Biomedical subjects

A Legrand

Publications and source records attributed to A Legrand.

At least 19 recordsLinked to original sources

PubMed2006

[Is entropy a monitor for the guidance of intraoperative analgesia?].

OBJECTIVE: Comparison between BIS (Bispectral Index) and state (SE) and response (RE) entropy during laparotomy for inflammatory bowel disease patients (IBD) and evaluation of the variations of RE and SE during nociceptive stimulation. STUDY DESIGN: Prospective, observational study. PATIENTS AND METHODS: Fourteen IBD's patients undergoing laparotomy were included. Anaesthesia aimed to maintain BIS between 40 and 60 by isoflurane and nitrous oxide. Analgesia was performed by sufentanil bolus administrated according to an increase of 20% of systolic blood pressure (SBP) and heart rate compared with the baseline values. BIS, RE and SE were measured at each nociceptive stimulation. A variance analysis (Anova) was used to assess BIS, RE and SE variations throughout surgery (p<0.05 as significant). Relationship between BIS, RE and SE was assessed by Pearson correlation (p<0.01 as significant). The ability for SE and RE to predict depth of anaesthesia and intraoperative analgesia was performed by calculating area under the receiver operated curves (AUC). RESULTS: BIS and entropy parameters had strictly the same evolution during anaesthesia. SBP increased significantly during nociceptive stimulation while no variation of RE was observed. A significant correlation was shown between BIS, RE and SE. The evaluation of anaesthesia depth was good for RE (AUC: 0.932+/-0.26) and SE (AUC: 0.926+/-0.27). There was however no difference between RE and SE to predict analgesic requirement. CONCLUSION: Because RE includes muscular frequency analysis, it does not allow analgesic requirement evaluation in paralyzed patients.

Adult↗

PubMed2006

Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase C.

Oxidative stress plays a major role in the pathogenesis and in the onset of macrovascular complications of diabetes. We previously reported that the antihyperglycaemic drug metformin was able to decrease significantly intracellular reactive oxygen species (ROS) production of bovine aortic endothelial cells (BAEC) activated by high levels of glucose and angiotensin II (ANG). The aim of the present study was to investigate whether the antioxidant effect of metformin on BAEC could be mediated through a modulation of protein kinase C (PKC) activity, which plays a key role in the pathophysiology of diabetes. The effects of metformin on intracellular ROS production, PKC translocation and activity were studied on endothelial cells stimulated by PMA (a direct PKC activator), ANG or high levels of glucose as pathophysiological stimuli of endothelial dysfunction in diabetes. We showed that metformin decreased ROS production on PMA-, ANG- and glucose-stimulated BAEC in a similar manner to that obtained by PKC specific inhibitors (calphostin C, chelerythrine) alone. On the other hand, metformin reduced both PKC membrane translocation and kinase activity in ANG-stimulated cells. In PMA-activated cells, metformin reduced membrane PKC activity but we did not observe any alteration of PKC membrane translocation. Finally, in vitro incubation with purified PKC indicated that metformin had no direct effect on PKC activity. Taken together, our results suggest that metformin exerted intracellular antioxidant properties by decreasing ROS production through the inhibition of PKC activity.

Angiotensins↗

PubMed2006

[Cellular sources of reactive oxygen and nitrogen species. Roles in signal transcription pathways].

The history of studies regarding reactive oxygen and nitrogen species (ROS/RNS) is approximatively of 50 years. ROS were shown initially for their deleterious effects on marcormolecules such as DNA and proteins, leading to deterioration of cellular functions as an oxidative stress. On the other hand, recent studies have demonstrated that ROS/RNS act as oxidative signalling in cells, resulting in various gene expressions. This brief review focuses on the main cellular origins of ERO/ERN, such as mitochondrial respiratory chain, NAD(P)H oxidase and NO synthases, and describe the modulation by the reactive species of two major signal transduction pathways, NF-KB and AP-1 pathways.

Animals↗

PubMed2005

Deoxyguanosine kinase mutations and combined deficiencies of the mitochondrial respiratory chain in patients with hepatic involvement.

The activity of deoxyguanosine kinase (DGUOK), a mitochondrial enzyme involved in the anabolism of mitochondrial (mt) deoxyribonucleotides, governs the maintenance of the mtDNA. Deleterious mutations of the DGUOK gene are thus associated with mtDNA depletion and result in combined deficiencies of mtDNA-encoded respiratory chain enzymes. With the aim to estimate the prevalence of DGUOK mutations in a cohort of 30 patients with hepatocerebral disease and combined respiratory chain deficiencies, we studied the DGUOK gene and identified previously unreported mutations in five families. Two patients and their affected sibs, born to non-consanguineous parents, were homozygous for a missense mutation (M1T, and L250S, respectively). One patient presented a homozygous 4 pb insertion (796 insTGAT) and two other patients, and their affected sibs, were compound heterozygous (E165V/L266R and E211G/L266R, respectively). These findings allowed us to propose prenatal diagnosis in two families. In conclusion, we observed a high prevalence of DGUOK mutations (17%) in patients with hepatic involvement and combined respiratory chain deficiencies with hepatic involvement.

Amino Acid Sequence↗

PubMed2005

First characterization of a large deletion of the PDHA 1 gene.

Pyruvate dehydrogenase complex (PDC) deficiency is one of the major recognized causes of congenital lactic acidosis. The most common form is due to PDHA 1 gene (Xp22.12) defects. Here, we report the case of a Polynesian girl presenting with delayed neurological development, cortical atrophy, and posterior corpus callosum agenesis. Elevated lactate and pyruvate levels in blood and cerebrospinal fluid suggested PDC deficiency. However, PDC activity was within the normal range in lymphocytes and the direct sequencing of the 11 exons and intron-exon junctions of the PDHA 1 gene did not show any changes. Long-range PCR amplification of the whole gene (16 kb) from blood DNA revealed a heterozygous deletion of approximately 4.2kb. Fine mapping of the deletion breakpoint was achieved using purified long-range PCR products for restriction enzyme analysis and direct sequencing. The deletion removed a 4,227 bp region covering part of intron 5 to part of intron 9 [g.10,145_14,371 del 4,227]. The deletion breakpoint contained a short direct repeat (GTAG), which may be derived either from the upstream or the downstream homologous sequence. The presence of a GAG triplet and inverted repeats in the vicinity of the deletion suggest replication slippage at a polymerase alpha arrest site. This is the first time that a large intragenic deletion of the PDHA 1 gene has been characterized.

Base Sequence↗

PubMed2005

Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome.

The mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal and neurological symptoms. It is a rare autosomal recessive mitochondrial disorder with multiple mitochondrial DNA deletions and/or depletion. It is caused by thymidine phosphorylase (TP) gene mutations resulting in a complete abolition of TP activity. We tested 31 unrelated patients presenting either with a complete MNGIE syndrome (8 patients), a severe intestinal pseudo-obstruction (10 patients), and multiple deletions and/or depletion of mitochondrial DNA (13 patients). All the tested patients presenting with a complete MNGIE had increased thymidine levels in plasma and urine, and no TP activity. The group with pseudo-obstruction syndrome had normal or partial reduction of TP activity. We found pathogenic mutations on TP gene only in the MNGIE syndrome group: all the MNGIE patients were compound heterozygous or homozygous for mutations in the TP gene. Eight of these mutations are yet unreported, confirming the lack of genotype/phenotype correlation in this syndrome. Enzymatic activity and thymidine level are thus rapid diagnosis tests to detect MNGIE affected patients prior to genetic testing for patients with gastrointestinal symptoms.

Adult↗

PubMed2005

[Perioperative management of asplenic patients].

OBJECTIVE: In 2003, asplenia had involved 250000 patients in France. These patients are at risk of severe infection, mostly with capsulated bacteria as pneumococci, meningococci and Haemophilus. The higher mortality and morbidity due to infection in asplenic patient led in June 2003 a French expert committee to propose preventive management based on vaccination and antibioprophylaxis. STUDY DESIGN: Update article. DATA SYNTHESIS: For vaccination, two vaccines against pneumococci are available. The first one, the antipolysaccharide (Pneumo 23) is recommended for adults. It is effective for the majority of the serotypes even if its efficacy can be variable. The second one a conjugated pneumococcal vaccine (Prenevar) is used for children under two years because it has higher activity on antibiotic resistant strains therefore increasing antibiotic prophylaxis efficiency. When splenectomy is required, vaccination against pneumococci, Haemophilus (b type) and C meningococci must be performed at least 15 days before surgery, in order to get better immune stimulation. In case of emergency, vaccines have to be administrated within 30 days after surgery. Antibioprophylaxis is based on cefazolin injection before splenectomy and by postoperative intravenous amoxicillin administration. As soon as oral intake is allowed, antibioprophylaxis is continued for at least two years in adults and five years in children. Both antibiotic and vaccination have been reported to reduce pneumococcus infections.

Anti-Bacterial Agents↗

PubMed2005

Antioxidant activity of melatonin and a pinoline derivative on linoleate model system.

This study aimed at investigating the in vitro protective effects of GWC22, a novel pinoline derivative [6-ethyl-1-(3-methoxyphenyl)-2-propyl-1,2,3,4-tetrahydro-beta-carboline] chlorhydrate, against radiation-induced oxidation of linoleate initiated by hydroxyl radicals ((*)OH). Using linoleate micelles (10(-2) m) as lipid model, two indexes of peroxidation have been measured, i.e. conjugated dienes and hydroperoxides. Similar determinations were performed with melatonin in order to compare the protective effects of the two compounds. It was observed that, the higher the concentration of GWC22 (or melatonin) (3 x 10(-5) to 10(-4) m), the stronger the antioxidant ability. In these in vitro assays, GWC22 showed a better antioxidant effect than melatonin for a given antioxidant concentration. A reaction scheme has been proposed to explain the inhibitory effect of an antioxidant via the propagating steps of the lipid peroxidation. Indeed, we have suggested that melatonin and GWC22 may compete with the fatty acid to scavenge lipid peroxyl radicals (LOO(*)). We have estimated a lower limit for the LOO(*) rate constant for GWC22 (>/=1.4 x 10(5)/m/s) and for melatonin (>/=2.8 x 10(4)/m/s) assuming that the k-value of the propagating step in linoleate (LOO(*) + linoleate) was 1.4 x 10(3)/m/s. The difference of reactivity between melatonin and GWC22 in this model system is assumed to be related to their relative lipophilicity.

Animals↗

PubMed2004

Liquid chromatographic/electrospray ionization mass spectrometric identification of the oxidation end-products of metformin in aqueous solutions.

Metformin is an antihyperglycemic drug that exhibits some antioxidant properties. HO*-induced oxidation of metformin was studied in aqueous solution, in both aerated and deaerated conditions. Gamma radiolysis of water was used to generate HO* free radicals, capable of initiating one-electron oxidation of metformin. Oxidation end-products were identified by direct infusion mass spectrometry (MS) and high-performance liquid chromatography/mass spectrometry (HPLC/MSn): for every product, structure elucidation was based on its mass (simple mass spectra confirmed by HPLC/MS). In addition, fragmentation spectra (MS2, MS3 and MS4) and the determination of deuterium-hydrogen exchange sites provided valuable information allowing the complete identification of some of the end-products. At low radiation dose, four products were identified as primary ones, since they result from the direct attack of HO* radicals on metformin. These primary oxidation end-products were identified respectively as hydroperoxide of metformin, covalent dimer of metformin, methylbiguanide and 2-amino-4-imino-5-methyl-1,3,5-triazine. At high radiation dose, seven other products were identified as secondary ones, resulting from the HO*-induced oxidation of the primary end-products. A reaction scheme was postulated for the interpretation of the results.

Antioxidants↗

PubMed2004

Activation of PAF receptor by oxidised LDL in human monocytes stimulates chemokine releases but not urokinase-type plasminogen activator expression.

BACKGROUND: We investigated whether the increase of urokinase-type plasminogen activator (uPA) monocyte expression and chemokine releases induced by oxidised low density lipoproteins (LDL), which participate to vascular tissue remodeling and to atherosclerotic plaque rupture, involved proinflammatory phospholipid products having platelet-activating factor (PAF)-like activity via the PAF-receptor pathway. METHODS: uPA monocyte expression was stimulated by either copper ions-oxidised or O2*-/HO* free radical-oxidised LDL. The effects of PAF and oxidised LDL on the production of monocyte chemoattractant protein-1 and interleukin-8 were also examined. RESULTS: Synthetic PAF significantly enhanced chemokine releases (P<0.001) without modifying uPA expression. Copper-oxidised LDL, which exhibit a higher content in lysophosphatidylcholines than free radical-oxidised LDL, induced a significantly higher enhancement in uPA expression (P<0.05). By contrast, free radical-oxidised LDL were more efficient than copper-oxidised LDL to increase chemokine releases (P<0.01). Oxidised LDL-enhanced uPA expressions were not altered by the PAF-receptor antagonist SR27417, whereas increases in chemokine releases induced by oxidised LDL and by PAF were abolished. PAF-acetylhydrolase activity was rapidly and largely inhibited in free radical-oxidised LDL when compared to copper-oxidised LDL, suggesting that free radical-oxidised LDL would contain a higher content in PAF-like products than copper-oxidised LDL. CONCLUSION: Our results indicated that PAF-like oxidation products are responsible for the monocyte chemokine releases, but did not contribute to the enhanced monocyte uPA expression by oxidised LDL.

Cells, Cultured↗

PubMed2004

[Diabetes mellitus, oxidative stress and advanced glycation endproducts].

Chronic hyperglycemia in diabetes mellitus is an oxidative stress created by an imbalance of prooxidants over antioxidant defenses. The pathogenesis would involve several mechanisms including glucose autoxidation, protein glycation, the polyol pathway, and overproduction of superoxide radicals in mitochondria and via NAD(P)H oxidase. Glycemic equilibrium plays a very important role in the prooxidant/antioxidant balance. Macromolecules such as found in the extracellular matrix, lipoproteins, and deoxyribonucleic acid also constitute targets for free radicals in diabetes mellitus. This oxidative tress is involved in the pathophysiology of diabetes complications. The chronic hyperglycemic status also favors glycation reactions (irreversible glucose binding on protein amino groups), thereby leading to advanced glycation endproducts. Via their recognition by cell receptors, advanced glycation endproducts also participate in the development of oxidative stress and the inflammatory status. Involvement of oxidative stress and advanced glycation endproducts in diabetes complications is the basis of the development of adjunct therapies with antioxidant and/or anti)advanced glycation endproducts molecules.

Antioxidants↗

PubMed2004

Human sperm lipid content is modified after migration into human cervical mucus.

The effect of the female genital tract on sperm is not well known. To investigate the effect of cervical mucus on the lipid content of human sperm, we co-incubated sperm and mucus samples in vitro such that the sperm were able to swim in and out of the mucus samples. High performance liquid chromatography and UV detection were used to measure the lipid contents of the sperm and cervical mucus before and after migration. The concentrations of cholesterol, vitamin E, sphingomyelin, diacyls and plasmalogens in sperm were all approximately 45% lower after migration in cervical mucus and the cervical mucus was found to be enriched in some of these lipid species after the sperm migration. These results suggest that the cervical mucus selects a subpopulation of sperm with a lower lipid content. However, a concomitant efflux of various lipid classes from the sperm to the cervical mucus cannot be ruled out.

Cervix Mucus↗

PubMed2004

Radical-induced oxidation of metformin.

Metformin (1,1-dimethylbiguanide) is an antihyperglycaemic drug used to normalize glucose concentrations in type 2 diabetes. Furthermore, antioxidant benefits have been reported in diabetic patients treated with metformin. This work was aimed at studying the scavenging capacity of this drug against reactive oxygen species (ROS) like *OH and (O2*-)-free radicals. ROS were produced by gamma radiolysis of water. The irradiated solutions of metformin were analyzed by UV/visible absorption spectrophotometry. It has been shown that hydroxyl free radicals react with metformin in a concentration-dependent way. The maximum scavenging activity was obtained for concentrations of metformin > or = 200 micromol.L(-1), under our experimental conditions. An estimated value of 10(7) L.mol(-1).s(-1) has been determined for the second order rate constant k(*OH + metformin). Superoxide free radicals and hydrogen peroxide do not initiate any oxidation on metformin in our in vitro experiments.

Hypoglycemic Agents↗

PubMed2004

Study of the effects of interferon a on several human hepatoma cell lines: analysis of the signalling pathway of the cytokine and of its effects on apoptosis and cell proliferation.

BACKGROUND: Interferon alpha (IFNalpha), currently used for the treatment of chronic viral hepatitis, is also known to prevent the development of hepatocellular carcinoma (HCC), the mechanism of this action being still debatable. AIMS: To study thoroughly in human hepatoma cell lines (HHL)--Hep3B, HepG2, HuH7, SKHep1, and Chang-Liver--submitted to rhIFNalpha, the signalling pathway of IFNalpha, the binding activity of the cytokine on specific gamma-activated sequence (GAS) and interferon-stimulated regulatory element (ISRE) nuclear sequences, and its effects on apoptosis and cell proliferation. METHODS: The behaviour of signal transducer and activator of transcription (STAT)1, STAT2, p48(IRF9) and the binding of nuclear proteins were investigated by immunoblot and electro-mobility shift assay. Expression of some IFNalpha-dependent proteins--p21/(WAF1), inducible nitric oxide synthase, IRF1 and 2--were studied by immunoblot. Apoptosis and the cell cycle were studied by morphological and biochemical methods. RESULTS: Transduction of INFalpha was unaltered, although there were some variations in the different HHL. Nuclear protein binding to GAS or ISRE showed that ISRE was mainly involved. Apoptosis did not occur. The cell cycle was slightly modified in HuH7. Three GAS- and/or ISRE-dependent proteins increased, suggesting that IFNalpha may have some biological effects on HHL. CONCLUSIONS: The IFNalpha signalling pathway is functional in several HHL, but the cytokine has no apoptotic effect and a moderate anti-proliferative effect. This suggests that the preventive role of IFNalpha on HCC cannot be explained by an apoptotic and/or an anti-proliferative effect, but possibly by its action on several specific nuclear sequences that protect liver cells from transformation.

Apoptosis↗

PubMed2003

A histopathologic investigation of PGE(2) pathways as predictors of proliferation and invasion in urothelial carcinomas of the bladder.

INTRODUCTION AND OBJECTIVES: The pattern of arachidonate acid (AA) transformation in tumor cells has been shown to play a role in determining tumor cell invasiveness. AA is released from membrane phospholipids by cPLA(2). Then it is metabolized into prostaglandins and PGE(2) especially via cyclooxygenase pathways. PGE(2) production seems to be necessary for rendering the cells invasive. We aimed to characterize cPLA(2), cyclooxygenase 2 (COX2) and prostaglandine E synthase (PGES) expression in human transitional carcinoma (TCC) of the urinary bladder and correlate with the Ki-67 proliferating marker. METHODS: Formalin-fixed human TCC tissues (n=54) obtained from TURB or cystectomies were evaluated for cPLA(2), COX2, PGES and Ki-67 expression using specific antibodies. There were 6 CIS, 9 pTaG1, 9 pTaG3, 10 pT1G3 and 10 pT2G3. 10 normal bladder tissues were also evaluated. Control slides were incubated without primary antibodies and treated in a similar way. RESULTS: cPLA(2), COX2 and PGES were not expressed in the 10 normal tissues. In the same normal tissues, Ki-67 expression was observed only in 1% of the cells. However, cPLA(2) was expressed in 1/6 CIS, 1/9 pTaG1, 3/9 pTaG3, 6/10 pT1G3 and 2/10 pT2G3. COX2 was expressed in 0/6 CIS, 0/10 pTaG1, 2/9 pTaG3, 3/10 pT1G3 and 1/10 pT2G3. PGES was expressed in 4/6 CIS, 0/9 pTaG1, 4/9 pTaG3, 2/10 pT1G3 and 5/10 pT2G3. Ki-67 expression was 39.5% for CIS, 6.5% in pTaG1, 37% in pTaG3, 34.5% in pT1G3 and 55% in pT2G3. If we consider it a positive result when at least one enzyme was expressed, there were 5/6 CIS positive, 1/9 pTaG1 positive, 9/9 pTaG3 positive, 10/10 pT1G3 positive and 10/10 pT2G3 positive. Also the Ki-67 is more often expressed in cells with high grade tumor. CONCLUSIONS: These results suggest that (i). not only COX2 is involved in the tumorogenesis of the TCC but also cPLA(2) and PGES, (ii). there is relationship between the AA metabolic PGE(2) pathway expression and the aggressiveness of the TCC of the urinary bladder.

Aged↗

PubMed2003

Mutational spectrum and DNA-based prenatal diagnosis in carnitine-acylcarnitine translocase deficiency.

Carnitine-acylcarnitine translocase (CAC) deficiency is a rare autosomal recessive disorder of long-chain fatty acid oxidation with a severe outcome. We report mutation analysis in a cohort of 12 patients. Twelve mutations were identified of which 9 have not been reported so far (G28C, D32N, R178Q, P230R, D231H, 179delG, 802delG, 69-70insTGTGC, and 609-1g>a). Altogether, including our results, 22 mutations of the CAC gene have been published to date in 23 patients demonstrating the allelic heterogeneity of CAC deficiency. DNA-based prenatal diagnosis was performed for the first time in pregnancies at risk for CAC deficiency. Two fetuses were affected and one pregnancy was terminated by family decision. Two other fetuses had normal genotype and five others were heterozygotes. All the offspring of these seven pregnancies are alive and apparently healthy.

Amniotic Fluid↗

PubMed2003

Impaired mitochondrial pyruvate importation in a patient and a fetus at risk.

The patient was the first child of healthy consanguineous parents. She presented at birth with hypotonia, mild facial dysmorphism, periventricular cysts, marked metabolic acidosis, hyperlactacidemia with normal lactate/pyruvate molar ratios, normoglycemia, and normal ammonia. Hyperlactacidemia was severe (5-14 mmol/l) and not corrected with bicarbonate, thiamine (10 mg/d), 2-chloropropionate (100 mg/kg/d) and a ketogenic diet. Pyruvate dehydrogenase (PDHC) activity was normal in lymphocytes and fibroblasts. Functional assays were performed in digitonin-permeabilized fibroblasts to measure oxidation rates from radiolabeled pyruvate and malate. The production of [14C]acetylcarnitine or [14C]citric cycle intermediates derived from [2-14C]pyruvate as well as the release of 14CO(2) from [1-14C]pyruvate was severely impaired, whereas decarboxylation of [U-14C]malate was normal. With increasing concentrations of [1-14C]pyruvate, the patient's fibroblasts behave like control fibroblasts incubated in the presence of alpha-cyano-4-hydroxycinnamate, a specific inhibitor of mitochondrial pyruvate uptake: a progressive increase in 14CO(2) production was observed, likely due to passive diffusion of [1-14C]pyruvate through the mitochondrial membranes. Our results are consistent with a defect of mitochondrial pyruvate transport in the patient. Mutational analysis was precluded as the cDNA sequence of the pyruvate carrier has not been identified as yet in any organism. An affected fetus was recognized in a subsequent dichorionic twin pregnancy using the coupled assay measuring [2-14C]pyruvate oxidation rates on digitonin-permeabilized trophoblasts. After selective feticide, the pregnancy was uncomplicated with delivery at 37w of a healthy female, who is currently 2-month old.

Algeria↗

PubMed2003

An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress.

Metformin (dimethylbiguanide) is an antihyperglycemic agent used in type 2 diabetes. Beyond its action on glycemic control, metformin exhibits other intrinsic effects that could play a role in prevention against diabetes complications. Some studies thus reported an improvement in the antioxidant status in patients treated with metformin. This might be in part related to its property to limit formation of advanced glycation end products (AGEs) and to decrease the overproduction of free radicals in diabetic subjects. The aim of this study was to investigate the in vitro ability of metformin to modulate the action of reactive oxygen species (ROS) generated either by water gamma radiolysis or by stimulated human leukocytes. Our results showed that metformin at pharmacologically relevant concentrations was in vitro able to scavenge hydroxyl ((.)OH) but not superoxide (O(.-)(2)) free radicals and that hydrogen peroxide did not react with metformin. Nevertheless, when polymorphonuclear cells (PMN) are stimulated by phorbol myristate acetate (PMA), or above all by formyl methionine leucyl phenylalanine (fMLP), a systematic (although nonsignificant) decrease of the ROS-induced chimiluminescence (CL) was observed. These results suggest that metformin could directly scavenge ROS or indirectly act by modulating the intracellular production of superoxide anion, of which NADPH oxidase constitutes the major source. This could contribute to the additional benefits of metformin, especially those related to the improvement in the cardiovascular outcomes in diabetes.

Free Radicals↗