Pretty awesome Ohm. A lot of what your talking about here may be why leronlimab 700 HM did so well in reducing Fat.
Leronlimab 700 HM achieved 27.88% fat reduction in PDFF. That is equivalent to the loss of 2 stages in NAS classification which ranges from 0-8.
So when ever microbes or Interferon Gamma are stimulating the Macrophage, the Macrophage will be Activated in the "Classical" Pathway. and remember, Interferon Gamma comes from T helper1 cell. Interferon Gamma and the microbes deactivate the Alternative Pathway. When the Macrophage is Activated in the Classical Pathway, that results in the formation of ROS, Reactive Oxygen Species. Nitric Oxide. Lysosomal Enzymes, All of this has a microbiocidal effect. The classical pathway is called M1. At the same time, M1 will produce a lot of Interleukins. IL-1; IL-12; IL-23 all leading to inflammation.
So what will happen when the Macrophages are Activated in the Alternative Pathway? Here the Macrophage needs to be induced by IL-4 and / or IL-13. which are coming from T helper 2 cells. And IL-4 and IL-13 deactivates the Classical Pathway. When the macrophage enters the M-2 Alternative Pathway for activation, it results in the liberation of a lot of growth factors, and Transforming Growth Factor Beta is one of the major growth factors among them. And that results in Repair and Fibrosis. So at the same time, there will be liberation of Interleukin 10 which will have ANTI-INFLAMMATORY effects.
Initially the Macrophages are involved in microbiocidal action M1, and during that time they are activated by interferon gamma and microorganism. So they are causing destruction. And the later half, when, we need to repair & fibrose, the Classical Pathway is no longer active and the Macrophages become activated through IL-4 and IL-13 to go to the Alternative Pathway, where they, as a matter of fact, prevent inflammation, and induce repair and fibrosis.
In NAFLD, the problem is in the mitochondrion and they take the glucose and convert it to lipids. They are creating fat instead of energy and they store that fat within the hepatocyte.
So you have written that IL-13 is decreased by CCR5 blockade leading to protection of mitochondria. That would mean that with strong CCR5 blockade, you would decrease IL-13 and improve mitochondrial function and reduce fat production and improve PDFF.
Giving 700 normal we know, did not have a positive effect on cT1. (But that was improper dosing). So IL-13 was reduced and the 700 normal patients were in M1 pathway and their PDFF was improved 3.75 vs 9.85 placebo. Not great, but ok. Looking at HM group, with more CCR5 receptors and 700 HM dosing, better dosed, we achieved 28% reduction PDFF. Here, it would make a ton of sense that the system was in M1 pathway and IL-13 was reduced and mitochondrion was working well reducing production of lipids.
Would you say we have made that connection between CCR5 blockade, IL-13, a1-antitrypsin and mediation of a variety of diseases?
Leronlimab 700 HM achieved 27.88% fat reduction in PDFF. That is equivalent to the loss of 2 stages in NAS classification which ranges from 0-8.
So when ever microbes or Interferon Gamma are stimulating the Macrophage, the Macrophage will be Activated in the "Classical" Pathway. and remember, Interferon Gamma comes from T helper1 cell. Interferon Gamma and the microbes deactivate the Alternative Pathway. When the Macrophage is Activated in the Classical Pathway, that results in the formation of ROS, Reactive Oxygen Species. Nitric Oxide. Lysosomal Enzymes, All of this has a microbiocidal effect. The classical pathway is called M1. At the same time, M1 will produce a lot of Interleukins. IL-1; IL-12; IL-23 all leading to inflammation.
So what will happen when the Macrophages are Activated in the Alternative Pathway? Here the Macrophage needs to be induced by IL-4 and / or IL-13. which are coming from T helper 2 cells. And IL-4 and IL-13 deactivates the Classical Pathway. When the macrophage enters the M-2 Alternative Pathway for activation, it results in the liberation of a lot of growth factors, and Transforming Growth Factor Beta is one of the major growth factors among them. And that results in Repair and Fibrosis. So at the same time, there will be liberation of Interleukin 10 which will have ANTI-INFLAMMATORY effects.
Initially the Macrophages are involved in microbiocidal action M1, and during that time they are activated by interferon gamma and microorganism. So they are causing destruction. And the later half, when, we need to repair & fibrose, the Classical Pathway is no longer active and the Macrophages become activated through IL-4 and IL-13 to go to the Alternative Pathway, where they, as a matter of fact, prevent inflammation, and induce repair and fibrosis.
Quote:A possible explanation - Mitochondria are powerplants within cells that are essential in the conversion of glucose to energy. Excessive damage to mitochondria means less efficient usage of glucose and more storage to fat. a1-antitrypsin is protective of mitochondria.
IL-13 is increased in inflammatory states. IL-13 can significantly decrease amounts of a1-antitrypsin. CCR5 blockade downregulates IL-13 leading to an increase in a1-antitrypsin and protection of mitochondria.
I originally ran into a1-antitrypsin while looking at Covid caused mitochondria damage. What's interesting is that low levels of a1-antitrypsin are also implicated in liver disease and pulmonary inflammation. No one seems to have made the connection between CCR5 blockade, IL-13, a1-antitrypsin and mediation of a variety of diseases.
In NAFLD, the problem is in the mitochondrion and they take the glucose and convert it to lipids. They are creating fat instead of energy and they store that fat within the hepatocyte.
So you have written that IL-13 is decreased by CCR5 blockade leading to protection of mitochondria. That would mean that with strong CCR5 blockade, you would decrease IL-13 and improve mitochondrial function and reduce fat production and improve PDFF.
Giving 700 normal we know, did not have a positive effect on cT1. (But that was improper dosing). So IL-13 was reduced and the 700 normal patients were in M1 pathway and their PDFF was improved 3.75 vs 9.85 placebo. Not great, but ok. Looking at HM group, with more CCR5 receptors and 700 HM dosing, better dosed, we achieved 28% reduction PDFF. Here, it would make a ton of sense that the system was in M1 pathway and IL-13 was reduced and mitochondrion was working well reducing production of lipids.
Would you say we have made that connection between CCR5 blockade, IL-13, a1-antitrypsin and mediation of a variety of diseases?
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