Oxidative stress and hepatotoxicity in rats induced by poisonous pufferfish (Lagocephalus lagocephalus) meat

This study was undertaken to evaluate the effect of pufferfish (Lagocephalus lagocephalus) meat poisoning on hepatic functions of Wistar rats. For this purpose, groups of rats (Lcr, Lcu+b and Lcu-b) received diet supplemented with 10% of raw or cooked meat, respectively, with or without cooking water of L. lagocephalus while groups Mcr and Mcu+b received diet supplemented with 10% of raw or cooked meat of Liza aurata, which were used as a negative control. In Lcu+b group, ALT, AST and ALP rates (hepatic enzyme markers) decreased after two months of treatment, indicating liver damage. We also observed an increase of 54 and 65% of thiobarbituric acid reactive substances (TBARS) in their livers respectively 48 hours and two months after treatment compared to controls. The catalase (CAT) activity in group Lcu+b decreased (p < 0.05) after two periods of treatment, whereas metallothionein (MT) level significantly increased and decreased, respectively after 48 hours and two months. In fact, in the histological analysis of the livers from Lcu+b treated group, we observed an increase in vacuolisation, necrosis, hepatocytes ballooning and sinusoids dilation. These results indicate that L. lagocephalus meat cooked with water produces hepatotoxicity and oxidative damage

Methidathion-induced hematological, biochemical and hepatohistological alterations in rat: Ameliorative effects of selenium and zinc

The aim of this study was to determine the effect of a sub-acute 4-week exposure to methidathion (MD) on the hematological system and hepatic integrity of rats. We also assessed whether co-administration of micronutrients such as selenium (Se) and zinc (Zn) prevented MD-induced hepatic damage. Rats were randomly divided into four groups of six each: the first group served as a control which received standard diet, the second group received both Se (0.5mg/kg of diet) and Zn (0.227 g/l drinking water), the third group received only MD (5 mg/kg b.w. by gavage using corn oil as a vehicle), and the fourth group received MD and combined selenium and zinc. After four weeks, exposure to MD induced a significant increase in plasmatic activities of AST, ALT, ALP, LDH, and liver malondialdehyde level. In contrast, reduced glutathione level (GSH), and the activities of catalase (CAT), superoxide dismutase (SOD), and the glutathione peroxidase (GPx) content of hepatic tissue decreased significantly. Moreover, treatment with Se and Zn in MD-treated rats maintained all the biochemical parameters cited above. In conclusion, the obtained results indicate the ability of Se and Zn to attenuate the MD-induced liver and erythrocytes oxidative damage.Key words: Biochemical studies, liver, methidathion, oxidative stress, rat, selenium, zinc

The global biopharma industry and the rise of Indian drug multinationals: implications for Australian generics policy

This article provides a synopsis of the new dynamics of the global biopharma industry. The emergence of global generics companies with capabilities approximating those of 'big pharma' has accelerated the blurring of boundaries between the innovator and generics sectors. Biotechnology-based products form a large and growing segment of prescription drug markets and regulatory pathways for biogenerics are imminent. Indian biopharma multinationals with large-scale efficient manufacturing plants and growing R&D capabilities are now major suppliers of Active Pharmaceutical Ingredients (APIs) and generic drugs across both developed and developing countries. In response to generic competition, innovator companies employ a range of life cycle management techniques, including the launch of 'authorised generics'. The generics segment in Australia will see high growth rates in coming years but the prospect for local manufacturing is bleak. The availability of cheap generics in international markets has put pressure on Pharmaceutical Benefits Scheme (PBS) pricing arrangements, and a new policy direction was announced in November 2006. Lower generics prices will have a negative impact on some incumbent suppliers but industrial renewal policies for the medicines industry in Australia are better focused on higher value R&D activities and niche manufacturing of sophisticated products

PI 3 Kinase Related Kinases-Independent Proteolysis of BRCA1 Regulates Rad51 Recruitment during Genotoxic Stress in Human Cells

The function of BRCA1 in response to ionizing radiation, which directly generates DNA double strand breaks, has been extensively characterized. However previous investigations have produced conflicting data on mutagens that initially induce other classes of DNA adducts. Because of the fundamental and clinical importance of understanding BRCA1 function, we sought to rigorously evaluate the role of this tumor suppressor in response to diverse forms of genotoxic stress.We investigated BRCA1 stability and localization in various human cells treated with model mutagens that trigger different DNA damage signaling pathways. We established that, unlike ionizing radiation, either UVC or methylmethanesulfonate (MMS) (generating bulky DNA adducts or alkylated bases respectively) induces a transient downregulation of BRCA1 protein which is neither prevented nor enhanced by inhibition of PIKKs. Moreover, we found that the proteasome mediates early degradation of BRCA1, BARD1, BACH1, and Rad52 implying that critical components of the homologous recombination machinery need to be functionally abrogated as part of the early response to UV or MMS. Significantly, we found that inhibition of BRCA1/BARD1 downregulation is accompanied by the unscheduled recruitment of both proteins to chromatin along with Rad51. Consistently, treatment of cells with MMS engendered complete disassembly of Rad51 from pre-formed ionizing radiation-induced foci. Following the initial phase of BRCA1/BARD1 downregulation, we found that the recovery of these proteins in foci coincides with the formation of RPA and Rad51 foci. This indicates that homologous recombination is reactivated at later stage of the cellular response to MMS, most likely to repair DSBs generated by replication blocks.Taken together our results demonstrate that (i) the stabilities of BRCA1/BARD1 complexes are regulated in a mutagen-specific manner, and (ii) indicate the existence of mechanisms that may be required to prevent the simultaneous recruitment of conflicting signaling pathways to sites of DNA damage