Biology subjects

Cruz-Diaz, N.

Publications and source records attributed to Cruz-Diaz, N..

8 recordsLinked to original sources

bioRxiv2025

Photoacoustic imaging assessment of acute kidney injury associated with experimental necrotizing enterocolitis

BackgroundNecrotizing enterocolitis (NEC) is a devastating gastrointestinal condition increasingly recognized to cause systemic complications, including acute kidney injury (AKI). However, the underlying mechanisms and variations in renal impairment remain largely unknown, and there is a lack of non-invasive imaging methods for detecting early kidney injury. MethodsWe evaluated kidney injury through a multimodal approach, using a neonatal rat model of experimental NEC. Plasma and renal tissue were analyzed for pro-inflammatory cytokines (TNF-, IL-6, IL-1{beta}) by ELISA. Histological analysis and immunofluorescence staining were used to identify renal abnormalities and expressions of KIM-1 and NGAL. Photoacoustic imaging (PAI) was used to assess renal oxygenation and total hemoglobin as functional imaging biomarkers of kidney injury. ResultsNEC pups showed significant elevations of systemic and renal cytokines, as well as increased expression of KIM-1, NGAL and CD31 in proximal tubules of the kidney. Histological examination further confirms renal injury in the NEC cohort. PAI demonstrated reduction in renal oxygen saturation, offering non-invasive assessment of physiological kidney damage. ConclusionThis study characterizes AKI associated with NEC as an inflammatory and hypoxic response in the neonatal rat NEC model and introduces PAI as a promising imaging modality for non-invasive evaluation of renal injury in NEC.

bioengineering↗

bioRxiv2025

Functional Imaging for Regenerative Medicine and Tissue-Engineered Constructs: Tracking Vascularization of Tissue-Engineered Small Intestine Scaffolds

Traditional approaches to tissue engineered small intestine (TESI) require implanting a construct in the omentum of the abdominal cavity to allow for vascularization of the construct and tissue maturation. A second operation is then needed to implant the construct in continuity with the intestine. The timing of the second operation has historically been chosen based on pre-determined biological endpoints. Currently, no well-validated method has been used to non-invasively monitor for vascular maturity which would better inform when the second operation should be performed. We hypothesized that photoacoustic imaging (PAI) could serve as a tool to non-invasively monitor regional and temporal changes in vascular maturity in scaffolds implanted in the omentum. For this pilot study, tubular scaffolds used for TESI were fabricated with electrospinning and implanted in the omentum of Sprague-Dawley rats for 1 and 2 months. Scaffolds were imaged with PAI and tissue oxygenation and hemoglobin concentration were quantified. PAI was then correlated with gross observations of vascularization at each time point. PAI was able to determine regional and temporal changes in tissue oxygenation and hemoglobin concentration. Specifically, the oxygenation and hemoglobin concentration of the top wall of the construct showed better vascular maturity compared to the bottom wall. In addition, vascular maturity seemed to improve in the top wall from 1 to 2 months. The bottom wall was not well covered by the omentum and thus did not vascularize as well as the top wall. The PAI findings were confirmed on gross examination of the scaffolds and upon quantification of the histological analysis of endothelial cell density. Thus, PAI may serve as a critical tool for monitoring vascular maturity in TE, specifically within the abdomen. This will be a critical tool in the pre-clinical development and clinical translation of TESI.

bioengineering↗

bioRxiv2025

NEST-Scoring, a Novel miRNA Target Gene Profile Network Analysis of Placenta-Derived Extracellular Vesicles in a Transgenic Rat Model of Preeclampsia

Preeclampsia is a multisystem hypertensive disorder of pregnancy and a leading cause of maternal morbidity and mortality. Despite its increasing incidence and the debilitating nature of its cerebrovascular complications, the underlying mechanisms remain incompletely understood. The goals of this study were to 1) determine whether middle cerebral artery (MCA) hemodynamics are altered in late gestation (LG) or two months postpartum in transgenic rats with preeclampsia compared to normal pregnant Sprague-Dawley (SD) rats, and 2) evaluate the microRNA (miRNA) profiles of circulating placental-derived extracellular vesicles (EVPD) using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway framework using NEST-Scoring [Node, Edge, System, Topology], a novel target gene profile network analysis. Our data showed elevated blood pressure in transgenic preeclampsia rats at both LG and two months post-partum (PP-2M) compared to normal pregnant SD rats in the setting of hypertension. The heart rate was also significantly higher in preeclampsia rats at LG. No differences were observed in left MCA (LMCA) velocities between strains or time points. However, LMCA resistance and pulsatility indexes were lower at PP-2M in transgenic preeclampsia rats compared to SD rats. Exposure to preeclampsia differentially altered the miRNA profiles of circulating EVPD in transgenic preeclampsia rats at both LG and PP-2M. The identified miRNA targets were associated with key vascular and cellular regulatory pathways, suggesting a mechanistic link between placental dysfunction and postpartum vascular alterations in this preeclampsia model. Overall, this study suggests that the TGA-PE rat model could be a valuable platform to study the mechanistic link between preeclampsia and cerebrovascular disease.

bioinformatics↗

bioRxiv2025

Dietary nitrate and nitrite protect against doxorubicin-induced cardiac fibrosis and oxidative protein damage in tumor-bearing mice

Anthracycline-induced cardiotoxicity remains a major limitation in cancer therapy, affecting long-term cardiovascular health in survivors. Dietary nitrate supplementation has shown cardioprotective effects in preclinical models of doxorubicin (Dox)-induced and ischemia-reperfusion injury. In this study, we evaluated the protective effects of nitrate and nitrite (NOx) supplementation in a syngeneic, tumor-bearing mouse model undergoing Dox chemotherapy (N=5 per group). NOx supplementation significantly reduced cardiac fibrosis and levels of 4-hydroxynonenal-modified proteins, a marker of oxidative stress. Tumor sizes varied, but most regressed by the final Dox dose. Importantly, NOx did not compromise the anti-tumor efficacy of Dox nor did it promote pulmonary metastasis. These findings support the potential clinical use of dietary nitrate and nitrite as adjuncts to Dox treatment to mitigate cardiotoxicity without impairing anti-cancer outcomes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/660942v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ec0e52org.highwire.dtl.DTLVardef@a03beaorg.highwire.dtl.DTLVardef@1bdb02eorg.highwire.dtl.DTLVardef@79d23e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Sex Differences in Middle Cerebral Artery Reactivity and Hemodynamics Independent from Changes in Systemic Arterial Stiffness in Adult Sprague-Dawley Rats

Young women are protected against cerebrovascular disease compared with men. However, the underlying mechanisms of sex differences in cerebrovascular function are not well understood. In this study, we determined whether sex differences in middle cerebral artery (MCA) reactivity are accompanied with changes in cerebral or systemic arterial resistance and stiffness in adult 25-week-old Sprague-Dawley (SD) rats. No differences in systolic or diastolic blood pressures were observed between sexes. Heart rate was higher in the female versus male SD. Left MCA pulsatility index (PI) was lower in female versus male SD, while no differences in left intracranial internal carotid artery (ICA) PI was observed between sexes. There were no differences in thoracic aorta or left common carotid artery pulse wave velocity (PWV) between sexes. In isolated MCA segments, female left MCA had lower contraction to potassium, but similar maximal contraction and sensitivity to thromboxane A2 receptor agonist U46619. Pre-incubation with indomethacin lowered maximal response and sensitivity to U46619 in male MCA but not female MCA suggesting that vasoconstrictor prostaglandins may have a greater role in male MCA vs. female MCA. Endothelial nitric oxide synthase (eNOS) and vascular smooth muscle layer thromboxane A2 receptor immunoreactivity were greater in female versus male SD. We conclude that sex differences in the MCA reactivity are associated with a differential functional profile of MCA in adult SD rats independent from changes in systemic PWV. NEW & NOTEWORTHYDespite the debilitating effects of cerebrovascular disease in women, the basis for sex differences in cerebrovascular dysfunction remains incompletely understood. Our study demonstrated that middle cerebral artery reactivity and hemodynamics are not accompanied by changes in central pulse wave velocity in mature adult Sprague-Dawley rats suggesting different mechanisms underlying baseline vascular reactivity of cerebral versus systemic arterial beds.

physiology↗

bioRxiv2023

Photoacoustic Imaging for Non-Invasive Assessment of Physiological Biomarkers of Intestinal Injury in Experimental Necrotizing Enterocolitis

BackgroundNecrotizing enterocolitis (NEC) is an often-lethal disease of the premature infants intestinal tract that is exacerbated by significant difficulties in early and accurate diagnosis. In NEC disease, the intestine often exhibits hypoperfusion and dysmotility, which contributes to advanced disease pathogenesis. However, these physiological features cannot be accurately and quantitively assessed within the current constraints of imaging modalities frequently used in the clinic (plain film X-ray and ultrasound). We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively and quantitively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model. As a first-in-disease application, we evaluated NEC pathogenesis using PAI to assess intestinal health biomarkers in a preclinical neonatal rat experimental model of NEC. MethodsNEC was induced in neonatal rat pups from birth to 4 days old via hypertonic formula feeding, full-body hypoxic stress, and lipopolysaccharide administration to mimic bacterial colonization. Healthy breastfed (BF) controls and NEC rat pups were imaged at 2- and 4-days old. Intestinal tissue oxygen saturation was measured with PAI imaging for oxy- and deoxyhemoglobin levels. To measure intestinal motility, ultrasound and co-registered PAI cine recordings were used to capture intestinal peristalsis motion and contrast agent (indocyanine green) transit within the intestinal lumen. Additionally, both midplane two-dimensional and volumetric three-dimensional imaging acquisitions were assessed for oxygenation and motility. ResultsNEC pups showed a significant decrease of intestinal tissue oxygenation as compared to healthy BF controls at both ages (2-days old: 55.90% +/-3.77% vs 44.12% +/-7.18%; 4-days old: 56.13% +/-3.52% vs 38.86% +/-8.33%). Intestinal motility, assessed using a computational intestinal deformation analysis, demonstrated a significant reduction in the intestinal motility index in both early (2-day) and established (4-day) NEC. Extensive NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay. ConclusionsThis study presents PAI as a successful emerging diagnostic imaging modality for both intestinal tissue oxygenation and intestinal motility disease hallmarks in a rat NEC model. PAI presents enormous significance and potential for fundamentally changing current clinical paradigms for detecting and monitoring intestinal pathologies in the premature infant.

bioengineering↗

bioRxiv2023

Photoacoustic Imaging as a Novel Non-Invasive Biomarker to Assess Intestinal Tissue Oxygenation and Motility in Neonatal Rats

BackgroundWithin the premature infant intestine, oxygenation and motility play key physiological roles in healthy development and disease such as necrotizing enterocolitis. To date, there are limited techniques to reliably assess these physiological functions that are also clinically feasible for critically ill infants. To address this clinical need, we hypothesized that photoacoustic imaging (PAI) can provide non-invasive assessment of intestinal tissue oxygenation and motility to characterize intestinal physiology and health. MethodsUltrasound and photoacoustic images were acquired in 2-day and 4-day old neonatal rats. For PAI assessment of intestinal tissue oxygenation, an inspired gas challenge was performed using hypoxic, normoxic, and hyperoxic inspired oxygen (FiO2). For intestinal motility, oral administration of ICG contrast agent was used to compare control animals to an experimental model of loperamide-induced intestinal motility inhibition. ResultsPAI demonstrated progressive increases in oxygen saturation (sO2) as FiO2 increased, while the pattern of oxygen localization remained relatively consistent in both 2-day and 4-day old neonatal rats. Analysis of intraluminal ICG contrast enhanced PAI images yielded a map of the motility index in control and loperamide treated rats. From PAI analysis, loperamide significantly inhibited intestinal motility, with a 32.6% decrease in intestinal motility index scores in 4-day old rats. ConclusionThese data establish the feasibility and application of PAI to non-invasively and quantitatively measure intestinal tissue oxygenation and motility. This proof-of-concept study is an important first step in developing and optimizing photoacoustic imaging to provide valuable insight into intestinal health and disease to improve the care of premature infants. HighlightsO_LIIntestinal tissue oxygenation and intestinal motility are important biomarkers of intestinal physiology in health and disease of premature infants. C_LIO_LIThis proof-of-concept preclinical rat study is the first to report application of photoacoustic imaging for the neonatal intestine. C_LIO_LIPhotoacoustic imaging is demonstrated as a promising non-invasive diagnostic imaging method for quantifying intestinal tissue oxygenation and intestinal motility in premature infants. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=145 HEIGHT=200 SRC="FIGDIR/small/545971v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@585d0forg.highwire.dtl.DTLVardef@145a2bcorg.highwire.dtl.DTLVardef@bf0c46org.highwire.dtl.DTLVardef@bed354_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Sulfonylureas target the neurovascular response to decrease Alzheimer's pathology

Hyperexcitability is a defining feature of Alzheimers disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATP channels, thereby stimulating insulin release. However, KATP channels are not limited to the pancreas and systemic modulation of KATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (A{beta}), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD. Graphical abstractTargeting vascular KATP channel activity for the treatment of Alzheimers disease pathology. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗