BACKGROUND: Chemotherapy-induced alimentary mucositis (AM) is difficult to prevent and treatment is rarely effective. Recent study have been showed that glucagon-like peptide (GLP)-1 and GLP-2 has protective in chemotherapy-induced AM. While the DPP-4 enzyme degrades this GLP-1, the DPP-4 inhibitor blocks the degradation process and raises the concentration of GLP-1. This study aimed to assess the role of DPP-4 inhibitor, a well-known hypoglycemic agent, on chemotherapy-induced AM. METHODS: Twenty-four 6-week-old male C57BL/6 mice were divided into 4 groups: control, 5-fluorouracil (5-FU), DPP-4 inhibitor, and saline (DPP-4i), and DPP-4 inhibitor and 5-FU (DPP-4i + 5-FU). Mucositis was induced by intraperitoneal injection of 5-FU (400 mg/kg). DPP-4 inhibitor (50 mg/kg) was administered orally for four days starting the day before 5-FU administration. Post 72 h of 5-FU injection, mice were sacrificed and body weight change, diarrhea score, villus height, villus/crypt ratio, histologic characteristics including goblet cell count, and mRNA expression of inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, were assessed. RESULTS: Daily body weight change was not statistically significant between the 5-FU and the DPP-4i + 5-FU group (P = 0.571). Diarrhea score was significantly different between these two groups (P = 0.033). In the 5-FU group, the villus height was not maintained well, the epithelial lining was irregular, and inflammatory cell infiltration was observed. Goblet cell count in the DPP-4i + 5-FU group was significantly higher than in the 5-FU group (P = 0.007). However, in the DPP-4i + 5-FU group, the villus height, epithelial lining, and crypt structure were better maintained than in the 5-FU group. Compared with the control group, mRNA expression of TNF-alpha was significantly up-regulated in the 5-FU group. Moreover, mRNA expression of TNF-alpha in the DPP-4i + 5-FU group was down-regulated compared to the 5-FU group. However, IL-6 in the 5-FU group was significantly down-regulated compared to the control, there was no significant difference in expression of IL-6 between the 5-FU and DPP4i + 5-FU group. CONCLUSION: DPP-4 inhibitor can improve 5-FU induced AM and, therefore, has potential as an alternative treatment for chemotherapy-induced AM.
BACKGROUND: Transposable elements are major evolutionary forces which can cause new genome structure and species diversification. The role of transposable elements in the expansion of nucleotide-binding and leucine-rich-repeat proteins (NLRs), the major disease-resistance gene families, has been unexplored in plants. RESULTS: We report two high-quality de novo genomes (Capsicum baccatum and C. chinense) and an improved reference genome (C. annuum) for peppers. Dynamic genome rearrangements involving translocations among chromosomes 3, 5, and 9 were detected in comparison between C. baccatum and the two other peppers. The amplification of athila LTR-retrotransposons, members of the gypsy superfamily, led to genome expansion in C. baccatum. In-depth genome-wide comparison of genes and repeats unveiled that the copy numbers of NLRs were greatly increased by LTR-retrotransposon-mediated retroduplication. Moreover, retroduplicated NLRs are abundant across the angiosperms and, in most cases, are lineage-specific. CONCLUSIONS: Our study reveals that retroduplication has played key roles for the massive emergence of NLR genes including functional disease-resistance genes in pepper plants.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 x 10(-20)), ER-negative BC (P=1.1 x 10(-13)), BRCA1-associated BC (P=7.7 x 10(-16)) and triple negative BC (P-diff=2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 x 10(-3)) and ABHD8 (P<2 x 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Title: Treadmill exercise ameliorates short-term memory disturbance in scopolamine-induced amnesia rats Heo YM, Shin MS, Lee JM, Kim CJ, Baek SB, Kim KH, Baek SS Ref: Int Neurourol J, 18:16, 2014 : PubMed
PURPOSE: Scopolamine is a nonselective muscarinic cholinergic receptor antagonist, which induces impairment of learning ability and memory function. Exercise is known to ameliorate brain disturbance induced by brain injuries. In the present study, we investigated the effect of treadmill exercise on short-term memory in relation to acetylcholinesterase (AChE) expression in the hippocampus, using a scopolamine-induced amnesia model in mice. METHODS: To induce amnesia, 1 mg/kg scopolamine hydrobromide was administered intraperitoneally once per day for 14 days. A step-down avoidance test for short-term memory was conducted. AChE histochemistry, immunohistochemistry for collagen IV, and doublecortin were performed. RESULTS: Short-term memory deteriorated in the mice with scopolamine-induced amnesia, concomitant with enhanced AChE expression and suppression of angiogenesis in the hippocampus. Critically, treadmill exercise ameliorated short-term memory impairment, suppressed AChE expression, and enhanced angiogenesis in the mice with scopolamine-induced amnesia. CONCLUSIONS: Overexpression of AChE is implicated in both brain and renal disease. The findings of our study indicate that treadmill exercise may be of therapeutic value in neurodegenerative and renal diseases by suppressing the effects of AChE expression.
In the present study, we determined the draft genome sequence of the entomopathogenic bacterium Serratia liquefaciens FK01, which is highly virulent to the silkworm. The draft genome is ~5.28 Mb in size, and the G+C content is 55.8%.
Title: Butyrylcholinesterase K and Apolipoprotein epsilon4 Affect Cortical Thickness and Neuropsychiatric Symptoms in Alzheimer's Disease Yoo HB, Lee HW, Shin S, Park SW, Choi JS, Jung HY, Cha J, Lee JM, Lee JY Ref: Curr Alzheimer Res, 11:137, 2014 : PubMed
Two major genotypes are known to affect the development and progression of Alzheimer's disease (AD) and its response to cholinesterase inhibitors: the apolipoprotein E (ApoE) and butyrylcholinesterase genes (BChE). This study analyzed the effects of the BChE and ApoE genotypes on the cortical thickness of patients with AD and examined how these genotypes affect the neuropsychiatric symptoms of AD. AD-drug-naive patients who met the probable AD criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association were recruited. Of 96 patients with AD, 65 were eligible for cortical thickness analysis. 3D T1-weighted images were acquired, and the cortical regions were segmented using the constrained Laplacian-based automated segmentation with proximities (CLASP) algorithm. Neuropsychiatric symptoms were measured by Neuropsychiatric Inventory (NPI) scores. BChE wild-type carriers (BChE-W) showed more thinning in the left dorsolateral prefrontal cortex, including the lateral premotor regions and anterior cingulate cortex, than did BChE-K variant carriers (BChE-K). ApoE-epsilon4 carriers had a thinner left medial prefrontal cortex, left superior frontal cortex, and left posterior cingulate cortex than did ApoE-epsilon4 non-carriers. Statistical analyses revealed that BChE-K carriers showed significantly less severe aberrant motor behavioral symptoms and that epsilon4 non-carriers showed less severe anxiety and indifference symptoms. The current findings show that, similar to ApoE-epsilon4 non-carriers, BChE-K carriers are protected from the pathological detriments of AD that affect frontal cortical thickness and neuropsychiatric symptoms. This study visually demonstrated the effects of the BChE-K and ApoE genotypes on the structural degeneration and complex aspects of the symptoms of AD.
OBJECTIVES: The safety and efficacy of early acetylcholinesterase inhibitors therapy in patients with cognitive impairment no dementia (CIND) after a cerebrovascular accident have not been examined. In this study, we investigated the safety and efficacy of rivastigmine in cognition, particularly executive function in patients with CIND because of cerebrovascular disease. METHODS: This study was a 24-week, double-blind, randomized, placebo-controlled trial of ischemic stroke patients seen at a tertiary hospital who had cognitive impairment no dementia because of cerebrovascular disease. The intervention was either rivastigmine or placebo up to 9 mg/day. The primary outcome of interest was mean change from baseline in the Ten-Point Clock Drawing and Color Trails 1 and 2. RESULTS: Fifty patients were randomized into rivastigmine (n = 25) and placebo (n = 25) arms. Patients in the rivastigmine group showed statistically significant improvement (1.70 vs 0.13, P = 0.02) on the animal subtask of the verbal fluency measure compared with placebo. There was also a trend (non-significant) towards improvement in Color Trails II. CONCLUSIONS: In this pilot study, we demonstrated that rivastigmine was well tolerated in patients with CIND because of cerebrovascular disease and may potentially improve executive functioning.
In the continuation of efforts to modify the structure of our novel DP-IV inhibitors, a series of pyrazolidine derivatives with heteroaryl urea was synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV (DP-IV).
Inhibition of dipeptidyl peptidase IV (DPP-IV) activity has been reported to improve nutrient-stimulated insulin secretion through the stabilization of glucagon-like peptide (GLP-1). In the present study, we identified novel DPP-IV inhibitors of pyrazolidine derivatives (Compounds 1 and 2) and characterized their biological effects in vitro and in vivo. Compound 1, an isoleucine pyrazolidide with a phenyl urea group, inhibited rat plasma DPP-IV, porcine kidney DPP-IV, as well as human Caco-2 DPP-IV with IC(50) values of 1.70, 2.26, and 2.02 microM, respectively. Because of the poor pharmacokinetic properties of Compound 1, further optimization was carried out, leading to the discovery of Compound 2, which had similar in vitro activities. Compound 2 acted as a selective and competitive inhibitor of DPP-IV. MALDI-TOF mass spectrometric analysis proved that the compound (20 microM) effectively blocked the degradation of active GLP-1 peptide by 61%. Although similar in in vitro potency, marked improvement of in vivo efficacy and pharmacokinetic properties was seen with Compound 2. Oral administration of Compound 2 resulted in potent and rapid inhibition of circulating DPP-IV in C57BL/6J mice, with ED(50) values of 26mg/kg (s.c.) and 42mg/kg (p.o.). In addition, this compound improved glucose tolerance in ob/ob mice, as determined by an oral glucose tolerance test (OGTT). These results indicate that Compound 2 is a potent and selective DPP-IV inhibitor with oral anti-hyperglycemic activity in vivo.
Title: Naringenin from Citrus junos has an inhibitory effect on acetylcholinesterase and a mitigating effect on amnesia Heo HJ, Kim MJ, Lee JM, Choi SJ, Cho HY, Hong B, Kim HK, Kim E, Shin DH Ref: Dementia & Geriatric Cognitive Disorders, 17:151, 2004 : PubMed
This study was performed to identify safe and more effective acetylcholinesterase (AChE) inhibitors in the treatment of Alzheimer's disease. The total methanol extract of Citrus junos had a significant inhibitory effect on AChE in vitro. By sequential fractionation of C.junos, the active component was finally identified as naringenin. Naringenin inhibited AChE activity in a dose-dependent manner. In this study, we also evaluated the anti-amnesic activity of naringenin, a major flavanone constituent isolated from C. junos, in vivo using ICR mice with amnesia induced by scopolamine (1 mg/kg body weight). Naringenin, when administered to mice at 4.5 mg/kg body weight, significantly ameliorated scopolamine-induced amnesia as measured in both the passive avoidance and the Y-maze test. These results suggest that naringenin may be a useful chemopreventive agent against Alzheimer's disease.
Title: Tactile assessment for the reversibility of rocuronium-induced neuromuscular blockade during propofol or sevoflurane anesthesia Kim KS, Cheong MA, Lee HJ, Lee JM Ref: Anesthesia & Analgesia, 99:1080, 2004 : PubMed
We sought to determine whether tactile train-of-four (TOF) count can predict the efficacy of neostigmine administration for rocuronium-induced blockade during propofol or sevoflurane anesthesia, and to follow subsequent recovery until the TOF ratio reached 0.9. One-hundred-sixty patients, divided into eight equal groups, were randomly allocated to maintenance of anesthesia with propofol or sevoflurane. The tactile response of the adductor pollicis to TOF stimulation was evaluated on one arm, and the mechanomyographic response was recorded on the other. Neuromuscular block was induced with rocuronium 0.6 mg/kg and maintained with rocuronium to 15% of the control first twitch in TOF. Neostigmine 0.07 mg/kg was administered on reappearance of the first (Group I), second (Group II), third (Group III), or fourth (Group IV) tactile TOF response in each anesthesia. At this time, sevoflurane or the propofol dosage was reduced in each group (n = 20 in each group). The times from administration of neostigmine until the TOF ratio recovered to 0.7, 0.8, and 0.9 were recorded. The times [median (range)] to TOF ratio = 0.9 were 8.6 (4.7-18.9), 7.5 (3.4-9.8), 5.4 (1.6-8.6), and 4.7 (1.3-7.2) min in Groups I-IV during propofol anesthesia, respectively, and 28.6 (8.8-75.8), 22.6 (8.3-57.4), 15.6 (7.3-43.9), and 9.7 (5.1-26.4) min in corresponding groups during sevoflurane anesthesia, respectively (P < 0.0001). We recommend more than 2 TOF responses with propofol anesthesia and 4 TOF responses with sevoflurane anesthesia for adequate reversal within 10 and 15 min, respectively. The more tactile TOF responses present at the time of reversal achieved greater adequate recovery; however, tactile TOF responses are not a completely reliable predictor within a reasonable time period.
Functional analysis of a genome requires accurate gene structure information and a complete gene inventory. A dual experimental strategy was used to verify and correct the initial genome sequence annotation of the reference plant Arabidopsis. Sequencing full-length cDNAs and hybridizations using RNA populations from various tissues to a set of high-density oligonucleotide arrays spanning the entire genome allowed the accurate annotation of thousands of gene structures. We identified 5817 novel transcription units, including a substantial amount of antisense gene transcription, and 40 genes within the genetically defined centromeres. This approach resulted in completion of approximately 30% of the Arabidopsis ORFeome as a resource for global functional experimentation of the plant proteome.
High molecular weight glycosaminoglycans GAG and proteoglycans PG affect pathological changes of the brain in Alzheimer's disease AD PG stimulate the processing and aggregation of amyloid-beta Abeta protect the protein from proteolysis and increase the formation of neurofibrillary tangles by inducing the hyperphosphorylation of tau protein These effects may be competitively inhibited by GAG.We have studied the effects of orally by gavage and subcutaneously s.c administered low molecular weight heparin C3 4-10 oligosaccharides MW 2.1 kDa USP value 12 U/mg on abnormal tau-2 protein immunoreactivity in the rat hippocampus following a single unilateral intra-amygdaloid administration of Abeta(25-35 Oral administration of C3 25 mg/kg once daily was initiated 3 days prior to Abeta(25-35 administration and was continued daily for an additional 14 days S.c administration of C3 2.5 mg/kg twice daily was started 3 days prior to and was continued for 32 days after Abeta(25-35 administration Animal brains were subsequently processed for tau-2 ChAT-immunoreactivity choline acetyltransferase ChAT activity and acetylcholinesterase AChE activity Both oral and s.c administration of C3 attenuated Abeta(25-35 induced appearance of tau-2-immunoreactive IR perikarya in the ipsilateral hippocampus P 0.05 Hippocampal cholinergic enzyme activity in C3 treated animals was not significantly different from control animals.The present findings suggest that C3 might be used successfully to prevent abnormal tau protein formation in chronic neurologic diseases such as AD Moreover our data demonstrate that the mechanism of this effect does not appear to influence the cholinergic system of the brain
The genome of the flowering plant Arabidopsis thaliana has five chromosomes. Here we report the sequence of the largest, chromosome 1, in two contigs of around 14.2 and 14.6 megabases. The contigs extend from the telomeres to the centromeric borders, regions rich in transposons, retrotransposons and repetitive elements such as the 180-base-pair repeat. The chromosome represents 25% of the genome and contains about 6,850 open reading frames, 236 transfer RNAs (tRNAs) and 12 small nuclear RNAs. There are two clusters of tRNA genes at different places on the chromosome. One consists of 27 tRNA(Pro) genes and the other contains 27 tandem repeats of tRNA(Tyr)-tRNA(Tyr)-tRNA(Ser) genes. Chromosome 1 contains about 300 gene families with clustered duplications. There are also many repeat elements, representing 8% of the sequence.
Title: Cloning and nucleotide sequence of the beta-galactosidase gene from Lactococcus lactis ssp. lactis ATCC7962. Lee JM, Chung DK, Park JH, Lee WK, Chang HC, Kim JH, Lee HJ Ref: Biotechnol Lett, 19:179, 1997 : PubMed
Title: Differential effects of ethanol on the striatal and cortical adenylate cyclase system Saito T, Luthin GR, Lee JM, Hoffman PL, Tabakoff B Ref: Japanese Journal of Pharmacology, 43:133, 1987 : PubMed
In the present study, effects of ethanol (EtOH) on C57/BL mouse cortical beta-adrenergic receptor coupled adenylate cyclase (AC) were shown to be different from the effects of EtOH on striatal dopaminergic-stimulated AC activity. The addition of EtOH (500 mM) increased the AC activity by 60% in cortical membrane and by less than 10% in striatal membrane preparations in the absence of guanine nucleotide. The dose-response relationship for EtOH stimulation of cortical AC activity in the presence of guanylylimidodiphosphate (Gpp(NH)p) was biphasic, whereas, in the striatum, a linear dose-response relationship for EtOH was found for stimulation of AC in the presence of Gpp(NH)p. Activation of AC by Gpp(NH)p occurred as an apparent pseudo-first order process. EtOH increased the pseudo-first order rate constant for activation of AC by Gpp(NH)p in the cortex, but not in the striatum. Following 10 min preincubation with Gpp(NH)p, catecholamines and Gpp(NH)p were not able to stimulate further the AC activities in either tissue. Nevertheless, EtOH increased AC activity in both cortex and striatum following the preincubation with Gpp(NH)p. These data suggest that one effect of EtOH in striatal tissue is to promote the interaction of an activated guanine nucleotide-binding regulatory protein (G-protein) with the catalytic unit of AC. In cortical tissue, the effects of EtOH may be attributable to direct actions on the catalytic activity of the enzyme, effects on the rate of activation of the G-protein, and an altered interaction of G-protein with the catalytic unit.
Title: Differential effects of ethanol on striatal and cortical adenylate cyclase Tabakoff B, Luthin GR, Saito T, Lee JM Ref: Psychopharmacol Bull, 20:481, 1984 : PubMed
