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ES ROTTLERIN
Rottlerin is a natural chemical compound from the polyketide group that comes from the fruits and hairs of the Mallotus philippinensis plant, also known as kamala. It has numerous health-promoting properties for the human body. As a powerful antioxidant and inhibitor of certain cell functions, rottlerin has been extensively studied for its potential to improve various aspects of human health.
There are over 1,100 scientific studies on this molecule, conducted both in vitro and in vivo. [ 1] Due to its previously inefficient extraction technology, obtaining rottlerin for human studies and at high doses has been a very expensive process, although it has been proven its range of pharmacokinetic properties (in vitro studies) and high bioavailability. According to tests from 2021, rottlerin has properties similar to drugs - it has a long action time (half-life) exceeding 2 hours and good oral absorption (over 35%), which is better than many other natural phenolic compounds. [ 2] In 2012 The New York Academy of Sciences emphasized that rottlerin is an underestimated molecule that may prove to be a promising drug in the fight against many diseases. human. [ 3] Only the recently discovered efficient method of its extraction in the form of high absorption by the human body allowed the introduction of rottlerin to tests on humans.
PROTECTIVE PROPERTIES AGAINST CANCER
One of the best-known benefits of rottlerin is its anti-cancer properties.
As the summary of one study emphasizes: “Because cancers are caused by deregulation of hundreds of genes, an ideal anticancer agent should target multiple gene products or signaling pathways simultaneously. (…) Rottlerin appears to have great potentiality for being used in chemotherapy because it affects several cell machinery involved in survival, apoptosis, autophagy, and invasion.” [ 4]
Rottlerin was originally considered an inhibitor of protein kinase C delta (PKCδ), which plays a key role in many cellular processes, such as regulation of cell growth, differentiation, stress responses, apoptosis, and inflammatory processes. However, it has been discovered that rottlerin can affect a number of different molecules and induce biological effects in various cell types [ 5], which is why it is being considered as a potential drug for the treatment of cancer and diseases related to cell proliferation.
ROTTLERIN - MULTIDIRECTIONAL ACTION
Rottlerin acts in many directions, not only activating known processes that destroy cancer cells, but also disrupting key protein synthesis mechanisms and blocking important molecules, which makes it more effective in the fight against cancer. It can bind directly to key molecules such as ERK and mTOR and block them. These molecules in tumors are often overactive, allowing cancer cells to grow, divide and avoid death rapidly. Importantly, rottlerin blocks them without the participation of other mechanisms that are "higher in the hierarchy" of cell signaling, i.e. it does not affect other elements that normally initiate their activation. [ 6]
Rottlerin also inhibits the activity at the molecular level of AQP3, a key protein in the process of carcinogenesis and metastasis, which is responsible for the transport of water and glycerol in the body. This makes it a promising candidate for the therapy of cancers in which AQP3 is overexpressed. [ 7]
Other studies have shown that Rottlerin helps cancer cells "turn on" the self-destruct mechanism by increasing the level of the DR5 (Death Receptor 5) protein, which is key in this process. Also in combination with TRAIL (a protein that naturally occurs in the body and helps fight cancer by causing programmed death), rottlerin may be a new, effective treatment for cancer that attacks only diseased cells, sparing healthy ones. [ 8]
ANGIOGENESIS IS ALSO A KEY PROCESS IN CANCER DEVELOPMENT
Cancers need new blood vessels to grow and spread throughout the body, delivering oxygen and nutrients to cancer cells. Inhibiting angiogenesis may be used as a cancer treatment strategy because it limits the supply of nutrients necessary for cancer growth.
The study results suggest that rottlerin may be useful in the development of new therapies that inhibit angiogenesis. Such therapies could be useful in the treatment of cancers in which angiogenesis supports tumor growth and spread. [ 9]
TESTS
Numerous studies have shown that rottlerin can inhibit cell growth in various types of cancer, including those that are very difficult to cure. [ 10]
The list below lists just some of the many documented studies:
- lung cancer [ 22]
- pituitary adenoma [ 28]
- sarcoma and lymphoma [ 29]
- human fibrosarcoma [ 30]
- stomach cancer [ 33]
- colon cancer [ 38]
- hepatocellular carcinoma [ 39]
- adrenal cortex cancer [ 40]
- nasopharyngeal cancer [ 41]
Additionally, rottlerin has also proven effective in overcoming resistance to the drug Rituximab, in this case, used in the treatment of lymphoma. [ 46]
Rottlerin has also been documented to be effective against another brain tumor, neuroblastoma. [ 47]
ANTI-INFLAMMATORY EFFECT
In addition to its anti-cancer properties, rottlerin has also been shown to have significant anti-inflammatory effects. Inflammation is the body's natural response to injury or infection, but chronic inflammation can lead to a variety of health problems.
Rottlerin has been found to have a strong effect in helping to reduce these conditions.
Studies emphasize that Mallotus fruit extract is a potential natural source of antioxidants that have a protective effect on human erythrocytes showing minimal hemolytic activity, which justifies its use in folk medicine. [ 48] [ 49]
ANTIMICROBIAL PROPERTIES
Rottlerin also has strong antimicrobial properties, making it a valuable tool in the fight against infections. Below is a list of just some types of bacteria, viruses, parasites and fungi that can cause many diseases in humans and animals and which Rottlerin helps combat.
This molecule has potential as a new drug against fungal infections caused by the Candida fungus. It is effective in inhibiting the growth of fungi, destroying their biofilms and reducing their ability to attack the body, and at the same time it is safe in tests on living organisms. This discovery may help develop new treatments for fungal infections. [ 50]
ROTTLERINE - HELPS FIGHT INFECTIONS
Rottleryna has potential as a new drug in the prevention and treatment of congenital toxoplasmosis (Toxoplasma gondii). It acts on both the parasite and host cells, limiting infection and supporting the body's defense mechanisms.
Most importantly, it has low toxicity, which makes it a promising therapeutic option for pregnant women and their children. [ 51]
Another study showed that rottlerin helps fight Toxoplasmosa gondii infection in two ways: indirectly, by increasing host cell autophagy (the process by which cells cleanse themselves of unnecessary or damaged elements) and directly, by blocking protein synthesis processes that are necessary for the parasite's multiplication. [ 52]
On a similar principle of increasing autophagy, it was discovered that rottlerin also has greater potential in the treatment of onchocerciasis and lymphatic Filariasis (tropical diseases caused by nematodes) than existing drugs to which the human body has either become resistant or their effectiveness was low. [ 53]
RABIES VIRUS
The rabies virus is a virus that attacks the nervous system and causes fatal encephalitis in humans and animals. It kills approximately 59,000 people worldwide each year.
Currently, only preventive (pre-infection) or post-exposure vaccines are available, but there are no drugs that can treat rabies once symptoms appear. Rottlerin turns out to be a promising solution because it inhibits the transcription process, i.e. the production of the virus's genetic material, which prevents its replication (multiplication).
It likely works by lowering levels of ATP (an energy-providing molecule in cells), which disrupts the processes necessary for virus reproduction. [ 54]
BABESIOSIS
Babesiosis, babesiosis, piroplasmosis (Latin: babesiosis) - a parasitic disease of animals (rarely in humans) caused by intraerythrocytic protozoa of the genus Babesia transmitted to the host by ticks.
The study shows that natural compounds such as rottlerin may be a source of new drugs against babesiosis, especially in the context of strains resistant to current therapies.
Rottlerin and lasalocidic acid can completely prevent parasite regrowth when used in appropriate doses. [ 55]
ROTTLERIN INHIBITS THE GROWTH OF CHLAMYDIA
Another study showed inhibition of the growth of Chlamydia trachomatis - a bacterium that causes infections of the urogenital system and eyes. The researchers wanted to check whether rottlerin inhibits the growth of chlamydia by affecting the PRAK (p38-regulated/activated protein kinase) protein - a kinase protein that is activated in cells infected with Chlamydia trachomatis. This was the target of action of rottlerin known to science. It turned out that this molecule does not act on Chlamydia trachomatis through its effect on PRAK, but through other mechanisms, probably related to other host factors. This finding indicates the broad potential of rottlerin to inhibit bacterial infections, regardless of the activity of this particular protein [ 56].
Another study showed that rottlerin inhibited the growth of Chlamydia in cell culture at very low concentrations. It is effective even when added in the middle phase of the infection cycle, which means it can inhibit bacteria after they have entered the cells. Rottlerin is effective against a variety of Chlamydia species and is active in a variety of host cell types. When rottlerin was given before infection, it also prevented the growth of this bacterium. This indicates that rottlerin acts mainly by affecting host factors rather than directly acting on bacteria. Its operation includes, among others: by blocking the transport of sphingolipids (important fatty molecules) from the Golgi apparatus of host cells to "chlamydial inclusions" - special structures in which bacteria develop. This disrupts bacterial replication and prevents these structures from growing. To sum up, rottlerin is a promising compound with a novel mode of action that may help in the treatment of infections caused by Chlamydia, especially in the case of antibiotic-resistant strains. [ 57]
NEW THERAPY
Rottlerin has proven effective against Helicobacter pylori, the bacterium responsible for stomach ulcers, gastritis and an increased risk of stomach cancer.
It also worked on strains resistant to two commonly used antibiotics in H. pylori therapy.
This research may contribute to the creation of new therapies that will be more effective and help fight infections in patients who do not respond to standard treatment. [ 58]
ROTTLERIN - RESEARCH AND EXPERIMENTS
Other studies have identified rottlerin as a potential agent in the treatment of HIV type 1 infections. Rottlerin may be a promising molecule supporting standard antiretroviral therapy. It works by targeted inhibition of CD4+ T cell activation, which reduces HIV-1 replication and hinders the creation of new viral reservoirs. Additionally, rottlerin significantly inhibited the integration of HIV-1 genetic material into the host DNA. Thanks to this, it can help in more effective management of the infection at its early stage. [ 59]
The aim of the next experiments was to check whether inhibitors of kinase C (PKC), which are enzymes involved in many cellular processes, could reduce the replication of the SARS-CoV-2 virus. Rottlerin, known in the scientific world for being a PKCδ inhibitor, has proven effective in inhibiting viral infection. This study indicates that C-kinase inhibitors, and in particular the PKCδ inhibitor (i.e. rottlerin), may be a promising group of drugs in the treatment of SARS-CoV-2 infections because they inhibit the early stages of infection and viral replication. [ 60] In another study for this virus , scientists indicated rottlerin as a molecule that is an important ingredient for the development of drugs in the fight against the SARS-CoV-2 virus. [ 61]
The researchers also showed that rottlerin plays an antiviral role in the early and late stages of Zika virus infection through two different mechanisms: inhibiting the entry of the virus into cells and blocking its maturation after infection. This virus can cause serious brain damage in newborns, including microcephaly, as well as other neurological problems. These studies showed that the antiviral effect of rottlerin is not related to its effect on PKCδ or ATP, meaning that it acts through a different mechanism.
Rottlerin could be developed as a drug to prevent or treat Zika virus infection, especially in the context of the lack of effective treatments available for the virus. Research suggests that rottlerin has the potential to be developed as a prophylactic (preventing infections) and therapeutic (treatment of existing infections and alleviation of neurological symptoms) drug [ 62].
Another study shows how important it is to develop appropriate protocols that enable testing of new antiviral therapies, especially in the context of viruses that have the ability to infect the central nervous system and can lead to severe neurological damage. The use of such protocols allows for effective testing of the effectiveness of drugs such as rottlerin in inhibiting viruses and protecting neurons from damage. Methodology for testing therapeutic compounds that can inhibit viral replication in neurons or prevent virally induced neuronal cell death [ 63] is discussed, which is important in the context of viruses such as herpes simplex virus (HSV), West Nile virus (WNV), La Crosse virus ( LACV), Zika virus (ZIKV) and tick-borne encephalitis virus (TBEV). All of these viruses can enter the central nervous system, causing serious neurological diseases, including encephalitis, which can lead to death.
Other scientists have focused on the shikimate pathway, which is crucial to bacteria, fungi, plants and algae but is absent from higher eukaryotes (including mammals). The enzymes involved in this pathway are promising targets for the development of selective antibacterial drugs that will not be harmful to humans. Rottlerin was found to have an inhibitory effect on the enzyme Shikimate Kinase, a key element of the shikimate pathway in mycobacteria. It acted on both bacteria outside the cells and bacteria inside the cells. Rottlerin can be used to develop new antimycobacterial drugs. Humans are threatened by 25 species of mycobacteria, which, depending on the species, cause tuberculosis, mycobacteriosis or leprosy. [ 64]
CARDIOPROTECTIVE PROPERTIES
The title of one of the studies itself indicates that „Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation” [ 65], and another study suggests that “rottlerin-induced BKCa channel activation impairs specific contractile responses and promotes vasodilation” [ 66].
The investigators concluded that activation of BKCa channels (high conductance calcium-activated potassium channels) rescues ischemic damage associated with cardioplegic cardiac arrest (CP/R), possibly by improving mitochondrial membrane potential and reducing reactive oxygen species production. Rottlerin, at a concentration-dependent dose, improved cardiac function by restoring left ventricular pressure and coronary flow to near baseline values. The study provides evidence that mitochondrial BKCa channels are crucial in protecting the heart from ischemia-reperfusion-related injury, and rottlerin may be developed as a cardioprotective drug in such situations [ 67].
To quote yet another study: „AMP-activated protein kinase (AMPK) is a cellular energy sensor involved in multiple cell signaling pathways that has become an attractive therapeutic target for vascular diseases. (…) These data suggest for the first time that LKB1 mediates rottlerin-induced activation of AMPK in vascular cells and tissues.” [ 68] This means that rottlerin may be an effective therapeutic strategy in the treatment of vascular diseases such as atherosclerosis or hypertension.
Rottlerin (or its modified derivative) also has the potential to develop a drug correcting the QT interval in the case of long QT syndrome, i.e. a disorder of the electrical activity of the heart in which the repolarization of heart cells is prolonged, which increases the risk of dangerous arrhythmias and sudden cardiac arrest. This may be a breakthrough solution in the treatment of this type of channelopathy, improving the function of Kv7 channels transporting potassium ions (K+) and shortening cardiac repolarization, i.e. accelerating the process in which heart muscle cells (cardiomyocytes) return to their resting state after the end of contraction. [ 69]
DISEASES OF JOINTS, BONES AND CONNECTIVE TISSUE
Many studies indicate that rottlerin has great potential in the treatment of rheumatic diseases.
Citrullinated vimentin (CV) contributes to excessive osteoclast activity and bone destruction in periodontitis. CV is formed in osteoclast precursors and stimulates processes leading to bone destruction. CV inhibition (e.g. with neutralizing antibodies or inhibitors such as rottlerin) may limit these processes and represent a potential treatment for bone loss diseases such as periodontitis [ 70].
CCN4, a protein that is involved in intercellular communication and regulates various processes in tissues, causes an increase in VCAM-1 (a molecule that plays a key role in the attachment of white blood cells, monocytes, to inflamed synovial cells) in synovial fibroblasts in osteoarthritis by activating specific signaling pathways. VCAM-1, in turn, increases the ability of monocytes to attach to these cells, which may increase inflammation in the joints. Inhibiting this process (e.g. with inhibitors such as rottlerin) may be a potential way to treat inflammation in osteoarthritis (also known as osteoarthritis). [ 71]
ROTTLERIN MAY HAVE POTENTIAL APPLICATION IN REGULATING INFLAMMATORY PROCESSES
Another study focuses on how thrombin (a factor responsible for various processes such as inflammation and angiogenesis) affects the production of the enzyme heme oxygenase (HO-1) in synovial fibroblasts (cells in joints). The HO-1 enzyme helps protect cells from oxidative damage (e.g. caused by oxidative stress). Rottlerin reduces the production of HO-1. In the context of inflammatory diseases such as osteoarthritis, rottlerin may have potential applications in regulating inflammatory processes and protecting cells against oxidative stress [ 72].
Neutrophils are white blood cells that play a key role in defense against rapidly multiplying bacteria. They usually live for a very short time (24-48 hours) and quickly undergo apoptosis (the natural process of cell death). However, during inflammation, their lifespan may be extended thanks to the action of pro-inflammatory proteins (cytokines). When neutrophils live too long, they can cause chronic inflammation and tissue damage, which is a problem in diseases such as rheumatoid arthritis. Rottlerin shows significant therapeutic potential in the context of the study described. It works by inhibiting a key signaling pathway that is responsible for extending the lifespan of neutrophils, which is a central element of chronic inflammation in diseases such as rheumatoid arthritis. [ 73]
Keratinocyte hyperproliferation disorders are pathological conditions in which there is excessive and uncontrolled multiplication of keratinocytes, i.e. the main cells of the epidermis. Hyperproliferation of these cells leads to thickening of the epidermis, disturbances of its structure and function, and visible skin changes.
Rottlerin helped alleviate this disorder. [ 74]
It has also been discovered that rottlerin is an inhibitor of melanin production, which may be useful in the treatment of hyperpigmentation disorders of the skin, e.g. lentigines, melasma or discoloration. [ 75]
In vitro and in vivo studies showed that rottlerin alleviated the symptoms of psoriasis by inhibiting keratinocyte proliferation, inflammatory cell infiltration and angiogenesis. The study suggests that rottlerin may be a promising therapeutic substance in the treatment of psoriasis, but its mechanism of action requires further research. [ 76]
NEUROPROTECTIVE PROPERTIES
Science has shown that rottlerin may help protect brain cells from damage and improve cognitive function. Some research suggests that rottlerin may be beneficial in the treatment of various neurodegenerative diseases.
The research results indicate that chemical modifications of rottlerin may be tested in the future as a promising strategy for modulating the aggregation of amyloidogenic proteins and the disintegration of existing fibrils. This may be important for the treatment of neurodegenerative diseases such as Alzheimer's.
However, cytotoxicity studies on Neuro 2a cells showed that rottlerin at low concentrations (micromolar) effectively prevented the formation of amyloid fibers in the case of each of the tested proteins. The mechanism of action is that rottlerin blocks the formation of amyloids by binding to the protein regions responsible for this process. Rottlerin was able to break down already existing amyloid fibers. The strongest effect of inhibiting and disassembling fibers was observed in the case of the Aβ1-40 peptide, key in Alzheimer's disease. [ 77]
Another study showed that rottlerin increases the autophagic degradation of phosphorylated Tau in neuronal cells, which also suggests that this compound may be used as a preventive and therapeutic drug for Alzheimer's disease [ 78].
ROTTLERIN - RESEARCH AND EXPERIMENTS
Several studies have also confirmed that rottlerin has great potential in therapies fighting Parkinson's disease, thanks to its ability to inhibit the activity of protein kinase C delta (PKCδ). As a result, it reduced the loss of nerve cells caused by the MPP+ toxin (a substance that mimics brain damage in Parkinson's). In mouse studies, rottlerin protected dopamine-producing neurons in the substantia nigra, improved the mice's ability to move (preventing motor deficits typical of Parkinson's), and reduced the loss of dopamine and its metabolites in the brain. [ 79] [ 80]
Rottlerin may also alter the normal process of memory consolidation, making it difficult to properly remember and recall information related to avoiding unpleasant situations. Increasing the level of brain-derived neurotrophic factor by rottlerin may influence neuroplasticity in the context of memory, which in turn may interfere with memory related to negative experiences. Rottlerine, by influencing the level of brain-derived neurotrophic factor, may help in the treatment of disorders such as Post-Traumatic Stress Disorder (PTSD) by interfering with the consolidation of traumatic memories and supporting the process of "forgetting" these memories, which may support therapy aimed at treating trauma. [ 81]
Another study indicates that rottlerin may help reduce delayed nerve cell death (apoptosis) by promoting neurogenesis (the creation of new nerve cells) and inhibiting the process of apoptosis itself. As a result, rottlerin may promote repair processes in the brain, raising hopes for its use in the treatment of brain damage, memory problems and depression. [ 82]
OTHER THERAPEUTIC PROPERTIES
Rottlerin is a compound that can protect cells from a type of cell death (necrosis) by reducing harmful reactive oxygen species. It helps protect cells against necrosis by blocking the protein that causes it. Necrosis is an uncontrolled process in which the cell bursts, releasing its contents into the environment, which causes inflammation. [ 83] Diseases associated with it include, for example, myocardial infarction (heart attack), stroke, acute pancreatitis, liver cirrhosis, fasciitis or damage after restoring blood flow.
Scientists conducted research on primary open-angle glaucoma, which is the leading cause of irreversible vision loss worldwide. Experiments have confirmed that rottlerin improves glaucoma-related features in in vitro studies (in laboratory conditions) and reduces high intraocular pressure and actin/extracellular matrix accumulation in in vivo studies (in animal models), without causing adverse effects. [ 84]
Rottlerin has also been tested in various animal models to assess its potential antihistamine effects. Rottlerin prevented typical allergic symptoms such as vasodilation, decreased body temperature, increased blood histamine levels, and mast cell degranulation in various experiments, such as cutaneous and systemic anaphylaxis. Additionally, rottlerin reduced bronchospasm, suggesting its effect in diseases such as allergic asthma [ 85].
POTENTIAL SIDE EFFECTS
Despite the numerous positive effects of rottlerin, several studies have appeared in the world of science suggesting that rottlerin may not be beneficial to health in some cases.
One study showed that rottlerin reduces energy levels in fat cells by affecting mitochondria (energy-producing structures), which play an important role in glucose and fat metabolism, and their dysfunction is one of the factors associated with the development of type 2 diabetes. Rottlerin, through reducing the availability of glucose in fat cells may deepen problems related to insulin resistance because it reduces its transport into cells. In this sense, although rottlerin affects insulin mechanisms, its effect does not seem to be beneficial in the fight against diabetes because it inhibits glucose transport, which may lead to further disruption of glucose metabolism. [ 86]
On the other hand, research on type 2 diabetes has shown that in some cases, controlling glucose transport can have a beneficial effect, especially when the mechanism of insulin resistance is related to excessive glucose uptake into fat cells. In this case, inhibiting this process could reduce cell load and improve insulin sensitivity in other tissues [ 87].
Other scientists tested whether rottlerin inhibited the activity of protein kinase PKCδ, an enzyme that regulates the translocation of the glutamate transporter GLAST to the cell membrane of astrocytes (cells that support neurons in the brain). Rottlerin blocked the trafficking of GLAST to the plasma membrane, but probably did not do so by inhibiting PKC-delta, as previously thought. Glutamate transport depends on energy and the action of enzymes such as (Na+, K+)-ATPase. Rottlerin reduced the activity of this enzyme, which is necessary to maintain the ion balance in cells and the transport of glutamate. Rottlerin also interfered with energy production in the mitochondria (a process called oxidative phosphorylation), which led to a decrease in energy available to the cell. From these studies, it can be concluded that rottlerin may interfere with energy production and the work of the enzyme responsible for ion balance. This causes problems with the transport of glutamate, a substance that nerve cells must remove to avoid damage. [ 88]
PKC inhibitors, particularly those targeting PKCdelta such as rottlerin, also delay skin barrier regeneration because they interfere with the mechanisms that regulate calcium levels within epidermal cells. PKCdelta plays an important role in lowering intracellular calcium levels after loss of the extracellular calcium gradient. Inhibitors of this enzyme, such as rottlerin, which is applied topically to damaged skin, can interfere with the regeneration process, which can lead to delayed skin healing. It slows down the regeneration of the epidermal barrier, probably by interfering with the regulation of intracellular calcium levels [ 89].
SUMMARY
Rottlerin is a powerful natural compound that offers many benefits to human health. It has anti-inflammatory and anticancer properties, as well as a protective effect on the nervous and cardiovascular systems, which makes it a versatile agent with great therapeutic potential. With further research and development, rottlerin may be a valuable addition to the arsenal of treatments for a variety of conditions.
Rottlerin is a molecule that is present in the highest content available on the market in the MAKAMALA product by Magavena. [ 90]
It is a dietary supplement/bioattractor made from kamala fruit from special organic crops. Thanks to the proprietary extraction method, MAKAMALA contains this active molecule in high concentration and high bioavailability, which means that the body absorbs it very easily, assimilates it and transforms it into its active form.
Before consuming MAKAMALA, read the product leaflet. If there are numerous parasites and other microorganisms in our body, after consuming this molecule, nausea, pain and dizziness may occur. This is due to the secretion of toxins by parasites when they die and are excreted from the body. This is a temporary symptom and is not a side effect caused by the product, but a natural effect in the process of detoxification and excretion of toxins. Also, when consuming MAKAMALA by people suffering from type 2 diabetes, it is worth paying attention to the blood sugar level.
It is worth emphasizing that MAKAMALA is not a medicine. It is a dietary supplement/bioattractor that helps in the processes of self-healing, self-regulation of the body and restoring homeostasis.
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