Mitochondria-targeted antioxidants protect pancreatic β-cells against oxidative stress and improve insulin secretion in glucotoxicity and glucolipotoxicity

Mitochondrial oxidative damage is thought to play a key role in pancreatic β-cell failure in the pathogenesis of type 2 diabetes. Despite this, the potential of mitochondria-targeted antioxidants to protect pancreatic β-cells against oxidative stress has not yet been studied. Therefore, we investigated if mitochondria-targeted antioxidants protect pancreatic β-cells such as RINm5F and HIT-T15 cells against oxidative stress under glucotoxic and glucolipotoxic conditions. When β-cells were incubated under these conditions, the expression levels of mitochondrial electron transport chain complex subunits, mitochondrial antioxidant enzymes (such as MnSOD and Prx3), β-cell apoptosis, lipogenic enzymes (such as ACC, FAS and ABCA1), intracellular lipid accumulation, oxidative stress, ER stress, mitochondrial membrane depolarization, nuclear NF- κB and sterol regulatory element binding protein 1c (SREBP1c) were all increased, in parallel with decreases in intracellular ATP content, citrate synthase enzymatic activity and glucose-stimulated insulin secretion. These changes were consistent with elevated mitochondrial oxidative stress, and incubation with the mitochondria-targeted antioxidants, MitoTempol or Mitoquinone (MitoQ), prevented these effects. In conclusion, mitochondria-targeted antioxidants protect pancreatic β-cells against oxidative stress, promote their survival, and increase insulin secretion in cell models of the glucotoxicity and glucolipotoxicity associated with Type 2 diabetes.     

Organochlorine contaminants in freshwater mussels; occurrence,bioaccumulation pattern,spatio-temporal distribution and human health risk assessment from the tributaries of River Ravi,Pakistan

The present study was conducted to investigate the bioavailable levels and human health risk of organochlorine contaminants (OCs), particularly organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in freshwater mussels from northern three tributaries of River Ravi, Pakistan that provides the pioneer data for the occurrence of POPs in the freshwater mussels from Pakistan. The Σ₂₃OCPs and Σ₃₅PCBs concentrations in mussels were ranged from 189.66–2049.40 ng/g and 25.81 to 135.38 ng/g, respectively. The comparison of current bioavailable levels of OCs with maximum residual limits (MRLs) established by Food and Agricultural Organization and European Union revealed that Σendosulfan (100%), ΣDDTs (93%), HCB (87%), β-HCH (77%), endrin (77%), γ-HCH (70%), heptachlor (67%), aldrin (67%), dielrin (67%), Chlordane (70%), α-HCH (40%), and WHO-TEQ (2005) values for PCB-126, PCB-169 and Σ₈DL-PCBs were exceeding the permissible limits. The human health risk assessment revealed the occurrence of substantial lifetime carcinogenic risk for OCPs and PCBs at both 50th and 95th percentile concentrations in freshwater mussels from the tributaries of River Ravi. Therefore, the freshwater mussels are recommended to be used in environmental toxicological studies to assess the bioavailable levels of pollution in hostile environment.     

Mice lacking Ran binding protein 1 are viable and show male infertility

The small GTPase Ran plays important roles in multiple aspects of cellular function. Maximal RanGAP activity is achieved with the aid of RanBP1 and/or presumably of RanBP2. Here, we show that RanBP1-knockout mice are unexpectedly viable, and exhibit male infertility due to a spermatogenesis arrest, presumably caused by down-regulation of RanBP2 during spermatogenesis. Indeed, siRNA-mediated depletion of RanBP2 caused severe cell death only in RanBP1-deficient MEFs, indicating that simultaneous depletion of RanBP1 and RanBP2 severely affects normal cell viability. Collectively, we conclude that the dramatic decrease in "RanBP" activity impairs germ cell viability and affects spermatogenesis decisively in RanBP1-knockout mice.     

The atmospheric deposition of phosphorus in Lake Victoria (East Africa)

Wet and dry atmospheric fluxes of total phosphorus (TP) and soluble reactive phosphorus (SRP) measured at four sites over a 12-month period were used to estimate lake-wide atmospheric phosphorus (P) deposition to Lake Victoria, East Africa. Atmospheric samples were collected in plastic buckets with top diameter of 25.5 cm by 30 cm deep. The highest P loading rates of 2.7 (TP) and 0.8 (SRP) kg ha^–2 year^–1 were measured at Mwanza compared to less than 1.9 (TP) and 0.65 (SRP) kg ha^–2 year^–1 measured in other three sites. By applying these loading rates to the lake surface, it was estimated that 13.5 ktons (13.5 × 10³ kg) of TP were deposited annually into the lake from the atmosphere. Thirty-two percent of the total was found to be in the SRP form. Dryfall, a component ignored in previous studies exceeded wet deposition by contributing 75% of the total P input. However, materials deposited by dryfall made a lesser contribution to soluble form of phosphorus, as SRP concentrations in the wet samples were 2–3 times higher than SRP concentrations in dry samples. The annual fluxes of phosphorus measured on the south and western shores of Lake Victoria (1.8–2.7 kg ha^–2 year^–1) are near the upper range of similar fluxes measured in the tropics. In comparison with the existing estimates of municipal and runoff P inputs from other studies, it is estimated that atmospheric deposition represent 55% of the total phosphorus input to the Lake Victoria. The four sampling sites were fairly clustered and wet and dry P deposition data were collected from shore/land stations and applied to open lake areas to estimate lake-wide P deposition. In this regard, the estimates determined here should be viewed as a first order approximation of actual P load deposited into the lake.     

Chemical modification results in hyperactivation and thermostabilization of Fusarium solani glucoamylase

Chemical modification of carboxyl groups of glucoamylase from a mesophilic fungus, Fusarium solani, was carried out using ethylenediamine as nucleophile in the presence of water-soluble 1-ethyl-3(3-dimethylaminopropyl)carbodiimide. Modification brought about a dramatic enhancement of catalytic activity and thermal stability of glucoamylase. Temperature and pH optima of ethylenediamine-coupled glucoamylase (ECG) increased as compared with those of native enzyme. The specificity constant (k(cat)/K(m)) of native, ECG-2, ECG-11, and ECG-17 was 136, 173, 225, and 170, respectively, at 55 degrees C. The enthalpy of activation (Delta H*) and free energy of activation (Delta G*) for soluble starch hydrolysis were lower for the chemically modified forms. All of the modified forms were stable at higher temperatures and possessed high Delta G* against thermal unfolding. The effects of alpha-chymotrypsin and subtilisin on the modified forms were activating as compared with native. Moreover, denaturation of ECG-2, ECG-11, and ECG-17 in urea at 4 mol x L(-1) also showed an activation trend. A possible explanation for the thermal denaturation of native and increased thermal stability of ECG-2, ECG-11, and ECG-17 at higher temperatures is also discussed.     

Mutagenic potency of some conjugated nitroaromatic compounds and its relationship to structure

The mutagenicities of 12 conjugated non-fused nitroaromatic compounds and 1 amino analogue were determined in strains TA100 and TA98 of Salmonella typhimurium. Reversions by p-nitroaromatics increased in the order of the acetophenone, benzaldehyde, styrene, chalcone, cinnamic acid and stilbene indicating the importance for mutagenic potency of extended conjugation to the p-nitrophenyl substituent. Highest mutagenicity was found with alpha-substituted 4-nitrostyryl derivatives of which the phenyl derivative (31 revertants per nmole in TA100) was the most active. Generally, the TA100 strain was more sensitive than TA98 to these mutagens and S9 treatment was unnecessary for activity, although 4-nitrochalcone required S9 activation. Para-nitro isomers of the cinnamic acids and chalcones were much more active than the corresponding ortho and meta isomers. The 4-aminocinnamic acid analogue was inactive suggesting that complete reduction in Salmonella of 4-nitrocinnamic acid to an active amino derivative is not response for the high mutagenicity of the former. Mutagenicity of these p-nitrostyryl compounds may be explained by the covalent interaction of the electrophilic benzylic carbon with Salmonella DNA.