RacGAP α2-Chimaerin Function in Development Adjusts Cognitive Ability in Adulthood

SummaryA major concern in neuroscience is how cognitive ability in adulthood is affected and regulated by developmental mechanisms. The molecular bases of cognitive development are not well understood. We provide evidence for the involvement of the α2 isoform of Rac-specific guanosine triphosphatase (GTPase)-activating protein (RacGAP) α-chimaerin (chimerin) in this process. We generated and analyzed mice with global and conditional knockouts of α-chimaerin and its isoforms (α1-chimaerin and α2-chimaerin) and found that α-chimaerin plays a wide variety of roles in brain function and that the roles of α1-chimaerin and α2-chimaerin are distinct. Deletion of α2-chimaerin, but not α1-chimaerin, beginning during early development results in an increase in contextual fear learning in adult mice, whereas learning is not altered when α2-chimaerin is deleted only in adulthood. Our findings suggest that α2-chimaerin acts during development to establish normal cognitive ability in adulthood

Advanced neoplasms after colonoscopy

This retrospective study aimed to clarify the clinical characteristics of advanced colorectal neoplasms after colonoscopy, likely to have been missed on the previous colonoscopy. We reviewed a total of 5,768 consecutive colonoscopies performed from April 2010 to September 2013 in 4,841 patients, and analyzed advanced colorectal neoplasms after colonoscopy, particularly focusing on their morphological characteristics and locations, as compared with primary lesions, defined as lesions detected in their first colonoscopy or in a subsequent colonoscopy >5 years after the previous one. Of the 5,768 examinations, 922 advanced neoplasms (including 217 cancers with≥T2) were detected, and 167 lesions (18.1%) were diagnosed within 5 years after a previous colonoscopy (post-colonoscopy advanced neoplasms). The incidence of right-sided lesions in the post-colonoscopy advanced neoplasms (48.5%, 81/167) was significantly higher than in the primary lesions (34.0%, 257/755 ; p<0.001). We excluded 217 cancers with≥T2 from the morphological analysis to characterize early-stage post-colonoscopy advanced neoplasms. The incidence of non-polypoid lesions in the post-colonoscopy advanced neoplasms (25.6%, 41/160) was significantly higher than that in the primary lesions (12.3%, 67/545 ; p<0.001). These findings suggest that extra attention should be paid to non-polypoid, right-sided advanced colorectal neoplasms during screening and surveillance colonoscopy

Neoadjuvant hormonal therapy for low-risk prostate cancer induces biochemical recurrence after radical prostatectomy via increased lymphangiogenesis-related parameters

Background: The effects of neoadjuvant hormonal therapy (NHT) on pathological features and lymphangiogenesis in patients with prostate cancer (PCa) for each pre-operative risk classification are unclear. Methods: To clarify the anti-cancer effects of NHT, we investigated 153 patients (non-NHT group?=?80 and NHT group?=?73) who underwent radical prostatectomy (RP) in Nagasaki University Hospital. Lymph vessel density and area (evaluated by D2-40-positive vessels), vascular endothelial growth factor (VEGF)-C and VEGF-D expressions, and biochemical recurrence (BCR)-free survival were compared between these two groups for each D\u27Amico risk classification (low?=?33, intermediate?=?58, high?=?62 patients). Results: In low-risk PCa patients, the risks of lymph vessel invasion and BCR were significantly higher in the NHT group than in the non-NHT group (P?=?0.040 and 0.022, respectively). Such significant difference was not seen in the intermediate- or high-risk PCa groups. Lymph vessel density of the peri-tumoral and intra-tumoral areas and the lymph vessel area were significantly higher (P?<?0.001) in the NHT group than in the non-NHT group in low-risk PCa. In regard to the expression of VEGF-C or VEGF-D, significant difference was not detected in low-risk PCa. Conclusions: NHT stimulated cancer cell progression and BCR via up-regulation of lymphangiogenesis-related parameters in patients with low-risk PCa. Although VEGF-C and VEGF-D expressions were not changed by NHT, lymph vessel density and area were increased in low-risk PCa patients. We suggest that NHT for patients with low-risk PCa may have a high risk for BCR after RP

Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors

Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity

イモチ病菌の分生胞子の発芽による附着器の形成とその病理学的意義について(農学部門)

1)イモチ病菌の分生胞子発芽による附着器の形成はツアペック培地(寒天6%)に於て形としては不完全なものであるが, 24時間培養でわずかに認められた。2)晩神力及びテテップの成長葉に於て24&acd;36時間後では前者の方が後者より附着器の形成がよく, イモチ病菌に対するイネの抵抗性に関係があるものと思われる。又最高分蘗期頃の成長葉では36時間後でも形成率は上昇の傾向が見られる。一方農林1号の苗葉上ではスライドグラス面上の附着器形成率と大体一致していて成長葉より良好である。3)附着器形成の最適温度は24&acd;28℃(90%以上の形成率)で, 最低温度は12&acd;14.5℃, 最高温度は36℃附近である。発芽の最適温度は附着器形成のそれよりもかなり温度範囲が広い。発芽は8時間後, 附着器形成は18時間後に於て90%以上の高率を示した。4)附着器は菌糸よりもリオゲン及び三共ボルドウに対して耐久性が大であつた。リオゲンでは附着器の生存限界は稀釈濃度400倍(倍量濃度)50分であるが, 三共ボルドウに対しては150倍(倍量濃度)60分間でも生存していた。5)58&acd;60℃の熱に対する附着器の耐久力は菌糸と同様乾熱よりも湿熱に対して小さい。前者では60分, 後者では10分が生存限界である。6)附着器の大さは7.8&acd;10.7×6.8&acd;12.3μ(硝子面上観察)で長さと巾との間に正の相関関係(相関係数0.684)がある。附着器形成率の良好な温度でも26℃に於ては附着器の大きさは大きく, 温度と附着器との間には有意差がある。胞子とそれから形成される附着器の大きさの間には低い相関(相関係数0.158)がある。1. The formation of appressorium, though imperfect in shape and scanty in number, was observed when the conidia of rice blast fungus, Piricularia oryzae, were allowed to germinate on CZAPEK medium containing 6% agar for 24 hours. 2. On the matured leaves of rice varieties "Late Shinriki" and "Tetep" there was more formation of appressorium on the former variety than on the latter. This was considered grade of varietal resistance to blast fungus. On such matured leaves in the peak tillering stage, there was a rising tendency in the percentage of appressorium formation even after 30 hours. While on seedling leaves of "Norin No. 1" variety, the percentage of appressorium formed nearly coincided with that on slide glasses, which was greater than that on matured leaves. 3. The optimum, minimum and maximum temperatures for the formation of appressorium (over 90% of germinated spores to form appressorium) was 24-28℃, 12-14.5℃ and near 36℃, respectively. The range of optimum temperature for spore germination is moderately wider than that for appressorium formation. Spore germination after 8 hours and appressorium formation after 18 hours both showed high percentages of over 90%. 4. The appressorium of the rice blast fungus showed a striking resistability to fungicides Liogen (organic mercurial) and Sankyo Bordeaux. The limit in the concentration for the appressorium to survive Liogen was immersion in 1/400 dilution for a period of 50 minutes (twice the concentration recommended for general use), but that for Sankyo Bordeaux it was much greater as the fungus was still alive after 60 minutes in 1/150 dilution (twice the recommended concentration for general practical use). 5. The thermal tolerance of appressorium and mycelium of rice blast fungus at 58-60℃ was less in wet heat than in dry heat, namely, its limits were 10 minutes for the former and 60 minutes for the latter. 6. The size of appressorium of rice blast fungus formed on the glass surface measured 7.8-10.7×8.6-12.3μ, and there was a positive correlation (correlation coefficient : 0.684) between the length and the width of appressorium. Within a favorable temperature range for appressorium formation, the size of appressorium of blast fungus was larger at 26℃, and there was a significant difference between size of appressorium and cultural temperature. Between size of spore and appressorium formed, there was a lower positive correlation (correlation coefficient : 0.158)

C57BL/KsJ-db/db-ApcMin/+ Mice Exhibit an Increased Incidence of Intestinal Neoplasms

The numbers of obese people and diabetic patients are ever increasing. Obesity and diabetes are high-risk conditions for chronic diseases, including certain types of cancer, such as colorectal cancer (CRC). The aim of this study was to develop a novel animal model in order to clarify the pathobiology of CRC development in obese and diabetic patients. We developed an animal model of obesity and colorectal cancer by breeding the C57BL/KsJ-db/db (db/db) mouse, an animal model of obesity and type II diabetes, and the C57BL/6J-ApcMin/+ (Min/+) mouse, a model of familial adenomatous polyposis. At 15 weeks of age, the N9 backcross generation of C57BL/KsJ-db/db-ApcMin/+ (db/db-Min/+) mice developed an increased incidence and multiplicity of adenomas in the intestinal tract when compared to the db/m-Min/+ and m/m-Min/+ mice. Blood biochemical profile showed significant increases in insulin (8.3-fold to 11.7-fold), cholesterol (1.2-fold to 1.7-fold), and triglyceride (1.2-fold to 1.3-fold) in the db/db-Min/+ mice, when compared to those of the db/m-Min/+ and m/m-Min/+ mice. Increases (1.4-fold to 2.6-fold) in RNA levels of insulin-like growth factor (IGF)-1, IRF-1R, and IGF-2 were also observed in the db/db- Min/+ mice. These results suggested that the IGFs, as well as hyperlipidemia and hyperinsulinemia, promoted adenoma formation in the db/db-Min/+ mice. Our results thus suggested that the db/db-Min/+ mice should be invaluable for studies on the pathogenesis of CRC in obese and diabetes patients and the therapy and prevention of CRC in these patients

Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis

Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals

Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice

<p>Abstract</p> <p>Background</p> <p>Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-<it>db/db </it>(<it>db/db</it>) obese mice.</p> <p>Methods</p> <p>Male <it>db/db </it>mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.</p> <p>Results</p> <p>At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of <it>TNF-α </it>and <it>interleukin-6 </it>mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.</p> <p>Conclusions</p> <p>Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.</p

Chronic Kidney Disease, Gut Dysbiosis, and Constipation: A Burdensome Triplet

Gut dysbiosis has been implicated in the progression of chronic kidney disease (CKD). Alterations in the gut environment induced by uremic toxins, the dietary restriction of fiber-rich foods, and multiple drugs may be involved in CKD-related gut dysbiosis. CKD-related gut dysbiosis is considered to be characterized by the expansion of bacterial species producing precursors of harmful uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, and the contraction of species generating beneficial short-chain fatty acids, such as butyrate. Gut-derived uremic toxins cause oxidative stress and pro-inflammatory responses, whereas butyrate exerts anti-inflammatory effects and contributes to gut epithelial integrity. Gut dysbiosis is associated with the disruption of the gut epithelial barrier, which leads to the translocation of endotoxins. Research on CKD-related gut dysbiosis has mainly focused on chronic inflammation and consequent cardiovascular and renal damage. The pathogenic relationship between CKD-related gut dysbiosis and constipation has not yet been investigated in detail. Constipation is highly prevalent in CKD and affects the quality of life of these patients. Under the pathophysiological state of gut dysbiosis, altered bacterial fermentation products may play a prominent role in intestinal dysmotility. In this review, we outline the factors contributing to constipation, such as the gut microbiota and bacterial fermentation; introduce recent findings on the pathogenic link between CKD-related gut dysbiosis and constipation; and discuss potential interventions. This pathogenic link needs to be elucidated in more detail and may contribute to the development of novel treatment options not only for constipation, but also cardiovascular disease in CKD