![]() ![]() As a control, a sham operation without aortic constriction was performed on age-matched mice ( n = 4 per group). Mice used for histology underwent 28 days of banding ( n = 10 mice per group). Hearts used for histologic analysis were sectioned from base to apex at 250-μm intervals. At the end of the experiment, the heart was excised, fixed in zinc-formalin, and embedded in paraffin for histologic studies. The degree of pressure overload was assessed by measuring right-to-left carotid artery flow velocity ratio after constricting the transverse aorta. Despite its potential role as a prognostic biomarker, galectin-3 is not a critical modulator of cardiac fibrosis but may delay the hypertrophic response. However, galectin-3 loss did not affect survival, systolic and diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy in the pressure-overloaded heart. Galectin-3 knockout mice exhibited accelerated cardiac hypertrophy after 7 days of pressure overload, whereas female galectin-3 knockouts had delayed dilation after 28 days of transverse aortic constriction. Correlation studies revealed that cardiomyocyte- but not macrophage-specific galectin-3 localization was associated with adverse remodeling and dysfunction. In vitro, cytokine stimulation suppressed galectin-3 synthesis by macrophages and cardiac fibroblasts. Early up-regulation of galectin-3 was localized in subpopulations of macrophages and myofibroblasts however, after 7 to 28 days of transverse aortic constriction, a subset of cardiomyocytes in fibrotic areas contained large amounts of galectin-3. In a mouse model of transverse aortic constriction, galectin-3 expression was markedly up-regulated in the pressure-overloaded myocardium. In normal mouse myocardium, galectin-3 was constitutively expressed in macrophages and was localized in atrial but not ventricular cardiomyocytes. We hypothesized that galectin-3 may be up-regulated in the pressure-overloaded myocardium and regulate hypertrophy and fibrosis. Galectin-3 regulates inflammatory and fibrotic responses however, its role in cardiac remodeling remains unclear. Gene Editing: Technology & Applications.The β-galactoside–binding animal lectin galectin-3 is predominantly expressed by activated macrophages and is a promising biomarker for patients with heart failure. Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. ![]() Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis. Which was measured by pilocarpine stimulation of whole saliva production. Saliva was collected 90 days post-IR, and the IR control group produced ∼65% less saliva compared to the non-IR group (baseline), irrespective of whether the AAV2-GFP was delivered pre- or post-IR ( Figures 1C–1E). All CERE-120 treatments pre-IR (10 6, 10 8, 10 10 vp/g) resulted in improved saliva flow compared to the IR-GFP group and were similar to the non-IR group at 90 and 300 days. At 120 days, there were differences in the 3 doses with CERE-120 at 10 8 and 10 10 vp/g being similar to non-IR. In comparison, CERE-120 post-IR treatment groups only showed similar saliva flow to the non-IR group at 300 days, not at 90 and 120 days post-IR ( Figures 1C and 1D).
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |