Evaluation of Nootropic Potential of Aerva persica Roots against D-galactose-induced Memory Impairment.

BACKGROUND: The primary phytoconstituents reported to have neuroprotective effects are flavonoids and phenolic compounds. Aerva persica roots are reported to be rich in flavonoids and phenolic compounds. Therefore, this study aimed to explore the nootropic potential of Aerva persica roots. OBJECTIVE: The objective of this study was to evaluate the nootropic potential of Aerva persica roots against D-galactose-induced memory impairment. METHODS: In this study, the roots of Aerva persica were extracted with 70% ethanol. The obtained extract was evaluated for total phenolic content using the Folin-Ciocalteu method and total flavonoid content using the aluminium chloride colorimetric assay. Afterward, the acute oral toxicity of the extract was determined following the Organisation for Economic Co-operation and Development (OECD) guideline 423. Additionally, two doses of Aerva persica (100 and 200 mg/kg body weight (BW)) were evaluated for their nootropic potential against D-galactose-induced memory impairment. The nootropic potential of the crude extract was assessed through a behavioural study and brain neurochemical analysis. Behavioural studies involved the evaluation of spatial reference- working memory using the radial arm maze test and the Y-maze test. Neurochemical analysis was performed to determine the brain's acetylcholine, acetylcholinesterase, glutathione (GSH), and malondialdehyde (MDA) levels. RESULTS: The total phenolic content and total flavonoid content were found to be 179.14 ± 2.08 µg GAE/mg and 273.72 ± 3.94 µg QE/mg, respectively. The Aerva persica extract was found to be safe up to 2000 mg/kg BW. Following the safety assessment, the experimental mice received various treatments for 14 days. The behavioural analysis using the radial maze test showed that the extract at both doses significantly improved spatial reference-working memory and reduced the number of total errors compared to disease control groups. Similarly, in the Y-maze test, both doses significantly increased the alteration percentage and the percentage of novel arm entry (both indicative of intact spatial memory) compared to disease control. In neurochemical analysis, Aerva persica at 200 mg/kg significantly normalised the acetylcholine level (p<0.0001) and GSH level (p<0.01) compared to disease control. However, the same effect was not observed with Aerva persica at 100 mg/kg. Additionally, Aerva persica at 200mg/kg BW significantly decreased the acetylcholinesterase level (p<0.0001) and decreased the brain's MDA level (p<0.01) compared to the disease control, whereas the effect of Aerva persica at 100 mg/kg BW in reducing acetylcholinesterase was non-significant. CONCLUSION: Based on the results, it can be concluded that the nootropic potential of Aerva persica was comparable to that of the standard drug, Donepezil, and the effect might be attributed to the higher content of flavonoids and phenolic compounds.

Protective effect of fustin against adjuvant-induced arthritis through the restoration of proinflammatory response and oxidative stress.

Rheumatoid arthritis causes irreparable damage to joints. The present research sought to check fustin's anti-arthritic efficacy against the complete Freund's adjuvant-induced arthritis paradigm in animals by altering the inflammatory response. In the rats, complete Freund's adjuvant was used to trigger arthritis and they received fustin at 50 and 100 mg/kg for 21 days. At regular intervals, the hind paw volume and arthritic score were assessed. After the trial period, hematological, antioxidant, pro-inflammatory cytokines, and other biochemical parameters were estimated. Fustin-treated rats showed the down-regulation of hind paw volume, arthritic score, and altered hematological parameters (TLC, DLC (neutrophil, lymphocyte, monocyte, eosinophil, basophil)). Furthermore, fustin significantly mitigates proinflammatory cytokine (reduced interleukin, tumor necrosis factor-a (TNF-α), IL-6, IL-1ß), oxidative stress (attenuated malondialdehyde (MDA), catalase (CAT), glutathione (GSH), superoxide dismutase (SOD)), attenuated production of prostaglandin E2 and myeloperoxidase (MPO) and improved nuclear factor erythroid 2-related factor (Nrf2) action. Fustin led to the benefit in arthritis-prone animals elicited by complete Freund's adjuvant via pro-inflammatory cytokine.

Hepatoprotective effect of taxifolin on cyclophosphamide-induced oxidative stress, inflammation, and apoptosis in mice: Involvement of Nrf2/HO-1 signaling.

Taxifolin (TA) is a natural flavonoid found in many foods and medicinal plants with well-documented antioxidant and anti-inflammatory properties. Cyclophosphamide (CP) is an effective antineoplastic and immunosuppressive agent; however, it is associated with numerous adverse events, including hepatotoxicity. Herein, we aimed to investigate the potential protective effects of TA using a mouse model of CP-induced hepatotoxicity. Mice were co-treated with TA (25 and 50 mg/kg, orally) and CP (30 mg/kg, i.p.) for 10 consecutive days and sacrificed 24 hours later. CP induced increased transaminases (ALT and AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) paralleled with pronounced histopathological alterations in the liver. Moreover, hepatic tissues of CP-injected mice showed increased malondialdehyde (MDA), protein carbonyl, and nitric oxide (NO) levels, accompanied by decreased antioxidant defenses (glutathione [GSH], superoxide dismutase [SOD], and catalase [CAT]). Livers of CP-injected mice also showed increased inflammatory response (nuclear transcription factor kappa-B [NF-κB] p65 activation, increased levels of proinflammatory cytokines tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1ß], and IL-6) and apoptosis (decreased Bcl-2 and increased Bax and caspase-3 expression levels). Remarkably, TA ameliorated markers of liver injury and histological damage in CP-injected mice. TA treatment also attenuated numerous markers of oxidative stress, inflammation, and apoptosis in the liver of CP-injected mice. This was accompanied by increased nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) expression in the liver tissues of CP-injected mice. Taken together, this study indicates that TA may represent a promising new avenue to prevent/treat CP-induced hepatotoxicity and perhaps other liver diseases associated with oxidative stress and inflammation.

Assessing the risk factors for myocardial infarction in diet-induced prediabetes: myocardial tissue changes.

BACKGROUND: Hyperglycaemia is known to result in oxidative stress tissue injury and dysfunction. Interestingly, studies have reported hepatic and renal oxidative stress injury during prediabetes; however, any injury to the myocardium during prediabetes has not been investigated. Hence this study aims to assess changes in the myocardial tissue in an HFHC diet-induced model of prediabetes. METHODS: Male Sprague Dawley rats were randomly grouped into non-prediabetes and prediabetes (n = 6 in each group) and consumed a standard rat chow or fed a high-fat-high-carbohydrate diet respectively for a 20-week prediabetes induction period. Post induction, prediabetes was confirmed using the ADA criteria. Aldose reductase, NADH oxidase 1, superoxide dismutase, glutathione peroxide, cardiac troponins were analysed in cardiac tissue homogenate using specific ELISA kits. Lipid peroxidation was estimated by determining the concentration of malondialdehyde in the heart tissue homogenate according to the previously described protocol. Myocardial tissue sections were stained with H&E stain and analysed using Leica microsystem. All data were expressed as means ± SEM. Statistical comparisons were performed with Graph Pad instat Software using the Student's two-sided t-test. Pearson correlation coefficient was calculated to assess the association. Value of p < 0.05 was considered statistically significant. RESULTS: The prediabetes group showed a markedly high oxidative stress as indicated by significantly increased NADH oxidase 1 and malondialdehyde while superoxide dismutase and glutathione peroxide were decreased compared to non-prediabetes group. There was no statistical difference between cardiac troponin I and T in the non-prediabetes and prediabetes groups. Cardiac troponins had a weak positive association with glycated haemoglobin. CONCLUSION: The findings of this study demonstrate that prediabetes is associated with myocardial injury through oxidative stress. Future studies are to investigate cardiac contractile function and include more cardiac biomarkers.

Therapeutic Management of Idiosyncratic Drug-Induced Liver Injury and Acetaminophen Hepatotoxicity in the Paediatric Population: A Systematic Review.

INTRODUCTION: Drug-induced liver injury (DILI) is a rare but serious adverse event that can progress to acute liver failure (ALF). The evidence for treatment of DILI in children is scarce. OBJECTIVE: We aimed to comprehensively review the available literature on the therapies for both acetaminophen overdose (APAP) and idiosyncratic DILI in the paediatric population. METHODS: We included original articles conducted in a paediatric population (< 18 years) in which a therapeutic intervention was described to manage APAP or idiosyncratic DILI. Findings were summarized based on age groups (preterm newborn neonates, term and post-term neonates, infants, children and adolescents). RESULTS: Overall, 25 publications (fifteen case reports, six case series and four retrospective cohort studies) were included, including a total of 140 paediatric DILI cases, from preterm newborn neonates to adolescents. N-acetylcysteine was used to treat 19 APAP cases. N-acetylcysteine (n = 14), ursodeoxycholic acid (n = 3), corticosteroids (n = 31), carnitine (n = 16) and the combination of glycyrrhizin, reduced glutathione, polyene phosphatidylcholine and S-adenosylmethionine (n = 31) were the therapeutic options for treating idiosyncratic DILI. The molecular adsorbent recirculating system was used in the management of either APAP (n = 4) or idiosyncratic DILI (n = 2), while 20 paediatric ALF cases received continuous renal replacement therapy. CONCLUSIONS: This systematic review identified DILI in the paediatric population who have received specific treatment. These interventions appear to be mainly extrapolated from low-quality evidence from the adult population. Thus, there is a need for high-quality studies to test the efficacy of known and novel therapies to treat DILI specifically addressed to the paediatric population. PROSPERO registration number CRD42021214702.

Hepatic TGFßr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure Through Inhibiting GSK3ß-Nrf2-Mediated Hepatocyte Apoptosis and Ferroptosis.

BACKGROUND & AIMS: Acute liver failure (ALF) is a condition with high mortality and morbidity, characterized by glutathione depletion, oxidative stress, and mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have shown that ferroptosis plays a significant role in ALF. However, the mechanism of ferroptosis in hepatocytes during ALF remains unknown. METHODS: Hepatic-specific transforming growth factor ß receptor 1 knockout (TGFßr1Δhep-CKO) mice and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice were generated and subjected to ALF. Electron microscopy was used to detect mitochondrial and other cell substructure changes during ALF. RESULTS: In this study, we noticed that lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced caspases-mediated apoptosis as current research reported, we also found lipid peroxidation, reactive oxygen species accumulation, and glutathione, co-enzyme Q10 system inhibition mediated ferroptosis during LPS/D-GalN-induced ALF. Rescue studies have shown that ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFOM), the inhibitor of ferroptosis, could alleviate LPS/D-GalN-induced ALF. In addition, we noticed that TGFß1 was increased during ALF, while ALF was relieved in TGFßr1Δhep-CKO mice. We also noticed that liver TGFßr1 deficiency alleviated LPS/D-GalN-induced apoptosis and ferroptosis by affecting the phosphorylation of glycogen synthase kinase 3ß and Nrf2, a key antioxidant factor, by up-regulating the levels of glutathione peroxidase 4 (GPX4), glutamine antiporter xCT (XCT), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1), and down-regulating transferrin receptor (TFR), prostaglandin-endoperoxide synthase (Ptgs2), chaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1), and cytochrome P450 reductase (POR) expression. The further supplemental experiment showed that ferroptosis was aggravated significantly in Nrf2-/- mice compared with its wild-type controls and reversed by ferrostatin-1. CONCLUSIONS: This study shows that TGFßr1 plays a critical role in mediating LPS/D-GalN-induced ALF by promoting apoptosis and ferroptosis.

The effects of silymarin plus glutathione on the prevention of liver ischemia-reperfusion injury

Abstract Liver ischemia-reperfusion (IR) injury is a major clinical trouble encountered in clinical practice. This study aimed to examine the therapeutic effects of silymarin (SM) plus glutathione (GSH) on hepatic IR injury using a rat model of liver IR. Fifty male rats were randomly divided into five groups, each consisting of 10 rats as follows: Sham, IR, SM-IR, GSH-IR and SM plus GSH-IR. All groups except sham were subjected to 30-min ischemia and 24-h reperfusion. The treated groups received 100 mg/kg of SM, GSH and a mixture of SM plus GSH, 60 min prior to the IR. After a period of 24 h, blood and liver samples were collected for biochemical and histopathological evaluations. Pretreatment with SM, GSH and SM plus GSH before hepatic IR significantly decreased IR-induced elevations of aminotransferases, and significantly reduced the histopathological damage scores of the liver in the late phase of IR injury. Moreover, SM plus GSH treatment prior to liver IR significantly suppressed inflammatory process and oxidative stress as demonstrated by attenuations in tumor necrosis factor-α, myeloperoxidase and the thiobarbituric acid-reactive substances. These findings suggest that administration of SM plus GSH prior to liver IR may protect the liver parenchyma from the effects of an IR injury

The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial.

The effect of oral glutathione (GSH) supplementation was studied in obese subjects with and without type 2 diabetes (T2DM) on measures of glucose homeostasis and markers of oxidative stress. Twenty subjects (10 patients with T2DM and 10 obese subjects) were recruited for the study, and randomized in a double-blinded placebo-controlled manner to consume either 1000 mg GSH per day or placebo for 3 weeks. Before and after the 3 weeks insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp and a muscle biopsy was obtained to measure GSH and skeletal muscle mitochondrial hydrogen peroxide (H2O2) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (∼19%) in the GSH group; no change was seen in GSH to glutathione disulfide ratio. Skeletal muscle mitochondrial H2O2 emission rate did not change in response to the intervention and neither did the urinary excretion of the RNA oxidation product 8-oxo-7,8-dihydroguanosine or the DNA oxidation product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), although 8-oxodG decreased as a main effect of time. Oral GSH supplementation improves insulin sensitivity in obese subjects with and without T2DM, although it does not alter markers of oxidative stress. The study has been registered in clinicaltrials.gov (NCT02948673). Novelty: Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without T2DM. H2O2 emission rate from skeletal muscle mitochondria was not affected by GSH supplementation.

Glutathione conjugates of the mercapturic acid pathway and guanine adduct as biomarkers of exposure to CEES, a sulfur mustard analog.

Sulfur mustard (SM), a chemical warfare agent, is a strong alkylating compound that readily reacts with numerous biomolecules. The goal of the present work was to define and validate new biomarkers of exposure to SM that could be easily accessible in urine or plasma. Because investigations using SM are prohibited by the Organisation for the Prohibition of Chemical Weapons, we worked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM. We developed an ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) approach to the conjugate of CEES to glutathione and two of its metabolites: the cysteine and the N-acetylcysteine conjugates. The N7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizing the specific biomarkers, a solid-phase extraction protocol and a UHPLC-MS/MS method with isotopic dilution were optimized. We were able to quantify N7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skin exposed to CEES. N7Gua-CEES was also detected in the culture medium of these two models, together with the glutathione and the cysteine conjugates. In contrast, the N-acetylcysteine conjugate was not detected. The method was then applied to plasma from mice cutaneously exposed to CEES. All four markers could be detected. Our present results thus validate both the analytical technique and the biological relevance of new, easily quantifiable biomarkers of exposure to CEES. Because CEES behaves very similar to SM, the results are promising for application to this toxic of interest.

Phase I studies of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: a pooled analysis of two phase I studies conducted in Japan and Korea.

OBJECTIVE: Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220). METHODS: Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles. RESULTS: Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile. CONCLUSIONS: These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study.

The Effect of Cardiac Preservation Solutions on Heart Transplant Survival.

BACKGROUND: Limited data exist that compare the predominant cardiac preservation solutions (CPSs). MATERIALS AND METHODS: The United Network for Organ Sharing database was retrospectively reviewed from January 1, 2004 to March 31, 2018, for donor hearts. Of 34,614 potential donors, 21,908 remained after applying the exclusion criteria. The CPS analyzed included saline, the University of Wisconsin (UW), cardioplegia, Celsior, and Custodiol. The primary endpoints were recipient survival and posttransplant rejection. Logistic and Cox models were used to quantify survival endpoints. RESULTS: Saline was used as the CPS in 2549 patients (12%), UW in 10,549 (48%), cardioplegia in 1307 (6%), Celsior in 5081 (23%), and Custodiol in 2422 (11%). Donor age ranged from 15 to 68 y (mean = 32.0 y, median = 30.0 y), and 71% were male. Adjusted survival probabilities of recipients whose donor hearts were procured with saline was 96% 30 d, 90% 1 y, UW: 97% 30 d, 92% 1 y, cardioplegia: 95% 30 d, 87% 1 y, Celsior: 96% 30 d, 90% 1 y, and Custodiol: 97% 30 d, 92% 1 y. When these comparisons were adjusted for donor age, sex, ethnicity, ischemic time, recipient age, sex, ethnicity, creatinine, ventricular assist device (VAD), length of stay, region and days on waiting list, cardioplegia solution was demonstrated to have a higher risk of death (30 d, 1 y, overall) and posttransplant rejection versus UW (odds ratio 1.70, P = 0.001; odds ratio 1.63, P < 0.001; hazard ratio 1.22, P < 0.001; hazard ratio 1.21, P < 0.001, respectively). CONCLUSIONS: Cardioplegia solutions for cardiac preservation are associated with a higher mortality in heart transplant recipients.

Myocardial protection in on-pump coronary artery bypass grafting surgery: analysis of the effectiveness of the use of retrograde Celsior®.

BACKGROUND: We analyzed the adequacy of the myocardial protection achieved with a single dose of retrograde crystalloid Celsior®, compared with an accepted standard (microplegia), in on-pump coronary artery bypass grafting surgery (CABG). METHODS: This was a retrospective comparative clinical study conducted in a single institution that included all the patients operated on who had elective isolated on-pump CABG, from March 2006 to June 2014. We evaluated maximum postoperative troponin T (TnT) as a marker of myocardial damage, adjusted for possible confounders using propensity score matching. We also analyzed markers of recovery of myocardial function, and the safety of the intravenous use of Celsior®. RESULTS: During the study period, 261 patients were included, divided in two groups: (a) continuous retrograde blood-based microplegia (114 patients); (b) retrograde single-dose crystalloid Celsior® (147 patients). The propensity score adjusted maximum TnT was significantly lower in the Celsior group [average treatment effect = -0.55 ng/dl; 95% confidence interval (CI) -1.10 to -0.1 ng/dl; p = 0.048]. There were no differences in the postoperative use of intra-aortic balloon of counterpulsation or in the requirements of high-dose inotropic medications. In-hospital mortality was equivalent in both study groups ( p = 0.73); surgical re-exploration because of bleeding was equivalent ( p = 0.37). There were no differences in prolonged mechanical ventilation ( p = 0.65) and intensive care unit length of stay ( p = 0.87). CONCLUSION: An isolated single dose of retrograde Celsior® may be an effective and safe myocardial protection strategy in on-pump CABG.

The Effect of Histidine-tryptophan-ketoglutarate Solution and University of Wisconsin Solution: An Analysis of the Eurotransplant Registry.

BACKGROUND: Both University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are currently used in the Eurotransplant region for preservation of liver allografts. Previous studies on their effect have led to a lot of discussion. This study aims to compare the effect of HTK and UW on graft survival. METHODS: First liver transplantations in recipients 18 years or older from January 1, 2007, until December 31, 2016, were included. Graft survival was compared for livers preserved with HTK and UW at 30 days, 1, 3, and 5 years. Multivariable analysis of risk factors was performed and outcome was adjusted for important confounders. RESULTS: Of all 10 628 first liver transplantations, 8176 (77%) and 2452 (23%) were performed with livers preserved with HTK and UW, respectively. Kaplan-Meier curves showed significant differences in graft survival between HTK and UW at 30 days (89% vs 93%, P=<0.001), 1 year (75% vs 82%, P=<0.001), 3 years (67% vs 72%, P<0.001), and at 5 years (60% vs 67%, P<0.001). No significant differences in outcome were observed in separate analyses of Germany or non-German countries. In multivariable analysis, UW was associated with a decreased risk of graft loss at 30 days (HR 0.772, P=0.002) and at 1 year (0.847 (0.757-0.947). When adjusted for risk factors, no differences in long term outcome could be detected. CONCLUSIONS: Because the use of preservation fluids is clustered geographically, differences in outcome by preservation fluids are strongly affected by regional differences in donor and recipient characteristics. When adjusted for risk factors, no differences in graft survival exist between transplantations performed with livers preserved with either HTK or UW.

Luminal Polyethylene Glycol Alleviates Intestinal Preservation Injury Irrespective of Molecular Size.

Intestinal preservation injury (IPI) and the resulting mucosa injury raise several serious challenges early after intestinal transplantation. The current clinical approach using only vascular perfusion allows the shortest preservation period among the abdominal organs. The experimental addition of luminal polyethylene glycol (PEG) solutions has been repeatedly suggested to alleviate preservation injury, improve graft quality, and prolong the preservation time. We investigated whether the molecular mass of PEG in solution influences the development of intestinal preservation injury. Small intestines of Sprague-Dawley rats were perfused with University of Wisconsin solution. Group 1 underwent vascular perfusion only (clinical control), group 2 received additional luminal PEG3350 Da, group 3 received luminal PEG10000 Da, and group 4 received luminal PEG20000 Da (n = 8/group). Tissue samples were obtained after 4, 8, and 14 hours. We studied the tissue damage (Chiu/Park score, Goblet cells, apoptosis, tight junctions), activation of c-Jun NH2-terminal kinase (JNK), and p38-mitogen-activated protein kinase (MAPK), and we performed Ussing chamber assessments. Mucosal morphologic and electrophysiologic parameters were significantly improved in the groups receiving luminal PEG. There was significantly less apoptotic activity in groups 2, 3, and 4. Both MAPKs revealed an activation peak after 4 hours with group 3 showing lesser p38-MAPK activation. PEG 20 kDa interfered with protein immunodetection. The results indicate that luminal solutions of PEG of medium and large molecular mass significantly delay the onset and development of IPI, providing further evidence that luminal interventions may allow for longer cold storage intervals of intestinal grafts.

Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury.

Bile acids are signaling molecules that critically control hepatocellular function. Disrupted bile acid homeostasis may be implicated in the pathogenesis of chronic liver diseases. Glutathione is an important antioxidant that protects the liver against oxidative injury. Various forms of liver disease share the common characteristics of reduced cellular glutathione and elevated oxidative stress. This study reports a potentially novel physiological function of bile acids in regulating hepatic sulfur amino acid and glutathione metabolism. We found that bile acids strongly inhibited the cysteine dioxygenase type-1-mediated (CDO1-mediated) cysteine catabolic pathway via a farnesoid X receptor-dependent mechanism. Attenuating this bile acid repressive effect depleted the free cysteine pool and reduced the glutathione concentration in mouse liver. Upon acetaminophen challenge, cholestyramine-fed mice showed impaired hepatic glutathione regeneration capacity and markedly worsened liver injury, which was fully prevented by N-acetylcysteine administration. These effects were recapitulated in CDO1-overexpressing hepatocytes. Findings from this study support the importance of maintaining bile acid homeostasis under physiological and pathophysiological conditions, as altered hepatic bile acid signaling may negatively impact the antioxidant defense mechanism and sensitivity to oxidative injury. Furthermore, this finding provides a possible explanation for the reported mild hepatotoxicity associated with the clinical use of bile acid sequestrants in human patients.

Combined Flush With Histidine-Tryptophan-Ketoglutarate and University of Wisconsin Solutions in Liver Transplantation: Preliminary Results.

INTRODUCTION: Ischemia reperfusion injury (IRI) is the main cause of early allograft dysfunction (EAD) and subsequent primary allograft failure (PAF). OBJECTIVES: The purpose of this study is to compare IRI, EAD, and PAF in liver transplantation in a cohort of patients perfused with histidine-tryptophan-ketoglutarate (HTK) solution and University of Wisconsin (UW) solution versus HTK alone. METHODS: A randomized trial was performed to compare outcomes in liver recipients who underwent transplantation surgery in the University Regional Hospital of Malaga, Spain. Forty patients were randomized to two groups. Primary endpoints included IRI, EAD, PAF, re-intervention, acute cellular rejection, retransplantation, arterial complications, and biliary complications at postoperative day 90. RESULTS: Postoperative glutamic oxaloacetic transaminase (1869.15 ± 1559.75 UI/L vs. 953.15 ± 777.27 UI/L; P = .004) and glutamic pyruvic transaminase (1333.60 ± 1115.49 U/L vs. 721.70 ± 725.02 U/L; P = .023) were significantly higher in patients perfused with HTK alone. A clear tendency was observed in recipients perfused with HTK alone to present moderate to severe IRI (7 patients in the HTK + UW solution group vs. 15 patients in the HTK-alone solution group; P = .06), EAD (0 patients in the HTK + UW solution group vs. 0 patients in the HTK-alone solution group; P = .76), and PAF (3 patients in the HTK + UW solution group vs. 8 patients in the HTK-alone solution group; P = .15). CONCLUSIONS: Initial perfusion with HTK solution followed by UW solution in liver transplantation improves early liver function as compared to perfusion with HTK alone.

Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia.

Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual-motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems.

Retrograde Flushing of Living Donor Renal Allografts via the Renal Vein: A Simple, Effective Technique.

BACKGROUND: Prograde flushing (PF) of living donor renal allografts with preservation solution via the renal artery or arteries is standard practice. PF may be difficult and potentially injurious to the donor kidney, especially in grafts with small or multiple arteries. In this report, we present our experience with retrograde flushing (RF) of 7 living donor kidneys via the renal vein. METHODS: Retrospective review of 7 consecutive living donor renal transplants performed using the RF technique was performed. The 7 preceding living donor renal transplants performed using the standard arterial PF technique served as a control group. RESULTS: All 7 recipients of RF kidneys experienced immediate graft function. At postoperative days 3 and 30, there was no difference in estimated glomerular filtration rate between the RF study group and PF controls. CONCLUSIONS: The RF technique is simple and safe, with results equivalent to the PF technique. The RF technique may be especially useful after recovering kidneys with small and/or multiple arteries.