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Nathan Goodyear

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde... - 0 views

  • Hydroxyl radicals cause oxidative damage to cells because they unspecifically attack biomolecules [22] located less than a few nanometres from its site of generation and are involved in cellular disorders such as neurodegeneration [23, 24], cardiovascular disease [25], and cancer [26, 27].
  • It is generally assumed that in biological systems is formed through redox cycling by Fenton reaction, where free iron (Fe2+) reacts with hydrogen peroxide (H2O2) and the Haber-Weiss reaction that results in the production of Fe2+ when superoxide reacts with ferric iron (Fe3+)
  • other transition-metal including Cu, Ni, Co, and V can be responsible for formation in living cells
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  • The hydroperoxyl radical () plays an important role in the chemistry of lipid peroxidation
  • The is a much stronger oxidant than superoxide anion-radical
  • Lipid peroxidation can be described generally as a process under which oxidants such as free radicals or nonradical species attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs) that involve hydrogen abstraction from a carbon, with oxygen insertion resulting in lipid peroxyl radicals and hydroperoxides as described previously
  • under medium or high lipid peroxidation rates (toxic conditions) the extent of oxidative damage overwhelms repair capacity, and the cells induce apoptosis or necrosis programmed cell death
  • The overall process of lipid peroxidation consists of three steps: initiation, propagation, and termination
  • Once lipid peroxidation is initiated, a propagation of chain reactions will take place until termination products are produced.
  • The main primary products of lipid peroxidation are lipid hydroperoxides (LOOH)
  • Among the many different aldehydes which can be formed as secondary products during lipid peroxidation, malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal (4-HNE) have been extensively studied
  • MDA has been widely used for many years as a convenient biomarker for lipid peroxidation of omega-3 and omega-6 fatty acids because of its facile reaction with thiobarbituric acid (TBA)
  • MDA is one of the most popular and reliable markers that determine oxidative stress in clinical situations [53], and due to MDA’s high reactivity and toxicity underlying the fact that this molecule is very relevant to biomedical research community
  • 4-HNE is considered as “second toxic messengers of free radicals,” and also as “one of the most physiologically active lipid peroxides,” “one of major generators of oxidative stress,” “a chemotactic aldehydic end-product of lipid peroxidation,” and a “major lipid peroxidation product”
  • MDA is an end-product generated by decomposition of arachidonic acid and larger PUFAs
  • Identifying in vivo MDA production and its role in biology is important as indicated by the extensive literature on the compound (over 15 800 articles in the PubMed database using the keyword “malondialdehyde lipid peroxidation” in December 2013)
  • MDA reactivity is pH-dependent
  • When pH decreases MDA exists as beta-hydroxyacrolein and its reactivity increases
  • MAA adducts are shown to be highly immunogenic [177–181]. MDA adducts are biologically important because they can participate in secondary deleterious reactions (e.g., crosslinking) by promoting intramolecular or intermolecular protein/DNA crosslinking that may induce profound alteration in the biochemical properties of biomolecules and accumulate during aging and in chronic diseases
  • MDA is an important contributor to DNA damage and mutation
  • This MDA-induced DNA alteration may contribute significantly to cancer and other genetic diseases.
  • Dietary intake of certain antioxidants such as vitamins was associated with reduced levels of markers of DNA oxidation (M1dG and 8-oxodG) measured in peripheral white blood cells of healthy subjects, which could contribute to the protective role of vitamins on cancer risk
  • 4-HNE is an extraordinarily reactive compound
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    Great review of lipid peroxidation
Nathan Goodyear

Implications of free radicals and antioxidant levels in carcinoma of the breast: A neve... - 0 views

  • Experimental investigations as well as clinical and epidemiological findings have provided evidence supporting the role of reactive oxygen metabolites or free radicals such as singlet oxygen O 2 - , superoxide anions (O 2 ), hydrogen peroxide (H­2 O2 ) and hydroxyl radical in the etiology of cancer.
  • Certain aldehydes such as Malonyldialdehyde (MDA), the end product of lipid peroxidation arising from free radical degeneration of polyunsaturated fatty acids can cause cross linking in lipids, proteins and nucleic acids leading to cellular damage.
  • In this study, patients with cancer exhibited higher levels of MDA, both in tissues and serum (p<0.001) compared to the control group [Table 1]. In tissue, the MDA level in stage IV was significantly higher as compared to stage I indicating increased free radical activity with increasing severity of cancer
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  • From these observations, it can be concluded that MDA levels play an important role in assessing the outcome of cancer
  • SOD and CAT are considered primary antioxidant enzymes, since they are involved in direct elimination of reactive oxygen metabolites. [13-16] They also act as anti-carcinogens and inhibitors at initiation and promotion/transformation stage in carcinogenesis
  • In our study, SOD and CAT levels were found to be low in all cancer patients as compared to controls
  • Fridovich and Tayarani have demonstrated in their respective studies that the reduction in SOD activity increases the toxic effects of O2 - and this might lead to severe cellular damage.
  • Mehrotra et al. in their study also observed high levels of MDA and low levels of SOD and CAT in patients of cancer cervix which is in sync with our observations.
  • strong evidence regarding the definitive role of free radicals in breast malignancy.
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    This study finds a strong correlation between advancing breast cancer, decreased catalase and SOD with increasing MDA.  The authors of this study conclude this is a key factor in carcinogenesis and not a by-product of cancer.  This flies in the face of traditional medicines fear of antioxidant therapy in cancer.
Nathan Goodyear

[Malondialdehyde (MDA) as a lipid peroxidation marker]. - PubMed - NCBI - 0 views

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    Only abstract her and it is an older article.  Malondialdehyde (MDA) is a great marker of oxidative stress.  Specifically, MDA is an end product of polyunsaturated fat peroxidation.
Nathan Goodyear

The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-nega... - 0 views

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    ART inhibited breast cancer cell proliferation via a reactive oxygen species (ROS)-dependent G2/M arrest and ROS-independent G1 arrest. ART-treated MDA-MB-468 and SK-BR-3 cells also experienced apoptotic cell death, which was both ROS- and iron-dependent. ART-induced oxidative stress caused the loss of mitochondrial outer membrane integrity and damage to the cellular DNA of MDA-MB-468 and SK-BR-3 cells. Only abstract available...I will post full article once available.
Nathan Goodyear

Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme ... - 0 views

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    CoQ10 supplementation of 150 mg in individuals with CAD found to have increased catalase activity, increased SOD activity, an increased MDA levels.  This reduced oxidative stress, TC, and LDL levels.
Nathan Goodyear

Calcium plus vitamin D supplementation influences biomarkers of inflammation and oxidat... - 0 views

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    Vitamin D plus calcium found to reduce inflammation and oxidative stress in women with PCOS.  CRP and MDA were decreased.  Notice dosing.
Nathan Goodyear

Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjec... - 0 views

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    1000 mg curcuminoids found to lower CRP in individuals with metabolic syndrome in just 8 weeks.  Curcumin also lowered SOD and MDA.
Nathan Goodyear

Thieme E-Journals - Hormone and Metabolic Research / Abstract - 0 views

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    Short study found that Selenium improved pregnancy rate compared to placebo, reduced DHEA, hirsutism, CRP and MDA
Nathan Goodyear

Progesterone metabolites in breast cancer - 1 views

  • P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting or -inhibiting regulatory agents
  • these P metabolites function as independent pro-or anti-cancer autocrine/paracrine hormones that regulate cell proliferation, adhesion, apoptosis and cytoskeletal, and other cell status molecules via novel receptors located in the cell membrane and intrinsically linked to cell signaling pathways
  • only a fraction of all breast cancer patients respond to this estrogen-based therapy and the response is only temporary
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  • P serves as the precursor for the major steroid hormones (androgens, estrogens, corticosteroids) produced by the gonadal and adrenal cortical tissues.
  • 5α-pregnane, 5β-pregnane, and 4-pregnene metabolites of P
  • These P-metabolizing enzymes included 5α-reductase, 5β-reductase, 3α-hydroxysteroid oxido-reductase (3α-HSO), 3β-HSO, 20α-HSO, 20β-HSO, 6α(β)-, 11β-, 17-, and 21-hydroxylase, and C17–20-lyase
  • Reduction of P to 5α-pregnanes is catalyzed by 5α-reductase and the direct 5α-reduced metabolite of P is 5α-pregnane-3,20-dione (5αP). The 5α-reductase reaction is irreversible
  • The two 4-pregnenes resulting from direct P conversion are 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αHP), catalyzed by the actions of 3α-HSO and 20α-HSO respectively
  • the P-metabolizing enzyme activities identified in human breast tissues and cell lines were: 5α-reductase, 3α-HSO, 3β-HSO, 20α-HSO, and 6α-hydroxylase
  • In normal breast tissue, conversion to 4-pregnenes greatly exceeded the conversion to 5α-pregnanes, whereas in tumorous tissue, conversion to 5α-pregnanes greatly exceeded that to 4-pregnenes
  • The results indicated that P 5α-reductase activity is significantly higher, whereas P 3α-HSO and 20α-HSO activities are significantly lower in tumor than in normal tissues
  • he results showed that production of 5α-pregnanes was higher and that of 4-pregnenes was lower in tumorigenic (e.g. MCF-7) than in nontumorigenic (e.g. MCF-10A) cells (Fig. 3c⇑), while differences in ER/P status did not appear to play a role
  • The 5α-pregnane-to-4-pregnene ratios were 7- to 20-fold higher in the tumorigenic than in the nontumorigenic cell lines
  • altered direction in P metabolism, and hence in metabolite ratios, was due to significantly elevated 5α-reductase and depressed 3α- and 20α-HSO activities in breast tumor tissues and tumorigenic cells. It appeared, therefore, that changes in P-metabolizing enzyme activities might be related to the shift toward mammary cell tumorigenicity and neoplasia
  • In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding for the enzyme, or from changes in the milieu in which the enzyme operates (such as temperature and pH, and concentrations of cofactors, substrates, products, competitors, ions, phospholipids, and other molecules)
  • Overall, the enzyme activity and expression studies strongly suggest that 5α-reductase stimulation and 3α- and 20α-HSO suppression are associated with the transition from normalcy to cancer of the breast
  • The level of expression of 5α-reductase is up-regulated by estradiol and P in the uterus (Minjarez et al. 2001) and by 5α-dihydrotestosterone (DHT) in the prostate
  • 3αHP inhibited whereas 5αP-stimulated proliferation
  • Stimulation in cell numbers was also observed when cells were treated with other 5α-pregnanes, such as 5α-pregnan-3α-ol-20-one, 5α-pregnan-20α-ol-3-one, and 5α-pregnane-3α,20α-diol, whereas other 4-pregnenes such as 20α-HP and 4-pregnene-3α,20α-diol resulted in suppression of cell proliferation
  • Stimulation of cell proliferation with 5αP and inhibition with 3αHP were also observed in all other breast cell lines examined, whether ER/P-negative (MCF-10A, MDA-MB-231) or ER/P-positive (T47D, ZR-75-1) and whether requiring estrogen for tumorigenicity (MCF-7, T47D) or not (MDA-MB-231), or whether they are nontumorigenic (
  • αHP resulted in significant increases in apoptosis and decreases in mitosis, leading to significant decreases in total cell numbers. In contrast, treatment with 5αP resulted in decreases in apoptosis and increases in mitosis.
  • The opposing actions of 5αP and 3αHP on both cell anchorage and proliferation strengthen the hypothesis that the direction of P metabolism in vivo toward higher 5α-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.
  • he effects on proliferation and adhesion were not due to P, but due to the 5α-reduced metabolites
  • The studies showed that binding of 5αP or 3αHP occurs in the plasma membrane fractions, but not in the nuclear or cytosolic compartments
  • separate high-specificity, high-affinity, low- capacity receptors for 5αP and 3αHP that are distinct from each other and from the well-studied nuclear/cytosolic P, estrogen, and androgen and corticosteroid receptors
  • The studies thus provided the first demonstration of the existence of specific P metabolite receptors
  • the receptor results suggest that the putative tumorigenic actions of 5αP may be significantly augmented by the estradiol-induced increases in 5αP binding and decreases in 3αHP binding.
  • Estradiol and 5αP resulted in significant dose-dependent increases, whereas 3αHP and 20αHP each resulted in dose-dependent decreases in total ER
  • In combination, estradiol + 5αP or 3αHP + 20αHP resulted in additive increases or decreases respectively in ER numbers.
  • The data suggest that the action of 5αP on breast cancer cells involves modulation of the MAPK signaling pathway
  • current evidence does not appear to support the notion that increased 5α-reductase activity/ expression might significantly alter androgen influences on breast tumor growth.
  • both testosterone and DHT inhibit cell growth more or less to the same extent
  • Note that 5α-reductase reaction is not reversible
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    Fantastic read on the effects of progesterone metabolism on tumor and cancer growth.  Tumorigenesis is not just about the hormone, hormone balance, but about the metabolism of hormones.  This is why premarin is so carcinogenic: it is primarily metabolized by the 4-OH estrone pathway.
Nathan Goodyear

Polysaccharides from Cordyceps sinensis mycelium ... [Pharm Biol. 2014] - PubMed - NCBI - 0 views

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    Mouse model finds that Cordyceps increased the interval to exhaustive exercise induced oxidative stress.  SOD, Cat, and GPx were increased in the low, intermediate, and high dose Cordyceps groups.  Oxidative stress markers MDA and 8-OHdG were lower in all groups
Nathan Goodyear

ScienceDirect - Food and Chemical Toxicology : Neuroprotective effect of ginger on anti... - 0 views

  • A marked decrease in anti-oxidant marker enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), reduced glutathione (GSH) and increase in malondialdehyde (MDA) was observed in the diabetic rats
  • inger may be used as therapeutic agent in preventing complications in diabetic patients.
  • These results suggest that ginger exhibit a neuroprotective effect by accelerating brain anti-oxidant defense mechanisms and down regulating the MDA levels to the normal levels in the diabetic rats
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    Ginger reduces oxidative stress in diabetic rat model
Nathan Goodyear

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydrox... - 0 views

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    Intra mammary progesterone metabolism and its associated metabolites found to be associated with tumorigenic activity in cell lines.  This was independent from ER PR status.  5 alpha-pregnanes were found to be pro-tumor and 4-pregnanes were anti-tumor.
Nathan Goodyear

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydrox... - 0 views

  • Exposure of human breast cell lines (MCF-7, MCF-10A, and ZR-75-1) to 5α-pregnanes results in changes associated with neoplasia, including increased proliferation and decreased attachment [1], depolymerization of F-actin [2] and decreases in adhesion plaque-associated vinculin
  • Exposure to 4-pregnenes results, in general, in opposite (anti-cancer-like) effects
  • 5αR1 has been detected in various androgen-independent organs, such as the liver and brain
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  • 5αR2 has been found predominantly in androgen-dependent organs, such as epididymis and prostate
  • The 5α-pregnanes:4-pregnenes ratio was about 8-fold higher in tumorous than in nontumorous breast tissue after an 8-hour incubation with [14C]progesterone
  • Studies with breast cell lines, showing that 5α-pregnanes stimulate proliferation and decrease attachment of cells
  • both tissue and breast cell line studies suggest that an elevated level of progesterone 5α-reductase activity may be an indicator of breast tumorigenesis, regardless of presence or absence of ER and/or PR
  • 5αR1 is the main isoform expressed in human breast carcinomas [29] and that 5αR2 may not be associated with risk of breast cancer
  • the differences in 5α-pregnane production between the cells is due primarily to a difference in 5αR1 expression
  • As in the case of 5α-reductase activity, the presence or absence of ER and PR do not appear to be related to 5α-reductase expression.
  • the conversion of progesterone to the cancer promoting 5α-pregnanes is significantly higher in the human tumorigenic breast cell lines
  • lthough both 5αR1 and 5αR2 are expressed by these cells, the elevated 5α-reductase activity appears to be the result of significantly greater expression of 5αR1
  • Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for promoting breast cancer progression due to increased production of tumor-promoting 5α-pregnanes and decreased production of anti-cancer 20α – and 3α-4-pregnenes
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    balance of enzyme production between 5alpha-reductase and 20alpha-hydroxysteroid oxidoreductase and 3alpha(beta)-hydroxysteroid oxidoreductase play role in carcinogenesis and proliferation in the balance of production of progesterone metabolites. The 5alpha pregnenes are pro carcinogenic  and the 4-pregnenes are anti carcinogenic.
Nathan Goodyear

BMC Cancer | Full text | Activity and expression of progesterone metabolizing... - 0 views

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    Might the enzymes be more important than the hormones themselves?  The number is important i.e. progesterone, but how the number came to be is more important as it points to the underlying etiology.  Here, the balance of enzymes are found to direct cell line tumor potential.  The enzyme 5alpha-reductase increased production of the 5alpha-pregnanes which increased tumor potential.  In contrast, the enzymes 20alpha-hydrosteroid oxidoreductase and 3alpha-hydroxysteroid oxidoreductase increase production of the 4alpha-pregnanes, which decreased tumor potential.
Nathan Goodyear

Positive effects of astaxanthin on lipid profiles and oxidative stress in overweight su... - 0 views

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    Astaxanthin at 20 mg found to reduce oxidized LDL and other oxidative stress biomarkers as assessed by Malondialdehydy, SOD, Isoprostane, and TAC.  The dose was 20 mg for 12 weeks. This higher dose was associated with minimal side effects--red stools.
Nathan Goodyear

Internet Scientific Publications - 0 views

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    Study of Iraqi population at elevated risk of stroke found that both serum and salivary levels of malondialdehyde, glutathione, superoxide dismutase, and uric acid proved useful as potential biomarkers of risk assessment.
Nathan Goodyear

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydrox... - 0 views

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    cell culture study finds that increased 5alpha reductase activity and resultant 5alpha-pregnanes are associated with breast cancer cell lines.  This is in contrast to the 4-pregnenes.  In fact, decreased 4-pregnenes are found in the same breast cancer cell lines; this suggests decreased 20alpha-HSO and 3alpha-HSO activity.
Nathan Goodyear

Cross-kingdom inhibition of breast cancer growth by plant miR159 - 0 views

  • MicroRNAs (miRNAs), a major family of small RNAs, are ∼23 nt-long single strands of RNA that bind to mRNA transcripts to inhibit their translation
  • A recent study by Zhang et al. reported that plant-derived miRNAs can be found in human serum.
  • The group demonstrates that the plant miRNA miR168 may be taken up through dietary intake to inhibit the expression of its target low-density lipoprotein receptor 1 in the liver21, providing the first evidence that miRNA in food may influence gene expression in mammalian organs.
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  • A more recent finding by the same group shows that a plant miRNA from honeysuckle is able to inhibit Influenza A replication22, indicating that plant miRNAs may be useful for treating human diseases.
  • We found that plant miR159 could be detected in human sera and its levels were inversely correlated with BC incidence and progression.
  • We further identified TCF7 as a mammalian target for miR159 and showed the anti-proliferative function of miR159 in BC cells using in vitro and in vivo models, demonstrating for the first time that a plant miRNA is able to influence BC cell growth.
  • certain dietary miRNAs from plants and other species may serve as highly affordable and powerful means of treatment with minimal inconvenience to patients.
  • miR159 which (using a synthetic mimic) targets TCF7 to inhibit the proliferation of cells whose growth is dependent on TCF7 such as the BC cells MDA-MB-231
  • our study using a BC model clearly indicates the anti-tumor effect of orally administered synthetic miR159 in its naturally existing form with the plant-specific 2'-O-methylation, suggesting the feasibility of using synthetic forms of plant miRNAs as dietary supplements in the treatment of human cancers, including those outside of the GI track
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    Plant microRNA found to exist in human serum from gut absorption to then alter genetic expression in in-vitro and in vivo studies.
Nathan Goodyear

Development of Resistance towards Artesunate in MDA-MB-231 Human Breast Cancer Cells - 0 views

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    Upregulation of NF-kappaB found to promote Artesunate resistance in breast cancer cell line.
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