Author Topic: Senescence in Essence  (Read 744 times)


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Senescence in Essence
« on: January 18, 2023, 04:21:49 PM »
As it happens a new study brought up the idea that antagonists of CD36 may be considered as senomorphic agents and CD36 acts as a major regulator of SASP. After looking into the matter a bit more it became apparent that its role conforms pretty well to earlier hypotheses and CD36 is most likely to be at the heart of POIS. Actually a lot of the supplements frequently used by members can be considered antagonists of CD36, thus senomorphic in nature. Estrogen receptor beta activation can downregulate CD36 through the ERB-PPARG-CD36 pathway, which could mean that even ERB agonists may be considered at least partially senomorphic. CD36 also fits well into the earlier model of metabolic syndrome, especially so as SIRT1 activators inhibit CD36. Long-term (about 2 weeks) overexpression of CD36 may establish senescence and SASP. It is not clear how reversible this state is, but it is interesting to note that two of our members presumably managed to cure themselves by the combination of mastic gum, oregano oil and medicinal mushrooms in a few weeks time. As all of these may act as CD36 antagonist, a potent suppression can be expected, which may lead to long-term changes. It has to be noted that different CD36 antagonists provided varying result for members (e.g. aged garlic), which may be related to SASP heterogeneity or receptor polymorphisms. Nevertheless a good strategy could be to combine a few effective CD36 inhibitors and hopefully it can be a blast on POIS. Of course there are some inconsistencies here-and-there as usual, but the theoretical evidence and both my and other POISer's experiences are so convergent that it practically proves that most POIS cases stem from cellular senescence of sexual organs and thus POIS can be clearly declared as a subclass of SASP. CD36 is also significantly elevated in severe covid-19, which may establish the connection to post-covid. It can also explain why we react adversely to coffee or gluten. Some controversy could be the role of p21 which is also involved in senescence development. P21 is induced by ERB, however Sirt1 activation inhibits this factor. A possible explanation may be that ERB also initiates apoptosis of senescent cells and acts as a senolytic, but who knows. Even so a similar problem exist with hTERT inhibition, as most senolytics are also known inhibitors of hTERT.

See the other thread for possible relations with hTERT and ERB:

Also don't forget to check the model of metabolic syndrome:

CD36 initiates the secretory phenotype during the establishment of cellular senescence. Cellular senescence is a unique cell fate characterized by stable proliferative arrest and the extensive production and secretion of various inflammatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). Ectopic CD36 expression in dividing mammalian cells is sufficient to initiate the production of a large subset of the known SASP components via activation of canonical Src–p38–NF-kB signaling, resulting in the onset of a full senescent state.
Senescent cells have increased expression of at least one cyclin-dependent kinase (CDK) inhibitor, typically p16 or p21, which functions to activate the Rb tumor suppressor, resulting in cell cycle arrest.
Upon senescence initiation, two transcription factors normally present in immune cells, NF-kB and CEBPbeta, are activated to promote the transcription of a set of relatively conserved pro-inflammatory cytokines, chemokines, growth factors, and proteases. Some canonical signal transduction cascades, such as the mTOR and p38 MAPK pathways, have been shown to stimulate NF-kB and SASP formation during senescence.
Previous studies have identified diverse CD36 ligands including collagen, thrombospondin, and various lipoproteins and lipids that bind CD36 in order to regulate vascular and adipose homeostasis.
Sustained exposure of CD36 to ligand drives pro-inflammatory cytokine production and cell cycle arrest in order to establish the overall senescent state in both epithelial cells and fibroblasts. Finally, loss-of-function experiments demonstrate that CD36 is strictly required for NF-kB phosphorylation and SASP initiation and maintenance during both oncogene- and chemical-induced senescence.
CD36 had a ~100-fold induction in aged mice, indicating a strong correlation between CD36 induction and bronchial cell senescence and aging.
Many well-recognized conventional SASP components were found to be consistently produced upon CD36 expression, including interleukin 6 (IL-6) and interleukin 8 (IL-8).
Long-term CD36 expression promotes a comprehensive senescent phenotype
Prolonged (14 days) CD36 expression led to a striking phenotype of cell cycle exit that was associated with increased levels of cyclin?dependent kinase inhibitors and SA-BGal activity.
The SASP comprises a combination of secreted molecules that collectively function to reinforce the overall senescent phenotype.
IL-6 administration produced a strong senescent phenotype in IMR90 fibroblasts, indicating cell type-specific differences in the ability of individual SASP components to induce senescence. At early time points, CD36 functions to drive NF-kB-mediated secretion of canonical SASP components, which in turn act in a feed-forward manner to promote stable cell cycle arrest and establish the senescent state.
Although CD36 knockdown did not rescue the cell cycle arrest or SA-BGal activity phenotypes caused by EGFR inhibition, we observed a major impairment in Src–p38–NF-kB activation after senescence induction when CD36 upregulation was suppressed. Consistent with this, a large cohort of SASP components was not induced during senescence after CD36 knockdown, and this subset largely coincides with the group of pro-inflammatory molecules induced by ectopic CD36 expression. These results demonstrate a functional requirement of CD36 for NF-kB-mediated SASP establishment in response to multiple senescent stimuli.
Here, we propose that the ability of senescent cells to adopt an immune-like secretory phenotype largely stems from their capacity to upregulate the expression of CD36 in response to various senescent stimuli.
CD36 is likely to be a more direct and rapid pathway for SASP activation in response to senescent stimuli. Indeed, nearly ten-fold CD36 upregulation was observed here only 6 h after senescence induction.

During regeneration, senescence was reduced by inhibiting ROS. Sen cells showed altered lipid-transport and lipoprotein-remodelling traits, consistent with the ability of oxidative stress to generate lipotoxicity that triggers inflammation and fibrosis.
Depending on cell type and conditions, the number of SASP components ranged from 78 to 363, highlighting SASP diversity. Pathway enrichment identified two major functions: (1) inflammation, including complement and coagulation, innate-immune system, lipoprotein remodelling and cytokine and TNF/NF-kB signalling (Ccl2, Ccl7, Ccl8 and Isg15); and (2) fibrosis, including matrix organization and collagen metabolism, and TGFB signalling.
The SASP of Sen cells, transiently present in injured young muscles, mimics aged-like inflammageing, which is exacerbated in injured aged muscle.
Lipid transport, which is tightly associated with inflammatory responses, was consistently included in the inflammatory hallmark of Sen cells and the SASP in all conditions. Sen cells had more lipid droplets compared with NSen cells. Numerous lipid metabolism and lipid-transport genes, including Fabp3, Apoe, Star, Lpl, Cd68 and Cd36, were upregulated in all Sen cells.
FunRes generated a CD36 signalling network that predicted downstream activation of NF-kB and other inflammation/stress-related pathways, and downstream SASP components, such as Il6, Tgfb1, Mmp3, Igfbp5, Ccl2 and Cxcl10, suggesting that CD36 might regulate the in vivo senescence secretory program, affecting regeneration.
All three Sen cell types had higher CD36 protein expression in injured muscles.
CD36 blockade did not affect the number of senescent cells, but reduced several SASP proteins, and many coincided with SASP genes in Sen SCs, FAPs and MCs encoding chemokines, cytokines and matrix metalloproteinases (Ccl2, Ccl3, Il1b, Il10 and Mmp3).
CD36 blockade improved regeneration in both young and old muscles while reducing inflammation and fibrosis and these muscles showed increased force.
In injured muscle, senescent cells modified their normal niche counterparts by creating an aged-like inflamed microenvironment that hijacked their proliferative programs and blunted regeneration. Reducing the number of senescent cells (and therefore their inflammatory secretome) resumed stem-cell proliferation and enhanced muscle regeneration.
After injury, a subset of niche cells accumulates ROS and DNA damage beyond a threshold, which leads to senescence and regenerative failure.
The senescent state can be influenced in vivo by its trigger, the cell that senesces, its environment and its temporal resolution by the immune system, resulting in a wide spectrum of phenotypic features.
We revealed that two major conserved universal hallmarks define senescent cells: inflammation and fibrosis. We also determined that, depending on their lineage of origin, senescent cells have unique features that are preserved throughout life, indicating that they share universal programs while maintaining identity traits, and adapt to the idiosyncrasies of their origin and age. Thus, our study provided a better definition of senescence in vivo: despite being a state of irreversible arrest, senescence encompasses features of molecular diversity and dynamism (sensitive to the pass of time and mode of injury) as well as conserved hallmarks.
A reduction in the number of senescent cells improved regeneration as a result of attenuating inflammatory and fibrotic SASPs. Finally, we identified CD36 (a scavenger receptor that is related to lipid metabolism and inflammatory function) as a cell receptor acting as a senomorphic in vivo.

The results indicated that in response to diosgenin stimulation, ERB could suppress the expression of PPARG1/2, which may contribute to the inhibition of adipocyte differentiation.
Moreover, when ERB was inhibited by ICI182 780, reduction of mRNA expression of aP2 and CD36 by diosgenin was remarkably suppressed. PPARG regulates adipocyte differentiation through transcriptionally modulating a battery of target genes responsible for the terminal maturation of fat cell, including aP2 and CD36. The results indicated that activation of ERB could reduce PPARG expression, resulting in reduction of adipocyte differentiation.

Absence of ERB in adipose tissue results in exaggerated coactivator binding to a PPARG target promoter. We demonstrate for the first time a pro-diabetogenic function of the ERB. Moreover, our cell culture experiments indicate that ERB is a negative regulator of ligand-induced PPARG activity in vitro. The role of PPARG in the control of glucose homeostasis expands beyond its primary action in adipose tissue, and involves the regulation of adipocytokine production such as adiponectin, leptin, and resistin. Consistently, reduced PPARG activity has important metabolic and cardiovascular pathophysiological consequences leading to insulin resistance, diabetes and end organ damage. Importantly, PPARG is sharing a similar pool of cofactors with ERB which provides a platform for mutual interactions between these two NHRs.
BetaERKO mice exhibited augmented PPARG signaling in adipose tissue corresponding to increased food efficiency and significantly elevated RQ (respiratory quotient).
Adipose mRNA expression of PPARG target genes involved in triglycerides (TG) synthesis such as lipoprotein lipase (Lpl), phosphoenolpyruvate carboxykinase (PEPCK) and CD36 was significantly upregulated in BetaERKO mice.
These data suggest that the coactivators SRC1 and TIF2 are involved in the negative regulation of PPARG by ERB in vitro and in vivo.

Increases in expression of enzymes for fatty acid beta oxidation (MCAD, CPT1 etc.) via activation of PPARA, and mitochondrial capacity via activation of nuclear respiratory factor 1(NRF-1) and NRF-2 contribute to increased fatty acid oxidation. It was reported that the promoter region of CD36 and FATP1 contains a peroxisome proliferator-responsive element (PPRE).

Expression and activation of either PPARG 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36. A PPARG agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARG agonization increased prostatic differentiation markers, whereas HFD downregulated PPARG-regulated genes and decreased prostate differentiation.

Senescent cells in benign prostate hyperplasia (BPH) tissue induce a senescence-associated secretory phenotype (SASP) which, by generating inflamed microenvironment and reactive stroma, promotes leukocyte infiltration, cellular hyperproliferation, and nodular prostate growth.
SASP induced mRNA expression for inflammatory cytokines (IL-1a, IL-6, IL-8, TNF-a); chemokines (GM-CSF, CXCL12); metalloproteases (MMP-1, MMP-3, MMP-10); growth factor binding IGFBP-3.
Senescent cells are metabolically active, but irreversibly arrested at the G1/S cell cycle check point. As a cell-intrinsic tumor-suppressive mechanism, cellular senescence bars aberrant proliferation of cells that are irreversibly damaged by insults such as oxidative stress induced by cell's metabolic activities, chromosomal instability from shortened telomeres, and DNA damage by chemicals or ionizing radiation. Elevated expression of the p16INK4a/CDKN2a tumor suppressor is associated with cellular senescence in many tissues. Senescence-associated beta-galactosidase (SA-BGal) activity at pH 6.0 is another marker for senescent cells. Cells of the BPH epithelium and late-passage epithelial cells isolated from the normal prostate transition zone showed elevated p16/INK4a and SA-BGal.
BPH-1 cells, showed increased AKT and ERK activities. The prevailing view on BPH pathogenesis is that the cumulative effects of low-level chronic stimulation of prostate cells by inflammatory secretions from the reactive stroma and infiltrated inflammatory cells promote excessive cell proliferation in aging prostate. AKT promotes cell growth and proliferation by activating mTORC1 and downstream effectors that stimulate protein synthesis and lipogenesis.

Please take notice that both 3a-Adiol and 3B-adiol are 5alpha metabolites.
As the metabolic clearance rate decreases in male senescence, the net result is an important decrease in the testosterone blood production rate. It was observed that testosterone metabolism in male senescence is characterized by a relative decrease of the formation of androstanediols, with a relative increase of 5beta over 5alpha metabolites; moreover a statistically significant correlation between the formation of 3a-Adiol and the free testosterone fraction was found.

The 5a-androstanediol analyte contains both the 3a-adiol and 3B-adiol subcomponents.

Age is associated with a decrease in 3a-diol production and 3a-diol administration reinstates cognitive and affective performance of aged male rats. 3a-diol has actions at GABAA receptors or at estrogen receptor beta in the hippocampus.

The present study demonstrated that SIRT1 activation attenuated HFD-induced liver steatosis and inflammation by inhibiting CD36 expression and the NF-kB signaling pathway.
In addition, another study reported that SIRT1 expression was decreased in aged mice, whereas CD36 was upregulated, which could explain the increasing prevalence and progression of NAFLD associated with age in the general human population. The AMPK-mediated effects of SIRT1 have been reported to promote the deacetylation of PGC-1a, which then stimulates PPARA, leading to the initiation of CD36 transcription.
Studies have shown that CD36 contributes to the development of NAFLD by modulating the rate of free fatty acid uptake. Some researchers regard CD36 as a protective metabolic sensor in the liver during lipid overload or metabolic stress.

LPS impairs steroidogenesis and ROS metabolism and induces PPAR transcriptional activity to disturb estrogen/androgen receptor expression in testicular cells. Inflammation can deregulate the testicular functions of steroidogenesis and spermatogenesis, consequently contributing to male infertility.
Our results suggested PPARA/PPARG mRNA was highly expressed in late spermatids, while PPARB mRNA was highly expressed in round spermatids.
PPARG were upregulated in primary Sertoli cells after LPS-treatment.
In MLTC1 cells and ERB mRNA in TM4 cells were significantly recovered after treatment with the specific PPARG-antagonist GW9662.
Meanwhile, PPARs (PPARA and PPARG) can interact with G-coupled membrane estrogen receptor to regulate the steroidogenic function of mouse Leydig cells.
The silent information regulator type 1 (SIRT1) protein, a deacetylase that catalyzes deacetylation reactions in an NAD+-dependent manner, can inhibit PPAR activation. Moreover, Sirt1 transcription is inhibited through a negative feedback loop by PPARG, which binds to promoter region of the Sirt1 gene to suppress its transcription.
PPARA was mainly localized in the nuclear regions of Leydig cells and that PPARG was mainly detected in Sertoli cells.
Sirtuins play a key role in many vital processes of cells. including the cellular oxidative stress response and energy metabolism. SIRT1, a member of the Sirtuin family, is a deacetylase that catalyzes deacetylation reactions in an NAD+-dependent manner to inhibit PPAR activation. Meanwhile, the transcription of the SIRT1 deacetylase gene is inhibited via a negative feedback loop by PPARG. PPARG can bind to the promoter region of the Sirt1 gene to inhibit Sirt1 expression at the transcriptional level. Moreover, the SIRT1 protein can also bind the Sirt1 promoter, resulting in the repression of the Sirt1 gene. Most Sirtuin mRNAs, except Sirt4, were expressed in spermatids.
Our results revealed that PparA and PparG mRNA expression was strongly increased after
LPS treatment. This decreased SIRT1 expression may have been caused by the upregulated PPARG protein abundance, as PPARG can bind to the Sirt1 promoter region to repress its gene expression via a negative feedback loop. In conclusion, the SIRT1- PPARG regulation loop may play a very important role in the primary mouse Sertoli cell model of LPS infection.
The molecular role of reactive oxygen species (ROS) is essential for male spermatogenesis and steroidogenesis.
The estrogen/androgen balance plays an important role in the maintenance of normal testicular morphology and spermatogenesis. After LPS treatment, ERB expression was strongly increased in TM4 Sertoli cells; in contrast, AR mRNA expression was decreased.
Taken together, our results suggest that LPS impairs steroidogenesis and ROS metabolism and induces PPAR transcriptional activity to disturb estrogen/androgen receptor expression in testicular cells.

On macrophages CD36 forms part of a non-opsonic receptor and is involved in phagocytosis. CD36 has also been implicated in hemostasis, thrombosis, malaria, inflammation, lipid metabolism and atherogenesis. CD36 ligands have also been shown to promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Recently, CD36 was linked to store-operated calcium flux, phospholipase A2 activation, and production of prostaglandin E2. Recent researches concluded that the CD36 is involved in the fat taste transduction (olegustus).
Upregulation of CD36 could contribute to membrane remodeling during senescence. In response to various senescence-inducing stimuli, CD36 stimulate NF-kB-dependent inflammatory cytokine and chemokine production, a phenomenon known as SASP. This secretory molecule production leads to the onset of a comprehensive senescent cell fate.

CD36 serves as a signaling hub protein at the crossroad of inflammation, lipid metabolism, and fatty acid metabolism. In addition, the level of soluble CD36 (unattached to cells) in the circulating blood was elevated in patients with atherosclerosis and other metabolic disorders.
CD36, a major class B scavenger receptor, exerts substantial effects on ox-LDL uptake by macrophages. Cumulative data have indicated the important role of CD36 in regulating key physiological processes and cellular events in the initial and progression phases of atherosclerosis, such as inflammation, lipid metabolism, endothelial dysfunction, smooth muscle cell dysfunction, and foam cell formation.
PPARG represents a primary transcription factor that binds to the promoter region of CD36 and modulates CD36 in a positive feedback manner.
STAT5 activated PPARG through inhibition of CD36. Pregnane X receptor (PXR) increased CD36 expression concomitant with lipid accumulation in macrophages.
In fact, the interaction between miRNA and CD36 is closely associated with lipid metabolic disorders.
The CD36 SNPs variants were associated with CD36 expression due to the methylation of CD36, indicating that SNPs and methylation appear to regulate CD36 mRNA expression.
Autophagy modulates cholesterol mobilization from macrophage to reverse cholesterol transport, which is deregulated in advanced atherosclerosis. Importantly, CD36 expression was also decreased due to the activation of autophagy upon empagliflozin treatment.
The ingestion of ox-LDL was inhibited by ubiquitin-proteasome system via promoting CD36 degradation. CD36 can transduce src family non-receptor tyrosine kinases, JNK, ERK 1/2, IRGM1 and TLR2/6-dependent signaling.
Interestingly, increased CD36 expression leads to mitochondrial ROS overproduction in aortic lesion macrophages upon stimulation of pro-atherogenic ox-LDL, which could switch the mitochondrial metabolism to superoxide production. However, inhibition of mitochondria-derived superoxide generation suppresses ox-LDL induced NF-kB activation and pro-inflammatory cytokine production. These findings suggest the therapeutic possibility to treat chronic inflammation and atherosclerosis by targeting oxidized LDL/CD36 signaling in macrophages via modulating dysregulated fatty acid metabolism and mitochondria ROS production.
CD36 expression was increased upon simulation with ox-LDL or high-fat diet feeding, which promoted aortic uptake of oxLDL or other modified lipids.
CD36 can take up FAs through enhancing the rate of intracellular esterification.
Ox-LDL can induce CD36 expression though PPARG, which in turn promotes ox-LDL uptake by the macrophages and entrapment of macrophages within the plaques, allowing for macrophages to become lipid-laden foam cells.
Testicular orphan nuclear receptor 4 (TR4) can sensor the increased generation of FA and promote the expression of CD36, which forms a vicious cycle that finally contributes to the formation of foam cells.
Pharmacological Modifiers of CD36
Statins, the most widely used lipid-lowering drugs, can inhibit CD36 expression/activity via a PPARG-dependent pathway in macrophages. Statins (fluvastatin and pitavastatin) also decreased CD36 expression in aortic VSMCs. Nifedipine, also suppressed CD36 expression and lipid uptake and deposition in macrophages. Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, decreased CD36 expression. Tamoxifen, an anti-breast cancer medicine also decreased CD36-dependent foam cell formation. Andrographolide inhibited CD36 level. Pomegranate peel polyphenols, spiromastixones, and puerarin could suppress CD36 expression. Tanshinone IIA from Danshen, prevented atherothrombosis by targeting platelet CD36. Orientin, a flavonoid from plants, quercetin and curcumin.
CD36 acts a multi-functional inflammatory-metabolic receptor by physiologically regulating lipid homeostasis and immune homeostasis.

Aging decreases Nrf2. Nrf2-/- mice displayed a significant reduction in the Serca2a expression below the baseline.

Nrf2 remains low under normal conditions but it is induced many-fold in response to endogenous or exogenous stresses or toxicants. Nrf2 target genes function in elimination of reactive oxygen species (ROS) and diminishing inflammation, drug and carcinogen detoxication, and intermediary metabolism.
Autophagy in cancer cells may have bimodal response of pro-death or a pro-survival role. Lower rate of autophagy may result in catabolic degradation of nonessential cellular proteins and debris creating a large amino acid pool that eventually helps in cancer cell survival. In contrary, uncontrolled autophagy mimicking to apoptotic cell death results in large scale tumor cell death. Hence, autophagy can either promote or suppress the survival and proliferation in the tumor microenvironment.

Activator protein 1 (AP-1) subunit c-Jun can dimerize with NRF2 and activate NRF2-induced transcription, while another AP-1 subunit c-Fos can suppress NRF2-induced transcription.
Nuclear receptors PPARG and estrogen receptor alpha (ERa) can directly bind to NRF2 and suppress the NRF2 activity.
Transient NRF2 activation as a stress response mediates the cellular programs trying to maintain the homeostasis if the damage caused by the toxic stimuli are reparable. NRF2 upregulates expression of genes involved in the glycolysis, glycogen metabolism, pentose phosphate pathway, one carbon metabolism, amino acid metabolism, nucleotide biosynthesis, glutaminolysis, fatty acid synthesis, heme metabolism, and glutathione synthesis and utilization. NRF2 downregulates the expression of genes involved in the gluconeogenesis.
In addition, NRF2 also activates CD36, the lipid uptake transporter/receptor in different cells to regulate lipid metabolism.
Misfolded protein accumulation and aggregation induce excessive production of ROS from mitochondria, ER, and other sources, which can activate NRF2. NRF2 is a hub that compiles emergency signals derived from misfolded protein accumulation to facilitate a coordinated transcriptional response.

Elevated free fatty acid (FFA) uptake via CD36 promotes epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). The Wnt and TGF-B signaling pathways were activated upon FFA treatment, potentially acting as upstream activators of the EMT program. We observed that Wnt and TGF-B signaling pathways were activated by palmitate and there could be several mechanisms involved. Oncogenic transcription factors, including NF-kB, AP-1 and STAT3, activated by inflammatory cytokines like TNF-a and IL-6 could connect the activation of Wnt and TGF-B signaling pathways with elevated FFA. The STAT3 transcription factor was shown to mediate the induction of EMT. A different mechanism of EMT induction could be the activation of the unfolded protein response or ER-stress pathway by FFA. CD36 crosstalk with TLR2/6 heterodimer results in activation of TLR-dependent cytokine production (NF-kB). In the context of EMT, the relationships of these pro-inflammatory pathways with CD36 point to a possibility that FFA may activate EMT via CD36 signaling.

Signal transducer and activator of transcription (STAT) proteins are a family of transcription factors that mediate gene expression in response to cytokines and growth factors. STAT3 regulates a variety of genes involved in cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, inflammation, and immunity.

Silencing CD36 gene expression results in the inhibition of latent-TGF-B1 activation and suppression of silica-induced lung fibrosis in the rat.

TGF-B1/TGF-B2 down-regulated CD36 expression by inactivating PPARG-mediated signaling. Our data demonstrate for the first time that TGF-B1 and TGF-B2 decrease expression of CD36 by a mechanism involving phosphorylation of MAP kinase, subsequent MAP kinase phosphorylation of PPARG, and a decrease in CD36 gene transcription by phosphorylated PPARG.

It has been known for decades that an increased provision of lipids to a working muscle (such as during exercise) promotes fatty acid oxidation (FAO). We have provided evidence that fatty acid translocase (FAT)/CD36 is a key regulator of lipid transport across both the sarcolemmal and mitochondrial membranes and, therefore, rates of skeletal muscle fatty acid oxidation.
Exercise-induced signaling cascades (potentially including calcium, ERK1/2, PKC, and AMPK) promote the translocation of intracellular stores of FAT/CD36 to both the sarcolemma and the mitochondria.
This acute redistribution of FAT/CD36 to the plasma membrane in response to exercise is hypothesized to be regulated, in part, by calcium-mediated signaling events as fatty acid transport is increased when muscle is exposed to caffeine (a cytosolic calcium level enhancer), and this increase in fatty acid transport occurs concomitantly with an increase in plasma membrane FAT/CD36. In addition, fatty acid transport is attenuated when muscles are exposed to inhibitors for calcium signaling (CaMKII and CaMKK), and this corresponds to a prevention of FAT/CD36 translocation to the plasma membrane.
The role of AMPK in regulating sarcolemmal FAT/CD36 translocation during exercise remains unclear. Inhibition of extracellular signaling receptor kinase (ERK1/2) seems to prevent contraction-induced FAT/CD36 translocation and activation of protein kinase C (PKC) in cardiac myocytes induces FAT/CD36 translocation.
In mature rodent muscle, overexpression of PGC-1a (a well-characterized exercise adaptation regulator) increases mitochondrial FAT/CD36 expression in concert with increasing FAO. The presence of FAT/CD36 on the sarcolemmal and/or the mitochondrial membrane can effectively enhance and promote fatty acid transport/oxidation with an increase in fatty acid provision.

The transcription factor STAT 6 accumulates in response to IL-4 and, along with its downstream effector PPARG, has a central role in the regulation of transcription of anti-inflammatory and pro-resolving genes. Additionally, IL-4 induces expression of CD36, a receptor of lipoproteins, whose uptake and metabolism may support fatty-acid oxidation, contributing to metabolic microglia reprogramming.

The entrance of SARS-CoV-2 using ACE2 receptor triggers an array of multiple molecular signaling beyond that of the angiotensin II/ACE2-Ang-(1–7) axis, such as down-regulation of PGC-1a/irisin, increased SREBP-1c activity, upregulation of CD36 and Sirt1 inhibition leading to insulin resistance.
TLR4, as an important component of the immune system, has direct interaction with CD36 in macrophages and monocytes. TLR4-induced up-regulation of CD36.
Angiotensin II resulted in indirect increased expression of CD36 through down-regulation of sirtuin 1.
The entrance of SARS-CoV-2 using ACE2 receptor triggers an array of multiple molecular signaling beyond that of the angiotensin II/ACE2-Ang-(1–7) axis such as down-regulation of PGC-1a/irisin, increased SREBP-1c activity, upregulation of CD36 and Sirt1 inhibition leading to insulin resistance.

All genes (PPARG, CD36, STAB1, ITGAV, and ANXA2) downregulated in surviving patients with COVID-19 are related to cholesterol homeostasis. We hypothesized that upregulation of CD36 expression could be a predictive factor for severe COVID-19 with possible lethal outcomes.
PPARG bridges the lipid microenvironment and immune cell’s function driving its differentiation and functional phenotypes. PPARG has an immunomodulatory function and plays a role in the resolution of inflammation, its upregulation in nonsurvivors may be a hallmark of nonresolved inflammation in condition of lipid depletion which is characteristic of severe COVID-19.

CD36 has been previously shown to be an important mediator of acute lung injury in animal models exposed to hydrogen peroxide or infected with malaria. Our results suggest that CD36 receptors may be implicated in the pathogenesis of severe infection in critically ill patients with COVID-19. sCD36 could be a potential biomarker for severe illness outcomes, and test novel anti-CD36 therapeutics in ARDS.

In addition to the regulation of mitochondrial function, PGC-1a increases mRNA content of enzymes involved in fat metabolism such as fatty-acid translocase/CD36, carnitine palmitoyltransferase I, and medium-chain acyl-coenzyme A dehydrogenase (MCAD) in skeletal muscle.

PGC-1a is also known to activate factors, e.g., PPARs, that increase the cellular and organelle uptake, and the catabolic oxidation, of fatty acids (FAO). This effect was reflected by a 3.5-fold increased expression in MCK-PGC-1a mouse muscle of CD36/FAT, a gene encoding the plasma membrane transporter of fatty acids. The expression of the FAO-related CD36/FAT gene was significantly increased in all treated groups.

COX-2 is regulated by a negative feedback loop mediated through PPARG, which makes possible a dynamic production of PG, especially in macrophages, and may be attributed to various expression patterns and physiological functions of COX-2.

Expression of ERB is found reduced in tumour tissue and inversely related to mortality. Epigenome-wide DNA methylation profiling was performed. Comparing tumours of high with tumours of negative ERB expression revealed 2,904 differentially methylated CpG sites of which 403 were replicated. Replicated CpGs were annotated to genes such as CD36, HK1 or LRP5.

Genes involved in spermatogenesis (TSSK2, HSP90AA1, SOX5, SPAG16, and SPATC1) were up-regulated in male macaques, and significant changes in genes (CD36), metabolites (cholesterol, 7- ketolithocholic acid, and 12-ketolithocholic acid), and microbiota (Lactobacillus) related to cholesterol metabolism were also found, suggesting the sexually mature males have stronger sperm fertility and cholesterol metabolism compared to sexually immature males.
In macaques, cholesterol is a recognized regulator of male fertility and cholesterol homeostasis is essential for sperm maturation. Here, the expression of CD36, which is associated with cholesterol transport, was decreased in the sexually mature male group. Endogenous CD36 mediates the endocytosis of native low-density lipoproteins (LDLs), which is required for cholesterol transfer. High intracellular cholesterol can reduce cholesterol uptake by inhibiting the expression of LDL receptor genes. Decreased CD36 expression may lead to elevated plasma cholesterol, suggesting that male macaques have sufficient cholesterol for the synthesis of various steroids in sex organs after sexual maturity.

Such a study revealed that with respect to control cells, the PPARG knock-out cells exhibited significant reduction in the expression of genes coding for PPARA, CD-36, LDL-R as well as significant increase in the expression of genes coding for IL-4, IL-8, IFN-g, CX3CR1, hTERT.

Most studies on cellular senescence (CS) have been conducted in vitro on normal and tumor cell lines. These different approaches lead to DNA damage, gene instability, telomerase inhibition, and/or chromatin alterations that primarily affect p53 - p21 signaling.
We found that senescent cells were mostly detected in hyperplastic and premalignant lesions and rarely in tumors. In MNU-mammary carcinogenesis model, tamoxifen, vorazole (an aromatase inhibitor), DHEA, retinoids [all-trans retinoic acid (atRA), 9-cis-retinoic acid (9cRA), 4-hydroxyphenyl-retinamide (4-HPR) and rexinoids (LDG1069), in addition to inhibition of cell proliferation also induced cellular senescence. Cellular senescence induced by tamoxifen, DHEA, aromatase inhibitors and rexinoids was associated with p21 and p16 up-regulation and with decrease in telomerase activity.

Although PPARA has been linked to hepatocarcinogenesis in rodents, several epidemiological studies suggest that this is unlikely to be observed in humans. Similarly, although PPARG activation has often been linked to proliferation inhibition and apoptosis induction in cancer cells, various studies have yielded contradictory results that suggest PPARG activation may promote cancer development.
« Last Edit: January 18, 2023, 04:58:40 PM by Progecitor »
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Senescence in Essence
« Reply #1 on: January 18, 2023, 04:43:32 PM »
Supplements affecting CD36

CD36 antagonists:

Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation. Whole muscle (+40%) and sarcolemmal membrane-associated FAT/CD36 were increased in high fat (HF)-fed rats compared with controls (+56%). All interventions resulted in significant reductions in whole muscle and sarcolemmal FAT/CD36 protein expression compared with HF-fed rats HF-Met (metformin): -15–27%; HF-Ex (exercise): -18–29%; HF-Ex+Met: -21–33%. FAT/CD36 can be translocated to the sarcolemmal membrane in the presence of various stimuli, including insulin, AICAR, and contraction, and regulates skeletal muscle FA uptake.

According to Dedoussis et al. the restoration of intracellular glutathione levels and downregulation of CD36 expression are pathways through which mastic triterpenes exert their antioxidant and antiatherogenic effects. This supports the idea that the overall effect of Chios mastic gum (CMG) on lipid metabolism is mediated via its function as a PPARA agonist. Oleanonic acid, a component of CMG, has been identified as a PPARG agonist, and may therefore partly regulate insulin-mediated gene expression via the activation of PPARG.

Oregano essential oil inhibited the lipogenesis pathway by downregulating transcripts and proteins, such as ACC, FASN, SREBP1 (fatty acid biosynthesis), and HMGCR (cholesterol biosynthesis). CD36 is a scavenger receptor that regulates lipid uptake, immunological recognition, inflammation, molecular adhesion, and death in a variety of cells. CD36 stimulates tumor development and metastasis by allowing cells to take up lipids from the extracellular microenvironment and promoting the oxidation of FAs to create ATP. CD36 mRNA expression has previously been linked to GC survival, and high CD36 expression has been linked to poor clinicopathological outcomes in GC patients. CD36 can also operate as a direct target molecule for hydrogen sulfide (H2S), activating long-chain FAs in the cytoplasm and causing lipid metabolic reprogramming. It has also been shown that high fatty acid uptake promotes CD36 transcription and functioning.

Both phytosterols (beta-sitosterol and stigmasterol) significantly increased the expression of PPARA and decreased the expression of CD36. The lower intestinal bile acid levels would decrease the absorption of lipids from the diet, leading to the attenuation of body weight gain and lipid accumulation in liver. In addition, the lowered expression of CD36 caused by phytosterols may decrease hepatic uptake of fatty acid from the blood. Stigmasterol is more effective than beta-sitosterol in these actions, possibly through its decreasing the expression of some lipogenic genes and lowering circulating CM levels.

Crocin significantly increased AMPK phosphorylation. Crocin inhibited the expression of mRNA of important adipogenesis-related regulators, including CEBPalpha, CEBPbeta, PPARG, aP2, FAS, and CD36. Crocin increased the expression of mRNA of key lipolysis-associated factors, including PPARA, LPL, and HSL. Crocin inhibits adipogenesis and promotes lipolysis via activation of AMPK.

Aged garlic extract inhibits CD36 expression in human macrophages via modulation of the PPARG pathway.

Quercetin notably inhibited both mRNA and protein expression of CD36 (reduced by 53% and 71%, resp.).

Resveratrol (15 mM) treatment enhanced protein levels of C/EBPdelta, C/EBPalpha and PPARG which are master transcription factors governing adipocyte differentiation. Furthermore, 15 mM resveratrol induced CD36, an adipogenesis promoter, whereas 35 mM resveratrol repressed it during adipogenesis. Resveratrol at 35 mM, but not 15 mM, up-regulated HO-1, a known adipogenesis inhibitor. These results suggest that CD36 and HO-1 at least partly mediate biphasic effects of resveratrol on adipogenesis, and that low doses of resveratrol enhance adipogenesis of 3T3-L1 cells by up-regulating CD36, whereas high doses of resveratrol inhibit adipogenesis by reducing CD36 and elevating HO-1.

Our results suggest that berberine improves the free-fatty-acid-induced insulin resistance in myotubes through inhibiting fatty acid uptake at least in part by reducing PPARG and FAT/CD36 expressions.

Berberine (BBR) increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both berberine and tauro-cholic acid (TCA) treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway.

Ganoderic acid A (GA) is one of the most abundant triterpenoids in Ganoderma lucidum, and has been proved to possess a wide range of beneficial health effects. Histological analysis also showed that the excessive accumulation of lipid droplets in the liver induced by HFD-feeding was greatly alleviated by GA intervention. In addition, GA intervention also increased the level of short chain fatty acids (SCFAs) in the intestine and promoted the excretion of bile acids (BAs) through feces. HFD significantly increased the hepatic mRNA levels of Hmgcr, Srebp-1c, Fas, Acc1, Acat2, C/ebpa, Cd36 and Fatp in comparison with the NFD group, while GA treatment at 75 mg/kg day obviously attenuated these abnormal transcription levels.

Hesperidin protected against varenicline-enhanced oxLDL net uptake by blocking the increased expression of CD36 and LOX-1 scavenger receptors.

Isosilybin treatment decreased the mRNA and protein expression of lipid synthesis genes Srebp-1c, Pnpla3, Acc and Fas, as well as the mRNA expression of fatty acid uptake gene CD36, whereas increased the mRNA levels of lipid oxidation genes PPARA, Acox1 and Cpt1a, as well as the mRNA expression of lipid export gene Mttp, in FFAs-induced HepG2 cells.

Fisetin, morin and myricetin attenuate CD36 expression and oxLDL uptake in U937-derived macrophages. The inhibition of CD36 by flavonols was mediated by interference with PPARG activation thus counteracting the deleterious autoamplification loop of CD36 expression stimulated by PPARG ligand.

Taurine normalized the protein and/or mRNA levels involved in ER stress signaling (IRE1a, p-IRE1a, ATF6, XBP1, BiP, and CHOP) and lipid metabolism (CD36, MTTP, and ApoB), which were dysregulated by tunicamycin treatment. Interestingly, the protein level of CD36, a fatty acid uptake transporter, was significantly increased in the livers of tunicamycin-treated mice. Consequently, taurine treatment significantly decreased its expression.

Salvianolic acid B inhibits macrophage uptake of modified low density lipoprotein (mLDL) in a scavenger receptor CD36-dependent manner. An assay for CD36 antagonist identified salvianolic acid B (SAB) from the herb Danshen (Salvia miltiorrhiza). SAB is an effective CD36 antagonist and suggest SAB as a potential anti-atherosclerotic agent.

DSS, RA, and SAB are members of phenolic acid compounds, which are the main type of hydrophilic components from Danshen, the dried roots of Salvia miltiorrhiza. Three active compounds, sodium danshensu (DSS), rosmarinic acid (RA), and salvianolic acid B (SAB), were shown to be antagonistic to sCD36-oxLDL binding. A soluble form of CD36 recently was demonstrated to be present in plasma, and it was suggested as a novel marker for metabolic syndrome and atherosclerosis. The relative order of magnitude of the activity of these CD36 antagonists is SAB > RA > DSS > hexarelin.

Pitavastatin prevents OxLDL uptake by macrophages through PPARG-dependent inhibition of CD36 expression. PPARG is activated by such diverse agents as long-chain fatty acids, arachidonic and linoleic acid metabolites. PPARG is a positive regulator for its target genes, whereas its phosphorylated form (PPARG-Pi) is a negative regulator.

Ursolic acid as an inhibitor of Amyloid beta Protein (AB) Interactions with Its Receptor CD36. AB binds to microglia via a receptor complex that includes CD36 leading to production of proinflammatory cytokines and neurotoxic reactive oxygen species and subsequent neurodegeneration. Interruption of AB binding to CD36 is a potential therapeutic strategy for Alzheimer disease.

RRR-alpha-tocopherol decreases the expression of the major scavenger receptor, CD36, in human macrophages via inhibition of tyrosine kinase (Tyk2). Protein kinase C inhibitors or NAC had no effect while there was a significant inhibition with tyrosine kinase inhibitors.

Apigenin binds to non-phosphorylated STAT3, reduces STAT3 phosphorylation and transcriptional activity in VAT, and consequently reduces the expression of STAT3 target CD36. The reduced CD36 expression in adipocytes reduces the expression of PPARG which is the critical nuclear factor in adipogenesis. Our data show that apigenin reduces CD36 and PPARG expressions and inhibits adipocyte differentiation.

Other supplements that may indirectly decrease or interact with CD36:

Agaricus bisporus-derived Beta-glucan enter macrophages and adipocytes by CD36 receptor. Beta-glucans are a heterogeneous group of natural polysaccharides. They are ubiquitously found in bacterial or fungal cell walls, cereals, seaweed, and mushrooms. B-glucan enters the small intestine and some can be captured by the macrophages. The structure of agaricus bisporus-derived B-glucan was different from that of reported b-glucan.

Agaricus bisporus-derived Beta-glucan prevents obesity through PPARG downregulation and autophagy induction in zebrafish fed by chicken egg yolk. B-Glucan lowered the level of C/EBPa, c SREBP1, LXR a, PPARG by WB analysis, which were accompanied by an increase level in LC3 II/LC3 I and a decline level in p62 in dose-dependent manner.
In the small intestine, cd36 exhibits a proximal to distal decreasing expression gradient, which is believed to facilitate in uptake of fatty acid and cholesterol for packing into lipoproteins. B-Glucan decreased the expression of pparg, and its target genes except cd36, the reason might be that cd36 could be one of the receptor for B-glucan enter adipocytes, we had proved it in 3T3-L1 mature adipocytes. The net result of cd36 expression was slightly declined or elevated without significance.

The excreted polysaccharide of Pleurotus eryngii inhibits the foam-cell formation via down-regulation of CD36.

Astaxanthin activates PPARA, inhibits PPARG expression, and reduces intrahepatic fat synthesis. In addition, astaxanthin inhibits the AKT-mTOR pathway, which also causes autophagy of liver cells and breaks down lipid droplets stored in the liver. Yang et al. confirmed that astaxanthin can reduce the expression of the TGF-B1-induced fibrosis genes alpha-SMA and Col1A1 and effectively inhibit fibrosis in LX-2 cells.

L-theanine treatment significantly reduced scavenger receptor A protein in a time-dependent manner, but did not affect levels of CD36. The protective effects of L-theanine on the atherosclerosis might be involved in inhibiting cholesterol uptake from macrophages by diminishing the protein stability of scavenger receptor A.

The mRNA expression of C/EBPa and PPARG was decreased by 55 and 37%, respectively, following red yeast rice extract exposure.

Therefore, these results suggest that scutellarin, a major component of Scutellaria baicalensis, attenuates fat cell differentiation by upregulating PPARA as well as downregulating the expression of PPARG and C/EBPalpha, thus showing therapeutic potential for obesity-related diseases.

This study examined whether trans-anethole (TA), a major component of the essential oils of fennel, induces UCP1-independent SERCA/SLN-based thermogenesis and promotes the lipid metabolism in muscle cells. TA enhanced myogenesis, lipolysis, and the oxidative metabolism in C2C12 muscle cells.

Increasing size and number of adipocytes correlate with higher lipid deposition. The main regulator of adipocyte gene expression and adipocyte differentiation is PPARG. Activation of PPARG causes lipoprotein lipase expression, adipocyte protein 2, as well as adiponectin and fatty acid synthase.
The treatment with Coprinus comatus (CC) reduced mRNA levels of PPARG and C/EBPB (CCAAT-enhancer-binding proteins) in a time- and concentration-dependent manner. CC prevented adipocyte differentiation because of its antagonistic effect on PPARG.

Endothelial-specific SIRT1 transgenic mice could significantly inhibit vascular endothelial senescence induced by hyperglycemia, accompanied by reduced expression of aging marker proteins such as p53 and p21 and oxidative stress-related enzymes. Conversely, knockdown of SIRT1 via siRNA in HUVEC significantly increased the percentage of senescence cell and ROS level. Hypoglycemic drug metformin, which has recently been considered as a promising antiaging drug, was also proved to prevent hyperglycemia-induced endothelial senescence through upregulation of SIRT1 expression.
The senescence marker p21, also known as cyclin-dependent kinase inhibitor 1, is an important negative regulator of cell proliferation. p21 prevents cell-cycle progression from G1 to S phase, thus promoting cellular senescence. Previous studies showed that p21 represents one of the major downstream targets of SIRT1. SIRT1 can specifically deacetylate p53 and then inhibited p21 activation and subsequent cellular senescence.
In the present study, we found high glucose increased the level of p21 protein, concomitantly with G1/G0 arrest. These senescence-related effects induced by high glucose can be inhibited by treatment with rutaecarpine. Mounting evidence indicates there is an antagonistic crosstalk between oxidative stress and SIRT1. ROS can directly suppress the expression and activity of SIRT1. N-acetyl-L-cysteine upregulated SIRT1 level and attenuated the premature senescence of adipose-derived mesenchymal stem cells.

Some controversy:

High-fat diet increased brown adipose tissue gene levels such as adrenoceptor beta 3 (ADRB3), PPARG, hormone-sensitive lipase (HSL), cluster of differentiation 36 (CD36), fatty acid-binding protein 4 (FABP4), PGC-1a, PPARA, and carnitine palmitoyltransferase 1B (CPT1B) compared with the NCD group; however, Polygonum multiflorum or Garcinia cambogia effectively reversed those levels. These results suggested that FA oxidation and lipolysis were up-regulated in response to fat overload.

HCA (Garcinia cambogia) supplementation, at 500 mg/day for 7 days, enhanced the glycogen synthesis rate and fatty acid translocase/CD36 mRNA expression in exercised human skeletal muscle and it also improved postmeal insulin sensitivity.

Niacin therapy attenuated hypertension, proteinuria, and tubulo-interstitial injury, reduced renal tissue lipids, CD36, ChREBP, LXR, ABCA-1, ABCG-1, and SR-B1 abundance and raised PPARA and L-FABP.

By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture.

Niacin can reduce serum level and adipose mRNA expression of leptin and up-regulate PPARG and CD36 mRNA expression in hypercholesterolemic rabbits.

Lycopene up-regulates mRNA expressions of SIRT and adiponectin and down-regulates PPARG and IL-6 in adipose tissue of hypercaloric diet-fed rats.

Lycopene has been demonstrated to protect LDL from oxidation in vitro, and some dietary studies have shown that lycopene-containing foods increase resistance of LDL to oxidation in vivo. We observed that lycopene dose-dependently induced the expression of both ABCA1 and cav-1 in THP-1 macrophages, favouring cholesterol efflux from macrophages through a potential mechanism involving RhoA inactivation and subsequent increase in PPARG and LXRa activity.
Treatment of lycopene alone rarely significantly decreased serum lipid peroxidation or in vitro LDL oxidation. On the contrary, interactions of lycopene with other nutrient compounds have been reported to strongly reduce LDL oxidation. A combination of lycopene with vitamin E (alpha-tocopherol) resulted in an inhibition of copper ion-induced LDL oxidation that was significantly greater than the expected additive individual inhibitions. The synergistic antioxidant effect of lycopene with vitamin E was not shared by gamma-tocotrienol. When lycopene was added to LDL in combination with glabridin, rosmarinic acid, carnosic acid, or garlic, synergistic antioxidative effects were obtained against LDL oxidation induced either by copper ions or by the radical generator AAPH.
Combinations of a phenolic compound (i.e. rutin) and carotenoids (i.e. lutein or lycopene) were also shown to exert supra-additive protection of LDL towards oxidation, which is most likely due to different allocation of the antioxidants in the LDL-particle and to different mechanisms of antioxidant action. A recent study indicated that ascorbic acid, alpha-tocopherol and lycopene can also inhibit LDL carbamylation and therefore may have a role in ameliorating atherosclerotic risk for patients with kidney failure.

Additionally, lycopene increased the mRNA and protein expression of NFE2-like bZIP transcription factor 2 (214.0% and 102.4%, respectively) and CD36 (100.8% and 145.2%, respectively) in the jejunum.

Unspecific cellular uptake and transport of lycopene are mediated via various binding proteins like Cluster of Differentiation 36, a non-specific carotenoid transporter protein (Cd36), Niemann-Pick C1-like 1 and scavenger receptor class B type I. Cd36 expression remained stable in testis, but we observed up-regulation of Cd36 expression after lycopene administration in liver. The two carotenoid metabolizing enzymes Bco-1 and Bco-2 may contribute to the lycopene metabolism and the non-specific carotenoid transporter Cd36 may contribute to lycopene uptake.

Lycopene also reduced the relative abundance of mRNA transcripts for scavenger receptor A (SR-A) in THP-1 macrophages treated with aggLDL. In contrast, levels of mRNA for CD36 in incubations with nLDL were significantly elevated by lycopene. Macrophages express a number of scavenger receptors, including SR-A, SR-B1, and CD36, with SR-A and CD36 thought to be the main receptors responsible for the uptake of modified LDLs. On the other hand, in contrast to vitamin E, lycopene did not decrease CD36 mRNA expression and also tended to cause proinflammatory rather than anti-inflammatory changes in cytokine secretion.

Conflicting reports exist with regard to the effect of ecdysterone, the predominating representative of steroid hormones in insects and plants, on hepatic and plasma lipid concentrations in different rodent models of obesity, fatty liver, and diabetes, indicating that the effect is dependent on the rodent model used. The present study clearly shows that ecdysterone supplementation does not exhibit lipid-lowering actions in the liver and plasma of lean and obese Zucker rats.

Both SOD2 and CD36 were upregulated in the heart of Honokiol treated mice and Honokiol rescued the impaired SOD2 and CD36 expression in Dox-treated hearts. These results indicate that Honokiol activates PPARG pathway in the heart in addition to repressing stress-induced protein acetylation.

Combined treatment of berberine, magnolol and honokiol significantly reduced cholesterol content in foam cells, also inhibited expression of TNF-a and CD36 in THP-1 macrophage. Co-administration of berberine, magnolol and honokiol can inhibit the formation of foam cells probably through, down-regulating the level of TNF-a and CD36.

The supplementation of honokiol as well as magnolol significantly downregulated the mRNA expression of FAS, SCD1, FAT/CD36 and IRS2 in the epididymal WAT of HFD-fed mice. Furthermore, honokiol- and magnolol-supplemented mice showed a significant decrease in the mRNA expression of their transcription factors, SREBP1c, and PPARG in the epididymal WAT compared to the control mice.

CD36, was observed to be unchanged in diabetic mice when compared to their corresponding control, while it was decreased in honokiol treated mice after 2 weeks and 10 weeks of hyperglycemia and also in honokiol treated control mice.

Ginsenoside Rg1 attenuates glomerular fibrosis by inhibiting CD36/TRPC6/NFAT2 signaling in type 2 diabetes mellitus mice.

The down-regulated expression of PPARG, FAS, CD36, FATP2 and up-regulated expression of CPT-1, UCP-2, PPARA, HSL, and ATGL in liver tissue was induced by Panax ginseng.

Korean red ginseng down-regulated gene expressions of sterol regulatory element binding protein 1c (SREBP1c) and its target proteins, such as fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD1) in time- and dose-dependent fashions. In contrast, gene expressions of PPARA and CD36 were increased. These effects were reversed in the presence of compound C, an AMPK inhibitor.


Gluten intake raises leukocytes infiltration and CD36 expression in the atherosclerotic lesion. Gluten intake increased the CD36 expression, indicating an increase in uptake of oxLDL by macrophages, favoring foam cell formation and accelerating plaque growth. Gluten intake increases oxidative stress in the atherosclerotic lesion. Although there was no effect on the production of proinflammatory cytokines, we observed a reduction in IL-10 in the gluten group. Gluten exacerbated the production of MMP2 and MMP9 in adipose tissue.

We have for the first time purified the CD36-positive gustatory cells from mouse CVP and demonstrated that linoleic acid induced increases in [Ca2+]i in these cells via CD36. We observed that inhibitors of PTKs and Src-related kinases significantly diminished the LA-induced increases in [Ca2+]i in CD36-positive gustatory cells.

Dietary oleic acid-induced CD36 promotes cervical cancer cell growth and metastasis via up-regulation Src/ERK pathway. Oleic acid up-regulated the expression of CD36. Inhibiting CD36 prevented the tumor-promoting effects of oleic acid, while overexpressing CD36 mimicked the effects of oleic acid.

Similar to rosiglitazone, madecassic acid promoted the expression of PPARG-responsive genes CD36 and LPL, induced PPARG translocation from cytoplasm to nucleus and the binding of PPARG to a reporter gene, which could be diminished by PPARG antagonists or PPARG siRNA.

Cannabis compounds exhibit anti-inflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and pro-inflammatory activity in macrophages. FCBD contained cannabidiol (CBD), cannabigerol (CBG) and tetrahydrocannabivarin (THCV), and multiple terpenes.
FCBD reduced IL-8 and IL-6 secretion in alveolar epithelial cells. FCBD treatment also led to an increase in FcgRII and CD36 gene expression (in macrophages). The increase of macrophage-secreted IL-6 and IL-8 levels by cannabis-based treatment may potentially lead to a worsening of the "cytokine storm" identified in severe COVID-19 patients.

An increased number of foam cells was detected in bronchoalveolar lavages and lungs after inhaling e-cigarette smoke from products containing cannabinoids and the vitamin E analogue, alpha-tocopherol acetate (aTA), that was present as vape-cartridge additive. In THP-1 macrophages, CD36 was only up-regulated by CBD and co-treatment with natural alpha-tocopherol acetate or synthetic racemic all-rac-alpha-tocopherol acetate reduced it. In THP-1 monocytes, cell cycle progression was only affected by CBD (increased G1, decreased S) and co-treatment with aTAn and aTAr restored it.

Highly specific ligands for MAO-A and MAO-B (clorgyline and deprenyl), 5-HT2A, imidazoline receptor I1 and I2 sites (clonidine and 2-BFI), and CDKs (roscovitine) did not promote adipocyte differentiation or PPARG expression.
Expression of PPARG1 and G2 and their downstream target genes involved in lipid storage and glucose metabolism such as aP2, CD36, LPL, GLUT4, Lipin-1a and -1b, C/EBPa, and Adipoq was increased in WAT of harmine-treated animals compared to controls. Furthermore, harmine reduced expression of the inflammatory mediators TNFa, IL-1B, and iNOS, as well as the macrophage markers F4/80 and Mac1, suggesting that adipose tissue inflammation was decreased. Interestingly, harmine also increased expression of PGC-1a and PPAR target genes involved in fatty acid oxidation in WAT.

I did not have time to do a more extensive research, but with a little search probably many more examples can be found.
« Last Edit: January 18, 2023, 04:55:20 PM by Progecitor »
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Senescence in Essence
« Reply #2 on: February 25, 2023, 11:09:16 AM »
My recent success with phosphatidylserine (PS) made me research it a bit more and some interesting findings turned up. For one it seems that PS has a role in SASP and other inflammatory conditions. Additionally CD36 counts as a PS binding receptor. Another significant finding is that PS is intimately involved in fertilization and it is abundant in sperm. Importantly the PS metabolizing enzyme called PLA1A is involved in many autoimmune diseases. What makes this even more important is that PLA1A is a 55 kDa protein and the abundance of a similar molecular weight protein was mentioned in the South Korean POIS study which makes this a very likely candidate, especially as it is highly expressed in the prostate gland. PLA1A and lysoPS is known to modulate the function of immune cells, such as T cells, dendritic cells, macrophages, and mast cells. PS is thought to be at the core of COVID-19 related thromboinflammation and could play a role in long COVID as well. While some of the functions of PS and phosphatidylcholine (PC) may be similar, they also have distinct features, thus testing both could be potentially worthwhile in the comprehension of the underlying mechanisms of POIS.

Cell senescence is well known to be associated with reduced function of the cell itself, and recently it has also been found that the accumulation of senescent cells damages the surrounding tissue.
In senescent cells, cell cycle is irreversibly stopped by tumor suppressor gene p53 or cyclin-dependent kinase inhibitor p16, and therefore cell senescence has been recognized as an anti-tumor mechanism. Recent studies, however, revealed negative effects of cell senescence; molecules secreted from senescent cells, such as inflammatory cytokines and matrix metalloproteinases (MMPs), damage the surrounding tissue and promote tumorigenesis.
Senescent cells in the heart lower the cardiac muscle function via SASP. Accumulation of senescent astrocytes in the brain impairs neural stem cells, which may cause anxiety disorder. The toxicity of senescent cells like these has been found in various tissues, and on the other hand, removal of such noxious senescent cells has been reported to improve age-associated dysfunction or damaged tissues. In the transgenic mice in which apoptosis is induced under the promoter of a senescence marker p16, removal of senescent cells was found to elongate the lifespan. Senescent cells are known to highly express anti-apoptosis factors such as BCL2, and thus resistant to apoptosis. Utilizing this characteristic of senescent cells, senolytic drugs, e.g. BCL2 inhibitors, which induce apoptosis selectively in senescent cells, have been tested for their effects and shown to have some positive effects on lifespan.
It is well known that macrophages deplete senescent blood cells or hepatocytes which have phosphatidylserine (PS) on their cell surface. While senescent cell clearance mechanism like this functions properly across the body, excessive accumulation of senescent cells could be avoided. However, given that the accumulation of senescent cells is seen in various tissues with aging, the clearance function is thought to become impaired.
PS exposed on the cell surface, which is characteristic of apoptotic cells. When macrophages engulf blood cells by phagocytosis, they recognized PS exposed on the surface of blood cells. Normally, PS is mainly localized in the inner surface of the cell membrane, and when the distribution of membrane phospholipids is disturbed by apoptosis or other reasons, PS gets out to the outer leaflet of the cell membrane. In senescent fibroblasts, unlike the blood cells, PS is not exposed on the outer cell surface, and hence senescent fibroblasts are not generally engulfed by macrophages. On the other hand, macrophages are known to induce apoptosis by secreting TNF-a. Our study suggested that senescent cells are cleared in two steps; first, TNF-a secreted from macrophages induces apoptosis in senescent fibroblasts, and secondly PS exposed on the surface of apoptotic cells is recognized by STAB1 on macrophages, resulting in engulfment and clearance. We also showed that both of the two processes were suppressed by SASP of senescent cells. This suggests that the increase of senescent cells (or SASP factors) excess a certain level impairs macrophage function and accelerates the accumulation of senescent cells. These dysfunctions of macrophages were possibly caused by shift of macrophage polarization.
One attractive measure for this problem would be selectively removing senescent cells using senolytic drugs, but in aged tissues even once senescent cells are removed, the recurrence of accumulation would be inevitable. Therefore, senolytic drugs might be able to partly help prevent tissue damage owing to senescent cells, but it is essential to keep the native clearance system in the body functioning properly. Homeostasis in the dermis requires constant clearance of senescent cells by macrophages, and hence keeping macrophage function should play a key role for the maintenance of homeostasis.

Here, we show that phosphatidylserine (PtdSer) is exposed on the head region of viable and motile sperm, with PtdSer exposure progressively increasing during sperm transit through the epididymis. Functionally, masking phosphatidylserine on sperm via three different approaches inhibits fertilization. On the oocyte, phosphatidylserine recognition receptors BAI1, CD36, Tim-4, and Mer-TK contribute to fertilization. Intriguingly, mammalian sperm could fuse with skeletal myoblasts, requiring PtdSer on sperm and BAI1/3, ELMO2, RAC1 in myoblasts.
Phosphatidylserine (PtdSer), exposed on viable sperm, is recognized by specific receptors located on the microvilli of the oocyte to promote sperm:egg fusion.
Although PtdSer has been noted on sperm previously, it was considered to mark dead or non-viable sperm because PtdSer is a key eat-me signal on cells undergoing apoptosis, which facilitates recognition and uptake by phagocytes. Interestingly, PtdSer can also be transiently exposed on viable cells in certain conditions (such as activated B and T cells, myoblasts, or macrophages).
We noticed a progressive increase in PtdSer exposure on sperm isolated from different segments of the epididymis, with the cauda epididymis, which contains the fertilization-competent sperm, displaying the highest percentage of PtdSer-positive sperm.
BAI members belong to the type II adhesion family of GPCRs (hence, also referred to as ADGBR family) with long extracellular region containing domains capable of directly binding PtdSer; CD36 is a member of the scavenger receptor family, and has also been linked to the binding of PtdSer. CD36 is also reported to function cooperatively with BAI1 on endothelial cells.
In the efferocytosis field, the PtdSer recognition by PtdSer receptors is known to include redundant mechanisms, as the charged head group of the lipid PtdSer can be recognized in a polyvalent fashion by multiple receptors to provide sufficient avidity and specificity. We decided to test all of the five potential PtdSer receptors detected in oocytes (CD36, BAI1, BAI3, Tim-4, and Mer-TK). Interestingly, CD36 has been shown to cooperatively function with BAI1 in endothelial cells. Antibodies to either BAI1/3 or CD36 alone did not inhibit fertilization, a combination of antibodies targeting both BAI1/3 and CD36 caused a reproducible and statistically significant inhibition of fertilization in vitro. Blocking three of the five PtdSer receptors (BAI1/BAI3, and CD36) expressed on oocytes can also impair fertilization in vitro, complementary to the masking of PtdSer on the sperm.
Single knockout of PtdSer receptors often show partial defects in apoptotic cell clearance, and defects are better revealed by deletion of more than one receptor.
Signaling downstream of PtdSer recognition receptors, CD36 has a rather short cytoplasmic tail without an obvious direct signaling, and CD36 can cooperatively signal with BAI1.
In summary, these data suggest that PtdSer on sperm and its receptors on oocytes as functional players that can work in conjunction with Izumo1 and Juno to promote sperm:egg fusion during fertilization.

Direct macrophage recognition of an externalized PS signal on senescent erythrocytes is a process of erythrophagocytic clearance that is in line with the general clearance process of all other circulating cells that become apoptotic. Advances in deciphering this process suggest that oxidation of the erythrocyte’s hemoglobin, the salient target of the free radicals encountered in the circulatory environment, may drive subsequent steps. The progressive accumulation of oxidized hemoglobin covalently bound to the membrane skeleton not only disrupts membrane organization but also threatens eventual phospholipid oxidation via a calcium-promoted quasi-lipoxygenase activity. The emergence on the cell surface of a threshold concentration of oxidized phospholipids, principally PS, signals recognition by the CD36 macrophage receptor.

Aging is an independent risk factor for the development of atherosclerosis, which is characterized by hyperlipemia. The senescence-accelerated mouse (SAMP8) is an animal model used in studies of aging, which is associated with a shift of fatty metabolism toward lipogenesis. Both dietary docosahexaenoic acid-enriched phosphatidylcholine (DHA-PC) and docosahexaenoic acid-enriched phosphatidylserine (DHA-PS) significantly decrease serum and hepatic lipid levels. Supplementary DHA-PS remarkably alters the ratio of phosphatidylethanolamine (PE) to PC in liver. Mechanistically, DHA-PC and DHA-PS suppresses hepatic SREBP-1c mediates lipogenesis and activates PPARA mediated fatty acid beta-oxidation in the liver.
In addition, DHA-PC and DHA-PS did not change the transcription levels of genes related to fatty acid transportation (Fatp, CD36) and triglyceride hydrolysis (LPL, HSL) in liver.
Both DHA-PC and DHA-PS decreased protein expression of FAS, which was responsible for lipid synthesis. DHA-PS revealed a better effect on inhibiting lipogenesis than DHA-PC. Our previous study also revealed that PS enriched EPA was more effective in reducing malic enzyme (ME) expression than EPA-PC, which indicated the better effect of EPA-PS on mediating lipogenenesis.
DHA-PC and DHA-PS improved age-related lipometabolic disturbance by inhibiting hepatic fatty acid synthesis and enhancing hepatic fatty acid beta-oxidation, in which DHA-PC should be the more effective structure for ameliorating hyperlipidemia than DHA-PS. Besides, these data are firstly to indicate that DHA-PS has beneficial effect on lipid metabolic disorder.

DHA-PC and DHA-PS remarkably recovered the lipid homeostasis in dementia mice.
DHA is the most abundant omega-3 fatty acid in the brain. Phosphatidylcholine (PC), transported by phosphatidylcholine transporter between membranes, is the main component of biofilm. It is sufficient to activate the endogenous ligand for the nuclear receptor peroxisome proliferator-activated receptors (PPARA) in hepatocytes. Phosphatidylserine (PS) is the major acidic phospholipid class that accounts for 13–15% of the phospholipids in the human cerebral cortex, and it is localized exclusively in the inner leaflet of the plasma membrane in neural tissues. PS can interact with Akt, Raf and protein kinase C to ensure the growth and differentiation of nerve cells. Our previous study showed that DHA-PS has more significant effect than DHA-PC on alleviating Abeta-induced cognitive deficiency. Daily intake of 100 mg DHA-PS could improve memory and maintain cognitive level in dementia patients.
The brain is a closed system isolated by blood-brain barrier, and supplementation of exogenous lipids may not cause significant changes in the lipid composition of the brain. Owing to the lipid and fatty acid composition, cerebral cortex has high peroxidability index. Therefore, the PUFA content in glycerophospholipid could reflect the oxidative stress status in the brain to some extent.
Plasmalogens are critical for human health and have established roles in neuronal development, the immune response and as endogenous antioxidants. Plasmalogen was decreased significantly in human brain with AD, in which ethanolamine plasmalogen was the main component. The ethanolamine plasmalogen has good antioxidant activity owing to its vinyl ether double bond and n-3 polyunsaturated fatty acids.
Both DHA-PC and DHA-PS significantly improved the cognitive deficits in SAMP8 mice fed with high-fat diet using maze tests. DHA-PS presented more notable benefits than DHA-PC on inhibiting Abeta pathology, mitochondrial damage, neuroinflammation. It has been reported that administration of egg PC could improve memory and maze-learning ability in mice with dementia by raising the acetylcholine level in brain. Phosphatidylserine, as an important nutrient for cell membrane, was essential for the activation of several key signaling pathways in neuronal signal transduction. PS supplementation could improve the memory functions of the elderly with memory complaints, increase acetylcholine release and the activity of Na1, K1-ATPase in synaptogenesis. DHA-PC could ameliorate cognitive impairment mainly through cholinergic system, while signal transduction molecules might be the main reason for the effect of DHA-PS on improving memory function.

The DHA-PS treatment ameliorated non-alcoholic fatty liver disease (NAFLD) and effectively decreased the serum total cholesterol, triglyceride, non-esterified fatty acid, and low-density lipoprotein cholesterol levels and considerably increased the serum high-density lipoprotein cholesterol levels. Moreover, the DHA-PS treatment reduced the levels of liver-function enzymes and pro-inflammatory cytokines and also the oxidative stress indices. Furthermore, DHA-PS increased the diversity and richness of the beneficial intestinal microorganisms, suggesting its potential as a dietary supplement and functional food to combat HFD-induced NAFLD.

Both EPA-PS and DHA-PS significantly protected the primary hippocampal neurons against Abeta-induced toxicity by inhibiting the mitochondrial-dependent apoptotic pathway and phosphorylation of JNK and p38. In addition, EPA-PS and DHA-PS significantly promoted the neurite outgrowth of primary hippocampal neurons.

In vitro, blood cells (BCs) and endothelial cells (ECs) exposed more PS in hypoglycemia or hyperglycemia. Uric acid induced PS exposure on cells (excluding platelets) at concentrations >6 mg/dL. Levels of PS+ BCs and microparticles were positively correlated with uric acid (UA) and proteinuria, but negatively correlated with glomerular filtration rate.
PS is a phospholipid that is abundant in eukaryotic plasma inner membranes, and exposed by the action of scramblase on the cell’s surface in biological processes such as apoptosis and cell activation. During these processes, microparticles (MPs) are released from the cell membrane having exposed PS and expressing membrane antigens specific to their origin. PS on cells and MPs creates a catalytic surface for blood-clotting factors, facilitating the conversion of prothrombin to thrombin.
We found that both hyperglycemia (25 mmol/L) and hypoglycemia (2.5 mmol/L) induced increased PS exposure on cells compared with normoglycemia (5 mmol/L). This finding is consistent with the evidence reported in cells and animals, suggesting that hyperglycemia after hypoglycemia produces a 'reperfusion-like' effect.

Among these endogenous phospholipids, only PS stimulated the 5a-reductase, suggesting that the lipid requirement is specific for PS in steroid 5a-reductase from liver microsomes.

Externalization of PS, has been implicated in a number of cell membrane processes including coagulation and apoptosis. Possible mechanisms for increased PS exposure include lower tight junction integrity, derangement of normal membrane polarization, malignant transformation into an undifferentiated state, and increased cell division. Surface exposure of PS has also been described as a signal for the removal of apoptotic cells and senescent RBCs. The role of PS in coagulation is especially interesting since the exposure of this phospholipid is required as a template for the assembly of the prothrombinase complex on the cell membrane surface. The rate of apoptosis in the kidney is thought to be quite high due to the constant remodeling in the kidney nephron. This cycle is normally tightly constrained but could become unregulated in response to ischemic or toxic insult to the kidney tubule resulting in an increased population of hyperplastic or apoptotic cells, both of which expose PS on their surfaces to a greater degree than normal cells.

In the presence of excess PS, 50-60% of total calcineurin associated with PS in a Ca2+-sensitive manner. Calcineurin did not associate with phosphatidylcholine. Calmodulin interfered with the association of calcineurin with phosphatidylserine.

In the case where PtdSer fails in exposure or mistakenly occurs, there are occurrences of certain immunological and haematological diseases, such as the Scott syndrome and Systemic lupus erythematosus. Besides, viruses (e.g., Human Immunodeficiency Virus (HIV), Ebola virus (EBOV)) can invade host cells through binding the exposed PtdSer.
Glycosphingolipid, sphingomyelin, and phosphatidylcholine (PtdCho) mainly distribute on the outer leaflet, while aminophospholipids such as phosphatidylethanolamine (PtdEtn) and phosphatidylserine (PtdSer) mostly distribute on the inner leaflet. PtdSer, as an aminophospholipid, its asymmetry distribution on membranes is essential for various biological processes.
The Receptor tyrosine kinases TAM family, protein S (PROS1), GLA domain, and C2 domain, binding to PtdSer, all participate in both blood coagulation and immune processes.
Phagocytes, recognizing PtdSer on the surface of apoptotic cells by its receptors, subsequently, engulf the apoptotic cells to avoid inflammation. This study shows that Xkr8-mediated PtdSer exposure in apoptotic lymphocytes and senescent neutrophils is a key step in apoptosis. After PtdSer exposure, these cells are engulfed, preventing the release of toxic substances from dying or senescent cells.
Macrophages only engulf apoptotic cells, but not healthy cells. This specificity depends on the "eat-me" signal on the surface of apoptotic cells. The most representative signal is PtdSer signal, the main "eat-me" signal. Due to PtdSer exposure, apoptotic cells can be quickly and effectively recognized and eliminated by phagocytes. On the contrary, once the clearance fails, the apoptotic cells may enter the secondary necrotic stage, cause the phagocytes, and release pro-inflammatory cytokines and trigger inflammation.
PtdSer receptor families are multiple, of which two types have been identified as PtdSer-sensing receptors TAM receptor protein tyrosine kinases family (TYRO3, AXL, and MER) and TIM family (T cell/transmembrane, immunoglobulin, and mucin). Additionally other receptors on immune cells include avB3 or avB5 integrins, CD300a, BAI1, Stabilin, RAGE, LOX-1, etc.
TAM are expressed by many cells, such as Macrophages, Dendritic Cells, Antigen presenting cell, immature natural killer (NK) cells, Cerebellar Purkinje cells, Hippocampal dentate gyrus, Retinal pigment epithelium (RPE) cells, and Sertoli cells and play a vital role in hemostasis and anti-inflammatory. The immune system uses many methods to eliminate inflammation, one of which is to activate TAM for anti-inflammation. For example, TAM prevents inflammation in our body by inhibiting the Toll-like receptor (TLR) and TLR-induced cytokine receptor cascade.
The human TIM family includes three TIM proteins, including TIM-1, TIM-3, and TIM-4. They share a common structure, Immunoglobulin variable (IgV)-like domain that allows them to recognize PtdSer exposed on the surface of apoptotic cells with a high degree of specificity. TIM family regulates immune responses, including autoimmunity, transplant tolerance, the response to viral infections, and the regulation of allergy and asthma.
PtdSer can also be exposed on the surface of apoptotic cells during the immune process as an “eat-me” signal, recognized by receptors on the surface of phagocytes (such as TAM or TIM). Then the apoptotic cells are engulfed by phagocytes, thereby avoiding inflammation in our body.
Apoptotic cells progress to secondary necrosis integrity when they are not cleared in an efficient and timely manner, which will lead the phagocytes to release pro-inflammatory cytokines (i.e., TNF-a, IL-1B), thereby inducing inflammation.
PtdSer on cancer cells can also bind to TIM-3 or TAM and promote immune escape.

PS receptors, TIM1 and AXL, bind to virion- or apoptotic body-associated PS, internalizing cargo into the endosomal compartment. These receptors enhance entry of a wide range of enveloped viruses, including filoviruses and flaviviruses. We show here that SARSCoV-2 also utilizes PS receptors to enhance entry.

It is also plausible that the RNA encoded spike protein itself may have triggered the production of aPL-PS, as autoimmunity to PS may itself serve as a mediator of inflammation in COVID-19-induced disease pathogenesis.

Autoimmune anti-DNA and anti-phosphatidylserine antibodies predict development of severe COVID-19. Statistical analysis identified strong correlations between anti-DNA antibodies and markers of cell injury, coagulation, neutrophil levels and erythrocyte size.

Plasma microparticles of intubated COVID-19 patients cause endothelial cell death, neutrophil adhesion and netosis, in a PS-dependent manner.

We found an unexpectedly high amount of blood cells loaded with PS+ platelet-derived microparticles (PMPs) for weeks after the initial COVID-19 diagnosis. Elevated frequencies of PS+PMP+ peripheral blood mononuclear cells (PBMCs) correlated strongly with increasing disease severity.
PS is a plasma membrane component actively retained by an ATP-requiring process at the inner membrane surface in living cells. PS retention stops, for example, during cell death or when cells release PS-containing microparticles or enveloped viruses. Prolonged adverse effects of PS+ PMPs on the immune system could contribute to 'long COVID'.

Phosphatidylserine is an overlooked mediator of COVID-19 thromboinflammation. A ubiquitous component of the inner surfaces of plasma membranes, PS is always present at sites of inflammation and cell death, but is never considered to be an active participant in causing tissue injury. Students of blood coagulation have concluded that exposure of PS is a major regulator of the blood coagulation system. In some clinical settings procoagulant phospholipids may play an active role in promoting tissue injury, inflammation and thrombosis, a condition that might appropriately be called a “procoagulant phospholipidopathy”. Physiologic or pathologic “activation” of cells can lead to exposure of PS on the external surface of cells, or microparticles released by cells.

Under physiological conditions, the PtdSer exposure on the outer leaflet of activated platelets provides a platform for the aggregation of various coagulation factors, is involved with red cell senescence, cell activation and/or death and with inhibition of activation of inflammatory and autoimmune mechanisms.
Activated macrophages are the main source of pro-inflammatory cytokines such as IL-1B, IL-6, IFN-g, IL-8, and TNF-a. These cytokines activate the acute inflammatory response due to increased endothelial permeability and a chemotactic effect on neutrophils, monocytes, and cytotoxic T lymphocytes.
Transient PtdSer exposure has been reported in conditions such as PKC activation and cytosolic Ca2+ elevation, showing that diverse stimulus that can lead to exposure of PtdSer to the outer membrane leaflet.
PtdSer exposure acts as a signal for dead cell phagocytosis by macrophages, avoiding the activation of inflammatory and autoimmune mechanisms.
Exposure of PtdSer on the outside of the cell membrane also occurs under certain biological conditions such as platelet activation, microvesicle shedding from cell surfaces, anoxia, red cell senescence, and cell activation or death.
PtdSer on the outer side of the cell membrane also plays an important role as a docking site for enzymes such as Src kinase and protein kinase C (PKC), establishing protein-lipid interactions sustained by electrostatic forces between the negatively charged phospholipid head group and cationic amino acid clusters.
PtdSer translocation is related to elimination of senescent and damaged cells via binding to membrane receptors on macrophages, avoiding spillage of cellular contents and inflammation. However, during sepsis or inflammatory events like SARS-CoV-2 infection, PtdSer exposure could be up-regulated on cell surfaces throughout the body, including endothelial cells, platelets, erythrocytes, neutrophils, lymphocytes, and extra cellular microparticles.

Increase in serum levels of phosphatidylserine-specific phospholipase A1 in COVID-19 patients
Lysophosphatidylserine (LysoPS) might play important roles in inflammation through three kinds of G protein-coupled receptors [1]; LysoPS reportedly suppresses activation of T cells [2] and secretion of inflammatory cytokines from macrophages [3] and promotes phagocytosis of apoptotic cells, including apoptotic neutrophils, by macrophages [4]. Phosphatidylserine-specific phospholipase A1 (PS-PLA1) has been proposed to be involved in the production of LysoPS. The serum PS-PLA1 levels were significantly higher in the asymptomatic COVID-19 patients than in the healthy control subjects.
To date, elevated serum PS-PLA1 levels have been noted only in a limited number of pathological states, including cancers, SLE, and hyperthyroidism.
Considering that LysoPS might have important roles in the resolution of inflammation, together with the result that the serum PS-PLA1 levels were lower in patients with severe COVID-19 than in those with moderate COVID-19, we propose the hypothesis that failure of the serum PS-PLA1 levels to increase adequately to suppress an overreactive immune system could result in the development of severe COVID-19 as a result of a cytokine storm.
Interestingly, the serum PS-PLA1 levels were negatively correlated with the serum anti-SARS-CoV-2 antibody levels. Considering that LysoPS plays important roles in the biology of lymphocytes, PS-PLA1 might affect the generation of anti-SARS-CoV-2 antibodies through LysoPS.
In summary, COVID-19 patients showed elevated serum levels of PS-PLA1, an enzyme involved in the synthesis of LysoPS, in a bell-shaped manner depending on the severity of COVID-19. The alteration of the serum PS-PLA1 levels might represent compensatory biological responses directed at suppressing immunological overreaction of the body in COVID-19, which is an important risk factor for mortality from the disease.

Various human tissues and cells express phospholipase A1 member A (PLA1A), including the liver, lung, prostate gland, and immune cells. The enzyme belongs to the pancreatic lipase family. PLA1A specifically hydrolyzes sn-1 fatty acid of PS or 1-acyl-lysophosphatidylserine (1-acyl-lysoPS). PS externalized by activated cells or apoptotic cells or extracellular vesicles is a potential source of substrate for the production of unsaturated lysoPS species by PLA1A. Maturation and functions of many immune cells, such as T cells, dendritic cells, macrophages, and mast cells, can be regulated by PLA1A and lysoPS. PLA1A may contribute to cardiometabolic disorders through mediating cholesterol transportation and producing lysoPS.
Purified PLA1A has an apparent molecular weight of 55-kDa on SDS-polyacrylamide gel electrophoresis.
Membrane-bound PLA1A can hydrolyze externalized PS and be internalized into living mammalian cells through binding to heparan sulfate proteoglycans. PLA1AdeltaC and PLA1A can synergistically induce lipid signaling through hydrolyzing PS exposed on damaged or activated cell surface and control the level of lysoPS.
Several human tissues express PLA1A including muscle, kidney, small intestine, spleen, placenta, and testis, with the highest expression in the liver and prostate gland. The liver might be a source of circulating PLA1A.
Exposure of PS on the outer membrane leaflet is the gold marker of cells undergoing apoptosis and is an eat-me signal for the clearance of dying cells by macrophages (Mfi), a process called efferocytosis. The engulfment of apoptotic cells does not induce inflammation but promotes the secretion of anti-inflammatory cytokines (IL-10 and TGF-B) and decreases the production of TNFa, IL-1B and IL-12. PS functions as an immunosuppressive mediator for silent clearance of apoptotic debris by Mfi.
The externalization of PS has been reported in viable monocytes, activated mast cells, CD8+ T cells, regulatory B cells, cancer cells and cancer cell-derived extracellular vesicles (EVs).
Compared with secreted phospholipase A2 group IIa (sPLA2-IIa), PLA1A produces lysoPS more efficiently and is more potent in inducing histamine release from rat peritoneal mast cells and stimulating alkaline phosphatase-tagged TGFa release. 2-acyl-lysoPS is a lipid mediator for mast cells, T cells, and neural cells.
A few reports suggested that PLA1A and lysoPS receptors could be involved in immune cell reprogramming, maturation, and modulation of immune cell functional responses.
The TLR4 agonist lipopolysaccharide (LPS) enhanced PLA1A mRNA expression in human THP-1 derived Mfi. Immunosuppressive agents, such as corticosteroids, prednisolone, 6a-methylprednisolone, dexamethasone, and beclomethasone reduced LPS-mediated PLA1A expression in THP-1 derived Mfi. Nerve growth factor (NGF) antibodies or inhibition of NGF receptor tyrosine kinase activity can completely block histamine release by rat peritoneal mast cells. Furthermore, histamine release by rat peritoneal mast cells incubated with PS+ erythrocytes and NGF required the presence of PLA1A, thereby suggesting a role for PLA1A-derived lysoPS in mast cell activation.
Under physiological conditions, the PS in the inner cell membrane layer is not accessible to secreted PLA1A. However, in cells undergoing apoptosis or during cell activation, externalized PS can be converted by secreted PLA1A to lysoPS, which potentially induces lysoPS receptor-dependent functional responses in various cell types.
High PLA1A expression levels in melanoma cells or subtypes of prostate cancers, autoimmune disorders such as SLE and Graves’ disease suggest a role for PLA1A in the regulation of tumor growth and autoimmunity. Disease treatment reduced serum PLA1A levels. However, serum PLA1A level inversely correlated with the daily dose of prednisolone.
Intestinal inflammation modulates the expression of PLA1A and lysoPS receptors. PLA1A expression was increased in inflamed ulcerated mucosa from Crohn’s disease, even in their noninflamed macroscopically normal-looking mucosa.
Expression of PLA1A is elevated in various diseased tissues and is possibly induced in response to inflammatory stimuli. By hydrolyzing PS, PLA1A might contribute to inflammation or interfere with processes involved in inflammation-resolution mechanisms through coving the recognition of apoptotic cells/debris by other immune cells, such as Mfi and dendritic cells (DCs), leading to the development of autoimmunity.
PLA1A can promote tumor progression through the generation of lysoPS. PLA1A is part of a signature gene set modulated by nongenotoxic hepatic tumorigens in rats, including PPAR agonists and steroid hormones.
Overexpression of Pla1a in human apoA-I transgenic C57BL/6 mice led to increases in serum phospholipids/apoA-I ratio and cholesterol efflux. The high high-density lipoprotein cholesterol levels and phospholipids/apoA-I ratio were associated with enhanced cholesterol efflux via the scavenger receptor class BI and reduced efflux via the ATP-binding cassette transporter 1, respectively.
Increased expression of PLA1A seems to be associated with fibrosis.
There is growing evidence suggesting roles for PLA1A in many pathological conditions, including autoimmune disorders, cancers, cardiometabolic disorders, antiviral innate immune responses, and other diseases. Elevated PLA1A expression and high PLA1A protein levels are associated with various pathologies. Increased PLA1A expression and release in tissues and biological fluids result in hydrolysis of surface exposed PS. Production of high level of lysoPS might subsequently contribute to disease development through lysoPS receptor activation.
« Last Edit: February 25, 2023, 11:13:16 AM by Progecitor »
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Senescence in Essence
« Reply #3 on: September 07, 2023, 06:24:52 PM »
Plasmalogens are critical for human health and have established roles in neuronal development, the immune response and as endogenous antioxidants. Plasmalogen was decreased significantly in human brain with AD, in which ethanolamine plasmalogen was the main component. The ethanolamine plasmalogen has good antioxidant activity owing to its vinyl ether double bond and n-3 polyunsaturated fatty acids.

High-dose Plasmalogen supplements:

Episode #186: Plasmalogens with Dr. Dayan Goodenowe, PhD

Plasmalogen level peak around age 40 - 60 years.
« Last Edit: September 07, 2023, 06:57:29 PM by Muon »