UG Krishnamurti
Member
- Joined
- Sep 28, 2020
- Messages
- 556
When I am in inflamed state I always felt extremely worse if I drink milk for example. The symptoms I experience were intestinal bleeding (I have Crohn's), extreme scalp hardness, psoriasis getting worse, fatigue, cramping etc. Even just drinking plain mineral water higher in calcium created intestinal bleeding [I've experimented with it just a month ago]. Now, looking back I probably assume this type (or similar kind) of mechanism made me bleed after using D3 supplement [Bleeding again, now after D3 supplement - SUPER CONFUSED]
This is the study which would maybe explain some mechanisms behind it. Apparently, higher dietary Ca & Ca/P would be a bad thing to consume when you are in an inflamed state when/if macrophages are activated.
Ray have also said that when you are in an energy deprived state, calcium will end up going inside the cell.
But I've never heard him saying to be careful with it. In some of my email exchange between us he never considered calcium could be a problem, or recommend caution.
Macrophage-Derived Matrix Vesicles
We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease and mineral imbalance accelerate calcification and the subsequent release of matrix vesicles (MVs), precursors of microcalcification.
Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and annexin V, which contribute to accelerated microcalcification in chronic renal disease.
Mouse macrophages stimulated with Ca/P possessed higher levels of mRNA encoding inducible nitric oxide synthase and interleukin-6 (Figure 2J), markers in mice of a proinflammatory M1 macrophage polarization, whereas M2 markers tended to decrease.
Figure 2. Macrophages release microcalcification-generating matrix vesicles (MVs).
A, Time-lapse imaging of mouse MV release from RAW264.7 (t=0–20 seconds; Online Movie). B and C, The intensity of Fluo-3, a calcium indicator, within human macrophages (hMac) increased with Ca/P stimulation, demonstrating calcium influx on Ca/P stimulation. The arrow represents the x axis on the graph. D and E, Various stimuli induce the release of MVs with increased calcium content from mouse and human macrophages (n=3–7, *P<0.05, **P<0.001, ***P<0.0001; mean±SD). F and G, Macrophage-derived MVs (Mac-MVs) from Ca/P-stimulated mouse macrophages were larger in size and potentially aggregated over time (n=3). H, Ultrastructure of mouse Mac-MVs released in vitro, showing membrane-bound MVs from control cells (top) and calcifying MVs (bottom). I, MVs expressed exosomal markers (TSG101 and CD9). J, Ca/P-stimulated mouse macrophages expressed proinflammatory markers (M1 phenotype; n=3, *P<0.01 vs control). Ca/P=3 mmol/L calcium/2 mmol/L phosphate. ARG1 indicates arginase 1; IL, interleukin; iNOS, inducible nitric oxide synthase; MRC1, mannose receptor, C type 1; and TNF, tumor necrosis factor.
The use of compound mutant mice, in addition to gain-of-function and loss-of-function in vitro experiments, permitted dissection of the role of S100A9 in the calcification of macrophage-derived MVs in vivo. Previous studies identified S100A9-positive macrophages in early atherosclerotic lesions and suggested the role of this calcium-binding protein in vascular inflammation.16 The present evidence implicates S100A9 in the mineralization of macrophage-derived MVs.
This study provides new insight into the pathogenesis of vascular calcification, particularly microcalcification, a contributor to the acute thrombotic complications of atherosclerosis.
This is the study which would maybe explain some mechanisms behind it. Apparently, higher dietary Ca & Ca/P would be a bad thing to consume when you are in an inflamed state when/if macrophages are activated.
Ray have also said that when you are in an energy deprived state, calcium will end up going inside the cell.
But I've never heard him saying to be careful with it. In some of my email exchange between us he never considered calcium could be a problem, or recommend caution.
Macrophage-Derived Matrix Vesicles
We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease and mineral imbalance accelerate calcification and the subsequent release of matrix vesicles (MVs), precursors of microcalcification.
Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and annexin V, which contribute to accelerated microcalcification in chronic renal disease.
Proinflammatory Macrophages Release Microcalcification-Generating MVs
Time-lapse imaging of macrophages loaded with Fluo-3, a calcium indicator, showed vesicle release from membranous protrusions (Figure 2A; provided in Online Movies) and calcium influx after Ca/P stimulation (Figure 2B and 2C). Ca/P-stimulated macrophages released MVs (Mac-MVs) capable of mineralization, with increased calcium content (Figure 2D and 2E), alkaline phosphatase activity (Online Figure VI), and suggested aggregation potential (Figure 2F and 2G).Mouse macrophages stimulated with Ca/P possessed higher levels of mRNA encoding inducible nitric oxide synthase and interleukin-6 (Figure 2J), markers in mice of a proinflammatory M1 macrophage polarization, whereas M2 markers tended to decrease.
Figure 2. Macrophages release microcalcification-generating matrix vesicles (MVs).
A, Time-lapse imaging of mouse MV release from RAW264.7 (t=0–20 seconds; Online Movie). B and C, The intensity of Fluo-3, a calcium indicator, within human macrophages (hMac) increased with Ca/P stimulation, demonstrating calcium influx on Ca/P stimulation. The arrow represents the x axis on the graph. D and E, Various stimuli induce the release of MVs with increased calcium content from mouse and human macrophages (n=3–7, *P<0.05, **P<0.001, ***P<0.0001; mean±SD). F and G, Macrophage-derived MVs (Mac-MVs) from Ca/P-stimulated mouse macrophages were larger in size and potentially aggregated over time (n=3). H, Ultrastructure of mouse Mac-MVs released in vitro, showing membrane-bound MVs from control cells (top) and calcifying MVs (bottom). I, MVs expressed exosomal markers (TSG101 and CD9). J, Ca/P-stimulated mouse macrophages expressed proinflammatory markers (M1 phenotype; n=3, *P<0.01 vs control). Ca/P=3 mmol/L calcium/2 mmol/L phosphate. ARG1 indicates arginase 1; IL, interleukin; iNOS, inducible nitric oxide synthase; MRC1, mannose receptor, C type 1; and TNF, tumor necrosis factor.
Discussion
We report a novel pathway of microcalcification that involves macrophage-derived MVs. Concentrations of extracellular Ca and P, similar to those found in serum of CRD patients on dialysis, induced the release of Mac-MVs with higher calcification potential. These findings support the operation of a new additional mechanism of arterial calcification that likely accelerates the excessive intimal and medial calcification associated with CRD. Because of the relative abundance of macrophages over SMCs [Smooth Muscle Cells] in rupture-prone plaques,1 we hypothesize that macrophage-derived MVs participate in the initiation of microcalcification.The use of compound mutant mice, in addition to gain-of-function and loss-of-function in vitro experiments, permitted dissection of the role of S100A9 in the calcification of macrophage-derived MVs in vivo. Previous studies identified S100A9-positive macrophages in early atherosclerotic lesions and suggested the role of this calcium-binding protein in vascular inflammation.16 The present evidence implicates S100A9 in the mineralization of macrophage-derived MVs.
This study provides new insight into the pathogenesis of vascular calcification, particularly microcalcification, a contributor to the acute thrombotic complications of atherosclerosis.
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