Manganese Superoxide Dismutase

Manganese Superoxide Dismutase


Antioxidant enzymes maintain cellular redox homeostasis. Manganese superoxide dismutase (MnSOD), an enzyme located in mitochondria, is the key enzyme that protects the energy-generating mitochondria from oxidative damage. Amounts of MnSOD are reduced in several disorders, including cancer, neurodegenerative diseases, and psoriasis. Overexpression of MnSOD in tumor cells can substantially attenuate the malignant phenotype. Past studies have reported that this enzyme really has the capacity to be utilized as an anti-inflammatory agent due to the superoxide anion scavenging ability. Superoxide anions possess a proinflammatory role in many disorders. The inflammatory reaction was suppressed by treatment of a rat model of lung pleurisy together with the MnSOD mimetic MnTBAP in a dose-dependent manner. In this paper, the mechanisms underlying the suppressive effects of MnSOD are studied, as well as the potential applications of this enzyme and its mimetics as anti inflammatory agents are discussed.

1. Introduction

ROS can damage proteins, lipids, and DNA, leading to aberrant downstream signaling or excitement of apoptosis [1, 2]. Oxidative stress has been implicated in pulmonary fibrosis, aging, cancer, neurodegenerative disorders, and vascular diseases [3-6]; elimination of unwanted ROS is, consequently, very important for organismal survival. Organisms have evolved various antioxidant enzymes, for example superoxide dismutase, catalase, and glutathione peroxidase to confront oxidative stress brought on by ROS. Nevertheless, ROS may also behave as cell and cause damage to foreign bodies [2]. ROS are, therefore, double-edged swords regarding biological processes.
Inflammation is a host defense response to tissue ischemia, and infectious agents, injury. Inflammation occurs due to the secretion of mediators of inflammation including cytokines, cyclooxygenase solutions and macrophage and lymphocyte invasion, and kinins [7]. Incorrect inflammation is a hallmark of numerous diseases. A large body of evidence indicates that antioxidant enzymes are essential regulators of inflammation. Manganese superoxide dismutase (MnSOD) is an enzyme within mitochondria that’s among the very first in a chain of enzymes to mediate the ROS created by the partial reduction of O2. MnSOD has been implicated in a number of oxidative stress-associated diseases. In this paper, we’ll discuss the function of MnSOD in various inflammation -related diseases and investigate the therapeutic potentials of agents that regulate its expression.
2. Regulation of MnSOD

The human MnSOD gene (sod2) has a housekeeping promoter with numerous duplicates of Sp1- and AP2- binding sequences. The promoter area also includes a GC-rich area and NF-?B transcription regulation components [14]. Several enhancers can also be present in the promoter area and in the next intron [15]. TNF and IL-1 inductions of sod2 mRNA require a 238-bp TNF response element (TNFRE), which is situated in intron 2. Both C/EBP and NF-?B bind to connect to the sod2 promoter, leading to the upregulation of MnSOD transcription [9]. TPA-induced MnSOD expression is because of the transcription factor specificity protein 1- (SP1-) mediated PKC signaling [16]. Dimeric SP1 can bind to GC-rich sequences of GGGCGG, but the binding affinity and transcription properties change based on the socializing cofactors [17-19].
As is upregulation, the downregulation of mRNA levels is as significant in biological processes. Maintaining proper amounts of these molecules is important for normal cellular function, because ROS can act as intracellular messengers that are secondary. This indicates that antioxidant enzymes are probably kept at low levels in cells.
Many tumour cell lines have mutations in the promoter area of the MnSOD gene that increase the number of AP-2-binding sites. AP2 can communicate with SP 1 within the promoter region and decrease advocate activity, thus downregulating transcription [17]. MnSOD mRNA levels can be upregulated by VEGF through the ROS-sensitive PKC-NF-?B and PI3K-Akt- Forkhead signaling pathways [11]. FOXO3a is a member of the Forkhead family of transcription factors.
Aging-related illnesses tend to be related to oxidative stress. Epigenetic silencing of the MnSOD gene has also been found in human breast cancers. Both DNA methylation and histone change contribute to this regulation [19]. Epigenetic change affects the abilities of SP1, AP-1, and NF-?B to bind to cis-elements in the promoter area of the MnSOD gene, resulting in silencing of this gene.
MnSOD mRNA upregulation always results in increased levels of MnSOD protein [20]. MnSOD is found in mitochondria; consequently, its major role appears to be restraining the levels of in mitochondria. H2O2 can become a second messenger or as a Fenton reaction agent, thus causing damage to cells. To elucidate the significance of MnSOD regulation, the function of MnSOD have to be looked at.

3. The Function of MnSOD

In cancer cells, specific transcription factors typically suppress MnSOD or through epigenetic change of cis- elements or chromatin. The phenotype in culture cans change; the cells lose the capability to form colonies, a trait characteristic of malignant cells [21]. A large number of studies have reported that ROS play a vital role in tumour metastasis [22, 23]. ROS can activate cell signaling pathways or mutate DNA, therefore promoting tumor proliferation and metastasis. This may explain why tumour cells nearly always express MnSOD at low levels. Exogenous MnSOD can block ROS signaling to inhibit tumorigenesis, indicating that MnSOD may be a possible antitumor therapeutic target.
A mouse knockout model of manganese superoxide dismutase has proven to be a helpful model for elucidating the function of MnSOD. The important function of MnSOD would be to protect mitochondria, as mentioned previously. However, although organisms can be damaged by ROS, they may be also mediators of cell signaling. Developing mice fetuses lacking manganese superoxide dismutase tend not to survive to arrival; overexpressions of other kinds of SOD cannot attenuate this symptom [25]. Newlyborn MnSOD knockout mice have extensive mitochondrial injuries in multiple tissues. Mitochondrial abnormalities characterize Illnesses including Leigh’s disease and Canavan disease. Decreases in the amounts of a number of energy metabolism enzymes, particularly those using a purpose in the TCA cycle, have also been noted in these ailments. mutant mice using the manganese superoxide dismutase mimetic manganese 5,10,15,20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) improved these mice and drastically prolonged their survival times [26-28].
Cytochrome c collected at an early stage and was considerably elevated in sod2?/ mice than it was in wild type mice. A remarkable escalation in DNA laddering was also discovered in the sod2 ?/ mice but not in the wild type mice, suggesting that MnSOD can block the discharge of cytosolic cytochrome c and prevent apoptosis [29]. Neurotoxins for example 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3-NP), and malonate are normally used in neurodegenerative functional models. Mice using a partial deficiency in MnSOD are sensitive to these mitochondrial toxins than are regular mice [30], suggesting that MnSOD is an antitoxin agent that scavenges free radicals generated by environmental toxins which could cause neurodegeneration.
MCF-7 human carcinoma cells exposed to single-dose radiation and radioresistant forms isolated from MCF-7 cells following fractionated ionizing radiation (MCF and FIR cells) were seen to possess raised MnSOD mRNA levels, action, and immunoreactive proteins. FIR and MCF These genes were suppressed in Sod2 knockout mice (?/?) and in MnSOD-silenced cells [31]. These six genes are survival genes [32-34] that protect cell -induced apoptosis.

4. MnSOD in Disorders with Inflammation

Inflammation is a complex response to dangerous stimulation, including tissue injury, pathogens, autoimmune damage, ischemia along with other irritants [35]. Numerous inflammation-related molecules and cells remove injurious stimulation and repair damaged tissues. The healing process comprises the destruction of “foreign objects” along with the repair of injured self-tissues. If repair that is associated and targeted destruction are not accurately programmed, inflammatory disorders resulting in ailments such as inflammatory bowel disease psoriasis, and neurodegenerative diseases develop [36, 37]. Superoxide anions have roles that are proinflammatory, causing peroxynitrite ion formation and oxidation, DNA damage, lipid peroxidation, and recruitment of neutrophils to sites of inflammation [38-40]. Elimination of superoxide anions by its isoenzymes and MnSOD can, thus, be regarded as anti-inflammatory

Lipid peroxidation is related to hydroxyl radicals and superoxide anions. In inflamed cells, levels of MnSOD are suppressed relative to all those of standard cells, suggesting that MnSOD may be a therapeutic target. The pathology of IBD needs additional investigation. Currently, drugs targeting NF-?B or ROS have been discovered to be somewhat effective.
The skin acts as a physical boundary to protect the internal organs from the environmental surroundings and is the biggest organ of the human body. Skin dysfunction could result in harm to deeper tissues. Skin harms can activate the acute inflammatory response, and this reaction can be heightened by disease. Psoriasis is a chronic disease disfiguring skin lesions, and frequently characterized by inflamed, scaly. Epidermal keratinocytes in this ailment show changed differentiation and hyperproliferation, and immune cells such as T cells and neutrophils can be found at lesion sites [45]. JunB is a part of the AP-1 transcription factor complex that regulates cell proliferation, differentiation, the anxiety response, and cytokine expression [46]. Both JunB and c-Jun are highly expressed in lesional skin, but amounts of JunB have been demonstrated to be intermediate in light psoriasis and low in severe psoriasis, while c-Jun is expressed in the opposite mode [47].
Most components of the AP-1 transcription factor -sensitive proteins regulated by ROS signaling. Exposure of keratinocytes to allergens, chemical irritants, or inflammatory stimuli activates activation of several anxiety-sensitive protein kinases that are mediated by ROS. ROS improve EGFR phosphorylation and activate ERKs and JNKs [48]. ROS additionally activate NF-?B during skin inflammation. These findings reveal that antioxidant enzymes might have potential as therapeutic agents.
MnSOD was found to be expressed in psoriasis, but this expression was not linked to the pathology of psoriasis [49]. A reasonable hypothesis is that lesional skin cells are induced to express MnSOD by cytokines released from inflammatory cells in order to counteract inflammation- induced oxidative stress. Although native MnSOD has shown promising anti-inflammatory properties against many ailments in both clinical and preclinical studies, there are several drawbacks to using native MnSOD as a curative agent and pharmacological tool. Low molecular weight mimetics of SOD were, therefore, developed to address a number of the drawbacks of native SOD use.
To date, often used SOD mimetics are MnTBAP, the Mn(III)-salen complex, and Mn II-pentaazamacrocyclic ligand-established SOD mimetics [50]. In a mouse model of lung pleurisy, treatment with MnTBAP before carrageenan administration was found to suppress inflammatory reactions in a dose-dependent way [51]. Until they react with nitric oxide, the mechanism of attenuation of inflammation by SOD mimetics is the decrease of peroxynitrite creation through the elimination of superoxide anions. Because peroxynitrites are numerous and have pro-inflammatory and cytotoxic effects, administration of SOD mimetics is clinically very important. M40403 (Figure 2) was derived from 1,4,7,10,13-pentaazacyclopentadecane containing added bis(cyclohexylpyridine) functionalities. It’s the very best merchandises reached high stability and catalytical activity according to the computer-aided design. M40403 gets a high specificity while other oxidants, such as hypochlorite, peroxynitrite, and hydrogen peroxide, are barely oxidative to Mn II packaged in the complex. The biological function of M40403 continues to be analyzed in several versions [52]. The global mechanism appears that M40403 could block nitrosation of tyrosine in proteins, suggesting that superoxide anion might lead to the nitrosation. While raising evidences are indicating that nitrosation plays important part in many inflammation-related diseases [50, 53], this low molecular mass synthetic is a potential therapeutic agent for curing inflammation.

5. Judgments

Inflammation is a complicated although traditional problem that still needs extensive investigation. ROS play a very important function in the activating and promotion of inflammation. Thus, antioxidant enzymes that could function as ROS scavengers are therapeutic agents that are perfect. Data generated from mouse models have demonstrated that native MnSOD has antiinflammatory properties but also some disadvantages that were practical. MnSOD mimetics were, thus, developed to deal with the shortcomings of native MnSOD. These low molecular weight molecules have been examined in several in vivo and in vitro models; they have all been proven to be successful mimics of SOD. Regardless of the great accomplishments made over the past few decades, however, there is still a need to develop much better and harmonious antiinflammatory agents ideal for clinical pharmaceutical treatment.




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