Verschiedenes » Inflammasom

Das Thema wurde ja bereits im Zusammenhang mit Krebs diskutiert. Gestern kam dies hier über
fight aging:

https://journal-inflammation.biomedcentr...2950-018-0198-3

https://www.fightaging.org/archives/2018...asome-in-aging/

Vll sollte man es doch nochmals aufgreifen, da es sicher micht nur im Zusammenhang
mit Krebs interessant ist. Wichtig bleibt natürlich immer, wie man es bekämpfen kann
bzw. welcher Level positiv ist.

Naja, letztlich nicht wirklich Neues. Das Leben besteht aus Entzündungen, bei allem was wir tun. Die vielleicht etwas weniger risikoreich sind (wenn man bewußter lebt und sich ernährt als in der verschwenderischen Jugend) und dennoch wird die Gefahr offensichtlich im Laufe des Lebens unaufhaltsam größer. Das kann ja nur bedeuten, daß das Immunsystem schwächer wird. Wie auch immer, ein ewiger Kreislauf und Kampf des Körpers, insb. des Immunsystems gegen Entzündungen, die letztlich jede Art der Ernährung und wenn man das Thema freie Radikale etc. miteinbezieht, auch jeder Atemzug verursacht. Also kein ausgewogenes, selbstregulierendes und (lang) lebenserhaltendes System, sondern ein ewiger Kampf der Biochemie und der Genetik, der in vielfacher Hinsicht "programmiert" ist. Verzögern ist sicher immer drin, mit den bekannten Faktoren, aber Lebensfreude und auch Zufall, Glück, Pech spielen da eine große Rolle. wie man nicht nur am Thema Krebs in den letzten Studien gesehen hat.

Wie auch immer, ein Kampf also, den wir schlußendlich verlieren werden und müssen. Ob man da ein paar Jahre "rausholt" oder nicht ist für die Natur völlig bedeutungslos. Ob der Kettenraucher und der Alkoholiker 100 Jahre werden und der Gesundheitsapostel und Veganer nicht, das interessiert die Natur nicht nur nicht, sondern das ist reine Statistik. Da wird gewürfelt und gestaunt, wird getrauert und gejubelt.

Ganz offensichtlich ist weder von der Evolution noch von Gott vorgesehen worden, das sich nun ausgerechnet unsere Spezies langes oder unendliches Leben einverleibt. Und wenn man den Planeten Erde und den Menschen so ansieht, ist das wiederum von der Natur (Gott) genial ausgedacht.

Für mich haben die schon seit dem es Menschen gibt ewig gleichen Gedanken, Ängste, Hoffnungen und Sorgen (mindestens seit Römern und Griechen haben sich die Menschen sehr intensiv und auch philosophisch zum Thema A-A im weitesten Sinne ernsthaft Gedanken gemacht) mit den Stoikern eine akzeptable Lösung gefunden. Es ist wie es ist, es kommt wie es kommt. Das sagt alles und sehr viel. Damit kann zumindest ich gut leben und auch dem Thema A-A sehr entspannt und neugierig entgegenblicken.

Übrigens, die Natur! Das beruhigt mich schon wieder!

Mit zunehmenden Alter wurde er jedoch ruhiger. Zuletzt litt er an Arthritis und sah auch nicht mehr so gut.

https://www.faz.net/aktuell/gesellschaft...r-15934125.html

Das mag ja so philosophisch betrachtet so stimmen, hilft aber konkret leider nicht weiter. Es geht um ansteigende Entzündungslevel
und zwar durch Aktivierung des innaten Immunsystems. Dies wird über bestimmte Botenstoffe aktiviert, wie sie u.a. von
senescenten Zellen ausgehen. Man kann etwas dagegen tun, wenn man den Mechanismus versteht. Insbesondere auch, wie genau der
Schaden entsteht. Offenbar geht es mal wieder um die Mitochondrien. Ich habs noch nicht genau verstanden, aber ich werde nochmals darauf zurückkommen.

Ob es die Natur interessiert, ist mir egal. Dass wir Autos bauen, interessiert die Natur auch nicht. Ebenso wenig, ob wir uns mit
dem Inflammation beschäftigen. Ich denke aber, es hat sich kein überirdischer Ingenieur ausgedacht.

"Gottes Werk und Teufels Beitrag ... "

Die Frage ist doch nicht, ob es etwas gibt, was bestimmte Dinge theoretisch bremsen oder im A-A-Sinne bewirken könnte, sondern wie das dann in der Praxis und Realität aussieht.

Ich bin jedenfalls sehr gespannt, ob die ganzen noch lebenden A-A und Ewig-Leben-Gurus wie Aubrey & Co., die alles wissen und alles machen können/könnten auch langlebig Methusalems werden oder ob eben doch alle ehrenwerte Theorie grau bleibt. Gerade weil sich die Natur einen Sch... darum schwert, was unzweifelhaft kluge Menschen sich ausdenken, um Gevatter Tod auszutricksen. Schaun wir mal.

Contribution of the inflammasome to inflammaging
Inflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer’s disease and Parkinson’s disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins.
https://link.springer.com/article/10.1186/s12950-018-0198-3


Immunology of Aging
https://www.frontiersin.org/research-top...nology-of-aging

Zitat von La_Croix im Beitrag #7

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Contribution of the inflammasome to inflammaging
Inflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer’s disease and Parkinson’s disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins.
https://link.springer.com/article/10.1186/s12950-018-0198-3


Immunology of Aging
https://www.frontiersin.org/research-top...nology-of-aging

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Researchers take a leap forward for new anti-inflammatory drugs
Treatments for chronic inflammatory diseases are one step closer as a new study discovers a way to stop inflammation in its tracks.

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Associate Professor Schroder said the team’s exciting discovery gave new insight into how to stop inflammation at the molecular level: “We previously identified a small molecule, MCC950, that inhibits the inflammasome to block inflammation in disease but, until now, we did not understand how it worked,” she said. “We discovered that MCC950 binds directly to the inflammasome and inactivates it, turning off inflammation.

“Now that we understand how a small molecule can inhibit the inflammasome, we are very excited about the potential of inflammasome inhibitors as anti-inflammatory drugs.”

Professor Robertson added: “We are keen to see results of these trials and hope that our discovery can lead to the efficient design of new molecules as anti-inflammatory drugs of the future.”

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https://www.drugtargetreview.com/news/43...searchers-leap/
https://medicalxpress.com/news/2019-05-i...tory-drugs.html

Die Wirkung die das Molekül MCC950 auf den Körper, durch Inhibierung von NLRP3 hat, scheint ja geradezu fantastisch zu sein.
Schade nur, dass MCC950 Entzündung nur blockiert, aber nicht pro-Resolutorisch zu wirken scheint.

Siehe auch:
Was schützt vor Alzheimer und Demenz im Alter? (12)

http://inflammasomelab.com/

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The molecule, MCC950, was produced by Pfizer two decades ago as a possible treatment for arthritis.
However, the company discontinued its efforts to bring the drug to market, and the intellectual property rights on it subsequently lapsed.
Around eight years ago, scientists at Trinity's Biomedical Sciences Institute led by Professor of Biochemistry Luke O'Neill came across the compound and began to explore its potential uses.

They subsequently discovered that it could effectively block the NLRP3 inflammasome.
Inflammasomes are a complex of molecules that trigger inflammation when exposed to infection or stress.
They have been identified as promising therapeutic targets for researchers in recent years.
The NLRP3 inflammasome has been found to be a common activator of a key process in certain inflammatory diseases.
The discovery by the research team, details of which are published in the journal Nature Medicine, confirms that all inflammatory diseases share a common process, although the part of the body which experiences the inflammation might differ.

The scientists subsequently carried out trials on mice and found that the molecule stopped the progression of multiple sclerosis and sepsis.
They also carried out testing on samples taken from humans with Muckle-Wells syndrome, a rare auto-inflammatory disorder, and discovered it was equally effective.
The scientists also say that it is likely the drug could produce fewer common side-effects, such as susceptibility to infection, than other anti-inflammatory drugs, and could prove cheaper and capable of being administered orally.
The next stage will involve testing the compound on humans and a wider group of diseases.

The researchers say for certain conditions, like Muckle-Wells syndrome and asthma, such trials could take place as early as two to three years from now, as the drug had already undergone some human testing by Pfizer.
However, even if the trials prove the drug is safe and effective, they stress that it could be ten-15 years before it could be fully approved for use in humans for the treatment of more complex diseases like multiple sclerosis or Alzheimer's.

They also stress that while the molecule could become an effective treatment, it will not be a cure, though it is possible it could be effective in undoing some of the damage done by well progressed cases of certain diseases.
Prof O'Neill and his team now plan to form a company to further develop and test the compound.
MCC950 is also currently being tested on mice in the US for anti-ageing properties, as there is a growing school of thought that inflammation is responsible for much of the ageing process - a theory which has come to be known as "inflammaging".

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https://www.rte.ie/news/2015/0216/680672...ses-scientists/

Inhibiting the Inflammasome: A Chemical Perspective

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Inflammasomes are high molecular weight complexes that sense and react to injury and infection. Their activation induces caspase-1 activation and release of interleukin-1β, a pro-inflammatory cytokine involved in both acute and chronic inflammatory responses. There is increasing evidence that inflammasomes, particularly the NLRP3 inflammasome, act as guardians against noninfectious material. Inappropriate activation of the NLRP3 inflammasome contributes to the progression of many noncommunicable diseases such as gout, type II diabetes, and Alzheimer’s disease. Inhibiting the inflammasome may significantly reduce damaging inflammation and is therefore regarded as a therapeutic target. Currently approved inhibitors of interleukin-1β are rilonacept, canakinumab, and anakinra. However, these proteins do not possess ideal pharmacokinetic properties and are unlikely to easily cross the blood–brain barrier. Because inflammation can contribute to neurological disorders, this review focuses on the development of small-molecule inhibitors of the NLRP3 inflammasome.

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https://pubs.acs.org/doi/abs/10.1021/acs...rnalCode=jmcmar


Parkinson’s Disease Drug That Cools “Brains on Fire” Could Enter Human Trials in 2020

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Researchers at the University of Queensland in Australia have identified a small molecule that can stop the progression of Parkinson’s disease (PD) and improve motor function in multiple mouse models. The team says human trials with an optimized compound could start within the next couple of years.

The prototype molecule, MCC950, blocks an immune system target, the NLRP3 inflammasome, which the researchers’ investigations showed is activated in the brains of PD patients and animal models. These studies, reported in Science Translational Medicine, indicated that chronic NLRP3 activation may be a key mechanism that drives the pathology of PD and dopaminergic neurodegeneration.

“We found a key immune system target, called the NLRP3 inflammasome, lights up in Parkinson’s patients, with signals found in the brain and even in the blood,” says research lead Trent Woodruff, Ph.D., an associate professor at the University of Queensland faculty of medicine. Referring to studies in mice he adds, “MCC950, given orally once a day, blocked NLRP3 activation in the brain and prevented the loss of brain cells, resulting in markedly improved motor function.”

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https://www.genengnews.com/news/parkinso...trials-in-2020/



NLRP3 Inflammasome Inhibition by MCC950 Reduces Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice—Brief Report

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Objective—
Inflammasomes are multiprotein complexes, and their activation has been associated with cardiovascular disease. Inflammasome activation leads to secretion of caspase-1 by innate immune cells, resulting in the activation of interleukin-1β. Recently, a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, was described. In this study, we investigated the effect of MCC950 on atherosclerotic lesion development in apoE−/− mice.

Approach and Results—
First, we determined the efficacy of MCC950 in vitro. Bone marrow–derived macrophages and dendritic cells were stimulated with lipopolysaccharide and cholesterol crystals resulting in high levels of interleukin-1β release, which was inhibited by MCC950. In vivo MCC950 treatment reduced lipopolysaccharide–induced interleukin-1β secretion, without affecting the tumor necrosis factor-α response. Subsequently, atherosclerotic plaques were induced in Western-type diet fed apoE−/− mice by semiconstrictive perivascular collar placement at the carotid arteries, after which the mice received MCC950 (10 mg/kg) or vehicle control 3× per week intraperitoneally for 4 weeks. After euthanize, atherosclerotic plaque size and volume were quantified in hematoxylin-eosin–stained 10-µm cryosections throughout the artery. MCC950 treatment significantly reduced the development of atherosclerotic lesions as determined by maximal stenosis, average plaque size, and plaque volume. Although the amount of collagen and the necrotic core size were not affected, the number of macrophages in the plaque was significantly reduced on treatment. In addition, VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) mRNA expression was significantly reduced in the carotids of MCC950-treated mice.

Conclusions—
These findings show that specific inhibition of the NLRP3 inflammasome using MCC950 can be a promising therapeutic approach to inhibit atherosclerotic lesion development.

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https://www.ahajournals.org/doi/full/10....baha.117.309575




Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension.

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AIMS:
Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension.

METHODS AND RESULTS:
C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25-40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na+], and albuminuria (each by 20-25%). None of the above parameters were altered by MCC950 in normotensive mice.

CONCLUSION:
MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.

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https://www.ncbi.nlm.nih.gov/pubmed/30357309





NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia.
https://www.ncbi.nlm.nih.gov/pubmed/30818045





MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice
https://www.nature.com/articles/s41598-018-26775-w

Vor wenigen Tagen, wurde veröffentlicht, wie genau MCC950 wirkt.

MCC950/CRID3 potently targets the NACHT domain of wildtype NLRP3 but not disease-associated mutants for inflammasome inhibition
https://www.biorxiv.org/content/10.1101/634493v1?rss=1



MCC950 closes the active conformation of NLRP3 to an inactive state
https://www.nature.com/articles/s41589-019-0278-6

3 neuere Artikel rund um Nlrp3. Beschreibung später.


https://pubmed.ncbi.nlm.nih.gov/34082381/

https://www.hindawi.com/journals/bmri/2021/7729238/


https://pubmed.ncbi.nlm.nih.gov/34992411/

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

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Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation—including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity—antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.

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