ABSTRACT
Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids was found to prevent native LDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.
Subject(s)
Macrophages , Toll-Like Receptor 8 , Animals , Mice , Toll-Like Receptor 8/genetics , RNAABSTRACT
Pancreatic cancer is the third leading cause of cancer death in the United States, with projections that it will become the second leading cause by the year 2030. It carries a dismal prognosis with a 5-year overall survival rate of less than 9% and is associated with numerous comorbidities, the most notable being cachexia. Defined as the loss of muscle mass not reversible by conventional nutritional support, cachexia is seen in over 85% of pancreatic cancer patients and contributes significantly to mortality, where nearly 30% of pancreatic cancer deaths are due to cachexia rather than tumor burden. Therefore, there is an urgent need to identify the mechanisms behind the development of muscle wasting in pancreatic cancer patients and design novel therapeutics targeting cachexia. This review highlights the current understanding surrounding the mechanisms underpinning the development of cachexia in pancreatic cancer, as well as the current mouse models of pancreatic cancer-induced muscle wasting described in the literature.
Subject(s)
Cachexia/etiology , Disease Models, Animal , Muscle Weakness/etiology , Pancreatic Neoplasms/complications , Animals , Cachexia/metabolism , Cachexia/prevention & control , Cytokines/metabolism , Humans , Mice , Muscle Weakness/metabolism , Muscle Weakness/prevention & control , Pancreatic Neoplasms/metabolism , Prognosis , Signal Transduction , Tumor BurdenABSTRACT
OBJECTIVES: Diabetes mellitus is a significant risk factor for total cancer incidence and mortality. Metformin, a commonly used antidiabetic drug, has been shown to be protective against different types of cancers; however, its role in esophageal cancer is unknown. The goal of this study was to determine whether the use of metformin modifies the risk of development of esophageal adenocarcinoma in patients with Barrett esophagus. METHODS: Patients with diagnoses of Barrett esophagus and esophageal cancer were identified during a 20-year period. Demographic and clinical data were collected. The outcome variable was esophageal adenocarcinoma. Univariate analysis was performed using two-sample t tests for continuous variables or the Fisher exact test for categorical variables. Multiple logistic regression analysis was then performed using the significant variables. RESULTS: A total of 583 patients were identified with the diagnosis of Barrett esophagus or esophageal adenocarcinoma from 1992 to 2012. Of these, 115 had esophageal adenocarcinoma and 468 had Barrett esophagus. Age, smoking, and diabetes mellitus were found to be significant risk factors for the development of esophageal cancer with the following results: age (P < 0.001), smoking (P = 0.003), diabetes mellitus (P = 0.007). Statin use was protective against the development of cancer with P = 0.001. Metformin use was neither associated with an increased nor a decreased risk of esophageal cancer. CONCLUSIONS: The three independent variables that predicted progression of Barrett esophagus to esophageal adenocarcinoma in our study were older age, smoking, and diabetes mellitus. Statin use showed protective effect against development of esophageal adenocarcinoma. Metformin use did not demonstrate any statistically significant protective effect.
