Synthesis of IB-01212 by multiple N-methylations of peptide bonds.

There are many natural peptides with multiple N-methylamino acids that exhibit potent attractive biological activities. N-methylation of a peptide bond(s) is also one of the standard approaches in medicinal chemistry of bioactive peptides, to improve the potency and physicochemical properties, especially membrane permeability. In this study, we investigated a facile synthesis process of N-methylated peptides via simultaneous N-methylation of several peptide bonds in the presence of peptide bonds that were not to be methylated. As a model study, we investigated the synthesis of the antiproliferative depsipeptide, IB-01212. We used a pseudoproline to protect the non-methylated peptide bond during a simultaneous N-methylation with MeI-Ag[2]O. Using further manipulations including a dimerization/cyclization process, IB-01212 and its derivatives were successfully synthesized. A preliminary structure-activity relationship study demonstrated that the symmetric structure contributed to the potent cytotoxic activity of IB-01212

Bayesian Inference of Absorption Spectra Based on Binomial Distribution

In this paper, we propose a Bayesian spectral deconvolution method for absorption spectra. In conventional analysis, the noise mechanism of absorption spectral data is never considered appropriately. In that analysis, the least-squares method, which assumes Gaussian noise from the perspective of Bayesian statistics, is frequently used. Since Bayesian inference is possible by introducing an appropriate noise model for the data, we consider the absorption process of a single photon to be a Bernoulli trial and develop a Bayesian spectral deconvolution method based on binomial distribution. We have evaluated our method on artificial data under several conditions by numerical experiments. The results show that our method not only allows us to estimate parameters with high accuracy from absorption spectral data, but also to infer them even from absorption spectral data with large absorption rates where the spectral structure is flattened, which was previously impossible to analyze

Synergistic effect of ubiquitin on lipopolysaccharide-induced TNF-α production in murine macrophage cell line RAW 264.7 cells

AbstractUbiquitin synergistically augmented the production of tumor necrosis factor alpha (TNF-α) in the presence of lipopolysaccharide (LPS) in murine macrophage cell line RAW 264.7. To investigate the mechanism of this augmentation, we analyzed the effect of ubiquitin during TNF-α mRNA synthesis and degradation, and TNF-α degradation on RAW 264.7 cells stimulated by LPS. It is found that ubiquitin augmented TNF-α mRNA synthesis. Ubiquitin did not affect the degradation of TNF-α mRNA and TNF-α. In the presence of LPS, extracellular accumulation of TNF-α by ubiquitin was twice than those by LPS, but intracellular accumulation of TNF-α produced by ubiquitin with LPS or by LPS had no difference. These data indicate that ubiquitin might induce TNF-α accumulation mainly by up-regulation of the TNF-α gene transcription. Although extracellular functions of ubiquitin remain largely unknown, we postulate that ubiquitin might be involved in the modulatory mechanisms of immune response

Effects of hydrogen-rich water on abnormalities in a SHR.Cg-Leprcp/NDmcr rat - a metabolic syndrome rat model

<p>Abstract</p> <p>Background</p> <p>Hydrogen (H₂), a potent free radical scavenger, selectively reduces the hydroxyl radical, which is the most cytotoxic of the reactive oxygen species (ROS). An increase in oxygen free radicals induces oxidative stress, which is known to be involved in the development of metabolic syndrome. Therefore, we investigated whether hydrogen-rich water (HRW) affects metabolic abnormalities in the metabolic syndrome rat model, SHR.Cg-<it>Lepr^cp</it>/NDmcr (SHR-cp).</p> <p>Methods</p> <p>Male SHR-cp rats (5 weeks old) were divided into 2 groups: an HRW group was given oral HRW for 16 weeks, and a control group was given distilled water. At the end of the experiment, each rat was placed in a metabolic cage for 24 h, fasted for 12 h, and anesthetized; the blood and kidneys were then collected.</p> <p>Results</p> <p>Sixteen weeks after HRW administration, the water intake and urine flow measured in the metabolic cages were significantly higher in the HRW group than in the control group. The urinary ratio of albumin to creatinine was significantly lower and creatinine clearance was higher in the HRW group than in the control group. After the 12-h fast, plasma urea nitrogen and creatinine in the HRW group were significantly lower than in the control group. The plasma total antioxidant capacity was significantly higher in the HRW group than in the control group. The glomerulosclerosis score for the HRW group was significantly lower than in the control group, and a significantly positive correlation was observed between this score and plasma urea nitrogen levels.</p> <p>Conclusion</p> <p>The present findings suggest that HRW conferred significant benefits against abnormalities in the metabolic syndrome model rats, at least by preventing and ameliorating glomerulosclerosis and creatinine clearance.</p

Blood Pressure-Independent Factors Determine the Susceptibility to Delayed Neuronal Death in the Stroke-Prone Spontaneously Hypertensive Rats.

The stroke-prone spontaneously hypertensive rat (SHRSP) is vulnerable to delayed neuronal death (DND) in the CA1 subfield of the hippocampus after the transient forebrain ischemia by the occlusion of the bilateral carotid arteries. The present study was designed to show that the genetic factors independent of high blood pressure contributed to the high incidence of DND in SHRSP. Male rats of the four strains, SHRSP/Izm, SHRSP/Ngsk, SHR/Izm and a congenic strain for the blood pressure quantitative trait locus on chromosome 1 [SHRSP.WKY-(D1Wox29-D1Arb21)/Izm]were used in the experiments. At 13 weeks of age, the bilateral carotid arteries of rats were occluded for 10 min under anesthesia with their body temperature kept at 37 degrees C. Seven days after the transient ischemia, the loss of the pyramidal cells in the CA1 was evaluated histologically. In some experiments, the blood flow was monitored with a laser Doppler flowmeter during the transient ischemia. The blood pressure in SHRSP/Izm was significantly greater than that in the other three strains. The incidence of DND, however, was not significantly different among SHRSP/Izm, SHRSP/Ngsk and the congenic strain (82, 74 and 65%, respectively), while SHR/Izm showed a significantly lower incidence (20%). Neither a significant correlation between the incidence of DND and the blood flow reduction during the occlusion, nor a significant inter-strain difference in the blood flow reduction was observed. The genetic factors independent of high blood pressure may contribute to the greater susceptibility to DND in SHRSP

A Ruptured Distal Posterior Inferior Cerebellar Aneurysm Our Case and Review of the Literature

We present a case of ruptured distal posterior inferior cerebellar artery (PICA) aneurysm, and review the literature and discuss the treatment strategy. A 77-year-old woman presented with the sudden onset of severe headache, nausea and vomiting. Computed tomography revealed an intraventricular hemorrhage, predominantly in the fourth ventricle and hydrocephalus with a thin subarachinoid hemorrhage (SAH). Angiography revealed an aneurysm arising at the turning point of the vessel, from the telovelotonsillar segment of the right PICA. On the 17 day after the onset, repeated angiography revealed a smaller aneurysm than the one detected on the first day at the same place and with no spasm. On the 22 day, the aneurysm was proved to be partially thrombosed and was safely clipped via a right lateral suboccipital approach. SAH with a fourth ventricular hemorrhage or an isolated fourth ventricle hemorrhage should raise the suspicion of a distal PICA aneurysm. Aneurysms of the distal PICA have often been reported to arise at a turning point of the artery rather than at a junction of the vessel. It is suggested that the pathogenesis could be hemodynamic stress that has developed due to embryological factors. Distal PICA aneurysms have often gone detected in many previous cases because of thrombosis inside the aneurysms. Thus, particularly in the case of intentionally delayed surgery, we recommend repeated angiography under various conditions to identify how the aneurysm develops just before surgery

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) and mixed dementia (MxD) comprise the majority of dementia cases in the growing global aging population. MxD describes the coexistence of AD pathology with vascular pathology, including cerebral small vessel disease (SVD). Cardiovascular disease increases risk for AD and MxD, but mechanistic synergisms between the coexisting pathologies affecting dementia risk, progression and the ultimate clinical manifestations remain elusive. To explore the additive or synergistic interactions between AD and chronic hypertension, we developed a rat model of MxD, produced by breeding APPswe/PS1ΔE9 transgenes into the stroke-prone spontaneously hypertensive rat (SHRSP) background, resulting in the SHRSP/FAD model and three control groups (FAD, SHRSP and non-hypertensive WKY rats, n = 8-11, both sexes, 16-18 months of age). After behavioral testing, rats were euthanized, and tissue assessed for vascular, neuroinflammatory and AD pathology. Hypertension was preserved in the SHRSP/FAD cross. Results showed that SHRSP increased FAD-dependent neuroinflammation (microglia and astrocytes) and tau pathology, but plaque pathology changes were subtle, including fewer plaques with compact cores and slightly reduced plaque burden. Evidence for vascular pathology included a change in the distribution of astrocytic end-foot protein aquaporin-4, normally distributed in microvessels, but in SHRSP/FAD rats largely dissociated from vessels, appearing disorganized or redistributed into neuropil. Other evidence of SVD-like pathology included increased collagen IV staining in cerebral vessels and PECAM1 levels. We identified a plasma biomarker in SHRSP/FAD rats that was the only group to show increased Aqp-4 in plasma exosomes. Evidence of neuron damage in SHRSP/FAD rats included increased caspase-cleaved actin, loss of myelin and reduced calbindin staining in neurons. Further, there were mitochondrial deficits specific to SHRSP/FAD, notably the loss of complex II, accompanying FAD-dependent loss of mitochondrial complex I. Cognitive deficits exhibited by FAD rats were not exacerbated by the introduction of the SHRSP phenotype, nor was the hyperactivity phenotype associated with SHRSP altered by the FAD transgene. This novel rat model of MxD, encompassing an amyloidogenic transgene with a hypertensive phenotype, exhibits several features associated with human vascular or "mixed" dementia and may be a useful tool in delineating the pathophysiology of MxD and development of therapeutics