Long bone histomorphogenesis of the naked mole‐rat: Histodiversity and intraspecific variation.
ONTOGENY; bone microstructure; bone modeling; endosteal bone; Heterocephalus glaber; lamellar bone; long bone growth; BONE growth; BODY temperature; HYPOTHERMIA; lamellar‐zonal bone; MORPHOGENESIS; NAKED mole rat; PERIOSTEUM; POLARIZATION microscopy; STRAINS & stresses (Mechanics)
Lacking fur, living in eusocial colonies and having the longest lifespan of any rodent, makes naked mole‐rats (NMRs) rather peculiar mammals. Although they exhibit a high degree of polymorphism, skeletal plasticity and are considered a novel model to assess the effects of delayed puberty on the skeletal system, scarce information on their morphogenesis exists. Here, we examined a large ontogenetic sample (n = 76) of subordinate individuals to assess the pattern of bone growth and bone microstructure of fore‐ and hindlimb bones by using histomorphological techniques. Over 290 undecalcified thin cross‐sections from the midshaft of the humerus, ulna, femur, and tibia from pups, juveniles and adults were analyzed with polarized light microscopy. Similar to other fossorial mammals, NMRs exhibited a systematic cortical thickening of their long bones, which clearly indicates a conserved functional adaptation to withstand the mechanical strains imposed during digging, regardless of their chisel‐tooth predominance. We describe a high histodiversity of bone matrices and the formation of secondary osteons in NMRs. The bones of pups are extremely thin‐walled and grow by periosteal bone formation coupled with considerable expansion of the medullary cavity, a process probably tightly regulated and adapted to optimize the amount of minerals destined for skeletal development, to thus allow the female breeder to produce a higher number of pups, as well as several litters. Subsequent cortical thickening in juveniles involves high amounts of endosteal bone apposition, which contrasts with the bone modeling of other mammals where a periosteal predominance exists. Adults have bone matrices predominantly consisting of parallel‐fibered bone and lamellar bone, which indicate intermediate to slow rates of osteogenesis, as well as the development of poorly vascularized lamellar‐zonal tissues separated by lines of arrested growth (LAGs) and annuli. These features reflect the low metabolism, low body temperature and slow growth rates reported for this species, as well as indicate a cyclical pattern of osteogenesis. The presence of LAGs in captive individuals was striking and indicates that postnatal osteogenesis and its consequent cortical stratification most likely represents a plesiomorphic thermometabolic strategy among endotherms which has been suggested to be regulated by endogenous rhythms. However, the generalized presence of LAGs in this and other subterranean taxa in the wild, as well as recent investigations on variability of environmental conditions in burrow systems, supports the hypothesis that underground environments experience seasonal fluctuations that may influence the postnatal osteogenesis of animals by limiting the extension of burrow systems during the unfavorable dry seasons and therefore the finding of food resources. Additionally, the intraspecific variation found in the formation of bone tissue matrices and vascularization suggested a high degree of developmental plasticity in NMRs, which may help explaining the polymorphism reported for this species. The results obtained here represent a valuable contribution to understanding the relationship of several aspects involved in the morphogenesis of the skeletal system of a mammal with extraordinary adaptations. [ABSTRACT FROM AUTHOR]
Montoya‐Sanhueza G; Bennett NC; Oosthuizen MK; Dengler‐Crish CM; Chinsamy A
Journal Of Anatomy
2021
2021-06
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journalArticle
<a href="http://doi.org/10.1111/joa.13381" target="_blank" rel="noreferrer noopener">10.1111/joa.13381</a>
Acoustilytix™: A Web-Based Automated Ultrasonic Vocalization Scoring Platform.
addiction; automated scoring; dopamine; drug development; drug discovery; machine learning; mental health; ultrasonic vocalization
Ultrasonic vocalizations (USVs) are known to reflect emotional processing, brain neurochemistry, and brain function. Collecting and processing USV data is manual, time-intensive, and costly, creating a significant bottleneck by limiting researchers' ability to employ fully effective and nuanced experimental designs and serving as a barrier to entry for other researchers. In this report, we provide a snapshot of the current development and testing of Acoustilytix™, a web-based automated USV scoring tool. Acoustilytix implements machine learning methodology in the USV detection and classification process and is recording-environment-agnostic. We summarize the user features identified as desirable by USV researchers and how these were implemented. These include the ability to easily upload USV files, output a list of detected USVs with associated parameters in csv format, and the ability to manually verify or modify an automatically detected call. With no user intervention or tuning, Acoustilytix achieves 93% sensitivity (a measure of how accurately Acoustilytix detects true calls) and 73% precision (a measure of how accurately Acoustilytix avoids false positives) in call detection across four unique recording environments and was superior to the popular DeepSqueak algorithm (sensitivity = 88%; precision = 41%). Future work will include integration and implementation of machine-learning-based call type classification prediction that will recommend a call type to the user for each detected call. Call classification accuracy is currently in the 71-79% accuracy range, which will continue to improve as more USV files are scored by expert scorers, providing more training data for the classification model. We also describe a recently developed feature of Acoustilytix that offers a fast and effective way to train hand-scorers using automated learning principles without the need for an expert hand-scorer to be present and is built upon a foundation of learning science. The key is that trainees are given practice classifying hundreds of calls with immediate corrective feedback based on an expert's USV classification. We showed that this approach is highly effective with inter-rater reliability (i.e., kappa statistics) between trainees and the expert ranging from 0.30-0.75 (average = 0.55) after only 1000-2000 calls of training. We conclude with a brief discussion of future improvements to the Acoustilytix platform.
Ashley CB; Snyder RD; Shepherd JE; Cervantes C; Mittal N; Fleming S; Bailey J; Nievera MD; Souleimanova SI; Nyaoga B; Lichtenfeld L; Chen AR; Maddox WT; Duvauchelle CL
Brain Sciences
2021
2021-06-29
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journalArticle
<a href="http://doi.org/10.3390/brainsci11070864" target="_blank" rel="noreferrer noopener">10.3390/brainsci11070864</a>
Fragment based screening and hit-based substructure search: Rapid discovery of 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic, nanomolar metallo β-lactamase inhibitor.
Metallo-β-lactamases (MBLs) are zinc containing carbapenemases that inactivate a broad range of β-lactam antibiotics. There is a lack of β-lactamase inhibitors for restoring existing β-lactam antibiotics arsenals against common bacterial infections. Fragment based screening of a non-specific metal chelator library demonstrates 8-hydroxyquinoline as a broad-spectrum nanomolar inhibitor against VIM-2 and NDM-1. A hit-based substructure search provided an early structure activity relationship of 8-hydroxyquinolines and identified 8-hydroxyquinoline-7-carboxylic acid as a low cytotoxic β-lactamase inhibitor that can restore β-lactam activity against VIM-2 expressing E. coli. Molecular modeling further shed structural insight into its potential mode of binding within the dinuclear zinc active site. 8-Hydroxyquinoline-7-carboxylic acid is highly stable in human plasma and human liver microsomal study, making it an ideal lead candidate for further development.
Shin WS; Nguyen ME; Bergstrom A; Jennings IR; Crowder MW; Muthyala R; Sham YY
Chemical Biology & Drug Design
2021
2021-06-20
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journalArticle
<a href="http://doi.org/10.1111/cbdd.13912" target="_blank" rel="noreferrer noopener">10.1111/cbdd.13912</a>
Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy.
Nucleoside and nucleotide analogs are an essential class of antivirals for COVID-19 treatment. Several nucleoside/nucleotide analogs have shown promising effects against SARS-CoV-2 in vitro ; however, their in vivo efficacy is limited. Nucleoside/nucleotide analogs are often formed as ester prodrugs to improve pharmacokinetics (PK) performance. After entering cells, the prodrugs undergo several enzymatic metabolism steps to form the active metabolite triphosphate nucleoside (TP-Nuc); prodrug activation is therefore associated with the abundance and catalytic activity of the corresponding activating enzymes. Having the activation of nucleoside/nucleotide prodrugs occur at the target site of action, such as the lung, is critical for anti-SARS-CoV-2 efficacy. Herein, we conducted an absolute quantitative proteomics study to determine the expression of relevant activating enzymes in human organs related to the PK and antiviral efficacy of nucleoside/nucleotide prodrugs, including the lung, liver, intestine, and kidney. The protein levels of prodrug-activating enzymes differed significantly among the tissues. Using catalytic activity values reported previously for individual enzymes, we calculated prodrug activation profiles in these tissues. The prodrugs evaluated in this study include nine McGuigan phosphoramidate prodrugs, two cyclic monophosphate prodrugs, two l-valyl ester prodrugs, and one octanoate prodrug. Our analysis showed that most orally administered nucleoside/nucleotide prodrugs were primarily activated in the liver, suggesting that parenteral delivery routes such as inhalation and intravenous infusion could be better options when these antiviral prodrugs are used to treat COVID-19. The results also indicated that the l-valyl ester prodrug design can plausibly improve drug bioavailability and enhance effects against SARS-CoV-2 intestinal infections. This study further revealed that an octanoate prodrug could provide a long-acting antiviral effect targeting SARS-CoV-2 infections in the lung. Finally, our molecular docking analysis suggested several prodrug forms of favipiravir and GS-441524 that are likely to exhibit favorable PK features over existing prodrug forms. In sum, this study revealed the activation mechanisms of various nucleoside/nucleotide prodrugs relevant to COVID-19 treatment in different organs and shed light on the development of more effective anti-COVID-19 prodrugs. (© 2021 American Chemical Society.)
Li J; Liu S; Shi J; Wang X; Xue Y; Zhu H-J
Acs Pharmacology & Translational Science
2021
2021-04-01
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journalArticle
<a href="http://doi.org/10.1021/acsptsci.1c00016" target="_blank" rel="noreferrer noopener">10.1021/acsptsci.1c00016</a>
Oxidative Stress and Hypoxia Modify Mitochondrial Homeostasis During Glaucoma.
glaucoma; oxidative stress; hypoxia; glycolysis; HIF-1α; PGC-1α
Aims: Cellular response to hypoxia can include transition from respiration to glycolysis via upregulation of glycolytic enzymes and transporters, as well as mitophagy induction to eliminate surplus mitochondria. Our purpose was to evaluate the impact of hypoxia-inducible factor-1α (HIF-1α) stabilization on mitochondrial homeostasis and oxidative stress in a chronic model of glaucoma. Results: Retina and optic nerve (ON) were evaluated from young and aged DBA/2J (D2) glaucoma model mice and the control strain, the DBA/2- Gpnmb + . Hypoxic retinal ganglion cells (RGCs) were observed in young and aged D2 retina, with a significant increase in HIF-1α protein in the aged D2 retina. Reactive oxygen species observed in young D2 retina and ON were followed by significant decreases in antioxidant capacity in aged D2 retina and ON. HIF-1α targets such as neuron-specific glucose transporter-3 and lactate dehydrogenase were decreased or unchanged, respectively, in aged D2 retina despite an increased hypoxia response in RGCs. Mitochondrial mass was decreased in aged D2 retina concomitant with decreased mitochondrially encoded electron transport chain transcripts despite a stable nuclear-encoded TFAM (mitochondrial transcription factor), suggesting a breakdown in the nuclear-mitochondrial communication. Decreased mitophagy-associated proteins p62 and Rheb were observed in aged D2 retina, although p62 was significantly increased in the aged D2 ON. Innovation and Conclusion: The increased reactive oxygen species concomitant with HIF-1α upregulation despite reduced glucose transporters, mis-match of nuclear- and mitochondrial-encoded transcripts, and signs of reduced mitophagy suggest that retinas from D2 mice with chronic intraocular pressure elevation transition to pseudohypoxia without consistent metabolic reprogramming before significant RGC loss.
Jassim AH; Fan Y; Pappenhagen N; Nsiah NY; Inman DM
Antioxidants & Redox Signaling
2021
2021-04-29
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journalArticle
<a href="http://doi.org/10.1089/ars.2020.8180" target="_blank" rel="noreferrer noopener">10.1089/ars.2020.8180</a>
Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.
pharmacokinetics; angiotensin-converting enzyme (ACE) inhibitors; Carboxylesterase1 (CES1); enalapril; pharmacogenetics
Background and Objective: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics, and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers.; Methods: Study participants were stratified to G143E non-carriers (n=15) and G143E carriers (n=6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72h PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established LC-MS/MS method.; Results: The CES1 G143E carriers had 30.9% lower enalaprilat C max (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC 0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. 515.91 ng*hr/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC 0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers.; Conclusions: The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers. (This article is protected by copyright. All rights reserved.)
Her LH; Wang X; Shi J; Choi HJ; Jung SM; Smith LS; Wu AH; Bleske Barry E; Zhu H-J
British Journal Of Clinical Pharmacology
2021
2021-05-07
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journalArticle
<a href="http://doi.org/10.1111/bcp.14888" target="_blank" rel="noreferrer noopener">10.1111/bcp.14888</a>
A new LC-MS/MS technique for separation of gangliosides using a phenyl-hexyl column: Systematic separation according to sialic acid class and ceramide subclass
mass spectrometry; Gangliosides; HPLC-MS; LC-MS; MS; phenyl-hexyl column
A LC-MS/MS technique separated the bovine and mouse brain gangliosides monosialotetrahexosylgangliosides (GM1), disialotetrahexosylgangliosides (GD1a), trisialotetrahexosylgangliosides (GT1b) and tetrasialotetrahexosylgangliosides (GQ1b) using a phenyl-hexyl HPLC column and employing a linear methanol gradient in water, which is 0.028% in ammonium hydroxide. The gangliosides were separated according to sialic acid class, and within a particular class, gangliosides having different ceramide carbon chain lengths were also separated. All gangliosides of a particular sialic acid class eluted in characteristic retention time windows in the order of GQ1b, (earliest), GT1b, GD1a, and GM1 (latest). Within each specific retention time window for a particular ganglioside class, gangliosides were separated in the order of increasing ceramide carbon chain length. The phenyl-hexyl column separation of gangliosides is advantageous over established hydrophilic interaction and conventional reversed-phase chromatography techniques, in that the former separates gangliosides according to sialic acid class but not ceramide composition and the latter distributes all the sialic acid ganglioside classes throughout the entire chromatogram. The mechanism of separation of the ganglioside sialic acid classes is proposed to be a pi-electron repulsion of negatively-charged gangliosides by the column phenyl moiety.
Gobburi ALP; Kipruto EW; Inman DM; Anderson DJ
Journal Of Liquid Chromatography & Related Technologies
2021
2021-01-20
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journalArticle
<a href="http://doi.org/10.1080/10826076.2020.1856136" target="_blank" rel="noreferrer noopener">10.1080/10826076.2020.1856136</a>
Microglial Function and Regulation during Development, Homeostasis and Alzheimer's Disease
inflammation; TREM2; neurodegenerative diseases; microglia; neuroinflammation; Alzheimer’s disease; s disease; Alzheimer’
Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer's disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD.
Casali BT; Reed-Geaghan EG
Cells
2021
2021-04
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journalArticle
<a href="http://doi.org/10.3390/cells10040957" target="_blank" rel="noreferrer noopener">10.3390/cells10040957</a>
Bone remodeling in the longest living rodent, the naked mole‐rat: Interelement variation and the effects of reproduction.
The pattern of bone remodeling of one of the most peculiar mammals in the world, the naked mole‐rat (NMR), was assessed. NMRs are known for their long lifespans among rodents and for having low metabolic rates. We assessed long‐term <italic>in vivo</italic> bone labeling of subordinate individuals, as well as the patterns of bone resorption and bone remodeling in a large sample including reproductive and non‐reproductive individuals (<italic>n</italic> = 70). Over 268 undecalcified thin cross‐sections from the midshaft of humerus, ulna, femur and tibia were analyzed with confocal fluorescence and polarized light microscopy. Fluorochrome analysis revealed low osteogenesis, scarce bone resorption and infrequent formation of secondary osteons (Haversian systems) (i.e., slow bone turnover), thus most likely reflecting the low metabolic rates of this species. Secondary osteons occurred regardless of reproductive status. However, considerable differences in the degree of bone remodeling were found between breeders and non‐breeders. Pre‐reproductive stages (subordinates) exhibited quite stable skeletal homeostasis and bone structure, although the attainment of sexual maturity and beginning of reproductive cycles in female breeders triggered a series of anabolic and catabolic processes that up‐regulate bone turnover, most likely associated with the increased metabolic rates of reproduction. Furthermore, bone remodeling was more frequently found in stylopodial elements compared to zeugopodial elements. Despite the limited bone remodeling observed in NMRs, the variation in the pattern of skeletal homeostasis (interelement variation) reported here represents an important aspect to understand the skeletal dynamics of a small mammal with low metabolic rates. Given the relevance of the remodeling process among mammals, this study also permitted the comparison of such process with the well‐documented histomorphology of extinct therapsids (i.e., mammalian precursors), thus evidencing that bone remodeling and its endocortical compartmentalization represent ancestral features among the lineage that gave rise to mammals. It is concluded that other factors associated with development (and not uniquely related to biomechanical loading) can also have an important role in the development of bone remodeling. [ABSTRACT FROM AUTHOR]
Montoya‐Sanhueza G; Bennett NC; Oosthuizen MK; Dengler-Crish CM; Chinsamy A
Journal Of Anatomy
2021
2021-02-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
Farey trees explain sequential effects in choice response time.
bimanual coordination; choice response time modeling; cognitive dynamics; nonlinear dynamics; oscillatory entrainment; sequential effects
The latencies of successive two-alternative, forced-choice response times display intricately patterned sequential effects, or dependencies. They vary as a function of particular trial-histories, and in terms of the order and identity of previously presented stimuli and registered responses. This article tests a novel hypothesis that sequential effects are governed by dynamic principles, such as those entailed by a discrete sine-circle map adaptation of the Haken Kelso Bunz (HKB) bimanual coordination model. The model explained the sequential effects expressed in two classic sequential dependency data sets. It explained the rise of a repetition advantage, the acceleration of repeated affirmative responses, in tasks with faster paces. Likewise, the model successfully predicted an alternation advantage, the acceleration of interleaved affirmative and negative responses, when a task's pace slows and becomes more variable. Detailed analyses of five studies established oscillatory influences on sequential effects in the context of balanced and biased trial presentation rates, variable pacing, progressive and differential cognitive loads, and dyadic performance. Overall, the empirical patterns revealed lawful oscillatory constraints governing sequential effects in the time-course and accuracy of performance across a broad continuum of recognition and decision activities.
Annand CT; Fleming SM; Holden JG
Frontiers In Physiology
2021
1905-07
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journalArticle
<a href="http://doi.org/10.3389/fphys.2021.611145" target="_blank" rel="noreferrer noopener">10.3389/fphys.2021.611145</a>
Irisin treatment lowers levels of phosphorylated tau in the hippocampus of pre-symptomatic female but not male htau mice.
Alzheimer disease; anti-inflammatory agents; Dementia; metabolic diseases; neurofibrillary tangles; physical exertion; tauopathies
AIMS: Irisin is a hormone cleaved from fibronectin type-III domain-containing protein 5 in response to exercise and may be therapeutic in Alzheimer's disease (AD). Irisin is shown to repair damage caused by midlife cardiometabolic risk factors for AD (i.e., diabetes mellitus; hypertension), prevent neural amyloid beta aggregation, and reduce neuroinflammation. However, there are no investigations of irisin's effect on AD-associated tauopathy in the brain. This study begins to address this gap in knowledge. METHODS: Transgenic htau mice that selectively develop age-related tauopathy were treated with recombinant irisin (100 ug/kg weekly i.p.) beginning at a pre-symptomatic age (4 months) to determine if irisin could prevent emergence of early neuropathology. One month later, mice were sacrificed to collect brain tissue and serum. Protein levels of ptau (serine 202), inflammatory cytokine tumour necrosis factor alpha (TNFα) and FNDC5 were quantified using capillary-based western blotting (Wes). RESULTS: Our data show that irisin treatment significantly reduced ptau and TNFα in hippocampus and serum of female htau mice compared to vehicle-treated controls. Irisin treatment did not alter ptau levels in male htau hippocampus and appeared to enhance both neural and systemic TNFα levels. CONCLUSIONS: This study provides the first evidence that enhancing the endogenous hormone irisin may be therapeutic against emerging neuropathology in a tauopathy-selective AD model. This is important because there are currently no disease-modifying therapeutics available for AD, and few agents in development address the multiple disease targets irisin appears to-making irisin an intriguing therapeutic candidate for further investigation.
Bretland KA; Lin Li; Bretland KM; Smith MA; Fleming SM; Dengler-Crish CM
Neuropathology And Applied Neurobiology
2021
2021-03-26
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journalArticle
<a href="http://doi.org/10.1111/nan.12711" target="_blank" rel="noreferrer noopener">10.1111/nan.12711</a>
Absence of cytochrome P450-1b1 increases susceptibility of pressure-induced axonopathy in the murine retinal projection.
axonal transport disruption; glaucoma; microbead occlusion model; nodes of Ranvier; retinal ganglion cell
Mutations in the cytochrome P450-1B1 (Cyp1b1) gene is a common genetic predisposition associated with various human glaucomas, most prominently in primary congenital glaucoma (PCG). The role of Cyp1b1 in the eye is largely unknown, however, its absence appears to drive the maldevelopment of anterior eye structures responsible for aqueous fluid drainage in murine models. Nevertheless, vision loss in glaucoma ultimately results from the structural and functional loss of retinal ganglion cells (RGCs). Cyp1b1's influence in the development and support of retinal ganglion cell structure and function under normal conditions or during stress, such as elevated ocular pressure; the most common risk factor in glaucoma, remains grossly unknown. Thus, to determine the role of Cyp1b1 in normal retinal projection development we first assessed the strucutrual integrity of RGCs in the retina, optic nerve, and superior colliculus in un-manipulated (naïve) Cyp1b1-knockout (Cyp1b1(-/-)) mice. In addition, in a separate cohort of Cyp1b1(-/-) and wildtype mice, we elevated and maintained intraocular pressure (IOP) at glaucomatous levels for 5-weeks, after which we compared RGC density, node of Ranvier morphology, and axonal transport between the genotypes. Our results demonstrate that naïve Cyp1b1(-/-) mice develop an anatomically intact retinal projection absent of overt glaucomatous pathology. Following pressure elevation, Cyp1b1(-/-) accelerated degradation of axonal transport from the retina to the superior colliculus and altered morphology of the nodes of Ranvier and adjacent paranodes in the optic nerves. Together this data suggests the absence Cyp1b1 expression alone is insufficient to drive murine glaucomatous pathology, however, may increase the vulnerability of retinal axons to disease relevant elevations in IOP.
Amirmokhtari N; Foresi BD; Dewan SS; Bouhenni RA; Smith MA
Frontiers In Cell And Developmental Biology
2021
1905-7
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journalArticle
<a href="http://doi.org/10.3389/fcell.2021.636321" target="_blank" rel="noreferrer noopener">10.3389/fcell.2021.636321</a>
Role of Markers of Heavy Metal Metabolism in Identification of Hepatic Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease (NAFLD)
Oxidative stress; hepatic fibrosis; non-alcoholic fatty liver disease; Heavy Metals; non-alcoholic steatohepatitis (NASH)
INTRODUCTION: Fibrosis & nonalcoholic steatohepatitis (NASH) are important predictors of long term prognosis in patients with non-alcoholic fatty liver disease (NAFLD). Oxidative stress (OS) has been shown to play a central role in progression of NAFLD, & changes in proteins associated with metal homeostasis may exacerbate OS. We investigated relationship of proteins related to transition metal metabolism with fibrosis in NAFLD. METHODS: Adult patients (>18y) who underwent liver biopsy for clinically suspected NAFLD at our institution were included. We retrospectively collected serum levels of ceruloplasmin (Cp), ferritin, iron, & transferrin saturation (Tsat) within 3 months of liver biopsy & calculated Cp/Tsat ratio (CT ratio) & Cp/Ferritin ratio (CF ratio). Histologic features were scored by an experienced pathologist using Non-alcoholic Steatohepatitis Clinical Research Network criteria. Fibrosis was staged as (0 - 4). Independent T test were used to compare the means & receiver operating characteristics (ROC) curves were plotted for assessing area under curve (AUC), sensitivity (Sn) & specificity (Sp). RESULTS: 174 patients were included in final analysis. The mean age of subjects was 48 y. Baseline features are depicted in Table 1. Biopsy proven NASH was seen in 61.5% of liver biopsies. No fibrosis was seen in 29.3% of liver biopsies & Stage 1, 2,3& 4 fibrosis were seen in 29.9%, 10.9%, 14.3% & 15.55% of samples. Mean Tsat was significantly higher (24.41% v/s 38.27%, P < 0.0001) & Cp (mg/dl) (27.82 v/s 24.91, P = 0.03) significantly lower between patients with advanced fibrosis (AF) (3-4) v/s early fibrosis (EF) (0-2). The mean CT ratio was also higher in patients with EF v/s AF (1.54 v/s 1.02, P = 0.01). The mean Tsat of patients with fibrosis v/s without fibrosis was higher (31.4% v/s 21.57% P < 0.005) however mean Cp (mg/dl) values were not significantly different (27.88 v/s 27.58, P = 0.42). The ROC curves show CF ratio (Figure 1) at a cut off of 0.10 had AUC = 0.61 (Sn = 70%, Sp = 52% P = 0.01) to detect any fibrosis & CT ratio (Figure 2) at a cut off 0.86 had AUC = 0.65 (Sn = 69%, Sp = 50% P = 0.002) for differentiating EF v/s AF. CONCLUSION: Our data reveals changes in ceruloplasmin: transferrin system, which decreases the content of toxic ions of Fe2+ in NAFLD. Tsat, Cp, CF ratio & CT ratio are useful non-invasive biomarkers in identifying NAFLD patients with fibrosis. Markers of heavy metal metabolism can spare patients from liver biopsies & can be potential therapeutic targets in future.
Aggarwal Manik;Mitchell B;Singh AD;Kasumov T;McCullough A
American Journal Of Gastroenterology
2020
2020-10
journalArticle
<a href="http://doi.org/10.14309/01.ajg.0000706532.82398.af" target="_blank" rel="noreferrer noopener">10.14309/01.ajg.0000706532.82398.af</a>
Bone remodeling in the longest living rodent, the naked mole-rat: Interelement variation and the effects of reproduction.
Bone resorption; Heterocephalus glaber; Female breeder; Haversian systems; Secondary osteons; Secondary reconstruction
The pattern of bone remodeling of one of the most peculiar mammals in the world, the naked mole-rat (NMR), was assessed. NMRs are known for their long lifespans among rodents and for having low metabolic rates. We assessed long-term in vivo bone labeling of subordinate individuals, as well as the patterns of bone resorption and bone remodeling in a large sample including reproductive and non-reproductive individuals (n = 70). Over 268 undecalcified thin cross-sections from the midshaft of humerus, ulna, femur and tibia were analyzed with confocal fluorescence and polarized light microscopy. Fluorochrome analysis revealed low osteogenesis, scarce bone resorption and infrequent formation of secondary osteons (Haversian systems) (i.e., slow bone turnover), thus most likely reflecting the low metabolic rates of this species. Secondary osteons occurred regardless of reproductive status. However, considerable differences in the degree of bone remodeling were found between breeders and non-breeders. Pre-reproductive stages (subordinates) exhibited quite stable skeletal homeostasis and bone structure, although the attainment of sexual maturity and beginning of reproductive cycles in female breeders triggered a series of anabolic and catabolic processes that up-regulate bone turnover, most likely associated with the increased metabolic rates of reproduction. Furthermore, bone remodeling was more frequently found in stylopodial elements compared to zeugopodial elements. Despite the limited bone remodeling observed in NMRs, the variation in the pattern of skeletal homeostasis (interelement variation) reported here represents an important aspect to understand the skeletal dynamics of a small mammal with low metabolic rates. Given the relevance of the remodeling process among mammals, this study also permitted the comparison of such process with the well-documented histomorphology of extinct therapsids (i.e., mammalian precursors), thus evidencing that bone remodeling and its endocortical compartmentalization represent ancestral features among the lineage that gave rise to mammals. It is concluded that other factors associated with development (and not uniquely related to biomechanical loading) can also have an important role in the development of bone remodeling.
Montoya-Sanhueza G;Bennett NC;Oosthuizen MK;Dengler-Crish CM;Chinsamy A
Journal Of Anatomy
2021
2021-02-07
journalArticle
<a href="http://doi.org/10.1111/joa.13404" target="_blank" rel="noreferrer noopener">10.1111/joa.13404</a>
Long bone histomorphogenesis of the naked mole-rat: Histodiversity and intraspecific variation.
bone microstructure; bone modeling; endosteal bone; Heterocephalus glaber; lamellar bone; lamellar-zonal bone; long bone growth; lamellar‐ zonal bone
Lacking fur, living in eusocial colonies and having the longest lifespan of any rodent, makes naked mole-rats (NMRs) rather peculiar mammals. Although they exhibit a high degree of polymorphism, skeletal plasticity are considered a novel model to assess the effects of delayed puberty on the skeletal system, scarce information on their morphogenesis exists. Here, we examined a large ontogenetic sample (n = 76) of subordinate individuals to assess the pattern of bone growth and bone microstructure of fore- and hindlimb bones by using histomorphological techniques. Over 290 undecalcified thin cross-sections from the midshaft of the humerus, ulna, femur, and tibia from pups, juveniles and adults were analyzed with polarized light microscopy. Similar to other fossorial mammals, NMRs exhibited a systematic cortical thickening of their long bones, which clearly indicates a conserved functional adaptation to withstand the mechanical strains imposed during digging, regardless of their chisel-tooth predominance. We describe a high histodiversity of bone matrices and the formation of secondary osteons in NMRs. The bones of pups are extremely thin-walled and grow by periosteal bone formation coupled with considerable expansion of the medullary cavity, a process probably tightly regulated and adapted to optimize the amount of minerals destined for skeletal development, to thus allow the female breeder to produce a higher number of pups, as well as several litters. Subsequent cortical thickening in juveniles involves high amounts of endosteal bone apposition, which contrasts with the bone modeling of other mammals where a periosteal predominance exists. Adults have bone matrices predominantly consisting of parallel-fibered bone and lamellar bone, which indicate intermediate to slow rates of osteogenesis, as well as the development of poorly vascularized lamellar-zonal tissues separated by lines of arrested growth (LAGs) and annuli. These features reflect the low metabolism, low body temperature and slow growth rates reported for this species, as well as indicate a cyclical pattern of osteogenesis. The presence of LAGs in captive individuals was striking and indicates that postnatal osteogenesis and its consequent cortical stratification most likely represents a plesiomorphic thermometabolic strategy among endotherms which has been suggested to be regulated by endogenous rhythms. However, the generalized presence of LAGs in this and other subterranean taxa in the wild, as well as recent investigations on variability of environmental conditions in burrow systems, supports the hypothesis that underground environments experience seasonal fluctuations that may influence the postnatal osteogenesis of animals by limiting the extension of burrow systems during the unfavorable dry seasons and therefore the finding of food resources. Additionally, the intraspecific variation found in the formation of bone tissue matrices and vascularization suggested a high degree of developmental plasticity in NMRs, which may help explaining the polymorphism reported for this species. The results obtained here represent a valuable contribution to understanding the relationship of several aspects involved in the morphogenesis of the skeletal system of a mammal with extraordinary adaptations.
Montoya-Sanhueza G; Bennett NC; Oosthuizen MK; Dengler-Crish CM; Chinsamy A
Journal of Anatomy
2020
2020-12-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1111/joa.13381" target="_blank" rel="noreferrer noopener">10.1111/joa.13381</a>
Measuring acetyl-coa and acetylated histone turnover in vivo: Effect of a high fat diet.
Acetyl-CoA; Acetylation; Heavy water; High resolution mass spectrometry; Histone; Turnover
Cellular availability of acetyl-CoA, a central intermediate of metabolism, regulates histone acetylation. The impact of a high-fat diet (HFD) on the turnover rates of acetyl-CoA and acetylated histones is unknown. We developed a method for simultaneous measurement of acetyl-CoA and acetylated histones kinetics using a single (2)H(2)O tracer, and used it to examine effect of HFD-induced perturbations on hepatic histone acetylation in LDLR(-/-) mice, a mouse model of non-alcoholic fatty liver disease (NAFLD). Mice were given (2)H(2)O in the drinking water and the kinetics of hepatic acetyl-CoA, histones, and acetylated histones were quantified based on their (2)H-labeling. Consumption of a high fat Western-diet (WD) for twelve weeks led to decreased acetylation of hepatic histones (p< 0.05), as compared to a control diet. These changes were associated with 1.5-3-fold increased turnover rates of histones without any change in acetyl-CoA flux. Acetylation significantly reduced the stability of histones and the turnover rates of acetylated peptides were correlated with the number of acetyl groups in neighboring lysine sites. We conclude that (2)H(2)O-method can be used to study metabolically controlled histone acetylation and acetylated histone turnover in vivo.
Arias-Alvarado A; Aghayev M; Ilchenko S; Rachdaoui N; Lepp J; Tsai T-H; Zhang G-F; Previs S; Kasumov T
Analytical Biochemistry
2021
2021-02-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.ab.2020.114067" target="_blank" rel="noreferrer noopener">10.1016/j.ab.2020.114067</a>
A comparative analysis of cone photoreceptor morphology in bowhead and beluga whales.
cone photoreceptor; magnetosensation; mysticetes; odontocetes; retina
The cetacean visual system is a product of selection pressures favoring underwater vision, yet relatively little is known about it across taxa. Previous studies report several mutations in the opsin genetic sequence in cetaceans, suggesting the evolutionary complete or partial loss of retinal cone photoreceptor function in mysticete and odontocete lineages, respectively. Despite this, limited anatomical evidence suggests cone structures are partially maintained but with absent outer and inner segments in the bowhead retina. The functional consequence and anatomical distributions associated with these unique cone morphologies remain unclear. The current study further investigates the morphology and distribution of cone photoreceptors in the bowhead whale and beluga retina and evaluates the potential functional capacity of these cells' alternative to photoreception. Refined histological and advanced microscopic techniques revealed two additional cone morphologies in the bowhead and beluga retina that have not been previously described. Two proteins involved in magnetosensation were present in these cone structures suggesting the possibility for an alternative functional role in responding to changes in geomagnetic fields. These findings highlight a revised understanding of the unique evolution of cone and gross retinal anatomy in cetaceans, and provide prefatory evidence of potential functional reassignment of these cells.
Smith MA; Waugh DA; McBurney DL; George JC; Suydam RS; Thewissen JGM; Crish SD
The Journal of Comparative Neurology
2020
2020-12-30
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1002/cne.25101" target="_blank" rel="noreferrer noopener">10.1002/cne.25101</a>
Isotope Fractionation during Gas Chromatography Can Enhance Mass Spectrometry-Based Measures of (2)H-Labeling of Small Molecules.
stable isotopes; data integration; gas chromatography-mass spectrometry; isotope fractionation; metabolic flux; Savitzky-Golay
Stable isotope tracers can be used to quantify the activity of metabolic pathways. Specifically, (2)H-water is quite versatile, and its incorporation into various products can enable measurements of carbohydrate, lipid, protein and nucleic acid kinetics. However, since there are limits on how much (2)H-water can be administered and since some metabolic processes may be slow, it is possible that one may be challenged with measuring small changes in isotopic enrichment. We demonstrate an advantage of the isotope fractionation that occurs during gas chromatography, namely, setting tightly bounded integration regions yields a powerful approach for determining isotope ratios. We determined how the degree of isotope fractionation, chromatographic peak width and mass spectrometer dwell time can increase the apparent isotope labeling. Relatively simple changes in the logic surrounding data acquisition and processing can enhance gas chromatography-mass spectrometry measures of low levels of (2)H-labeling, this is especially useful when asymmetrical peaks are recorded at low signal:background. Although we have largely focused attention on alanine (which is of interest in studies of protein synthesis), it should be possible to extend the concepts to other analytes and/or hardware configurations.
Downes DP; Kasumov T; Daurio NA; Wood NB; Previs MJ; Sheth PR; McLaren DG; Previs SF
Metabolites
2020
2020-11-20
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3390/metabo10110474" target="_blank" rel="noreferrer noopener">10.3390/metabo10110474</a>
Intrastriatal injection of alpha-synuclein preformed fibrils results in cognitive dysfunction and L-DOPA reversible sensorimotor impairments in rats
Fleming S;Patterson J;Yan L;Kemp C;Miller K;Stoll A;Duffy M;Herman D;Lipton J;Luk K;Goudreau J;Sortwell C
Movement Disorders
2020
2020-09
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
Effect of a high fat "western type" diet on dynamics of hepatic acetylated mitochondrial proteins in a mouse model of NAFLD
Kasumov T;Arias-Alvarado A;Aghayev M;Ilchenko S;McCullough AJ
Hepatology
2020
2020-11
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
The role of the bile acid receptor TGR5 in Alzheimer's Disease
Ferrell JM;Boehme S;Gilliland T;Lin Li;Dengler-Crish CM;Takahashi S;Gonzalez FJ;Chiang JYL
Hepatology
2020
2020-11
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
Early pro-inflammatory remodeling of HDL proteome in a model of diet-induced obesity: 2H2O-metabolic labeling-based kinetic approach.
inflammation; NAFLD; proteome dynamics; dyslipidemia; insulin resistance; diet-induced obesity; acute-phase proteins; high-density lipoprotein; high-fat diet
Mice fed a high-fat diet for 12 weeks or longer develop hyperglycemia, insulin resistance, dyslipidemia, and fatty liver. Additionally, a high-fat diet induces inflammation that remodels and affects the anti-inflammatory and antiatherogenic property of the high-density lipoprotein (HDL). However, the precise time course of metabolic disease progression and HDL remodeling remains unclear. Short-term (four weeks) high-fat feeding (60% fat calories) was performed in wild-type male C57BL/6J mice to gain insights into the early metabolic disease processes in conjunction with a HDL proteome dynamics analysis using a heavy water metabolic labeling approach. The high-fat diet-fed mice developed hyperglycemia, impaired glucose tolerance, hypercholesterolemia without hypertriglyceridemia or hepatic steatosis. A plasma HDL proteome dynamics analysis revealed increased turnover rates (and reduced half-lives) of several acute-phase response proteins involved in innate immunity, including complement C3 (12.77 ± 0.81 vs. 9.98 ± 1.20 h, p < 0.005), complement factor B (12.71 ± 1.01 vs. 10.85 ± 1.04 h, p < 0.05), complement Factor H (19.60 ± 1.84 vs. 16.80 ± 1.58 h, p < 0.05), and complement factor I (25.25 ± 1.29 vs. 19.88 ± 1.50 h, p < 0.005). Our findings suggest that an early immune response-induced inflammatory remodeling of the plasma HDL proteome precedes the diet-induced steatosis and dyslipidemia.
Sadana P;Lin Li;Aghayev M;Ilchenko S;Kasumov T
International Journal of Molecular Sciences
2020
2020-10-10
journalArticle
<a href="http://doi.org/10.3390/ijms21207472" target="_blank" rel="noreferrer noopener">10.3390/ijms21207472</a>
Transient receptor potential vanilloid 4 channel deletion regulates pathological but not developmental retinal angiogenesis.
neovascularization; TRPV4; mechanotransduction; ECM stiffness; human retinal endothelial cells
Transient receptor potential vanilloid 4 (TRPV4) channels are mechanosensitive ion channels that regulate systemic endothelial cell (EC) functions such as vasodilation, permeability, and angiogenesis. TRPV4 is expressed in retinal ganglion cells, Müller glia, pigment epithelium, microvascular ECs, and modulates cell volume regulation, calcium homeostasis, and survival. TRPV4-mediated physiological or pathological retinal angiogenesis remains poorly understood. Here, we demonstrate that TRPV4 is expressed, functional, and mechanosensitive in retinal ECs. The genetic deletion of TRPV4 did not affect postnatal developmental angiogenesis but increased pathological neovascularization in response to oxygen-induced retinopathy (OIR). Retinal vessels from TRPV4 knockout mice subjected to OIR exhibited neovascular tufts that projected into the vitreous humor and displayed reduced pericyte coverage compared with wild-type mice. These results suggest that TRPV4 is a regulator of retinal angiogenesis, its deletion augments pathological retinal angiogenesis, and that TRPV4 could be a novel target for the development of therapies against neovascular ocular diseases.
Cappelli HC;Guarino BD;Kanugula AK;Adapala R K;Perera V;Smith MA;Paruchuri S;Thodeti CK
Journal of Cellular Physiology
2020
2020-10-20
journalArticle
<a href="http://doi.org/10.1002/jcp.30116" target="_blank" rel="noreferrer noopener">10.1002/jcp.30116</a>
L-plastin, a novel regulator of microglial activation in parkinsons disease
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide behind Alzheimer’s disease. One prominent feature of PD is the marked loss of dopaminergic and motor dysfunction. Currently, there are no therapies to effectively slow disease progression. Neuroinflammation is a major contributing factor in neurodegeneration diseases including PD. Microglia, a type of glial cell, are primary regulators of neuroinflammation and these cells are capable of assuming activation states ranging from inflammatory to anti‐inflammatory and reparative. Thus methods to combat microglial inflammation or promote microglial anti‐inflammatory and reparative effects show promise as treatments to slow neurodegeneration. L‐plastin (LPL) is an acting bundling protein and other research has shown that LPL plays a role in osteoclast function, T‐cell activation, and it may be involved in the NLRP3 inflammasome activation in macrophages. It has been shown in osteoclasts, that LPL phosphorylation at serine 5 plays a role in sealing zone formation. Using a peptide inhibitor to block phosphorylation of serine 5 on LPL prevented sealing zone formation and inhibited osteoclast‐mediated bone resorption. Given the evidence that LPL may play a role in inflammasome activation in macrophages, we investigated if LPL may play a role in microglial activation. To assess the function of LPL in the microglial inflammatory response, we utilized qPCR, Western blot, and immunofluorescence techniques. We show here that lipopolysaccharide (LPS) treatment induces LPL phosphorylation at serine 5, as well as increased Lcp1 mRNA expression. Furthermore, using a TAT‐fused peptidomimetic inhibitor of LPL phosphorylation significantly reduced LPS‐induced inflammatory gene (Il‐1b, Il‐6, Tnfa) expression. For this study, an acute 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model was also used. Male (10‐week‐old) C57BL/6N mice were treated with four injections (one every two hours) of either saline or 15mg/kg of MPTP. Mice were then sacrificed two days after the last injection and striatum and hindbrain were isolated. Two days after MPTP treatment is when peak inflammation occurs in the brain. We found that Lcp1 mRNA expression was significantly increased in the striatum of MPTP‐treated mice compared to saline‐treated mice. These results suggest that LPL may play a role in the microglial inflammatory response, and that LPL inhibition may be a novel way to combat neuroinflammation and neurodegeneration. We are currently staining for phosphorylated LPL in the microglia of MPTP treated mice. Furthermore, we have obtained LPL KO mice to assess the in vivo function of LPL in mouse models of PD.
Budge K;Richardson JR;Safadi F
Faseb Journal
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.09750" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.09750</a>
Deltamethrin exposure inhibits adult hippocampal neurogenesis and causes deficits in learning and memory in mice.
mice; pyrethroid; cognition; adult neurogenesis
Deficits in learning and memory are often associated with disruption of hippocampal neurogenesis, which is regulated by numerous processes, including precursor cell proliferation, survival, migration, and differentiation to mature neurons. Recent studies demonstrate that adult born neurons in the dentate gyrus (DG) in the hippocampus can functionally integrate into the existing neuronal circuitry and contribute to hippocampal-dependent learning and memory. Here, we demonstrate that relatively short-term deltamethrin exposure (3 mg/kg every 3 days for 1 month) inhibits adult hippocampal neurogenesis and causes deficits in learning and memory in mice. Hippocampal-dependent cognitive functions were evaluated using two independent hippocampal-dependent behavioural tests, the novel object recognition task and Morris water maze. We found that deltamethrin-treated mice exhibited profound deficits in novel object recognition and learning and memory in water maze. Deltamethrin exposure significantly decreased bromodeoxyuridine (BrdU)-positive cells (39%) and Ki67+ cells (47%) in the dentate gyrus (DG) of the hippocampus, indicating decreased cellular proliferation. In addition, deltamethrin-treated mice exhibited a 44% decrease in nestin-expressing neural progenitor cells and a 38% reduction in the expression of doublecortin (DCX), an early neuronal differentiation marker. Furthermore, deltamethrin exposed mice exhibited a 25% reduction in total number of granule cells in the DG. These findings indicate that relatively short-term exposure to deltamethrin causes significant deficits in hippocampal neurogenesis that is associated with impaired learning and memory. (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Hossain MM;Belkadi A;Al-Haddad S;Richardson JR
Toxicological Sciences
2020
2020-09-25
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1093/toxsci/kfaa144" target="_blank" rel="noreferrer noopener">10.1093/toxsci/kfaa144</a>
Examining targeted protein degradation from physiological and analytical perspectives: Enabling translation between cells and subjects.
The ability to target specific proteins for degradation may open a new door toward developing therapeutics. Although effort in chemistry is essential for advancing this modality, i.e., one needs to generate proteolysis targeting chimeras (bifunctional molecules, also referred to as PROTACS) or "molecular glues" to accelerate protein degradation, we suspect that investigations could also benefit by directing attention toward physiological regulation surrounding protein homeostasis, including the methods that can be used to examine changes in protein kinetics. This perspective will first consider some metabolic scenarios that might be of importance when one aims to change protein abundance by increasing protein degradation. Specifically, could protein turnover impact the apparent outcome? We will then outline how to study protein dynamics by coupling stable isotope tracer methods with mass spectrometry-based detection; since the experimental conditions could have a dramatic effect on protein turnover, special attention is directed toward the application of methods for quantifying protein kinetics using in vitro and in vivo models. Our goal is to present key concepts that should enable mechanistically informed studies which test targeted protein degradation strategies.
Daurio NA;Zhou H;Chen Y;Sheth PR;Imbriglio JE;McLaren DG;Tawa P;Rachdaoui N;Previs MJ;Kasumov T;O'Neil J;Previs SF
ACS Chemical Biology
2020
2020-09-30
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1021/acschembio.0c00380" target="_blank" rel="noreferrer noopener">10.1021/acschembio.0c00380</a>
Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits.
Sex differences; Neuroinflammation; Parkinson's; Neurotoxicity; Pesticide; PARKINSON'S disease; SUBSTANTIA nigra; Synuclein; CORN oil; ORGANOCHLORINE pesticides; SALINE injections
Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to α-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3–4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal α-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn aggregation (pSyn) in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific exacerbation of synucleinopathy-induced behavioral and biochemical deficits. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD. Unlabelled Image • Developmental dieldrin exposure increases α- syn -PFF-induced motor deficits. • Developmental dieldrin exposure increases PFF-induced deficits in DA handling. • Developmental dieldrin exposure does not affect PFF-induced loss of nigral neurons. • This is a novel paradigm modeling how environmental factors increase risk of PD. • Female mice show PFF-induced pathology, but no PFF-induced motor deficits. [ABSTRACT FROM AUTHOR]
Gezer AO; Kochmanski J; VanOeveren SE; Cole-Strauss A; Kemp CJ; Patterson JR; Miller KM; Kuhn NC; Herman DE; McIntire A; Lipton JW; Luk KC; Fleming SM; Sortwell CE; Bernstein AI
Neurobiology of Disease
2020
2020-07-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104947" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104947</a>
The role of the community pharmacist in veterinary patient care: A cross-sectional study of pharmacist and veterinarian viewpoints.
United States; Surveys and Questionnaires; Professional Role; Pharmacists; Counseling; Drug Compounding; Intersectoral Collaboration; Pharmacies; Veterinarians
BACKGROUND: The role of the community pharmacist is rapidly expanding to encompass the care of veterinary patients in the United States of America This change makes it imperative for pharmacists and veterinarians who practice in community settings to establish mutual agreement on the roles of pharmacists in the care of these patients. OBJECTIVE: To examine community-based pharmacist and veterinarian viewpoints on interprofessional collaboration and the role of the community pharmacist in veterinary patient care. METHODS: Cross-sectional surveys were sent to pharmacists and veterinarians who practice in a community setting in Ohio. Surveys collected demographic information and addressed the following themes: attitudes toward collaboration, perceived roles of the pharmacist, expectations of the pharmacist, and previous collaborative experiences. A chi-square test was used for statistical analysis. RESULTS: In total, 357 pharmacists and 232 veterinarians participated in the study. Both professions agreed that pharmacist-veterinarian collaboration is important in order to optimize veterinary patient care (chi-square (1, N=589)=7.7, p=0.006). Overall, veterinarians were more likely to identify an important role of the community pharmacist to be compounding medications (chi-square (1, N=589)=26.7, p<0.001) compared to counseling pet owners (chi-square (1, N=589)=171.7, p<0.001). Both groups reported similar levels of agreement regarding the importance for pharmacists to have adequate knowledge of veterinary medicine. CONCLUSIONS: Our study found that while both pharmacists and veterinarians conveyed a positive attitude regarding interprofessional collaboration, they disagreed on what role the pharmacist should play in the care of veterinary patients. Rectifying the discordant perceptions of these health care professionals may be critical to developing collaborative initiatives and optimizing veterinary patient care.
Fredrickson ME; Terlizzi H; Horne RL; Dannemiller S
Pharmacy Practice
2020
2020-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.18549/PharmPract.2020.3.1928" target="_blank" rel="noreferrer noopener">10.18549/PharmPract.2020.3.1928</a>
Overcoming barriers confronting application of protein therapeutics in bone fracture healing.
Osteoporosis; Drug delivery; Implants; Bone regeneration; Osteoinductive proteins; Osteopenia
Bone fracture is a major contributor to debilitation and death among patients with bone diseases. Thus, osteogenic protein therapeutics and their delivery to bone have been extensively researched as strategies to accelerate fracture healing. To prevent morbidity and mortality of fractures, which occur frequently in the aging population, there is a critical need for development of first-line therapeutics. Bone morphogenic protein-2 (BMP-2) has been at the forefront of bone regeneration research for its potent osteoinduction, despite safety concerns and biophysiological obstacles of delivery to bone. However, continued pursuit of osteoinductive proteins as a therapeutic option is largely aided by drug delivery systems, playing an imperative role in enhancing safety and efficacy. In this work, we highlighted several types of drug delivery platforms and their biomaterials, to evaluate the suitability in overcoming challenges of therapeutic protein delivery for bone regeneration. To showcase the clinical considerations for each type of platform, we have assessed the most common route of administration strategies for bone regeneration, classifying the platforms as implantable or injectable. Additionally, we have analyzed the commonly utilized models and methodology for safety and efficacy evaluation of these osteogenic protein-loaded systems, to present clinical opinions for future directions of research in this field. It is hoped that this review will promote research and development of clinically translatable osteogenic protein therapeutics, while targeting first-line treatment status for achieving desired outcomes of fracture healing. Graphical abstract.
Czech T; Oyewumi MO
Drug delivery and Translational Research
2020
2020-08-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1007/s13346-020-00829-x" target="_blank" rel="noreferrer noopener">10.1007/s13346-020-00829-x</a>
Aberrant epigenetic silencing of neuronatin is a frequent event in human osteosarcoma.
DNA methylation; neuronatin; osteosarcoma; tumor suppressor genes
The paternally imprinted neuronatin (NNAT) gene has been identified as a target of aberrant epigenetic silencing in diverse cancers, but no association with pediatric bone cancers has been reported to date. In screening childhood cancers, we identified aberrant CpG island hypermethylation in a majority of osteosarcoma (OS) samples and in 5 of 6 human OS cell lines studied but not in normal bone-derived tissue samples. CpG island hypermethylation was associated with transcriptional silencing in human OS cells, and silencing was reversible upon treatment with
Saeed H; Sinha S; Mella C; Kuerbitz JS; Cales ML; Steele MA; Stanke J; Damron D; Safadi F; Kuerbitz SJ
Oncotarget
2020
2020-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.18632/oncotarget.27583" target="_blank" rel="noreferrer noopener">10.18632/oncotarget.27583</a>
Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies.
Microglia; Inflammation; Neuroprotection; AD; Barrier; CSF1R; Plaques
Alzheimer's disease (AD) is a prominent neurodegenerative disorder characterized by deposition of β-amyloid (Aβ)-containing extracellular plaques, accompanied by a microglial-mediated inflammatory response, that leads to cognitive decline. Microglia perform many disease-modifying functions such as phagocytosis of plaques, plaque compaction, and modulation of inflammation through the secretion of cytokines. Microglia are reliant upon colony-stimulating factor receptor-1 (CSF1R) activation for survival. In AD mouse models, chronic targeted depletion of microglia via CSF1R antagonism attenuates plaque formation in early disease but fails to alter plaque burden in late disease. It is unclear if acute depletion of microglia during the peak period of plaque deposition will alter disease pathogenesis, and if so, whether these effects are reversible upon microglial repopulation. To test this, we administered the CSF1R antagonist PLX5622 to the 5XFAD mouse model of AD at four months of age for approximately one month. In a subset of mice, the drug treatment was discontinued, and the mice were fed a control diet for an additional month. We evaluated plaque burden and composition, microgliosis, inflammatory marker expression, and neuritic dystrophy. In 5XFAD animals, CSF1R blockade for 28 days depleted microglia across brain regions by over 50%, suppressed microgliosis, and reduced plaque burden. In microglial-depleted AD animals, neuritic dystrophy was enhanced, and increased diffuse-like plaques and fewer compact-like plaques were observed. Removal of PLX5622 elicited microglial repopulation and subsequent plaque remodeling, resulting in more compact plaques predominating microglia-repopulated regions. We found that microglia limit diffuse plaques by maintaining compact-like plaque properties, thereby blocking the progression of neuritic dystrophy. Microglial repopulation reverses these effects. Collectively, we show that microglia are neuroprotective through maintenance of plaque compaction and morphologies during peak disease progression.
Casali BT; MacPherson KP; Reed-Geaghan EG; Landreth GE
Neurobiology of Disease
2020
2020-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104956" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104956</a>
Transgenic Overexpression of GPNMB Protects Against MPTP-Induced Neurodegeneration.
GPNMB; Microglia; MPTP; Neuroinflammation; Neuroprotective; Parkinson's disease
Parkinson's disease (PD) is a progressive neurodegenerative disease highlighted by a marked loss of dopaminergic cell loss and motor disturbances. Currently, there are no drugs that slow the progression of the disease. A myriad of factors have been implicated in the pathogenesis and progression of PD including neuroinflammation. Although anti-inflammatory agents are being evaluated as potential disease-modifying therapies for PD, none has proven effective to date, suggesting that new and novel targets are needed. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that has recently been shown to reduce inflammation in astrocytes and to be increased in post-mortem PD brain samples. Here we show that transgenic overexpression of GPNMB protects against dopaminergic neurodegeneration in a
Budge Kevin; Neal Matthew L; Richardson Jason R; Safadi Fayez F
Molecular neurobiology
2020
2020-05-20
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1007/s12035-020-01921-6" target="_blank" rel="noreferrer noopener">10.1007/s12035-020-01921-6</a>
MCT2 overexpression rescues metabolic vulnerability and protects retinal ganglion cells in two models of glaucoma.
Glaucoma; Metabolism; Monocarboxylate transporter; Ocular hypertension; Retinal ganglion cell
Improving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2 J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2(fl/+) mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2 J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration.
Harun-Or-Rashid Mohammad; Pappenhagen Nathaniel; Zubricky Ryan; Coughlin Lucy; Jassim Assraa Hassan; Inman Denise M
Neurobiology of disease
2020
2020-05-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104944" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104944</a>
Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of alpha-synuclein-preformed fibril-induced toxicity and motor deficits.
Neuroinflammation; Neurotoxicity; Parkinson's; Pesticide; Sex differences; Synuclein
Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the alpha-synuclein (alpha-syn)-preformed fibril (PFF) model, which better reflects the alpha-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to alpha-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3-4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal alpha-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated
Gezer Aysegul O; Kochmanski Joseph; VanOeveren Sarah E; Cole-Strauss Allyson; Kemp Christopher J; Patterson Joseph R; Miller Kathryn M; Kuhn Nathan C; Herman Danielle E; McIntire Alyssa; Lipton Jack W; Luk Kelvin C; Fleming Sheila M; Sortwell Caryl E; Bernstein Alison I
Neurobiology of disease
2020
2020-05-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104947" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104947</a>
Relationships between Very Low-Density Lipoproteins-Ceramides, -Diacylglycerols, and -Triacylglycerols in Insulin-Resistant Men.
biomarkers; Ceramides; disease; humans; inflammation; kinetics; ldl; Lipids; Metabolic syndrome; NAFLD; NAFLD; obese men; secretion; sphingolipids; VLDL; VLDL
This short report describes the relationships between concentrations of ceramides (CER), diacylglycerols (DAG), triacylglycerols (TAG) in very low-density lipoproteins (VLDL) particles, and hepatic lipid accumulation. VLDL particles were isolated from male subjects (n = 12, mean +/- SD, age 42.1 +/- 5.4 years, BMI 37.4 +/- 4.1 kg/m(2) , ALT 45 +/- 21 U/L) and apolipoprotein B100 (apoB100),
Mucinski Justine M; Manrique-Acevedo Camila; Kasumov Takhar; Garrett Timothy J; Gaballah Ayman; Parks Elizabeth J
Lipids
2020
2020-05-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1002/lipd.12244" target="_blank" rel="noreferrer noopener">10.1002/lipd.12244</a>
Plaque-associated myeloid cells derive from resident microglia in an Alzheimer's disease model
accumulation; distinct; dynamics; fate; macrophages; monocytes; pathology; reveals; system; turnover
Alzheimer's disease (AD) is accompanied by a robust inflammatory response mediated by plaque-associated myeloid cells of the brain. These cells exhibit altered gene expression profiles and serve as a barrier, preventing neuritic dystrophy. The origin of these cells has been controversial and is of therapeutic importance. Here, we genetically labeled different myeloid populations and unequivocally demonstrated that plaque-associated myeloid cells in the AD brain are derived exclusively from resident microglia, with no contribution from circulating peripheral monocytes.
Reed-Geaghan Erin G; Croxford Andrew L; Becher Burkhard; Landreth Gary E
Journal of Experimental Medicine
2020
2020-04
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journalArticle
<a href="http://doi.org/10.1084/jem.20191374" target="_blank" rel="noreferrer noopener">10.1084/jem.20191374</a>
MITOCHONDRIAL DYSFUNCTION IN OSTEOARTHRITIS AND AGED CARTILAGE TRIGGERS INFLAMMATORY RESPONSE AND MATRIX DEGRADATION VIA ROS MEDIATED ACTIVATION OF JNK-MAPK/CFOS-AP1 AXIS IN CHONDROCYTES
Ansari M Y; Ahmad N; Voleti S; Wase S; Malik M; Novak K; Haqqi Tariq M
Osteoarthritis and Cartilage
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
n/a
Temporal Dynamics of High-Density Lipoprotein Proteome in Diet-Controlled Subjects with Type 2 Diabetes.
apolipoproteins; HDL dysfunction; heavy water; proteomics; type 2 diabetes
We examined the effect of mild hyperglycemia on high-density lipoprotein (HDL) metabolism and kinetics in diet-controlled subjects with type 2 diabetes (T2D). (2)H2O-labeling coupled with mass spectrometry was applied to quantify HDL cholesterol turnover and HDL proteome dynamics in subjects with T2D (n = 9) and age- and BMI-matched healthy controls (n = 8). The activities of lecithin-cholesterol acyltransferase (LCAT), cholesterol ester transfer protein (CETP), and the proinflammatory index of HDL were quantified. Plasma adiponectin levels were reduced in subjects with T2D, which was directly associated with suppressed ABCA1-dependent cholesterol efflux capacity of HDL. The fractional catabolic rates of HDL cholesterol, apolipoprotein A-II (ApoA-II), ApoJ, ApoA-IV, transthyretin, complement C3, and vitamin D-binding protein (all p < 0.05) were increased in subjects with T2D. Despite increased HDL flux of acute-phase HDL proteins, there was no change in the proinflammatory index of HDL. Although LCAT and CETP activities were not affected in subjects with T2D, LCAT was inversely associated with blood glucose and CETP was inversely associated with plasma adiponectin. The degradation rates of ApoA-II and ApoA-IV were correlated with hemoglobin A1c. In conclusion, there were in vivo impairments in HDL proteome dynamics and HDL metabolism in diet-controlled patients with T2D.
Kheniser Karim G; Osme Abdullah; Kim Chunki; Ilchenko Serguei; Kasumov Takhar; Kashyap Sangeeta R
Biomolecules
2020
2020-03-30
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journalArticle
<a href="http://doi.org/10.3390/biom10040520" target="_blank" rel="noreferrer noopener">10.3390/biom10040520</a>
Songling Xuemaikang Capsule inhibits isoproterenol-induced cardiac hypertrophy via CaMKIIdelta and ERK1/2 pathways.
ERK1/2; Cardiac hypertrophy; Isoproterenol; CaMKIIdelta; Songling xuemaikang capsule; CaMKIIδ
ETHNOPHARMACOLOGICAL RELEVANCE: Cardiac hypertrophy is a key pathologic process in heart failure. Songling Xuemaikang Capsule (SXC), is a formulae of Chinese Medicine commonly used in China to treat hypertension and heart failure. However, its mechanism of effects on cardiac hypertrophy is still unclear. AIM OF THE STUDY: The aims of the present study were to investigate the cardio-protection roles and detailed mechanisms of SXC on cardiac hypertrophy in vivo and in vitro. MATERIALS AND METHODS: A rat model of cardiac hypertrophy was constructed by isoproterenol (ISO) intraperitoneal injection (i.p), 10 mg/kg/day for 3 days, and 4 groups were compared: CON (n = 8), ISO (n = 8), MET (metoprolol, positive drug treatment, n = 7), and SXC (SXC treatment, n = 6). Cardiac structure and function were evaluated with echocardiography in vivo. Dose-dependent curve was obtained with SXC different concentrations. In addition, H9C2 rat cardiomyocytes were cultured in vitro and the phosphorylation of ERK1/2, p38, JNK, AKT, and protein expression of CaN, CaMKIIdelta, GATA4 were detected with Western blot test. RESULTS: The results showed that SXC reduced diastolic thickness of left ventricular posterior wall, while did not change ejection fraction and fraction shortening significantly (P > 0.05). SXC inhibit ISO-induced cardiac hypertrophy dose-dependently with 50% inhibiting concentration (IC50) is 0.504 g/kg/day. Moreover, SXC inhibited the protein expression of CaMKIIdelta, and the phosphorylation of ERK1/2, so inhibiting protein expression of GATA4 in nucleus, and brain natriuretic peptide in serum (P < 0.001). CONCLUSION: The mechanism of SXC in the treatment of heart diseases involves SXC dose-dependently inhibited the ISO-induced cardiac hypertrophy via inhibiting CaMKIIdelta and ERK1/2/GATA4 signaling pathway.
Qi Jianyong; Tan Yafang; Fan Dancai; Pan Wenjun; Yu Juan; Xu Wen; Wu Jiashin; Zhang Minzhou
Journal of ethnopharmacology
2020
2020-02
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Journal Article
<a href="http://doi.org/10.1016/j.jep.2020.112660" target="_blank" rel="noreferrer noopener">10.1016/j.jep.2020.112660</a>
Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.
Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programs. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate transcriptional programs that support neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.
Singhal Naveen K; Sternbach Sarah; Fleming Sheila; Alkhayer Kholoud; Shelestak John; Popescu Daniela; Weaver Alyx; Clements Robert; Wasek Brandi; Bottiglieri Teodoro; Freeman Ernest J; McDonough Jennifer
Epigenetics
2020
2020-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1080/15592294.2020.1735075" target="_blank" rel="noreferrer noopener">10.1080/15592294.2020.1735075</a>