Comparison of Gene Expression Responses in the Small Intestine of Mice Following Exposure to 3 Carcinogens Using the S1500+ Gene Set Informs a Potential Common Adverse Outcome Pathway.

Carcinogenesis of the small intestine is rare in humans and rodents. Oral exposure to hexavalent chromium (Cr(VI)) and the fungicides captan and folpet induce intestinal carcinogenesis in mice. Previously (Toxicol Pathol. 330:48-52), we showed that B6C3F1 mice exposed to carcinogenic concentrations of Cr(VI), captan, or folpet for 28 days exhibited similar histopathological responses including villus enterocyte cytotoxicity and regenerative crypt epithelial hyperplasia. Herein, we analyze transcriptomic responses from formalin-fixed, paraffin-embedded duodenal sections from the aforementioned study. TempO-Seq technology and the S1500+ gene set were used to analyze transcription responses. Transcriptional responses were similar between all 3 agents; gene-level comparison identified 126/546 (23%) differentially expressed genes altered in the same direction, with a total of 25 upregulated pathways. These changes were related to cellular metabolism, stress, inflammatory/immune cell response, and cell proliferation, including upregulation in hypoxia inducible factor 1 (HIF-1) and activator protein 1 (AP1) signaling pathways, which have also been shown to be related to intestinal injury and angiogenesis/carcinogenesis. The similar molecular-, cellular-, and tissue-level changes induced by these 3 carcinogens can be informative for the development of an adverse outcome pathway for intestinal cancer.

Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice.

Autophagy and lysosomal function are important for protein homeostasis and their dysfunction have been associated with Alzheimer's disease (AD). Increased immunoreactivities of an important lysosomal protease, cathepsin D (Cat D), are evident in amyloid plaques and neurons in patients with AD. This study tests the hypothesis that deleting one allele of the cathepsin D gene (Ctsd) impacts cerebral ß-amyloidosis in amyloid-ß precursor protein (APP)sw/PS1dE9 (APP/PS1) double transgenic mice. Despite a significant 38% decrease in Cat D level in APP/PS1/Ctsd+/- compared with APP/PS1/Ctsd+/+ mice, no changes in steady state levels and deposition of Aß were found in the brain. There were also no differences in APP processing, the levels of two other Aß-degrading proteases, the levels of autophagy related protein, such as LAMP2, P62, LC3-I, LC3-II, and Beclin-1, or the markers of neuroinflammation, observed between the APP/PS1/Ctsd+/+ and APP/PS1/Ctsd+/- mice. Our findings demonstrate that in wild-type mice, Cat D protein levels are either in excess or redundant with other factors in the brain, and at least one allele of Ctsd is dispensable for cerebral ß-amyloidosis and autophagy in APP/PS1 transgenic mice.

Stability of High Speed 3D Printing in Liquid-Like Solids.

Fluid instabilities limit the ability of features to hold their shape in many types of 3D printing as liquid inks solidify into written structures. By 3D printing directly into a continuum of jammed granular microgels, these instabilities are circumvented by eliminating surface tension and body forces. However, this type of 3D printing process is potentially limited by inertial instabilities if performed at high speeds where turbulence may destroy features as they are written. Here, we design and test a high-speed 3D printing experimental system to identify the instabilities that arise when an injection nozzle translates at 1 m/s. We find that the viscosity of the injected material can control the Reynold's instability, and we discover an additional, unanticipated instability near the top surface of the granular microgel medium.

Triptolide preserves cognitive function and reduces neuropathology in a mouse model of Alzheimer's disease.

Triptolide, a major bioactive ingredient of a widely used herbal medicine, has been shown to possess multiple pharmacological functions, including potential neuroprotective effects pertinent to Alzheimer's disease (AD) in vitro. However, the therapeutic potential of triptolide for AD in vivo has not been thoroughly evaluated. In the present study, we investigated the impact of peripherally administered triptolide on AD-related behavior and neuropathology in APPswe/PS1ΔE9 (APP/PS1) mice, an established model of AD. Our results showed that two-month treatment with triptolide rescued cognitive function in APP/PS1 mice. Immunohistochemical analyses indicated that triptolide treatment led to a significant decrease in amyloid-ß (Aß) deposition and neuroinflammation in treated mice. In contrast to previous findings in vitro, biochemical analyses showed that triptolide treatment did not significantly affect the production pathway of Aß in vivo. Intriguingly, further analyses revealed that triptolide treatment upregulated the level of insulin-degrading enzyme, a major Aß-degrading enzyme in the brain, indicating that triptolide treatment reduced Aß pathology by enhancing the proteolytic degradation of Aß. Our findings demonstrate that triptolide treatment ameliorates key behavioral and neuropathological changes found in AD, suggesting that triptolide may serve as a potential therapeutic agent for AD.