Radiation therapy for head and neck cancer causes damage to the surrounding salivary glands, resulting in salivary gland hypofunction and xerostomia. Current treatments do not provide lasting restoration of salivary gland function following radiation; therefore, a new mechanistic understanding of the radiation-induced damage response is necessary for identifying therapeutic targets. The purpose of the present study was to investigate the metabolic phenotype of radiation-induced damage in parotid salivary glands by integrating transcriptomic and metabolomic data. Integrated data were then analyzed to identify significant gene-metabolite interactions. Mice received a single 5 Gy dose of targeted head and neck radiation. Parotid tissue samples were collected 5 days following treatment for RNA sequencing and metabolomics analysis. Altered metabolites and transcripts significantly converged on a specific region in the metabolic reaction network. Both integrative pathway enrichment using rank-based statistics and network analysis highlighted significantly coordinated changes in glutathione metabolism, energy metabolism (TCA cycle and thermogenesis), peroxisomal lipid metabolism, and bile acid production with radiation. Integrated changes observed in energy metabolism suggest that radiation induces a mitochondrial dysfunction phenotype. These findings validated previous pathways involved in the radiation-damage response, such as altered energy metabolism, and identified robust signatures in salivary glands, such as reduced glutathione metabolism, that may be driving salivary gland dysfunction.

Preeclampsia is a progressive hypertensive disorder of pregnancy affecting 2%-8% of pregnancies globally. Preexisting chronic hypertension is a major risk factor associated with developing preeclampsia, and growing evidence suggests a role for the gut microbiome in the development of preeclampsia. However, neither alterations in the gut microbiome associated with preeclampsia nor the mechanisms involved are fully understood. In this study, we tested the hypothesis that normal gestational maternal gut microbiome remodeling is impaired in the Dahl salt-sensitive (Dahl S) rat model of superimposed preeclampsia. Gut microbiome profiles of pregnant Dahl S, normal pregnant Sprague-Dawley (SD), and matched virgin controls were assessed by 16S rRNA gene sequencing at baseline; during early, middle, and late pregnancy; and 1-wk postpartum. Dahl S rats had significantly higher abundance in Proteobacteria, and multiple genera were significantly different from SD rats at baseline. The pregnant SD displayed a significant increase in Proteobacteria and genera such as Helicobacter, but these were not different between pregnant and virgin Dahl S rats. By late pregnancy, Dahl S rats had significantly lower α-diversity and Firmicutes compared with their virgin Dahl S controls. β-diversity was significantly different among groups (P < 0.001). KEGG metabolic pathways including those associated with short-chain fatty acids were different in Dahl S pregnancy but not in SD pregnancy. These results reveal an association between chronic hypertension and gut microbiome dysbiosis which may hinder pregnancy-specific remodeling in the gut microbial composition during superimposed preeclampsia.

Heart failure (HF) patients with deteriorating right ventricular (RV) structure and function have a nearly twofold increased risk of death compared with those without. Despite the well-established clinical risk, few studies have examined the molecular signature associated with this HF condition. The purpose of this study was to integrate morphological, molecular, and functional data with the transcriptome data set in the RV of a preclinical model of cardiometabolic HF. Ossabaw swine were fed either normal diet without surgery (lean control, n = 5) or Western diet and aortic-banding (WD-AB; n = 4). Postmortem RV weight was increased and positively correlated with lung weight in the WD-AB group compared with CON. Total RNA-seq was performed and gene expression profiles were compared and analyzed using principal component analysis, weighted gene co-expression network analysis, module enrichment analysis, and ingenuity pathway analysis. Gene networks specifically associated with RV hypertrophic remodeling identified a hub gene in MAPK8 (or JNK1) that was associated with the selective induction of the extracellular matrix (ECM) component fibronectin. JNK1 and fibronectin protein were increased in the right coronary artery (RCA) of WD-AB animals and associated with a decrease in matrix metalloproteinase 14 protein, which specifically degrades fibronectin. RCA fibronectin content was correlated with increased vascular stiffness evident as a decreased elastin elastic modulus in WD-AB animals. In conclusion, this study establishes a molecular and transcriptome signature in the RV using Ossabaw swine with cardiometabolic HF. This signature was associated with altered ECM regulation and increased vascular stiffness in the RCA, with selective dysregulation of fibronectin.