Fetal Exposure to Maternal Inflammation Does Not Affect Postnatal Development of Genetically-Driven Ileitis and Colitis

Background: Chronic inflammatory disorders have been increasing in incidence over the past decades following geographical patterns of industrialization. Fetal exposure to maternal inflammation may alter organ functions and the offspring''s disease risk. We studied the development of genetically-driven ileitis and colitis in response to maternal inflammation using mouse models.Methods: Disease susceptible (Tnf^ΔARE/+ and IL10^−/−) and disease-free (Tnf^+/+ and IL10^−/+) offspring were raised in inflamed and non-inflamed dams. Ileal, caecal and colonic pathology was evaluated in the offspring at 8 or 12 weeks of age. Ly6G-positive cells in inflamed sections from the distal ileum and distal colon were analysed by immunofluorescence microscopy. Gene expression of pro-inflammatory cytokines was measured in whole tissue specimens by quantitative PCR. Microarray analyses were performed on laser microdissected intestinal epithelium. Caecal bacterial communities were assessed by Illumina sequencing of 16S rRNA amplicons.Results: Disease severity, the number of infiltrated neutrophils as well as Tnf and Il12p40 mRNA expression were independent of maternal inflammation in the offspring of mouse models for ileitis (Tnf^ΔARE/+) and colitis (IL10^−/−). Although TNF-driven maternal inflammation regulated 2,174 (wild type) and 3,345 (Tnf^ΔARE/+) genes in the fetal epithelium, prenatal gene expression patterns were completely overwritten after birth. In addition, co-housing experiments revealed no change in phylogenetic diversity of the offspring''s caecal microbiota in response to maternal inflammation. This is independent of the offspring''s genotype before and after the onset of tissue pathology.Conclusions: Disease risk and activity in mouse models of chronic ileitis and colitis was independent of the fetal exposure to maternal inflammation. Likewise, maternal inflammation did not alter the diversity and composition of offspring''s caecal microbiota, clearly demonstrating that changes of the gene expression program in the fetal gut epithelium were not relevant for the development of chronic inflammatory disorders in the gut.     

Opposing Actions of Sevoflurane on GABAergic and Glycinergic Synaptic Inhibition in the Spinal Ventral Horn

Background

The ventral horn is a major substrate in mediating the immobilizing properties of the volatile anesthetic sevoflurane in the spinal cord. In this neuronal network, action potential firing is controlled by GABA_A and glycine receptors. Both types of ion channels are sensitive to volatile anesthetics, but their role in mediating anesthetic-induced inhibition of spinal locomotor networks is not fully understood.

Methodology/Principal Findings

To compare the effects of sevoflurane on GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) whole-cell voltage-clamp recordings from ventral horn interneurons were carried out in organotypic spinal cultures. At concentrations close to MAC (minimum alveolar concentration), decay times of both types of IPSCs were significantly prolonged. However, at 1.5 MAC equivalents, GABAergic IPSCs were decreased in amplitude and reduced in frequency. These effects counteracted the prolongation of the decay time, thereby decreasing the time-averaged GABAergic inhibition. In contrast, amplitudes and frequency of glycinergic IPSCs were not significantly altered by sevoflurane. Furthermore, selective GABA_A and glycine receptor antagonists were tested for their potency to reverse sevoflurane-induced inhibition of spontaneous action potential firing in the ventral horn. These experiments confirmed a weak impact of GABA_A receptors and a prominent role of glycine receptors at a high sevoflurane concentration.

Conclusions

At high concentrations, sevoflurane mediates neuronal inhibition in the spinal ventral horn primarily via glycine receptors, and less via GABA_A receptors. Our results support the hypothesis that the impact of GABA_A receptors in mediating the immobilizing properties of volatile anesthetics is less essential in comparison to glycine receptors.     

Recovery of Soil Ammonia Oxidation After Long-Term Zinc Exposure Is Not Related to the Richness of the Bacterial Nitrifying Community

A soil sterilization–reinoculation approach was used to manipulate soil microbial diversity and to assess the effect of the diversity of the ammonia-oxidizing bacteria (AOB) on the recovery of the nitrifying community to metal stress (zinc). Gamma-irradiated soil was inoculated with 13 different combinations of up to 22 different soils collected worldwide to create varying degrees of AOB diversity. Two months after inoculation, AOB amoA DGGE based diversity (weighted richness) varied more than 10-fold among the 13 treatments, the largest value observed where the number of inocula had been largest. Subsequently, the 13 treatments were either or not amended with ZnCl₂. Initially, Zn amendment completely inhibited nitrification. After 6 months of Zn exposure, recovery of the potential nitrification activity in the Zn amended soils ranged from <10 % to >100 % of the potential nitrification activity in the corresponding non-amended soils. This recovery was neither related to DGGE-based indices of AOB diversity nor to the AOB abundance assessed 2 months after inoculation (p?>?0.05). However, recovery was significantly related (r?=?0.75) to the potential nitrification rate before Zn amendment and only weakly to the number of soil inocula used in the treatments (r?=?0.46). The lack of clear effects of AOB diversity on recovery may be related to an inherently sufficient diversity and functional redundancy of AOB communities in soil. Our data indicate that potential microbial activity can be a significant factor in recovery.     

Long-Term Methionine Exposure Induces Memory Impairment on Inhibitory Avoidance Task and Alters Acetylcholinesterase Activity and Expression in Zebrafish (Danio rerio)

Hypermethioninemic patients exhibit a variable degree of neurological dysfunction. However, the mechanisms involved in these alterations have not been completely clarified. Cholinergic system has been implicated in many physiological processes, including cognitive performances, as learning, and memory. Parameters of cholinergic signaling have already been characterized in zebrafish brain. Since zebrafish is a small freshwater teleost which is a vertebrate model for modeling behavioral and functional parameters related to human pathogenesis and for clinical treatment screenings, in the present study we investigated the effects of short- and long-term methionine exposure on cognitive impairment, AChE activity and gene expression in zebrafish. For the studies, animals were exposed at two methionine concentrations (1.5 and 3.0 mM) during 1 h or 7 days (short- or long-term treatments, respectively). We observed a significant increase in AChE activity of zebrafish brain membranes after long-term methionine exposure at 3.0 mM. However, AChE gene expression decreased significantly in both concentrations tested after 7 days of treatment, suggesting that post-translational events are involved in the enhancement of AChE activity. Methionine treatment induces memory deficit in zebrafish after long-term exposure to this amino acid, which could be related, at least in part, with cognitive impairment observed in hypermethioninemia. Therefore, the results here presented raise a new perspective to use the zebrafish as a complementary vertebrate model for studying inborn errors of metabolism, which may help to better understand the pathophysiology of this disease.     

Inhibition of p42 and p44 Mitogen-Activated Protein Kinase Activity by PD98059 Does Not Suppress Nerve Growth Factor-Induced Survival of Sympathetic Neurones

Abstract: Nerve growth factor (NGF) induces persistent p42 and p44 mitogen-activated protein kinase (MAPK) activity in sympathetic neurones in parallel to its survival-promoting activity. To investigate whether these MAPK activities are necessary for NGF-induced survival, we have inhibited NGF-stimulated p42/p44 MAPK activity over extended periods using the compound 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059). Despite attaining up to 95% inhibition of p42/p44 MAPK activity in cultures treated with NGF and PD98059, neuronal survival is maintained undiminished, although a decrease in the density of the neuritic network is observed. Because p21Ras activity is essential for NGF-induced survival, we conclude that p21Ras-linked activities other than p42 and p44 MAPKs are responsible for mediating NGF-dependent survival of rat sympathetic neurones.     

Impairment of Cognitive Function and Synaptic Plasticity Associated with Alteration of Information Flow in Theta and Gamma Oscillations in Melamine-Treated Rats

Changes of neural oscillations at a variety of physiological rhythms are effectively associated with cognitive performance. The present study investigated whether the directional indices of neural information flow (NIF) could be used to symbolize the synaptic plasticity impairment in hippocampal CA3-CA1 network in a rat model of melamine. Male Wistar rats were employed while melamine was administered at a dose of 300 mg/kg/day for 4 weeks. Behavior was measured by the Morris water maze(MWM)test. Local field potentials (LFPs) were recorded before long-term potentiation (LTP) induction. Generalized partial directed coherence (gPDC) and phase-amplitude coupling conditional mutual information (PAC_CMI) were used to measure the unidirectional indices in both theta and low gamma oscillations (LG, ∼30–50 Hz). Our results showed that melamine induced the cognition deficits consistent with the reduced LTP in CA1 area. Phase locking values (PLVs) showed that the synchronization between CA3 and CA1 in both theta and LG rhythms was reduced by melamine. In both theta and LG rhythms, unidirectional indices were significantly decreased in melamine treated rats while a similar variation trend was observed in LTP reduction, implying that the effects of melamine on cognitive impairment were possibly mediated via profound alterations of NIF on CA3-CA1 pathway in hippocampus. The results suggested that LFPs activities at these rhythms were most likely involved in determining the alterations of information flow in the hippocampal CA3-CA1 network, which might be associated with the alteration of synaptic transmission to some extent.     

Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.     

Protein Levels and Activity of Some Antioxidant Enzymes in Hippocampus of Subjects with Amnestic Mild Cognitive Impairment

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive aging and early dementia or clinically probable Alzheimer’s disease (AD). Most individuals with amnestic MCI eventually develop AD, which suggests that MCI may be the earliest phase of AD. Oxidative stress is observed in brain from subjects with both AD and MCI. Among others, two possibilities for elevated oxidataive stress are decreased activity or elevated expression of antioxidant enzymes, the latter as a response to the former. Accordingly, in the current study, the protein levels and activity of some antioxidant enzymes in the hippocampus of control and MCI brain were measured using Western blot analysis and spectrophotometric methods, respectively. Alterations in the levels and activity of a number of antioxidant enzymes in MCI brain compared to age-matched controls were found. These results are consistent with the hypothesis that oxidative stress may be an early event in the progression of amnestic MCI to AD. Special issue article in honor of Dr. Anna Maria Giuffrida-Stella.     

Effect of Long-Term Exposure to Aluminum on the Acetylcholinesterase Activity in the Central Nervous System and Erythrocytes

Aluminum (Al), a neurotoxic agent, has been associated with Alzheimer’s disease (AD), which is characterized by cholinergic dysfunction in the central nervous system. In this study, we evaluated the effect of long-term exposure to aluminum on acetylcholinesterase (AChE) activity in the central nervous system in different brain regions, in synaptosomes of the cerebral cortex and in erythrocytes. The animals were loaded by gavage with AlCl₃ 50 mg/kg/day, 5 days per week, totalizing 60 administrations. Rats were divided into four groups: (1) control (C); (2) 50 mg/kg of citrate solution (Ci); (3) 50 mg/kg of Al plus citrate (Al + Ci), and (4) 50 mg/kg of Al (Al). AChE activity in striatum was increased by 15% for Ci, 19% for Al + Ci and 30% for Al, when compared to control (P < 0.05). The activity in hypothalamus increased 23% for Ci, 26% for Al + Ci and 28% for Al, when compared to control (P < 0.05). AChE activity in cerebellum, hippocampus and cerebral cortex was decreased by 11%, 23% and 21% respectively, for Al, when compared to the respective controls (P < 0.05). AChE activity in synaptosomes was increased by 14% for Al, when compared to control (P < 0.05). Erythrocyte AChE activity was increased by 17% for Al + Ci and 11% for Al, when compared to control (P < 0.05). These results indicate that Al affects at the same way AChE activity in the central nervous system and erythrocyte. AChE activity in erythrocytes may be considered a marker of easy access of the central cholinergic status.     

Biochemical Modifications and Neuronal Damage in Brain of Young and Adult Rats After Long-Term Exposure to Mobile Phone Radiations

This study investigated the effect of exposure to mobile phone radiations on oxidative stress and apoptosis in brain of rats. Rats were allocated into six groups (three young and three adult). Groups 1 and 4 were not subjected to the radiation source and served as control groups. In groups 2 and 5, the mobile phones were only connected to the global system for mobile communication, while in groups 3 and 6, the option of calling was in use. Microwaves were generated by a mobile test phone (SAR = 1.13 W/kg) during 60 days (2 h/day). Significant increments in conjugated dienes, protein carbonyls, total oxidant status, and oxidative stress index along with a significant reduction of total antioxidant capacity levels were evident after exposure. Bax/Bcl-2 ratio, caspase-3 activity, and tumor necrosis factor-alpha level were enhanced, whereas no DNA fragmentation was detected. The relative brain weight of young rats was greatly affected, and histopathological examination reinforced the neuronal damage. The study highlights the detrimental effects of mobile phone radiations on brain during young and adult ages. The interaction of these radiations with brain is via dissipating its antioxidant status and/or triggering apoptotic cell death.     

Gender Differences in the Association of Smoking and Drinking with the Development of Cognitive Impairment

Modifiable lifestyle-related factors such as smoking and alcohol drinking are associated with cognitive impairment in the elderly population but the relationships have shown various results. To evaluate the relationship of alcohol drinking and smoking in the early 60 s with the risk of developing incident cognitive impairment. In 1999, we evaluated cognitive function, smoking, and drinking status in 3,174 inhabitants aged 60–64 years in a rural area of Korea, with a follow-up assessment of cognitive function 7 years later. A total of 1,810 individuals who did not show cognitive impairment at baseline were included. A stratified analysis was applied to evaluate how smoking and alcohol drinking affected the risk of developing cognitive impairment based on gender. Current smokers showed a higher risk for developing cognitive impairment than did never smokers (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.09–2.15). The OR for female current smokers compared with never smokers was 1.62 (95% CI, 1.05–2.52), and smokers with higher pack-years were more likely to develop cognitive impairment than never smokers, showing a dose–response relationship (P for trend = 0.004). Frequent alcohol consumption increased the risk of developing cognitive impairment (OR, 1.68; 95% CI, 1.01–2.78), and a dose–response relationship was observed among male subjects (P for trend = 0.044). Infrequent drinking in females decreased the odds of developing cognitive impairment (OR, 0.67; 95% CI, 0.42–1.00), whereas frequent drinking tended to increase the odds, although this trend was not significant, suggesting a U-shaped relationship. Although the sample was small for some analyses, especially in female, our data suggest that smoking and drinking in the early 60 s are associated with a risk of developing cognitive impairment, and this relationship is characterized by gender differences.     

Enhanced Slow-Wave EEG Activity and Thermoregulatory Impairment following the Inhibition of the Lateral Hypothalamus in the Rat

Neurons within the lateral hypothalamus (LH) are thought to be able to evoke behavioural responses that are coordinated with an adequate level of autonomic activity. Recently, the acute pharmacological inhibition of LH has been shown to depress wakefulness and promote NREM sleep, while suppressing REM sleep. These effects have been suggested to be the consequence of the inhibition of specific neuronal populations within the LH, i.e. the orexin and the MCH neurons, respectively. However, the interpretation of these results is limited by the lack of quantitative analysis of the electroencephalographic (EEG) activity that is critical for the assessment of NREM sleep quality and the presence of aborted NREM-to-REM sleep transitions. Furthermore, the lack of evaluation of the autonomic and thermoregulatory effects of the treatment does not exclude the possibility that the wake-sleep changes are merely the consequence of the autonomic, in particular thermoregulatory, changes that may follow the inhibition of LH neurons. In the present study, the EEG and autonomic/thermoregulatory effects of a prolonged LH inhibition provoked by the repeated local delivery of the GABA_A agonist muscimol were studied in rats kept at thermoneutral (24°C) and at a low (10°C) ambient temperature (Ta), a condition which is known to depress sleep occurrence. Here we show that: 1) at both Tas, LH inhibition promoted a peculiar and sustained bout of NREM sleep characterized by an enhancement of slow-wave activity with no NREM-to-REM sleep transitions; 2) LH inhibition caused a marked transitory decrease in brain temperature at Ta 10°C, but not at Ta 24°C, suggesting that sleep changes induced by LH inhibition at thermoneutrality are not caused by a thermoregulatory impairment. These changes are far different from those observed after the short-term selective inhibition of either orexin or MCH neurons, suggesting that other LH neurons are involved in sleep-wake modulation.     

Chronic Cadmium Exposure Lead to Inhibition of Serum and Hepatic Alkaline Phosphatase Activity in Wistar Rats

Alkaline phosphatase (ALP) activity in the serum and liver from rats administered with cadmium (Cd) in drinking water was studied. After metal administration, Cd showed a time‐dependent accumulation in the liver, meanwhile metallothionein had a maximum increase at 1 month, remaining in this level until the end of the study. On the other hand, serum and liver ALP activity was decreased after 3 months exposure. To determine if Cd produced an inhibition on enzyme, apo‐ALP prepared from both nonexposed and exposed rats was reactivated with Zn, showing 60% more activity as compared with the enzyme isolated from nonexposed rats. In vitro assays showed that Cd‐ALP was partially reactivated with Zn; however, in the presence of cadmium, Zn‐ALP was completely inhibited. Kinetic studies indicate a noncompetitive inhibition by Cd; these results suggest that Cd can substitute Zn, and/or Cd can interact with nucleophilic ligands essential for the enzymatic activity.     

Inhibition of Phosphoinositide 3-Kinase p110delta Does Not Affect T Cell Driven Development of Type 1 Diabetes Despite Significant Effects on Cytokine Production

Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3⁺ CD4⁺ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.     

Application of Methods of Wavelet and Recurrent Analysis to Studies of Bioelectrical Activity of the Brain in Moderate Cognitive Impairment

Human Physiology - The dynamic changes in the patterns of electroencephalograms of patients with moderate cognitive impairments and the quantitative indicators of these patterns, determined by the...     

Antioxidant Activity of Inulin and Its Role in the Prevention of Human Colonic Muscle Cell Impairment Induced by Lipopolysaccharide Mucosal Exposure

Background

Fructans, such as inulin, are dietary fibers which stimulate gastro-intestinal (GI) function acting as prebiotics. Lipopolysaccharide (LPS) impairs GI motility, through production of reactive oxygen species. The antioxidant activity of various fructans was tested and the protective effect of inulin on colonic smooth muscle cell (SMC) impairment, induced by exposure of human mucosa to LPS, was assessed in an ex vivo experimental model.

Methods

The antioxidant capacity of fructans was measured in an in vitro system that simulates cooking and digestion processes. Human colonic mucosa and submucosa, obtained from disease-free margins of resected segments for cancer, were sealed between two chambers, with the mucosal side facing upwards with Krebs solution with or without purified LPS from a pathogenic strain of Escherichia coli (O111:B4) and inulin (Frutafit IQ), and the submucosal side facing downwards into Krebs solution. The solutions on the submucosal side were collected following mucosal exposure to Krebs in the absence (N-undernatant) or presence of LPS (LPS-undernatant) or LPS+inulin (LPS+INU-undernatant). Undernatants were tested for their antioxidant activity and the effects on SMCs contractility. Inulin protective effects on mucosa and submucosa layers were assessed measuring the protein oxidation level in the experimental conditions analyzed.

Results

Antioxidant activity of inulin, which was significantly higher compared to simple sugars, remained unaltered despite cooking and digestion processes. Inulin protected the mucosal and submucosal layers against protein oxidation. Following exposure to LPS-undernatant, a significant decrease in maximal acetylcholine (Ach)-induced contraction was observed when compared to the contraction induced in cells incubated with the N-undernatant (4±1% vs 25±5% respectively, P<0.005) and this effect was completely prevented by pre-incubation of LPS with Inulin (35±5%).

Conclusions

Inulin protects the human colon mucosa from LPS-induced damage and this effect appears to be related to the protective effect of inulin against LPS-induced oxidative stress.     

Insecticidal Activity and Expression of Cytochrome P450 Family 4 Genes in Aedes albopictus After Exposure to Pyrethroid Mosquito Coils

Mosquito coils are insecticides commonly used for protection against mosquitoes due to their toxic effects on mosquito populations. These effects on mosquitoes could induce the expression of metabolic enzymes in exposed populations as a counteractive measure. Cytochrome P450 family 4 (CYP4) are metabolic enzymes associated with a wide range of biological activities including insecticide resistance. In this study, the efficacies of three commercial mosquito coils with different pyrethroid active ingredients were assessed and their potential to induce the expression of CYP4 genes in Aedes albopictus analyzed by real-time quantitative PCR. Coils containing 0.3 % d-allethrin and 0.005 % metofluthrin exacted profound toxic effects on Ae. albopictus, inducing high mortalities (≥90 %) compared to the 0.2 % d-allethrin reference coil. CYP4H42 and CYP4H43 expressions were significantly higher in 0.3 % d-allethrin treated mosquitoes compared to the other treated populations. Short-term (KT₅₀) exposure to mosquito coils induced significantly higher expression of both genes in 0.005 % metofluthrin exposed mosquitoes. These results suggest the evaluated products provided better protection than the reference coil; however, they also induced the expression of metabolic genes which could impact negatively on personal protection against mosquito.     

Chemokine-Like Receptor 1 Deficiency Does Not Affect the Development of Insulin Resistance and Nonalcoholic Fatty Liver Disease in Mice

The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1), are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD), which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1^-/-) mice and wild type (WT) mice into low-density lipoprotein receptor knock-out (Ldlr^-/-) mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS). Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1^-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr^-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution.     

Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation

Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions.