bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypokalemia induced by loss of Kir5.1 initiates WNK-SPAK/OSR1 signaling in Dahl salt-sensitive rats
Authors: Xu Biyang , Mutig Kerim , Klemens Christine , Palygin Oleg , Staruschenko Alexander 
Published: May 2023

In the distal convoluted tubule (DCT), Na+ and K+ transport is tightly regulated by Na+-Cl- cotransporter (NCC). A K+-restrictive diet activates NCC through with no lysine (K) kinase (WNK)-Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1) pathway, which increases NaCl retention in the distal tubule. Our previous work demonstrated that deletion of Kcnj16 (the gene that encodes Kir5.1) in Dahl salt-sensitive (SS) rats (SSKcnj16-/-) affecting Na+/K+ transport in the kidney and cause profound hypokalemia with a compensatory increase in both NCC and phospho-NCC (pNCC) activity and expression. Here, we hypothesized that hypokalemia induced by the loss of the Kir5.1 initiates WNK-SPAK/OSR1 signalling and correspondingly upregulate the expression of Na+ transporters without the changes in apical potassium transport or blood pressure increase.12-week-old male SSWT and SSKcnj16-/- rats fed by the normal salt diet (0.4% Na+, 1.36% K+) were used in our studies (N=5 per group). SSKcnj16-/- rats exhibit previously described phenotype with the presence of salt wasting, hypokalemia, and low blood pressure. At the end of the experiment, kidneys were flushed and processed for Western blot, immunofluorescence, and electron microscopy analysis.Electron micrographs of kidney sections of SSKcnj16-/- rats show the significant developing of large WNK body clusters compared to SSWT rats. Total and phosphorylated SPAK signalling were dramatically increased in the DCTs of SSKcnj16-/- rats as determined by immunofluorescent labelling and Western blot. In addition, the expression of cleaved α-ENaC was significantly upregulated in SSKcnj16-/- rats. The expression of apical potassium transporters responsible for renal outer medullary K+ (ROMK) and α- and β4-subunits of Ca2+-activated K+ (BK) channels remained unchanged despite the severe hypokalemia in SSKcnj16-/- rats.Our results demonstrated that hypokalemia induced by loss of Kir5.1 activated the WNK-SPAK/OSR1-NCC pathway and corresponding distal Na+ transport, however it does not impact electrolyte wasting phenotype or promote an increase in blood pressure in SSKcnj16-/- rats. Funding sources: National Institute of Health Grants R35 HL135749 (to AS), Department of Veterans Affairs grant I01 BX004024 (to AS). This is the full abstract presented at the American Physiology Summit 2023 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.
Oxidative stress contributes to attenuated insulin-mediated dilation in the microvasculature of women with a history of gestational diabetes
Authors: Hernandez Paola , Halstead Kristen , Schwartz Kelsey , Brustkern Kaila , Jalal Diana , Stanhewicz Anna 
Published: May 2023

Women with a history of gestational diabetes mellitus (GDM) are at greater risk for cardiovascular disease (CVD) and type II diabetes mellitus (T2DM). Endothelium- and nitric oxide-dependent dilation are attenuated in the microvasculature of otherwise healthy women with a history of GDM and this reduction is mediated, in part, by increased oxidative stress. However, whether this attenuation also reduces insulin-mediated microvascular responses in these women is unknown. We hypothesized that 1) insulin-mediated vasodilation would be attenuated, and that 2) antioxidant treatment would increase these responses, in women with a history of GDM compared to matched women with a history of healthy pregnancy (HC). Nine HC (32±6 yrs.) and 8 GDM (33±6 yrs.) participated in 1 experimental visit. Three microdialysis fibers were placed in the ventral forearm for the local delivery of lactated Ringer’s (control), 15mM N G-nitro-L-arginine methyl ester (L-NAME; NO synthase-inhibition), or 5mM ascorbate (non-specific antioxidant). Following baseline measurements, increasing doses of insulin [10-8 -10-4 M] were added to the site-specific perfusates. Red blood cell flux was measured continuously with laser-Doppler flowmetry, and cutaneous vascular conductance was calculated (CVC=flux/MAP) and standardized to maximum (%CVC max; 28mM SNP + 43°C). Subjects with GDM had attenuated insulin-mediated vasodilation (GDM:16.0 ± 3.0 vs. HC: 31.3 ± 4.7 %CVCmax; p= 0.02) at the control site. L-NAME attenuated insulin-mediated dilation in HC (14.7 ± 3.5 %CVCmax, p=0.004) but not in GDM (12.2 ± 1.9 %CVCmax, p=0.48). Local ascorbate perfusion increased insulin-mediated dilation in GDM (27.6 ± 7.2 %CVCmax; p=0.04) but had no effect in HC (p=0.85). These data suggest that women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and that this attenuation is mediated, in part, by increased oxidative stress. Supported by The UI Fraternal Order of Eagles Diabetes Research Center This is the full abstract presented at the American Physiology Summit 2023 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.
Relative influence of individual characteristics on critical WBGT limits in young adults (PSU HEAT Project)
Authors: Wolf S. Tony , Havenith George , Kenney W. Larry 
Published: May 2023

Critical environmental limits are temperature-humidity thresholds above which heat balance cannot be maintained for a given metabolic heat production. This study examined the association between individual characteristics [sex, body surface area (AD), aerobic capacity (V̇O2max; L∙min-1), and body mass (mb)] and critical environmental limits in young adults. Forty-four (20 M/24 F; 23±4 yr) subjects were exposed to progressive heat stress in an environmental chamber at two low net metabolic rates (Mnet); minimal activity (MinAct; Mnet = 160±35 W) and light ambulation (LightAmb; Mnet = 259±54 W). In 2 hot-dry (HD; <25% rh) environments, ambient water vapor pressure (Pa = 12 or 16 mmHg) was held constant and dry-bulb temperature (Tdb) was systematically increased. In 2 warm-humid (WH; >50% rh) environments, Tdb was held constant at 34 or 36 °C and Pa was systematically increased. The critical wet-bulb globe temperature (WBGTcrit) was determined for each condition. There were no sex differences in WBGTcrit for any condition ( p ≥ 0.21). During MinAct, only mb was retained in a backward linear regression model explaining the variance in WBGTcrit in WH (R2adj = 0.08, p < 0.001), whereas mb and V̇O2max were retained for HD environments (R2adj = 0.09, p < 0.001). During LightAmb, mb and AD were retained in the model for both WH (R2adj = 0.46, p < 0.001) and HD environments (R2adj = 0.22; p < 0.001). These data demonstrate the relative importance of individual characteristics on WBGTcrit during low-intensity weight-bearing (LightAmb) and non-weight-bearing (MinAct) activity in extreme thermal environments. This work was supported by NIH R01 AG067471. This is the full abstract presented at the American Physiology Summit 2023 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.
Oxidative stress induces non-apoptotic cell death and release of placental derived mitochondrial DNA
Authors: Gardner Jennifer , Cushen Spencer , Bradshaw Jessica , Garlotte Isabelle , Zhou Zhengyang , Phillips Nicole , Goulopoulou Styliani 
Published: May 2023

Introduction: The placenta, a metabolically active tissue, forms a critical interface between the developing fetus and mother. Stressors such as oxidative stress contribute to placental inflammation, cell death, and release of proinflammatory factors into the maternal circulation. Extracellular mitochondrial DNA (mtDNA) is a proinflammatory factor that can be found in blood circulation in response to cellular stress. Circulating cell-free mtDNA increases during healthy pregnancy and is dysregulated in pregnancies with preeclampsia. Mechanisms underlying the release of mtDNA into circulation from the placenta remain unclear. The objective of this study is to elucidate the relationship between oxidative stress, cell death, and the release of mtDNA from the placenta. We hypothesized that human placental cells exposed to oxidative stressors release mtDNA into the extracellular space via cell death-dependent mechanisms. Methods: BeWo cells (ATCC® CCL-98), a model of placental trophoblast, were treated with the oxidative stressors, rotenone (0.8, 5, 10, 25, 50 μM) or antimycin A (10, 50, 100, 320 μM) and their respective vehicles for 4 hours. Supernatants were collected and the following experiments were performed: absolute real-time qPCR quantification with TaqMan™ probes and chemistry to quantify intracellular and extracellular mtDNA (amplification target: MT-ND5gene) and nuclear DNA (nDNA), assays to measure reactive oxygen species, flow cytometry to assess cell death mechanisms. Results: Exposure of placental cells to antimycin A induced the release of mtDNA (p<0.0001) and nDNA (p=0.024), whilst intracellular mtDNA copy number was unaffected (p=0.62). Antimycin A (320 μM) reduced cell viability (vehicle: 64.44 ± 5.46% vs antimycin A: 18.14 ± 5.78%, p=0.0005), increased non-apoptotic cell death (vehicle: 10.39± 3.11% vs antimycin A (100, 320 μM): 30.51 ± 4.43%, 40.16± 5.08%, p=0.0001), and did not affect apoptosis (p=0.11). In addition, there was no change in the release of mtDNA (p=0.43) or nDNA (p=0.82), cell viability (p=0.94), non-apoptotic cell death (p=0.52), or apoptosis (p=0.85) in cells treated with rotenone. Conclusions: Placental cells exposed to oxidative stressors undergo non-apoptotic cell death and release mtDNA. These responses are only observed at high concentrations of antimycin A, a pharmacological inhibitor of complex III of the electron transport chain (ETC), but not rotenone, an inhibitor of complex I of the ETC, suggesting the presence of cytoprotective or rescue mechanisms against oxidative stressors in the placenta. NIH R01 HL146562, AHA 22PRE-900431, AHA 22POST-903250, NIH T32 AG 020494 This is the full abstract presented at the American Physiology Summit 2023 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.
Interoceptive receptive fields and functional architecture of physiological control in the mouse brainstem
Authors: Ran Chen , Boettcher Jack , Kaye Judith , Gallori Catherine , Wang Yandan , Liberles Stephen 
Published: May 2023

Our external senses of sight, smell, sound, touch, and taste enable us to perceive the external world. In addition, our viscerosensory system monitors the physiological state of peripheral organs. This bodily sensory system orchestrates multi-organ physiological responses, regulating feeding, drinking, sickness behaviors, and generating the internal senses such as satiety, hunger, nausea, visceral malaise. In comparison to external sensory systems, the principles that define visceral sensory processing remain poorly defined. We developed a two-photon calcium imaging preparation to understand internal organ representations in the nucleus of the solitary tract (NTS), a sensory gateway in the brainstem that receives bodily signals mostly via the vagus nerve. Combining the imaging platform with stimulation of multiple visceral organs, we uncover diverse neuronal responses to internal stimuli, while functionally defined cell-types are highly organized within the NTS. Combining functional imaging with pharmacogenetic manipulations and viral tracing from genetically defined vagal sensory cell types, we show that the highly organized representations of internal senses are generated by vagal axon sorting and higher-order sensory processing within the NTS. Using a newly developed spatially patterned optogenetic stimulation system, we showed that stimulating different spatial domains of the NTS differentially modulates autonomic functions. Together, our study reveals basic coding principles used by the brain to process visceral inputs and sheds light on the treatment of viscerosensory and autonomic diseases, including obesity, diabetes, eating disorders, and neuroimmune diseases. The work was supported by NIH grants to S.D.L. (DP1 AT009497, R01 DK122976 and R01 DK103703), the Food Allergy Science Initiative, and a Leonard and Isabelle Goldenson Postdoctoral Fellowship, a Harvard Brain Science Initiative Young Investigator Transitions Award, and an American Diabetes Association Postdoctoral Fellowship to C.R. S.D.L. is an investigator of the Howard Hughes Medical Institute. This is the full abstract presented at the American Physiology Summit 2023 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 comparison between heat and temperate-cool environment regarding changes in core temperature with regular exercise: A meta-analysis of randomized controlled trials
Authors: Okazaki Kazunobu , Toya Atsuya , Igarashi Yutaka 
Published: May 2023

Purpose: Previous several meta-analyses reported that regular exercise decreased core temperature. However, those meta-analyses included non-randomized controlled trials and did not consider a difference in environment. This meta-analysis aimed to limit studies to randomized controlled trials (RCTs) and evaluate the differences in effects of regular exercise under heat and cool environment on core temperature. Methods: Inclusion criteria were RCTs involving healthy adults, performing exercise in heat index (HI; according to National Weather Service) ≥27°C as the heat environment group (HEAT) and in HI <27°C as the temperate-cool environment group (NORMAL), performing same exercise protocol on both groups, and reporting core temperature at rest or the end of exercise tests. In statistical analyses, the mean differences ([mean value at postintervention in the HEAT – mean value at baseline in the HEAT] – [mean value at postintervention in the NORMAL – mean value at baseline in the NORMAL]) in core temperature were converted into the Hedges’ g values; these values were pooled, and heterogeneity (i.e., a difference among RCTs) was assessed using a Q value. Results: RCTs evaluating core temperature at rest and the end of exercise tests were 5 studies (100 subjects; mean age, 22 to 28 years) and 7 studies (128 subjects; age, 21 to 28 years), respectively. The duration of intervention ranged from 3 to 12 days. Results of the meta-analyses indicated that the pooled g value in core temperature at rest did not decrease significantly (-0.08 [95% confidence interval: -0.18 to 0.03]), and significant heterogeneity was not contained (Q=8.9; P=0.11); in addition, that the pooled g value in core temperature at the end of exercise tests decreased significantly (-0.63 [95% confidence interval: -1.24 to -0.02]), but significant heterogeneity was contained (Q=18.0; P<0.01). Conclusions: The present study is a finding with few RCTs but indicates that regular exercise under heat environment decreases core temperature at the end of exercise than that under normal environment. However, since the results of the meta-analysis contained heterogeneity, the effect may also depend on other factors. This is the full abstract presented at the American Physiology Summit 2023 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.
6-month treatment with galectin-1 improves LGMD2B disease pathology in dysferlin-deficient mice
Authors: Kartchner Braden , Spallino Jonathan , Westhoff Luke , Durham Ethan , Nelson Parker , Hansen Colton , Van Ry Pam 
Published: May 2023

Limb-girdle muscular dystrophy type 2B (LGMD2B) is a devastating autosomal recessive disease for which there are no current FDA-approved treatments. Our previous research shows that short-term recombinant human Galectin-1 (rHsGal-1) treatment is effective in improving muscle repair and decreasing fat deposition in the BLA/J mouse model. Our current objective is to determine the efficacy of a long-term (6-month) weekly treatment with rHsGal-1 in improving disease pathology in BLA/J mice. Mice treated weekly with intraperitoneal injections of 2.7 mg/kg rHsGal-1 show significant improvements in the time it takes to cross a 10 mm wide balance beam in comparison with saline-injected mice. Treated mice also show less decline over time in how often they rear on their hind legs while exploring a new environment, which suggests improved pathology of the psoas and gluteus muscles, which are especially affected in the BLA/J model. Oil Red O staining of the psoas muscles shows decreased lipid deposition in the muscle of rHsGal-1 treated mice. Other histological stains show improved pathology in various affected muscles. We conclude that weekly treatment with rHsGal-1 is a promising therapeutic for individuals with LGMD2B. This research is funded by the Jain Foundation This is the full abstract presented at the American Physiology Summit 2023 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.
Epoxyeicosatrienoic Acid Mimics Protect Mesangial Cells from Sorafenib Induced Cell Death
Authors: Mishra Abhishek , El-Meanawy Ashraf , Belayet Jawad , Wang Weicang , Wang Yuxin , Hammock Bruce , Bourg Marcus , Mohammad Rawand , Vik Anders , Imig John 
Published: May 2023

Study objective: Sorafenib an antiangiogenic drug which are widely used in cancer treatment, and it inhibits vascular endothelial growth factor (VEGF) and tyrosine kinases (TK)involved in both tumor cell proliferation and angiogenesis. Unfortunately, VEGF and TK inhibitors cause severe kidney glomerular injury and proteinuria. Kidney injury that occurs with sorafenib chemotherapeutic treatment is a major clinical challenge that lacks a drug to revert or reduce this kidney glomerular cell damage. Hypothesis: Epoxyeicosatrienoic acid (EET) mimics reduce the nephrotoxic effects of sorafenib on glomerular mesangial cells. Methodology: Human renal mesangial cells (HRMCs) were cultured at 37˚C in RPMI 1640 medium containing 10% FBS, 100 U/ml penicillin, and 0.1 mg/ml streptomycin. Live cell imaging was performed to monitor real-time cell death activity in HRMCs. Apoptosis was determined using the caspase 3/7 dye and the HRMCs cells were imaged every 2 hours for 72 hours using the Incucyte system. HMRCs were tested under four conditions: 1) Sorafenib (10 μM), 2) Sorafenib (10 μM) plus 8,9-EET analogs (1 μM), 3) Sorafenib (10 μM) plus 8,9-EET analogs (3 μM), 4) Sorafenib (10 μM) plus 8,9-EET analogs (10 μM). Thirteen 8,9-EET analogs were also tested for soluble epoxide hydrolase (sEH) inhibitory activity against human sEH recombinant protein. Results: Sorafenib caused significant cell death and increased caspase 3/7 activity in HRMCs. Nine of the 8,9-EET analogs were ineffective in reducing sorafenib induced HRMC cell death and caspase 3/7 activity. Four 8,9-EET analogs in a dose-dependent manner reduced sorafenib induced cell death in HRMCs. This preliminary structure activity relationship analysis revealed an oxamide group as a bioisostere for the epoxide in the 8,9-position of the fatty acid chain, producing protective effects against sorafenib induced cell death in HRMCs. Gratifyingly, this group lacked significant sEH-inhibitory activity. The 8,9-EET analogs RM-84 and MBD-32 reduced sorafenib induced caspase 3/7 activity by 20-40% in HRMCs. Additional protective action was found with the 8,9-EET analogs MDB-52-I the MDB-52-II which dose dependently reduced sorafenib induced caspase 3/7 activity by 60-90% in HRMCs. Conclusion: Collectively, these findings demonstrate the potential for 8,9-EET analogs as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity. Arkansas Research Alliance This is the full abstract presented at the American Physiology Summit 2023 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.
Protective effect of Securiniga suffruticosa on Diesel vehicles-derived PM2.5 induces lung and cardiovascular injury
Authors: Han Byung Hyuk , Yoon Jung Joo , Tai Ai Lin , Lee Ho Sub , Kang Dae Gill 
Published: May 2023

Respiratory exposure to Particulate Matter (PM), including Diesel exhaust particulate (DEP), causes oxidative stress-induced lung inflammation. Especially, fine particulate matter with an aerodynamic diameter less than 2.5 μm (PM2.5) is a serious air pollutant associated with various health problems. DEP and PM2.5 pollutants in the air are enter into pulmonary and even bloodstream, and can be causes of inflammatory disorders that are related with respiratory response. The present study aimed to examine the inhibitory effect of Securiniga suffruticosa (S. suffruiticosa) on DEP-induced lung and cardiovascular diseases. The mice groups are follows; sham group: C57BL6 male mice, DEP group: C57BL6 male mice inhaled DEP, S. suffruiticosa Low group: DEP + 100 mg/kg/day S. suffruiticosa, and S. suffruiticosa High group: DEP + 300 mg/kg/day S. suffruiticosa. Mice inhaled DEP by using nebulizer chamber and were sacrificed 48 hours after final exposure of DEP. Treatment with S. suffruiticosa reduced the expression of inducible CXCL1 and CXCL2 in bronchoalveolar lavage fluid and Muc5ac, ICAM-1, TNF-α, IL-6 mRNA in lung were also attenuated by S. suffruiticosa. In thoracic aorta, DEP increased CAMs, TNF-α and inflammasome markers such as NLRP3, Caspase-1, and ASC. However, S. suffruiticosa suppressed these levels. In HUVECs, S. suffruiticosa inhibited PM2.5 induced production of intracellular reactive oxygen species (ROS); and inhibited the translocation of NF-κB p65 to the nucleus in HUVECs (human umbilical vein endothelial cells). Taken together, this study proved that exposure to PM2.5 induced both lung and vascular inflammation, however, S. suffruiticosa attenuated this injury via the downregulation of the NLRP3 signaling pathway. These findings suggest that S. suffruiticosa may have potential therapeutic benefit against air pollution-mediated lung and cardiovascular diseases. This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIP) (2017R1A5A2015805) (2021R1I1A1A01056937). This is the full abstract presented at the American Physiology Summit 2023 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.