Chronic, Intracellular Infection and Autophagy
Chronic infections(intracellular through phagocytosis or macrophagy) prompt autophagy( self-eating) and ubiquitin/proteosome degradation due to stress or damage incurred. Autophagy maintains DNA stabilty.
Chaperone-mediated autophagy recognizes, binds, unfolds then transports damaged components to lysosomes. Hsp 70(heat shock protein70) carries out this function.
In microphagy, invaginations and protrusions in lysosomes trap substrates--proteins, mitochondria, peroxisomes, lipid droplets. Hsp 70 action, here, in microphagy, does not require the unfolding of the substrate as opposed to its action in the chaperone-mediated autophagy. Mitophagy is microphagy involving the mitochondria. We also have pexophagy, ER-phagy, ribophagy and lipophagy.
Macro(auto)phagy needs the double membrane autophagosomes. Xenophagy is a macrophagy and recognizes microbes and ubiquitinates them. Bacteria in damaged phagosomes/phagolysomes are ubiquitinated by recognition of carbohydrates in the lumen of these double membranes. This is one step to prevent cellular damage from the 'spill'.
Dysfunctional autophagy leads to aging with accumulation of damaged cells and tissue malfunction. Failure of autophagy leads to senescence or aging of physiological satelite cells with mitochondrial dysfunction, and reactive oxygen species production, being the cause of senescence. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells, indicating that autophagy is necessary to normal regenerative activity of muscle tissue by maintaining satellite stem cell in a quiescent state.
Once senescence is activated, cells undergo morphological and functional modifications, which include arrest of proliferation, resistance to apoptotic signals, and alteration in gene expression . Phenotypically, senescent cells present flat morphology and increased cell size, secretory of cytokines, mucin and metalloproteases.
Epithelial and satelite cells prefer senescence, while lymphocytes prefer apoptosis. Sensecent cells are easily phagocytosed since damaged and expose 'eat me' tags. Autophagy inhibits senescence, but overwhelmed autophagy leads to senescence. NF-kB(beta amyloid former, in tandem with metalloproteases) through autophagy controls senescence. However, too much autophagy will lead to huge amyloid formation and cetrimide production from metalloproteases activation by NF-kB and that will promote senescence.
Amyloid formation is accompanied by ceramide formation(through MMP/NF-kB effect and its activation of lipase). Serotonin is produced in response to autophagy. Serotonin stimulates osteoclasts to break down bone tissue, to release calcium, for signaling. Vitamins D and A(converging pathways to NF-kB), calcium and cumin are pro-autophagy. Serotonin also inhibits sphingomyelinase to prevent cetrimide production and so promote autophagy and inhibit inflammation. Serotonin also promotes mucin secretion which encourages binding of substrate to phagocytic receptors.
Damage in mitotic cells leads to autophagy, then senescence, cancer or apoptosis. In non-mitotic cells, cancer and neurodegeneration are generated. Macrophages proliferate in situ. Large increase in macrophages during infection is the result of expansion of resident population rather than recruitment from blood and arise from bone marrow precursor cell different from monocyte precursor.
Macrophages become quiescent at high confluence and senescent in the long run. Although senescent macrophages lose the ability to phagocytose, quiescent macrphages do. Frustrated phagocytosis is exhausting metabolically and compels macrophages to senescence. In frustration, failing to phagocytose, quiescent giant cells(macrophages) release their toxic content, including amyloid, into the environment. Quiescent and senescent macrophages are long-lived and found in granulomas. They are rescued by autophagy or killed by autophagy, T-cell cytotoxity, depending on the extent of damage. .
Microbes use sensecence to survive by keeping themselves alive for much longer, the same as the host uses autophagy to kill them. The tug of war continues until one dominates the other. Granolomas are sites of damage and autophagy, where vitamine D production by macrophages promotes calcium uptake and autophagy upon activation. Late infection autophagy activation can eliminate reclcitrant infection if it does not go out of hand and instill high grade inflammation and damage(flares).
After autophagy there is anti-oxidation, repair cell proliferation and differentiation(growth), that is rejuvenation. Antigen presentation and cytotoxic T-cell activity are boosted and massive killing of senescent cells will lead to inflammation, different from inflammaging(inflammation in aging or senescence) which is chronic and low grade.
Serotonin assists in autophagy by supplying calcium and calcium is required in the synthesis of serotonin. Serotonin is anti-inflammatory. Serotonin syndrome includes confusion, agitation, retlessness, dilated pupils, headache, changes in blood pressure and temperature, nausea/vomiting, diarrhea, rapid heart rate, tremor, loss of muscle coordination and twitching muscles, shivering and goose bumps, heavy sweating(clammy hands).
Dr. Oliver Verbe Birnso, MD.
Chaperone-mediated autophagy recognizes, binds, unfolds then transports damaged components to lysosomes. Hsp 70(heat shock protein70) carries out this function.
In microphagy, invaginations and protrusions in lysosomes trap substrates--proteins, mitochondria, peroxisomes, lipid droplets. Hsp 70 action, here, in microphagy, does not require the unfolding of the substrate as opposed to its action in the chaperone-mediated autophagy. Mitophagy is microphagy involving the mitochondria. We also have pexophagy, ER-phagy, ribophagy and lipophagy.
Macro(auto)phagy needs the double membrane autophagosomes. Xenophagy is a macrophagy and recognizes microbes and ubiquitinates them. Bacteria in damaged phagosomes/phagolysomes are ubiquitinated by recognition of carbohydrates in the lumen of these double membranes. This is one step to prevent cellular damage from the 'spill'.
Dysfunctional autophagy leads to aging with accumulation of damaged cells and tissue malfunction. Failure of autophagy leads to senescence or aging of physiological satelite cells with mitochondrial dysfunction, and reactive oxygen species production, being the cause of senescence. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells, indicating that autophagy is necessary to normal regenerative activity of muscle tissue by maintaining satellite stem cell in a quiescent state.
Once senescence is activated, cells undergo morphological and functional modifications, which include arrest of proliferation, resistance to apoptotic signals, and alteration in gene expression . Phenotypically, senescent cells present flat morphology and increased cell size, secretory of cytokines, mucin and metalloproteases.
Epithelial and satelite cells prefer senescence, while lymphocytes prefer apoptosis. Sensecent cells are easily phagocytosed since damaged and expose 'eat me' tags. Autophagy inhibits senescence, but overwhelmed autophagy leads to senescence. NF-kB(beta amyloid former, in tandem with metalloproteases) through autophagy controls senescence. However, too much autophagy will lead to huge amyloid formation and cetrimide production from metalloproteases activation by NF-kB and that will promote senescence.
Amyloid formation is accompanied by ceramide formation(through MMP/NF-kB effect and its activation of lipase). Serotonin is produced in response to autophagy. Serotonin stimulates osteoclasts to break down bone tissue, to release calcium, for signaling. Vitamins D and A(converging pathways to NF-kB), calcium and cumin are pro-autophagy. Serotonin also inhibits sphingomyelinase to prevent cetrimide production and so promote autophagy and inhibit inflammation. Serotonin also promotes mucin secretion which encourages binding of substrate to phagocytic receptors.
Damage in mitotic cells leads to autophagy, then senescence, cancer or apoptosis. In non-mitotic cells, cancer and neurodegeneration are generated. Macrophages proliferate in situ. Large increase in macrophages during infection is the result of expansion of resident population rather than recruitment from blood and arise from bone marrow precursor cell different from monocyte precursor.
Macrophages become quiescent at high confluence and senescent in the long run. Although senescent macrophages lose the ability to phagocytose, quiescent macrphages do. Frustrated phagocytosis is exhausting metabolically and compels macrophages to senescence. In frustration, failing to phagocytose, quiescent giant cells(macrophages) release their toxic content, including amyloid, into the environment. Quiescent and senescent macrophages are long-lived and found in granulomas. They are rescued by autophagy or killed by autophagy, T-cell cytotoxity, depending on the extent of damage. .
Microbes use sensecence to survive by keeping themselves alive for much longer, the same as the host uses autophagy to kill them. The tug of war continues until one dominates the other. Granolomas are sites of damage and autophagy, where vitamine D production by macrophages promotes calcium uptake and autophagy upon activation. Late infection autophagy activation can eliminate reclcitrant infection if it does not go out of hand and instill high grade inflammation and damage(flares).
After autophagy there is anti-oxidation, repair cell proliferation and differentiation(growth), that is rejuvenation. Antigen presentation and cytotoxic T-cell activity are boosted and massive killing of senescent cells will lead to inflammation, different from inflammaging(inflammation in aging or senescence) which is chronic and low grade.
Serotonin assists in autophagy by supplying calcium and calcium is required in the synthesis of serotonin. Serotonin is anti-inflammatory. Serotonin syndrome includes confusion, agitation, retlessness, dilated pupils, headache, changes in blood pressure and temperature, nausea/vomiting, diarrhea, rapid heart rate, tremor, loss of muscle coordination and twitching muscles, shivering and goose bumps, heavy sweating(clammy hands).
Dr. Oliver Verbe Birnso, MD.
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