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Article ; Online: Behavioral analysis through the lifespan of

Pluimer, Brock R / Harrison, Devin L / Boonyavairoje, Chanon / Prinssen, Eric P / Rogers-Evans, Mark / Peterson, Randall T / Thyme, Summer B / Nath, Anjali K

iScience

2023 Volume 26, Issue 7, Page(s) 107099

Abstract: ... ...

Abstract	DISC1
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107099
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Article ; Online: Electrical impedance myography detects age-related skeletal muscle atrophy in adult zebrafish.

Rutkove, Seward B / Callegari, Santiago / Concepcion, Holly / Mourey, Tyler / Widrick, Jeffrey / Nagy, Janice A / Nath, Anjali K

Scientific reports

2023 Volume 13, Issue 1, Page(s) 7191

Abstract: Age-related deficits in skeletal muscle function, termed sarcopenia, are due to loss of muscle mass and changes in the intrinsic mechanisms underlying contraction. Sarcopenia is associated with falls, functional decline, and mortality. Electrical ... ...

Abstract	Age-related deficits in skeletal muscle function, termed sarcopenia, are due to loss of muscle mass and changes in the intrinsic mechanisms underlying contraction. Sarcopenia is associated with falls, functional decline, and mortality. Electrical impedance myography (EIM)-a minimally invasive, rapid electrophysiological tool-can be applied to animals and humans to monitor muscle health, thereby serving as a biomarker in both preclinical and clinical studies. EIM has been successfully employed in several species; however, the application of EIM to the assessment of zebrafish-a model organism amenable to high-throughput experimentation-has not been reported. Here, we demonstrated differences in EIM measures between the skeletal muscles of young (6 months of age) and aged (33 months of age) zebrafish. For example, EIM phase angle and reactance at 2 kHz showed significantly decreased phase angle (5.3 ± 2.1 versus 10.7 ± 1.5°; p = 0.001) and reactance (89.0 ± 3.9 versus 172.2 ± 54.8 ohms; p = 0.007) in aged versus young animals. Total muscle area, in addition to other morphometric features, was also strongly correlated to EIM 2 kHz phase angle across both groups (r = 0.7133, p = 0.01). Moreover, there was a strong correlation between 2 kHz phase angle and established metrics of zebrafish swimming performance, including turn angle, angular velocity, and lateral motion (r = 0.7253, r = 0.7308, r = 0.7857, respectively, p < 0.01 for all). In addition, the technique was shown to have high reproducibility between repeated measurements with a mean percentage difference of 5.34 ± 1.17% for phase angle. These relationships were also confirmed in a separate replication cohort. Together, these findings establish EIM as a fast, sensitive method for quantifying zebrafish muscle function and quality. Moreover, identifying the abnormalities in the bioelectrical properties of sarcopenic zebrafish provides new opportunities to evaluate potential therapeutics for age-related neuromuscular disorders and to interrogate the disease mechanisms of muscle degeneration.
MeSH term(s)	Humans ; Animals ; Zebrafish ; Sarcopenia ; Electric Impedance ; Reproducibility of Results ; Myography/methods ; Muscle, Skeletal/physiology ; Atrophy
Language	English
Publishing date	2023-05-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-34119-6
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Article: Surface Electrical Impedance Myography Detects Skeletal Muscle Atrophy in Aged Wildtype Zebrafish and Aged

Rutkove, Seward B / Chen, Zsu-Zsu / Pandeya, Sarbesh / Callegari, Santiago / Mourey, Tyler / Nagy, Janice A / Nath, Anjali K

Biomedicines

2023 Volume 11, Issue 7

Abstract: Throughout a vertebrate organism's lifespan, skeletal muscle mass and function progressively decline. This age-related condition is termed sarcopenia. In humans, sarcopenia is associated with risk of falling, cardiovascular disease, and all-cause ... ...

Abstract	Throughout a vertebrate organism's lifespan, skeletal muscle mass and function progressively decline. This age-related condition is termed sarcopenia. In humans, sarcopenia is associated with risk of falling, cardiovascular disease, and all-cause mortality. As the world population ages, projected to reach 2 billion older adults worldwide in 2050, the economic burden on the healthcare system is also projected to increase considerably. Currently, there are no pharmacological treatments for sarcopenia, and given the long-term nature of aging studies, high-throughput chemical screens are impractical in mammalian models. Zebrafish is a promising, up-and-coming vertebrate model in the field of sarcopenia that could fill this gap. Here, we developed a surface electrical impedance myography (sEIM) platform to assess skeletal muscle health, quantitatively and noninvasively, in adult zebrafish (young, aged, and genetic mutant animals). In aged zebrafish (~85% lifespan) as compared to young zebrafish (~20% lifespan), sEIM parameters (2 kHz phase angle, 2 kHz reactance, and 2 kHz resistance) robustly detected muscle atrophy (
Language	English
Publishing date	2023-07-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11071938
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Article ; Online: Investigating the Replacement of Carboxylates with Carboxamides to Modulate the Safety and Efficacy of Platinum(II) Thioether Cyanide Scavengers.

Behymer, Matthew M / Mo, Huaping / Fujii, Naoaki / Suresh, Vallabh / Arzumanian, Ari S / Chan, Adriano / Nath, Anjali K / McCain, Robyn / MacRae, Calum A / Peterson, Randall / Boss, Gerry R / Davisson, Vincent Jo / Knipp, Gregory T

Toxicological sciences : an official journal of the Society of Toxicology

2023

Abstract: Cyanide represents a persistent threat for accidental or malicious misuse due to easy conversion into a toxic gas and access to large quantities through several industries. The high safety index of hydroxocobalamin is a cornerstone quality as a cyanide ... ...

Abstract	Cyanide represents a persistent threat for accidental or malicious misuse due to easy conversion into a toxic gas and access to large quantities through several industries. The high safety index of hydroxocobalamin is a cornerstone quality as a cyanide scavenger. Unfortunately, intravenous infusion of hydroxocobalamin limits the utility in a mass casualty setting. We previously reported platinum(II) [Pt(II)] complexes with trans-directing sulfur ligands as an efficacious alternative to hydroxocobalamin when delivered by a bolus intramuscular injection in mice and rabbits. Thus, to enable Pt(II) as an alternative to hydroxocobalamin, a high safety factor is needed. The objective is to maintain efficacy and mitigate the risk for nephrotoxicity. Platinum amino acid complexes with the ability to form five- or six-membered rings and possessing either carboxylates or carboxamides are evaluated in vitro for cyanide scavenging. In vivo efficacy was evaulated in the zebrafish and mice cyanide exposure models. In addition, Pt(II) complex toxicity and pharmacokinetics were evaluated in a cyanide naive Sprague-Dawley model. Doses for toxicity are escalated to 5x from the efficacious dose in mice using a body surface area adjustment. The results show the carboxamide ligands display a time and pH dependence on cyanide scavenging in vitro and efficacy in vivo. Additionally, exchanging the carboxylate for carboxamide showed reduced indications of renal injury. A pharmacokinetic analysis of the larger bidentate complexes displayed rapid absorption by intramuscular administration and having similar plasma exposure. These findings point to the importance of pH and ligand structures for methionine carboxamide complexes with Pt(II).
Language	English
Publishing date	2023-11-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfad119
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Article ; Online: Top2a promotes the development of social behavior via PRC2 and H3K27me3.

Geng, Yijie / Zhang, Tejia / Alonzo, Ivy G / Godar, Sean C / Yates, Christopher / Pluimer, Brock R / Harrison, Devin L / Nath, Anjali K / Yeh, Jing-Ruey Joanna / Drummond, Iain A / Bortolato, Marco / Peterson, Randall T

Science advances

2022 Volume 8, Issue 47, Page(s) eabm7069

Abstract: Little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused ... ...

Abstract	Little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused defects in social interaction and communication, which are behaviors that relate to core symptoms of autism. Mutation of Top2a in zebrafish caused down-regulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets have binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation (H3K27me3). Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of the PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.
Language	English
Publishing date	2022-11-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abm7069
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Article ; Online: Intramuscular administration of glyoxylate rescues swine from lethal cyanide poisoning and ameliorates the biochemical sequalae of cyanide intoxication.

Bebarta, Vik S / Shi, Xu / Zheng, Shunning / Hendry-Hofer, Tara B / Severance, Carter C / Behymer, Matthew M / Boss, Gerry R / Mahon, Sari / Brenner, Matthew / Knipp, Gregory T / Davisson, Vincent Jo / Peterson, Randall T / MacRae, Calum A / Rutter, Jared / Gerszten, Robert E / Nath, Anjali K

Toxicological sciences : an official journal of the Society of Toxicology

2022 Volume 191, Issue 1, Page(s) 90–105

Abstract: Cyanide-a fast-acting poison-is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational exposure in addition to being a terrorist agent. FDA-approved cyanide antidotes must ...

Abstract	Cyanide-a fast-acting poison-is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational exposure in addition to being a terrorist agent. FDA-approved cyanide antidotes must be given intravenously, which is not practical in a mass casualty setting due to the time and skill required to obtain intravenous access. Glyoxylate is an endogenous metabolite that binds cyanide and reverses cyanide-induced redox imbalances independent of chelation. Efficacy and biochemical mechanistic studies in an FDA-approved preclinical animal model have not been reported. Therefore, in a swine model of cyanide poisoning, we evaluated the efficacy of intramuscular glyoxylate on clinical, metabolic, and biochemical endpoints. Animals were instrumented for continuous hemodynamic monitoring and infused with potassium cyanide. Following cyanide-induced apnea, saline control or glyoxylate was administered intramuscularly. Throughout the study, serial blood samples were collected for pharmacokinetic, metabolite, and biochemical studies, in addition, vital signs, hemodynamic parameters, and laboratory values were measured. Survival in glyoxylate-treated animals was 83% compared with 12% in saline-treated control animals (p < .01). Glyoxylate treatment improved physiological parameters including pulse oximetry, arterial oxygenation, respiration, and pH. In addition, levels of citric acid cycle metabolites returned to baseline levels by the end of the study. Moreover, glyoxylate exerted distinct effects on redox balance as compared with a cyanide-chelating countermeasure. In our preclinical swine model of lethal cyanide poisoning, intramuscular administration of the endogenous metabolite glyoxylate improved survival and clinical outcomes, and ameliorated the biochemical effects of cyanide.
MeSH term(s)	Swine ; Animals ; Cyanides/toxicity ; Disease Models, Animal ; Antidotes/pharmacology ; Antidotes/therapeutic use ; Hemodynamics ; Glyoxylates/therapeutic use ; Poisoning/drug therapy
Chemical Substances	Cyanides ; Antidotes ; Glyoxylates
Language	English
Publishing date	2022-11-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfac116
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Article ; Online: Identification of Platinum(II) Sulfide Complexes Suitable as Intramuscular Cyanide Countermeasures.

Behymer, Matthew M / Mo, Huaping / Fujii, Naoaki / Suresh, Vallabh / Chan, Adriano / Lee, Jangweon / Nath, Anjali K / Saha, Kusumika / Mahon, Sari B / Brenner, Matthew / MacRae, Calum A / Peterson, Randall / Boss, Gerry R / Knipp, Gregory T / Davisson, Vincent Jo

Chemical research in toxicology

2022 Volume 35, Issue 11, Page(s) 1983–1996

Abstract: The development of rapidly acting cyanide countermeasures using intramuscular injection (IM) represents an unmet medical need to mitigate toxicant exposures in mass casualty settings. Previous work established that cisplatin and other platinum(II) or ... ...

Abstract	The development of rapidly acting cyanide countermeasures using intramuscular injection (IM) represents an unmet medical need to mitigate toxicant exposures in mass casualty settings. Previous work established that cisplatin and other platinum(II) or platinum(IV)-based agents effectively mitigate cyanide toxicity in zebrafish. Cyanide's
MeSH term(s)	Mice ; Rabbits ; Animals ; Platinum/chemistry ; Zebrafish ; Cyanides ; Dimethyl Sulfoxide ; Ligands ; Sulfides ; Antineoplastic Agents/pharmacology
Chemical Substances	Platinum (49DFR088MY) ; Cyanides ; Dimethyl Sulfoxide (YOW8V9698H) ; Ligands ; Sulfides ; Antineoplastic Agents
Language	English
Publishing date	2022-10-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.2c00157
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Article: Weight Loss Outcomes Among Early High Responders to Exenatide Treatment: A Randomized, Placebo Controlled Study in Overweight and Obese Women.

Rodgers, Megan / Migdal, Alexandra L / Rodríguez, Tahereh Ghorbani / Chen, Zsu-Zsu / Nath, Anjali K / Gerszten, Robert E / Kasid, Natasha / Toschi, Elena / Tripaldi, Juliet / Heineman, Brent / Phan, Minh / Ngo, Long / Maratos-Flier, Eleftheria / Dushay, Jody

Frontiers in endocrinology

2021 Volume 12, Page(s) 742873

Abstract: Objective: As there is significant heterogeneity in the weight loss response to pharmacotherapy, one of the most important clinical questions in obesity medicine is how to predict an individual's response to pharmacotherapy. The present study examines ... ...

Abstract	Objective: As there is significant heterogeneity in the weight loss response to pharmacotherapy, one of the most important clinical questions in obesity medicine is how to predict an individual's response to pharmacotherapy. The present study examines patterns of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment compared to those treated with hypocaloric diet and matched placebo injections. Methods: We randomized 182 women (BMI 25-48 kg/m2) to treatment with exenatide alone or matched placebo injections plus hypocaloric diet. In both treatment groups, women who demonstrated ≥ 5% weight loss at 12 weeks were characterized as high responders and those who lost ≥10% of body weight were classified as super responders. Our primary outcome was long-term change in body weight among early high responders to either treatment. An exploratory metabolomic analysis was also performed. Results: We observed individual variability in weight loss with both exenatide and hypocaloric diet plus placebo injections. There was a trend toward a higher percentage of subjects who achieved ≥ 5% weight loss with exenatide compared to diet (56% of those treated with exenatide, 76% of those treated with diet, p = 0.05) but no significant difference in those who achieved ≥ 10% weight loss (23% of individuals treated with exenatide and 36% of those treated with diet, p = 0.55). In both treatment groups, higher weight loss at 3 months of treatment predicted super responder status (diet p=0.0098, exenatide p=0.0080). Both treatment groups also demonstrated similar peak weight loss during the study period. We observed lower cysteine concentrations in the exenatide responder group (0.81 Conclusion: In a population of early high responders, longer term weight loss with exenatide treatment is similar to that achieved with a hypocaloric diet. Clinical trial registration: www.clinicaltrialsgov, identifier NCT01590433.
MeSH term(s)	Adult ; Anti-Obesity Agents/therapeutic use ; Body Mass Index ; Combined Modality Therapy ; Cysteine/metabolism ; Diet, Reducing ; Double-Blind Method ; Exenatide/therapeutic use ; Female ; Humans ; Metabolomics ; Middle Aged ; Obesity/drug therapy ; Overweight/drug therapy ; Treatment Outcome ; Weight Loss
Chemical Substances	Anti-Obesity Agents ; Exenatide (9P1872D4OL) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2021-11-17
Publishing country	Switzerland
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2021.742873
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Article: Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19.

Schmaier, Alec A / Hurtado, Gabriel Pajares / Manickas-Hill, Zachary J / Sack, Kelsey D / Chen, Siyu M / Bhambhani, Victoria / Quadir, Juweria / Nath, Anjali K / Collier, Ai-Ris Y / Ngo, Debby / Barouch, Dan H / Gerszten, Robert E / Yu, Xu G / Peters, Kevin / Flaumenhaft, Robert / Parikh, Samir M

medRxiv : the preprint server for health sciences

2021

Abstract: Profound endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. In the quiescent state, the endothelial surface is anticoagulant, a property maintained at least in part via constitutive signaling through ... ...

Abstract	Profound endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. In the quiescent state, the endothelial surface is anticoagulant, a property maintained at least in part via constitutive signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from activated endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant dysfunction of the endothelium and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. On lung autopsy specimens from COVID-19 patients, we found a prothrombotic endothelial signature as evidenced by increased von Willebrand Factor and loss of anticoagulant proteins. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed profound endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Moreover, our findings provide novel rationale for current trials of Tie2 activating therapy with AKB-9778 in severe COVID-19 disease.
Language	English
Publishing date	2021-05-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.05.13.21257070
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Article: The roles of nitric oxide in murine cardiovascular development.

Nath, Anjali K / Madri, Joseph A

Developmental biology

2006 Volume 292, Issue 1, Page(s) 25–33

Abstract: Nitric oxide (NO) participates in a diverse array of biological functions in mammalian organ systems. Depending on the biochemical environment, the production of NO may result in cytoprotection or cytotoxicity. The paradoxical actions of NO arise from ... ...

Abstract	Nitric oxide (NO) participates in a diverse array of biological functions in mammalian organ systems. Depending on the biochemical environment, the production of NO may result in cytoprotection or cytotoxicity. The paradoxical actions of NO arise from the complexities generated by the redox milieu, NO concentration/bioavailability, and tissue/cell context, which ultimately result in the wide range of regulatory roles observed. Additionally, in physiological versus pathological states, NO often displays diametrically opposing affects in several organ systems. Here, we will discuss the roles of NO during reproduction, organ system development, in particular, the cardiovascular system, and its potential implications in diabetes-induced fetal defects.
MeSH term(s)	Animals ; Cardiovascular System/embryology ; Cardiovascular System/metabolism ; Cardiovascular System/pathology ; Cardiovascular System/physiopathology ; Diabetes Mellitus, Experimental/embryology ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Experimental/physiopathology ; Humans ; Mice ; Nitric Oxide/physiology
Chemical Substances	Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2006-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2005.12.039
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