Traumatic brain injury (TBI) is associated with primary and secondary injury. A thorough understanding of secondary injury will help to develop effective treatments and improve patient outcome. In this study, the GM model of controlled cortical impact injury (CCII) of Lighthall (1988) was used with modification to induce lateral TBI in rats. Forebrain mitochondria isolated from ipsilateral (IH) and contralateral (CH) hemispheres to impact showed a distinct difference. With glutamate + malate as substrates, mitochondria from the IH showed a significant decrease in State 3 respiratory rates, respiratory control indices (RCI), and P/O ratios. This decrease occurred as early as 1 h and persisted for at least 14 days following TBI. The State 3 respiratory rates, RCI, and P/O ratios could be restored to sham values by the addition of EGTA to the assay mixture. A significant amount of Ca2+ was found to be adsorbed to the mitochondria of both the IH and the CH with higher values seen in the IH. The rate of energy-linked Ca2+ transport in the IH was significantly decreased at 6 and 12 h. These data indicate that CCII-induced TBI perturbs cellular Ca2+ homeostasis and results in excessive Ca2+ adsorption to the mitochondrial membrane, which subsequently inhibits the respiratory chain-linked electron transfer and energy transduction.

Background: Diabetes mellitus is an important risk factor for cardiomyopathy. Increasing oxidative stress may be one of the main factors of diabetic cardiomyopathy. A13, a newly synthesized curcumin analog, was proved to be superior to curcumin in biological activity. However, little know about how A13 performed in diabetic models. In this study, we evaluated the ability of curcumin analog A13 to alleviate oxidative stress and ameliorate fibrosis in the myocardium, and explore the underlying mechanisms. Methods: Intraperitoneal injection of streptozotocin (30 mg/kg in 0.1 M sodium citrate buffer, pH 4.5) induced diabetes in high-fat fed rats. The rats were respectively treated with a daily dose of curcumin or A13 via intragastric intubation for 8 weeks. Myocardial tissue sections were stained with hematoxylin-eosin; oxidative stress was detected by biochemical assays; activation of the Nrf2/ARE pathway was detected by Western blot, immunohistochemical staining and RT-qPCR; myocardial fibrosis was identified by Western blot and Masson trichrome staining. Results: Treatment with curcumin analog A13 reduced the histological lesions of the myocardium in diabetic rats. Curcumin and A13 treatment decreased the malondialdehyde level and increased the activity of superoxide dismutase in the myocardium of diabetic rats. Molecular analysis and immunohistochemical staining demonstrated that dose of 20 mg/kg of A13 could activate the Nrf2/ARE pathway. Molecular analysis and Masson staining showed that curcumin analog A13 treatment significantly ameliorated fibrosis in myocardium of these diabetic rats. Conclusion: Treatment with curcumin analog A13 protects the morphology of myocardium, restores the MDA levels and SOD activity, activates the Nrf2/ARE pathway and ameliorates myocardial fibrosis in diabetic rats. It may be a useful therapeutic agent for some aspects of diabetic cardiomyopathy.

ScopeThe present study was designed to examine the damage caused by high-fat diet and streptozotocin-induced diabetes on the testis of rats and the effects of curcumin against oxidative stress and apoptosis from high-fat diet and diabetes.MethodsDiabetes was induced by intraperitoneal injection of streptozotocin (30 mg/kg in 0.1 M sodium citrate buffer, pH 4.5) in obese rats. The rats in the obese and diabetic groups were treated with a daily dose of curcumin by intragastric intubation (100 mg/kg body weight) for 8 weeks. Testis tissue sections were stained with hematoxylin–eosin, and apoptosis was identified in situ by using terminal deoxynucleotidyl transferase dUTP nick end labeling.ResultsCurcumin treatment improved the histological appearance of the testis and significantly reduced the apoptosis level in the testicular cells of the obese and the diabetic rats. The expression of proliferating cell nuclear antigen (PCNA) was restored in the testis tissues of diabetic rats at the end of curcumin treatment. Molecular analysis demonstrated that curcumin treatment significantly and simultaneously decreased Bax and increased Bcl-2 expressions, therefore elevating the ratio of Bcl-2/Bax. Furthermore, curcumin treatment significantly decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) levels in testis tissue samples of the diabetic rats.ConclusionCurcumin treatment preserved the morphology of testes; restored the expression of PCNA, MDA, and SOD; and inhibited testicular cell death in diabetic rats. The capability of curcumin in inhibiting oxidative stress and modulating the Bax/Bcl-2-mediated cell death pathway reveals its potential as a therapeutic agent against diabetes.

The efficiency of ATP synthesis coupled to cell respiration, commonly referred to as the P/O ratio, has been the subject of extensive studies for more that 50 years. The general conclusion from these studies is that respiring mitochondria can convert external ADP to ATP at a maximal P/O ratio of 3 for NAD-linked substrates and 2 for succinate. However, in recent years the validity of these "integral" values has been questioned on both mechanistic and thermodynamic grounds, and a mechanistic P/O ratio of 2.5 for NAD-linked substrates and 1.5 for succinate have been concluded on the basis of experiments with isolated mitochondria. These values have been widely adopted in the scientific literature, including several recent textbooks. In this paper we report that under optimal conditions with respect to preparation and assay procedures, the P/O ratios obtained with isolated rat liver mitochondria consistently exceed 2.5 with NAD-linked substrates and 1.5 with succinate. These results, although not excluding "nonintegral" P/O ratios due to various energy-dissipating side reactions, warrant caution in accepting the reported lower values and, in general, in referring to mechanistic considerations unless the underlying molecular mechanisms are understood.