Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice

Diabesity-associated metabolic stresses modulate the development of Alzheimer’s disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson’s correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.     

Is Zolpidem Associated with Increased Risk of Fractures in the Elderly with Sleep Disorders? A Nationwide Case Cross-Over Study in Taiwan

Background

We conducted a study using a case-crossover design to clarify the risk of acute effects of zolpidem and benzodiazepine on all-sites of fractures in the elderly.

Design of study

Case-crossover design.

Methods and Materials

Elderly enrollees (n = 6010) in Taiwan’s National Health Insurance Research Database with zolpidem or benzodiazepine use were analyzed for the risk of developing fractures.

Results

After adjusting for medications such as antipsychotics, antidepressants, and diuretics, or comorbidities such as hypertension, osteoarthritis, osteoporosis, rheumatoid arthritis and depression, neither zolpidem nor benzodiazepine was found to be associated with increased risk in all-sites fractures. Subjects without depression were found to have an increased risk of fractures. Diazepam is the only benzodiazepine with increased risk of fractures after adjusting for medications and comorbidities. Hip and spine were particular sites for increased fracture risk, but following adjustment for comorbidities, the associations were found to be insignificant.

Conclusion

Neither zolpidem nor benzodiazepine was associated with increased risk of all-site fractures in this case cross-over study after adjusting for medications or comorbidities in elderly individuals with insomnia. Clinicians should balance the benefits and risks for prescribing zolpidem or benzodiazepine in the elderly accordingly.     

Vital population statistics based on length frequency analysis of the exploited Japanese eel (Anguilla japonica) stock in the Kao‐Ping River,southern Taiwan

Vital statistics such as growth, mortality, and maturity parameters are crucial in understanding the population dynamics of a species. A total of 7 074 Japanese eels (Anguilla japonica) in the lower reach of the Kao‐Ping River, southern Taiwan, were collected with eel tubes in 1998 ～ 2004 and shrimp nets in 2004 ～ 2007. Data from 2004 were excluded due to mixed gear information and escapement of cultured eels; in subsequent years escaped cultured eels were identified and excluded from analyses. The estimated asymptotic length in the von Bertalanffy growth function (84.5–110 cm) was smaller, while the Brody growth parameter (0.30–0.44 year^?1) was higher using electronic length frequency analysis (ELEFAN) than when using Shepherd’s length composition analysis (SLCA). The total instantaneous mortality rate (Z) was around 1 for periods 1998–2003 and 2 year^?1 for 2005–2007 using length‐converted catch curves. The 95% confidence intervals of Z did not overlap for two of the periods, suggesting that the mortality rates were significantly higher during 2005–2007, possibly due to the introduction of shrimp nets. The maturity function differed significantly between sexes, indicating that females become silver eels at a larger size. The Japanese eels in the lower reach of the Kao‐Ping River were likely heavily exploited, thus management and conservation actions are strongly recommended.     

Phylogenetic analysis of two putative Nosema isolates from Cruciferous Lepidopteran pests in Taiwan

In this study, a new microsporidian, PX2, was isolated from the diamondback moth, Plutella xylostella, and then compared with another isolate (PX1), and with Nosema spodopterae and N. bombycis. Sequence data showed that the rRNA gene organizations of PX1 and PX2 exhibited a typical Nosema-specific organization: 5'-LSUrRNA (large subunit ribosomal RNA)-ITS (internal transcribed spacer)-SSUrRNA-IGS (intergenic spacer)-5S-3'. Phylogenetic analysis (maximum likelihood, neighbor joining, maximum parsimony, and Bayesian analysis) of the LSUrRNA and SSUrRNA gene sequences, and the sequences of the alpha-tubulin, beta-tubulin, and RPB1 (DNA dependent RNA polymerase II largest subunit) genes found that PX1 was closer to N. bombycis and N. spodopterae than to PX2. Comparison of the identities of the rRNA domains and of the other three genes showed a high divergence in the sequences of the rRNA spacer regions (ITS and IGS). This is consistent with the hypothesis that PX2, if not PX1, might represent a new Nosema species.     

Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats

The present study was conducted to explore the effects of myricetin on insulin resistance in rats fed for 6 weeks with a diet containing 60% fructose. Repeated intravenous (i.v.) injection of myricetin (1 mg/kg per injection, 3 times daily) for 14 days was found to significantly decrease the high glucose and triglyceride levels in plasma of fructose chow-fed rats. Also, the higher degree of insulin resistance in fructose chow-fed rats as measured by homeostasis model assessment of basal insulin resistance was significantly decreased by myricetin treatment. Myricetin increased the whole-body insulin sensitivity in fructose chow-fed rats, as evidenced by the marked elevation of composite whole-body insulin sensitivity index during the oral glucose tolerance test. Myricetin was found to reverse the defect in expression of insulin receptor substrate-1 (IRS-1) and the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) in soleus muscle of fructose chow-fed rats under the basal state, despite the protein expression of insulin receptor (IR). Increased basal phosphorylation of IR and IRS-1 as well as Akt was observed in parallel. The reduced level of insulin action on phosphorylation of IR, IRS-1 and Akt in soleus muscle of fructose chow-fed rats was reversed by myricetin treatment. Furthermore, myricetin treatment improved the defective insulin action on the translocation of glucose transporter subtype 4 (GLUT 4) in insulin-resistant soleus muscle. These findings indicate that myricetin improves insulin sensitivity through the enhancement of insulin action on IRS-1-associated PI 3-kinase and GLUT 4 activity in soleus muscles of animals exhibiting insulin resistance.     

Molecular and functional studies of tilapia (Oreochromis mossambicus) NMDA receptor NR1 subunits

The Pin-tailed Manakin (Ilicura militaris) is a small, sexually dimorphic, frugivorous suboscine songbird (Pipridae; Passeriformes; Aves) endemic to the Atlantic Forest of Brazil. A variant individual of this species was recently described in which the red patches that characterise the male's Definitive plumage were replaced by orange-yellow ones. We show here that the pigments in the feathers of the colour variant are common dietary carotenoids (zeaxanthin, beta-cryptoxanthin), not carotenoids synthesised by birds, lending support to the suggestion that the individual is a colour mutant lacking the capability to transform yellow dietary pigments into the red pigments normally present in these feathers. By comparison, the yellow crown feathers of a close relative, the Golden-winged Manakin (Masius chrysopterus), contained predominantly endogenously produced epsilon-caroten-3'-ones. Surprisingly, the normal-coloured feathers of the male Pin-tailed Manakin owe their red hue to rhodoxanthin, an unusual carotenoid more commonly found in plants, rather than 4-keto-carotenoids typically found in red plumages and found lacking in previously characterised bird colour variants. The implication is that birds, like the tilapia fish, may be able to synthesise this unusual pigment endogenously from dietary precursors. A newly described carotenoid, 6-hydroxy-epsilon,epsilon-carotene-3,3'-dione, here named piprixanthin, present in the red feathers of the Pin-tailed Manakin, provides a plausible intermediate between epsilon,epsilon-carotene-3,3'-dione (canary-xanthophyll B), a bright yellow pigment found in this and other songbirds, and rhodoxanthin. It is apparent that pigeons (Columbidae, Columbiformes) also have the capability to produce rhodoxanthin, and a structurally related pigment, endogenously. The ability to synthesise rhodoxanthin might have arisen at least twice in birds.     

Polyphenols from green tea prevent antineuritogenic action of Nogo‐A via 67‐kDa laminin receptor and hydrogen peroxide

Axonal regeneration after injury to the CNS is hampered by myelin‐derived inhibitors, such as Nogo‐A. Natural products, such as green tea, which are neuroprotective and safe for long‐term therapy, would complement ongoing various pharmacological approaches. In this study, using nerve growth factor‐differentiated neuronal‐like Neuroscreen‐1 cells, we show that extremely low concentrations of unfractionated green tea polyphenol mixture (GTPP) and its active ingredient, epigallocatechin‐3‐gallate (EGCG), prevent both the neurite outgrowth‐inhibiting activity and growth cone‐collapsing activity of Nogo‐66 (C‐terminal domain of Nogo‐A). Furthermore, a synergistic interaction was observed among GTPP constituents. This preventive effect was dependent on 67‐kDa laminin receptor (67LR) to which EGCG binds with high affinity. The antioxidants N‐acetylcysteine and cell‐permeable catalase abolished this preventive effect of GTPP and EGCG, suggesting the involvement of sublethal levels of H₂O₂ in this process. Accordingly, exogenous sublethal concentrations of H₂O₂, added as a bolus dose (5 μM) or more effectively through a steady‐state generation (1–2 μM), mimicked GTPP in counteracting the action of Nogo‐66. Exogenous H₂O₂ mediated this action by bypassing the requirement of 67LR. Taken together, these results show for the first time that GTPP and EGCG, acting through 67LR and elevating intracellular sublethal levels of H₂O₂, inhibit the antineuritogenic action of Nogo‐A.

     

Xanthine Oxidoreductase Function Contributes to Normal Wound Healing

Chronic, nonhealing wounds result in patient morbidity and disability. Reactive oxygen species (ROS) and nitric oxide (NO) are both required for normal wound repair, and derangements of these result in impaired healing. Xanthine oxidoreductase (XOR) has the unique capacity to produce both ROS and NO. We hypothesize that XOR contributes to normal wound healing. Cutaneous wounds were created in C57Bl6 mice. XOR was inhibited with dietary tungsten or allopurinol. Topical hydrogen peroxide (H₂O₂, 0.15%) or allopurinol (30 μg) was applied to wounds every other day. Wounds were monitored until closure or collected at d 5 to assess XOR expression and activity, cell proliferation and histology. The effects of XOR, nitrite, H₂O₂ and allopurinol on keratinocyte cell (KC) and endothelial cell (EC) behavior were assessed. We identified XOR expression and activity in the skin and wound edges as well as granulation tissue. Cultured human KCs also expressed XOR. Tungsten significantly inhibited XOR activity and impaired healing with reduced ROS production with reduced angiogenesis and KC proliferation. The expression and activity of other tungsten-sensitive enzymes were minimal in the wound tissues. Oral allopurinol did not reduce XOR activity or alter wound healing but topical allopurinol significantly reduced XOR activity and delayed healing. Topical H₂O₂ restored wound healing in tungsten-fed mice. In vitro, nitrite and H₂O₂ both stimulated KC and EC proliferation and EC migration. These studies demonstrate for the first time that XOR is abundant in wounds and participates in normal wound healing through effects on ROS production.     

Protein dynamics and allostery: an NMR view

Allostery, the process by which distant sites within a protein system are energetically coupled, is an efficient and ubiquitous mechanism for activity regulation. A purely mechanical view of allostery invoking only structural changes has developed over the decades as the classical view of the phenomenon. However, a fast growing list of examples illustrate the intimate link between internal motions over a wide range of time scales and function in protein-ligand interactions. Proteins respond to perturbations by redistributing their motions and they use fluctuating conformational states for binding and conformational entropy as a carrier of allosteric energy to modulate association with ligands. In several cases allosteric interactions proceed with minimal or no structural changes. We discuss emerging paradigms for the central role of protein dynamics in allostery.