University of Central Florida Foundation, Inc. (Orlando, FL)
A method for treating patients with elevated levels of peroxynitrite includes administering an amount that is therapeutically effective of cerium oxide nanoparticles the subject. The cerium oxide nanoparticles reduce the peroxynitrite levels in the patient.
The term neurodegeneration refers to the impairment or loss of function, structure, or the function of neurons. This also includes the dismemberment and death of neurons. Neurodegeneration results from various different causes including genetic mutation,mitochondrial dysfunction, and the inability to handle increasing levels of oxidative or nitrosative stress can also lead to the progression of neurodegeneration (67). Evidence from numerous in vitro and in vivo studies suggests that there is acommonality of the causes that lead to the development of a variety of neurodegenerative diseases that are a result of aging. A few of these neurodegenerative disorders include Huntington’s disease, Amyotrophic Lateral Sclerosis (ALS) and one of the most frequent of the neurodegenerative disorders is Alzheimer’s disease (AD). AD is a severe and progressive disease that could cause irreversible damage to patients, caregivers, society, and even the environment. There is increasing evidence in AD and other neurodegenerative diseases which suggests a link between both nitrosative and oxidative stress. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), create the nitrosative stress within cells.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) occur during normal metabolism . However, an imbalance may be caused by the increase in the production of free radicals or from the inability of antioxidants or antioxidant enzymes to effectively scavenge damaging molecules. The imbalance has been shown as a contributing factor in AD (69). Several studies provide clear evidence that RNS, in particular peroxynitrite (ONOO.sup.-) formation, contributes to the pathologies of chronicneurodegenerative diseases such as AD, Parkinson’s disease, multiple sclerosis, and Amyotrophic lateral sclerosis (4). Peroxynitrite is formed from the reaction of nitric oxide radical (NO) with superoxide (O2.sup .-). The most important cause of neurotoxic effects that ONOO.sup. promoting neurotoxic effects are mitochondrial injuries (5 6, 7). The increase in protein nitration within neurons may indicate extensive ONOO.sup.-mediated brain damage.
The administration of antioxidants and antioxidant enzymes for the treatment of illnesses caused by increased ROS and RNS in human clinical trials has so far been less than satisfactory due to issues with bioavailability as well as stability following administration.
This demand was satisfied with synthetic catalytic scavengers that scavenge ROS and RNS. They have been tested in various models. Copious metalloporphyrins have been synthesized to show high reactivity to, O.sub.2.sup.-, H.sub.2O.sub.2 NO andONOO.sup.(14-17). (14-17). Most studies affirm metalloporphyrins are effective tools in study and understanding the roles that ROS and RNS may play in diseases However, their potential toxicity caused by metals has frequently come into question for their use in humans.
Neurons have a high energy requirement and contains many hundred mitochondria in each cell. This means they are more prone to ROS and NNS. Mitochondria are a primary site of the intercellular formation of ONOO.sup.- (12) and mitochondrialdysfunction has been shown to contribute to disease or neuronal death (13). The ability to remove ONOO.sup.- – is crucial for therapeutic intercession in degenerative diseases that are characterized by the overproduction or unbalanced production of O.sub.2.sup.- and NOand thus, ONOO.sup.-.
The mitochondria are constantly divided and fusion in order to continue to produce energy. Evidence suggests that an imbalance in mitochondrial division and fusion is the cause in AD (78). Mitochondrial division and fusion is regulatedby large GTPases of the dynamin family. For mitochondrial division, Dynamin-related Protein 1 (DRP1) must be expressed. The presence of the GTPase defective DRP1.sup.K38A mutant guards against excess NO, NMDA, or A.beta. (5). It is unclear what causes mitochondrial break-up caused by NO. A recent report suggested that S-nitrosylation of DRP1 at cysteine 644 increases DRP1 activity and is the cause for theperoxynitrite-induced mitochondrial fragmentation in AD (85, 50). The work is still controversial and suggests that other pathways may be involved (85,86). DRP1 Serine 616 (S616) the phosphorylation process is fast under nitrosative stress, and promotes its translocation to organelle and mitochondrial division (86-87). DRP1 5616 phosphorylation in mitotic cells is controlled by Cdk1/cyclinB1, a protein that is synchronized with the division of mitochondria and cell division (88-89). It is interesting to note that p-DRP1 S616 levels are markedly increased in brains of individuals with AD and suggests that this process could contribute to the alteration in mitochondrial morphology as well as energy metabolism in AD (86, and 88). While the kinase that causes DRP1 5616 hyperphosphorylation is unknown Cdk5/p25 may be a possible kinase that mediates the process (7,90). Notably, aberrant Cdk5/p25 signaling causes tau hyperphosphorylation in postmitotic neurons and is involved in A.beta.-mediated neurodegeneration (88, 90-93).
The brain’s physical changes are just a few of the effects that Alzheimer disease or other neurodegenerative disorders have in the brain. One example of these changes is the formation of plaque-like and neurofibrillary tangles. Microglia activation due to illness, injury or aging, among other reasons, can trigger events that are classified as an inflammation process. These processes are first controlled through the proinflammatory cytokine Interleukin 1. This is overexpressed by activated microglia. Through different channels, interleukin 1 triggers neuronal death, which activates the microglia. The microglia in turn releases more interleukin 1, in self-sustaining, self-amplifying way. Over time, this slow, smolderinginflammation in the brain destroys sufficient neurons to cause the clinical signs of Alzheimer disease.
Cerium oxide nanoparticles (CeO.sub.2 NPs) have been recently demonstrated to efficiently scavenge reactive oxygen species within a variety of model systems. The mechanism by the nanoparticles of cerium oxide activate these redox reactions is tied to the surface chemistry as well as the the redox state of cerium, and is dependent on the preparation. Peroxynitrite is a neurotoxic nitrogen compound which plays a role in the development of numerous neurodegenerative disorders. Scavengingperoxynitrite provides beneficial therapeutic effects in both neurodegenerative diseases and in many diseases where inflammation in the brain is a critical contributing factor. Conventional antioxidants primarily scavenge only reactive oxygen species and are not effective against nitrogen species that are reactive. Cerium oxide, which is a rare-earth oxide nanomaterial, is utilized to eliminate peroxynitrite in vitro. This newly discovered catalytic property of cerium oxide offers protection in aprimary neuronal cell model. Cerium oxide nanoparticles are absorbed by neurons and are accumulated within mitochondria, which is the main source of reactive nitrogen species within neurons. The Cerium oxide nanoparticles against endogenousnitric dioxide or endogenous peroxynitrite. This is possible via mitochondrial toxins or excess glutamate or A.beta.eta.peptide. The rare earth nanoparticles offer protection against neurodegeneration. They also have lower levels protein tyrosine as well as fewer reactive nitrogenspecies. A new discovery that cerium oxide nanoparticles are utilized to reduce the levels of peroxynitrite to stop neurodegeneration was discovered.
Cerium oxide nanoparticles exhibit low toxicity (18, 19). It was discovered that their ability to change between the 3.sup.+ and 4.sup.+ state of oxidation gives CeO.sub.2 nanoparticles an unique antioxidant role.
CeO.sub.2 NPs have been shown to protect several cell types and animal models against ROS mediated illnesses (20). Nanoparticles generally exhibit unique features on their surfaces that may alter their chemistry as well as their interaction with biological systems. CeO.sub.2NPs possess a crystal structure and are made up of reactive sites. CeO.sub.2NPs can interchange between the 3.sup.+ and 4.sup.+ states of the oxidation process (21). It’s difficult to control the relative levels of vacancies and reactive sites, but CeO.sub.2 has been able to create NPs that are able to switch between the3.sup.+ and 4.sup.+ state of oxidation (21). It should be noted that CeO.sub.2 NPNs with lower3.sup.+/4.sup.+ ratio exhibit higher catalase mimetic activity (23). CeO.sub.2NPs have been demonstrated to be neuroprotective in variety of neuronal culture models (24-25). Recent studies in vivo confirm the antioxidant properties of CeO.sub.2 NPs, which have low toxicity to the brain in rodent models (27 28). The capability of CeO.sub.2 NPs to react with ONOO.sup.In vitro as well as an evaluation of the neuroprotective properties of CeO.sub.2 NPs during the nitrosative stress process is described herein. Also provided hereinis a demonstration that certain CeO.sub.2 NPs protect against A.beta.-induced DRP1 5616 hyperphosphorylation, mitochondrial fragmentation and neuronal cell death
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The first step in getting your patent is to do an internet search for patents. You can do a google patent search or do a USPTO search. After the patent application has been filed, the item subject to the patent can be referred to as patent-pending and you can find the patent application online on the public pair. Once the patent office approves the application, you will be able to do a patent number search to find the issued patent. Your product will now be patented. You can also utilize the USPTO search engine. Read on for more details. Patent lawyers or a patent attorney can advise you on the procedure. Patents granted in the United States are granted by the US trademark and patent office as well as the United States patent office. This office also reviews trademark applications.
Are you interested in finding similar patents? These are the steps to follow:
1. Brainstorm terms that describe your invention, based on the purpose, composition and application.
Start by writing down a succinct detailed description of your idea. Don’t use generic terms like “device”, “process” or “system”. Instead, consider synonyms to the terms you initially chose. Next, note important technical terms and key words.
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- What is the basis of the invention? What is the invention’s physical composition?
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- What are the technical terms and phrases that define the characteristics of an invention? A technical dictionary can help you locate the right terms.
2. Use these terms to search for pertinent Cooperative Patent Classifications for your invention at the Classification Text Search Tool. If you’re not able to locate the appropriate classification to describe your invention, go through the classification’s Schemas of classes (class schedules). If you don’t get any results using the Classification Text Search, you might consider substituting your words to describe your invention with synonyms.
3. Check the CPC Classification Definition for confirmation of the CPC classification you’ve found. If the chosen classification includes a blue square with the letter “D” on its left, the hyperlink will direct you to the CPC classification’s description. CPC classification definitions will help identify the specific classification’s scope and therefore you’re sure to select the most relevant. They may also provide research tips or other suggestions that could be helpful for further study.
4. The Patents Full-Text Database and the Image Database allow you to search for patent documents that have the CPC classification. By focusing on the abstracts and drawings that are representative it is possible to narrow your search to the relevant patent documents.
5. Take advantage of this list of most pertinent patent documents to study each one thoroughly for similarities to your invention. Be sure to read the specification and claims. Consult the applicant and patent examiner to obtain additional patents.
6. Retrieve published patent applications with the CPC classification you picked in Step 3 from the Applications Full-Text and Image Database. The same method of searching can be employed as Step 4. You can narrow your search results in order to locate the most relevant patent applications by reviewing the abstracts and representative drawings on each page. Next, examine the patent applications that have been published carefully, paying special attention to the claims as well as other drawings.
7. You can look up additional US patent publications by keyword searching in AppFT or PatFT databases, as well as the classification search of patents that are that aren’t from the United States as in the following table. You can also use web search engines to find non-patent documents that describe inventions in the literature. Examples:
- Add keywords to your search. Keyword searches may turn up documents that are not well-categorized or have missed classifications during Step 2. For example, US patent examiners often supplement their classification searches with keyword searches. Think about the use of technical engineering terminology rather than everyday words.
- Search for foreign patents using the CPC classification. Then, re-run the search using international patent office search engines such as Espacenet, the European Patent Office’s worldwide patent publication database of over 130 million patent publications. Other national databases include:
- European Patent Office (EPO) provides esp@cenet to access a network of Europe’s patent databases with access to machine translation of European patents.
- Japan Patent Office (JPO) – with access to machine translations of Japanese patents.
- World Intellectual Property Organization (WIPO) offers PATENTSCOPE with a full-text search of published international patent applications and machine translations for some documents, as well as a list of international patent databases.
- Korean Intellectual Property Rights Information Service (KIPRIS)
- State Intellectual Property Office (SIPO) with machine translation of Chinese patents.
- Other International Intellectual Property Offices with online patent databases include Australia, Canada, Denmark, Finland, France, Germany, Great Britain, India, Israel, Netherlands, Norway, Sweden, Switzerland, and Taiwan.
- Search non-patent literature. Inventions can be made public in many non-patent publications. It is recommended that you search journals, books, websites, technical catalogs, conference proceedings, and other print and electronic publications.
To review your search, you can hire a registered patent attorney to assist. A preliminary search will help one better prepare to talk about their invention and other related inventions with a professional patent attorney. In addition, the attorney will not spend too much time or money on patenting basics.