Inverse Correlation Between Alzheimer's Disease and Cancer: Short Overview.

The negative association between Alzheimer's disease (AD) and cancer suggests that susceptibility to one disease may protect against the other. When biological mechanisms of AD and cancer and relationship between them are understood, the unsolved problem of both diseases which still touches the growing human population could be overcome. Actual information about biological mechanisms and common risk factors such as chronic inflammation, age-related metabolic deregulation, and family history is presented here. Common signaling pathways, e.g., p53, Wnt, role of Pin1, and microRNA, are discussed as well. Much attention is also paid to the potential impact of chronic viral, bacterial, and fungal infections that are responsible for the inflammatory pathway in AD and also play a key role to cancer development. New data about common mechanisms in etiopathology of cancer and neurological diseases suggests new therapeutic strategies. Among them, the use of nilotinib, tyrosine kinase inhibitor, protein kinase C, and bexarotene is the most promising.

Neurotrophic Activity of Cultured Cell Line U87 is Up-Regulated by Proline-Rich Polypeptide Complex and Its Constituent Nonapeptide.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor, as well as cytokines, for example, interleukin-6 (IL-6) play an important role in neuroprotection and in the control of the central nervous system (CNS) function. Reduced expression of neurotrophic factors can lead to dysregulation of neuron function and neuronal death. There is also evidence for mutual interactions between neurotrophins and IL-6. Therefore, the up-regulating the level of neuroprotective substances is one of the key manners to control the nervous system development and function. It can be a promising aim in the therapy of neurodegenerative disease in which the decreased level of neurotrophins is observed. In our recent studies, the role of proline-rich polypeptide complex (PRP) and its nonapeptide fragment (NP) in the regulation of neurotrophic activity in cultured astrocytes was shown. PRP and NP stimulate human astrocytoma cell line U87 to release the significant amounts of NGF to the extracellular space both in its precursor and mature form. We also provide the evidence that in NP-treated cells, the level of ßNGF mRNA was increased. NP-treated cells used in this study produced also increasing amounts of IL-6. This finding indicates that PRP and its nonapeptide fragment NP up-regulate neurotrophic activity of U87 cell line by increase of NGF synthesis and its release into the extracellular space. It was also shown that NP-dependent increased production of IL-6 can enhance the NGF activity.

Can proline-rich polypeptide complex mimic the effect of nerve growth factor?

Naturally occurring compounds that can act as prosurvival factors and neurite formation stimulants in the conditions of reduced neurotrophins production are important both in neuronal protection and therapy of neurodegenerative disorders. Therefore, the role of proline-rich polypeptide complex (PRP) and its nonapeptide fragment (NP) in the promotion of pheochromocytoma cell line (PC12) survival and neurite outgrowth pathway is presented. It was shown that PRP/NP did not affect the neuronal nitric oxide synthase (nNOS) at the transcriptional and protein level. However, the activity of nNOS and intracellular nitric oxide (NO) concentration was markedly increased after treatment of PC12 cells with peptides. This reaction was inhibited by L-NAME-nNOS inhibitor. It was shown that PRP and NP induce the soluble guanylyl cyclase to release higher amount of cyclic GMP (cGMP), and subsequently, the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) is observed. This effect was abolished by both U0126 (inhibitor of ERK1/2) and also by L-NAME. Reduction of ERK1/2 activity observed in the presence of nNOS inhibitor suggests that its activation is NO-dependent. The presented results shed some light on the mechanism of action of PRP complex. PRP and NP can activate NO/cGMP/ERK1/2 signaling pathway, similarly to nerve growth factor (NGF). The prosurvival action and short fibers formation suggest the role of PRP and NP in neuroprotection and the initiation of neuritogenesis. They can also participate in the amplification of signals controlling the survival and differentiation of neurons effect when the deficit of NGF takes place.

Peptides accompanying chicken egg yolk IgY--alternative methods of isolation and immunoregulatory activity.

In the hen immune system the egg content plays as significant a role in the development of the chick as colostrum does in newborn mammals. One of the most important proteins in this system seems to be the main yolk immunoglobulin IgY. It has been shown that IgY is accompanied by an immunostimulatory polypeptide complex named yolkin. In this report the biological activities of yolkin separated by means of four different procedures are presented. It was shown that yolkin acts as an inducer rather than a modulator of cytokine and nitric oxide release, and does not participate in the protection of cells against destructive effects of reactive oxygen species. However, using the perchloric acid procedure it is possible to obtain a peptide fraction with higher inducing activity, stronger antioxidant properties and ability to decrease the NO level induced by lipopolysaccharide. The results obtained show that it is feasible to select one of the presented methods of yolkin isolation that yields a product of particular activity. The properties of yolk peptides not only indicate their roles in the development of chicks, but can also be useful for the regulation of some immunological disturbances.

Immunologically active peptides that accompany hen egg yolk immunoglobulin Y: separation and identification.

The protein mixture of cytokine-inducing activity accompanying chicken immunoglobulin Y, named yolkin, consists of several peptides of molecular weight (MW) ranging from over 1 to 35 kDa. Yolkin and its constituent peptides were found to be efficient inducers of interleukin (IL)-1ß, IL-6 and IL-10 secretion. N-terminal amino acid sequences of eight of the electrophoretically purified yolkin constituents revealed that all of them are homological to some fragments of the C-terminal domain of vitellogenin II. The fractions of MW about 4 and 12 kDa are free of carbohydrates and start at position 1732 in the vitellogenin amino acid sequence; whereas the other fractions (MW about 16, 19, 23, 29, 32 and 35 kDa) appeared to be glycoproteins corresponding to the amino acid sequence of vitellogenin starting at position 1572. From these data, it is concluded that yolkin most likely represents vitellogenin-derived peptides that possess cytokine-inducing activity and are, at least partially, responsible for such properties of separated immunoglobulin Y preparation. This finding reveals a new role for vitellogenin as a reservoir of polypeptides that may play an important role in the innate immune system of the developing embryo.

Effect of the proline-rich polypeptide complex/colostrinin™ on the enzymatic antioxidant system.

Proline-rich polypeptide complex (PRP) and its constituent nonapeptide (NP) possess immunoregulatory and procognitive properties. PRP in the form of sublingually administered tablets called Colostrinin™ improves the outcome of patients with Alzheimer's disease (AD). Free radical-induced oxidative stress has been implicated in the pathogenesis of AD. It has been previously shown that PRP and NP inhibit overproduction of reactive oxygen species, nitric oxide and proinflammatory cytokines induced by lipopolysaccharide or PMA. Antioxidant defense includes both low molecular weight components and enzymatic systems including dismutases, catalase, glutathione reductase (GSSGR) and glutathione peroxidase (GSHPx). An early event during the development of AD is lipid and protein peroxidation. PRP and NP showed no modulatory effect on lipid peroxidation. A protective effect on protein oxidation was found only when high doses of NP were used. We have previously shown, in a model of human peripheral blood mononuclear cells, that PRP/NP affects activities of superoxide dismutase and NF-κB. In the present study with the use of the same cell model and whole blood cells we observed an activatory effect of PRP/NP on GSHPx and GSSGR activity but not catalase. The observed effect suggests that PRP/NP can act as a modulatory agent of the "first line" of antioxidant defense. It can be assumed therefore that PRP/Colostrinin by regulation of the early phase of the redox system does not reduce but rather prevents oxidative damage. This effect may shed some light on the beneficial effect of PRP/Colostrinin in AD patients.

A proline-rich polypeptide complex (PRP) influences inducible nitric oxide synthase in mice at the protein level.

A proline-rich polypeptide complex (PRP) with immunoregulatory and procognitive properties showed a beneficial effect in Alzheimer's disease (AD) when administered orally in the form of Colostrinin(R) tablets. The mechanism of action of PRP/Colostrinin in AD has not been yet clarified. It is known that oxidative stress enhances neurodegenerative processes. It was previously shown that the PRP regulates the secretion of cytokines and inhibits NO and O(2)(-) release in cell cultures. Since the results on isolated cells or cell lines frequently do not reflect events in vivo, the effect of PRP on NO release and iNOS protein synthesis in mice treated with LPS was studied. The PRP did not induce the production of NO. However, in the presence of PRP applied 6h after LPS, about 40% inhibition of NO release was observed. This effect was accompanied by lower iNOS protein expression in peritoneal cells. In the liver sections of mice treated with PRP 6h after LPS application, the number of iNOS-positive cells was significantly reduced. These results indicate that PRP can act as a regulator of inflammatory processes. The inhibition of iNOS activity/expression could be one of the mechanisms of the therapeutic effect of PRP/Colostrinin in AD.

Proline-rich polypeptide complex (PRP) regulates secretion of inflammatory mediators by its effect on NF-kappaB activity.

A proline-rich polypeptide complex (PRP) with immunoregulatory and procognitive activities shows beneficial effects in the Alzheimer's disease (AD). The mechanism of action of PRP is not yet fully clarified, we have shown that the PRP complex inhibits overproduction of reactive oxygen species, nitric oxide and proinflammatory cytokines induced by lipopolysaccharide (LPS). LPS stimulation exerts its inflammatory effects through the activation of the classical nuclear factor-kappaB (NF-kappaB) pathway. The results presented in this study showed the ability of PRP to inhibit the NF-kappaB activity induced by LPS while it increased activity of NF-kappaB in untreated cells. Examining the effect of PRP on IkappaB it was shown that relative level of IkappaB was lowered in the presence of PRP. It seems that in cells untreated with LPS, PRP can activate proteasome system and stimulate IkappaB degradation. Our results suggest that the regulatory effect of PRP on inflammatory processes may be associated with the influence of PRP on NF-kappaB translocation. Inhibitory effect of PRP on NF-kappaB activity might, at least in part, contribute to the beneficial therapeutic effects in the case of Alzheimer's disease.

Ovine colostrum nanopeptide affects amyloid beta aggregation.

A colostral proline-rich polypeptide complex (PRP) consisting of over 30 peptides shows beneficial effects in Alzheimer's disease (AD) patients when administered in the form of sublinqual tablets called Colostrinin. The aim of the present studies was to investigate whether nanopeptide fragment of PRP (NP) - one of the PRP complex components can affect aggregation of amyloid beta (Abeta1-42). The effect of NP on Abeta aggregation was studied using Thioflavin T (ThT) binding, atomic force microscopy, and analyzing circular dichroism spectra. Results presented suggest that NP can directly interact with amyloid beta, inhibit its aggregation and disrupt existing aggregates acting as a beta sheet breaker and reduce toxicity induced by aggregated forms of Abeta.

[Alzheimer's disease: new prospects in therapy and applied experimental models]. / Choroba Alzheimera--nowe mozliwosci terapeutyczne oraz stosowane modele eksperymentalne.

Neurodegenerative disorders such as Alzheimer's disease (AD) are the most common disease of modern society. The gradual and irreversible disturbances in homeostasis are characteristic features of the disease process. The cardinal features of AD include the formation of extracellular protein deposits in the brain that consist predominantly of aggregates of b amyloid protein(senile plaques), neurofibrilary tangles (hyperfosforylated tau protein) in the intracellular compartments,disturbances in calcium homeostasis, and degeneration/loss of synapses and neurons. An inflammatory process in the central nervous system is believed to play an important role in the pathway leading to neuronal cell death. The inflammatory response is mediated by activated microglia, resident immune cells of the central nervous system. Chronic activation of the microglia and astrocytes may cause damage of the brain-blood barrier and neuronal damage through the release of potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen species, NO, and complement proteins. These alterations cause influx of immunocompetent cells from the periphery and their active participation in the local inflammatory reaction. Disturbances in the control mechanism of the inflammatory processes leads to perturbations in function and extensive brain degeneration. A characteristic symptom of AD dementia, is associated with dysfunctions of cognitive memory such as calculation, space orientation, and speech impairment. By tracking the sequence of events leading to the Alzheimer's type of dementia, the therapeutic possibilities can be combined with modulation of secretase activation responsible for the formation of amyloidogenic forms Abeta(40-43), inhibition of aggregation or beta amyloid deaggregation,and regulation of the inflammatory response. Several strategies for drug intervention in both the treatment and prevention of AD has been pursued, but so far there is no fully effective cure without side effects. Transplantation of nerve cells and genetic therapy are looked upon as new perspectives. Research is being conducted on the application of proteins deforming beta-sheet structures. Due to the pluricausal and multidirectional type of biological changes characteristic of AD, it seems likely that multidrug therapy or multidirectional medicine would be more efficient. Post-mortem experiments as well as neurochemical and anatomical brain studies helps to reveal new facts about the mechanisms underlying brain diseases. However limited access to fresh brain tissues or primary cell lines, which would be the best experimental models, compel researchers to look for other experimental models allowing investigation of disease occurrence. It seems that transgenic animals fulfill the requirements of relecting the disease process. In spite of the wide range of applied experimental models it is difficult to fi nd clear answers to such questions as what are the exact stages of neurodegenerative process? How and what kind of factor could stop, slow down, or prevent this alterations? These questions are still open.

[The two faces of reactive oxygen species]. / Dwa oblicza wolnych rodników tlenowych.

Oxidative stress has been implicated in playing a crucial role in aging and in the pathogeneses of a number of diseases, including neurodegenerative disorders such as Alzheimer's disease. Oxidative stress occurs due to an imbalance in prooxidant and antioxidant levels. Reactive oxygen species (ROS) are highly reactive and may modify and inactivate proteins, lipids, DNA, and RNA and induce cellular dysfunctions. To prevent free radical-induced cellular damage, the organism has developed a defense mechanism, the antioxidative system. This system includes antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), and glutathione reductase (GSSGR) and low-molecular antioxidants such as glutathion and plasma proteins. Glutathion plays a key role in maintaining the physiological balance between prooxidants and antioxidants. Plasma proteins can inhibit ROS generation and lipid peroxidation by chelating free transition metals. The major exogenous antioxidants are vitamins E, C, and A.

[Structure and function of the central nervous system]. / Struktura i funkcjonowanie osrodkowego ukladu nerwowego.

The main elements of the central nervous system are the brain and the spinal cord. It contains millions of neurons and glial cells: astrocytes, oligodendrocytes, and microglia. The main role of the CNS is to process information, analyze signals, and activate effector organs. The role of the glial cells is the creation of the blood-brain barrier, the protection and feeding of neuronal cells, antioxidant activity, and immunological control. Unbalanced glial activation may cause neurodegeneration.

A proline-rich polypeptide complex (PRP) isolated from ovine colostrum. Modulation of H2O2 and cytokine induction in human leukocytes.

A proline-rich polypeptide complex (PRP) has immunoregulatory properties and also shows beneficial effects in Alzheimer's disease (AD). It is known that the unregulated activation of microglial cells in AD may result in chronic inflammatory response. There is a link between the activation of immune cells on the periphery and in the central nervous system (CNS). Therefore, we studied the effect of the PRP on human peripheral blood mononuclear cells (PBMCs) stimulated by LPS with PHA (LP) or PMA as proinflammatory activators. PRP and its nonapeptide fragment (NP) inhibited by 40-60% production of H(2)O(2) induced by PMA. The peptides also inhibited activity of superoxide dismutase. Both peptide preparations showed differential effects on the secretion of cytokines. NP induced TNF-alpha only while PRP induced IL-6, IL-10 and TNF-alpha. On the other hand, the release of TNF-alpha and IL-10 induced by LP in PBMCs was inhibited by PRP while NP inhibited the release of IFN-gamma and IL-10. The results obtained showed that PRP may affect not only adaptive immunity but also innate immunity and thus may regulate secretions of mediators of inflammation. The regulatory effect of the PRP on the innate immunity may shed some light on understanding the beneficial effects of this polypeptide complex in AD patients.

Studies on the mechanism of action of a proline-rich polypeptide complex (PRP): effect on the stage of cell differentiation.

A proline-rich polypeptide complex (PRP) with immunoregulatory and procognitive activities shows beneficial effects in Alzheimer's disease (AD). The mechanism of action of PRP in AD is not yet clarified. Here, we present results of the effect of PRP on Vitamin D3-induced phenotypic (CD11b and CD14) and functional (phagocytic) differentiation/maturation of monocytes/macrophages using the premonocytic HL-60 cell line as a model. This cell line can be induced to differentiate into monocyte/macrophage cells by incubation with Vitamin D3. However, when Vitamin D3 was applied together with PRP, a 30-40% inhibition of the expression of the differentiation markers and an over-60% inhibition of phagocytic ability were observed. When PRP was administered to the cells after treatment with Vitamin D3, no attenuation of the differentiation/maturation process of the HL-60 cells was observed. This indicates that PRP affects the early stages of differentiation/maturation of these cells. Our results, therefore, suggest that PRP, which affects the differentiation/maturation processes of cells of monocyte/macrophage lineage, may regulate in this way the inflammatory processes in which these cells participate.

A proline-rich polypeptide complex and its nonapeptide fragment inhibit nitric oxide production induced in mice.

A proline-rich polypeptide complex (PRP) isolated from ovine colostrum shows immunoregulatory and procognitive activities. It shows beneficial effects in Alzheimer's disease (AD) patients when orally administered in the form of tablets called Colostrinin. The mechanism of action of PRP/Colostrinin in AD has not been yet clarified. It is known that oxidative stress and overproduction of NO may enhance neurodegenerative processes. PRP regulates the secretion of cytokines, inhibits NO and O2- release in cell cultures. Since the results on isolated cells or cell lines frequently do not reflect the events in vivo, the effect of PRP and its nonapeptide fragment (NP) on the level of NO2- in sera of mice untreated or intraperitoneally treated with LPS was studied. PRP and NP did not induce production of NO. However, when applicated 6 h after LPS, they inhibited the release of NO induced by LPS in about 30-50%. The results in vivo presented in this paper confirm the results obtained in cell cultures and indicate that the beneficial effects of PRP/Colostrinin observed in AD patients may be, among others, due to an inhibition of overproduction of NO.

Colostrinin proline-rich polypeptide complex from ovine colostrum--a long-term study of its efficacy in Alzheimer's disease.

BACKGROUND: Colostrinin, a proline-rich polypeptide complex (PRP) isolated from ovine colostrum, with immunoregulatory and procognitive properties, has shown positive effects in the treatment of Alzheimer's disease (AD). The aim of the present study was to evaluate the effects of long-term Colostrinin treatment of AD patients. MATERIAL/METHODS: The patients were taking Colostrinin tablets (containing 100 mg of PRP complex) every other day for three weeks, followed by a 2-week hiatus to avoid the development of hyporeactivity. This mode of application, '3+2 weeks,' was used consistently throughout the trial. The efficacy of treatment was assessed by the MMSE scale, and each patient was evaluated at 4-month intervals. 33 patients were treated for 16 months. However, 13 patients from this group had already been treated with Colostrinin for 12 months during placebo-controlled studies, and thus participated in the trial for a total of 28 months. RESULTS: The results we obtained showed that Colostrinin induced slight but statistically significant improvement or stabilization of the health status of the patients in the trial. The adverse reactions observed, if any, were remarkably mild, including anxiety, logorrhea, and insomnia, and subsided spontaneously within a short period of time (3-4 days). CONCLUSIONS: Colostrinin is a very promising preparation which can be used to retard the development of AD.