Effect of amlodipine on the circulating renin-angiotensin-aldosterone system in healthy cats

Background: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin-angiotensin-aldosterone system (RAAS) in cats is incompletely characterized.Hypothesis/Objectives: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. Animals: Twenty healthy client-owned cats. Methods: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4-week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time-weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank-sum testing. Results: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%-86%; P = .009), angiotensin I (59% increase; IQR 27-101%; P = .006), angiotensin II (56% increase; IQR 5-70%; P = .023), angiotensin IV (42% increase; −19% to 89%; P = .013); and angiotensin 1-7 (38% increase; IQR 9-118%; P = .015). Conclusions and Clinical Importance: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways.This article is published as Garcia Marrero, Tatiana M., Jessica L. Ward, Melissa A. Tropf, Agnes Bourgois‐Mochel, Emilie Guillot, Oliver Domenig, Lingnan Yuan, Debosmita Kundu, and Jonathan P. Mochel. "Effect of amlodipine on the circulating renin‐angiotensin‐aldosterone system in healthy cats." Journal of Veterinary Internal Medicine (2024). doi: https://doi.org/10.1111/jvim.17006. © 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs

Establishment and characterization of turtle liver organoids provides a potential model to decode their unique adaptations

Painted turtles are remarkable for their freeze tolerance and supercooling ability along with their associated resilience to hypoxia/anoxia and oxidative stress, rendering them an ideal biomedical model for hypoxia-induced injuries (including strokes), tissue cooling during surgeries, and organ cryopreservation. Yet, such research is hindered by their seasonal reproduction and slow maturation. Here we developed and characterized adult stem cell-derived turtle liver organoids (3D self-assembled in vitro structures) from painted, snapping, and spiny softshell turtles spanning ~175My of evolution, with a subset cryopreserved. This development is, to the best of our knowledge, a first for this vertebrate Order, and complements the only other non-avian reptile organoids from snake venom glands. Preliminary characterization, including morphological, transcriptomic, and proteomic analyses, revealed organoids enriched in cholangiocytes. Deriving organoids from distant turtles and life stages demonstrates that our techniques are broadly applicable to chelonians, permitting the development of functional genomic tools currently lacking in herpetological research. Such platform could potentially support studies including genome-to-phenome mapping, gene function, genome architecture, and adaptive responses to climate change, with implications for ecological, evolutionary, and biomedical research

Blood product usage and factors associated with transfusions in cats with hemoperitoneum: 33 cases (2018–2022)

Objective: To evaluate blood product usage in cats with hemoperitoneum. To secondarily evaluate factors associated with transfusion administration and the outcome of cats with hemoperitoneum. Design: Retrospective study between the years 2018–2022. Setting: University veterinary teaching hospital and private practice hospital. Animals: 33 cats admitted to the hospital diagnosed with hemoperitoneum from January 2018 to September 2022. Measurements and main results: Medical records were retrospectively reviewed; signalment, point-of-care diagnostics, effusion characteristics, and transfusion administration information was recorded. The most common etiology associated with hemoperitoneum was neoplasia (51.5%). Fifty-one percent (51.5%) of cats received a blood transfusion during hospitalization with the majority of cats receiving multiple transfusion types (69%). The etiology of hemoperitoneum was not associated with receiving a transfusion (p = 0.28) Point-of-care diagnostics including packed cell volume (PCV), total solids (TS) and platelet count were not significantly associated with receiving a transfusion (p = 0.317, p = 0.11 and p = 0.82, respectively). The PCV and TS of the effusion was also not significantly associated with transfusions (p = 0.91 and p = 0.63, respectively). Sixteen cats (48%) survived to discharge. Transfusions were significantly associated with outcome and cats that received a transfusion were more likely to survive to discharge (p = 0.008). Conclusion: In conclusion, hemoperitoneum from a variety of etiologies in cats is associated with a high proportion of transfusions. None of the evaluated point-of-care diagnostics were associated with transfusion administration in this study. Cats that received a transfusion were more likely to survive to discharge.This article is published as Bunnell N, Blong A, Kundu D, Mochel JP and Walton R (2023) Blood product usage and factors associated with transfusions in cats with hemoperitoneum: 33 cases (2018–2022). Front. Vet. Sci. 10:1204864. doi: 10.3389/fvets.2023.1204864. Posted with permission.This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms

Effect of amlodipine on the circulating renin‐angiotensin‐aldosterone system in healthy cats

Abstract Background Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin‐angiotensin‐aldosterone system (RAAS) in cats is incompletely characterized. Hypothesis/Objectives To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. Animals Twenty healthy client‐owned cats. Methods Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4‐week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time‐weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank‐sum testing. Results Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%‐86%; P = .009), angiotensin I (59% increase; IQR 27‐101%; P = .006), angiotensin II (56% increase; IQR 5‐70%; P = .023), angiotensin IV (42% increase; −19% to 89%; P = .013); and angiotensin 1‐7 (38% increase; IQR 9‐118%; P = .015). Conclusions and Clinical Importance In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways

Effect of the Probiotic <i>Bacillus subtilis</i> DE-CA9^TM on Fecal Scores, Serum Oxidative Stress Markers and Fecal and Serum Metabolome in Healthy Dogs

Background: There is increasing interest in the use of Bacillus species as probiotics since their spore-forming ability favors their survival in the acidic gastric environment over other probiotic species. The subsequent germination of B. subtilis to their vegetative form allows for their growth in the small intestine and may increase their beneficial effect on the host. B. subtilis strains have also previously been shown to have beneficial effects in humans and production animals, however, no reports are available so far on their use in companion animals. Study design: The goal of this study was therefore to investigate the daily administration of 1 × 109 cfu DE-CA9TM orally per day versus placebo on health parameters, fecal scores, fecal microbiome, fecal metabolomics, as well as serum metabolomics and oxidative stress markers in ten healthy Beagle dogs in a parallel, randomized, prospective, placebo-controlled design over a period of 45 days. Results: DE-CA9TM decreased the oxidative status compared to controls for advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances (TBARS) and reactive oxygen metabolites (d-ROMS), suggesting an antioxidant effect of the treatment. Fecal metabolomics revealed a significant reduction in metabolites associated with tryptophan metabolism in the DE-CA9TM-treated group. DE-CA9TM also significantly decreased phenylalanine and homocysteine and increased homoserine and threonine levels. Amino acid metabolism was also affected in the serum metabolome, with increased levels of urea and cadaverine, and reductions in N-acetylornithine in DE-CA9TM compared to controls. Similarly, changes in essential amino acids were observed, with a significant increase in tryptophan and lysine levels and a decrease in homocysteine. An increase in serum guanine and deoxyuridine was also detected, with a decrease in beta-alanine in the animals that ingested DE-CA9TM. Conclusions: Data generated throughout this study suggest that the daily administration of 1 × 109 cfu of DE-CA9TM in healthy Beagle dogs is safe and does not affect markers of general health and fecal scores. Furthermore, DE-CA9TM administration had a potential positive effect on some serum markers of oxidative stress, and protein and lipid metabolism in serum and feces

Characterization of the First Turtle Organoids: A Model for Investigating Unique Adaptations with Biomedical Potential

Painted turtles are remarkable for their well-developed freeze tolerance and associated resilience to hypoxia/anoxia, oxidative stress, and ability to supercool. They are, therefore, an ideal model for biomedical research on hypoxia-induced injuries (including strokes), tissue cooling during extensive surgeries, and organ cryopreservation. Yet, the seasonal reproduction and slow maturation of turtles hinder basic and applied biomedical research. To overcome these limitations, we developed the first adult stem cell-derived turtle hepatic organoids, which provide 3D self-assembled structures that mimic their original tissue and allow for in vitro testing and experimentation without constantly harvesting donor tissue and screening offspring. Our pioneering work with turtles represents the first for this vertebrate Order and complements the only other organoid lines from non-avian reptiles, derived from snake venom glands. Here we report the isolation and characterization of hepatic organoids derived from painted, snapping, and spiny softshell turtles spanning ∼175 million years of evolution, with a subset being preserved in a biobank. Morphological and transcriptomics revealed organoid cells resembling cholangiocytes, which was then compared to the tissue of origin. Deriving turtle organoids from multiple species and life stages demonstrates that our techniques are broadly applicable to chelonians, permitting the development of functional genomic tools currently missing in most herpetological research. When combined with genetic editing, this platform will further support studies of genome-to-phenome mapping, gene function, genome architecture, and adaptive responses to climate change, among others. We discuss the unique abilities of turtles, including their overwintering potential, which has implications for ecological, evolutionary, and biomedical research.This is a pre-print of the article Zdyrski, Christopher, Vojtech Gabriel, Thea B. Gessler, Abigail Ralston, Itzel Sifuentes-Romero, Debosmita Kundu, Sydney Honold et al. "Characterization of the First Turtle Organoids: A Model for Investigating Unique Adaptations with Biomedical Potential." bioRxiv (2023): 2023-02. DOI: 10.1101/2023.02.20.527070. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). Copyright 2023. The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. Posted with permission

A Preclinical Model of Obesity-Independent Metabolic Syndrome for Studying the Effects of Novel Antidiabetic Therapy Beyond Glycemic Control

Accumulating data from several large, placebo-controlled studies suggests that sodium-glucose transporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor (GLP-1) receptor agonists offer therapeutic benefits in the management of cardiovascular diseases, regardless of the patient's diabetic status. In addition to their effects on glucose excretion, SGLT2-inhibitors have a positive impact on systemic metabolism by reducing inflammation and oxidative stress, shifting metabolism towards ketone body production, and suppressing glycation end-product signaling. The aim of this study was to establish a non-invasive preclinical model of metabolic syndrome (MetS) to investigate the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed isocalorically a Western diet (WD) adjusted from parameters of the National Health and Nutrition Examination Survey for ten weeks. Blood samples were collected at baseline (BAS1) when dogs were fed their regular diet, and then again after ten weeks of WD feeding (BAS2) for measurement of blood count and serum chemistry, lipoprotein profiling, fasting blood glucose, glucagon, insulin, NT-proBNP, BUN, creatinine, angiotensins and oxidative stress biomarkers. Blood pressure (BP) was measured at BAS1 and BAS2 using Doppler. Serum, urine and fecal metabolomics were derived by mass spectrometry to assess general metabolism, complex lipids and biogenic amines. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed rank testing with continuity correction, as appropriate. Body weight changes did not exceed 13% after ten weeks of feeding with the WD. The isocaloric WD model induced significant variations in several markers of MetS, including (1) elevated BP, (2) increased fasting glucose levels, and (3) reduced HDL-cholesterol. It also triggered a significant decrease in circulating insulin, as well as an increase in circulating NT-proBNP levels and a decrease in serum bicarbonate levels. Marked and significant changes in overall metabolism, lipids, and biogenic amines were finally reported at BAS2. Short-term, isocaloric feeding with a WD in dogs replicates key biological features of MetS, while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.This is a preprint from Mochel, Jonathan P., Jessica L. Ward, Thomas Blondel, Debosmita Kundu, Maria M. Merodio, Claudine Zemirline, Emilie Guillot et al. "A Preclinical Model of Obesity-Independent Metabolic Syndrome for Studying the Effects of Novel Antidiabetic Therapy Beyond Glycemic Control." (2023). doi: https://doi.org/10.21203/rs.3.rs-3569600/v1. Copyright The Authors 2023. This work is licensed under a Creative Commons Attribution 4.0 International License