Department of Chemical Pathology

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Antrocaryon micraster (A. Chev. And Guillaumin) stem bark extract demonstrated anti-malaria action and normalized hematological indices in Plasmodium berghei infested mice in the Rane’s test.
(University of Ghana, 2020-09-26) Appiah-Opong, R.
Ethnopharmacological relevance: Malaria is caused by infection with some species of Plasmodium parasite which leads to adverse alterations in physical and hematological features of infected persons and ultimately results in death. Antrocaryon micraster is used to treat malaria in Ghanaian traditional medicine. However, there is no scientific validation of its anti-malaria properties. The plant does not also have any chemical fingerprint or standardization parameters. Aim of the study: This study sought to evaluate the anti-malaria activity of standardized A. micraster stem bark extract (AMSBE) and its effect on mean survival time (MST) and body weight reduction of Plasmodium berghei infested mice. And to study the effect of treatment of AMSBE on hematological indices of the P. berghei infested mice in order to partly elucidate its anti-malarial mechanism of action. Materials and methods: Malaria was induced in female ICR mice by infecting them with 0.2 mL of blood (i.p.) containing 1.0 × 107 P. berghei-infested RBCs from a donor mouse and leaving them without treatment for 3 days. AMSBE or Lonart (standard control) was then orally administered at 50, 200 and 400 mg/kg or 10 mg/kg once daily for 4 consecutive days. The untreated control received sterile water. Malaria parasitemia reduction, anti-malarial activity, mean change in body weight and MST of the parasitized mice were evaluated. Furthermore, changes in white blood cells (WBCs), red blood cells (RBCs), platelets count, hemoglobin (HGB), hematocrit (HCT) and mean corpuscular volume (MCV) were also determined in the healthy animals before infection as baseline and on days 3, 5 and 8 after infection by employing complete blood count. Standardization of AMSBE was achieved by quantification of its constituents and chemical fingerprint analysis using UHPLC-MS. Results: Administration of AMSBE, standardized to 41.51% saponins and 234.960 ± 0.026 mg/g of GAE phenolics, produced significant (P < 0.05) reduction of parasitemia development, maximum anti-malaria activity of 46.01% (comparable to 32.53% produced by Lonart) and significantly (P < 0.05) increased body weight and MST of P. berghei infected mice compared to the untreated control. Moreover, there were significant (P > 0.05) elevation in WBCs, RBCs, HGB, HCT and platelets in the parasitized-AMSBE (especially at 400 mg/kg p.o.) treated mice compared to their baseline values. Whereas, the non-treated parasitized control recorded significant reduction (P < 0.05) in all the above-mentioned parameters compared to its baseline values. The UHPLC-MS fingerprint of AMSBE revealed four compounds with their retention times, percentage composition in their chromatograms and m/z of the molecular ions and fragments in the spectra. Conclusions: These results show that A. micraster stem bark possessed significant anti-malaria effect and also has the ability to abolish body weight loss, leucopenia, anemia and thrombocytopenia in P. berghei infected mice leading to prolonged life span. The UHPLC-MS fingerprint developed for AMSBE can be used for rapid authentication and standardization of A. micraster specimens and herbal preparations produced from its hydroethanolic stem bark extract to ensure consistent biological activity. The results justify A. micraster’s use as anti-malaria agent.
Serum lipids and antioxidants in Ghanaian diabetic, hypertensive and healthy subjects
(Ghana Medical Journal, 2003-06) Nyarko, A.K.; Asiedu-Larbi, J.; Ofosuhene, M.; Asare-Anane, H.; Addy, M.E.
Medication Adherence and Its Association with Glycaemic Control, Blood Pressure Control, Glycosuria and Proteinuria among People Living with Diabetes (PLWD) in the Ho Municipality, Ghana
(Open Public Health Journal, 2018-12) Osei-Yeboah, J.; Lokpo, S.Y.; Owiredu, W.K.B.A.; Johnson, B.B.; Orish, V.N.; Botchway, F.; Ussher, F.A.; Avorkliyah, R.
Background: Adherence is the active, voluntary, and collaborative involvement of the patient in a mutually acceptable course of behaviour to produce a therapeutic result. The study is aimed at assessing adherence to medication and its relation to therapeutic outcomes among people living with diabetes in the Ho Municipality. Methodology: A cross-sectional study was conducted involving 150 diabetic patients attending the diabetic clinic at the Ho Municipal Hospital. Urine glucose and urine protein were measured using a two-parameter dipstick. The current fasting blood glucose and blood pressure, as well as the measurements of two previous visits, were documented. A semi-structured questionnaire including the Diabetes Complication Checklist and the Morisky, Green and Levine Adherence Scale were used to capture biodata, clinical information and medication adherence. Results: Optimal medication adherence was 60.67%. Glycaemic control and controlled blood pressure were 33.33% and 58.67%, respectively. The prevalence of glycosuria and proteinuria was 10.67% and 3.3%, respectively. Percentage glycaemic control and controlled blood pressure were found to be higher among the medication adherent group, while glycosuria and proteinuria were the highest among participants presenting with low medication adherence. Conclusion: In this group of patients living with diabetes in the Ho Municipality, high level of uncontrolled glycaemia and blood pressure exist. However, these two treatment outcomes may be modulated by optimal medication adherence.
Adipocytokines in obese Ghanaian subjects with or without type 2 diabetes
(BMC Research Notes, 2018-02) Adams, Y.; Ofori, E.K.; Asare-Anane, H.; Amanquah, S.D.; Ababio, G.K.; Abendau, E.; Nabia, R.
Objective This study aimed to evaluate serum leptin and high sensitivity C-reactive protein (hsCRP) concentrations in obese Ghanaians with or without type 2 diabetes and to find out the extent to which their levels are influenced by underlying disorders. Results Obese subjects with type 2 diabetes had lower leptin but higher hsCRP levels compared with obese non-diabetic controls. There were negative correlations within the control group for glucose vs % muscle mass (r = − 0.378, p = 0.016), leptin vs % muscle mass (r = − 0.555, p = 0.001) and within the obese diabetic group for leptin vs % muscle mass (r = − 0.602, p = 0.001). Obese persons without diabetes were about three times more likely to have higher leptin levels compared with their obese diabetic counterparts (Odds ratio = 3.315, p < 0.001). Obese females independently had a tenfold increase in leptin levels compared with obese males.
Biomarkers of renal dysfunction among Ghanaian patients with type 2 diabetes mellitus- a cross-sectional study
(International Journal of Diabetes in Developing Countries, 2018-10) Amoah, B.Y.; Asare, G.A.; Yeboah, F.A.; Obirikorang, C.; Asiedu, B.; Mohammed, A.O.
Type 2 diabetes mellitus (T2DM) is a heterogeneous collection of disorders characterized by reduced insulin sensitivity and increased glucose output. The abnormal vascular architecture observed within the first few years of diabetes onset suggests that complications such as nephropathy develop earlier in affected individuals than is generally known. Prompt determination of decline in renal function among diabetics is therefore very crucial. In the present study, we evaluated circulating levels of adiponectin, neutrophil gelatinase-associated lipocalin (NGAL), asymmetric dimethyl arginine (ADMA), and endothelial nitric oxide synthase traffic inducer (NOSTRIN) as novel biomarkers of renal dysfunction. One hundred and eight Ghanaian patients with T2DM were recruited for this study. Biochemical and immunoassays were employed in measuring the levels of the biomarkers for all participants. Metabolic syndrome indices including body mass index (BMI), serum glucose, and uric acid levels were not found to be associated with adiponectin concentrations. Fifteen participants had normal estimated glomerular filtration rate (eGFR), 79 had a mildly reduced eGFR, and 24 had moderately reduced eGFR representing 12.8, 66.9, and 20.3%, respectively. Proteinuria correlated significantly with decreasing eGFR. Serum levels of adiponectin, ADMA, and NOSTRIN (p = 0.002; p = 0.001; p = 0.012, respectively) were, however, found to be independently associated with estimated glomerular filtration rate (eGFR) among the type 2 diabetics. We observed that elevated circulating levels of adiponectin, ADMA, and NOSTRIN could be important in characterizing early CKD stages among type 2 diabetics.
Dyslipidaemia is common among patients with type 2 diabetes: a cross-sectional study at Tema Port Clinic
(BMC Research Notes, 2019-04) Ofori, E.K.; Owusu-Ababio, D.; Tagoe, E.A.; Asare-Anane, H.
Objective This study aimed to evaluate dyslipidemia in Ghanaian subjects with type 2 diabetes. Results Hundred individuals with type 2 diabetes and 61 apparently healthy controls participated. The prevalence of hypercholesterolemia among persons with type 2 diabetes was 53%. Blood pressure, fasting blood glucose (FBG), triglyceride (TG), low-density lipoproteins (LDL) and alanine transaminase (ALT) levels were higher in persons with type 2 diabetes compared with the control group (p < 0.01). Positive correlations were found within persons with type 2 diabetes for triglyceride vs FBG; ALT vs age and aspartate transaminase (AST) vs TG (p < 0.05 respectively). This study demonstrated hyperlipidemia and poor liver health in persons with type 2 diabetes.
Human immunodeficiency virus, hepatitis B virus and syphilis infections among longdistance truck drivers in, a Port City in Ghana
(Obafemi Awolowo University, 2016) Adjei, A.A.; Atta, P.B.; Krampa, F.; Lartey, M.; Rahman, M.A.; Agyeman, S.; Adiku, T.K.; Tettey, Y.; Gyasi, R.K.
Background: Although the high prevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV) and syphilis infections among longdistance truck drivers has been well documented globally, such data are sparse from Africa, and there has been no such data from Ghana. This study carried out between the months of January and June 2013 sought to determine the sero-prevalence and risk factors of HIV, HBV and syphilis infections among long distance truck drivers at the Tema sea port, Ghana. Materials and Methods: Of a total of 800 eligible drivers, 106 (13.25%) drivers consented to take part in the study. Subjects voluntarily completed a risk factor questionnaire and provided blood specimen for testing for HIV, syphilis and the surface antigen of HBV (HBsAg). Results: The mean age of the drivers was 40.56 ± 11.56 years. The sero-prevalence of HIV was 0.94%, 14.2% had HBsAg and reactive syphilis serology was 3.8%. On multivariate analysis, the main determinants of HBV infection were; multiple sexual partnership (OR, 6.36; 95% CI: 1.35- 29.79), patronage of commercial sex workers (OR, 6.85; 95% CI: 0.88 - 52.89), cross-border travelers (OR: 6.89-fold, 95% CI: 0.86 - 55.55) and prolonged duration of trips for more than two weeks (OR: 4.76; 95% CI: 0.59 - 38.02). The main determinant of syphilis infection on multivariate analysis was being a Muslim (OR, 2.19; 95% CI: 0.22 - 21.74). Conclusion: The data indicate a lower sero-prevalence of HIV but a higher sero-prevalence of syphilis. However, the sero-prevalence of HBV infection is comparable to that of the general population.
Urinary Lysosomal Enzyme Activities and Albuminuria in Ghanaian Patients with Type 2 Diabetes Mellitus
(Disease Markers, 2016-08) Asare-Anane, H.; Twum, F.; Kwaku Ofori, E.; Torgbor, E.L.; Amanquah, S.D.; Osafo, C.
Renal tubular lysosomal enzyme activities like alanine aminopeptidase (AAP) and N-acetyl- β -D-glucosaminidase (NAG) have been shown to increase in patients developing diabetic nephropathy and nephrosclerosis. This study aimed to determine the activities of N-acetyl- β -D-glucosaminidase and alanine aminopeptidase and albumin concentration in urine samples of patients with type 2 diabetes. One hundred and thirty (65 type 2 diabetic and 65 nondiabetic) subjects participated in this study. Blood samples were drawn for measurements of fasting blood glucose, albumin (Alb), lipids, and creatinine (Cr). Early morning spot urine samples were also collected for activities of alanine aminopeptidase (AAP), N-acetyl- β -D-glucosaminidase (NAG), and concentration of albumin (U-Alb) and creatinine (U-Cr). Both NAG/Cr and AAP/Cr were significantly increased in diabetic subjects compared to controls (p < 0.001). There was positive correlation between NAG/Cr and Alb/Cr (r = 0.49, p < 0.001) and between NAG/Cr and serum creatinine (r = 0.441, p < 0.001). A negative correlation was found between NAG/Cr and eGFR (r = - 0.432, p < 0.05). 9.3% and 12% of diabetics with normoalbuminuria had elevated levels of AAP/Cr and NAG/Cr, respectively. We conclude that measuring the urinary enzymes activities (NAG/Cr and AAP/Cr) could be useful as a biomarker of early renal involvement in diabetic complications. © 2016 Henry Asare-Anane et al.
Adiposity and hyperleptinemia during the first trimester among pregnant women with preeclampsia
(International Journal of Women's Health, 2017-06) Yeboah, F.A.; Ngala, R.A.; Bawah, A.T.; Asare-Anane, H.; Alidu, H.; Hamid, A.-W.M.; Wumbee, J.D.K.
Background: Leptin levels start increasing from the early stages of pregnancy, irrespective of the maternal body mass index. Leptin levels are increased in pregnant women with preeclampsia (PE) and may precede the clinical onset of the disease, with peaks occurring around 28 weeks of gestation. This study was aimed at determining whether serum leptin concentration and body fat percentage are significantly altered during the first trimester in pregnancies that subsequently develop PE and whether such changes are useful in predicting the disease. Materials and methods: This was a prospective longitudinal study conducted among pregnant women in Ho municipality. A cohort of 314 pregnant women was monitored from the first antenatal visit to delivery period at the Volta Regional Hospital, Ho, Ghana. Maternal serum leptin and lipid profile were analyzed and body fat percentage determined during first trimester. Body mass index was also calculated. Results: First trimester serum leptin level (P<0.0001) and body fat percentage (P<0.0001) were significantly higher in those who developed PE than those who did not; while triglycerides (P=0.8600), total cholesterol (P=0.5620), high-density lipoprotein (P=0.5880), low-density lipoprotein (P=0.4870) and very low-density lipoprotein (P=0.6540) did not show any significant difference between those with PE and those without PE. Conclusion: Leptin levels are increased significantly during the first trimester of pregnancy in obese women with PE, and these increases precede the onset of PE. © 2017 Yeboah et al.
Shift work and the risk of cardiovascular disease among workers in cocoa processing company, Tema
(BioMed Central Ltd., 2015) Asare-Anane, H.; Abdul-Latif, A.; Ofori, E.K.; Abdul-Rahman, M.; Amanquah, S.D.
Objective: Shift work has been implicated in cardiovascular disease (CVD), a major cause of death globally. The aim of this study was to evaluate the risk of developing CVD in shift work. Design: A cross-sectional study involving secondary analysis of shift and non-shift work from an industry in Ghana. Participants: Two hundred (113 shift and 87 non-shift) consecutive workers who consented were recruited into the study. A structured questionnaire was administered to deduce information on participant's age, alcohol consumption pattern, smoking habits, history of diabetes, stroke and hypertension. Results: Shift workers were found to be associated with higher body mass index (26.9 ± 4.6 vs 25.2 ± 3.3, p = 0.013); fasting blood glucose (5.9 ± 1.8 vs 5.3 ± 0.8, p ≤ 0.0001); glycated haemoglobin (4.9 ± 0.9 vs 4.2 ± 0.8, p ≤ 0.0001); high sensitivity C-reactive protein (2.5 ± 1.1 vs 1.8 ± 1.1, p < 0.0001); total cholesterol (5.9 ± 1.3 vs 5.2 ± 1.7, p = 0.002); triglycerides (1.3 ± 0.8 vs 1.1 ± 0.6, p = 0.015) and LDL cholesterol (3.6 ± 0.9 vs 3.2 ± 1.3, p = 0.04) than controls. Shift work however, had no associations with HDL-cholesterol. Conclusion: It can be concluded that shift work is associated with risk factors of CVD.
Calcium - Magnesium imbalance implicated in benign prostatic hyperplasia and restoration by a phytotherapeutic drug - Croton membranaceus Müll.Arg
(BioMed Central Ltd., 2017) Asare, G.A.; Ngala, R.A.; Afriyie, D.; Adjei, S.; Nyarko, A.; Anang-Quartey, Y.; Asiedu, B.; Doku, D.; Amoah, B.Y.; Bentum, K.; Musah, I.; Mossanda, K.
Background: Calcium (Ca)- magnesium (Mg) imbalance is implicated in prostate cancer. Ca/Mg ratio increases or decreases with proliferation or apoptosis, respectively. The study examined whether this Ca/Mg imbalance exists in BPH patients and the effect of a phytotherapeutic drug on the Ca/Mg ratio. Methods: Thirty (30) BPH patients who used the ethanolic root extract of Croton membranaceus (60 mg/day) for 3 months were examined for serum Ca, Mg, phosphate, parathyroid hormone (PTH), vitamin D, prostate specific antigen (PSA) levels and renal function tests (RFT) before (BT) and after treatment (AT) alongside thirty (30) controls. Twenty (20) trace element including Mg and Ca were determined in the drug by neutron activation analysis (NAA). Results: RFT, PTH and vitamin D for BT, AT and controls (C) were normal. Mean PSA was 1.0 ± 0.64 (C), 27.9 ± 19.0 (BT) and 16.2 ± 11.8 ng/mL (AT) (p = 0.002). Mg, Ca/Mg ratio BT, AT and control were significantly different (p = 0.0001, respectively). After treatment, Mg and Ca/Mg ratio were not different from controls. The prevalence of Ca/Mg imbalance was 80% (BT), 13.3% (AT) and 3.3% (control group). Conclusion: Ca/Mg ratio imbalance is associated with BPH. This has previously not been demonstrated. The imbalance was significantly corrected after treatment with the phytotherapeutic drug.
Onchocerciasis control: vision for the future from a Ghanian perspective
(2009-01-21) Taylor, M.J.; Awadzi, K.; Basáñez, M.; Biritwum, N.; Boakye, D.; Boatin, B.; Bockarie, M.; Churcher, T.S.; Debrah, A.; Edwards, G.; Hoerauf, A.; Mand, S.; Matthews, G.; Osei-Atweneboana, M.; Prichard, R.K.; Wanji, S.; Adjei, O.
Abstract Since 1987 onchocerciasis control has relied on the donation of ivermectin (Mectizan®, Merck & Co., Inc.) through the Mectizan Donation Programme. Recently, concern has been raised over the appearance of suboptimal responses to ivermectin in Ghana – highlighting the potential threat of the development of resistance to ivermectin. This report summarises a meeting held in Ghana to set the research agenda for future onchocerciasis control. The aim of this workshop was to define the research priorities for alternative drug and treatment regimes and control strategies to treat populations with existing evidence of suboptimal responsiveness and define research priorities for future control strategies in the event of the development of widespread ivermectin resistance.
Immunization with different PfAMA1 alleles in sequence induces clonal imprint humoral responses that are similar to responses induced by the same alleles as a vaccine cocktail in rabbits
(2011-02-14) Kusi, K.A.; Faber, B.W.; van der Eijk, M.; Thomas, A.W.; Kocken, C.H.M.; Remarque, E.J.
Abstract Background Antibodies to key Plasmodium falciparum surface antigens have been shown to be important effectors that mediate clinical immunity to malaria. The cross-strain fraction of anti-malarial antibodies may however be required to achieve strain-transcending immunity. Such antibody responses against Plasmodium falciparum apical membrane antigen 1 (PfAMA1), a vaccine target molecule that is expressed in both liver and blood stages of the parasite, can be elicited through immunization with a mixture of allelic variants of the parasite molecule. Cross-strain antibodies are most likely elicited against epitopes that are shared by the allelic antigens in the vaccine cocktail. Methods A standard competition ELISA was used to address whether the antibody response can be further focused on shared epitopes by exclusively boosting these common determinants through immunization of rabbits with different PfAMA1 alleles in sequence. The in vitro parasite growth inhibition assay was used to further evaluate the functional effects of the broadened antibody response that is characteristic of multi-allele vaccine strategies. Results A mixed antigen immunization protocol elicited humoral responses that were functionally similar to those elicited by a sequential immunization protocol (p > 0.05). Sequential exposure to the different PfAMA1 allelic variants induced immunological recall of responses to previous alleles and yielded functional cross-strain antibodies that would be capable of optimal growth inhibition of variant parasites at high enough concentrations. Conclusions These findings may have implications for the current understanding of the natural acquisition of clinical immunity to malaria as well as for rational vaccine design.
Felbamate efficacy and tolerability in patients with refractory epilepsy: An open add-on multicentric study.
(1997) Perniola, T.; Margari, L.; Spina, A.; Chindemi, A.; Bello, A.; De Iaco, M.G.; De Giacomo, A.; Galluzzi, R.; Marzocco, P.L.; Piscitelli, L.
A multicenter study that evaluated felbamate efficacy and tolerability in 19 patients with refractory epilepsy was performed. One patient (5,3%) became seizure-free during felbamate treatment, 11 patients (57,9%) achieved a seizure reduction of 50% or more, 6 patients (31,6%) evidenced an unchanged seizure frequency and 1 patient (5,3%) had increase in seizure frequency. Of the 7 patients (36,8%) who had a diagnosis of Lennox-Gastaut syndrome, 5 (71,4%) had >50% reduction in seizure frequency, 1 (14,2%) had unchanged seizure frequency and 1 (14,2%) had an increase in seizure frequency.
Metabolism of (-)-(S)-nicotine in the isolated perfused rabbit lung.
(1997) Aislaitner, G.; Bello, A.; Tan, S.C.; Hutt, A.J.; Marriott, C.; Gorrod, J.W.
The metabolism of (-)-(S)-nicotine has been investigated following intratracheal administration to the recirculating perfused rabbit lung model. The metabolic products present in the perfusate were identified by co-chromatography (HPLC and GC) with authentic standards and quantified by HPLC. After the 180 min perfusion period, nicotine was found to be metabolically transformed to cotinine (33.7%), 3-hydroxycotinine (10.4%), cotinine-1-N-oxide (3.4%) and nicotine-1'-N-oxide (14.4%). Norcotinine, nornicotine, 3-pyridyl-4-oxo-N-methylbutyramide and an uncharacterised metabolite were also detected in low amounts. Following the perfusion experiment, part of the lung tissue was homogenised in the presence of [14C]-sodium cyanide. Subsequent analysis of the homogenates indicated the formation of 2'-cyanonicotine, 1'-cyanomethylnornicotine and the diastereoisomeric 5'-cyanonicotines.
Isolation and characterization of mineral oxidizing bacteria from the obuasi gold mining site, Ghana.
(1999) Asmah, R.H.; Bosompem, K.M.; Osei, Y.D.; Rodrigues, F.K.; Addy, M.E.; Clement, C.; Wilson, M.D.
Ghana has one of the largest gold ore deposits in the world. Gold extraction by bioleaching technology which is more environmentally friendly and efficient compared to conventional mining methods is therefore preferred for processing refractory gold ores. The Ashanti Goldfields Company Limited in Ghana operates the world's largest commercial bioleaching plant.However, the same organisms are used to leach gold from surface arsenopyrite and underground sulphide ores even though the use of adapted local organisms for the different ore may improve gold recovery. Efforts were therefore made to isolate and characterize local acidophilic bioleaching bacteria from surface arsenopyrite gold ore, underground sulphide gold ore, underground mine water and slurry from the commercial biooxidation tank at Obuasi. Isolation of the organisms was made using 9K enrichment medium and the bacteria identified using physiological, morphological, cultural and biochemical criteria.Thiobacillus ferrooxidans and ‘Leptospirillum ferrooxidans were isolated from each of the samples analysed. However, Thiobacillus thiooxidans was not found in underground mine water even though it was isolated from the other samples. It was also observed that bacteria isolates obtained from surface arsenopyrite and underground sulphide gold ores had higher oxidation rates compare with the isolates from the underground mine water. Further characterization was done using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) which clearly differentiated the various bacteria isolates at the species level.
Hepatocellular carcinoma caused by iron overload: A possible mechanism of direct hepatocarcinogenicity.
(2006-02-16) Asare, G.A.; Mossanda, K.S.; Kew, M.C.; Paterson, A.C.; Kahler-Venter, C.P.; Siziba, K.
BACKGROUND/AIMS: Excess hepatic iron may be both directly and indirectly carcinogenic. The aim of this study was to determine if generation of reactive oxygen species and the resulting oxidative damage induced by free hepatic iron is directly hepatocarcinogenic. METHODS: Sixty male Wistar albino rats were iron-loaded by ferrocene supplementation of their diet. Biochemical parameters of oxidative damage and lipid peroxidation, DNA unwinding and strand breaks, and the Ames Mutagenesis Test were measured at 4 monthly intervals and correlated with the degree of hepatic iron overload, the presence of iron-free preneoplastic foci in the liver, and the development of hepatocellular carcinoma in comparison with 60 control rats. RESULTS: Levels of lipid hydroperoxides, malonaldehyde, 8-isoprostane and 8-hydroxy-2'-deoxyguanosine increased, reaching peak concentrations at 20-24 months, and correlating with an increase in the rate of DNA unwinding, strand breaks, and positive Ames Tests. Iron-free neoplastic foci became evident at 16 months and thereafter increased in number. Preneoplastic foci were present in five of eight rats remaining at 32 months and HCC had developed in one of the five. CONCLUSIONS: Our findings are compatible with the hypothesis that the direct hepatocarcinogenic effect of free iron is mediated by the generation of oxygen reactive species and oxidative damage that are mutagenic and carcinogenic.
Comparative effects of aflatoxins G1 and B1 at levels within human exposure limits on mouse liver and kidney.
(1993) Ankrah, N.A.; Addo, P.G.; Ekuban, F.A.; Addae, M.M.
ddy mice were exposed to aflatoxins B1 and G1 via their feed (4.8 ng AFG1, 0.8 ng AFB1 or both/kg body wt./day) while in utero. At six months of age, hepatorenal studies were carried out. The AFG1 caused significant accumulation of only neutral fat in the liver, a slight rise in serum triglyceride and intensified hepatorenal inflammation, necrosis and bile duct proliferation. The AFB1, caused the accumulation of both neutral fat and fatty acids in the liver, and was cytotoxic to the liver and kidney. Iron storage of the liver, hematological indices, serum total protein and albumin levels were not affected by the aflatoxins.
Angiotensin-converting enzyme secretase is inhibited by zinc metalloprotease inhibitors and requires its substrate to be inserted in a lipid bilayer
(Biochemical Journal, 1997) Parvathy, S.; Oppong, S.Y.; Karran, E.K.; Buckle, D.R.; Turner, A.J.; Hooper, N.M.
Mammalian angiotensin-converting enzyme (ACE; EC 3.4.15.1) is one of several proteins that exist in both membrane-bound and soluble forms as a result of a post-translational proteolytic processing event. For ACE we have previously identified a metalloprotease (secretase) responsible for this proteolytic cleavage. The effect of a range of structurally related zinc metalloprotease inhibitors on the activity of the secretase has been examined. Batimastat (BB94) was the most potent inhibitor of the secretase in pig kidney microvillar membranes, displaying an IC50 of 0.47 microM, whereas TAPI-2 was slightly less potent (IC50 18 microM). Removal of the thienothiomethyl substituent adjacent to the hydroxamic acid moiety or the substitution of the P2' substituent decreased the inhibitory potency of batimastat towards the secretase. Several other non-hydroxamate-based collagenase inhibitors were without inhibitory effect on the secretase, indicating that ACE secretase is a novel zinc metalloprotease that is realted to, but distinct from, the matrix metalloproteases. The full-length amphipathic form of ACE was labelled selectively with 3-trifluoromethyl-3-(m-[125I]iodophenyl)diazirine in the membrane-spanning hydrophobic region. Although trypsin was able to cleave the hydrophobic anchoring domain from the bulk of the protein, there was no cleavage of full-length ACE by a Triton X-100-solubilized pig kidney secretase preparation when the substrate was in detergent solution. In contrast, the Triton X-100-solubilized secretase preparation released ACE from pig intestinal microvillar membranes, which lack endogenous secretase activity, and cleaved the purified amphipathic form of ACE when it was incorporated into artificial lipid vesicles. Thus the secretase has an absolute requirement for its substrate to be inserted in a lipid bilayer, a factor that might have implications for the development of cell-free assays for other membrane protein secretases. ACE secretase could be solubilized from the membrane with Triton-X-100 and CHAPS, but not with n-octyl beta-D-glucopyranoside. Furthermore trypsin could release the secretase from the membrane, implying that like its substrate, ACE, it too is a stalked integral membrane protein
Characterization of a secretase activity which releases angiotensin-converting enzyme from the membrane
(. Biochemical Journal, 1993) Oppong, S.Y.; Hooper, N.M.
Angiotensin-converting enzyme (ACE; EC 3.4.1.15.1) exists in both membrane-bound and soluble forms. Phase separation in Triton X-114 and a competitive e.l.i.s.a. have been employed to characterize the activity which post-translationally converts the amphipathic, membrane-bound form of ACE in pig kidney microvilli into a hydrophilic, soluble form. This secretase activity was enriched to a similar extent as other microvillar membrane proteins, was tightly membrane-associated, being resistant to extensive washing of the microvillar membranes with 0.5 M NaCl, and displayed a pH optimum of 8.4. The ACE secretase was not affected by inhibitors of serine-, thiol- or aspartic-proteases, nor by reducing agents or alpha 2-macroglobulin. The metal chelators, EDTA and 1,10-phenanthroline, inhibited the secretase activity, with, in the case of EDTA, an inhibitor concentration of 2.5 mM causing 50% inhibition. In contrast, EGTA inhibited the secretase by a maximum of 15% at a concentration of 10 mM. The inhibition of EDTA was reactivated substantially (83%) by Mg2+ ions, and partially (34% and 29%) by Zn2+ and Mn2+ ions respectively. This EDTA-sensitive secretase activity was also present in microsomal membranes prepared from pig lung and testis, and from human lung and placenta, but was absent from human kidney and human and pig intestinal brush-border membranes. The form of ACE released from the microvillar membrane by the secretase co-migrated on SDS/PAGE with ACE purified from pig plasma, thus the action and location of the secretase would be consistent with it possibly having a role in the post-translational proteolytic cleavage of membrane-bound ACE to generate the soluble form found in blood, amniotic fluid, seminal plasma and other body fluids

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