Advanced Oxidative Protein Products Cause Pain Hypersensitivity in Rats by Inducing Dorsal Root Ganglion Neurons Apoptosis via NADPH Oxidase 4/c-Jun N-terminal Kinase Pathways

Pain hypersensitivity is the most common category of chronic pain and is difficult to cure. Oxidative stress and certain cells apoptosis, such as dorsal root ganglion (DRG) neurons, play an essential role in the induction and development of pain hypersensitivity. The focus of this study is at a more specific molecular level. We investigated the role of advanced oxidative protein products (AOPPs) in inducing hypersensitivity and the cellular mechanism underlying the proapoptotic effect of AOPPs. Normal rats were injected by AOPPs-Rat serum albumin (AOPPs–RSA) to cause pain hypersensitivity. Primary cultured DRG neurons were treated with increasing concentrations of AOPPs–RSA or for increasing time durations. The MTT, flow cytometry and western blot analyses were performed in the DRG neurons. A loss of mitochondrial membrane potential (MMP) and an increase in intracellular reactive oxygen species (ROS) were observed. We found that AOPPs triggered DRG neurons apoptosis and MMP loss. After AOPPs treatment, intracellular ROS generation increased in a time- and dose-dependent manner, whereas, N-acetyl-L-cysteine (NAC), a specific ROS scavenger could inhibit the ROS generation. Proapoptotic proteins, such as Bax, caspase 9/caspase 3, and PARP-1 were activated, whereas anti-apoptotic Bcl-2 protein was down-regulated. AOPPs also increased Nox4 and JNK expression. Taken together, these findings suggest that AOPPs cause pain hypersensitivity in rats, and extracellular AOPPs accumulation triggered Nox4-dependent ROS production, which activated JNK, and induced DRG neurons apoptosis by activating caspase 3 and PARP-1

Advanced oxidation protein products sensitized the transient receptor potential vanilloid 1 via NADPH oxidase 1 and 4 to cause mechanical hyperalgesia

Oxidative stress is a possible pathogenesis of hyperalgesia. Advanced oxidation protein products (AOPPs), a new family of oxidized protein compounds, have been considered as a novel marker of oxidative stress. However, the role of AOPPs in the mechanism of hyperalgesia remains unknown. Our study aims to investigate whether AOPPs have an effect on hyperalgesia and the possible underlying mechanisms. To identify the AOPPs involved, we induced hyperalgesia in rats by injecting complete Freund’s adjuvant (CFA) in hindpaw. The level of plasma AOPPs in CFA-induced rats was 1.6-fold in comparison with what in normal rats (P<0.05). After intravenous injection of AOPPs-modified rat serum albumin (AOPPs-RSA) in Sprague-Dawley rats, the paw mechanical thresholds, measured by the electronic von Frey system, significantly declined. Immunofluorescence staining indicated that AOPPs increased expressions of NADPH oxidase 1 (Nox1), NADPH oxidase 4 (Nox4), transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the dorsal root ganglia (DRG) tissues. In-vitro studies were performed on primary DRG neurons which were obtained from both thoracic and lumbar DRG of rats. Results indicated that AOPPs triggered reactive oxygen species (ROS) production in DRG neurons, which were significantly abolished by ROS scavenger N-acetyl-l-cysteine (NAC) and small-interfering RNA (siRNA) silencing of Nox1 or Nox4. The expressions of Nox1, Nox4, TRPV1 and CGRP were significantly increased in AOPPs-induced DRG neurons. And relevant siRNA or inhibitors notably suppressed the expressions of these proteins and the calcium influxes in AOPPs-induced DRG neurons. In conclusion, AOPPs increased significantly in CFA-induced hyperalgesia rats and they activated Nox1/Nox4-ROS to sensitize TRPV1-dependent Ca2+ influx and CGRP release which led to inducing mechanical hyperalgesia

Measuring Indoor Air Quality and Engaging California Indian Stakeholders at the Win-River Resort and Casino: Collaborative Smoke-Free Policy Development

Most casinos owned by sovereign American Indian nations allow smoking, even in U.S. states such as California where state laws restrict workplace smoking. Collaborations between casinos and public health workers are needed to promote smoke-free policies that protect workers and patrons from secondhand tobacco smoke (SHS) exposure and risks. Over seven years, a coalition of public health professionals provided technical assistance to the Redding Rancheria tribe in Redding, California in establishing a smoke-free policy at the Win-River Resort and Casino. The coalition provided information to the casino general manager that included site-specific measurement of employee and visitor PM2.5 personal exposure, area concentrations of airborne nicotine and PM2.5, visitor urinary cotinine, and patron and staff opinions (surveys, focus groups, and a Town Hall meeting). The manager communicated results to tribal membership, including evidence of high SHS exposures and support for a smoke-free policy. Subsequently, in concert with hotel expansion, the Redding Rancheria Tribal Council voted to accept a 100% restriction of smoking inside the casino, whereupon PM2.5 exposure in main smoking areas dropped by 98%. A 70% partial-smoke-free policy was instituted ~1 year later in the face of revenue loss. The success of the collaboration in promoting a smoke-free policy, and the key element of air quality feedback, which appeared to be a central driver, may provide a model for similar efforts

Measuring Indoor Air Quality and Engaging California Indian Stakeholders at the Win-River Resort and Casino: Collaborative Smoke-Free Policy Development

Most casinos owned by sovereign American Indian nations allow smoking, even in U.S. states such as California where state laws restrict workplace smoking. Collaborations between casinos and public health workers are needed to promote smoke-free policies that protect workers and patrons from secondhand tobacco smoke (SHS) exposure and risks. Over seven years, a coalition of public health professionals provided technical assistance to the Redding Rancheria tribe in Redding, California in establishing a smoke-free policy at the Win-River Resort and Casino. The coalition provided information to the casino general manager that included site-specific measurement of employee and visitor PM2.5 personal exposure, area concentrations of airborne nicotine and PM2.5, visitor urinary cotinine, and patron and staff opinions (surveys, focus groups, and a Town Hall meeting). The manager communicated results to tribal membership, including evidence of high SHS exposures and support for a smoke-free policy. Subsequently, in concert with hotel expansion, the Redding Rancheria Tribal Council voted to accept a 100% restriction of smoking inside the casino, whereupon PM2.5 exposure in main smoking areas dropped by 98%. A 70% partial-smoke-free policy was instituted ~1 year later in the face of revenue loss. The success of the collaboration in promoting a smoke-free policy, and the key element of air quality feedback, which appeared to be a central driver, may provide a model for similar efforts

Measuring Indoor Air Quality and Engaging California Indian Stakeholders at the Win-River Resort and Casino: Collaborative Smoke-Free Policy Development

Most casinos owned by sovereign American Indian nations allow smoking, even in U.S. states such as California where state laws restrict workplace smoking. Collaborations between casinos and public health workers are needed to promote smoke-free policies that protect workers and patrons from secondhand tobacco smoke (SHS) exposure and risks. Over seven years, a coalition of public health professionals provided technical assistance to the Redding Rancheria tribe in Redding, California in establishing a smoke-free policy at the Win-River Resort and Casino. The coalition provided information to the casino general manager that included site-specific measurement of employee and visitor PM2.5 personal exposure, area concentrations of airborne nicotine and PM2.5, visitor urinary cotinine, and patron and staff opinions (surveys, focus groups, and a Town Hall meeting). The manager communicated results to tribal membership, including evidence of high SHS exposures and support for a smoke-free policy. Subsequently, in concert with hotel expansion, the Redding Rancheria Tribal Council voted to accept a 100% restriction of smoking inside the casino, whereupon PM2.5 exposure in main smoking areas dropped by 98%. A 70% partial-smoke-free policy was instituted ~1 year later in the face of revenue loss. The success of the collaboration in promoting a smoke-free policy, and the key element of air quality feedback, which appeared to be a central driver, may provide a model for similar efforts