Mitochondrial permeability transition pore is a potential drug target for neurodegeneration.

Mitochondrial permeability transition pore (mPTP) plays a central role in alterations of mitochondrial structure and function leading to neuronal injury relevant to aging and neurodegenerative diseases including Alzheimer's disease (AD). mPTP putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT) and cyclophilin D (CypD). Reactive oxygen species (ROS) increase intra-cellular calcium and enhance the formation of mPTP that leads to neuronal cell death in AD. CypD-dependent mPTP can play a crucial role in ischemia/reperfusion injury. The interaction of amyloid beta peptide (Aß) with CypD potentiates mitochondrial and neuronal perturbation. This interaction triggers the formation of mPTP, resulting in decreased mitochondrial membrane potential, impaired mitochondrial respiration function, increased oxidative stress, release of cytochrome c, and impaired axonal mitochondrial transport. Thus, the CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of AD. Designing small molecules to block this interaction would lessen the effects of Aß neurotoxicity. This review summarizes the recent progress on mPTP and its potential therapeutic target for neurodegenerative diseases including AD.

Overexpression of 17ß-hydroxysteroid dehydrogenase type 10 increases pheochromocytoma cell growth and resistance to cell death.

BACKGROUND: 17ß-hydroxysteroid dehydrogenase type 10 (HSD10) has been shown to play a protective role in cells undergoing stress. Upregulation of HSD10 under nutrient-limiting conditions leads to recovery of a homeostatic state. Across disease states, increased HSD10 levels can have a profound and varied impact, such as beneficial in Parkinson's disease and harmful in Alzheimer's disease. Recently, HSD10 overexpression has been observed in some prostate and bone cancers, consistently correlating with poor patient prognosis. As the role of HSD10 in cancer remains underexplored, we propose that cancer cells utilize this enzyme to promote cancer cell survival under cell death conditions. METHODS: The proliferative effect of HSD10 was examined in transfected pheochromocytoma cells by growth curve analysis and a xenograft model. Fluctuations in mitochondrial bioenergetics were evaluated by electron transport chain complex enzyme activity assays and energy production. Additionally, the effect of HSD10 on pheochromocytoma resistance to cell death was investigated using TUNEL staining, MTT, and complex IV enzyme activity assays. RESULTS: In this study, we examined the tumor-promoting effect of HSD10 in pheochromocytoma cells. Overexpression of HSD10 increased pheochromocytoma cell growth in both in vitro cell culture and an in vivo xenograft mouse model. The increases in respiratory enzymes and energy generation observed in HSD10-overexpressing cells likely supported the accelerated growth rate observed. Furthermore, cells overexpressing HSD10 were more resistant to oxidative stress-induced perturbation. CONCLUSIONS: Our findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction. This suggests that blockade of HSD10 may halt and/or prevent cancer growth, thus providing a promising novel target for cancer patients as a screening or therapeutic option.

Field rates of Sivanto™ (flupyradifurone) and Transform® (sulfoxaflor) increase oxidative stress and induce apoptosis in honey bees (Apis mellifera L.).

Pesticide exposures can have detrimental impacts on bee pollinators, ranging from immediate mortality to sub-lethal impacts. Flupyradifurone is the active ingredient in Sivanto™ and sulfoxaflor is the active ingredient in Transform®. They are both relatively new insecticides developed with an intent to reduce negative effects on bees, when applied to bee-attractive crops. With the growing concern regarding pollinator health and pollinator declines, it is important to have a better understanding of any potential negative impacts, especially sub-lethal, of these pesticides on bees. This study reports novel findings regarding physiological stress experienced by bees exposed to field application rates of these two insecticides via a Potter Tower sprayer. Two contact exposure experiments were conducted-a shorter 6-hour study and a longer 10-day study. Honey bee mortality, sugar syrup and water consumption, and physiological responses (oxidative stress and apoptotic protein assays) were assessed in bees exposed to Sivanto™ and Transform®, and compared to bees in control group. For the longer, 10-day contact exposure experiment, only the Sivanto™ group was compared to the control group, as high mortality recorded in the sulfoxaflor treatment group during the shorter contact exposure experiment, made the latter group unfeasible to test in the longer 10-days experiment. In both the studies, sugar syrup and water consumptions were significantly different between treatment groups and controls. The highest mortality was observed in Transform® exposed bees, followed by the Sivanto™ exposed bees. Estimates of reactive oxygen/nitrogen species indicated significantly elevated oxidative stress in both pesticide treatment groups, when compared to controls. Caspase-3 protein assays, an indicator of onset of apoptosis, was also significantly higher in the pesticide treatment groups. These differences were largely driven by post exposure duration, indicating sub-lethal impacts. Further, our findings also emphasize the need to revisit contact exposure impacts of Sivanto™, given the sub-lethal impacts and mortality observed in our long-term (10-day) contact exposure experiment.

Functional mechanics of beetle mandibles: Honest signaling in a sexually selected system.

Male stag beetles possess colossal mandibles, which they wield in combat to obtain access to females. As with many other sexually selected weapons, males with longer mandibles win more fights. However, variation in the functional morphology of these structures, used in male-male combat, is less well understood. In this study, mandible bite force, gape, structural strength, and potential tradeoffs are examined across a wide size range for one species of stag beetle, Cyclommatus metallifer. We found that not only does male mandible size demonstrate steep positive allometry, but the shape, relative bite force, relative gape, and safety factor of the mandibles also change with male size. Allometry in these functionally important mandibular traits suggests that larger males with larger mandibles should be better fighters, and that the mandibles can be considered an honest signal of male fighting ability. However, negative allometry in mandible structural safety factor, wing size, and flight muscle mass suggest significant costs and a possible limit on the size of the mandibles. J. Exp. Zool. 325A:3-12, 2016. © 2015 Wiley Periodicals, Inc.

Identification of human ABAD inhibitors for rescuing Aß-mediated mitochondrial dysfunction.

Amyloid beta (Aß) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aß)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer's disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Aß-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.

High-resolution crystal structures of two crystal forms of human cyclophilin D in complex with PEG 400 molecules.

Cyclophilin D (CypD) is a key mitochondrial target for amyloid-ß-induced mitochondrial and synaptic dysfunction and is considered a potential drug target for Alzheimer's disease. The high-resolution crystal structures of primitive orthorhombic (CypD-o) and primitive tetragonal (CypD-t) forms have been determined to 1.45 and 0.85 Šresolution, respectively, and are nearly identical structurally. Although an isomorphous structure of CypD-t has previously been reported, the structure reported here was determined at atomic resolution, while CypD-o represents a new crystal form for this protein. In addition, each crystal form contains a PEG 400 molecule bound to the same region along with a second PEG 400 site in CypD-t which occupies the cyclosporine A inhibitor binding site of CypD. Highly precise structural information for CypD should be extremely useful for discerning the detailed interaction of small molecules, particularly drugs and/or inhibitors, bound to CypD. The 0.85 Šresolution structure of CypD-t is the highest to date for any CypD structure.