bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Non-alcoholic Fatty Liver Disease on development of diabetes complications
Authors: Burkhanova Maftunakhon , Shamansurova Zulaykho , Rakhmonova Gulzor , Rustamov Sardor , Maksutova Nigora , Aykhodjaeva Mokhira 
Published: May 2024

Introduction. Non-alcoholic Fatty Liver Disease (NAFLD) shown frequent future in patients with type 2 Diabetes Mellitus (DM2). By affecting insulin metabolism, glucose production and gluconeogenesis liver disorders probably involved into DM2 clinical future and development of complications. We studied the role of the NAFLD in the development of diabetic complications such as retinopathy (DR), neuropathy (DPNP), nephropathy (DN). Material and methods. 62 patients with DM2 who were admitted into Republican Specialised Scientific Practical Medical Centre of Endocrinology named after acad. Y.Kh. Turakulov were observed. In all patient blood glucose, HbA1c, total blood count, urine test, blood lipids, AlT, AsT, alkaline and acid phosphatase, … were measured. Liver, pancreas, gall bladder were visualised by ultrasound. Results. Among patients with DM NAFLD were detected in 45% of patients with DM2. Patients average age, BMI, HbA1c, blood fibrinogen level were greater in NAFLD group, whereas there were no found any differences between ALT, AST, BUN, creatinine levels. Blood total platelets were decreased in NAFLD group (10.6%, p<0,05). Fib4 score was higher in NAFLD group by 1.5 times, where comparison of Fib4 score according to DN stages shown 2.57 times higher score in patients with DN4 and DN5. Patients with NAFLD diabetes complications were higher, especially DR by 1.2 times, DPNP 1.3 times and DN by 1.5 times than without NAFLD. Moreover, number of patients with NAFLD treated by insulin were 2 times more than without NAFLD. Conclusion. NAFLD is a frequent future among patients with DM2, have linkage with patients’ age, BMI, HbA1c level, depend from severity of DR, DPNP and DN. Blood platelets were lower in NAFLD group, where Fib4 score was 1.5 times higher. Results suggested about involving of NAFLD into diabetic complication development. NA. 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.
Loss of nitric oxide bioavailability promotes arterial stiffening in a tissue transglutaminase-dependent manner
Authors: Ramirez-Perez Francisco I. , Lateef Olubodun M. , Foote Christopher A. , Manrique-Acevedo Camila , Martinez-Lemus Luis A. , Padilla Jaume 
Published: May 2024

Although arterial stiffening undeniably contributes to cardiovascular disease, the cellular and molecular mechanisms leading to increased arterial stiffness are not well understood. Increased arterial stiffness in disease states such as obesity and type 2 diabetes typically coexists with indices of endothelial dysfunction including diminished nitric oxide (NO) bioavailability. In fact, it is commonly assumed that endothelial dysfunction precedes, and causally contributes to, arterial stiffening; yet the molecular underpinnings for this causal relationship remain elusive. We and others previously showed that activation of tissue transglutaminase (TG2), a crosslinking enzyme that also works as a G-protein and cellular scaffold, promotes cytoskeletal actin polymerization and stiffening of vascular smooth muscle cells (VSMC), thus contributing to whole-artery stiffening. It is also reported that NO is an endogenous inhibitor of TG2. Accordingly, herein, we tested the hypothesis that increased exposure of VSMC to NO suppresses TG2 activity and actin polymerization. Conversely, we hypothesized that loss of NO bioavailability promotes arterial stiffening, and that this effect is mediated by TG2 activity and downstream activation of LIM kinase (LIMK), an enzyme that modulates fibrillar (F)-actin severing via cofilin phosphorylation. All differences reported herein are significant at P<0.05. In support of our hypotheses, we show that treatment of cultured human aortic VSMC with the NO donor S-nitrosoglutathione (200μM for 2 hours) reduces TG2 activity (N-epsilon gamma glutamyl Lysine presence) and F-actin formation (phalloidin staining) induced by TG2 activation (dithiothreitol, 200μM). Furthermore, we show that exposure of mouse isolated mesenteric arteries to the NO synthase inhibitor L-NAME (300μM for 18 hours) causes an increase in arterial stiffness ( i.e., increased incremental modulus of elasticity) as determined using pressure myography and videomicroscopy. Of note, L-NAME-induced arterial stiffening is prevented when arteries are co-treated with a TG2 inhibitor (cystamine, 1mM) or LIMK inhibitor (LIMKi, 1μM). Taken together, these findings support the notion that NO is a key downregulator of TG2 activity and demonstrate that reduced NO bioavailability promotes arterial stiffening in a VSMC TG2-LIMK-F-actin dependent manner. As such, this work provides insight into plausible molecular mechanisms by which endothelial dysfunction leads to arterial stiffening. R01HL153264 (to LAML and JP), and MU Research Excellence Program (REP) postdoctoral fellowship (to FIRP). 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.
Automating Polysomnography in an Under-Explored Animal Model: Preliminary Results from Hibernating Bears
Authors: Tøien Øivind , Pittaras Elsa Cecile , Huang Yi-Ge , Brodersen Paul , Allocca Giancarlo , Barnes Brian M. , Heller H. Craig 
Published: May 2024

Animal hibernation is a hypometabolic state that may inform translational research to improve clinical outcomes for hypoxic patients whose oxygen supply does not match their demand. Bears are an excellent animal model, as they decrease their body temperature to only 30-35°C during hibernation and suppress their metabolism down to 25% of normal resting levels while having a more comparable physiology to humans than deep hibernators such as small rodents. As little is known about their sleep patterns during hibernation, we continuously monitored for more than 3500 days via biotelemetry a variety of physiological parameters from 16 captive American black bears in and out of hibernation. We recorded EEG, EOG and EMG signals that are commonly used to determine wake, REM sleep and NREM sleep vigilance states in conventional animal models (polysomnography). Such a data set is too large to fully annotate manually, so we compared two automated approaches. We first manually annotated two one-day recordings at body temperature extremes from each of 6 bears during hibernation when body temperatures were oscillating widely in multiday cycles with intermittent bouts of shivering (Tøien et al. 2011). We also manually scored a one-day, non-hibernating recording at normal (summer) body temperature from these bears. Based on this reference data set, we evaluated two automated scoring applications based on different machine learning classifiers: open source Somnotate (author Paul Brodersen), which is trained on multiple files, and proprietary Somnivore (author Giancarlo Allocca), which is trained on a subset of epochs from each individual recording. Somnotate gave best results during hold-one-out testing when using separate models for hibernating and non-hibernating data, and then performed comparably for both conditions. Somnivore was by design trained on a small subset (100 epochs of each kind) of each file to be tested. Both applications provided typical F-measures against manual reference scores in the 0.90-0.97 range. Outliers in the lower 0.72-0.88 range were highly correlated between the two applications, indicating that specific files are more challenging to annotate — either manually, automatically, or both. We conclude that both applications have accuracies on par with manual scorers when trained on high quality data. Supported by NIH COBRE under grant number [P20GM130443]. 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.
Molecular Basis of Different Flow-Induced Responses of Small Intra- and Extracranial Cerebral Arteries: Role of Arachidonic Acid and Nitric Oxide Pathways
Authors: Koller Akos , Nemeth Zoltan 
Published: May 2024

Background / Objectives. Previous studies showed that increases in intraluminal flow elicit primarily dilations in isolated rat extracranial basilar arteries (BA), whereas constrictions in the intracranial middle cerebral arteries (MCA) (Koller A, Toth P. J Vasc. Res. 2012, PMID: 22739136). These responses are most likely due to the absence or presence of physical constraints (rigid cranium). Thus, we hypothesized that the underlying molecular pathways are also different, corresponding to the functional vasomotor responses. Material and Methods. Protein and gene expression of key AA-pathway enzymes and receptors, such as cyclooxygenase (COX1 and COX2) and thromboxane A2 receptor (TxA2R), and vasodilator enzymes, such as prostacyclin synthase (PGIS) were measured in isolated BA and MCA from male rats (3 months old, n=18). Results. By western blotting protein expression of vasoconstrictor metabolites COX1/2, Cyp4A and receptor TBXA2R were significantly higher whereas expression of dilator PGIS was significantly lower in MCA than in BA. Using qPCR we found that expression of genes coding vasoconstrictor enzymes COX1/2, Cyp4A and receptor TBXA2R was significantly higher, whereas gene coding dilator PGIS was significantly lower in intracranial compared to extracranial arteries. In addition, RNAseq analysis demonstrated that expression of multiple genes coding vasoconstrictor molecules is higher in intracranial compared to extracranial arteries. Conclusions. These findings provide mechanistic basis for the observed different functional, vasomotor responses of BA and MCA to increases in flow, by showing the different expression of enzymes (COX1/2, Cyp) producing constrictor prostanoids (such as 20-HETE), receptors (TxA2R) and dilator prostanoid (PGIS). In addition, these findings reinforce the importance of regional differences in the regulation of cerebral arterial resistance, thereby providing appropriate blood flow to the brain, and at the same time, autoregulation of cerebral blood flow. Ministry of Innovation and Technology (MIT) of Hungary-NRDI TKP2020-NKA-17, TKP2021-EGA-37, and National Research, Development, and Innovation Offce (NKFIH) OTKA K 132596 K_19, and Hungarian Academy of Sciences, Post-Covid 2021-34, and HUN-REN-SU: 02068 of Hungary. 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.
ASK1-mediated Apoptosis in Human Lung Fibroblasts
Authors: Huffman Emily , Gordon Elizabeth , Dong Brittany , Camus Sarah , Freeberg Margaret , Thatcher Thomas , Sime Patricia 
Published: May 2024

Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating lung disease characterized by progressive fibrosis and dysregulated wound repair that negatively affect lung function. Although lung fibroblasts are important in repair mechanisms following lung injury, differentiation into myofibroblasts in the presence of TGF-β and resistance to apoptosis can promote the progression of pulmonary fibrosis. Apoptosis signal regulating kinase 1 (ASK1) is a member of the mitogen activated protein (MAP) kinase family that is known to promote apoptosis. The objective of this study was to test the hypothesis that ASK1 is an important mediator of apoptosis in lung fibroblasts. Normal human lung fibroblasts were obtained from five donors and cultured in the presence or absence of TGF-β (1ng/mL) for 72h. Apoptosis was assessed by a Caspase-Glo® 3/7 assay following treatment with a combination of cycloheximide and Fas ligand antibody with or without the ASK1 inhibitor, selonsertib. Expression of α-smooth muscle actin (α-SMA), collagen, ASK1, and survivin (a member of the inhibitor of apoptosis protein family) were determined by western blot. Apoptosis was induced in three of the five donor lines, and selonsertib treatment reduced caspase-3/7 activity. These donor lines expressed lower levels of survivin compared with the non-responding lines. TGF-β did not significantly affect these results. As expected, TGF-β stimulated expression of collagen and α-SMA in all donor lines, but this was reduced by treatment with selonsertib. Interestingly, TGF-β caused a reduction in the expression of ASK1 which is consistent with the idea that myofibroblasts in IPF are resistant to apoptosis. These results suggest that ASK1 can promote apoptosis in normal lung fibroblasts, but this is dependent upon the expression of survivin. Supported by VA Merit Award BX005889 (CMW) and NIH grant HL131526 (CMW). 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.
Selective KCNQ2/3 Potassium Channel Opener ICA069673 Inhibits Excitability in Mouse Vagal Sensory Neurons
Authors: Sun Hui , Meeker Sonya , Undem Bradley 
Published: May 2024

The excitability of vagal sensory neurons is abnormally enhanced in inflammatory visceral diseases, contributing to the unproductive and diffcult-to-treat neuronally based symptoms such as non-cardiac chest pain and excessive coughing. Identification of targets and modulators capable of regulating the excitability of vagal sensory neurons may lead to novel therapeutic options. The KCNQ/KV7/M-channel is increasingly recognized as an intrinsic regulator of excitability in neurons, and several neuronal KCNQ2/3-selective M-channel openers have been developed. This study aimed to characterize the effects of one of these KCNQ2/3-selective activators, ICA-069673, on the M-current (IM) in mouse nodose neurons, and to determine its effects on excitability and action potential firings using perforated patch-clamp technique. The results showed that ICA-069673 enhanced IM density, accelerated the activation and delayed the deactivation of M-channels in a concentration-dependent manner. The EC50 of ICA-069673 in enhancing IM determined at -30 mV is 0.52 μM. ICA-069673 at 10 μM shifted the voltage-dependent activation of IM in hyperpolarizing direction by -25.5 ± 4.1 mV (p<0.001) and increased the maximal conductance from 8.1 ± 4.0 to 12.6±7.4 nS/pF (p=0.031). In a total of 48 nodose neurons studied on voltage-clamp mode, ICA-069673 enhanced IM in 41 neurons (~85%). Consistent with its effects on IM, ICA-069673 induced a marked hyperpolarization of resting potential and reduced the input resistance. The hyperpolarizing effect was more pronounced in partially depolarized neurons. Moreover, ICA-069673 caused a 3-fold increase in the minimal amount of depolarizing current needed to evoke an action potential, and significantly limited the action potential firings in response to sustained suprathreshold stimulations. These results indicate that opening KCNQ2/3-mediated M-channels is suffcient to suppress the excitability and enhance spike accommodation in vagal sensory neurons, and provide evidence supporting further investigation into the effcacy of ICA-069673 in normalizing the aberrant vagal visceral nociception. The study is supported by NIH Grant R35HL155671. 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.
Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus Induce Salt Sensitivity of Blood Pressure in Humanized Mice
Authors: Saleem Mohammad , Ahmad Taseer , Haynes Alexandria Porcia , Major Amy , Ormseth Michelle , Stein Michael , Kirabo Annet 
Published: May 2024

Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular disease (CVD), even in normotensive people. Systemic lupus erythematosus (SLE) is also a risk factor for CVD and hypertension. SLE and CVD are on the rise, and it is not known if this is attributable to the increased dietary salt in the modern diet and SSBP. Isolevuglandins (IsoLGs) adduct self-proteins forming neoantigens in antigen presenting cells (APC) to activate T cells and produce cytokines that promote sodium retention, kidney damage, salt sensitivity of blood pressure, and SLE. We hypothesized that high salt intake increases both blood pressure and the proinflammatory milieu in mice humanized with the immune cells of patients with SLE. We humanized female NSG/MHCI/MHCII−/− immunodeficient mice with peripheral blood mononuclear cells (PBMCs) isolated from patients with SLE (n=5) and controls without autoimmune disease (n=4). The blood pressure was measured with radiotelemetry, immune phenotyping was performed with flow cytometry, and vascular reactivity was assessed in mesenteric arteries using wire myography after two weeks of a 4% high salt diet. High salt treatment significantly increased systolic blood pressure in lupus mice compared to the controls (135.5 vs. 123.8 mmHg, p=0.014). APC infiltration (macrophages, monocytes, dendritic cells), their activation (CD86) and proinflammatory markers (IL-23 p19, TNF-alpha), and oxidative stress (Isolevuglandins, Nox2) were significantly higher in the kidneys of lupus mice. Moreover, the signaling molecule p-STAT3 was significantly higher in myeloid cells in the kidneys of lupus mice. The classical monocyte and proinflammatory markers were significantly elevated in the spleen lymphocytes, and proinflammatory markers were increased in the kidney, spleen, and aorta in lupus mice. These mice exhibited vascular dysfunction (p<0.05), suggesting reduced vascular compliance. We measured urine albumin and found that lupus mice tended to excrete more albumin than the controls (17.24 vs. 25.89 μg/ml p=0.142), suggesting greater kidney injury. In conclusion, our findings suggest that immune cells from patients with SLE, in response to high salt intake, increase blood pressure and the proinflammatory milieu in the kidney, aorta, and spleen; impair vascular compliance; and worsen albuminuria in immunodeficient mice. 1R01HL144941-01A1 1R03HL155041 23CDA1053072. 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.
Reorganization of Actin Cytoskeleton and Reduction of Cortical Elasticity in Podocytes Lacking Acid Ceramidase: Role of Sphingomyelinase-Like Phosphodiesterase 3b
Authors: Li Guangbi , Huang Dandan , Ren Jenna , Zou Yao , Kidd Jason , Gehr Todd , Li Pin-Lan 
Published: May 2024

Podocytopathy and associated nephrotic syndrome have been reported in a mouse strain (Asah1fl/fl/Podocre) with a podocyte-specific deletion of α subunit (the main catalytic subunit) of acid ceramidase (AC). Nevertheless, the pathogenic mechanism of podocytopathy in these mice remains poorly understood. Given that sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) has been recently reported to play a vital role in maintaining the actin cytoskeleton and normal function of podocytes, the present study tested whether Asah1 gene deletion-induced podocytopathy is attributed to altered SMPDL3b activity and reorganized actin cytoskeleton in podocytes. By Western blot analysis and SMPDL3b enzyme activity assay, we demonstrated that Asah1 gene knockout remarkably decreased both expression and function of SMPDL3b in podocytes isolated from Asah1fl/fl/Podocre mice compared to podocytes of wild type (WT/WT) mice. As a monoclonal antibody which can bind to and stabilize SMPDL3b on podocytes, rituximab was found to significantly recover SMPDL3b expression and activity in podocytes lacking Asah1 gene. Correspondingly, Asah1 gene deletion reduced podocin expression in podocytes, which was attenuated by rituximab treatment. Phalloidin staining of F-actin showed elevation of cortical actin and reduction of stress fiber in podocytes lacking Asah1 gene. Such actin cytoskeleton redistribution was significantly attenuated by rituximab. Moreover, atom force microscopy was used to study the impact of actin cytoskeleton remodeling on mechanical properties of podocytes. Asah1 gene knockout was found to increase podocyte height but decrease cortical elasticity in these cells. These pathological changes were significantly inhibited by rituximab, suggesting the restoration of actin cytoskeleton in podocytes lacking Asah1 gene by rituximab. In vivo, intraperitoneal injection of rituximab markedly attenuated proteinuria and albuminuria in Asah1fl/fl/Podocre mice compared to control groups. In summary, our findings suggest that alteration of SMPDL3b activity and reorganization of actin cytoskeleton in podocytes may contribute to the pathogenesis of podocytopathy in mice with podocyte-specific Asah1 gene deletion. This study was supported by NIH grants DK054927 and DK120491. 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.