Dynamics of Oxidative Stress Evoked by Myocardial Ischemia Reperfusion After Off-Pump Coronary Artery Bypass Grafting Elucidated by Bilirubin Oxidation.

BACKGROUND: Revascularization therapy relieves myocardial ischemia, but can also result in ischemia-reperfusion injury caused by oxidative stress. However, the biokinetics of oxidative stress after myocardial ischemia-reperfusion are uncertain. This study aimed to evaluate the dynamics of oxidative stress after off-pump coronary artery bypass grafting (OPCAB) by measuring urinary biopyrrin levels. Biopyrrin is an oxidative metabolite of bilirubin thought to reflect oxidative stress, along with reactive nitrogen species (RNS).Methods and Results:The study included 18 patients who underwent OPCAB; patients were divided into effort angina pectoris (EAP; n=11) and unstable angina pectoris (UAP; n=7). Urinary biopyrrin and RNS levels were measured during the perioperative period (≤48 h after surgery). Biopyrrin levels transiently increased 4-12 h post-surgery (early phase), followed by a prolonged increase approximately 24-32 h post-surgery (late phase). The delayed increase in biopyrrin tended to be higher in patients with UAP, with a simultaneous increase in RNS. The patients in the UAP group had generally high pulmonary capillary wedge pressure (PCWP), although the cardiac index was within a normal range during the delay phase. CONCLUSIONS: The dynamics of biopyrrin levels revealed a biphasic pattern of oxidative stress after OPCAB. Delayed production of oxidative stress may be influenced by preoperative severity of myocardial ischemia and delayed RNS production.

Analysis of oxidative stress expressed by urinary level of biopyrrins and 8-hydroxydeoxyguanosine in patients with chronic schizophrenia.

AIMS: Previous studies have supported the claim that psychological stress induces the production of reactive oxygen species. Several authors have suggested that patients with psychiatric disorders show high levels of oxidative stress markers. We examined different oxidative stress markers in patients with chronic schizophrenia. METHODS: This study included 29 patients with chronic schizophrenia and 30 healthy volunteers. The concentration of urinary biopyrrins and 8-hydroxydeoxyguanosine (8-OHdG), as measured by enzyme-linked immunosorbent assay, were normalized to the urinary concentration of creatinine. Psychiatric symptoms were assessed by the administration of the Brief Psychiatric Rating Scale (BPRS). RESULTS: The concentration of biopyrrins in patients with chronic schizophrenia was significantly higher when compared with healthy volunteers. The correlation between biopyrrin level and the duration of illness was highly significant. There were no significant differences in the levels of urinary 8-OHdG between the two groups. In schizophrenic patients, the level of urinary biopyrrins showed correlations with BPRS scores, while the level of urinary 8-OHdG did not show correlations with BPRS. CONCLUSIONS: Urinary biopyrrins are increased in patients with chronic schizophrenia while urinary 8-OHdG is not increased. These findings suggest that patients with chronic schizophrenia are under the condition of certain oxidative stresses.

A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression.

Sickle cell disease (SCD) is a heritable disorder caused by ß-globin gene mutations. Induction of fetal γ-globin is an established therapeutic strategy. Recently, epigenetic modulators, including G9a inhibitors, have been proposed as therapeutic agents. However, the molecular mechanisms whereby these small molecules reactivate γ-globin remain unclear. Here we report the development of a highly selective and non-genotoxic G9a inhibitor, RK-701. RK-701 treatment induces fetal globin expression both in human erythroid cells and in mice. Using RK-701, we find that BGLT3 long non-coding RNA plays an essential role in γ-globin induction. RK-701 selectively upregulates BGLT3 by inhibiting the recruitment of two major γ-globin repressors in complex with G9a onto the BGLT3 gene locus through CHD4, a component of the NuRD complex. Remarkably, BGLT3 is indispensable for γ-globin induction by not only RK-701 but also hydroxyurea and other inducers. The universal role of BGLT3 in γ-globin induction suggests its importance in SCD treatment.

Complex of branched cyclodextrin and lidocaine prolonged the duration of peripheral nerve block.

Although laboratories have tried to synthesize new local anesthetics, currently available local anesthetics rarely provide prolonged regional blockade. New models of sustained-release preparations of local anesthetics with liposomes and microspheres have been studied to prolong the duration of the effects of the local anesthetics. In the present study, we examined whether a complex of a branched cyclodextrin (CD), 6-O-alpha-D-maltosyl-beta-cyclodextrin (G2-beta-CD) and lidocaine could prolong local nerve block when compared with plain lidocaine. The sciatic nerve in male Sprague-Dawley rats was blocked with plain lidocaine (n = 10), the complex of G2-beta-CD + lidocaine (n = 10), or plain G2-beta-CD (n = 4). Sensory block was assessed with a hotplate set at 56 degrees C. The median duration of the block was longer in the complex group than in the plain lidocaine group (110 min; range, 70-150 min vs 55 min; range, 40-80 min; P < 0.05), thus demonstrating that the complex with CyD significantly prolonged the nerve block effect of lidocaine. In conclusion, the present study showed that this encapsulating technique with CyD is useful to expand local anesthetic effect in peripheral nerve blockade.

Bilirubin and its oxidative metabolite biopyrrins in patients with acute myocardial infarction.

This study aimed to assess the involvement of bilirubin and its oxidative metabolite biopyrrin in patients with acute myocardial infarction (AMI) and to determine the responsible organs that overproduce these molecules. One hundred thirteen consecutive patients hospitalized for AMI were analyzed. Levels of serum bilirubin, plasma and urinary biopyrrins were measured on the day of admission, day 2, 3, 7 and 14. Expressions of biopyrrins and heme oxygenase-1 (HO-1), a stress-responsive bilirubin-producing enzyme, in heart, aorta, kidney, liver and lung were immunostained with autopsied specimens. Serum bilirubin, plasma and urinary biopyrrins were increased within 24 hr, formed a peak on day 3 and then decreased by day 14. These three parameters were well correlated to each other. The maximum biopyrrin elevation was higher in death cases and associated with impaired left ventricular function. Immunohistochemical analyses revealed biopyrrin accumulation and HO-1 expression in the infracted myocardium. Immunoreactive HO-1 and biopyrrins were also observed in renal tubular cells, aortic wall and lung. Serum bilirubin and its metabolite biopyrrins were elevated in patients with AMI. Plasma and urinary biopyrrin elevation were associated with mortality and morbidity. Induction of anti-oxidative enzyme HO-1 seemed to be involved in the activation of bilirubin/biopyrrin pathway.

5-HT(2C) receptor activation is a common mechanism on proerectile effects of apomorphine, oxytocin and melanotan-II in rats.

5-Hydroxytryptamine (5-HT), dopamine, oxytocin and melanocortin pathways are known to be involved in the induction of penile erections in rats. Although a dopamine-oxytocin-5-HT link in the central nervous system has been suggested to be important to the control of penile erections, the 5-HT receptor subtype that mediates dopamine-oxytocin-5-HT action and the relationship between the dopamine-oxytocin-5-HT pathway and melanocortin pathway have not been fully elucidated. In this study, in order to clarify these matters, we examined the effects of a selective 5-HT(2B)/5-HT(2C) receptors antagonist, 1-(1-methylindol-5-yl)-3-(3-pyridyl)urea (SB200646) and a selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline (SB242084) on penile erections induced by a dopamine receptor agonist, 10, 11-dihydroxyaporphine (apomorphine), oxytocin, or a melanocortin receptor agonist, melanotan-II (MT-II) in rats. SB200646 at 10 mg/kg and SB242084 at 3 mg/kg, these doses which completely antagonize penile erections induced by 5-HT(2C) receptor agonists, m-chlorophenylpiperazine (mCPP) and (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348), significantly inhibited penile erections elicited by apomorphine, oxytocin or MT-II. In addition, in order to clarify further the suggestion that the 5-HT pathway projecting from medulla oblongata to lumbosacral spinal site and lumbosacral 5-HT(2C) receptor are involved in the induction of penile erection, we also examined the proerectile effect of YM348 in spinal and a 5-HT depletor, p-chlorophenyl alanine (pCPA)-treated rats. YM348 induced intracavernous pressure increase in spinal and pCPA-treated rats as well as normal rats. These results suggest that 5-HT(2C) receptor in lumbosacral spinal sites mediates not only dopamine-oxytocin-5-HT action but melanocortin action on penile erections, and that the 5-HT pathway is located downstream from melanocortin pathway as well as the dopamine-oxytocin pathway.

Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress.

Stress-induced downregulation of spermatogenesis remains poorly understood. This study examined the induction of heme oxygenase-1 (HO-1), a carbon monoxide-generating inducible enzyme, in modulation of spermatogenesis. Rats were exposed to cadmium chloride (CdCl(2)), a stressor causing oligozoospermia, and HO-1-induction was monitored by following HO isozyme expression. CdCl(2)-treated testes increased HO-1 activity and suppressed microsomal cytochromes P450, which are required for steroidogenesis. CdCl(2)-elicited HO-1 occurred mostly in Leydig cells and coincided with CO generation, as judged by bilirubin-IXalpha immunoreactivity. Under these circumstances, germ cells in peripheral regions of seminiferous tubules exhibited apoptosis; laser flow cytometry revealed that these apoptotic cells involve diploid and tetraploid germ cells, suggesting involvement of spermatogonia and primary spermatocytes in CdCl(2)-elicited apoptosis. Pretreatment with zinc protoporphyrin-IX, an HO inhibitor, but not copper protoporphyrin-IX, which does not block the enzyme, attenuated the CdCl(2)-induced apoptosis. Such antiapoptotic effects of zinc protoporphyrin-IX were repressed by supplementation of dichloromethane, a CO donor. Upon CdCl(2)-treatment, both Sertoli cells and the germ cells upregulated Fas ligand; this event was also suppressed by zinc protoporphyrin-IX and restored by dichloromethane. Thus, Leydig cells appear to use HO-1-derived CO to trigger apoptosis of premeiotic germ cells and thereby modulate spermatogenesis under conditions of stress.

Carbon monoxide from heme oxygenase-2 Is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation.

Although the brain generates NO and carbon monoxide (CO), it is unknown how these gases and their enzyme systems interact with each other to regulate cerebrovascular function. We examined whether CO produced by heme oxygenase (HO) modulates generation and action of constitutive NO in the rat pial microcirculation. Immunohistochemical analyses indicated that HO-2 occurred in neurons and arachnoid trabecular cells, where NO synthase 1 (NOS1) was detectable, and also in vascular endothelium-expressing NOS3, suggesting colocalization of CO- and NO-generating sites. Intravital microscopy using a closed cranial window preparation revealed that blockade of the HO activity by zinc protoporphyrin IX significantly dilates arterioles. This vasodilatation depended on local NOS activities and was abolished by CO supplementation, suggesting that the gas derived from HO-2 tonically regulates NO-mediated vasodilatory response. Bioimaging of NO by laser-confocal microfluorography of diaminofluorescein indicated detectable amounts of NO at the microvascular wall, the subdural mesothelial cells, and arachnoid trabecular cells, which express NOS in and around the pial microvasculature. On CO inhibition by the HO inhibitor, regional NO formation was augmented in these cells. Such a pattern of accelerated NO formation depended on NOS activities and was again attenuated by the local CO supplementation. Studies using cultured porcine aortic endothelial cells suggested that the inhibitory action of CO on NOS could result from the photo-reversible gas binding to the prosthetic heme. Collectively, CO derived from HO-2 appears to serve as a tonic vasoregulator antagonizing NO-mediated vasodilatation in the rat cerebral microcirculation.

Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: role of bilirubin and carbon monoxide generated by the enzyme.

Monocyte chemoattractant protein 1 (MCP-1) and the receptor for MCP-1, CCR2, play a pivotal role in the recruitment of monocytes to the subendothelium, which is the initial event in atherosclerosis. Heme oxygenase (HO) is a microsomal enzyme that catalyzes the degradation of heme into biliverdin, which is subsequently reduced to bilirubin, free iron, and carbon monoxide, and induction of HO-1 is potentially associated with cellular protection, especially against oxidative insults. The present study was designed to examine the role of HO-1 in monocytes in angiotensin II (Ang II)-induced chemotactic response. Ang II significantly stimulated superoxide formation in monocytes, as measured by nitro blue tetrazolium reduction assay, as well as the chemotactic response to MCP-1 with the increased expression of CCR2 determined by RT-PCR and western blotting analysis. Hemin-treated monocytes displayed an enhanced HO activity with the increased accumulation of bilirubin determined by immunostaining, when compared with control monocytes. The induction of HO-1 in monocytes suppresses not only Ang II-stimulated superoxide formation, but also Ang II-enhanced chemotactic activity. Exogenously applied bilirubin and carbon monoxide mimicked the inhibitory effect of HO-1 on the chemotactic response. These findings suggest that monocytic HO-1 might be a new therapeutic target for atherosclerosis.

Carbon monoxide stimulates mrp2-dependent excretion of bilirubin-IXalpha into bile in the perfused rat liver.

Although carbon monoxide (CO) has been reported to protect against hepatobiliary dysfunction, mechanisms for its actions remain unknown. This study aimed to examine actions of physiologically relevant concentrations of CO on biliary excretion. The effects of transportal administration of CO on bile output and constituents were examined in perfused rat livers. In livers of fed rats, CO regulated bile output biphasically in a dose-dependent manner; transportal administration of CO at 4 micro mol/L stimulated bile output by 10%. Under these circumstances, CO increased paracellular junctional permeability and consequently decreased biliary excretion of bile salts. Choleresis elicited by 4 micro mol/L CO coincided with significant increases in biliary excretion of bilirubin-IXalpha and glutathione. The CO-induced choleresis occurred independently of cyclic GMP, coincided with elevated excretion of K(+) and HCO(3)(-), and was abolished by tetraethylammonium, suggesting stimulatory effects of the gas on potassium channels. CO-mediated choleresis and increased excretion of organic anions appeared to be mediated by mrp2, because Eisai hyperbilirubinemia rats, which genetically lack the transporter, did not exhibit choleresis upon the CO administration. These results suggest that CO stimulates mrp2-dependent excretion of bilirubin-IXalpha through mechanisms involving potassium channels, serving as a cooperator standing behind the heme oxygenase reaction to facilitate hepatic heme detoxification.

Effect of AMPA receptor antagonist YM872 on cerebral hematoma size and neurological recovery in the intracerebral hemorrhage rat model.

[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate (YM872 or zonampanel), an AMPA receptor antagonist, is in clinical development for acute ischemic cerebral infarction. Stroke patients are prone to have subsequent intracerebral hemorrhages. In order to predict potential adverse effects, YM872 was tested in a rat model with collagenase-induced intracerebral hemorrhage. The morphologically determined hematoma volumes after 24 h were compared between animal groups intravenously infused with 3600 U/kg/h heparin for 30 min, or with 20 or 40 mg/kg/h of YM872, or placebo for 4 h. Heparin enlarged hematoma volume, but neither dose of YM872 affected hematoma size. In a separate study, neurological deficits were scored at various days after intracerebral hemorrhage induction in animals with intravenous infusion for 24 h of 10 or 20 mg/kg/h YM872, or saline. The YM872 groups scored significantly better than the saline group at 14 days. These data suggest that YM872 does not exacerbate intracerebral hemorrhage and might accelerate recovery.

Suppression of fully kindled seizure and retardation of kindling acquisition by YM928 in the rat kindling model of epilepsy.

We investigated the effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in the rat kindling model of complex partial seizures. YM928 (10 and 30 mg/kg p.o.) markedly suppressed the motor seizures and afterdischarge induced by electrical stimulation of the amygdala at generalized seizure-triggering threshold intensity. YM928 (10 mg/kg p.o.) did not induce apparent abnormal behavior, but did induce sedation at a dose of 30 mg/kg p.o. YM928 (30 mg/kg p.o.) showed a similar anticonvulsant effect at twice the threshold intensity as it did at threshold intensity. Diazepam (10 mg/kg p.o.) and phenobarbital (60 mg/kg p.o.) also exerted anticonvulsant activities. Diazepam (10 mg/kg) showed a similar effect at twice the threshold as at threshold, but the anticonvulsant effect of phenobarbital (60 mg/kg p.o.) was reversed when the stimulus was doubled. When YM928 (10 mg/kg p.o.) was administered 60 min before daily stimulation of the amygdala, the development of kindling seizure was significantly retarded. These results indicate that YM928 has anticonvulsant effects and suppresses kindling acquisition without sedative effects, and may be suitable as an antiepileptic drug for the treatment of complex partial seizures in humans.

Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist.

YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, showed a high affinity for cloned human 5-HT(2C) receptors (K(i): 0.89 nM). The functional selectivity for 5-HT(2C) receptors in the 5-HT(2) receptor family was the highest among 5-HT(2C) receptor agonists, including m-chlorophenylpiperazine (mCPP) and Ro60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine). Oral administration of YM348 induced penile erections and hypolocomotion in rats, being completely inhibited by a selective 5-HT(2C) receptor antagonist, SB242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline). The dose-response curve for penile erections, unlike that for hypolocomotion, was an inverted U-shape in the dose range of 0.0677-2.03 mg/kg. A selective 5-HT(2A) receptor antagonist, MDL100907 (R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol), and a selective 5-HT(2B) receptor antagonist, RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine), had no effect on the decline in penile erection frequency at 2.03 mg/kg of YM348. YM348 did not affect blood pressure at 2.03 mg/kg. In conclusion, YM348 is a novel, potent and orally active 5-HT(2C) receptor agonist, and neither the activation of 5-HT(2A) or 5-HT(2B) receptors nor a cardiovascular effect is likely to contribute to the inverted U-shape dose-response curve for penile erections.

Effect of YM928, a novel AMPA receptor antagonist, on seizures in EL mice and kainate-induced seizures in rats.

Kainate-induced seizures and seizures induced by tossing stimulation in epilepsy-prone EL mice are considered as models of complex partial seizures. We used these models to evaluate the anticonvulsive effects of 2-[ N-(4-chlorophenyl)- N-methylamino]-4 H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. In the kainate-induced seizure test in rats, wet-dog shakes (WDS) were reduced by oral administration of YM928 at doses of 7.5 mg/kg and 30 mg/kg. YM928 (15 mg/kg) reduced the number of WDS within the first 80 min, but then prolonged the time of occurrence compared with the other groups. Significant reduction in kainate-induced motor seizure was observed with 4-30 mg/kg. YM928 did not induce apparently abnormal behaviour at doses of 2-15 mg/kg but did induce sedation at 30 mg/kg. Carbamazepine (40 or 80 mg/kg), valproate (600 mg/kg), diazepam (2.5 mg/kg), and phenobarbital (20 or 40 mg/kg) exerted anticonvulsant effects against motor seizures, but only valproate, at a dose that also caused sedation, suppressed WDS. Phenytoin and ethosuximide did not show significant anti-kainate effects. In the tossing stimulation test in EL mice, i.p. injection of YM928 at 5 mg/kg or 10 mg/kg significantly increased the number of stimulations required to elicit generalized seizure. Carbamazepine (4 or 8 mg/kg), phenytoin (8 or 16 mg/kg), valproate (100-400 mg/kg), diazepam (0.5 mg/kg), phenobarbital (1.3 or 2.5 mg/kg) and ethosuximide (75-300 mg/kg) exerted significant anticonvulsant effects against these seizures. These results indicate that YM928 has anticonvulsant effects on seizure models that are characteristic of partial onset seizures in humans. YM928 is expected to have beneficial effects against human complex partial seizure with secondary generalization or temporal lobe epilepsy.

The effect of the selective 5-HT(3) receptor agonist on ferret gut motility.

The effect of the selective 5-hydroxytryptamine (5-HT)(3) receptor agonist YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate) on gut motility of fed ferrets was investigated. YM-31636 (0.1 mg/kg p.o.) induced a giant migrating contraction (GMC)-like, high-amplitude, ungrouped colonic contraction although it did not change the basal colonic motility pattern. This GMC-like contraction was always accompanied by defecation. Both GMC-like contraction and defecation were inhibited with the selective 5-HT(3) receptor antagonist ramosetron. YM-31636 affected gastric, duodenal and ileal motility pattern only slightly. These results suggest that 5-HT(3) receptor agonists such as YM-31636 are useful in treating constipation since they facilitate GMC-like contractions and defecation without undesired changes in gut motility pattern.

Urinary excretion of oxidative metabolites of bilirubin in fenofibrate-treated rats.

Bilirubin oxidative metabolites (BOM) were shown to be excreted into the urine in rats in which exaggerated oxidative stress was induced. We measured bilirubin (BR) and biopyrrins in the urine of rats treated with fenofibrate, a peroxisome proliferator, which is known to cause oxidative stress. Male Crj:CD(SD)IGS rats aged 6 weeks were treated orally with fenofibrate at 10, 400 and 800 mg/kg for 2 weeks. Urinary excretion of BR and BOM, and the plasma BOM levels were determined after the first dose and after 1-week and 2-week treatment. Urinary excretion of BOM was significantly and dose-dependently increased by fenofibrate treatment at 400 and 800 mg/kg. This became more prominent as the dosing period progressed and reached an 8-fold increase in the 400 mg/kg group and 11-fold increase in the 800 mg/kg group compared with the data before dosing on Day 14. Plasma BOM levels were increased 1.8-fold and 2.7-fold, respectively, at 400 and 800 mg/kg in fenofibrate-treated rats. At 800 mg/kg, there was also increased urinary excretion of BR (2-fold) on Day 14. These changes of BOM in the urine and plasma indicated that BR was oxidized by reactive oxygen species (ROSs), which were produced by treatment with fenofibrate. In conclusion, urinary excretion of BOM, which is a marker for oxidative stress, urinary excretion of BR and the plasma BOM levels were increased in rats treated with fenofibrate. Increased urinary excretions of BR and BOM, and increased plasma BOM levels are likely to be the consequence of physiological protection against the oxidative stress produced by fenofibrate. These findings suggest a possibility that analysis of BOM in the urine and plasma could be helpful in evaluating the degree of oxidative stress in vivo.

Effects of lifestyle factors on urinary oxidative stress and serum antioxidant markers in pregnant Japanese women: A cohort study.

Oxidative stress plays a major pathological role in pregnancy-related complications. Although oxidative stress is induced by exogenous toxins in association with a poor lifestyle in normal subjects, there is little information on the factors altering oxidative stress and antioxidant levels during pregnancy. The purpose of this study was to determine the relationship between lifestyle factors and oxidative stress/antioxidant levels during each trimester and 1-month postpartum. This prospective cohort study followed 54 healthy women through pregnancy; first, second, and third trimester and 1-month postpartum. Participants were administered a questionnaire on characteristics and lifestyle factors. Morning blood and urine samples were obtained to measure urinary biopyrrins and serum coenzyme Q10 (CoQ10) levels. The levels of urinary biopyrrins and serum CoQ10 increased significantly throughout pregnancy, with peak values registered during the third trimester. Higher biopyrrin levels were significantly associated with non-consumption of morning meal during the first trimester, smoking during the third trimester and 1-month postpartum, alcohol consumption during the third trimester, high food-based polyunsaturated fatty acid intake during the third trimester, and poor mental health scores during the first and third trimesters. Higher CoQ10 levels were significantly associated with no smoking during pregnancy and at 1-month postpartum, and with a high frequency of exercise during the third trimester and 1-month postpartum. Thus, pregnancy represents a state of oxidative stress, which can be counterbalanced by increased levels of antioxidants, such as CoQ10. We speculate that certain lifestyle choices such as avoiding smoking can reduce oxidative stress and increase antioxidant levels during pregnancy.

HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-ß type I receptor.

Viruses sometimes mimic host proteins and hijack the host cell machinery. Hepatitis C virus (HCV) causes liver fibrosis, a process largely mediated by the overexpression of transforming growth factor (TGF)-ß and collagen, although the precise underlying mechanism is unknown. Here, we report that HCV non-structural protein 3 (NS3) protease affects the antigenicity and bioactivity of TGF-ß2 in (CAGA)9-Luc CCL64 cells and in human hepatic cell lines via binding to TGF-ß type I receptor (TßRI). Tumor necrosis factor (TNF)-α facilitates this mechanism by increasing the colocalization of TßRI with NS3 protease on the surface of HCV-infected cells. An anti-NS3 antibody against computationally predicted binding sites for TßRI blocked the TGF-ß mimetic activities of NS3 in vitro and attenuated liver fibrosis in HCV-infected chimeric mice. These data suggest that HCV NS3 protease mimics TGF-ß2 and functions, at least in part, via directly binding to and activating TßRI, thereby enhancing liver fibrosis.