bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel, engineered fusogenic liposome-based anti-oxidant delivery system improves the blood-brain barrier integrity in aging
Authors: Shanmugarama Santny , Csik Boglarka , Nyúl-Tóth Ádám , Gronemann Till , Gulej Rafal , Tarantini Stefano , Ungvari Zoltan 
Published: May 2024

Vascular dysfunction plays a pivotal role in age-related cognitive decline and neurodegeneration. The aging process often leads to a loss of integrity in the blood-brain barrier (BBB), initiating neuroinflammation and contributing to a decline in cognitive function. In previous research, we demonstrated the potential of resveratrol (RSV), a natural polyphenol, to target cerebromicrovascular endothelial cells (CMVECs), effectively countering age-related oxidative stress and improving vascular function, both in vitro and in vivo. However, the limited bioavailability of resveratrol raised questions about its effectiveness concerning the BBB and neuroinflammation. Our study aimed to address this challenge by introducing a novel drug delivery system designed to enhance the effciency of polyphenol delivery. This innovative approach involved the use of fusogenic liposomes (FL) integrated with a bioengineered protein corona (PC) featuring specific apolipoprotein E (ApoE). Our central hypothesis posited that PC formation could be harnessed to directly target CMVECs and enhance liposomal uptake, with the ultimate objective of effectively delivering RSV to the brain's microvessels in aging subjects (ApoE-FL-RSV). Our investigation encompassed the characterization of ApoE-FL uptake by CMVECs, along with an analysis of its biodistribution and pharmacokinetics in vivo. Remarkably, our findings revealed a significant increase in ApoE-FL-RSV accumulation within CMVECs in vivo, compared to control FL uptake. We employed advanced in vivo multiphoton imaging to longitudinally monitor the effects of ApoE-FL-RSV on the BBB, which demonstrated a significant rejuvenation of the endothelial barrier function in aged mice treated with ApoE-FL-RSV. In light of these results, we concluded that the fusogenic liposomal delivery system holds promise as a viable pharmacological intervention for addressing age-related vascular cognitive impairment. AHA834339, RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614, R01NS100782, R01CA255840, and Presbyterian Health Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Use of Milk Bovine Extracellular Vesicles to Mitigate Gut-Liver Axis Dysfunction Under Pediatric Parenteral Nutrition
Authors: Antunes Karen , Mims Tahliyah , Leathem Cameron , Willis Nathaniel , Pierre Joseph 
Published: May 2024

Parenteral Nutrition (PN) is a lifesaving strategy that provides intravenous nutrition in patients when enteral feeding is contraindicated, or access is insuffcient to prevent malnutrition. PN is used in low-birth-weight neonates whereprolonged use is associated with severe metabolic complications, including parenteral nutrition-associated liver disease (PNALD). PNALD is characterized by hepatitis, cholestasis, fibrosis, steatosis, and eventual organ failure. Elevated rates of PNALD in pediatric patients may be driven by liver immaturity, aberrant metabolic adaptation, and leaky gut barrier.To characterize the etiology of PNALD, we recently established a pediatric mouse model of PN. Using this model, we explored the intravenous use of bioactive milk components to augment hepatic immune response in pediatric mice without enteral milk intake. Extracellular vesicles (EVs) are involved in cell-to-cell communication, contain immune-augmenting microRNA, and are enriched in bovine milk. After isolating EVs from bovine milk and characterizing them, we explored EV use in vitro via M1 macrophage responses, showing TNF-alpha inhibition in the presence of LPS. Wethen hypothesized that EVs would protect the pediatric liver from hepatitis under PN feeding in vivo. Mouse pups were randomized to intravenous PN, PN + EV (1.39x109 particles/uL), or sham surgery control for 6 days. Flow cytometry showed PN elevated hepatic macrophages (CD11b+F4/80+), myeloid-derived suppressor cells (CD11b+GR1+) andreduced relative T cell populations compared with sham controls. PN+EV treatment restored hepatic immune profiles to patterns observed in sham controls. Spleen and liver cytokines also mirrored changes in hepatic flow results, where elevated proinflammatory IL-1 beta was induced with PN alone, but similar levels were found in sham and PN+EVanimals. MicroRNA sequencing showed the EV isolates contain 48% Let-7, a described myeloid suppressor microRNA. This data demonstrates that intravenous EV administration - or future synthetic microRNA - may provide a noveltherapeutic approach for patients requiring PN nutrition support, especially those with elevated risk of PNALD induced inflammation and organ dysfunction. Dairy Innovation Hub, UW-Madison. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Age-Related Vascular Mitochondrial Dysfunction Is Ameliorated by Time-Restricted Feeding Intervention
Authors: Sanford Madison , Negri Sharon , Reyff Zeke , Ballard Cade , Nyul-Toth Adam , Gulej Rafal , Brown Jacob 
Published: May 2024

Endothelial dysfunction constitutes a hallmark of vascular aging that can have serious implications for disease risk. In addition, aging is associated with mitochondrial dysfunction, which can lead to increased oxidative stress and create associated damages. Time-restricted feeding (TRF) is a dietary intervention known to have many benefits on age-related disease risk. The objective of this study is to elucidate the effects of TRF upon endothelial mitochondrial function of aorta during aging. We hypothesized that TRF protects the aorta from age-related endothelial mitochondrial dysfunction. Adult C57BL/6 mice underwent TRF regimen, including six hours of ad libitum feeding daily. Young and age-matched control mice were fed ad libitum. After 12 months of TRF, wire myography was performed on aorta tissue as a measure of endothelial function. The aorta received pharmacological treatments to induce contraction, and dose-dependent dilation was quantified. For the first time, simultaneous measurement of reactive oxygen species (ROS) and oxygen consumption were completed in aorta tissue using Oroboros O2K Fluorespirometry. Dihydroethidium (DHE) fluorescent staining of ROS in aorta tissue was used to validate ROS measurements from O2K. Serum ketone body levels related to metabolic switching and relevant to mitochondrial biogenesis were determined. TRF improved endothelial-dependent dilation of aorta tissue, representing the intervention’s protection of endothelial function in aging. Aged TRF mice had greater oxygen consumption and less ROS in aorta tissue than age-matched control mice, indicating improved vascular mitochondrial function after TRF intervention. Aged TRF mice had elevated serum levels of ketone bodies involved in mitochondrial biogenesis. This supports the hypothesis that age-related changes in vascular mitochondrial health are alleviated by TRF. The knowledge gained from this study is relevant to understanding the mechanisms of age-related vascular dysfunction. Stephenson Cancer Center, National Institute of Aging R03 AG070479, American Heart Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sex Differences in Kidney Damage in BUF/MnaMcwi Rats
Authors: Royster Darcel , Kwitek Anne , Holl Katie , Wagner Valerie 
Published: May 2024

Kidney disease is commonly found in the BUF (Buffalo) strain of rats. It has been observed that male BUF rats show signs of focal glomerulosclerosis (FSGS). They are known to have proteinuria, hypoalbuminemia, and hyperlipidemia as they age. This is preceded by renal macrophage activation and Th2 lymphocyte polarization. There is no prior literature that explores kidney disease in female BUF rats.We previously observed that kidneys in female BUF rats appeared more damaged than their male mates, leading to the hypothesize that the female BUF/MnaMcwi (BUF) breeder rats have greater kidney damage features than male mates. To determine the relationship between sex and function, we collected urine samples using metabolic cages (at 12, 17, and 23 weeks of age), harvested organ tissue (heart left, ventricle, spleen, thymus, and kidneys), and used histopathological examination of formalin-fixed paraffn-embedded kidney samples to determine cortex tubule damage and glomerular area. We expected to see sex differences in relative sizes (mg/g BW) of the thymus, heart left ventricle, kidneys, and spleen. We found that the male BUF rats had larger absolute body weight (g), as expected. We also found that there were no significant sex differences in relative sizes (mg/g BW) of the thymus, heart left ventricle, and spleen. There was a significant sex difference in relative total kidney size (mg/g BW), with the females having larger kidney sizes compared to their body weight. In addition, there was increased microalbumin in the female BUF overnight urine collection that was significantly higher than the male BUF rats. There was no significant sex difference in the microalbumin: creatinine ratio. Finally, we found no significant sex difference in cortex tubular damage between the age-matched BUF rats, but there was a significant difference in glomeruler area (mm 2), with male glomeruler areas being significantly larger. Future studies will be done to replicate the findings and determine if virgin females show the same results. ASPIRE Program (R25HL 168782) Medical College of Wisconsin. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Electronic cigarette-induced adipose tissue inflammation is rescued by acipimox
Authors: Gilbertson Robert F. , Xu Justin , Rivera Juan Carlos , Hasan Kamrul M. , Sinha-Hikim Amiya P. , Shao Xueshi M. , Espinoza-Derout Jorge 
Published: May 2024

Objective: Electronic cigarettes (e-cigarettes) are the most commonly used tobacco product in the U.S. with high frequency among youth. Our laboratory has shown that e-cigarettes induce metabolic changes and cardiac dysfunction associated with elevated serum free fatty acids (FFAs). Adipose tissue dysfunction is a proinflammatory state that mediates multiple pathogenic mechanisms in the well-known associations between cardiovascular pathology, hypertension, and metabolic syndrome. In adipose tissue, crown-like structures (CLSs) are signs of metabolic dysfunction and adipose tissue inflammation. CLSs are composed of macrophages surrounding dead or dying adipocytes. Hypothesis: We hypothesize that e-cigarettes produce inflammation in adipose tissue, which is mediated by lipolysis. Methods: C57BL/6J wild-type mice on high fat diet were treated with saline aerosol, e-cigarette with 2.4% nicotine [e-cig (2.4%)], and e-cig (2.4%) plus acipimox (an inhibitor of lipolysis) [e-cig (2.4%)+ACIP], for 12 weeks. Adipose tissue was stained with Hematoxylin and Eosin (H&E). CD45 is the surface marker of immune cells. Therefore, we quantified the number of CD45+ cells in adipose tissue. Additionally, we performed a transcriptomic evaluation with Gene Set Enrichment Analysis (GSEA). Results: H&E staining showed abundant CLSs in mice exposed to e-cigarettes in adipose tissue. The number of CLSs was normalized in the e-cig (2.4%)+ACIP group. E-cigarettes induced an increase of CD45+ cells in adipose tissue, which was also normalized by acipimox. GSEA of the RNA-seq data revealed upregulation of inflammatory pathways in adipose tissue from e-cigarette-treated mice, including Interferon-g and Interferon-a response, which were rescued by acipimox treatment. Summary: Inhibiting lipolysis with acipimox normalizes the inflammatory changes induced by e-cigarettes in adipose tissue. These findings suggest a functional interplay between adipose tissue and metabolic dysfunction caused by e-cigarettes. Funding: JE-D work was supported by the NIH grants: NIGMS (SC2GM135127), NIMHD (S21MD000103), the CDU Accelerating Excellence in Translational Science (AXIS) (U54MD007598-14S2), and a voucher from UCLA CTSI (UL1TR001881). TCF was supported by the California TRDRP grant (28CP-0040), DODCDMRP grant (PR190942), and NIDA (R25DA050723) grants. XMS was supported by a NIDA (R42DA044788) grant. KPR was supported DODCDMRP grant (PR190942-P1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Retrograde optimized AAV tracer fails to transduce dorsal raphe nucleus projections to the basolateral amygdala
Authors: Hammack Robert , Daws Lynette , Toney Glenn 
Published: May 2024

Key in aversive emotional states are serotonergic (5-HT) projections to the basolateral amygdala (BLA) originating from the dorsal raphe nucleus (DRN). Despite being critical in aversive states, the precise anatomical location of 5-HT DRN neurons that project to the BLA is not well delineated. Vital in recent advancements in neuroscience are neurotropic adeno-associated viral (AAV) vectors, which allow for long-term expression of transgenes. However, a recent study using retrograde transport optimized AAV (rAAV2-retro) tracers has shown that transfection of axon terminals and subsequent retrograde transport may not be as ubiquitous as traditional non-transgenic tracer techniques. In this study, we wanted to not only map the precise location of neurons within the DRN that project to the BLA but also test the extent to which rAAV2-retro vectors were useful tools to study these projection neurons. In C57 mice, we iontophoretically deposited (+3-μA positive current at 7s intervals for 10 min, n=3 mice) or pressure nanoinjected (100 nl, n=3 mice) rAAV2-retro expressing the fluorescent reporter GFP (rAAV2-retro-CAG-GFP) into the BLA. After allowing two weeks for GFP expression, coronal sections were prepared from perfusion-fixated tissue and GFP expression was assessed in the DRN as well as the medial entorhinal cortex (mEC), a well validated input to the BLA. We found that iontophoretic deposition failed to robustly label the DRN and mEC. In contrast, while pressure nanoinjection failed to label many DRN neurons, the mEC was robustly labeled. These results may suggest a lack of DRN axon terminals within the viral injection sites or a failure of AAV retrograde tracer transduction in DRN projections to the BLA. Future studies comparing traditional retrograde tracer techniques to our results are warranted. In sum, these results caution the use of rAAV2-retro vectors to study DRN inputs to the BLA. MH093320 (LCD & GMT). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A novel preclinical model of fentanyl-induced cardiorespiratory collapse to investigate resuscitation outcomes
Authors: Piao Lin , Fang Yonghu , Garcia Alfredo J. , Sharp Willard 
Published: May 2024

Introduction: Opioid-related morbidities have become a critical public health concern, with ultrapotent synthetic opioids (UPSO) such as fentanyl contributing to the rise in opioid-related fatalities. Respiratory depression is the cardinal trait of fentanyl overdose, leading to systemic hypoxia and subsequent cardiorespiratory collapse (CRC). There is growing recognition that fentanyl induced CRC (fiCRC) is unique from other forms of sudden CRC. Yet, the consequences of fiCRC and its reversal remain poorly understood. This is due in part to the limited preclinical studies investigating rescue from fiCRC. Objective: using a novel model of fiCRC and subsequent reversal, this ongoing study aims to define the impact of UPSO and naloxone rescue on in vivo survival outcomes. Methods and Results: Male and female C57BL/6J mice were used. UPSO fentanyl i.v. administration (30 to 500 mcg/kg) suppressed breathing and subsequently led to fiCRC. The return of spontaneous circulation (ROSC) was achieved by performing manual chest compressions in combination of epinephrine administration after 8 minutes of fiCRC. In subset of mice, naloxone was administered post ROSC. Outcomes after 72 hours were accessed. The latency of fiCRC (mean arterial pressure at 40 mmHg) exhibited a negative correlation with the doses of fentanyl administered. Resuscitation from fiCRC was unreliable across the dose spectrum, while naloxone consistently rescued the majority of fiCRC animals. Naloxone increased ROSC rate from 54% to 86% when the dose of fentanyl was 30 mcg/Kg (n=22). With naloxone rescue, we compared fiCRC with non-opioid-induced cardiac arrest followed by potassium chloride injection (0.8 mg/g). Both models showed severe lung edema as evidenced by Evans Blue staining. However, the lung wet/dry weight ratio was higher in fiCRC group than in the non-opioid treatment group (5.50±0.05 vs. 6.60±0.60, n=4, p<0.05). Survival in fiCRC group was significantly worse than in non-opioid treatment group (survival rate: 25% vs. 83%, n=17, p<0.05). Conclusions: Our study highlights two important findings. First, the reliable resuscitation of fiCRC necessitates the use of naloxone. Second, the likelihood of injury is significant following successful rescue from fiCRC by naloxone. Our continued work using this fiCRC model will lead to insights that can be leveraged for strategies to mitigate injury and improve survival following fentanyl overdose. R01 HL163965 & R01 DA057767. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Regeneration of Neuromuscular Synapses by Inhibition of the Prostaglandin Degrading Enzyme 15-PGDH
Authors: Monti Elena , Afshar Mohsen , Wang Yu Xin , Su Shi Qi , Kraft Peggy , Alexandrova Ludmila , Wheeler Joshua R. 
Published: May 2024

Background: Skeletal muscles require voluntary activation to move, which is supplied via motor neurons. The terminal axons of motor neurons innervate muscle fibers at the neuromuscular junction (NMJ). NMJ degeneration increases with age and injury, decreasing muscle contractility and strength and severely reducing individuals’ quality of life. Treatments able to restore NMJ integrity and muscle innervation after injury and in aging are currently lacking. Aim: Our lab has recently shown that boosting prostaglandin E2 (PGE2) levels in aged mice by inhibiting its degrading enzyme 15-prostaglandin dehydrogenase (15-PGDH) stimulates muscle growth and restores muscle strength and endurance. The present study aimed at investigating whether 15-PGDH inhibition promotes muscle reinnervation and NMJ restoration, thus improving muscle function. Methods and results: We treated young (3-month) and old (27-month) mice with a small molecule compound with high specificity for 15-PGDH inhibition for 30 days. Old treated mice displayed increased muscle mass and strength (p<0.05) compared to aged control mice. While aged control displayed, as expected, a high percentage of denervated NMJ (21.6%), denervation was partially rescued by 15-PGDH inhibition (12.1%, p<0.05). Similarly, NMJ fragmentation was lower in treated versus control mice (18.1% vs 29.3%, p<0.05). To translate our findings to a more acute scenario, we induced nerve-crush injury in young mice (3-month) and treated animals with 15-PGDH inhibition during injury recovery. Treated mice were able to exert a 37.2% higher tetanic force 14 days after injury compared to control mice. This was accompanied by increased muscle mass and specific force (+32.2%, p<0.05) and an increased percentage of innervated NMJs (97.4% versus 84.5%) in treated versus control mice, suggesting that 15-PGDH inhibition was promoting NMJ restoration and muscle reinnervation after injury. Conclusion: In this study we identify 15-PGDH inhibition as a new potential therapeutic strategy to promote reinnervation of NMJs and strength recovery after acute or chronic denervation due to injury or aging. Funding: E.M. is supported by a “Wu Tsai Human Performance Alliance” fellowship. This study was supported by the Donald E. and Delia B. Baxter Foundation, the Li Ka Shing Foundation, Milky Way Research Foundation MWRF-216064, California Institute for Regenerative Medicine grant DISC2-10604, and U.S. National Institutes of Health (NIH) grants R01-AG020961, R01-AG069858, and R01-RHG009674 to H.M.B. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
In vitro examination of the antioxidants, osajin and pomiferin, in cultured rat mesangial cells
Authors: Gnalian Aleena , Carvalho Paulo , Ford Bridget 
Published: May 2024

Purpose: The goal of this study was to identify concentrations of osajin and pomiferin, purified compounds originating from Maclura pomifera, that work as effective antioxidants while maintaining cell viability in cultured rat mesangial cells. Rationale and Significance: Diabetic nephropathy (DN) is a serious complication faced by type 1 and type 2 diabetic patients alike. Oxidative stress has emerged as an important pathogenic mechanism in the development of glomerular and tubular injury in DN. Identifying novel antioxidants found in natural compounds could serve as an effective treatment in DN to prevent renal cell damage. Methodology: Rat mesangial cells (NMS) were grown to confluency in RPMI 1640 medium with 17% fetal bovine serum and 1x antibiotic/antimycotic. NMS cells were exposed to vehicle (control) or varying concentrations of pomiferin or osajin. MTT cell survival assays were used to assess cell viability for the selected concentrations. Antioxidant status was assessed using the Total Antioxidant Capacity Assay from Sigma-Aldrich and quercetin was selected as a positive control. Findings: Data from MTT cell viability assays demonstrated several concentrations (25, 50, and 100 mM) of both osajin and pomiferin maintained cell viability in NMS cells. Antioxidant capacity assay plans will be discussed as this is an ongoing project and we hope to identify the total antioxidant capacity and antioxidant response in NMS cells. Future plans also include moving forward with selected concentrations to identify the effectiveness of osajin and/or pomiferin in preventing high glucose-induced damage to glomerular cells and proximal tubular epithelial cells as this will be essential for investigating the benefit of using either compound in diabetic nephropathy. Research reported in this poster was supported by the University of the Incarnate Word Offce of Research and Graduate Studies. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.