reduces plasma triacylglycerol and NEFA accompanied by decreased hepatic cholesterol and triacylglycerol contents in rodents.

In the present study we examined whether oral administration of bovine lactoferrin (bLF) reduces plasma or hepatic triacylglycerol and cholesterol in mice. When bLF mixed with a standard commercial diet (10 g/kg) was given to mice for 4 weeks, plasma triacylglycerol and NEFA decreased, while plasma HDL-cholesterol levels increased (P<0.01).

Oral administration of lactoferrin inhibits inflammation and nociception in rat adjuvant-induced arthritis.

Lactoferrin (LF) is a ubiquitous protein which exists in milk, plasma, synovial fluids, cerebrospinal fluid and other biological fluids. LF is also well known as a natural immunomodulator. Recently, we found that bovine milk-derived LF (BLF) produced micro-opioid receptor-mediated analgesia.

Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats.

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids. Under inflammatory conditions, LF production is increased in the periphery by neutrophils. However, the cardiovascular function of LF is still unknown.

Ascochlorin derivatives as ligands for nuclear hormone receptors.

Nuclear receptor family proteins are structurally related transcription factors activated by specific lipophilic compounds. Because they are activated by a variety of hormonal molecules, including retinoic acid, vitamin D, and steroid hormones, they are assumed to be promising targets for clinical drugs. We previously found that one ascochlorin (1) derivative, 4-O-carboxymethyl-ascochlorin (2), is a potent agonist of peroxisome proliferator activated receptor gamma (PPARgamma).

Persorption of bovine lactoferrin from the intestinal lumen into the systemic circulation via the portal vein and the mesenteric lymphatics in growing pigs.

The absorption and the transportation of intestinally administrated bovine lactoferrin (LF) were immunohistochemically and physiochemically investigated in the small intestine of growing pigs. At the apical halves of the small intestinal villi, bovine LF was absorbed by transcytosis as small vesicles through villous columnar epithelial cells. The presence of bovine LF-positive membranes of transcytotic vesicles suggests that the absorption was mediated by LF-binding factors on the epithelial cell membranes.

Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord.

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids, and its receptors have also been identified in the central nervous system. Recently, we found that bovine milk-derived LF (BLF) produced analgesia via a mu-opioid receptor-mediated response in the spinal cord. However, the precise mechanism of this analgesic effect remains unclear.

Novel function of bovine milk-derived lactoferrin on antinociception mediated by mu-opioid receptor in the rat spinal cord.

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids. Although LF and the LF receptor have been identified in the central nervous system (CNS), the physiological role of LF remains unknown. We found that bovine milk-derived LF (BLF) reduces nociception in various pain models, as shown by the formalin test, hot plate test, and acetic acid writhing test in rats.

PPARgamma activation and adipocyte differentiation induced by AS-6, a prenyl-phenol antidiabetic antibiotic.

The prenyl-phenol antibiotics ascochlorin-related compounds, are known to reduce serum cholesterol and triglyceride, suppress hypertension, and ameliorate types-I and II diabetes. However, little is known about the molecular mechanism for these physiological effects. Here we report that the ascochlorin derivative, 4-O-carboxymethyl ascochlorin (AS-6) acts as a potent activator of the nuclear hormone receptor, PPARgamma, although it does not activate the related receptors, PPARalpha, PPARdelta or RARalpha.