bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydrogen sulfide improves endothelial dysfunction through inhibition of the vicious circle of NLRP3 and oxidative stress in spontaneously hypertensive rats
Authors: Wu Yuming , Li Jiabao 
Published: June 2021

AimsThe aim of this study is to elucidate whether the inhibition of inflammasome and oxidative stress mediated the ameliorative effect of hydrogen sulfide (H2S) on endothelial dysfunction in hypertension.MethodsSpontaneously hypertensive rats (SHR) and normotensive Wistar kyoto rats (WKY) were injected with 100 μM NaSH intraperitoneally daily for 16 weeks. Systolic blood pressure (SBP) and plasma MDA and IL‐1β were measured. Renal vascular was used to determine endothelial dependent contraction (EDC) and endothelial dependent relaxation (EDR). Protein levels were detected by Western blot. Human umbilical vein endothelial cells (HUVECs) were used to confirm the protective role of H2S against AngII‐induced cell injury.ResultsExogenous NaSH administration significantly lowered SBP and ameliorated damaged EDR and EDC. H2S reduced the activation of NLRP3 inflammasome and oxidative stress in SHR. The endothelial protective and anti‐oxidant effect of H2S was abolished by LPS, an inducer of NLRP3 inflammasome. In HUVECs, H2S significantly ameliorated AngII‐induced cellular impairment, NLRP3 inflammasome and ROS generation. After knocking down of Nrf2, the above protective effect of H2S was abolished.ConclusionHydrogen sulfide could inhibit vicious circle of oxidative stress and inflammation, resulted in improved endothelial function and ameliorated hypertension. Our results throw light on the crucial role of H2S in regulation of endothelial function, which might provide the new target for treatment of hypertension.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (31171098, 31671185), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20121323110008), the Hebei Province for Innovation Talents Support Plan (LJRC017) and the Natural Science Foundation of Hebei (C2012206063, H2016206264).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endoplasmic Reticulum Stress Drives High Selenium‐Induced Endothelial Dysfunction
Authors: Agouni Abdelali , Zachariah Matshediso , Maamoun Hatem , Meira Lisiane , Rayman Margaret P. 
Published: June 2021

BackgroundSelenium is an essential trace element important to human health. Nonetheless, supra‐nutritional selenium intake is reported to be associated with insulin resistance and may therefore increase the risk of diabetes and disrupt endothelial function (ED), the initial step in atherosclerosis development. However, the underpinning molecular mechanisms are not clear. High selenium concentrations cause apoptosis in cancer cells through the induction of endoplasmic reticulum (ER) stress, a mechanism also involved in the pathogenesis of ED. Therefore, we hypothesised here that high selenium intake could cause ED through the activation of ER stress response.MethodsHuman Umbilical Vein Endothelial Cells (HUVECs) were cultured with selenite at either physiological (0.5μM) or supra‐nutritional concentrations (5–20μM) for 8 to 24 hours in the presence or absence of a chemical chaperone, 4‐phenylbutryic acid (PBA). Then, mRNA expression of key ER stress response markers was analysed by qPCR. To assess endothelial function, we evaluated NO (Griess assay) release and Reactive Oxygen Species (ROS, flow cytometry) production. Finally, apoptosis (flow cytometry) and caspases 3/7 activity were measured.ResultsHigh selenium concentrations (5–20μM of selenite) compared to physiological concentration (0.5μM) or control enhanced mRNA expression of several ER stress markers such as CAAA/enhanced‐binding homologous protein (CHOP) [control (2.25±0.88), 0.5 μM (3.9±0.85), 10μM (36.2±6); n=5]. The pre‐incubation of cells with PBA completely reversed high selenium‐mediated ER stress. High selenite (5–20μM) also reduced NO production [control (2.27±0.07), 0.5μM (2.4±0.04), 10μM (1.8±0.05); n=5] and enhanced ROS production [control (18.9±1.93), 0.5μM (21.7±2.14), 10μM (68±0.65); n=5] compared to physiological concentration of selenite while cells pre‐treated with PBA were fully protected. Finally, supra‐nutritional concentrations of selenite increased the percentage of apoptotic HUVECs [control (2.96%±0.94), 0.5μM (3.92%±0.85), 10μM (43.7%±5.1); n=7] and augmented caspases 3/7 activity [0.5μM (0.45±0.08), 5μM (1.92±0.3) fold of control; n=5] compared to physiological concentration. Importantly, pre‐treatment of cells with PBA completely reversed high selenium‐mediated cell death.ConclusionsWe show here that high selenium treatment causes ED and cell death through the activation of ER stress. These results highlight the importance of a balanced selenium intake in order to achieve maximal health benefits. These findings underscore the importance to monitor cardiovascular risk development in cancer patients supplemented with high amounts of selenium as part of their chemotherapeutic intervention.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Ilex Guayusa Tea on Glycaemia, Cardiovascular Autonomic Modulation and Oxidative Stress in Streptozotocin‐Diabetic Rats
Authors: Stoyell‐Conti Filipe Fernandes , Mello Tafne C. , Dias Danielle S. , Bernardes Nathalia , Araujo Amanda A. , Santos Camila P. , Llesuy Susana F. , De Angelis Kátia 
Published: June 2021

The incidence of cardiovascular diseases (CVD) increases significantly worldwide. Furthermore, it is the main cause of morbidity and mortality among diabetic patients. Rats induced to diabetes by streptozotocin (STZ) and untreated with insulin have similar alterations seen in humans, such as hyperglycemia, polydipsia, polyuria and weight loss, as well as cardiomyopathy, diabetic neuropathy and increased oxidative stress. Thus, the aim of this study was to verify the effects of ilex guayusa tea consumption on cardiovascular, autonomic, metabolic and oxidative stress alterations of an experimental model of diabetes. Thirteen Wistar rats were divided into two groups: Diabetic (D; n=7) and Diabetic + Ilex Guayusa (DG; n=6). Diabetes was induced by a single injection of STZ (50 mg/kg, iv.). Guayusa tea was administered for 21 days (3.0 g/L). Arterial pressure (AP) was directly measured. Oxidative stress was measured on heart and brain. At the beginning of the protocol glycaemia was similar between the groups (D: 330±32 vs. DG: 332±20 mg/dL). However, throughout the protocol, the D group showed a raise of glycaemia, evidenced by a greater area under the curve (AUC) (D: 1222±43 vs. DG: 1049±59 mg/dL*3 weeks). Indeed, increased glycaemia was associated with an increased oxidative profile. Positive correlations were observed between AUC of glycaemia and lipoperoxidation in the brain (r: 0.58; p: 0.04) and damage to protein in the heart (r: 67; p: 0.01). No differences in AP, heart rate and heart rate variability were observed between groups. However, regarding vascular sympathetic modulation, the D group had a reduction in LF‐SAP (1.3±0.3 vs. DG: 3.5±0.8 mmHg2) and VAR‐SAP (8.0±1.7 vs. DG: 15.0±1.7 mmHg2). This reduction in vascular sympathetic modulation, which in this model is considered a poor prognosis, was negatively correlated with AUC of glycaemia (AUC of glycaemia and VAR‐SAP, r: −0.57, p: 0.04). The results suggest a beneficial potential of guayusa tea consumption on metabolic, autonomic and oxidative stress in this model of diabetes.Support or Funding InformationUniversidade Nove de JulhoThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Lack of endothelium‐derived ET‐1 accelerates diabetes‐mediated renal damage in female, but not male, mice
Authors: De Miguel Carmen , Pollock David M. , Pollocks Jennifer S. 
Published: June 2021

Premenopausal females have smaller incidence and slower progression of kidney disease than males; however, diabetes‐induced kidney damage progresses similarly in both sexes. The vasoactive peptide endothelin‐1 (ET‐1) is upregulated in patients and animal models of diabetic nephropathy (DN), yet the specific role of endothelium‐derived ET‐1 in the development of DN remains unclear. These studies were designed to examine the role of vascular ET‐1 in diabetic kidney disease, and to determine if it is responsible for the loss of renal protection in diabetic females. Hyperglycemia was induced in male and female vascular endothelial cell ET‐1 knockout (VEET KO) and floxed mice via STZ (50 mg/kg i.p., 5 consecutive days). After 10 weeks of diabetes, urine and kidneys were collected and markers of glomerular damage, apoptosis (TUNEL assay) and immune cell infiltration were assessed. Histological examination revealed no significant differences in glomerular injury among the groups. However, in response to diabetes, female VEET KO mice presented significantly greater urinary protein excretion (6.0 ± 1.7 vs. 2.4 ± 0.8 mg/day; p<0.05; n=5–7/group) and cortical tubule dilation than diabetic male VEET KO mice. Albumin excretion and renal apoptosis were not significantly different between sexes or genotypes. Both diabetic female genotypes presented similar macrophage influx in renal cortex (VEET KO vs. floxed: 8.0 ± 0.8 vs. 7.9 ± 1.0 ED1+cells/field; n=9/group), and these values were significantly greater than diabetic males (VEET KO vs. floxed: 2.8 ± 0.9 vs. 3.7 ± 0.6 ED‐1+ cells/field; p<0.05; n=4–5/group). In addition, absence of vascular ET‐1 in females led to increased T cell infiltration in cortex (VEET KO vs. floxed: 8.7 ± 1.2 vs. 5.2 ± 0.4 CD3+ cells/field; p<0.05; n=9/group), but not in males (VEET KO vs. floxed: 5.7 ± 0.9 vs. 4.6 ± 1.0 cells/field; n=4–5/group). In conclusion, lack of endothelium‐derived ET‐1 accelerates the development of diabetes‐induced kidney damage in female, but not male, mice. These results highlight the protective role that vascular ET‐1 plays in females, but not males, against the development of DN.Support or Funding InformationFunded by NIH T32 DK007545 to CDM and P01 HL95499 and P01 HL69999 and HL136936 to DMP and JSP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibition of Necrosis Via Necrox‐5 Attenuates The Development Of Hypertension In Male, But Not Female Spontaneously Hypertensive Rats (SHR)
Authors: Abdelbary Mahmoud , Onyilo Chukwuemeka , Crislip G Ryan , Gillis Ellen , Brands Micahel , Sullivan Jennifer C. 
Published: June 2021

It is well established that hypertension is accompanied by cell death, however, less is known regarding the role of cell death in blood pressure (BP) control. Necrosis is an uncontrolled pathologic form of cell death that is associated with inflammation. Therefore, the goal of the current study was to test the hypothesis that necrosis contributes to the development of hypertension in SHR. Initial studies measured renal necrosis in 13 wk old male and female SHR (n=9) using flow cytometry. Male SHR had greater renal necrosis compared to female SHR (3.7±0.4% vs. 0.4±0.2% of total renal cells, respectively; p<0.0001). Additional male and female SHR were then randomized to receive vehicle or Necrox‐5 from 6–12 weeks of age (1 mg/kg via IP injection twice weekly; n=4); Necrox‐5 is a cell permeable inhibitor of necrosis that blocks oxidative stress induced necrotic cell death. BP was measured weekly via tail‐cuff analysis and via carotid catheter at sacrifice. Following 6 wks of treatment, kidneys were isolated and necrosis was measured by flow cytometry. Treatment with Necrox‐5 beginning at 6 wks of age attenuated maturation‐induced increases in BP in male SHR (Necrox‐5: 152±11 vs Control: 177±4 mmHg; p=0.07). BP in female SHR was not altered by chronic Necrox‐5 treatment (Necrox‐5: 152±14 vs. Control: 146±11 mmHg; p=0.72). In addition, the sex difference in BP apparent in control rats was abolished by Necrox‐5 treatment. Consistent with these results, Necrox‐5 treatment for 6 wks decreased renal necrosis only in males (Necrox‐5: 1.5±0.5% vs Control: 3±0% of total renal cells). Taken together, our data suggest that greater cell death in male SHR compared to female SHR contributes to sex differences in BP by exacerbating age‐related increases in BP in males.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Senescent Skeletal Muscle Produces a Distinct Cytokine Secretory Profile in Response to Endotoxin Exposure in Vitro
Authors: Mattingly Alex J. , Laitano Orlando J. , Clanton Thomas L. 
Published: June 2021

Skeletal muscles are thought to contribute to both pathogen detection and cytokine secretion as a part of the innate immune response. Skeletal muscle fibers contain toll like receptors (TLRs) that bind a wide array of bacterial, viral, and fungal ligands, inducing signal transduction and subsequent cytokine production. Aging populations have significantly greater mortality annually from influenza, incidence of bacterial and fungal infections, and diminished vaccine efficacy. In senescent mice, macrophage TLR expression and cytokine secretion are known to decline in some tissues. It is unknown if skeletal muscle also exhibits age associated changes in innate immune contribution. The objective of this experiment was to determine if there are alterations in cytokine secretory response of aged skeletal muscle to lipopolysaccharide (LPS), a potent TLR2 and TLR4 ligand.Matched solei muscles from 12–15‐week‐old male C57BL/6 mice (n=8; “young”) and 16‐month‐old (n=10; “old”) were excised in oxygenated (95%O2/5%CO2) Krebs solution and placed under 1 g of tension in 2 ml baths at 35°C. After a 30‐min acclimation period (T0), the buffer was changed and muscles were exposed to 1 μg/ml LPS. Bath samples at T0, 1 hr (T1) and 2 hr (T2) were taken, combined with a protease inhibitor cocktail and frozen at −80°C prior to Luminex multiplex analysis.In conclusion, solei from old mice generally displayed a diminished cytokine secretory response, with particularly large decrements in IL‐12p70, IL‐6, MCP‐1, KC, and G‐CSF compared to young controls (see Table 1). Interestingly, solei from old mice displayed relatively large increases in IL‐1α, with smaller, yet also significant increases in IL‐10 and TNFα. The drastically lowered IL‐6 secretion in older mice may diminish the normal inhibition on IL‐1α and subsequent TNFα production. The small rise in IL‐10 in the elder mice may serve as a compensatory mechanism to lower IL‐1α due to diminished IL‐6 response. It may also contribute towards the severely lowered KC production, as is seen with the inhibition of human KC homologue IL‐8 by elevated IL‐10. The combination of radically lower IL‐6 and KC secretion, and increased IL‐1α and TNFα may produce an environment favoring excessive inflammatory, yet reduced chemotactic responses to pathogen exposure in older mice.Support or Funding InformationSupported by NIGMS R01GM118895‐01 and the BK and Betty Stevens Endowment.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
PGC‐1α Overexpression Increases Lysosome Abundance and Autophagy in Dystrophic Skeletal Muscle
Authors: Ludwig Amanda , Spaulding Hannah Rose , Hudson Matthew , Selsby Joshua 
Published: June 2021

Duchenne muscular dystrophy is a severe muscle wasting disease caused by the absence of functional dystrophin protein. We have previously established that increased peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) pathway activity is therapeutic in dystrophic muscle. The purpose of this study was to determine the extent to which increased PGC‐1α pathway activity increased nuclear localization and activity of transcription factor EB (TFEB), a transcription factor that leads to lysosomal biogenesis. We hypothesized that increased PGC‐1α pathway activity would increase TFEB nuclear migration, lysosome abundance, and the restoration of impaired autophagosome degradation. To address this hypothesis, 3‐week‐old mdx mice were injected in one limb with an adeno‐associated virus that drives PGC‐1α gene expression and the other limb was injected with an empty capsid. Animals were sacrificed at 6 weeks of age and the gastrocnemii were harvested. PGC‐1α overexpression was confirmed by qPCR. Total TFEB protein abundance was similar between groups, however, nuclear TFEB was significantly increased in PGC‐1α treated limbs consistent with our hypothesis. We also discovered that Lamp2, a lysosomal marker, was significantly elevated in PGC‐1α treated muscle. Finally, abundance of autophagy‐related proteins were compared between treated and control gastrocnemii of mdx mice as well as to gastrocnemii from adult C57 mice. LC3 II, an indicator of autophagosome formation, was significantly elevated in PGC‐1α‐treated limbs compared to both the C57 and mdx‐control muscles. However, p62, an inverse correlate of autophagosome degradation, was similar between groups suggesting elevated degradation of autophagosomes in PGC‐1α treated limbs. These data suggest increased PGC‐1α pathway activity increased lysosomal degradation of autophagosomes in dystrophic muscle, likely through a TFEB‐mediated mechanism.Support or Funding InformationSupported by the American Physiological Society.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
PETCO2 in Women at Sea‐Level and Upon Acute Exposure to a Normobaric Hypoxic Environment Simulating 3,500 m
Authors: Yasukawa Michio , Degarmo Anna , Quiroga Leonardo , Muza Stephen , Kambis Ken 
Published: June 2021

While prior work (Muza, J. Appl. Physiol. 91: 2001) suggests that women and men have similar responses to high altitude, no studies have attempted to develop gender specific predictive values for end‐tidal CO2 (EtCO2) in a normobaric hypoxic (NH) environment simulating acute exposure to an altitude of 3,500 m based on sea‐level (SL) EtCO2 values. As part of a larger study examining individual variability upon acute exposure to NH, EtCO2, heart rate (HR), and respiratory rate (RR) were measured in 107 subjects at sea level (SL) who, no sooner than two days later, entered a normobaric hypoxia chamber at approximating O2 partial pressures equivalent to those found at 3,500 m.METHODSParticipants in this IRB‐approved study included: 63 informed volunteer female subjects (56 Treatment [NH]: 20.5±1.5 yr.; 165.8±6.9 cm; 63.011.1 kg; 22.93.3 BMI; 7 SHAM: 20.31.1 yr; 167.56.2 cm; 57.26.2 kg; 20.46.4 BMI); 44 informed volunteer male subjects (35 Treatment [NH]: 20.31.3 yr; 178.26.8 cm; 77.414.0 kg; 24.23.2 BMI; and 9 SHAM: 20.71.0 yr; 179.87.8 cm; 73.310.0 kg; 22.73.1 BMI). All subjects were tested at SL then again 2+ days later after entering a NH (FiO2=13.55%) chamber where EtCO2, HR, and RR were measured after 30 minutes of rest.RESULTSBonferroni t‐tests revealed no difference in female or male EtCO2 between the SL and SHAM conditions while, as expected, there was a difference (P≤0.05) in EtCO2 between the SL and NH conditions in the female treatment group (37±3 vs. 36±3 mmHg) and the male treatment group (39±3 vs. 37±2 mmHg). RR and HR remained unchanged in the female and male groups in all conditions.CONCLUSIONSUsing the following algorithm, we were able to predict EtCO2 in female subjects at the P 0.001 level of confidence [Actual vs. Predictive (EtCO2 at FiO2 = 13.55%) Y = 86.394 – 0.221X1‐ 0.541X2 (Where Y = EtCO2_HYPO, X1 = RR_NH, X2 = SpO2_NH, R2 = 0.520, P<0.001] while the predictive value of the male data was not significant (R2 = 0.099, P = 0.187). Therefore, female responsiveness to acute exposure to simulated altitude may be greater than that of male peers.Support or Funding Information: The Chuo University Oversea Research Program, The Doug Morton/Marilyn Brown Endowment for Biomedical Research, The Foundation for Aging Studies and Exercise Science Research, and The Borgenicht Program
Swelling of the Subcutaneous Adipose, but not the Dermis, in Burn Wound Edema is Exacerbated by IV Fluids
Authors: Burmeister David M. , Chao Tony , Gomez Belinda I. , Little Joshua S. , Dubick Michael A. , Christy Robert J. 
Published: June 2021

Intravenous (IV) resuscitation of burn patients has greatly improved outcomes and become a cornerstone of modern burn care. However, the large volumes of crystalloid given can lead to various comorbidities such as compartment syndromes and acute respiratory distress syndrome. Simultaneously, it is well established that vascular leak leads to significant edema in the severely burned patient. The objective of this study was to begin to examine the interaction of edema of burn wounds and IV fluids. Anesthetized Yorkshire swine sustained 40% total body surface area (TBSA) full‐thickness contact burns with brass probes heated to 100°C placed on the skin for 30 seconds. Animals were recovered from anesthesia and randomized to one of four treatment groups: no IV fluids (n=6), IV lactated Ringer's (LR) resuscitation with the modified Brooke formula (MB; 2 ml/kg/%TBSA, n=6), 15 mL/kg/d of IV LR (LR: n=6), or 15 mL/kg/d fresh frozen plasma (FFP: n=6). Unburned sham animals (n=4) and injured animals were assessed for 48 hours, at which point animals were humanely euthanized and dorsal and ventral dermis was taken to determine wet to dry weight ratios. Additionally, 3 biopsies to include dermis and the entire subcutaneous fat were taken from both the dorsal and ventral aspects of the animal for histological determination of tissue thickness. Burn wound edema was demonstrated by a significantly higher wet:dry ratio in all groups compared to sham animals for dorsal (P=0.017) and ventral (P=0.044) dermis. However, there was no difference amongst the various IV regimens. Moreover, neither burn nor IV fluids induced a difference in the thickness of the dermis on dorsal or ventral locations. In contrast, the thickness of the subcutaneous fat was significantly elevated in both dorsal (P=0.028) and ventral (P=0.0045) samples, depending on IV fluid regimen. Thickness of the dorsal fat layer was 1865 ± 327 μm, 2170 ± 205 μm, 3466 ± 421 μm, 2452 ± 271 μm, and 2707 ± 302 μm for Sham, no IV, MB, LR, and FFP groups, respectively. Thickness of the ventral fat layer was 1557 ± 164 μm, 2728 ± 184 μm, 2618 ± 172 μm, 2368 ± 236 μm, and 3329 ± 352 μm for Sham, no IV, MB, LR, and FFP groups, respectively. Collectively, these data demonstrate that volumes and types of IV fluids can alter burn‐induced edema in an anatomically‐dependent manner. Elucidating the specific drivers of burn wound edema may lead to personalized medicine approaches that can minimize comorbidities associated with over/under resuscitation of the burn patient.Support or Funding InformationThis study was supported by Military Burn Research Program Award# W81XWH‐16‐2‐0041.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.