Gut Bacterial Species Distinctively Impact Host Purine Metabolites during Aging in Drosophila.

Gut microbiota impacts the host metabolome and affects its health span. How bacterial species in the gut influence age-dependent metabolic alteration has not been elucidated. Here we show in Drosophila melanogaster that allantoin, an end product of purine metabolism, is increased during aging in a microbiota-dependent manner. Allantoin levels are low in young flies but are commonly elevated upon lifespan-shortening dietary manipulations such as high-purine, high-sugar, or high-yeast feeding. Removing Acetobacter persici in the Drosophila microbiome attenuated age-dependent allantoin increase. Mono-association with A. persici, but not with Lactobacillus plantarum, increased allantoin in aged flies. A. persici increased allantoin via activation of innate immune signaling IMD pathway in the renal tubules. On the other hand, analysis of bacteria-conditioned diets revealed that L. plantarum can decrease allantoin by reducing purines in the diet. These data together demonstrate species-specific regulations of host purine levels by the gut microbiome.

Local Necrotic Cells Trigger Systemic Immune Activation via Gut Microbiome Dysbiosis in Drosophila.

Necrotic cells elicit an inflammatory response through their endogenous factors with damage-associated molecular patterns. Blocking apoptosis in Drosophila wings leads to the necrosis-driven systemic immune response by unknown mechanisms. Here, we demonstrate that immune activation in response to necrotic cells is mediated by commensal gut microbiota. Removing the microbiome attenuates hyperactivation of the innate immune signaling IMD pathway in necrosis-induced flies. Necrotic cells in wings trigger Gluconobacter expansion in the gut. An isolated Gluconobacter sp. strain is sufficient for pathological IMD activation in necrosis-induced flies, while it is not inflammatory for control animals. In addition, bacterial colonization shifts the host metabolome and shortens the lifespan of necrosis-induced flies. This study shows that local necrosis triggers a pathological systemic inflammatory response through interaction between the host and the dysbiotic gut microbiome.

Histologic evaluation of human benign prostatic hyperplasia treated by dutasteride: a study by xenograft model with improved severe combined immunodeficient mice.

OBJECTIVE: To evaluate histologic change in human prostate samples treated with dutasteride and to elucidate direct effects of dutasteride on human prostate tissue, the present study was conducted by using a xenograft model with improved severe combined immunodeficient (super-SCID) mice, although it is well known that dutasteride reduces prostate volume. METHODS: After establishment of a xenograft model of human benign prostatic hyperplasia in morphology and function, samples implanted into super-SCID mice with and without dutasteride were evaluated pathohistologically at 2 and 6 months after initiation of dutasteride administration. RESULTS: The proliferative index evaluated by Ki-67 staining was significantly lower in the dutasteride group than the control at 2 and 6 months after administration. Apoptotic index evaluated by the terminal transferase TdT-mediated dUTP-biotin nick end labeling staining was higher in the dutasteride group than the control at 2 and 6 months after administration. Quick scores in the dutasteride group for staining of both cyclooxygenase-2 (Cox-2) and Ras homolog gene family, member A (RhoA) were significantly lower than those in the control group at 2 and 6 months after administration. CONCLUSION: Dutasteride inhibits cell proliferation and induces apoptosis of prostatic cells, causing a reduced prostate volume. Furthermore, decreased expression of Cox-2 and RhoA within benign prostatic hyperplasia tissue by dutasteride may induce an early effect on improvement of lower urinary tract symptoms, probably by attenuating inflammation reaction of the prostate and decreasing intraurethral pressure, other than the mechanism of reduced prostate volume.

Assessment of non-viral amyloid-ß DNA vaccines on amyloid-ß reduction and safety in rhesus monkeys.

We recently demonstrated that newly developed non-viral amyloid-ß (Aß) DNA vaccines are safe and effective in reducing Aß burdens in the brains of Alzheimer's disease (AD) model mice. The present study was undertaken to examine whether DNA vaccines effectively and safely reduce Aß deposition in the brain of rhesus monkeys. For this purpose, DNA vaccines or empty vector at a dose of 3 mg were injected intramuscularly on a biweekly basis into rhesus monkeys (15-18 years old). Before and during vaccination, blood was drawn once a month and used for hematological and biochemical examinations. Six months after the first vaccination, it was demonstrated that anti-Aß antibodies in plasma of vaccinated monkeys were significantly elevated than that of control monkeys. Immunohistochemical examinations revealed that DNA vaccination reduced the Aß burden to approximately 50% of that found in control monkeys (p=0.026). There was neither inflammation nor microhemorrhage in the brain and no significant changes in cytokine and chemokine levels in the blood throughout the observation period. Taken together, DNA vaccination to monkeys is safe and effective in Aß reduction and provides useful information for performing preclinical and clinical trials.

Effects of fission neutrons on human thyroid tissues maintained in SCID mice.

Morphology and function (secretion of thyroid hormone) of human thyroid tissues from Graves' disease patients are well maintained in C57BL/6J-scid mice. Serum level of thyroid hormone was reduced by fission neutrons from the nuclear reactor UTR-KINKI, and changes in thyroid hormone by fission neutrons were bigger than those by low LET radiations, X-rays and (137)Cs gamma-rays, suggesting high relative biological effectiveness (RBE; 6.5) of fission neutrons. Microarray analyses revealed that about 3% of genes showed more than 4-fold change in gene expression in the unexposed thyroid tissues against surgically resected thyroid tissues from the same patient, probably due to the difficult oxygen and nutrient supply shortly after transplantation. Dose-dependent changes in gene expression against unexposed concurrent controls were observed with increasing doses of fission neutrons (0.2-0.6Gy) and (137)Cs gamma-rays (1.0-3.0Gy) and showed high RBE (4.2). Furthermore, there were some specific genes which showed more than 4-fold change in gene expression in all the thyroid tissues exposed to higher doses of radiation, especially neutrons (0.4 and 0.6Gy), but none at lower doses (0.2Gy of neutrons and 1.0 and 2.0Gy of gamma-rays). These genes related to degeneration, regeneration, apoptosis, and transcription, respond specifically and very sensitively to neutron injury in human thyroid tissues. This is the first experimental report that fission neutrons can induce some morphological and functional disorders in human tissues, showing high RBE against gamma-ray exposure. These results are useful to evaluate the risks of fission neutrons and cosmic rays to humans.