Utilizing data from the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial, this hub model was developed to limit seventeen Renin-Angiotensin-Aldosterone System (RAAS) components as three entrance and four exits, to facilitate the calculation of a model as one egress unknown, the angiotensin type 1 (AT1) receptor. Following previous evidence relating renin levels to mortality, this study found controls were more like sepsis patients with levels < renin quartile 1 (Q1) for calculated AT1, while more like sepsis patients with renin levels > quartile 3 (Q4) for measured aldosterone levels. Additionally differential discrete correlate summation (DCS) analysis indicates AT1, aldosterone and renin as major hub nodes in this independent DCS model of metabolic data inputs.
View Article and Find Full Text PDFMen and women have different cardiovascular responses to spaceflight; however, few studies have focused on direct comparisons between sexes. We investigated the mechanisms of aortic stiffening in socially and sexually mature 20-week-old male and female Sprague Dawley (SD) rats exposed to hindlimb unloading (HLU) for 14 days. Pulse wave velocity (PWV) was greater in the aortic arch of females after HLU versus control females (n = 6-8).
View Article and Find Full Text PDFWe present a model of directed investigation of KEGG pathway analysis, beginning with discrete correlate summation (DCS) clustering of Swiss-Prot sets. Dopamine and angiotensin related proteins define the boundary for pathway analyses upon a network of proteins also associated with a compositely defined matrix of Swiss-Prot keywords to provide a framework for their biological indices (Figure 1).
View Article and Find Full Text PDFMost women diagnosed with breast cancer (BC) have estrogen receptor alpha-positive (ER+) disease. The current mouse models of ER+ BC often rely on exogenous estrogen to encourage metastasis, which modifies the immune system and the function of some tissues like bone. Other studies use genetically modified or immunocompromised mouse strains, which do not accurately replicate the clinical disease.
View Article and Find Full Text PDFThe presence of cell surface protein CD47 allows cancer cells to evade innate and adaptive immune surveillance resulting in metastatic spread. CD47 binds to and activates SIRPα on the surface of myeloid cells, inhibiting their phagocytic activity. On the other hand, CD47 binds the matricellular protein Thrombospondin-1, limiting T-cell activation.
View Article and Find Full Text PDFThrombospondin-1 (TSP1) is a matricellular protein with many important roles in mediating carcinogenesis, fibrosis, leukocyte recruitment, and metabolism. We have previously shown a role of diet in the absence of TSP1 in liver metabolism in the context of a colorectal cancer model. However, the metabolic implications of TSP1 regulation by diet in the liver metabolism are currently understudied.
View Article and Find Full Text PDFMuscadine grapes are abundant in dietary polyphenols, but their effect on hypertension-induced cardiac damage is limited. This study assessed whether a muscadine grape skin/seed extract supplement (MGES) prevents hypertension-induced cardiac damage and oxidative stress. Male Sprague Dawley rats were treated for four weeks with drinking water, angiotensin II (Ang II) to induce hypertension, MGES, or both Ang II and MGES.
View Article and Find Full Text PDFDoxorubicin (Dox), an effective chemotherapeutic, can cause cumulative dose-dependent cardiovascular toxicity, which may manifest as vascular dysfunction leading to long-term end-organ damage. Currently, there are no effective treatments to mitigate Dox-induced vascular damage in cancer patients, particularly pediatric patients. We showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone, mitigated cardiac damage in Dox-treated juvenile rats.
View Article and Find Full Text PDFPurpose: Immunotherapy with checkpoint inhibitors is improving the outcomes of several cancers. However, only a subset of patients respond. Therefore, predictive biomarkers are critically needed to guide treatment decisions and develop approaches to the treatment of therapeutic resistance.
View Article and Find Full Text PDFWe previously reported that isolated proximal tubules (PT) internalize the precursor protein angiotensinogen and that the Iodine-labeled protein accumulated in the nuclear and mitochondrial fractions of the PT cells; however, whether internalization of angiotensinogen occurs in non-renal epithelial cells is unknown. Therefore, the present study assessed the cellular uptake of I-angiotensinogen in human retinal pigment ARPE-19 epithelial cells, a widely utilized cell model for the assessment of retinal injury, inflammation and oxidative stress. ARPE-19 cells, maintained in serum-free media to remove extracellular sources of bovine serum angiotensinogen and renin, were incubated with Iodine-angiotensinogen at 37 °C and revealed the time-dependent uptake of angiotensinogen over 24 h.
View Article and Find Full Text PDFAm J Physiol Regul Integr Comp Physiol
March 2021
Type 2 diabetes (T2D) development may be mediated by skeletal muscle (SkM) function, which is responsible for >80% of circulating glucose uptake. The goals of this study were to assess changes in global- and location-level gene expression, remodeling proteins, fibrosis, and vascularity of SkM with worsening glycemic control, through RNA sequencing, immunoblotting, and immunostaining. We evaluated SkM samples from health-diverse African green monkeys () to investigate these relationships.
View Article and Find Full Text PDFPurpose: To address whether differential regulation of the renin-angiotensin-aldosterone system occurs in pre-eclampsia, we performed an analysis of the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1-7)] peptides in normal pregnant (NP) and pre-eclamptic (PE) women.
Methods: Urine and plasma samples from 86 nulliparous women were collected prospectively; 67 subjects continued as NP and 19 developed PE. Subjects were enrolled prior to 12 weeks of gestation and plasma and spot urine samples were obtained throughout gestation.
Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer.
View Article and Find Full Text PDFAm J Physiol Heart Circ Physiol
August 2019
Children with orthostatic intolerance (OI) have exaggerated decreases in heart rate variability (HRV) and suppression of baroreflex sensitivity (BRS) with standing. Accompanying brain transmitter and metabolite profiles are unknown. In this study, we used proton (H) magnetic resonance spectroscopy (H-MRS) to quantify markers of neuronal and glial integrity in a pilot study of children with OI compared with asymptomatic controls.
View Article and Find Full Text PDFBackground: A perennial challenge in systemic cytotoxic cancer therapy is to eradicate primary tumors and metastatic disease while sparing normal tissue from off-target effects of chemotherapy. Anthracyclines such as doxorubicin are effective chemotherapeutic agents for which dosing is limited by development of cardiotoxicity. Our published evidence shows that targeting CD47 enhances radiation-induced growth delay of tumors while remarkably protecting soft tissues.
View Article and Find Full Text PDFAntenatal betamethasone (BM) therapy for women in jeopardy of premature delivery accelerates the lung development in preterm infants and reduces infant mortality rates, but may induce early programming events with chronic cardiovascular consequences. In a sheep model of fetal programming, BM-exposed (BMX) offspring as adults exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for the control of heart rate and insulin resistance accompanied by dysregulation of the brain renin-angiotensin (Ang) system (RAS). However, the status of signaling mechanisms in the brain dorsomedial medulla (DMM) of the BMX sheep that comprise both the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cellular pathways is unknown.
View Article and Find Full Text PDFThe unfolded protein response (UPR) is a stress pathway controlled by GRP78 to mediate IRE1, PERK, and ATF6 signaling. We show that targeting GRP78, IRE1, and PERK differentially regulates macrophage polarization. Specifically, PERK targeting enhanced macrophage proliferation and macrophage-mediated killing but not GRP78 or IRE1.
View Article and Find Full Text PDFProtein function identification remains a significant problem. Solving this problem at the molecular functional level would allow mechanistic determinant identification-amino acids that distinguish details between functional families within a superfamily. Active site profiling was developed to identify mechanistic determinants.
View Article and Find Full Text PDFThrombospondin 1 is a glycoprotein that regulates cellular phenotype through interactions with its cellular receptors and extracellular matrix-binding partners. Thrombospondin 1 locally regulates angiogenesis and inflammatory responses that contribute to colorectal carcinogenesis in Apc(Min/+) mice. The ability of thrombospondin 1 to regulate responses of cells and tissues to a variety of stresses suggested that loss of thrombospondin 1 may also have broader systemic effects on metabolism to modulate carcinogenesis.
View Article and Find Full Text PDFEvidence of endogenous angiotensin-(1-12) [Ang-(1-12)] may necessitate revision of the accepted view that Ang I is the immediate peptide product derived from the precursor protein angiotensinogen. As the processing of this peptide has not been fully elucidated, we characterized Ang-(1-12) metabolism in the serum and kidney of the mRen2.Lewis rat, a model of high circulating renin and ACE expression.
View Article and Find Full Text PDFJ Health Organ Manag
December 2011
Purpose: This study aims to investigate the mediating role of organizational subculture between job satisfaction, organizational commitment (dependent variables) and leadership, culture (independent variables) in health care organizations.
Design/methodology/approach: A survey on nurses from 26 wards from various types of hospital was used. A total of 251 usable returns were collected for the analysis (i.
Transgenic hypertensive (mRen2)27 rats overexpress the murine Ren2 gene and have impaired baroreflex sensitivity (BRS) for control of the heart rate. Removal of endogenous angiotensin (Ang)-(1-7) tone using a receptor blocker does not further lower BRS. Therefore, we assessed whether blockade of Ang II with a receptor antagonist or combined reduction in Ang II and restoration of endogenous Ang-(1-7) levels with Ang-converting enzyme (ACE) inhibition will improve BRS in these animals.
View Article and Find Full Text PDFIn Fischer 344 (F344) rats, renin-angiotensin system (RAS) blockade for 1 yr with the angiotensin II type 1 (AT(1)) receptor blocker L-158,809 prevents age-related impairments in metabolic function, similar to transgenic rats with low glial angiotensinogen (Aogen). Brain RAS regulation may contribute to the benefits of long-term systemic AT(1) antagonism. We assessed the mRNA of RAS components in the dorsomedial medulla of F344 rats at 3 (young; n = 8) or 15 mo of age (old; n = 7) and in rats treated from 3 to 15 mo of age with 20 mg/l of the AT(1) receptor antagonist L-158,809 (Old+L; n = 6).
View Article and Find Full Text PDFBackground: Angiotensin-(1-12) [Ang-(1-12)] functions as an endogenous substrate for the productions of Ang II and Ang-(1-7) by a non-renin dependent mechanism. This study evaluated whether Ang-(1-12) is incorporated by neonatal cardiac myocytes and the enzymatic pathways of ¹²⁵I-Ang-(1-12) metabolism in the cardiac myocyte medium from WKY and SHR rats.
Methodology/principal Findings: The degradation of ¹²⁵I-Ang-(1-12) (1 nmol/L) in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase.