| |
A Novel Perspective on the Biology of Bilirubin in Health and Disease....."Unconjugated bilirubin (UCB) is known to be one of the most potent endogenousantioxidant substances....to ameliorate atherosclerosis, cancer, autoimmunity, and/or neurodegenerative conditions.....BLB has also potent anti-inflammatory activities in brain tissue"
|
| |
| |
Download the PDF here
---------------------------------
IWCADRH: Hyperbilirubinemia During ATV/r Initiation May Slow the Progression of Carotid Wall Thickening Through its Effects on Glucose and Lipid Metabolism: - (09/22/16)
IWCADRH: (1) Association between bilirubin and cardiovascular and cerebrovascular disease events among persons living with HIV across the US - (2) Association between initial antiretroviral therapy regimen and cardiovascular disease events among persons living with HIV in the US - (09/22/16)
IWCADRH: One Third Lower MI Risk With Atazanavir Than Other ARVs in US Veterans -Cardiovascular outcomes with atazanavir versus non-atazanavir containing antiretroviral regimens among HIV-infected veterans: a US national study (09/22/16)
---------------------------
A Novel Perspective on the Biology of Bilirubin in Health and Disease....."Unconjugated bilirubin (UCB) is known to be one of the most potent endogenousantioxidant substances....to ameliorate atherosclerosis, cancer, autoimmunity, and/or neurodegenerative conditions.....BLB has also potent anti-inflammatory activities in brain tissue"
"BLB has also potent anti-inflammatory activities in brain tissue......Mildly elevated BLB levels, as seen in patients withGilbert syndrome, have been shown to be protective against an array of diseases associated with increased oxidative stress, such as cardiovascular diseases (CVD), diabetes and cancer......These concepts provide the basis for a new understanding of BLB metabolism, raising the possibility that modulating the levels and/or activities of serum BLB, HMOX, and BLVR (the'yellow players')could be a novel therapeutic tool to ameliorate atherosclerosis, cancer, autoimmunity, and/or neurodegenerative conditions.....BLB acts not only against oxidative stress. The protective effects of mild hyperbilirubinemia are complex, affecting multiple stages of cell and tissue biology, as evidenced by both clinical and experimental studies. These have included reducing the effects of lipids on body weight in overweight and obese human subjects [43, blood pressure in hypertension (each micromolar increase in serum BLB decreased systolic blood pressure by 0.13 mm Hg [44), and serum homocysteine concentrations in diabetic retinopathy [45. BLB has also been reported to have immunomodulatory and anti-inflammatory effects [46, to modulate platelet functions and hemostasis [47, to influence vascular dysfunction, cell-cell adhesion [6, NO production in HUVEC and H5V cells [48, and intracellular signaling upon vascular injury in rats....Insulin-like activities of BLB were reported in rat fat cells as early as 1980, and were recently confirmed by the observations that BLB can increase insulin sensitivity, ameliorate obesity, and suppress chronic inflammation and endoplasmic reticulum stress in leptin receptor-deficient (db/db) and diet-induced obese mice (DIO) [49. BLB also exerts beneficial effects in DIO mice by reducing leptin, glycemia, and cholesterol concentrations, and by increasing adiponectin
-----BLB has also potent anti-inflammatory activities in brain tissue.......Oxidative imbalance is a common feature of neurological conditions due to the high lipid content and oxygen consumption, and limited antioxidant mechanisms in the brain....Clinical evidence indicates that lower serum BLB levels occur in a range of neurological diseases, such as Alzheimer disease (AD), dementia, multiple sclerosis, and cerebral infarctions....The protective activity of HMOX2 is due to BLB and inducible NO synthase (iNOS) expression and NO production acting on synaptic plasticity, improving memory processes (reviewed in [64) and specifically reducing apoptosis but not necrosis [68. These effects are present at low BLB concentrations [25-50 nanomolar free bilirubin (Bf)] in primary neuronal and granular cells [68. Comparable BLB concentrations (3-30 nanomolar Bf for 24-48 h)
impairedlong-term potentiation(LTP) andlong-term depression(LTD) in rat hippocampal organotypic cultures by calpain-mediated proteolytic cleavage of NMDA receptor subunits NR1, NR2a, NR2b, without altering interleukin (IL)-1β, or tumor necrosis factor (TNF)-α secretion [69. Thus, the loss of neurons in the CNS results in the loss of constitutive HMOX2, which further increases cellular damage....BLB has also potent anti-inflammatory activities in brain tissue. This effect has been well documented in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis [4.in vitro, 20-150 μmol total BLB inhibited T cell proliferation, and IL2, TNFα, IL4, and IL10 release, as well as MHC class II expression in macrophages via NF-κB signaling. The beneficial effect of BLB was confirmedin vivoby the reduction of the above-mentioned markers of inflammation and neurological damage when the serum BLB level was increased by eight- to tenfold in EAE rats [4. Consistent with anti-inflammatory activity, increased release of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) has been reported to lead to reduced neuronal loss in the substantia nigra in animal models of Parkinson disease (PD) via extracellular signal-regulated kinases (ERK), phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B (PI3K-Akt), and NF-κB signaling [70. In turn,J series prostaglandins (PGs)have been shown to induce HMOX1 and protect primary mouse neuron cultures from oxidative stress [71. HMOX1 induction has also been found to increase autophagyin vitro, a controlled modality of cell death"
"Concluding Remarks
Here, we present several lines of evidence to support the notion that BLB and all the machinery involved in its production and metabolism (the yellow players) are deeply involved in several crucial steps of cellular pathways and homeostasis. As shown in Figure 2, this occurs by a complex, intricate network involving several genes and pathways, indicating that BLB and related enzymes have more important functions than merely representing waste products, as had been described during the 1980s. They may undoubtedly represent fundamental players in both health and disease, although future experiments are required to validate many of their putative functions, particularly in humans (see Outstanding Questions). Interestingly, the antioxidant, anti-inflammatory, antiproliferative, and immunomodulatory activities of BLB and the yellow players lead to the intriguing idea that the regulation of, and by, these molecules could be used in preventative or therapeutic modalities in several common conditions, including metabolic, cardiovascular, oncogenic, and neurological disorders, as discussed here."
---------------------
Opinion
A Novel Perspective on the Biology of Bilirubin in Health and Disease
Sept 2016 Trends in Molecular Medicine
Silvia Gazzin,1,z Libor Vitek,2,z,* Jon Watchko,3 Steven M. Shapiro,4,5,6,7 and Claudio Tiribelli1,8,*
Unconjugated bilirubin (UCB) is known to be one of the most potent endogenous antioxidant substances. While hyperbilirubinemia has long been recognized as an ominous sign of liver dysfunction, recent data strongly indicate that mildly elevated bilirubin (BLB) levels can be protective against an array of diseases associated with increased oxidative stress. These clinical observations are supported by new discoveries relating to the role of BLB in immunosuppression and inhibition of protein phosphorylation, resulting in the modulation of intracellular signaling pathways in vascular biology and cancer, among others. Collectively, the evidence suggests that targeting BLB metabolism could be considered a potential therapeutic approach to ameliorate a variety of conditions.
Trends
Historically known for its toxicity but recently recognized as a powerful protective molecule, BLB is gaining more attention due to its pleiotropic biomolecular effects and those of the enzymes involved in BLB metabolism (the 'Yellow Players').
Both heme oxygenase (HMOX) and biliverdin reductase (BLVR) (the main enzymes in BLB metabolism) act on numerous signaling pathways, with unsuspected biological consequences. The interconnections of such pathways highlight an incredibly complex biomolecular network. Yellow player molecules can have important physiological and pathological biological outcomes. Their still unexplored roles merit attention, offering the possibility of being targeted for therapeutic benefit.
The moderately high levels of UCB in the blood of patients with Gilbert syndrome are suggestive of the protective role of BLB in non-neurological pathologies (cardiovascular diseases, cancer, and metabolic syndrome).
Cells and tissues might actively maintain the intracellular homeostasis of BLB, with the yellow players being viewed as novel antioxidant mechanisms in a cell.
This new point of view might also be applicable to neurological diseases, where BLB levels are lower than in healthy subjects.
From a Biological Waste Product to a Potent Biological Compound
UCB (see Glossary), the end product of the heme catabolic pathway, has long been recognized as a sign of liver dysfunction or a potential toxic factor causing severe brain damage in newborns. Mildly elevated BLB levels, as seen in patients with Gilbert syndrome, have been shown to be protective against an array of diseases associated with increased oxidative stress, such as cardiovascular diseases (CVD), diabetes and cancer [1, 2]. These clinical observations are consistent with recent discoveries relating to how BLB might affect the pathophysiology of these diseases (Box 1). BLB is recognized as the most potent endogenous antioxidant due to its continuous recovery in the BLB/biliverdin (BLV) redox cycle (Figure 1), resulting in protective lipid peroxidation both in vitro [HEK293 cells in which biliverdin reductase (BLVR) was silenced] and in vivo [heme oxygenase (HMOX) 2 knockout versus wild-type mice] [3. BLB also exerts immunosuppressive effects on antigen-presenting cells [4 and T cells [5, as well as in the inhibition of adhesion molecule expression [6 and immune cell migration [7 (see below). Moreover, BLB exerts widespread inhibitory effects on protein phosphorylation, resulting in the substantial modulation of intracellular signaling pathways with multiple implications in vascular and autoimmune pathologies, as well as in cancer. Indeed, BLB has been shown to inhibit neointimal and vascular smooth muscle cell hyperplasia in vivo and in vitro [8, in addition to arresting tumor cell growth, possibly inducing apoptosis [9. These concepts provide the basis for a new understanding of BLB metabolism, raising the possibility that modulating the levels and/or activities of serum BLB, HMOX, and BLVR (the 'yellow players') could be a novel therapeutic tool to ameliorate atherosclerosis, cancer, autoimmunity, and/or neurodegenerative conditions. As we proceed in understanding the multiple roles of these yellow players in modulating various cellular pathways, we suggest using the term 'bilirubinomics' to describe this field of study.
A New Perspective on the Bilirubin-Biliverdin Antioxidant Cellular Cycle
Until recently, intracellular BLB was mainly considered to either derive from the blood or be regenerated from BLV via the BLV/BLB cycle [10. The cycle is initiated by the microsomal HMOX1/2 (HMOX1 is inducible, whereas HMOX2 is constitutive) originating from BLV, and continued by the cytosolic BLV reductases (BLVRA and BLVRB) (Figure 1). The BLB antioxidant system involves de novo synthesis of heme mediated by the rate-limiting enzyme 5-aminolevulinic acid (ALA) synthase. The beneficial effect of ALA is well known in plant biology, and ALA is a potent supplement in commercial fertilizers to increase plant tolerance to environmental stress. In fact, protective effects of ALA against increased oxidative stress have been demonstrated in vivo in a mouse model of chronic hypoxia-induced pulmonary hypertension [11. In this study, sufficient intracellular heme concentration in pulmonary cells was not only required for the production of heme proteins involved in an array of biological functions, such as mitochondrial superoxide production or nitric oxide (NO) generation, but was also an important stimulus for HMOX1 induction, one of the major antioxidant enzymes [12. Indeed, clear therapeutic effects of hemin itself have been reported for several experimental oxidative stress-mediated as well as metabolic diseases, such as arterial hypertension [13 and diabetes [14 in rat experimental models. More recently, de novo intracellular synthesis of heme, which is then transformed into UCB [15, appears to have a crucial role in the defense against oxidative damage in human cell lines, including epidermal, kidney, hepatic, breast, colon, and erythroleukemia cancer cells [15. A similar cytoprotective role of BLB was also noted in vivo based on the observation that UCB binds the fatty acid-binding protein (FABP) UnaG in the muscles of freshwater eels [16. The resulting UnaG-UCB complex has been interpreted as an attempt to preserve and store this antioxidant to manage oxidative muscle metabolism during long-distance migration [16. We speculate that BLB is also likely to have an important role in phylogenesis, because there is evidence for the widespread occurrence of FABPs in nature, with it being present across several vertebrate orders [17.
As for the BLB-BLV redox cycle, the mitochondrial cytochrome P450 monooxygenase 2A6 isoform (CYP 2A6) is also able to oxidize UCB back to BLV, as shown in yeast transfected with the human enzyme [18); thus, CYP2A6 appears to be the 'missing enzyme' needed to complete the BLV-UCB cycle. It is not surprising that this enzymatic system operates to maintain intracellular BLB homeostasis, fine-tuning the 'yellow players' (Figure 2) with biological consequences that were unsuspected until recently.
As shown in mouse liver, the BLB-metabolizing enzymes are sequestrated within the cell in a highly integrated way, distinguishing between mitochondrial and cytoplasmic compartments (Figure 1) [19. According to the current concept, the fate of intracellular BLB depends on the degree of oxidative stress. This has been shown in mouse hepatic tissue, where the equilibrium is regulated by mitochondrial Cyp2A5 (the mouse ortholog of CYP2A6) preventing an excess of intracellular BLB [19.
Other mechanisms are also likely to have an important role in intracellular BLB homeostasis. Examples of these include the glucuronosylation of BLB by the enzyme uridine diphosphoglucoronosyl transferase 1A1 (UGT1A1) [19, resulting in increased BLB water solubility and allowing its excretion in bile. Alternatively, cellular BLB flux is regulated by the ATP-binding cassette transporters ABCC1/2/3, ABCG2, and ABCB1, together with the organic anion transporting polypeptide (OATP), which is involved in the regulation of the intracellular levels of heme (Figure 1).
Both UCB and BLV exert regulatory functions in multiple biological processes (Figure 2), and are potent endogenous activators of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor acting on various genes, including HMOX1 [20, CYP1A1/2, CYP2A6, UGT1A1 [21, SLCO1B1 (encoding OATP2) [22, and ABCs, involved in BLB biotransformation and transport. Indeed, the AhR signaling pathway appears to have a wider impact, since it is known to be part of a complex network including cell cycle regulation, mitogen-activated protein kinase (MAPK) cascade activation, and nuclear factor-erythroid-2-like 2 signaling [encoded by NFE2L2 (also known as Nrf2)]. These pathways induce a battery of genes linked to AhR/Nrf2 signaling [23, and the biological implications of this are illustrated in Figure 2. The modulatory role of AhR in kinase reactions may account for the potent inhibitory effects of UCB on protein phosphorylation, although this has not yet been extensively investigated. As shown in Figure 2, target genes include those involved in apoptosis, T helper-mediated immune responses [24, 25], and cellular proliferation and differentiation (vascular endothelial cells, smooth muscle cells, and macrophages), with important implications in carcinogenesis [20. Although AhR activation may induce proliferation, stimulation by endogenous substrates, such as UCB, may mediate cell cycle arrest, as demonstrated in LoVo human colon cancer cells in vitro, where AhR activation was shown to inhibit cell proliferation, inducing G1 cell cycle arrest via the downregulation of cyclin D1 and Rb protein phosphorylation [26. Similar results were previously observed in rat mammary and human pancreatic cancer cells [27. Thus, AhR-mediated mechanisms may contribute to the apparent anticancer effects of BLB, reported in the Third National Health and Nutrition Examination Survey of more than 176 million subjects [28. AhR per se is regulated by Nrf2, further strengthening the regulatory interplay between both factors (Figure 2, point 13) [29. In addition, AhR has been reported to have a role in immune responses, regulating T regulatory (Treg) and T helper 17 (Th17) cell differentiation [25, 30].
The HMOX and BLVR enzymes are expressed in a range of tissues and are synergistically induced by multiple stimuli provoking oxidative stress. In addition to producing UCB, BLVRA has several other biologically important actions [31 (Figure 2), including the unique multispecific (serine/threonine/tyrosine) kinase activity that contributes to cell signaling, as indicated from studies on human embryonic kidney cells transfected with hBLVR [32. BLVRA, as well as HMOX1, can translocate from the cytosol into the nucleus, activating, in an oxidative stress-induced manner, transcription in a variety of signaling pathways (Figure 2), including those involving survival, the stress response, Jak-Stat [33, transforming growth factor (TGF)-β, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and p38 MAPK [34, as well as modulating the expression of HMOX itself and AP-2-regulated genes [35. BLV and BLVRA have also been shown to modulate protein kinase C (PKC), a Ser/Thr kinase implicated in carcinogenesis [36. This complex network suggests that intracellular UCB should be considered a part of the antioxidant cellular system, via which cells can modulate their content and functions.
Thus, it is reasonable to assume that each cell and/or tissue may have different thresholds of intracellular UCB concentrations that result in either protective or dangerous outcomes. Indeed, different amounts of UCB have been quantified in both physiological and pathological conditions in animal tissues [37, and different levels of toxicity have been reported for different cells.
Bilirubin in Cardiovascular Disease, Inflammatory Metabolic Syndrome, and Diabetes
In humans, a low (<7 μmol/l) total BLB concentration has been shown to be a risk factor for systemic diseases associated with increased oxidative stress, such as cardiovascular diseases (CVD), diabetes, metabolic syndrome, certain cancers, and autoimmune and neuropsychiatric diseases (reviewed in [38). A meta-analysis study performed on a large male population with CVD showed that each micromolar decrease in serum BLB significantly increased the risk of atherosclerotic diseases [1, with a BLB concentration of 10 μmol/l being defined as the discriminating cut-off value. Compared with a BLB concentration > 10 μmol/l, a serum BLB concentration < 7 μmol/l was reported to increase the risk of CVD in the general population by 30%, comparable with that of high-density lipoprotein cholesterol [39, resulting in a new proposed cardiovascular risk calculation algorithm that includes the BLB concentration [40.
Recent studies on patients with colorectal cancer and Crohn's disease suggested a role of serum BLB as a global defense molecule against increased oxidative stress [41, 42]. These clinical observations were supported by an in vivo model of inflammatory colitis in mice, where BLB concentrations were found to prevent injury [7. Based on migration studies in T cell lines, it was suggested that vascular cell adhesion molecule 1 (VCAM-1)-mediated immune cell migration processes contributed to ameliorating the disease [7.
BLB acts not only against oxidative stress. The protective effects of mild hyperbilirubinemia are complex, affecting multiple stages of cell and tissue biology, as evidenced by both clinical and experimental studies. These have included reducing the effects of lipids on body weight in overweight and obese human subjects [43, blood pressure in hypertension (each micromolar increase in serum BLB decreased systolic blood pressure by 0.13 mm Hg [44), and serum homocysteine concentrations in diabetic retinopathy [45. BLB has also been reported to have immunomodulatory and anti-inflammatory effects [46, to modulate platelet functions and hemostasis [47, to influence vascular dysfunction, cell-cell adhesion [6, NO production in HUVEC and H5V cells [48, and intracellular signaling upon vascular injury in rats [8.
The progress in advancing our knowledge of the molecular mechanisms of BLB action is exemplified by the protective effect of BLB in diabetes and metabolic syndrome. Insulin-like activities of BLB were reported in rat fat cells as early as 1980, and were recently confirmed by the observations that BLB can increase insulin sensitivity, ameliorate obesity, and suppress chronic inflammation and endoplasmic reticulum stress in leptin receptor-deficient (db/db) and diet-induced obese mice (DIO) [49. BLB also exerts beneficial effects in DIO mice by reducing leptin, glycemia, and cholesterol concentrations, and by increasing adiponectin [50.
In obese mice, increased production of BLB activates peroxisome proliferator-activated receptor (PPAR)-α, fibroblast growth factor (FGF)-21 and glucose transporter (Glut)-1, resulting in reduced lipid droplet size, fatty acid synthase levels, body weight, and blood glucose [51. These effects were confirmed in a PPARα-knockout mouse model [52. Interestingly, the activating effects of PPARα on bile pigments were of the same magnitude as those of fenofibrate, a potent and clinically used activator of this nuclear receptor, and a recent in silico analysis revealed that PPARα ligands bear close structural similarities to BLB [52. Of note, BLV enhances the expression of CD36 [50, which is involved in fatty acid oxidation and control of diabetes [53, and BLB increases the expression of PPARγ [50, another master regulator of adipogenesis and obesity [54. The effects of BLB on AhR and PPARα-induced expression of FGF21 [55, a systemic insulin sensitizer, suggest that BLB itself harbors this property, which may account for the lower incidence of diabetes mellitus and metabolic syndrome in patients with Gilbert syndrome [38. These mechanisms are likely to be implicated in conditions where HMOX1 is induced [51.
Based on the agonist effects of BLB on PPARγ, BLB metabolism appears to be interweaved with bile acid metabolism [56. The link between both pathways might be PPARγ, since activation of this nuclear receptor in the intestine modulates bile acid metabolism via the FGF15/19 pathway [57.
Finally, heme is a strong modulator of adipogenesis, promoting the differentiation of fibroblasts to adipocytes in mouse 3T3-F442A cells; in line with this, it was demonstrated that increased heme catabolism by HMOX1 induction could increase adipogenesis in obesity and metabolic syndrome [58.
Bilirubin in Neurological Diseases
Clinical evidence indicates that lower serum BLB levels occur in a range of neurological diseases, such as Alzheimer disease (AD), dementia, multiple sclerosis, and cerebral infarctions (Table S1 in the supplemental information online). As described in AD, this may be mainly related to impairment in BLB production in the brain, rather than reduced supply from the blood to the brain, as has been described for other neurological diseases (see below).
Oxidative imbalance is a common feature of neurological conditions due to the high lipid content and oxygen consumption, and limited antioxidant mechanisms in the brain. In brain trauma [59, hemorrhage and hypoxic/ischemic conditions [60, heme released into extracellular spaces may contribute to vasospasms and induce oxidative stress leading to cell death [59, 60, 61] (Figure 3). Inside the cell, heme becomes a substrate for the constitutive HMOX2, which is highly and widely expressed in neurons (Figure 3). The protection may thereafter be potentiated by HMOX1 induction [59, 60], by heme itself, or by the carbon monoxide (CO)-mediated Nrf2 interaction with antioxidant response elements on the HMOX1 gene promoter [62. As a result, HMOX1 expression is upregulated in astrocytes, macrophages, endothelial cells [63, and in microglia surrounding brain lesions [61. HMOX1 modulation contributes to limiting lipid peroxidation, ameliorating brain damage and improving recovery from cell loss and motor impairment [59.
Several in vivo observations suggest a differential role for HMOX2 and HMOX1 in the central nervous system (CNS). As shown in a knockout mouse model, HMOX2 is protective (see above), whereas the induction of HMOX1 may be harmful, and its role different in other organs [63. HMOX2 may participate via CO in the development and inhibition of apoptosis in both primary cell cultures and in vivo ischemic and traumatic brain injury [64. By increasing NO levels, CO also impacts the long-term potentiation of signal transmission in the hippocampus, vessel tone, anti-inflammatory, and antioxidant activity, and modulates the activity of soluble guanylate cyclase, opening calcium-activated potassium channels [65. These results were demonstrated by exposing rodents or cells to CO, or by modulating HMOX activity in vitro [65.
Heme oxygenase activity counteracts glutamate excitotoxicity [66, another major mechanism of neuronal damage (Figure 3), both in vitro and in vivo in murine HMOX1-knockout models [67.
The protective activity of HMOX2 is due to BLB and inducible NO synthase (iNOS) expression and NO production acting on synaptic plasticity, improving memory processes (reviewed in [64) and specifically reducing apoptosis but not necrosis [68. These effects are present at low BLB concentrations [25-50 nanomolar free bilirubin (Bf)] in primary neuronal and granular cells [68. Comparable BLB concentrations (3-30 nanomolar Bf for 24-48 h) impaired long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal organotypic cultures by calpain-mediated proteolytic cleavage of NMDA receptor subunits NR1, NR2a, NR2b, without altering interleukin (IL)-1β, or tumor necrosis factor (TNF)-α secretion [69. Thus, the loss of neurons in the CNS results in the loss of constitutive HMOX2, which further increases cellular damage.
BLB has also potent anti-inflammatory activities in brain tissue. This effect has been well documented in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis [4. in vitro, 20-150 μmol total BLB inhibited T cell proliferation, and IL2, TNFα, IL4, and IL10 release, as well as MHC class II expression in macrophages via NF-κB signaling. The beneficial effect of BLB was confirmed in vivo by the reduction of the above-mentioned markers of inflammation and neurological damage when the serum BLB level was increased by eight- to tenfold in EAE rats [4. Consistent with anti-inflammatory activity, increased release of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) has been reported to lead to reduced neuronal loss in the substantia nigra in animal models of Parkinson disease (PD) via extracellular signal-regulated kinases (ERK), phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B (PI3K-Akt), and NF-κB signaling [70. In turn, J series prostaglandins (PGs) have been shown to induce HMOX1 and protect primary mouse neuron cultures from oxidative stress [71. HMOX1 induction has also been found to increase autophagy in vitro, a controlled modality of cell death [72.
From another perspective, brain deposition of iron, an important pathogenic factor in many diseases, has been documented for AD lesions, and shown to accelerate amyloid-β (Aβ) aggregation and increased cell death in vitro in cell lines exposed to Aβ fibrils in the presence of varying iron concentrations [73. In AD, the upregulation of HMOX1/BLVRA axis represents the early response to increased oxidative, nitrosative, and inflammatory reactions documented in the brains of patients with AD [64. Nevertheless, compared with other organs, the brain has a limited capability to counteract oxidative stress, and oxidative and nitrosative stress may lead to structural modifications in cellular enzymes. BLVRA appears to be especially sensitive to this effect, being functionally inactivated via reduced phosphorylation and autophosphorylation (necessary for its functions) despite the upregulation of its mRNA and protein levels. Consequently, the regeneration of cytoprotective BLB by the HMOX/BLVR cycle may be disrupted, resulting in damage and disease progression [64. Indeed, high concentrations of iron in the rat brain have been observed to rapidly increase NF-κB DNA binding, which may contribute to limiting oxygen reactive species-dependent damage by impacting the activity of the antioxidant enzyme, catalase [74.
|
|
| |
| |
|
|
|
