Lack of genotoxic mechanisms in early‐stage furan‐induced hepatocellular tumorigenesis in gpt delta rats

Furan has been used as an intermediate in the chemical‐manufacturing industry and has been shown to contaminate various foods. Although furan induces hepatocellular tumors in rodents, equivocal results from in vitro and in vivo mutagenicity tests have caused controversy regarding the involvement of genotoxic mechanisms in furan‐induced carcinogenesis. In the present study, to elucidate the possible mechanisms underlying furan‐induced hepatocarcinogenesis, a comprehensive medium‐term analysis was conducted using gpt delta rats treated with furan at carcinogenic doses for 13 weeks. In the liver, the frequencies of gpt and Spi^‐ mutants derived mainly from point and deletion mutations, respectively, were not changed, and there were no furan‐specific gpt mutations in furan‐treated rats. In contrast, the number and area of glutathione S‐transferase placental form (GST‐P)‐ positive foci were significantly increased in the high‐dose group. Also, the ratio of PCNA‐positive hepatocytes was significantly elevated in the same group, as supported by significant increases in cyclin d1 and cyclin e1 mRNA levels. Thus, it is highly probable that cell proliferation, but not genotoxic mechanisms, contribute to the development of GST‐P foci in furan‐treated rats. Based on the close relationship between GST‐P and neoplastic hepatocytes, these data allowed us to hypothesize that cell proliferation following signal transduction other than the mitogen‐activated protein kinase (MAPK)/ERK pathway may play a crucial role in early‐stage furan‐induced hepatocarcinogenesis. Copyright © 2016 John Wiley & Sons, Ltd.     

Diphenyl diselenide in its selenol form has dehydroascorbate reductase and glutathione S‐transferase‐like activity dependent on the glutathione content

Objectives The antioxidant action of diphenyl diselenide ((PhSe)₂) is attributed to the mechanism by which (PhSe)₂ has pharmacological activity. Although (PhSe)₂ has glutathione peroxidase mimetic activity, the exact mechanism involved in its antioxidant effect has not yet been completely elucidated. In the present study, mechanisms involved in the antioxidant property of (PhSe)₂ (1–50 µm ) were investigated. Methods Dehydroascorbate (DHA) reductase‐ and glutathione S‐transferase (GST)‐like activity, 2,2′‐diphenyl‐1‐picrylhydrazyl (DPPH) and 2,2′‐azino‐bis(3‐ethylbenzthiazoline‐6‐sulfonic acid) (ABTS) radical‐scavenging activity and the protection against the oxidation of Fe²⁺ were evaluated. Key findings (PhSe)₂ at concentrations equal to, or greater than, 5 µm showed DHA reductase‐ and GST‐like activity. (PhSe)₂ was not a scavenger of DPPH or ABTS radicals and did not protect against the oxidation of Fe²⁺. Conclusions These results clearly indicated that DHA reductase‐ and GST‐like activity are the mechanisms involved in the antioxidant effect of (PhSe)₂.     

(E)‐2‐Benzylidene‐4‐phenyl‐1,3‐diselenole ameliorates signals of renal injury induced by cisplatin in rats

The present study investigated the protective role of antioxidant (E)‐2‐benzylidene‐4‐phenyl‐1,3‐diselenole (BPD), an organoselenium compound, against the renal injury induced by cisplatin in rats. Canola oil or BPD (50 mg kg^?1) was administered orally by gavage once a day for 6 days to rats. The first dose of BPD was given 24 h before a single intraperitoneal injection of saline or cisplatin (7 mg kg^?1). At day 7, animals were killed and parameters related to renal injury were determined. The histological analysis showed that cisplatin caused renal injury in rats, which was accompanied by an increase in urea and creatinine levels in plasma. The increase of plasma creatinine levels negatively correlated with renal antioxidant defenses including ascorbic acid (AA) and reduced glutathione (GSH) content as well as glutathione S‐transferase (GST), glutathione peroxidase (GPx) and catalase (CAT) activities. As revealed by histological analysis, BPD ameliorated tubular injury in rat kidney and reduced plasma markers altered by cisplatin. The administration of BPD to rats attenuated the reduction of renal AA and GSH content in animals exposed to cisplatin. The decrease of GST activity, but not GPx and CAT activities, in rats exposed to cisplatin was totally reversed by BPD administration. BPD was also effective in attenuating the inhibition of a sulfhydryl enzyme sensitive to oxidative stress, δ‐aminolevulinic dehydratase, in kidneys of rats exposed to cisplatin. The present study demonstrated that BPD reduced renal injury induced by cisplatin in rats and this effect seems to be related to antioxidant mechanisms. Copyright © 2012 John Wiley & Sons, Ltd.     

Ameliorative effects of Saussurea lappa root aqueous extract against Ethephon‐induced reproductive toxicity in male rats

This study was designed to evaluate protective effect of Saussurea lappa root aqueous extract against Ethephon (2‐chloroethylphosphonic acid)‐induced reproductive toxicity in rats. Control group received distilled water. Second group was given S. lappa extract at a dose 50 mg/kg bw. Third group was given Ethephon at a dose 200 mg/kg bw. Fourth, fifth, and sixth groups were given S. lappa extract before, with or after Ethephon administration, respectively. Ethephon intoxication significantly decreased serum levels of follicle stimulating hormone, luteinizing hormone, testosterone, and prolactin. Also, it significantly decreased sperms count, vitality, morphology index, total motility, progressive motility, and proliferating cell nuclear antigen protein expressions in spermatogonia. However, it significantly increased sperms abnormalities, testicular tissue and DNA damages, P53 protein expressions, noprogressive motility, and immotile sperms. In contrast, S. lappa extract ameliorated these alterations. These results indicated that S. lappa had potential preventive and curative effects against Ethephon‐induced reproductive toxicity in rats.     

A review of the pharmacological effects of <Emphasis Type="Italic">Arctium lappa</Emphasis> (burdock)

Arctium lappa, commonly known as burdock, is being promoted/recommended as a healthy and nutritive food in Chinese societies. Burdock has been used therapeutically in Europe, North America and Asia for hundreds of years. The roots, seeds and leaves of burdock have been investigated in view of its popular uses in traditional Chinese medicine (TCM). In this review, the reported therapeutic effects of the active compounds present in the different botanical parts of burdock are summarized. In the root, the active ingredients have been found to “detoxify” blood in terms of TCM and promote blood circulation to the skin surface, improving the skin quality/texture and curing skin diseases like eczema. Antioxidants and antidiabetic compounds have also been found in the root. In the seeds, some active compounds possess anti-inflammatory effects and potent inhibitory effects on the growth of tumors such as pancreatic carcinoma. In the leaf extract, the active compounds isolated can inhibit the growth of micro-organisms in the oral cavity. The medicinal uses of burdock in treating chronic diseases such as cancers, diabetes and AIDS have been reported. However, it is also essential to be aware of the side effects of burdock including contact dermatitis and other allergic/inflammatory responses that might be evoked by burdock.     

Metabolic profile of the bioactive compounds of burdock (Arctium lappa) seeds, roots and leaves

In this work the bioactive metabolic profile, the antioxidant activity and total phenolic content of burdock (Arctium lappa) seeds, leaves and roots were obtained. TEAC values and total phenolic content for hydro-alcoholic extracts of burdock ranged from 67.39 to 1.63 μmol Trolox equivalent/100 g dry weight (DW), and from 2.87 to 45 g of gallic acid equivalent/100 g DW, respectively. Phytochemical compounds were analyzed by liquid chromatography coupled to electrospray tandem mass spectrometry (LC/MS/MS) in negative mode. The main compounds of burdock extracts were caffeoylquinic acid derivatives, lignans (mainly arctiin) and various flavonoids.The occurrence of some phenolic acids (caffeic acid, chlorogenic acid and cynarin) in burdock seeds; arctiin, luteolin and quercetin rhamnoside in burdock roots; phenolic acids, quercetin, quercitrin and luteolin in burdock leaves was reported for the first time.     

The protective mechanism of Nigella sativa against diethylnitrosamine‐induced hepatocellular carcinoma through its antioxidant effect and EGFR/ERK1/2 signaling

A wide variety of natural products have powerful chemopreventive effects due to their antioxidant, antimutagenic, and anti‐inflammatory activities that enable them to arrest cell proliferation in several cancer models. In the present study, we shed light on the protective mechanism of Nigella sativa extract against diethylnitrosamine (DENA)‐induced preneoplastic stage of hepatocellular carcinoma (HCC) in rats. We studied the extract effect on EGFR/ERK1/2 signaling pathway as one of the major signaling pathways controlling cell proliferation during hepatocarcinogenesis as well as the investigation of its antioxidant activity. The study also compared the effects of NSEE to those of (thymoquinone) TQ and silymarin as hepatoprotective substances. Rats received daily doses of NSEE (150, 250, 350 mg/kg BW), a dose per three alternative days/week of TQ (20 mg/kg BW) and a daily dose of silymarin (100 mg/kg BW). The doses were administered orally by gavage for 12 days before DENA and CCl₄ administration, and then the supply of NSEE, TQ or silymarin was continued until the end of the experiment (16 weeks). DENA administration activated EGFR/ERK1/2 signaling and caused a significant increase in P‐EGFR and P‐ERK1/2 as well as a significant up‐regulation of expression of target genes such as PCNA, c‐fos and Bcl2, which indicated the increase in cell proliferation. Furthermore, a significant elevation in alpha‐fetoprotein (AFP) and hepatic enzymes was observed in DENA‐treated rats in addition to a decrease in the antioxidant status. The protection with NSEE, TQ, or silymarin has the potential to inhibit the EGFR/ERK1/2 activation and improve the antioxidant status. Moreover, the action of NSEE against the hepatocarcinogenesis was supported by high antioxidant activity and the histopathological observations of the liver. These data suggest that NSEE has a chemopreventive role in DENA‐induced HCC through the inhibition of the EGFR/ERK1/2 signaling pathway and their target genes in addition to its role as an antioxidant.     

The peroxisome proliferator‐activated receptor‐γ agonist pioglitazone protects against cisplatin‐induced renal damage in mice

Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non‐diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR‐γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg^–1). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg^–1 day^–1, per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non‐enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S‐transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin‐induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR‐γ agonists in human application for protecting against drugs‐induced nephrotoxicity. Copyright © 2012 John Wiley & Sons, Ltd.     

Effects of cadmium alone and in combination with low molecular weight chitosan on metallothionein,glutathione‐S‐transferase,acid phosphatase,and ATPase of freshwater crab Sinopotamon yangtsekiense

Cadmium (Cd) is an environmental contaminant showing a variety of deleterious effects, including the potential threat for the ecological environment and human health via food chains. Low molecular weight chitosan (LMWC) has been demonstrated to be an effective antioxidant. Metallothionein (MT) mRNA levels and activities of glutathione‐S‐transferase (GST), superoxide dismutase (SOD), acid phosphatase (ACP), Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase as well as malondialdehyde (MDA) contents in the gills of the freshwater crab Sinopotamon yangtsekiense were analyzed in vivo in order to determine the injury of Cd exposure on the gill tissues as well as the protective effect of LMWC against this injury. The results showed that there was an apparent accumulation of Cd in the gills, which was lessened by the presence of LMWC. Moreover, Cd²⁺ significantly increased the gill MT mRNA levels, ACP activity and MDA content while decreasing the activities of SOD, GST, Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase in the crabs relative to the control. Cotreatment with LMWC reduced the levels of MT mRNA and ACP but raised the activities of GST, Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase in gill tissues compared with the crabs exposed to Cd²⁺ alone. These results suggest that LMWC may exert its protective effect through chelating Cd²⁺ to form LMWC‐Cd²⁺ complex, elevating the antioxidative activities of GST, Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase as well as alleviating the stress pressure on MT and ACP, consequently protecting the cell from the adverse effects of Cd. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 298–309, 2014.     

Modulatory effects of Saussurea lappa root aqueous extract against ethephon‐induced kidney toxicity in male rats

Ethephon (2‐chloroethyl phosphonic acid) is a plant growth promoter used to control the plant growth process by liberating ethylene and stimulating the production of endogenous ethylene. Medicinal plants are sources of novel drug discovery targets. Costus (Saussurea lappa) has been used as traditional Chinese medicine. The current study was conducted to examine the possible modifying effects of costus (S. lappa) root aqueous extract against kidney toxicity induced by ethephon in male rats. A total of 50 adult male rats were divided into five groups (first, control; second, costus; third, ethephon; fourth, posttreated ethephon with costus; fifth, ethephon self‐healing). There is a significant increase in the serum levels of urea, creatinine, potassium ions, chloride ions, kidney injury, DNA damage, and proliferating cell nuclear antigen expressions in treated rats with ethephon when compared to the control group. In contrast, the treated rats with ethephon revealed a significant decrease in the levels of sodium ions and an insignificant decrease in the calcium ions. Saussurea lappa extract modified these alterations when compared to the control group. As a result, costus root extract significantly reduced rat kidney toxicity after ethephon administration. We recommend costus to be included in diet for its valuable effects, and also producers and consumers should become more aware about the toxic effects of ethephon.     

The synthesis of tritiated (R)‐2‐methoxy‐N‐n‐propyl‐nor‐apomorphine (MNPA)

A method for the preparation of [³H]‐MNPA ((R)‐2‐methoxy‐N‐n‐propyl‐norapomorphine) has been developed addressing the regioisomer problem as well as the oxidation problem. (R)‐2, 10, 11‐trihydroxy‐N‐n‐propyl‐norapomorphine was protected with 10, 11‐dibenzyl or 10, 11‐acetonide. The pure precursor was then methylated using [³H]‐methyliodide. The product was isolated after deprotection and high‐pressure liquid chromatography (HPLC) purification. Ascorbic acid was used as an antioxidant in the HPLC eluent and the stock solution. Characterization of the intermediates and products with ³H‐ and ¹H‐NMR was performed. A specific activity of 3.1 TBq/mmol (83.8 Ci/mmol) and 98.9% purity was obtained. Copyright © 2007 John Wiley & Sons, Ltd.     

Meta‐analysis: antioxidant supplements for liver diseases – the Cochrane Hepato‐Biliary Group

Aliment Pharmacol Ther 2010; 32: 356–367

Summary

Background Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal. Aim To assess the benefits and harms of antioxidant supplements for patients with liver diseases. Methods We identified trials through electronic and manual searches until August 2009. We included randomized trials comparing antioxidant supplements (beta‐carotene, vitamin A, C, E and selenium) vs. placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease and cirrhosis (any aetiology). Random‐effects and fixed‐effect meta‐analyses were conducted. Results were presented as relative risks (RR), or mean difference (MD), both with 95% confidence intervals (CI). Results Twenty randomized trials with 1225 participants were included. The trials assessed beta‐carotene (3 trials), vitamin A (2 trials), vitamin C (9 trials), vitamin E (15 trials) and selenium (8 trials). The majority of the trials had high risk of bias and showed heterogeneity. Overall, the assessed antioxidant supplements had no significant effect on all‐cause mortality [relative risk (RR) 0.84, 95% confidence interval (CI) 0.60–1.19, I² = 0%] or liver‐related mortality (RR 0.89, 95% CI 0.39–2.05, I² = 37%). Stratification according to the type of liver disease assessed did not affect the conclusions. Antioxidant supplements significantly increased the activity of gamma glutamyl transpeptidase (MD 24.21 IU/L, 95% CI 6.67–41.75, I² = 0%). Conclusions We found no evidence to support or refute antioxidant supplements in patients with liver disease. Antioxidant supplements may increase liver enzymes.     

Phoxim‐induced damages of Bombyx mori larval midgut and titanium dioxide nanoparticles protective role under phoxim‐induced toxicity

Phoxim (O,O‐diethyl O‐(alpha‐cyanobenzylideneamino) phosphorothioate) is a powerful organophosphorus pesticide with high potential for Bombyx mori larvae of silkworm exposure. However, it is possible that during the phoxim metabolism, there is generation of reactive oxygen species (ROS) and phoxim may produce oxidative stress and neurotoxicity in an intoxicated silkworm. Titanium dioxide nanoparticles (TiO₂ NPs) pretreatment has been demonstrated to increase antioxidant capacity and acetylcholinesterase (AChE) activity in organisms. This study was, therefore, undertaken to determine phoxim‐induced oxidative stress and neurotoxicity to determine whether phoxim intoxication alters the antioxidant system and AChE activity in the B. mori larval midgut, and to determine whether TiO₂ NPs pretreatment attenuates phoxim‐induced toxicity. The findings suggested that phoxim exposure decreased survival of B. mori larvae, increased malondialdehyde (MDA), carbonyl and 8‐OHdG levels, and ROS accumulation in the midgut. Furthermore, phoxim significantly decreased the activities of AChE, superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR), glutathione‐S‐transferase (GST), and levels of ascorbic acid (AsA), reduced glutathione (GSH), and thiol in the midgut. TiO₂ pretreatment, however, could increase AChE activity, and remove ROS via activating SOD, CAT, APX, GR, and GST, and accelerating AsA–GSH cycle, thus attenuated lipid, protein, and DNA peroxidation and improve B. mori larval survival under phoxim‐induced toxicity. Moreover, this experimental system would help nanomaterials to be applied in the sericulture. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1355–1366, 2014.     

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Aliment Pharmacol Ther 2010; 32: 487–497

Summary

Background Progression of non‐alcoholic fatty liver disease (NAFLD) can be facilitated by soluble molecules secreted by visceral adipose tissue (VAT). MicroRNAs (miRNAs) are likely to regulate some of these molecular pathways involved in pathogenesis of NAFLD. Aim To profile miRNA expression in the visceral adipose tissue of patients with NAFLD. Methods Visceral adipose tissue samples were collected from NAFLD patients and frozen. Patients with biopsy‐proven NAFLD were divided into non‐alcoholic steatohepatitis (NASH) (n = 12) and non‐NASH (n = 12) cohorts controlled for clinical and demographic characteristics. Extracted total RNA was profiled using TaqMan Human MicroRNA arrays. Univariate Mann–Whitney comparisons and multivariate regression analysis were performed to compare miRNA profiles. Results A total of 113 miRNA differentially expressed between NASH patients and non‐NASH patients (P < 0.05). Of these, seven remained significant after multiple test correction (hsa‐miR‐132, hsa‐miR‐150, hsa‐miR‐433, hsa‐miR‐28‐3p, hsa‐miR‐511, hsa‐miR‐517a, hsa‐miR‐671). Predicted target genes for these miRNAs include insulin receptor pathway components (IGF1, IGFR13), cytokines (CCL3, IL6), ghrelin/obestatin gene, and inflammation‐related genes (NFKB1, RELB, FAS). In addition, two miRNA species, hsa‐miR‐197 and hsa‐miR‐99, were significantly associated with pericellular fibrosis in NASH patients (P < 0.05). Levels of IL‐6 in the serum negatively correlated with the expression levels of all seven miRNAs capable of down regulating IL‐6 encoding gene. Conclusions miRNA expression from VAT may contribute to the pathogenesis of NAFLD – a finding which may distinguish relatively simple steatosis from NASH. This could help identify potential targets for pharmacological treatment regimens and candidate biomarkers for NASH.     

3‐Keto‐1,5‐bisphosphonates Alleviate Serum‐Oxidative Stress in the High‐fat Diet Induced Obesity in Rats

Obesity has become a leading global health problem owing to its strong association with a high incidence of oxidative stress. Many epidemiologic studies showed that an antioxidant supplementation decreases the state of oxidative stress. In the present work, a HFD ‐induced rat obesity and oxidative stress were used to investigate the link between fat deposition and serum‐oxidative stress markers. We also studied the effect of a chronic administration of 3‐keto‐1,5‐bisphosphonates 1 (a & b) (40 μg/kg/8 weeks/i.p.). Exposure of rats to HFD during 16 weeks induced fat deposition, weight gain and metabolic disruption characterized by an increase in cholesterol, triglyceride and glycemia levels, and a decrease in ionizable calcium and free iron concentrations. HFD also induced serum‐oxidative stress status vocalized by an increase in ROS ( H ₂ O ₂ ), MDA and PC levels, with a decrease in antioxidant enzyme activity ( CAT , GP x , SOD ). Importantly, 3‐keto‐1,5‐bisphosphonates corrected all the deleterious effects of HFD treatment in vivo, but it failed to inhibit lipases in vitro and in vivo. These studies suggest that 3‐keto‐1,5‐bisphosphonates 1 could be considered as safe antioxidant agents that should also find other potential biological applications.     

Neurotoxic effects of lambda‐cyhalothrin modulated by piperonyl butoxide in the brain of Oreochromis niloticus

The objective of this research was to investigate the neurotoxic effects of pyrethroid pesticide lambda‐cyhalothrin by the modulation of cytochrome P450 with piperonyl butoxide in the brain of juvenile Oreochromis niloticus. The fish were exposed to 0.48 μg L^?1 (1/6 of the 96‐h LC₅₀) lambda‐cyhalothrin and 10 μg L^?1 piperonyl butoxide for 96 h and 15 days. tGSH, GSSG, TBARS contents, GPx, GR, GST, and AChE enzymes activities were determined by spectrophotometrical methods and Hsp70 content was analyzed by ELISA technique. Lambda‐cyhalothrin had no significant effect on the components of GSH redox system, lipid peroxidation and Hsp70 levels but inhibited AChE activity. In the presence of piperonyl butoxide, lambda‐cyhalothrin caused increases in tGSH, GSSG, TBARS and Hsp70 contents, GST activity, and decrease in AChE activity. Present results showed that in the presence of piperonyl butoxide, lambda‐cyhalothrin caused neurotoxic effects by increasing oxidative stress. Adaptation to its oxidative stress effects may be supplied by GSH‐related antioxidant system. Piperonyl butoxide revealed neurotoxic effect of lambda‐cyhalothrin. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1275–1282, 2014.     

Increased ratio of neutrophil elastase to α1‐antitrypsin is closely associated with liver inflammation in patients with nonalcoholic steatohepatitis

An imbalance between neutrophil elastase (NE) and its inhibitor α1‐antitrypsin (A₁AT) is known to contribute to the development of obesity‐related inflammation. This study aimed to investigate the role of the NE‐A₁AT system in the histological progression of non‐alcoholic fatty liver disease (NAFLD), and to evaluate the ability of it to predict nonalcoholic steatohepatitis (NASH). A total of 252 adults (NAFLD group, n = 202; healthy group, n = 50) were recruited. Clinical biochemical characteristics, NE and A₁AT concentrations were measured in all subjects. Among the NAFLD group, 86 patients had previously undergone liver biopsy and information on histological characteristics was consequently available. The area under the receiver operating characteristic curve (AUC) was used to determine the predictive accuracy of the NE‐A₁AT system for NASH. NAFLD patients had an elevated serum NE concentration and a reduced A₁AT level with consequent NE/A₁AT imbalance. NE increased in the early stage of steatosis, preceding the decline in A₁AT, dating from the onset of NASH (NAS 3–4), and subsequently NE/A₁AT increased in the presence of NASH. Nonetheless, this increase began to resolve as the disease state progressed to advanced fibrosis. A₁AT had a sensitivity (SEN) of 83.8% and a specificity (SP) of 83.3% with the optimal cut‐off of ?1459.43, NE/A₁AT had a SEN of 88.8% and a SP of 83.3% with cut‐off of 0.363 to predict NASH. An increased NE: A₁AT ratio is closely associated with liver Inflammation in patients with NASH and could serve as a novel marker to predict NASH in humans.     

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc‐1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12‐16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc‐1β^?/? (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1‐adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc‐1β^?/? genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino‐atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc‐1β^?/? mice. Moreover, Pgc‐1β^?/? mice displayed electrocardiographic features consistent with the existence of a pro‐arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc‐1β^?/? mice had shorter repolarisation intervals. These were likely attributable to altered K⁺ conductance properties, ultimately resulting in a shortened QT_c interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc‐1β^?/? systems in widespread cardiac regions.