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The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.

We reform to group IT literacy education classes for freshmen and survey the effect by questionnaire in Saitama Campus from 2008 to 2013. The purpose of the reform was to improve degree of both their understanding and satisfaction. Our survey reveals that the reform influences the level of students’ satisfaction in the college of cross-cultural communication and business.

São apresentados nesta tese os resultados dos estudos visando a síntese total assimétrica do populeno D, um produto natural extraído do troco da árvore Thespesia populnea. A proposta sintética era obter a molécula alvo em 14 etapas, entretanto, não foi possível finalizar a síntese. Foi obtido o último intermediário da síntese em 13 etapas em um rendimento global de 8%, a partir do L-lactato de etila, comercialmente disponível. A rota sintética proposta tem como etapa chave uma reação de ciclização de Prins catalisada por iodo molecular. Tal metodologia foi utilizada para sintetizar quatro análogos do populeno D, compostos inéditos que foram caracterizados e enviados para ensaios de atividade biológica. Dois destes quatro compostos apresentaram bons resultados contra linhagens celulares do ovário com fenótipo de resistência a múltiplos fármacos. Apresenta-se também uma metodologia de meta-alquilação de N-aril-2- aminopirimidinas com haletos secundários catalisada por rutênio. No total, foram obtidos vinte compostos inéditos que foram completamente caracterizados. Studies aiming the asymmetric total synthesis of populene D are presented in this thesis. Populene D is a natural product extracted from Thespesia populnea tree trunk. Synthetic proposal for the target molecule comprised 14 steps, however, total synthesis was not achieved. Last intermediate of the proposed route was obtained, in 13 steps and 8% global yield, starting from commercially available ethyl L-lactate. An iodine-catalyzed Prins cyclization reaction is the key step of proposed synthesis. This methodology was applied to synthesize four analogues of populene D, all unknown compounds which were fully characterized, and submitted to biological activity tests. Among these four compounds, two of them have shown good results against ovary cell lines with with multidrug resistance phenotype. A new protocol of ruthenium-catalyzed site-selective alkylation of N-aryl-2- aminopyrimidines is also presented in this thesis. 20 unknown compounds were obtained using this protocol and they were fully characterized as well.

The aim of this study was to examine whether metformin, a biguanide anti-hyperglycemic drug, dilates retinal blood vessels in rats. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo and diameters of retinal blood vessels were measured. Both systemic blood pressure and heart rate were continuously recorded. Metformin (0.01-0.3mg/kg/min) increased diameters of retinal blood vessels in a dose-dependent manner. This retinal vasodilator effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase. Similar results were obtained with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR, 0.01-1mg/kg/min). Neither metformin nor AICAR exerted significant effect on mean blood pressure and heart rate. However, a significant pressor response to AICAR was observed upon inhibition of NO synthase. These results suggest that metformin dilates retinal blood vessels through activation of AMPK, and NO plays an important role in the retinal vasodilator response following AMPK activation.

Background : Porphyromonas gulae are black-pigmented anaerobic bacteria isolated from the gingival sulcus of various animal hosts and are distinct from Porphyromonas gingivalis originating in humans. We previously reported the antigenic similarities of 41-kDa fimbriae between P. gulae ATCC 51700 and P. gingivalis ATCC 33277. In this study, to clarify the presence of another type of fimbriae of P. gulae , we have purified and characterized the secondary fimbrial protein from P. gulae ATCC 51700. Methods : The secondary fimbrial protein was purified from P. gulae ATCC 51700 using an immunoaffinity column coupling with antibodies against the 41-kDa fimbrial protein. The expression of fimbriae on the cell surface of P. gulae ATCC 51700 was investigated by transmission electron microscopy. The N -terminal amino acid sequence was determined by an amino acid sequencer system. Results : The molecular mass of this protein was approximately 53-kDa, as estimated by SDS-PAGE. The polyclonal antibodies against the 53-kDa protein did not react with the 41-kDa fimbrial protein of P. gulae ATCC 51700. Immunogold electron microscopy revealed that anti-53-kDa fimbrial serum bound to fimbria on the cell surface of P. gulae ATCC 51700. The amino acid sequence of the N -terminal 15 residues of the 53-kDa fimbrial protein showed only 1 of 15 residues identical to the 41-kDa fimbrial protein . Conclusion: The 53-kDa fimbriae are different in molecular weight and antigenicity from the 41-kDa fimbrial protein of P. gulae ATCC 51700. These results clearly suggest that the 41-kDa and the 53-kDa fimbriae are distinct types of fimbriae expressed simultaneously by this organism. Keywords : Porphyromonas gulae; Porphyromonas gingivalis; periodontal disease; purification; fimbriae; 53-kDa protein; oral microbiology (Published: 20 September 2012) Citation: Journal of Oral Microbiology 2012, 4 : 19076 - http://dx.doi.org/10.3402/jom.v4i0.19076

Intra-arterial high-dose cisplatin chemoradiation (CRT-IA) with sodium thiosulfate (STS) causes relatively less severe cisplatin ototoxicity than intravenous cisplatin chemoradiation without STS (CRT-IV). The results of this study also suggest that early detection of ototoxicity is possible by testing the hearing loss at ultra-high frequencies.To investigate protective effects of STS against cisplatin ototoxicity.Between 2011 and 2013, 18 patients with head and neck carcinomas were treated with intra-arterial infusions of high-dose cisplatin (range 100-180 mg/body, mean 111 mg/body; range 2-5 courses, mean 3.6 courses) and systemic administration of cisplatin (range 66-185 mg/body, mean 130 mg/body; range 1-3 courses, mean 2.6 courses) and concurrent radiation therapy (range 60-70 Gy, mean 69 Gy). Cisplatin was neutralized by STS in CRT-IA but not in CRT-IV.Intra-arterial infusion in the high-dose cisplatin group caused significant hearing loss at ultra-high frequencies of 10 and 12 kHz (p = 0.028, 0.039, respectively), whereas the group receiving systemic administration of cisplatin had significant hearing loss at high frequencies of 8 and 10 kHz (p = 0.016, 0.027, respectively).

Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a role in esophageal function. However, the distribution of TRPV1 nerve fibers in the esophagus is currently not well understood. In the present study, we investigated the distribution of TRPV1 and neurotransmitters released from TRPV1 nerve fibers in the mouse lower esophagus. Furthermore, we investigated changes in the presence of TRPV1 in the mouse model of esophagitis. Numerous TRPV1-immunoreactive nerve fibers were seen in both the submucosal layer and myenteric plexus of the lower esophagus and colocalized with calcitonin gene-related peptide (CGRP). TRPV1 colocalized with substance P in axons in the submucosal layer and myenteric plexus. TRPV1 colocalized with neuronal nitric oxide synthase in the myenteric plexus. We observed some colocalization of CGRP with the vesicular acetylcholine (ACh) transporter, packaging of ACh into synaptic vesicles after its synthesis in terminal cytoplasm, in the submucosal layer and myenteric plexus. In the esophagitis model, the number of the TRPV1 nerve fibers did not change, but their immunoreactive intensity increased compared with sham-operated mice. Inhibitory effect of exogenous capsaicin on electrically stimulated twitch contraction significantly increased in esophagitis model compared with the effect in sham-operated mice. Overall, these results suggest that TRPV1 nerve fibers projecting to both the submucosal and muscle layer of the esophagus are extrinsic spinal and vagal afferent neurons. Furthermore, TRPV1 nerve fibers contain CGRP, substance P, nitric oxide, and ACh. Therefore, acid influx-mediated TRPV1 activation may play a role in regulating esophageal relaxation.

Incubation of rat thymocytes with the inhibitors of protein phosphatase such as calyculin A and okadaic acid resulted in an increase in DNA fragmentation. These effects were dependent on the concentration of the inhibitors and the incubation time. Analyses of the fragmented DNA revealed the production of approximately 50 kbp of DNA and a 180 bp DNA ladder. In addition, a laser scanning-microscopic analysis showed that these compounds caused nuclear condensation. Thus, these results demonstrated that protein phosphatase inhibitors induced thymocyte apoptosis. The inhibitors of protein phosphatase increased the phosphorylation of proteins of approximately 15 kDa. The phosphorylation of proteins preceded the DNA fragmentation induced by these inhibitors. Judging from acetic acid-urea-Triton X-100 gel electrophoresis, the phosphorylated proteins were histone H1 and H2A/H3. Therefore, these results suggest that phosphorylation of histones triggers the DNA fragmentation of thymocytes undergoing apoptosis.

Bacteroides gingivalis were serologically investigated by the immunodiffusion technique using autoclave-extracted antigens and antisera against whole cells. Fifteen strains of B. gingivalis used in this study, were classified in two distinct serological groups. Eleven strains include strain 381, ATCC 33277 were classified Group A and four strains include strain Su63 were classified in Group B. The group specific antigens from B. gingivalis strain 381 (Group A) and Su63 (Group B) were partially purified from autoclave extracts by 75% ethanol precipitation and anion exchange chromatography, and were identified as polysaccharides composed of glucose (82.3%, 23.7%), rhamnose (7.1%, 12.7%), galactose (4.9%, 18.2%), mannose (2.3%, 1.7%), glucosamine (0.4%, 28.0%) and galactosamine (3.0%, 15.3%).

Shared Prosperity through Inclusive Business: How Successful Companies Reach the Base of the Pyramid summarizes the practical lessons learned from IFC clients that successfully reach low-income people as suppliers or customers. There are lessons for each phase of the value chain—including procurement, product development, distribution and retail, and marketing and sales. The lessons—each of them illustrated with a profile of an IFC client—can also be adapted to the context of a particular sector or region.