Radiation protection of the gastrointestinal tract and growth inhibition of prostate cancer xenografts by a single compound.

Normal tissue toxicity markedly reduces the therapeutic index of genotoxic anticancer agents, including ionizing radiation. Countermeasures against tissue damage caused by radiation are limited by their potential to also protect malignant cells and tissues. Here, we tested a panel of signal transduction modifiers for selective radioprotection of normal but not tumor tissues. These included three inhibitors of GSK3 (LiCl, SB216763, and SB415286) and two inhibitors of NF-κB (ethyl pyruvate and RTA 408). Among these, the thiol-reactive triterpenoid RTA 408 emerged as a robust and effective protector of multiple organ systems (gastrointestinal, skin, and hemopoietic) against lethal doses of radiation. RTA 408 preserved survival and proliferation of intestinal crypt cells in lethally irradiated mice while reducing apoptosis incidence in crypts and villi. In contrast, RTA 408 uniformly inhibited growth of established CWR22Rv1, LNCaP/C4-2B, PC3, and DU145 xenografts either alone or combined with radiation. Antitumor effects in vivo were associated with reduced proliferation and intratumoral apoptosis and with inhibition of NF-κB-dependent transcription in PC3 cells. Selective protection of normal tissue compartments by RTA 408 critically depended on tissue context and could not be replicated in vitro. Collectively, these data highlight the potential of RTA 408 as a cytoprotective agent that may be safely used in chemoradiation approaches

Down-Regulation of Honey Bee IRS Gene Biases Behavior toward Food Rich in Protein

Food choice and eating behavior affect health and longevity. Large-scale research efforts aim to understand the molecular and social/behavioral mechanisms of energy homeostasis, body weight, and food intake. Honey bees (Apis mellifera) could provide a model for these studies since individuals vary in food-related behavior and social factors can be controlled. Here, we examine a potential role of peripheral insulin receptor substrate (IRS) expression in honey bee foraging behavior. IRS is central to cellular nutrient sensing through transduction of insulin/insulin-like signals (IIS). By reducing peripheral IRS gene expression and IRS protein amount with the use of RNA interference (RNAi), we demonstrate that IRS influences foraging choice in two standard strains selected for different food-hoarding behavior. Compared with controls, IRS knockdowns bias their foraging effort toward protein (pollen) rather than toward carbohydrate (nectar) sources. Through control experiments, we establish that IRS does not influence the bees' sucrose sensory response, a modality that is generally associated with food-related behavior and specifically correlated with the foraging preference of honey bees. These results reveal a new affector pathway of honey bee social foraging, and suggest that IRS expressed in peripheral tissue can modulate an insect's foraging choice between protein and carbohydrate sources

A Review of Federal and Statewide Guidelines and Their Effects on Orthopedics

In the past three decades, the use of opioids has risen tremendously. Pain was named the “fifth patient vital sign” in the 1990s, and from that point, opioid usage has continued to grow throughout the 2010s leading to its recognition as a crisis. The United States is responsible for 80% of the global opioid usage while only accounting for less than 5% of the global population. Previously opioids were mostly used to treat acute pain, however, opioids have been most recently used to manage chronic pain as well. The opioid crisis has presented new challenges in treating pain while preventing the abuse of these medications in a system that lacks standardization of treatment guidelines across the United States. Therefore, the authors of this review examine the current national recommendations to help manage the ongoing opioid crisis and explore how they may impact orthopedic patient care

A CD44/Brg1 nuclear complex confers mesenchymal progenitor cells with enhanced fibrogenicity in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. We previously identified fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of patients with IPF who serve as drivers of progressive fibrosis. Recent single-cell RNA sequencing work revealed that IPF MPCs with the highest transcriptomic network entropy differ the most from control MPCs and that increased CD44 was a marker of these IPF MPCs. We hypothesize that IPF MPCs with high CD44 (CD44hi) expression will display enhanced fibrogenicity. We demonstrate that CD44-expressing MPCs are present at the periphery of the IPF fibroblastic focus, placing them in regions of active fibrogenesis. In a humanized mouse xenograft model, CD44hi IPF MPCs are more fibrogenic than CD44lo IPF MPCs, and knockdown of CD44 diminishes their fibrogenicity. CD44hi IPF MPCs display increased expression of pluripotency markers and enhanced self-renewal compared with CD44lo IPF MPCs, properties potentiated by IL-8. The mechanism involves the accumulation of CD44 within the nucleus, where it associates with the chromatin modulator protein Brahma-related gene 1 (Brg1) and the zinc finger E-box binding homeobox 1 (Zeb1) transcription factor. This CD44/Brg1/Zeb1 nuclear protein complex targets the Sox2 gene, promoting its upregulation and self-renewal. Our data implicate CD44 interaction with the epigenetic modulator protein Brg1 in conveying IPF MPCs with cell-autonomous fibrogenicity

Time related effects of non-steroidal anti-inflammatory drugs on Achilles tendinopathy in a murine model

Category: Basic Sciences/Biologics Introduction/Purpose: Tendinopathy has been identified to result from work and sports-related activities, in many patients. Common treatment for such degenerative tendon pathology includes non-steroidal anti-inflammatory drugs (NSAIDs). Although they provide pain relief, their mechanistic effects, on modulating inflammation associated with tendinopathy is poorly understood. Recent reports suggest impaired functional healing of rat rotator cuff tear repairs when treated in the early postoperative period with ibuprofen, while delayed treatment did not affect healing. We have now identified, using a murine model, a cascade of genes associated with innate inflammation, which influence premature fibrotic scarring without repair. The objective of this study was to evaluate the effects of orally administered ibuprofen on inflammation and wound-healing responses after initiation and during progression of Achilles tendinopathy in a murine model. Methods: All animal experimentation was carried out under IACUC approval. C57BL/6 wild-type male mice (12 wks) received two injections, two days apart, of 100ng rhTGF-β1 into the midportion of the Achilles tendon. Ibuprofen (IBU) was administered orally as described by Ezell et al5, for 7 days either 1 day (Early) or 8 days (Late) after the initiating injury. Experimental groups were 1) Tendinopathy + NO drug, 2) Tendinopathy + IBU Early, 3) Tendinopathy + IBU Late, 4) Naïve mice + IBU Early. Following sacrifice of the mice at 28 days post injury, Achilles tendons were harvested, and RNA was prepared as described by Trella et al6, for transcriptomic analyses using wound healing and NfKb target gene platforms (PAMM-121A, PAMM-225ZA Qiagen, Valencia, CA). Tendon histopathology was assessed on paraffin embedded thin sections using standard methods for HE and Safranin O staining. Results: Both early and late dosing times with ibuprofen prolonged the innate inflammation response genes (e.g., PGE Synthase, Interleukin1b, Interferon gamma, Cxcl3 chemokine), relative to untreated tendinopathy. Furthermore, early dosing also elevated collagen genes (Collagens 1, 3 and 5), and such a response has been associated with fibrotic scarring. Drug administration to naïve mice showed no significant effects on gene expression in the tendons. Conclusion: This study represents the first report of the time related effect of ibuprofen on mechanisms involved in healing of tendinopathy. If the drug is administered early after the initiating injury, a prolonged increase in inflammation and potential for scarring in the tendon was observed, whereas later administration resulted in persistent inflammation only. The data suggest that the anti-inflammatory action of such NSAID may occur outside of the tendon (such as the bone marrow) resulting in a dysregulated systemic mechanism that controls the innate (tendon) inflammation and healing pathways