Activation of ryanodine receptors is required for PKA-mediated downregulation of A-type K+ channels in rat hippocampal neurons.

A-type K+ channels (IA channels) contribute to learning and memory mechanisms by regulating neuronal excitabilities in the CNS, and their expression level is targeted by Ca2+ influx via synaptic NMDA receptors (NMDARs) during long-term potentiation (LTP). However, it is not clear how local synaptic Ca2+ changes induce IA downregulation throughout the neuron, extending from the active synapse to the soma. In this study, we tested if two major receptors of endoplasmic reticulum (ER), ryanodine (RyRs), and IP3 (IP3 R) receptors, are involved in Ca2+ -mediated IA downregulation in cultured hippocampal neurons of rats. The downregulation of IA channels was induced by doubling the Ca2+ concentration in culture media (3.6 mM for 24 hrs) or treating with glycine (200 µM for 3 min) to induce chemical LTP (cLTP), and the changes in IA peaks were measured electrophysiologically by a whole-cell patch. We confirmed that Ca2+ or glycine treatment significantly reduced IA peaks and that their effects were abolished by blocking NMDARs or voltage-dependent Ca2+ channels (VDCCs). In this cellular processing, blocking RyRs (by ryanodine, 10 µM) but not IP3 Rs (by 2APB, 100 µM) completely abolished IA downregulation, and the LTP observed in hippocampal slices was more diminished by ryanodine rather than 2APB. Furthermore, blocking RyRs also reduced Ca2+ -mediated PKA activation, indicating that sequential signaling cascades, including the ER and PKA, are involved in regulating IA downregulation. These results strongly suggest a possibility that RyR contribution and mediated IA downregulation are required to regulate membrane excitability as well as synaptic plasticity in CA3-CA1 connections of the hippocampus. © 2017 Wiley Periodicals, Inc.

The Short Isoform of DNAJB6 Protects against 1-Methyl-4-phenylpridinium Ion-Induced Apoptosis in LN18 Cells via Inhibiting Both ROS Formation and Mitochondrial Membrane Potential Loss.

In a previous study, we found that the short isoform of DNAJB6 (DNAJB6(S)) had been decreased in the striatum of a mouse model of Parkinson's disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). DNAJB6, one of the heat shock proteins, has been implicated in the pathogenesis of PD. In this study, we explored the cytoprotective effect of DNAJB6(S) against 1-methyl-4-phenylpyridinium ion- (MPP+-) induced apoptosis and the underlying molecular mechanisms in cultured LN18 cells from astrocytic tumors. We observed that MPP+ significantly reduced the cell viability and induced apoptosis in LN18 glioblastoma cells. DNAJB6(S) protected LN18 cells against MPP+-induced apoptosis not only by suppressing Bax cleavage but also by inhibiting a series of apoptotic events including loss of mitochondrial membrane potential, increase in intracellular reactive oxygen species, and activation of caspase-9. These observations suggest that the cytoprotective effects of DNAJB6(S) may be mediated, at least in part, by the mitochondrial pathway of apoptosis.

Porphyrinuria in Korean children with autism: correlation with oxidative stress.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder believed to be associated with heavy metal exposure, especially mercury (Hg), and is characterized by disturbances in metal elimination. Various studies correlated elevated heavy metal body burden with ASD diagnoses as evidenced by increased urinary porphyrin levels in patients. Urinary porphyrins were also determined in Korean patients diagnosed with ASD (n = 65) who visited AK Eastern Medicinal Clinic in Kangnam-gu, Seoul, from June 2007 to September 2008, compared to controls (n = 9) residing in the same area, by means of Metametrix (CLIA-approved) laboratory testing. Further, urinary organic acids as indicators of hepatic detoxification/oxidative stress were also analyzed among patients diagnosed with ASD. Significant increases were found in patients diagnosed with ASD for proporphyrins, pentacarboxyporphyrin, precoproporphyrin, coproporphyrins, and total porphyrins. Significant correlations were observed between hepatic detoxification/oxidative stress markers and urinary porphyrins. In agreement with published data, the present results demonstrated that measurement of porphyrins serves as a reliable tool for diagnosis of heavy metal involvement in ASD.

A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey.

BACKGROUND: Some studies have found an association of obesity with type 2 diabetes only among individuals with high normal serum gamma-glutamyltransferase (GGT) activity, not in those with low serum GGT. If this interaction reflected pathophysiology, it would have scientific and clinical importance. The findings failed to reach statistical significance, however, and no articles have focused on the topic. We investigated possible interactions between serum GGT and body mass index (BMI) and their effects on the risk of prevalent type 2 diabetes and homeostasis model assessment (HOMA) insulin resistance. METHODS: We analyzed 4011 adults > or =40 years old who participated in the 3rd US National Health and Nutrition Examination Survey. RESULTS: BMI was associated with prevalent diabetes only among persons with high normal serum GGT activity (P for interaction = 0.002). In the highest serum GGT quartile, adjusted odds ratios for BMI 25-29.9, 30-34.5, and > or =35 kg/m(2) compared with BMI<25 kg/m(2) were 3.1, 5.1, and 6.2, respectively (P for trend <0.001). In the lowest serum GGT quartile, BMI was not associated with diabetes; corresponding adjusted odds ratios were 1.0, 0.9, 1.8, and 0.8 (P for trend = 0.551). After prevalent diabetes was excluded, there was a parallel interaction with HOMA levels (P for interaction <0.001). CONCLUSIONS: BMI was not associated with prevalent type 2 diabetes when GGT was low normal, suggesting that obesity itself may not be a sufficient risk factor for type 2 diabetes. Practically, this interaction can be useful in clinical settings to identify individuals at high risk for type 2 diabetes.

Association between serum concentrations of persistent organic pollutants and insulin resistance among nondiabetic adults: results from the National Health and Nutrition Examination Survey 1999-2002.

OBJECTIVE: We reported strong relations between serum concentrations of persistent organic pollutants (POPs), especially organochlorine (OC) pesticides or nondioxin-like polychlorinated biphenyls (PCBs), and prevalence of diabetes in a U.S population with background exposure to POPs. Here, we investigated POPs and insulin resistance, a frequent pathogenic precursor of type 2 diabetes. RESEARCH DESIGN AND METHODS: Serum POPs and homeostasis model assessment of insulin resistance (HOMA-IR) were investigated cross-sectionally in 749 nondiabetic participants aged > or = 20 years. Nineteen POPs in five subclasses were selected, detectable in > or = 60% of participants. RESULTS: Among subclasses, OC pesticides were most strongly associated with HOMA-IR. Adjusted geometric means of HOMA were 3.27, 3.36, 3.48, and 3.85 (P for trend <0.01) across quartiles of OC pesticides. The relationship strengthened with increasing HOMA-IR percentile: adjusted odds ratios comparing the highest versus lowest POPs quartile were 1.8 for being > or = 50th percentile of HOMA-IR, 4.4 for being > or = 75th percentile, and 7.5 for being > or = 90th percentile. Associations with elevated HOMA-IR appeared to be specific to oxychlordane and trans-nonachlor but also were found for two nondioxin-like PCBs. No HOMA-IR associations were seen in the other three POP subclasses. The association between OC pesticides and HOMA-IR tended to strengthen as waist circumference increased, with no apparent association in the lowest quartile of OC pesticide concentrations. CONCLUSIONS: These findings, coupled with those concerning diabetes prevalence, suggest that OC pesticides and nondioxin-like PCBs may be associated with type 2 diabetes risk by increasing insulin resistance, and POPs may interact with obesity to increase the risk of type 2 diabetes.

[Relationships among Oxidative Stress Markers, Life Style Factors and Biochemical Findings.].

BACKGROUND: In many studies, oxidative stress markers have been employed to serve as a measure of a disease process or to reflect oxidative status. These oxidative stress markers must have some degree of predictive validity, but full substantiation of this relation is still lacking. This paper presents data on levels of three biomarkers, oxidized low-density lipoproteins (LDL), carbonyl, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and a number of life style factors associated with oxidative stress in healthy adults. METHODS: For 237 healthy adults aged 40-60 years, a number of life style factors, biochemical characteristics and oxidative status were evaluated. Markers of oxidative stress were measured by an ELISA method. RESULTS: Waist-hip ratio and use of vitamin supplement were associated with serum oxidized LDL (P<0.05). Body mass index and stress had a relationship (P<0.05) with protein carbonyl. Creactive protein was related to serum oxidized LDL (P<0.01). There was no correlation among three oxidative stress markers, oxidized LDL, carbonyl, and 8-OHdG. CONCLUSIONS: The oxidative stress markers used in this study could not be regarded as a general estimate of the healthy individual oxidative status. Further studies focusing on the development of biomarkers to reflect changes in the oxidative status under normal, non-pathological conditions in humans will be required.

The association between the DRD2 TaqI A polymorphism and smoking cessation in response to acupuncture in Koreans.

OBJECTIVES: The response to acupuncture is presumed to differ with the individual; this variation might be due to genetic differences. Therefore, we examined whether the DRD2 TaqI A polymorphism is associated with the response to acupuncture in the treatment of smoking cessation in a Korean population. SUBJECTS: A total of 231 healthy Korean male smokers participated in this study. INTERVENTIONS: The subjects underwent three manual auricular acupuncture treatments in one week. DESIGN AND OUTCOME MEASURES: After 1 week, high and low responders to the acupuncture treatment were selected according to their cigarette consumption and the desire to smoke. A DRD2 TaqI A restriction enzyme fragment length polymorphism (RFLP) study examined genomic DNA extracted from blood samples. RESULTS: The proportions of high, intermediate, and low responders were 28.6, 55.4, and 16.0%, respectively. The RFLP study showed that the distribution of the DRD2*A genotype and allele frequencies differed significantly between the high and low responders (chi(2) test, p = 0.031 and 0.016, respectively), and that high responders had a higher DRD2*A2 allele frequency than low responders. CONCLUSIONS: Our findings suggest that DRD2 TaqI A polymorphism is related to acupuncture response in smoking cessation treatment.