bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early life vincristine exposure does not prime the developing pain circuitry for subsequent injury
Authors: Styczynski Lauren , Baccei Mark 
Published: June 2021

Our recent work has demonstrated that the early life administration of vincristine (VNC), commonly used to treat pediatric leukemias, evokes peripheral neuropathy and mechanical pain hypersensitivity in rats that persists into adolescence. However, whether neonatal VNC treatment alters baseline pain sensitivity throughout adulthood remains unknown. It is also unclear if pediatric VNC exposure can ‘prime’ developing nociceptive pathways, and thereby exacerbate chronic pain, following subsequent trauma later in life. Therefore, the present study investigated the degree to which neonatal VNC administration influences mechanical and thermal pain hypersensitivity in the absence or presence of tissue injury sustained during adulthood. Rats received five total doses of 60 mg/kg VNC (or vehicle) on postnatal days (P) 11, 13, 17, 19 and 21, which is known to evoke mechanical pain and skin denervation by P26 (Schappacher et al., 2017). Immunohistochemical analysis of the skin suggested that a resolution of the peripheral neuropathy occurs by 13–15 weeks of age, as there were no differences in the density of intraepidermal nerve fibers or activated Langerhans cells between the VNC and vehicle‐treated groups at this time point. Baseline mechanical pain sensitivity, as measured with von Frey hairs, was also similar between the experimental groups during adulthood, confirming recovery to neonatal VNC treatment. To explore the potential long‐term effects of early life VNC on the behavioral response to subsequent insults, a surgical incision of the hindpaw was administered to adult rats exposed to either VNC or vehicle during the neonatal period. We observed no significant overall effect of early life VNC on the magnitude of post‐operative pain following adult incision. In addition, in order to model the clinical scenario where cancer relapse necessitates a second round of chemotherapy, separate groups of rats that had been treated with VNC (or vehicle) as neonates were subsequently administered VNC during adulthood (five injections at 100 mg/kg). There was no significant effect of prior VNC exposure on the level of mechanical pain hypersensitivity produced by adult VNC treatment. Collectively, these findings suggest that neonatal VNC does not increase the susceptibility to develop chronic pain as adults.Support or Funding InformationSupported by National Institutes of Health (NS080889 to MLB).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Gut microbiome and its potential role in obesity‐induced neuropathy
Authors: BONOMO RAIZA , Cook Tyler , Gavini Chaitanya , Mansuy‐Aubert Virginie 
Published: June 2021

Obesity is considered a 21st century epidemic, affecting over 2 billion people worldwide1. This condition is often accompanied by several complications, including peripheral neuropathy (PN). PN is a highly prevalent disease, characterized by a distal‐to proximal nerve degeneration with current no available treatment2. The initial stages of PN are clinically presented as peripheral tactile allodynia and thermal hyperalgesia, that later progress to numbness and loss of sensation3. Despite high prevalence, the molecular mechanisms underlying the disease onset are poorly understood, and affected patients have no choice other than to use pain killers. Using sensory neurons‐specific transgenic mice, we observed expression of short chain fatty acid receptors (FFAR) at the surface of neurons expressing Nav1.8 (sensory neurons proven to be involved in type II diabetes painful neuropathy4,5). Because, short chain fatty acids are metabolites secreted by gut bacteria, this data potentially links the microbiome with obesity‐induced pain. Numerous studies have demonstrated that the gut microbiome may play a role in the development of obesity and its associated comorbidities6. Moreover, fecal microbiome transplantation (FMT) has been used to treat innumerous metabolic disorders7. Still, the relationship between gut microbiome and PN onset and progression has yet to be explored. To investigate whether gut microbiome is involved in allodynia onset and/or progression in obesity, we utilized an obesity‐induced allodynia mouse model developed in our lab. Our results show that mice fed Western diet (WD) had reduced mechanical allodynia and thermal sensitivity threshold when compared to mice fed normal chow (NC). Our data showed that WD fed mice subjected to FMT, exhibited improved mechanical and thermal sensitivity when compared to WD alone and respective control groups. In addition, glucose tolerance was improved in the aforementioned groups. We also evaluated changes in i) gut bacterial composition following FMT, assessed by 16S sequencing, ii) in plasma short chain fatty acid and iii) in the gene expression in neurons of the dorsal root ganglia and sciatic nerve. In summary, the data presented shows that transplantation of gut bacteria from lean mice to WD‐fed mice improve PN symptoms in obese mice. Our data also suggest that the gut microbiome metabolites may change sensory neurons function via modulating short chain fatty acid receptor located at the surface of sensory neurons. This line of study could provide alternative therapeutic targets to replace the use of addictive pain killers. The gut microbiome, its metabolites and short chain fatty acid receptors could be a novel valuable target to study the delay or cure of debilitating pain associated with obesity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Exercise Pressor Reflex Evoked by Static Contraction is influenced by the Active Skeletal Muscle Mass in Decerebrated Rats
Authors: Estrada Juan A , Ducrocq Guillaume P , Kaufman Marc P 
Published: June 2021

The decerebrated rat is a useful preparation to study the neural mechanisms controlling the circulation during exercise. One of these mechanisms, the exercise pressor reflex, is evoked by statically contracting the hindlimb muscles. However, contraction of only one hindlimb may not always be enough to achieve threshold for activation of the exercise pressor reflex in the decerebrated rat preparation. Here we demonstrate that simultaneous contraction of both hindlimbs evoked a greater pressor response than did contraction of one hindlimb. This was found to be the case when we analyzed the pressor response to contraction as either the area under the curve or the peak (n=4). Static contraction was induced by electrically stimulating the sciatic nerve for thirty seconds at currents that did not activate the axons of group III and IV afferents. When analyzing the area under the curve, we found that simultaneous contraction of both hindlimbs yielded a pressor response averaging 138 ± 64 mmHg seconds, whereas individual contraction of either hindlimb yielded a pressor response averaging either 48 ± 48 or 76 ± 23 mmHg seconds (right limb vs left limb, respectively). When analyzing the peak, simultaneous contraction of both hindlimbs yielded a pressor response averaging 12 ± 4 mmHg, whereas individual contraction of either hindlimb yielded a pressor response averaging 8 ± 6 mmHg or 9 ± 4 mmHg (right limb vs left limb, respectively). Additionally, the sum of the pressor responses to contraction analyzed as either the area under the curve or as the peak appeared to be additive. Our results suggest that the total active muscle mass influences the magnitude of the exercise pressor reflex.Support or Funding InformationSupported by NIH grant P01 HL 134609.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exaggerated Pressor Response to Intermittent Contraction in Type 1 Diabetic Rats
Authors: Grotle Ann‐Katrin , Huo Yu , Ybarbo Kai M , Stone Audrey J. 
Published: June 2021

Type 1 diabetes mellitus (T1DM) is associated with an impaired regulation of autonomic and cardiovascular responses during exercise, an effect attributable, in part, to the exercise pressor reflex. Previously, we have found that the pressor responses to both static muscle contraction and to tendon stretch are exaggerated in the early stage of T1DM. However, it is not known whether a similar response is present during dynamic exercise. Moreover, other studies have suggested that endothelial dysfunction manifests early in T1DM, which may impair muscle perfusion during exercise leading to an increased stimulation of the exercise pressor reflex. Therefore, the purpose of this study was to test whether T1DM rats have an exaggerated pressor and an attenuated blood flow response to intermittent contraction. To do this, we measured the exercise pressor reflex in unanesthetized, decerebrated T1DM (Streptozotocin 50mg/kg i.p; STZ: body weight: 328 ± 39g) and healthy (CTL: body weight: 264 ± 17g, n=5) Sprague Dawley rats by intermittently contracting the hindlimb for 30 s while continuously measuring mean arterial pressure (MAP), heart rate (HR) and popliteal arterial blood flow (BF). Popliteal vascular conductance was estimated by dividing popliteal BF by MAP. BF and VC are reported as mean change from baseline.Muscle contraction significantly increased peak MAP (STZ: 32 ± 4 mmHg, n=3; CTL: 17 ± 4 mmHg, n=5, p<0.05) but not HR (STZ: 20 ± 4 mmHg, n=3; CTL: 14 ± 6 mmHg, n=5, p>0.05) to similar developed tensions (p>0.05) in T1DM rats compared to CTL rats. Muscle contraction increased hindlimb BF (STZ: 858 ± 379 μl/min, n=3; CTL: 220 ± 40 μl/min, n=2) and hindlimb vascular conductance (STZ: 7.4 ± 4.1 μl/min/mmHg, n=3; CTL: 2.2 ± 0.3 μl/min/mmHg, n=2) from baseline in STZ and CTL rats, however, this was not significantly different between groups (p>0.05). These findings are consistent with our previous studies that found that early stage T1DM rats had an exaggerated pressor response to static muscle contraction. Furthermore, the finding that blood flow delivery was not impaired in the T1DM rats may suggest that a mismatch between metabolic demand and oxygen delivery is not contributing to the exaggerated response.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Nitrate increases in skeletal muscle peak power do not involve changes in sarcomeric protein phosphorylation and require whole‐body physiological pathways
Authors: Kumar Ravi , Hahn Dongwoo , Kelley Rachel , Ferreira Leonardo 
Published: June 2021

Acute dietary nitrate supplementation in humans (within 2 hours) increases limb muscle peak power. In old mice, chronic (14 days) dietary nitrate supplementation increases diaphragm peak power. However, mechanisms of dietary nitrate effects on contractile mechanics are not fully understood. It is unclear whether nitrate ions directly or products downstream of the nitrate‐nitrite‐nitric oxide (NO) reductive pathway are responsible for changes in muscle contractile function. Increases in power likely involve post‐translational modification of myofibrillar proteins – phosphorylation being an established effect of NO signaling. We determined the phosphorylation status of myofibrillar proteins from diaphragms of 24 month old mice supplemented with nitrate (n = 8) or control (n = 6) and found no difference for myosin regulatory light chain, myosin binding protein c, tropomyosin, desmin or troponin I. Regulatory light chain phosphorylation signal normalized to total protein was 1.696 ± 0.139 and 1.699 ± 0.105 for control and nitrate‐supplemented animals, respectively. To examine a direct effect of nitrate on muscle cells, we exposed isolated diaphragm bundles from young mice in vitro to increasing concentrations of NaNO3. In vitro NaNO3 (15 min) had no effect on diaphragm peak power or isometric force (P > 0.05). Specifically, power (% control) was −1.06 ± 0.20 (0.5 mM), −1.73 ± 0.79 (1 mM), −2.64 ± 2.14 (2 mM), and −2.40 ± 2.40 (4 mM). Overall, our study shows that the increase in diaphragm power of aged mice elicited by chronic dietary nitrate supplementation does not involve changes in phosphorylation of key sarcomeric proteins that regulate contractile function. Moreover, our data from in vitro experiments suggest no direct effect of nitrate ions on mammalian skeletal muscle contractile function. Instead, dietary nitrate effects on muscle function appear to require whole‐body physiological mechanisms and actions of molecules downstream of nitrate.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Physiological Basis For Novel Drug Hydrogen Sulfide‐Related Therapy Used To Treat Oxidative Stress In The Model Of Fructose‐Induced Injury
Authors: Zayachkivska Oksana , Pavlovskiy Yaroslav , Revenko Oleh , Yashchenko Antonina 
Published: June 2021

Recent extensive research into accelerated aging and age‐related health problems confirmed the key role of metabolic dysfunction in multiple organ functions by overloaded fructose diet. Among important bioregulators of prostaglandin‐independent mechanisms of cytoprotection are sulfur compounds, and the key ones is Hydrogen Sulfide (H2S). However, it is little known about its physiological effects on fructose‐induced gastrointestinal mucosal (GIM) injury.AimTo test the hypothesis whether there is the interplay between H2S catalytic expression and age‐related GIM malfunction and oxidative stress with underlying high fructose diet (HFD), and evaluate effects of ATB 340 [4‐(5‐thioxo‐5H‐dithiol‐3‐yl)phenyl 2‐acetoxybenzoate].MethodsCystathionine‐γ‐lyase (CSE), cystathionine‐β‐synthase (CBS), and sulfite oxidase (SO) activities in GIM and oxidative stress indicators malonic dialdehyde (MDA) and carbonyl groups of oxide‐modified proteins (COMP) were estimated by standard biochemical methods in adult and old rats with standard diet (SD) and HFD, during stress exposure with vehicle and ATB 340 (17.5 mg/kg per 9 days per os) treatment. GIM injuries evaluated via histological damage index (DI). EC Approval: Committee on Bioethics of Lviv National Medical University protocol No 4, 23.04.2018.ResultsOxidative stress was associated with increased MDA and COMP (р<0,05), and changes in CSE, CBS, fall of SO activities in older vs young rats, while HSD‐induced decline of GIM tolerance and indicators of oxidation were increased (р<0,05), coinciding with decreased SO (р<0,05) expression and DI value of GIM. Preprocessing ATB 340 reduces these description responses of serum MDA and COMP, DI values and increased SO activity (р<0,05) which may be aggravated stress tolerance.ConclusionsPhysiological basis of GIM injury during aging is associated with SO‐related mitochondrial dysfunction and increased MDA, COMP accumulations. ATB 340 ultimately improves the capacity of oxidative stress tolerance in hyperglycemia in older rats. These findings provide further insights into H2S‐mediated GIM protection and implicate the benefits of using H2S‐based therapies clinically for the treatment of age‐related changes and oxidative stress tolerance.Support or Funding InformationWe thank Prof. Natalia Zaichko (National Pirogov Memorial Medical University, Vinnytsia, Ukraine), Prof. J. Wallace (Antibes, Canada) for their support of our work.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Nanoformulation of bisphosphonates with a cationic peptide improves its activity against breast cancer cells
Authors: Fahmy Usama Ahmed , Ahmed Osama Abdulhakim , Alhakamy Nabil Abdulhafiz 
Published: June 2021

Alendronate sodium (ALS) is one of the class bisphosphonates used to treat osteoporosis. Recent studies suggest that ALS may induce cell death and inhibit the proliferation of estrogen‐sensitive MCF‐7 breast cancer cells. The aim of this work is a combination of ALS and Trans‐activating regulatory protein (TAT) to potentiate ALS cytotoxicity against MCF‐7 breast cancer cells. ALS and TAT were prepared as nanostructured lipid carriers (NLCs). The formed NLCs were characterized for particle size and zeta potential. Cell viability was also carried out for the prepared NLCs. The results revealed that the prepared NLCs were spherical, with particle sizes of 285.2 ± 14.1 nm, with a polydispersity index of 0.51 and zeta potential of +21.1 ± 3.4 mV. The ALS %EE of the prepared NLCs was 12.2 ± 1.1%. ALS IC50 was decreased by about 30 % when compared with the raw drug. According to cell viability, The IC50 values for the treatments were as follows: ALS, 2.77 ± 0.36 μM; ALS‐TAT NLCs, 1.98 ± 0.17 μM; TAT, 1066.67 ± 21.22 μM and plain formula 10816.2 ± 112.32 μM. Which makes their combination with ALS a promising candidate for breast cancer therapy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CO2 expirograms during ERV expiration
Authors: Rueda Luis Antonio , Cruz Julio Cesar , Caucha Luis Jhony 
Published: June 2021

Expired CO2 is usually recorded during normal breathing. There are few CO2 records beyond functional residual capacity (FRC) (Flores & Cruz. Chest 102:438‐443, 1992). However, the effect of apnea upon expired CO2 during the expiratory reserve volume (ERV) is not known. Thus, we are reporting CO2 expired curves (see figure of one subject) during ERV expiration, after holding the breath at FRC for several seconds (8s to 33s) which include the expiration time. Five subjects provided a written consent to this study, which was approved by the IRB of the University. The pattern of the curves shown was similar in all subjects to the one presented. Initial PCO2 values at 0s are the FRC end‐tidal values. The abrupt rise of CO2 corresponds to the elimination of CO2 from the dead space, followed by a waving alveolar plateau. The control curve agrees with Flores and Cruz (follows the model of West). With apnea, the expected increase in alveolar PCO2 is evident. After 8s the alveolar plateau starts to rise (positive slope) and becomes flat at 33s. Finally, the behavior of the curves, during the last 2s of expiration, suggests that the apex‐to‐base CO2 concentration difference is reversed. We must remember that the expirograms presented reflect the uneven emptying of parallel regions of the lung where the apical regions contribute more than the basal regions.Supported in part by ONG ‐ Centro de Enseñanza Investigación y Servicios.
Anti‐inflammatory effects of pyruvate‐enriched cardioplegia in pigs undergoing cardiopulmonary bypass
Authors: Mallet Robert T , Ryou Myoung‐Gwi , Flaherty Devin C , Hoxha Besim , Sun Jie , Bellard Monica , Hodge Lisa M , Olivencia‐Yurvati Albert H 
Published: June 2021

BackgroundReactive oxygen species produced during cardiopulmonary bypass (CPB) can elicit inflammation. Cardioplegia enriched with the intermediary metabolite pyruvate exerts antioxidant protection in myocardium of pigs subjected to CPB.HypothesisPyruvate‐fortified cardioplegia mitigates myocardial inflammation by increasing anti‐inflammatory cytokines, enhancing myocardial antioxidant defenses, and suppressing matrix metalloproteinase activity and neutrophil infiltration.MethodsIn situ swine hearts were arrested for 1 h with 4:1 blood:crystalloid cardioplegia, where the crystalloid component contained 188 mM glucose ± 24 mM pyruvate, then the hearts were reperfused and the pigs weaned from CPB. At 4 h post‐CPB, left ventricular myocardium was sampled for immunoblot analyses of the acute inflammation marker C‐reactive peptide (CRP), matrix metalloproteinase‐3 (MMP3) and tissue inhibitor of metalloproteinase‐2 (TIMP2), and to assess neutrophil infiltration by histology and myeloperoxidase activity.ResultsMyocardial CRP content increased over fivefold following CPB with control cardioplegia, but pyruvate cardioplegia prevented this increase. Circulating IL‐10 temporarily increased during and immediately after CPB; pyruvate cardioplegia provoked more sustained and robust enhancement of this anti‐inflammatory cytokine. CPB increased myocardial neutrophil infiltration and myeloperoxidase activity, but pyruvate‐fortified cardioplegia prevented these effects.ConclusionPyruvate‐enriched cardioplegia suppresses CPB‐induced inflammation, an effect potentially mediated by anti‐inflammatory cytokines and TIMP‐2. Support: OHF 02‐18‐522
Short‐term insulin infusion alone has negative effect on skin protein mass in fasted pigs
Authors: Tuvdendorj Demidmaa , Børsheim Elisabet , Sharp Carwyn P , Zhang Xiaojun , Aarsland Asle , Herndorn David N , Chinkes David L , Wolfe Robert R 
Published: June 2021

The effect of insulin (INS) on skin protein turnover (fractional synthesis and breakdown rates, FSR and FBR, respectively) in pigs is presented.MethodsPigs were divided into 4 groups: Control (CNT), Insulin (INS), Amino Acid (AA) and INS+AA. L‐[ring‐2H5]‐phenylalanine (Phe), INS and/or AAs were infused during the study. FBR was estimated from enrichment ratio of arterial Phe to intracellular free Phe.ResultsPlasma INS was increased in INS and INS+AA (p<0.05). Plasma glucose was constant in all groups. In INS group tissue intracellular branched and essential AA pools were lower than in other groups although did not reach statistical significance. The ratio of Phe inward transport to intracellular breakdown increased in AA (p<0.05) and INS+AA groups (p=0.05) compared to CNT. Hyperinsulinemia increased pig skin protein FSR and FBR, decreasing Net Balance (NB) (Table 1).ConclusionIns infusion alone has a negative effect on protein mass in normal fasted pig skin because of insufficient AA availability.Fundings: NIH AR0490380‐05, Shriners 8490.
A Three‐Year Anatomical Study of Lower Limb Length Discrepancy (LLLD) in an Urban Population Group
Authors: Jeanty Hamerton D , Weedon Jeremy , Marquez Samuel 
Published: June 2021

LLLD patients as a group exhibit significantly poorer postoperative total hip/knee replacement outcomes with considerably more limping than preoperative patients with an anatomical LLLD; implicating compensatory mechanisms at play for the latter group. This three‐year study examines the frequency of LLLD and identifies the bony segments of the lower limb that contributes to the sample variance. 287 femora and tibial measures were taken from donor specimens at the SUNY Downstate Anatomy programs (males: n=37) and (females: n=35); examining side dominance and sex interaction effects.Mixed Linear modeling was used to predict tibia and femur length; using gender side of body and their interaction as predictors. As expected there was a statistical significant difference between sexes for mean tibial length (F[1,70]=29.11, p<0.001). There was no difference found according to side of body (F[1,46]=0.25, p=0.622) and no sex interaction (F[1,46]=0.18, p=0.673). Similarly, a statistical difference between mean femur length by sex was revealed (F[1,70]=26.49, p<0.001) and a significant difference found in side of body (F[1,55]=5.84, p=0.019) but no sex interaction (F[1,55]=0.07, p=0.787). Results implicate the femora as the significant contributor to LLLD with the right femora being longer than the left in both males and females. Sex interaction effects did not contribute to this difference, appearing to be of similar extent in both sexes.LLLD research continues to demonstrate the importance of accounting for asymmetric functionality in the preoperative evaluation for total hip/knee replacements. Our preliminary results may prove particularly useful in orthopedic surgery where a better understanding of LLLD would lead to improved outcomes in this unique patient demographic.