Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2

Understanding mechanisms that contribute to the regression of glomerulosclerosis is important for developing new strategies to treat chronic kidney disease. We reported that transient high-dose treatment with an angiotensin receptor blocker causes regression of renal arteriolar hypertrophy and hypertension in spontaneously hypertensive rats. To extend those findings to another form of kidney disease, we examined the short- and long-term effects of transient high-dose angiotensin receptor blocker treatment in a mouse model of adriamycin-induced glomerulosclerosis. A 2-week course of candesartan caused a dose-dependent regression of established glomerulosclerotic lesions sustained for over 6 months following cessation of treatment. Highly sensitive in situ zymography and activity assays showed that glomerular matrix metalloproteinase (MMP)-2 activity was increased after high-dose angiotensin blocker therapy. Treatment of cultured podocytes with candesartan resulted in an increase in MMP-2 activity. The regression of glomerulosclerosis was partially attenuated in mice pretreated with the MMP inhibitor doxycycline, as well as in MMP-2 knockout mice. Our results suggest that transient high-dose angiotensin receptor blocker treatment effectively induced sustained regression of glomerulosclerosis by a mechanism mediated, in part, by changes in MMP-2 activity

A Model for the 3He(\vec d, p)4He Reaction at Intermediate Energies

Polarization correlation coefficients have been measured atRIKEN for the \vec 3He(\vec d,p)4He reaction at intermediate energies. We propose a model for the (\vec d, p) reaction mechanism using the pd elastic scattering amplitude which is rigorously determined by a Faddeev calculation and using modern NN forces. Our theoretical predictions for deuteron polarization observables A_y, A_{yy}, A_{xx} and A_{xz} at E_d=140, 200 and 270 MeV agree qualitatively in shape with the experimental data for the reaction 3He(\vec d,p)4He.Comment: 6 pages, 11 figures, 1 table, reference: http://www.phys.ntu.edu.tw/english/fb16/contribution/topic4/Uesaka_Tomohiro1. ps in Contribution for the XVIth IUPAP International Conference on Few-Body Problems in Physics, (Taipei, Taiwan 6-11, March 2000

Optimized Method of Extracting Rice Chloroplast DNA for High-Quality Plastome Resequencing and de Novo Assembly

Chloroplasts, which perform photosynthesis, are one of the most important organelles in green plants and algae. Chloroplasts maintain an independent genome that includes important genes encoding their photosynthetic machinery and various housekeeping functions. Owing to its non-recombinant nature, low mutation rates, and uniparental inheritance, the chloroplast genome (plastome) can give insights into plant evolution and ecology and in the development of biotechnological and breeding applications. However, efficient methods to obtain high-quality chloroplast DNA (cpDNA) are currently not available, impeding powerful sequencing and further functional genomics research. To investigate effects on rice chloroplast genome quality, we compared cpDNA extraction by three extraction protocols: liquid nitrogen coupled with sucrose density gradient centrifugation, high-salt buffer, and Percoll gradient centrifugation. The liquid nitrogen–sucrose gradient method gave a high yield of high-quality cpDNA with reliable purity. The cpDNA isolated by this technique was evaluated, resequenced, and assembled de novo to build a robust framework for genomic and genetic studies. Comparison of this high-purity cpDNA with total DNAs revealed the read coverage of the sequenced regions; next-generation sequencing data showed that the high-quality cpDNA eliminated noise derived from contamination by nuclear and mitochondrial DNA, which frequently occurs in total DNA. The assembly process produced highly accurate, long contigs. We summarize the extent to which this improved method of isolating cpDNA from rice can provide practical progress in overcoming challenges related to chloroplast genomes and in further exploring the development of new sequencing technologies

Usefulness of percutaneous estradiol-loaded PLGA-PEG-PLGA nanoparticles for the treatment of osteoporosis

Compared with poly (dl-lactide-co-glycolide) (PLGA) nanoparticles, triblock copolymer (PLGA-PEG-PLGA) nanoparticles composed of PLGA and polyethylene glycol (PEG) may improve the skin permeability of drugs. In this study, the usefulness of estradiol-loaded (E2-loaded) PLGA-PEG-PLGA nanoparticles in the treatment of osteoporosis was investigated by comparison with E2-loaded PLGA nanoparticles. The cumulative E2 permeation of each nanoparticle through rat skin was quantified using a Franz cell. The results showed that PLGA-PEG-PLGA nanoparticles had significantly higher permeation than PLGA nanoparticles. Next, in vivo treatment experiments were conducted using an ovariectomized rat model of osteoporosis. Nanoparticles were administered once per week in combination with iontophoresis. At 6 weeks after the initiation of treatment, significant improvement in bone density was observed in the treated group compared with the untreated group. The improvement in bone density tended to be greater in the PLGA-PEG-PLGA nanoparticle group versus the PLGA nanoparticle group. This may be attributed to the higher hydrophilicity of the particle surface of PLGA-PEG-PLGA nanoparticles compared with PLGA nanoparticles and the improved skin permeability of the particles through the trans-adnexal pathway

Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model

AbstractAnticholinergics, and drugs with anticholinergic properties, are widely and frequently prescribed, especially to the elderly. It is well known that these drugs decrease cognitive function and increase the risk of dementia. Although the mechanism of anticholinergic drug-induced cognitive impairment has been assumed to be functionally reduced acetylcholine (ACh) neurotransmission, some data have indicated that anticholinergics might enhance the pathology of Alzheimer's disease. In this study, we investigated the pathological effects of anticholinergics on neurodegeneration. We chronically administered two anticholinergics, trihexyphenidyl (TP) and propiverine (PP) (the latter with less central anticholinergic action), to neurodegenerative tauopathy model mice 2 to 10months old. Furthermore, because the ACh nervous system regulates both central and peripheral inflammation, we administered TP or PP to PS19 mice in which we had artificially induced inflammation by lipopolysaccharide injection. Tau pathology, synaptic loss, and neurodegeneration in the hippocampal region, as well as tau insolubility and phosphorylation, were markedly increased in TP-treated mice and mildly increased in PP-treated mice. Furthermore, immunohistochemical analysis revealed microglial proliferation and activation. Moreover, anticholinergics increased interleukin-1β expression in both the spleen and brain of the tauopathy model mice intraperitoneally injected with lipopolysaccharide to induce systemic inflammation. Interestingly, these alterations were more strongly observed in TP-treated mice than in PP-treated mice, consistent with the level of central anticholinergic action. Anticholinergic drugs not only impair cognitive function by decreased ACh neurotransmission, but also accelerate neurodegeneration by suppressing an ACh-dependent anti-inflammatory system. Anticholinergics should be less readily prescribed to reduce the risk of dementia