bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post‐traumatic stress sensitizes the angiotensin II‐elicited hypertensive response
Authors: Xue Baojian , Yu Yang , Wei Shun‐Guang , Beltz Terry G , Guo Fang , Felder Robert B , Johnson Alan Kim 
Published: November 2023

Post‐traumatic stress disorder (PTSD) is associated with an activated renin‐angiotensin system (RAS) and elevated levels of proinflammatory cytokines (PICs) in the circulation and in the central nervous system (CNS). Using an Induction‐Delay‐Expression experimental paradigm, our previous studies demonstrated that activation of central RAS and inflammation by various challenges sensitizes angiotensin (ANG) II‐elicited hypertension. The present study investigated whether the ANG II‐elicited hypertensive response is also sensitized in a model of PTSD. The resident‐intruder paradigm was used to model PTSD. Each intruder rat (male Sprague‐Dawley) was exposed to a different resident (male Long‐Evans) for 2 hours on three days with each session separated by 1 day. Beginning on day 3 after the last exposure, the intruder (PTSD) rats and unstressed control rats received a subcutaneous infusion of ANG II (120 ng/kg/min) for 2 weeks. The PTSD rats had a significantly enhanced hypertensive response to the ANG II infusion when compared to control rats (Δ35.9±2.5 mmHg vs. Δ17.9±3.9 mmHg). In a separate group of rats, the brains of control and PTSD rats were collected on day 3 after the last exposure to determine mRNA expression of RAS and PIC components in the lamina terminalis (LT) and the hypothalamic paraventricular nucleus (PVN). The results showed that PTSD had upregulated expression of angiotensin type 1 receptor, tumor necrosis factor‐α, interleukin (IL)‐1β and IL‐6 in the LT, but not in the PVN. These results support the hypothesis that conditions upregulating the central RAS and PICs sensitize ANG II‐induced hypertension, and suggest that disorders such as PTSD may predispose individuals to exacerbation of renin‐angiotensin‐elicited hypertension.Support or Funding InformationThis work was supported by the NIH grants HL‐14388 (AKJ), HL‐98207 (AKJ), HL‐096671 (RBF) HL‐073986 (RBF), with partial support from the Department of Veterans Affairs (RBF).
Deletion of Secreted Form of Prorenin in the Subfornical Organ Attenuates the Development of DOCA‐salt Induced Hypertension
Authors: Worker Caleb J. , Buller Sophie A , Jensen Dane , Sigmund Curt D. , Feng Yumei 
Published: November 2023

We and others have previously reported that the (pro)renin receptor plays an important role in the development of hypertension, possibly by non‐proteolytic activation of prorenin in the central nervous system. In the brain, there are two alternate transcripts encoding prorenin; the secreted form of prorenin (sProrenin) encoded by renin‐a, and an intracellular form of prorenin (icProrenin) encoded by renin‐b. The importance of brain sProrenin in the development of hypertension is not yet fully understood. We found that sProrenin is expressed in the subfornical organ (SFO) of the brain, a key brain circumventricular organ involved in BP regulation and body fluid homeostasis. Here, we hypothesize that sProrenin in the SFO regulates BP and body fluid homeostasis, and contributes to the development of hypertension. To test this hypothesis, C57Bl/6J mice were treated with either deoxycorticosterone acetate (DOCA)‐salt (2.5mg/g of DOCA pellet, 0.9% NaCl in drinking water) or Sham (Sham pellet, with tap drinking water) for 2 weeks. SFO tissues were fixed for immuno‐labeling (n=3) of mouse prorenin. We found that prorenin immuno‐reactivity in the SFO was higher in the DOCA‐salt (0.29 ± 0.03 RFU) compared with the Sham (0.10 ± 0.04 RFU, P=0.01) treated mice, suggesting an elevation of prorenin protein level in the SFO. To further examine the functional importance of sProrenin in the SFO, we used Cre‐LoxP recombination to knockdown sProrenin, but not icProrenin, in the Renin‐aFlox mice by micro‐injecting either control adeno‐associated virus (AAV2‐eGFP, n=4) or AAV2‐Cre‐eGFP (n=5) directly to the SFO. Two weeks prior to injection, telemetric transmitters were implanted into the carotid artery and mice were allowed to recover for BP recording in a conscious free moving state. One week following AAV2 injection, mice were given DOCA‐salt (2.5mg/g DOCA, 0.9% NaCl in drinking water) for 2 weeks. The baseline BP (mmHg) was similar between mice that received AAV2‐eGFP (104.2 ± 2.3) compared to AAV2‐Cre‐eGFP (98.1 ± 2.50; p>0.05). DOCA‐salt significantly increased BP in mice that received either AAV2‐eGFP (147.8 ± 5.7) or AAV2‐Cre‐eGFP (130.4 ±1.7) compared with their respective baseline (p<0.0001). However, mice received AAV2‐Cre‐eGFP had significantly lower BP compared with mice received AAV2‐eGFP (p<0.01). Surprisingly, fluid intake was similar between the mice that received AAV2‐Cre‐eGFP (13 ± 1 ml/day) compared to the AAV2‐eGFP treated mice (20 ± 4 ml/day, P=0.15). In sum, the prorenin protein level in the SFO is elevated in DOCA‐salt‐induced hypertensive mice. Selective deletion of sProrenin in the SFO attenuates hypertension without affecting fluid intake following DOCA‐salt treatment. We conclude that sProrenin produced locally within the SFO is involved in regulation of blood pressure and contributes to the pathophysiology of neurogenic hypertension.Support or Funding InformationNIH/NHLBI (1R01HL122770) TO YUMEI FENG
Characteristic changeable shape of the otolith organs in Meniere's disease
Authors: Tanioka Hisaya 
Published: November 2023

INTRODUCTIONTheprimary function of the otolith organs is the determination of bodily positionand movements. Meniere's disease is characterized by recurrent spontaneousattacks of vertigo, fluctuating hearing loss, tinnitus, and aural fullness. Theotolith organs are correlated with vertigo.OBJECTIVETo investigatethe shape of the otolith organs in Meniere's disease according with clinicalcourse and non‐affected ear. No one knows the shape of the otolith organs inthe living subject suffered from Meniere's disease.METHOD3Dvirtual histology of the otolith organs by a volume rendering was reconstructedby a conventional temporal HR‐CT. The analysis of the otolith organs was undergone by the bone algorithm of a volume rendering.RESULTSIn Meniere's disease, the affected utricular otolith was thin, and the saccular otolith was large. In the clinical course of Meniere's disease, during the attack period, the utricular otolith was thinner, and the saccular otolith was larger than both pre and post status like the figure.DISCUSSIONI provide 3D virtual image of the otolith organs in the inner ear by which the internal state of living subjects can be observed in detail using misinformation associated with calcium carbonate. During suffering from Meniere's disease, the utricular otolith was decreased in volume. Otherwise, the saccular otolith was increased in volume. After effective treatments, the utricular otolith was increased and the saccular otolith was decreased in volume. These quantitative methods for assessment of vestibular otopathology have defined the changeable otolith in the utricle and saccule.Support or Funding InformationNone
Role of Dlx5 in the development of the palatal‐pharyngeal region in higher vertebrates
Authors: Chai Yang , Sugii Hideki , Grimaldi Alexandre , Ho Thach‐Vu , Parada Carolina 
Published: November 2023

Distal‐less (Dll) genes belong to an evolutionarily conserved family of homeobox transcriptional regulators, which are important for the early embryonic development of bone in the limbs and craniofacial region. Mutations in human Dll orthologs, Dlx5/6, cause split‐hand/split‐foot type 1 malformation (SHFM1) associated with sensorineural deafness, cleft palate, developmental delay, and micrognathia. Dlx5 mutant mice have craniofacial abnormalities including cleft soft palate and micrognathia. However, the role of Dlx5 in the palatal‐pharyngeal development, which is important for speech, remains unclear. This study examines the role of Dlx5 in the formation of the soft palate, the Eustachian tube (ET), and the pharyngeal region. Gene expression analysis demonstrates that Dlx5 is expressed in muscles and osteogenic progenitor cells. Homozygous Dlx5 mutant mice lack soft palatal muscles including the levator veli palatini (LVP) and palatopharyngeus (PLP). The posterior regions of the hard palate and pterygoid plate are smaller in Dlx5−/− mice than in controls. Morphometric analyses of the premaxilla, maxilla, palatine bone, and mandible show that these bones are smaller in height, width, and length in Dlx5−/− mice compared to controls. Taken together, our data reveal that Dlx5−/− mice recapitulate craniofacial phenotypes similar to those of SHFM patients. Further studies of Dlx5 expression in the proximal region of the mandible, posterior palate, and pharyngeal region may reveal the mechanism responsible for the pharyngeal morphology. These studies hold potential for improving our understanding of the evolution of speech in the human lineage.Support or Funding InformationSupported by the NIDCR, NIH R37 DE012711
Functional specializations of hypoglossal motoneurons innervating intrinsic and extrinsic tongue muscles
Authors: Wealing Jesse Cole , Cholanian Marina , Fregosi Ralph 
Published: November 2023

The mammalian tongue contains eight muscles that collaborate to ensure that breathing, swallowing, suckling and other important behaviors are robust and reliable. Seven of these muscles are innervated by hypoglossal motoneurons (XIIMNs). Most studies of XIIMNs have considered them to be a homogeneous population, however a given tongue movement requires precisely allocated contributions from all tongue muscles. Thus, XIIMNs may have unique functional properties that reflect the usage pattern of the muscle that they innervate. To better understand the functional specializations of muscle‐specific XIIMNs, intrinsic (superior longitudinalis) and extrinsic (genioglossus) muscles were injected with dextran‐rhodamine to illuminate the XIIMNs innervating those muscles. The labeled XIIMNs were anatomically and electrophysiologically differentiable. Intrinsic XIIMNs were located more medial and dorsal, and extrinsic muscles more lateral and ventral. Whole‐cell patch‐clamp experiments showed that resting membrane potential was on average 10 millivolts more depolarized in intrinsic compared to extrinsic XIIMNs, and that the firing rate response to current injection was higher in intrinsic compared to extrinsic XIIMNs. These observations show muscle‐specific functional specializations in XIIMNs, and this information lays the foundation for more detailed experiments, and the development of “neuron‐specific” therapeutic approaches for tongue‐related respiratory disorders.Support or Funding InformationNIH (R01 HD071302).
Aging‐Related Deficits in Neuromuscular Transmission and Force Loss in the Diaphragm Muscle
Authors: Mantilla Carlos B. , Gransee Heather M. , Greising Sarah M. , Sieck Gary C. 
Published: November 2023

The diaphragm muscle (DIAm) must be able to generate sufficient forces to sustain ventilatory and non‐ventilatory behaviors throughout the lifespan. Aging‐related decreases in DIAm fiber cross‐sectional area and specific force, i.e., sarcopenia, may impair the ability to generate transdiaphragmatic pressures (Pdi) necessary to accomplish expulsive, non‐ventilatory behaviors essential for airway clearance. We examined the effects of aging on DIAm function in mice at 6, 18, and 24 months of age. At each age, DIAm‐phrenic nerve preparations were used to determine maximal force by ex vivo contractility of the DIAm as well as neuromuscular transmission failure by repetitive nerve and muscle stimulation. By 18 months, animals had reduced Pdi during maximal forces (e.g., during tracheal occlusion) and increased DIAm neuromuscular transmission failure compared to 6 months, but no change in DIAm maximum specific force. By 24 months, Pdi remained reduced during occlusion, DIAm neuromuscular transmission failure remained increased compared to 6 months, and DIAm maximum specific force was decreased compared to both 6 and 18 months. Using this global measure of neuromuscular transmission, it is evident that impaired transmission precedes muscle weakness.Support or Funding InformationSupported by R01‐AG044615.
Functional evaluation of prorrenin/renin receptor in immune cells from rats with pregnancy‐induced hypertension
Authors: Galicia‐Galicia Erick , Anguiano‐Robledo Liliana , Lopez‐Sanchez Pedro , Hernandez‐Campos Maria Elena 
Published: November 2023

Pregnancy‐induced hypertension (PIH), known before as preeclampsia, is a multisystemic disorder characterized by hypertension, proteinuria and low intrauterine development. Its etiology remains unknown. Several systems seem to participate in PIH genesis. The renin‐angiotensin system (RAS) has been implicated in PIH development. RAS is essential for blood pressure control and hydro‐saline balance. The prorrenin/renin receptor (PRR) is a component of this system. Recent studies have shown that PRR activates PLZF, MAPK pathways (ERK1, ERK2), as well as the Wnt pathway. V‐ATPase has also been related with PRR activation, lowering pH within cells. It is not described yet, however, if PRR activates these mechanisms in leukocytes during pregnancy. In the present work, we evaluated if PRR activates MAPK (ERK 1‐2, TGF‐beta), WNT (β‐catenin, DVL‐1, PKC alfa) pathways and V‐ATPase in leukocytes from normal pregnant and pregnancy‐induced hypertensive rats. We induced PIH in female Wistar rats using sub‐renal aortic coarctation (CASR). We measured proteinuria, systolic and diastolic blood pressure, pups body weight, length, and number. The expression of PRR, β‐catenin, PLZF, ERK1‐2, pERK 1‐2, PCK alfa and TGF‐b was determined by immunoblot in leukocytes from spleen. Our results show a significant increase in PRR and PLZF expression in the PIH model compared to normal pregnancy groups. β‐catenin and, ERK 1‐2 showed a moderate increase. However, DVL‐1 and PKC alfa increased significantly, indicating that PRR seems to activate WNT preferentially over MAPK pathways. Intracellular pH was not modified significantly. Our findings indicate that PRR is functional in immune cells during healthy and complicated pregnancySupport or Funding InformationSIP 20150467 and SIP20160667
LRP‐1 Targeted Neuroprotection in a Mouse Model of Diabetic Retinopathy
Authors: El‐Desoky Dalia Hany , Bhattacharjee Partha , Hossain Ahamed 
Published: November 2023

Human apolipoprotein E (apoE) is known to exert neuroprotective function in central nervous system disorders through low‐density lipoprotein receptor‐ related protein‐1 (LRP‐1). Retina being the same embryological origin like the brain, we rationale that retinal neurodegeneration can be inhibited by peptidomimetic blocking of LRP‐1. Thus, we predict a short peptide (apoEdp) mimicking the LRP‐1 binding region of apoE may have a role in the protection of retinal neuronal cells in the diabetic mouse eye model. Vascular changes in the retina are traditionally considered as classic diagnostic feature of Diabetic Retinopathy (DR). However, color blindness, lack of contrast sensitivity and abnormal electroretinogram characteristic to retinal neurodegeneration are documented in diabetic patients before clinically evident blood vessel changes. In fact, diabetes‐induced retinal neurodegeneration precedes vascular damage. Critical barriers to the development of adequate therapeutic strategies for the treatment of DR are related to the lack of information about the mechanism of early retinal neurodegeneration and its progression to late vascular abnormalities. Our studies with diabetic mouse retina suggest a signaling pathway involving low‐density lipoprotein receptor‐ related protein‐1 (LRP‐1) protects neurons from apoptosis by regulating the pro‐survival pathways of PI3k/Akt and MAPK/Erk pro‐survival pathway. We found apoEdp has anti‐PP2A activity in the diabetic retina and is effective in the treatment of retinal neurodegeneration in vivo. Our study suggests that intravitreal administration of apoEdp and its possible therapeutic neuroprotection will generate a proof of principle for treating diabetic neuronal complications.Support or Funding InformationSupport is provided in part by grant number 2G12MD007595‐06 from the National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS) and its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIMHD or NIH.
Effect of PPAR Partial Agonist, GQ‐16, on Viability of Breast Cancer Cells in Culture
Authors: Ferreira Anna Paula B , Coelho Michella Soares , Amato Angélica Amorim , de Assis Rocha Neves Francisco , Rodrigues Izabel Cristina , Royer Carine 
Published: November 2023

Breast cancer (BC) is the most frequent cancer in women around the world. Tumor cells have several mechanisms of resistance to chemotherapy treatment, so the relevance of searching for new drugs for the treatment of this pathology. Studies have shown that agonists of peroxisome proliferator‐activated receptors g (PPARg) are a promising target in the development of drugs for treatment of various cancers, including BC. Drugs in this class include thiazolidinediones (TZDs), total PPARg agonists with serious side‐effects. Recently, it was proposed that adverse effects of totals PPARg agonists could be avoided using partial agonists. Previous studies showed that GQ‐16 presents partial agonist activity and specificity to PPARg, as well as similar performance to TZDs with decreased adipogenic effect.ObjectiveTo investigate the antitumor activity of partial PPARg partial agonist, GQ‐16, in human breast tumor cell line (MCF‐7).MethodsMTT (3 bromide (4, 5dimetiltiazol‐2il)‐diphenyl tetrazolium‐ ‐2.5) assay was used in human BC tumor cell lines (MCF‐7) with different doses of rosiglitazone and GQ‐16 (10−8 – 10−4 M) for 24 and 48 hours and DMSO 0.01% as negative control.ResultsRosiglitazone decreased cell viability (49%) after 48 h of treatment on concentration of 10−4 M. On the other hand, GQ‐16 was able to decrease cell viability after 48h of treatment on several concentrations (36.92% at 10−6 M; 39.08% at 10−5 M; 75.81% at 10−4 M).ConclusionPartial PPARg agonist, GQ‐16, proved to be more potent than rosiglitazone on reducing the viability of breast cancer cells line MCF‐7. This effect was shown to be dose and time‐dependent. Therefore, it is suggested that this drug can be studied as an antitumor agent. Our results indicate that GQ‐16 is a promising target for antitumor activity researchSupport or Funding InformationCNPq/CAPES/FAPDF
Vanadium Complex Induced Cancer Cell Death via RIPK3 Activated Necroptosis
Authors: Rana Savannah R , McCaffrey Vanessa , Rabquer Bradley James 
Published: November 2023

PurposeCancer, at the cellular level, is characterized by uncontrolled cell proliferation caused by a loss of control of the cell's normal cycle of growth and division. This loss of control usually results from irreversible cell damage, primarily mutation of the cell's DNA, which would normally result in programmed cell death, or apoptosis. Many anti‐cancer therapies, such as cytotoxic chemotherapy, trigger activation of pathways that induce this cell death. Previous studies in our lab have shown the efficacy of using dioxovanadium complexes with substituted salicylaldehyde derivatives (VCs) to inhibit cancer cell growth, yet not the activation of the caspase 3/7 apoptosis pathway. The necroptosis pathway is a mode of inflammatory programmed cell death characterized by the phosphorylation of Receptor Interacting Protein Kinase 3 (RIPK3) and Multi Lineage Kinase Like (MLKL). Here, we hypothesized that vanadium complex treated HT‐29 cells are being terminated by means of the necroptosis pathway.Methods and ResultsHT‐29 cells were used as a model for colon cancer. Previously synthesized VCs with 5‐Br and 3‐OMe functional groups were used as treatments in vitro. Immunofluorescence assays were performed on cells treated with functional group only controls (0.5 mM), 3‐OMe (0.5mM), and 5‐Br (0.5mM) VCs for incubation periods of 24 hours and 3 hours (n=2). The treated cells were probed with anti‐phosphorylated RIPK3. An increase in phosphorylated RIPK3 was evident after both 3 and 24 hour incubation periods in the experimental groups, but not the controls, indicating activation of the necroptosis pathways. For Western blotting, cells were treated with DMSO, 5‐Br (0.5mM) and 3‐OMe (0.5mM) VCs respectively for incubation periods of 3 and 24 hours (n=3). Protein lysates were collected and western blots were run to detect the presence of total and phosphorylated receptor interacting protein kinase‐3 (RIPK3), however activation of the RIPK3 necroptosis pathway was not confirmed.ConclusionVCs induce HT‐29 cell death via the activation of RIPK3 and the necroptosis pathway.Support or Funding InformationThis work was supported by the Albion College Biology and Chemistry Departments, the Foundation for Undergraduate Research, Scholarship, and Creative Activity (FURSCA), and the Hewlett‐Mellon Fund for Faculty Development at Albion College.
The Role of Sirtuin 2 in the Regulation of Myogenesis
Authors: Stanton David A. , Alway Stephen E , Mohamed Junaith S. 
Published: November 2023

The postnatal growth and regenerative capacity of skeletal muscle rely on the successful activation and differentiation of muscle stem cells known as satellite cells. Although the NAD+‐dependent protein deacetylase sirtuin‐2 (SIRT2) has been suggested to have a role as a redox sensor during myogenesis, and in the regulation of metabolism, microtubule dynamics, and exit from the cell cycle exit, it is not known if SIRT2 has a regulatory role in muscle stem cell proliferation or differentiation.PurposeThe objective of this study was to investigate the role of SIRT2 in the molecular and genetic control of myogenesis.MethodsC2C12 myoblasts were cultured in growth medium containing DMEM and fetal bovine serum. Myoblasts were treated with BML‐266, a pharmacological inhibition of SIRT2 deacetylase activity. CRISPR/CAS9 technology was used to generate a stable SIRT2 knockout C2C12 cell line. GFP positive cells that were negative for SIRT2 were collected by flow cytometry. The control and SIRT2 knockout myoblasts were placed in 2% horse serum to differentiate the myoblasts to myotubes. The cells were harvested for analysis 12 or 24 hours after initiation of differentiation.ResultsSIRT2 protein expression was upregulated during early differentiation in C2C12 myoblasts after both 12 and 24 hours after the initiation of differentiation. Inhibition of SIRT2 pharmacologically or by gene knockout, impaired myotube fusion but it did not affect proliferation of C2C12 myoblasts. We have also identified downstream targets of SIRT2 activation that appear to be involved in modulation of differentiation.ConclusionsThese data suggest that SIRT2 may be a key contributor to the regulation of myoblast differentiation. Furthermore, SIRT2 may be an important target protein for treatment strategies of muscle wasting conditions including aging, muscular dystrophy, cachexia, or sepsis.