DataSheet2_Neuroprotective effect of dexmedetomidine on autophagy in mice administered intracerebroventricular injections of Aβ25–35.PDF

Alzheimer’s disease (AD), one of the most prevalent neurodegenerative diseases is associated with pathological autophagy-lysosomal pathway dysfunction. Dexmedetomidine (Dex) has been suggested as an adjuvant to general anesthesia with advantages in reducing the incidence of postoperative cognitive dysfunction in Dex-treated patients with AD and older individuals. Several studies reported that Dex improved memory; however, evidence on the effects of Dex on neuronal autophagy dysfunction in the AD model is lacking. We hypothesized that Dex administration would have neuroprotective effects by improving pathological autophagy dysfunction in mice that received an intracerebroventricular (i.c.v.) injection of amyloid β-protein fragment 25–35 (Aβ25–35) and in an autophagy-deficient cellular model. In the Y-maze test, Dex reversed the decreased activity of Aβ25–35 mice. Additionally, it restored the levels of two memory-related proteins, phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII) and postsynaptic density-95 (PSD-95) in Aβ25–35 mice and organotypic hippocampal slice culture (OHSC) with Aβ25–35. Dex administration also resulted in decreased expression of the autophagy-related microtubule-associated proteins light chain 3-II (LC3-II), p62, lysosome-associated membrane protein2 (LAMP2), and cathepsin D in Aβ25–35 mice and OHSC with Aβ25–35. Increased numbers of co-localized puncta of LC3-LAMP2 or LC3-cathepsin D, along with dissociated LC3-p62 immunoreactivity following Dex treatment, were observed. These findings were consistent with the results of western blots and the transformation of double-membrane autophagosomes into single-membraned autolysosomes in ultrastructures. It was evident that Dex treatment alleviated impaired autolysosome formation in Aβ mice. Our study demonstrated the improvement of memory impairment caused by Dex and its neuroprotective mechanism by investigating the role of the autophagy-lysosomal pathway in a murine Aβ25–35 model. These findings suggest that Dex could be used as a potential neuroprotective adjuvant in general anesthesia to prevent cognitive decline.</p

DataSheet1_Neuroprotective effect of dexmedetomidine on autophagy in mice administered intracerebroventricular injections of Aβ25–35.PDF

Alzheimer’s disease (AD), one of the most prevalent neurodegenerative diseases is associated with pathological autophagy-lysosomal pathway dysfunction. Dexmedetomidine (Dex) has been suggested as an adjuvant to general anesthesia with advantages in reducing the incidence of postoperative cognitive dysfunction in Dex-treated patients with AD and older individuals. Several studies reported that Dex improved memory; however, evidence on the effects of Dex on neuronal autophagy dysfunction in the AD model is lacking. We hypothesized that Dex administration would have neuroprotective effects by improving pathological autophagy dysfunction in mice that received an intracerebroventricular (i.c.v.) injection of amyloid β-protein fragment 25–35 (Aβ25–35) and in an autophagy-deficient cellular model. In the Y-maze test, Dex reversed the decreased activity of Aβ25–35 mice. Additionally, it restored the levels of two memory-related proteins, phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII) and postsynaptic density-95 (PSD-95) in Aβ25–35 mice and organotypic hippocampal slice culture (OHSC) with Aβ25–35. Dex administration also resulted in decreased expression of the autophagy-related microtubule-associated proteins light chain 3-II (LC3-II), p62, lysosome-associated membrane protein2 (LAMP2), and cathepsin D in Aβ25–35 mice and OHSC with Aβ25–35. Increased numbers of co-localized puncta of LC3-LAMP2 or LC3-cathepsin D, along with dissociated LC3-p62 immunoreactivity following Dex treatment, were observed. These findings were consistent with the results of western blots and the transformation of double-membrane autophagosomes into single-membraned autolysosomes in ultrastructures. It was evident that Dex treatment alleviated impaired autolysosome formation in Aβ mice. Our study demonstrated the improvement of memory impairment caused by Dex and its neuroprotective mechanism by investigating the role of the autophagy-lysosomal pathway in a murine Aβ25–35 model. These findings suggest that Dex could be used as a potential neuroprotective adjuvant in general anesthesia to prevent cognitive decline.</p

Hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer according to fasting glucose level and history of diabetes mellitus (DM) in the Korean Multi-center Cancer Cohort, 1993–2005.

<p>Hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer according to fasting glucose level and history of diabetes mellitus (DM) in the Korean Multi-center Cancer Cohort, 1993–2005.</p

Fasting glucose and risk of colorectal cancer in the Korean Multi-center Cancer Cohort

<div><p>Previous cohort studies have demonstrated a positive association between diabetes mellitus (DM) and colorectal cancer (CRC). However, there are few comparisons between DM groups categorized by fasting glucose level. This study examined associations between diabetes as defined by fasting glucose level and self-reported history of DM and CRC risk among Korean adults. Data from the Korean Multi-center Cancer Cohort between 1993 and 2005 were analyzed. The study population comprised 14,570 participants aged 20 years or older. Participants were followed until December 31, 2012 (median follow-up: 11.9 years). Among participants with high fasting glucose (≥126mg/dL), the risk of developing CRC was significantly higher (HR: 1.51 [1.02–2.25]) than among participants with low fasting glucose (<126mg/dL). Risk was not significantly higher among participants with self-reported history of DM (HR: 1.34 [0.78–2.31]). When both fasting glucose and history of DM were considered together, the risk of CRC among participants with both high fasting glucose and history of DM was 54% (HR: 1.54 [0.97–2.43]), and the risk of CRC among participants with high fasting glucose and no history of DM was 50% (HR: 1.50 [0.73–3.05]). When the first 5 years of follow-up were excluded, among participants with high fasting glucose, the risk of developing CRC was significantly higher (HR: 1.61 [1.02–2.56]) than among participants with low fasting glucose. Risk of CRC was also significantly higher among participants with high fasting glucose and no history of DM (HR: 1.69 [1.01–2.84]). High fasting glucose and self-reported history of DM were associated with increased risk of CRC in this Korean population.</p></div

Diabetes mellitus and risk of colorectal cancer

The Korean Multi-center Cancer Cohort is a population-based prospective cohort study designed to investigate the relationship between exposures to environmental factors, lifestyle factors, and the risk of cancer in Korea. A total of 20,636 participants (8,235 men and 12,401 women) were recruited from six geographic areas of Korea from 1993 to 2005. For these analyses, we excluded participants who had no information on age at cohort recruitment (1,182 men and 1,792 women), whose FSG level information was incomplete or who had no information about history of diabetes mellitus (1,007 men and 1,575 women), who were aged 20 years or younger (156 men and 334 women), who had a prior diagnosis of colorectal cancer (6 men and 13 women), or who were censored within one month from the baseline survey (1 man). After these exclusions, 14,570 participants (5,883 men and 8,687 women) were included in the final analysis. Data were created using SAS software version 9.4 (SAS Institute Inc., Cary, North Carolina, United States)

Hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer according to fasting glucose level and history of diabetes mellitus (DM) after excluding the first 5 years of follow-up in the Korean Multi-center Cancer Cohort, 1993–2005.

<p>Hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer according to fasting glucose level and history of diabetes mellitus (DM) after excluding the first 5 years of follow-up in the Korean Multi-center Cancer Cohort, 1993–2005.</p

General characteristics of the study participants according to history of diabetes mellitus (DM) and fasting glucose levels, Korean Multi-center Cancer Cohort, 1993–2005.

<p>General characteristics of the study participants according to history of diabetes mellitus (DM) and fasting glucose levels, Korean Multi-center Cancer Cohort, 1993–2005.</p

Transcriptomic Analysis of Insulin-Sensitive Tissues from Anti-Diabetic Drug Treated ZDF Rats, a T2DM Animal Model

<div><p>Gene expression changes have been associated with type 2 diabetes mellitus (T2DM); however, the alterations are not fully understood. We investigated the effects of anti-diabetic drugs on gene expression in Zucker diabetic fatty (ZDF) rats using oligonucleotide microarray technology to identify gene expression changes occurring in T2DM. Global gene expression in the pancreas, adipose tissue, skeletal muscle, and liver was profiled from Zucker lean control (ZLC) and anti-diabetic drug treated ZDF rats compared with those in ZDF rats. We showed that anti-diabetic drugs regulate the expression of a large number of genes. We provided a more integrated view of the diabetic changes by examining the gene expression networks. The resulting sub-networks allowed us to identify several biological processes that were significantly enriched by the anti-diabetic drug treatment, including oxidative phosphorylation (OXPHOS), systemic lupus erythematous, and the chemokine signaling pathway. Among them, we found that white adipose tissue from ZDF rats showed decreased expression of a set of OXPHOS genes that were normalized by rosiglitazone treatment accompanied by rescued blood glucose levels. In conclusion, we suggest that alterations in OXPHOS gene expression in white adipose tissue may play a role in the pathogenesis and drug mediated recovery of T2DM through a comprehensive gene expression network study after multi-drug treatment of ZDF rats.</p></div

Effects of anti-diabetic drugs on the oral glucose tolerance test (OGTT) in ZDF rats.

<p>(A) OGTT in diabetic ZDF rat (▪, black squares), normal ZLC rats (□, white squares), rosiglitazone (○, white circles), metformin (◊, white diamonds) and glimepiride (Δ, white triangles)-treated diabetic ZDF rats. (B) The glucose area under the curve (AUC) during the course of the experiments was calculated. * <i>p</i><0.05, ** <i>p</i><0.01.</p

Selected enriched sub-networks.

<p>The color of the pie chart in the node illustrates the proportion of treatment condition and the angle size is the observed frequency of differentially expressed genes (DEGs) for specific drugs in the four tissues. Border color indicates expression patterns. Node shape is tissue type. Enriched pathway: (A) oxidative phosphorylation, (B) chemokine signaling pathway, (C) systemic lupus erythematosus.</p