Antidiabetic and Plasma Endogenous Antioxidant Activity of alstonia boonei in Alloxan-Induced Male Diabetic Rabbits

Alstonia boonei is a well-known plant of medicinal value but its effect on endogenous plasma antioxidant in diabetes remains unknown. Thus, need to investigate the effects of the methanolic extract of the plant on plasma bilirubin and uric acid level in alloxan induced diabetes rabbits. Twenty five rabbits divided into five groups of four rabbits each were used. There was a significant change in the levels of total bilirubin and uric acid in the plasma of treated groups as compared with both non diabetes and untreated diabetes group, while conjugated bilirubin level was relatively unchanged in the treated group. This work clearly indicates that methanolic extract of Alstonia boonei stem bark is effective in the management of diabetes as well as restoration of lost endogenous plasma antioxidants experienced in diabetes mellitus

Bilirubin deficiency renders mice susceptible to hepatic steatosis in the absence of insulin resistance.

BACKGROUND & AIMS: Plasma concentrations of bilirubin, a product of heme catabolism formed by biliverdin reductase A (BVRA), inversely associate with the risk of metabolic diseases including hepatic steatosis and diabetes mellitus in humans. Bilirubin has antioxidant and anti-inflammatory activities and may also regulate insulin signaling and peroxisome proliferator-activated receptor alpha (PPARα) activity. However, a causal link between bilirubin and metabolic diseases remains to be established. Here, we used the global Bvra gene knockout (Bvra-/-) mouse as a model of deficiency in bilirubin to assess its role in metabolic diseases. APPROACH & RESULTS: We fed mice fat-rich diets to induce hepatic steatosis and insulin resistance. Bile pigments were measured by LC-MS/MS, and hepatic lipids by LC-MS/MS (non-targeted lipidomics), HPLC-UV and Oil-Red-O staining. Oxidative stress was evaluated measuring F2-isoprostanes by GC-MS. Glucose metabolism and insulin sensitivity were verified by glucose and insulin tolerance tests, ex vivo and in vivo glucose uptake, and Western blotting for insulin signaling. Compared with wild type littermates, Bvra-/- mice contained negligible bilirubin in plasma and liver, and they had comparable glucose metabolism and insulin sensitivity. However, Bvra-/- mice exhibited an inflamed and fatty liver phenotype, accompanied by hepatic accumulation of oxidized triacylglycerols and F2-isoprostanes, in association with depletion of α-tocopherol. α-Tocopherol supplementation reversed the hepatic phenotype and observed biochemical changes in Bvra-/- mice. CONCLUSIONS: Our data suggests that BVRA deficiency renders mice susceptible to oxidative stress-induced hepatic steatosis in the absence of insulin resistance

Effect of Diabetes Mellitus on the Excretory Function of the Liver

Diabetes mellitus is an internationally recognized health problem and a leading cause of death worldwide. However, the most significant increase in prevalence is expected to occur in Asia and Africa, where most patients will be found by 2030. Diabetic Mellitus is a clinical and metabolic syndrome characterized by abnormal carbohydrate, protein, and fat metabolism resulting in hyperglycemia, increased protein breakdown, Ketosis or acidosis due to absolute or relative deficiency, and insulin resistance, thereby leading to vascular complications such as retinopathy, neuropathy, and nephropathy. This study evaluated the levels of plasma bilirubin, ALP, and GGT among diabetic patients. A total of eighty (80) individuals were recruited for the study comprising of forty (40) diabetes patients with age range 25-80 years and forty (40) control subjects with the age range of 20-30 years in Irrua/Ekpoma, Edo State, Nigeria. The study was carried out within six months (December 2018 - May 2019). All patients were diabetes. The serum Alkaline Phosphatase (ALP), gamma-glutamyl transferase (GGT), total and conjugated bilirubin were assayed by spectrophotometric method, and the data obtained were statistically analyzed using SPSS version 23.0 software. Serum levels of ALP, GGT, Total and unconjugated bilirubin were significantly elevated (P<0.05) among diabetes patients than control subjects except for conjugated bilirubin which was lower (P>0.05)  when compared with that of the control subjects. The mean serum levels of  ALP, GGT, total, unconjugated and conjugated bilirubin of male diabetes patients were non statistically significant (P>0.05) when compared with female diabetes subjects except the age (P<0.05). These findings indicate that hepatic injury was more likely among diabetes, and liver enzymes (ALP, GGT) are critical for monitoring glucose control concomitant with hepatic injury. Bilirubin is a potentially important biomarker for the assessment of the hepatic excretory system in diabetes mellitus

The value of blood-based measures of liver function and urate in lung cancer risk prediction: A cohort study and health economic analysis

BACKGROUND: Several studies have reported associations between low-cost blood-based measurements and lung cancer but their role in risk prediction is unclear. We examined the value of expanding lung cancer risk models for targeting low-dose computed tomography (LDCT), including blood measurements of liver function and urate. METHODS: We analysed a cohort of 388,199 UK Biobank participants with 1873 events and calculated the c-index and fraction of new information (FNI) for models expanded to include combinations of blood measurements, lung function (forced expiratory volume in 1 s - FEV1), alcohol status and waist circumference. We calculated the hypothetical cost per lung cancer case detected by LDCT for different scenarios using a threshold of ≥ 1.51 % risk at 6 years. RESULTS: The c-index was 0.805 (95 %CI:0.794-0.816) for the model containing conventional predictors. Expanding to include blood measurements increased the c-index to 0.815 (95 %CI: 0.804-0.826;p < 0.0001;FNI:0.06). Expanding to include FEV1, alcohol status, and waist circumference increased the c-index to 0.811 (95 %CI: 0.800-0.822;p < 0.0001;FNI: 0.04). The c-index for the fully expanded model containing all variables was 0.819 (95 %CI:0.808-0.830;p < 0.0001;FNI:0.09). Model expansion had a greater impact on the c-index and FNI for people with a history of smoking cigarettes relative to the full cohort. Compared with the conventional risk model, the expanded models reduced the number of participants meeting the criteria for LDCT screening by 15-21 %, and lung cancer cases detected by 7-8 %. The additional cost per lung cancer case detected relative to the conventional model was £ 1018 for adding blood tests and £ 9775 for the fully expanded model. CONCLUSION: Blood measurements of liver function and urate made a modest improvement to lung cancer risk prediction compared with a model containing conventional risk factors. There was no evidence that model expansion would improve the cost per lung cancer case detected in UK healthcare settings

Prior induction of heme oxygenase-1 with glutathione depletor ameliorates the renal ischemia and reperfusion injury in the rat

AbstractHeme oxygenase (HO)-1 catalyzes the rate-limiting step in heme degradation releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 occurs as an adaptive and protective response to oxidative stress. Ischemia and reperfusion (IR) injury seems to be mainly caused by the oxidative stress. In this study, we have examined whether prior induction of HO-1 with buthionine sulfoximine (BSO), a glutathione (GSH) depletor, affects the subsequent renal IR injury. BSO (2 mmol/kg body weight) was administered intraperitoneally into rats, the levels of HO-1 protein increased within 4 h after the injection. When BSO was administered into rats at 5 h prior to the renal 45 min of ischemia, the renal IR injury was assessed by determining the levels of blood urea nitrogen and serum creatinine, markers for renal injury, after 24 h of reperfusion. The renal injury was significantly improved as compared to the rats treated with IR alone. Administration of zinc-protoporphyrin IX, an inhibitor of HO activity, reduced the efficacy of BSO pretreatment on the renal IR injury. Our findings suggest that the prior induction of HO-1 ameliorates the subsequent renal IR injury

Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency

金沢大学医薬保健研究域医学系The first known human case of heme oxygenase-1 (HO-1) deficiency is presented in this report. The patient is a six-year-old boy with severe growth retardation. He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin. An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage. Electron microscopy of renal glomeruli revealed detachment of endothelium, with subendothelial deposition of an unidentified material. Iron deposition was noted in renal and hepatic tissue. Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium- stimulated Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production. An LCL derived from the patient was extremely sensitive to hemin-induced cell injury. Sequence analysis of the patient\u27s HO-1 gene revealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele. Growth retardation, anemia, iron deposition, and vulnerability to stressful injury are all characteristics observed in recently described HO-1 targeted mice. This study presents not only the first human case of HO-1 deficiency but may also provide clues to the key roles played by this important enzyme in vivo

Heme, Heme Oxygenase, and Endoplasmic Reticulum Stress: a New Insight into the Pathophysiology of Vascular Diseases

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