 | This article possibly contains original research .(September 2010) |
Colostrinin (also known as CLN, proline-rich polypeptides or PRP) is a naturally occurring mixture of proline-rich polypeptides derived from colostrum.
| This article possibly contains original research .(September 2010) |
Colostrinin (also known as CLN, proline-rich polypeptides or PRP) is a naturally occurring mixture of proline-rich polypeptides derived from colostrum.
Colostrinin was originally identified by scientists working in Poland in the 1970s. [1] [ citation needed ] Colostrinin is derived from colostrum, which is present in the pre-milk fluid produced from mammary glands in the first few days after parturition. It is also known as proline-rich polypeptides, since sequence analysis of the peptides present in this mixture reveals an unusually high proportion of this amino acid residue. The amino acid compositions of Colostrinin from ovine, bovine, and human colostrum are very similar. [2] Colostrinin was first characterized in animal and in-vitro studies as a substance that generally stimulates the immune response. [3] Such an immunomodulatory action may be important in the treatment of a variety of diseases and is consistent with the beneficial effect of colostrum in promoting the development of the immune system in newborn mammals.
Colostrinin is obtained from bovine colostrum by alcohol extraction and filtration. A patented method [4] outlines the steps that can be used to produce this substance on an industrial scale. In this method, an alcohol, such as ethanol or methanol, is used to create an alcohol phase. This phase is enriched with the peptide fraction, from which Colostrinin is recovered and purified.
Colostrinin is incompletely defined chemically. Initially, it was assumed to consist of a single protein with a molecular weight of approximately 17 to 18 kDa. However, subsequent studies showed that Colostrinin largely consists of a mixture of at least 32 peptides ranging in size from 0.5 to 3 kDa. [5] Most of the peptides appear to be derived from proteolytic processing of the milk proteins β-casein and a β-casein homolog. Whether non-peptide components of the mixture contribute to the biological activity is unknown. However, the biological activity of Colostrinin does seem to be due to more than one of the components, since its effects cannot be completely mimicked by any one of the peptide components tested so far.
PRP-rich preparations from bovine colostrum have shown possible efficacy against various illnesses including neurodegenerative diseases (such as Alzheimer's), viral infections, and ailments characterized by an overactive immune system, such as allergies, asthma and autoimmune diseases. [6] Some recent research has also indicated possible efficacy in combating obesity. [7] Colostrinin's potential as a cognitive enhancer is fairly well-documented.
Significant research has been done on Colostrinin's possible efficacy in Alzheimer's disease, [8] the most common form of dementia. The disease is characterized by extracellular senile plaques consisting mainly of aggregated amyloid-beta (Aß) and intracellular neurofibrillary tangles, containing the cytoskeletal protein tau. [9]
A placebo-controlled clinical trial with Colostrinin in 106 people with Alzheimer's over 30 weeks was completed in 2002 and the results appeared to demonstrate efficacy in a significant proportion of patients treated. [10] The results showed that approximately 40% of patients on Colostrinin were stabilized or improved after 15 weeks of therapy, based on an Analysis of Overall Response. 33% of patients continued to show stabilization or improvement after 30 weeks of treatment, although levels of benefit were slightly higher at the 15-week stage of the trial. The dosage regimen used for the trial was 100 micrograms of Colostrinin administered every second day for three weeks followed by a two-week period without Colostrinin.
A 2010 study demonstrated that Colostrinin significantly relieved amyloid-beta (Aß)-induced cytotoxicity, alleviated the effect of Aß-induced cytotoxicity and caused a significant reduction in the elevated levels of the antioxidant enzyme SOD1. [11]
An in-vitro study completed in 2005 showed that Colostrinin can increase the lifespan of cells isolated from inbred mice predisposed to premature aging and death. [12] [ unreliable medical source? ] This study showed the effect of Colostrinin on the mitochondria of cells isolated from strains of senescence-prone (SAMP1) and senescence-resistant (SAMR1) mice. The data showed that cells from SAMP1 mice produce more reactive oxygen species (ROS), exhibit severe mitochondrial dysfunction, and have a decreased lifespan compared to the cells from SAMR1 mice. Addition of Colostrinin to SAMP1 cells significantly decreased ROS levels, normalized mitochondrial function and increased the lifespan to levels similar to those in SAMR1 cells. This in-vitro effect was followed up in actual mice as well.
Another study showed that Colostrinin induces neurite outgrowth of pheochromocytoma cells and inhibits beta amyloid-induced apoptosis. [13] The neurite outgrowth caused by Colostrinin appears to activate signaling pathways common to cell proliferation and differentiation, and to mediate a wide spectrum of activities that are similar to those of hormones and known nerve growth factors. These findings would seem to suggest that Colostrinin treatment may control the expression of genes that are involved in the development, maintenance, and regeneration of neurons in the central nervous system, and thus may also explain the improvements observed in Alzheimer's patients with mild-to-moderate dementia during treatment with Colostrinin. Colostrinin affects the early stages of Vitamin D3-induced phenotypic (CD11b and CD14) and functional (phagocytic) differentiation/maturation of monocytes/macrophages. When Colostrinin was administered to the cells after treatment with Vitamin D3, no attenuation of the differentiation/maturation process of the HL-60 cells was observed. Therefore, Colostrinin may regulate in this way the inflammatory processes in which these cells participate. [14]
Another study in day-old domestic chicks showed enhancement of long-term memory retention. [15] A study conducted at the University of Texas Medical Branch and published online in March 2008 in the International Archives of Allergy and Immunology showed that Colostrinin is non-allergenic and can prevent allergic inflammation due to common indoor and outdoor allergens. [16] The study used a well characterized mouse model of allergic airway inflammation. Colostrinin (given orally, intranasally or intraperitoneally) significantly decreased IgE/IgG1 production, airway eosinophilia, mucin production and hypersensitivity induced by allergenic extracts from ragweed pollen and house dust mites. In contrast, colostrum induced positive inflammatory responses.
A 2006 study published in the Journal of Experimental Therapeutics and Oncology indicated that Colostrinin may affect the aging process by reducing the spontaneous or induced mutation frequency in the DNA of cells. [17] Such DNA damage is implicated in the general process of aging. The study, which was performed in both hamster and human cells, looked at the effect of Colostrinin on the frequency of defined DNA mutations in these cells as they occur naturally and when induced by various known chemical or physical agents. In cells stressed oxidatively, Colostrinin reduced the frequency of mutation induced by reactive oxygen species (ROS) to nearly background levels in a dose-dependent manner. Likewise, Colostrinin reduced the frequency of mutation caused by two mutagenic agents, methyl methane sulfonate and mitomycin-C, the latter often used in cancer chemotherapy. Notably Colostrinin decreased UVA and UVB radiation induced mutation frequency. These damaging radiations are a natural part of sunlight. UVA radiation plays a role in the induction of malignant melanoma and UVB radiation is the primary cause of squamous cell carcinomas. It is suggested that the antimutagenic properties of Colostrinin are achieved via multiple mechanisms - by decreasing intracellular levels of ROS and so preventing DNA damage and by increasing the efficiency of natural DNA repair mechanisms.
There were also studies of the Colostrinin components and their possible effect on aggregation of amyloid beta (Abeta1-42). Results presented suggest that NP - Colostrinin component, 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. [18]
There has been very little mention of toxicity in most published animal studies using Colostrinin, which may suggest that it exhibits low toxicity. Generally, treatment with Colostrinin in clinical studies has been well tolerated [10] by both animals and humans, with any side-effects being mild and transient. [8]
Tablets or capsules containing Colostrinin are available in many countries in the world and are sold as an OTC dietary supplement under various trade names.
Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs.
Colostrum, or first milk, is the first form of milk produced by the mammary glands of humans and other mammals immediately following delivery of the newborn. It may be called beestings when referring to the first milk of a cow or similar animal. Most species will begin to generate colostrum just prior to giving birth. Colostrum has an especially high amount of bioactive compounds compared to mature milk to give the newborn the best possible start to life. Specifically, colostrum contains antibodies to protect the newborn against disease and infection, and immune and growth factors and other bioactives that help to activate a newborn's immune system, jumpstart gut function, and seed a healthy gut microbiome in the first few days of life. The bioactives found in colostrum are essential for a newborn's health, growth and vitality. Colostrum strengthens a baby's immune system and is filled with white blood cells to protect it from infection.
Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.
Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons.
The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.
In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.
Insulin-degrading enzyme, also known as IDE, is an enzyme.
Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.
Early-onset Alzheimer's disease (EOAD), also called Younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.
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Rudolph Emile 'Rudy' Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, Vice-chair of Neurology, Director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH). Dr. Tanzi has been investigating the genetics of neurological disease since the 1980s when he participated in the first study that used genetic markers to find a disease gene. Dr. Tanzi co-discovered all three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including that responsible for Wilson’s disease. As the leader of the Cure Alzheimer's Fund Alzheimer's Genome Project, Dr. Tanzi has carried out multiple genome wide association studies of thousands of Alzheimer's families leading to the identification of novel AD candidate genes, including CD33 and the first two rare mutations causing late-onset AD in the ADAM10 gene. His research on the role of zinc and copper in AD has led to clinical trials at Prana Biotechnology. He is also working on gamma secretase modulators for the prevention and treatment of Alzheimer's. He also serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and Director the Cure Alzheimer's Fund Alzheimer's Genome Project™.
A cholinergic neuron is a nerve cell which mainly uses the neurotransmitter acetylcholine (ACh) to send its messages. Many neurological systems are cholinergic. Cholinergic neurons provide the primary source of acetylcholine to the cerebral cortex, and promote cortical activation during both wakefulness and rapid eye movement sleep. The cholinergic system of neurons has been a main focus of research in aging and neural degradation, specifically as it relates to Alzheimer's disease. The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in Alzheimer's disease.
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