bluuebunny/crossref_metadata_2025_split huggingface dataset:
RhoBTB1 is a Novel Gene Protecting Against Hypertension
Authors: Mukohda Masashi , Ibeawuchi Stella‐Rita C , Hu Chunyan , Lu Ko‐Ting , Nair Anand R , Agbor Larry N , Wu Jing , Quelle Frederick W , Sigmund Curt D 
Published: November 2023

Peroxisome proliferator‐activated receptor gamma (PPARγ) is a ligand activated transcription factor regulating metabolic and vascular function. We previously reported that mice (S‐DN) expressing dominant‐negative PPARγ in smooth muscle cells (SMC) are hypertensive, exhibit impaired vasodilation, augmented vasoconstriction and reduced expression of a novel PPARγ target gene, RhoBTB1. RhoBTB1 belongs to class of proteins which act as substrate adaptors for the Cullin‐3 E3 ubiquitin ligase. Delivery of substrates to the Cullin‐3 CRL3 complex leads to ubiquitination of the substrate protein targeting it for degradation by the proteasome. We hypothesized that loss of RhoBTB1 expression in S‐DN mice may be responsible for impaired vasodilation. In this study, we tested the hypothesis that RhoBTB1 may play a protective role by preventing hypertension in response to stressors which cause hypertension, such as Angiotensin‐II (Ang‐II). To test this, we generated double transgenic mice with tamoxifen‐inducible, Cre‐dependent overexpression of RhoBTB1 specifically in SMC (S‐RhoBTB1). S‐RhoBTB1 and non‐transgenic (NT) mice were treated with tamoxifen (Tx; 75 mg/kg, ip, 5 days) or vehicle (corn oil) and then Ang‐II was infused (490 ng/kg/min, 2 weeks). Overexpression of RhoBTB1 did not alter baseline blood pressure (BP) in the absence of Ang‐II. However, increased BP caused by Ang‐II infusion was significantly attenuated by RhoBTB1 overexpression in S‐RhoBTB1 with Tx compared to Ang‐II‐infused control mice (either NT with Tx, NT with corn oil, or S‐RhoBTB1 with corn oil) in which RhoBTB1 was not overexpressed (p<0.05, n=4–5). We also observed increased heart weight in Ang II‐infused control mice, which was reversed in S‐RhoBTB1 with Tx (n=4). Thoracic aorta, carotid and basilar artery from Ang‐II‐infused control mice showed impaired acetylcholine (ACh)‐induced endothelial‐dependent relaxation (p<0.05, n=4–5), which was reversed by overexpression of RhoBTB1 in SMC (p<0.05, n=4–5). Aorta and carotid artery from Ang‐II‐infused control mice also displayed decreased sodium nitroprusside (SNP)‐induced endothelial‐independent relaxation with a right‐shifted dose‐response (p<0.05, n=4–5), which was reversed in Tx‐treated S‐RhoBTB1 mice (p<0.05, n=5). Despite the marked improvement in vasodilation, augmented vasoconstriction to serotonin (5‐HT) was preserved in aorta and carotid artery from Ang‐II‐infused mice and was not reversed in Ang‐II‐infused S‐RhoBTB1 with Tx (n=4–5). We conclude that the novel PPARγ target gene, RhoBTB1, functions in SMC to specifically facilitate vasodilation and through this mediates a protective anti‐hypertensive effect. We are currently assessing which proteins may be substrates for Cullin‐3 through RhoBTB1.Support or Funding InformationGrants from the NIH and AHA; Support from the Roy J. Carver Trust
Treatment with Lisinopril Delays the Early Progression of Proteinuria in a Novel Model of Prepubertal Obesity
Authors: McPherson Kasi C , Pennington Alyssa , Williams Jan M 
Published: November 2023

Prepubertal childhood obesity (PPO) has emerged as an epidemic and major health problem in the United States. Recent studies suggest that PPO is associated with increased risk of renal injury in children. Approximately 37% of obese children develop microalbuminuria. However, an understanding of the mechanisms involved in PPO‐mediated renal disease remains unclear. Recently, we reported that the Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant – PPO model) strain develops proteinuria and podocyte injury independent of hyperglycemia and elevations in arterial pressure prior to puberty. Since renal hyperfiltration is a major characteristic of the early development of proteinuria associated with obesity, the current study determined the time course changes of glomerular filtration rate (GFR) in our model of PPO, the SSLepRmutant rat. GFR was significantly elevated in the PPO model compared to values measured to lean Control rats at 6 weeks of age indicating renal hyperfiltration (2.87±0.29 vs. 2.03±0.25 mL/min/gkwt, respectively). By 18 weeks of age, GFR decreased by 74% in the PPO model and by 46% in Control rats. The standard care of treatment for obese children with hypertension and increased risk of renal disease is lisinopril, an angiotensin converting enzyme inhibitor (ACEi). Therefore, the next set of experiments examined whether treatment with lisinopril prevents the early development of proteinuria and podocyte injury in the PPO model. Experiments were performed on four week‐old Control and PPO rats that were either treated with vehicle or lisinopril (20 mg/kg/day, drinking water) for four weeks. Protein excretion was significantly higher in the PPO model compared to Control rats at baseline (130±29 vs. 14±3 mg/day, respectively) and remained elevated during the course of the study (661±107 vs. 54±10 mg/day, respectively). While treatment with lisinopril had no effect on the progression of proteinuria in Control rats, it reduced protein excretion by 50% in the PPO model by the end of the study. In conclusion, these data indicate that our novel model of PPO, the SSLepRmutant strain, develops proteinuria associated with hyperfiltration at an early age that ultimately progresses to chronic kidney disease later in life. Moreover, treatment with lisinopril slowed the progression of proteinuria in the PPO model indicating that the renin‐angiotensin system plays an important role in the progression of proteinuria during PPO.Support or Funding InformationThis work was supported by funding from PhRMA predoctoral fellowship and the NIH/NIDDK Award Number 1 F31 DK109571‐01 awarded to K.C.M and AHA SDG 12SDG9440034 and by the NIGMS of the National Institutes of Health under Award Number P20GM104357 awarded to J.M.W.
Dairy Cheese Ingestion Does Not Improve Acute Sodium‐Induced Cutaneous Microvascular Dysfunction through Arginase or Inducible Nitric Oxide Synthase Mechanisms
Authors: Alba Billie K. , Stanhewicz Anna E. , Kenney W. Larry , Alexander Lacy M. 
Published: November 2023

Epidemiological studies suggest that chronic dairy consumption is associated with improved cardiovascular health; alternately high dietary sodium (Na) ingestion is associated with increased cardiovascular disease risk. Natural cheeses are often high in sodium, thus increasing dairy cheese intake may increase dietary Na intake. We recently demonstrated that single‐meal cheese consumption ameliorates Na‐induced impairments in nitric oxide (NO)‐dependent vasodilation through ascorbate sensitive mechanisms. However, the role of additional inflammatory mediators sensitive to the non‐specific antioxidant ascorbate, including arginase and inducible NO synthase (iNOS), is unknown. We hypothesized that local inhibition of arginase or iNOS would improve NO‐dependent vasodilation following Na ingestion from non‐dairy sources but not Na ingestion from dairy‐based cheese. On 5 separate visits, 14 subjects (61±2 yrs) consumed 85 g natural cheddar cheese (560 mg Na), 85 g soy cheese (560 mg Na), 65 g pretzels (560 mg Na), 170 g natural cheddar cheese (1120 mg Na), or 130 g pretzels (1120 mg Na). Three intradermal microdialysis fibers were inserted in the forearm skin for local delivery of 1) lactated Ringer's solution (control site) 2) 5 mM (S)‐(2‐boronoethyl)‐L‐cysteine (arginase‐inhibited site) and 3) 0.1 mM 1400w (iNOS‐inhibited site). Red cell flux was measured using laser‐Doppler flowmetry during standardized local skin heating (42°C) to stimulate endothelial NOS‐dependent vasodilation. Once a plateau in cutaneous vascular conductance (CVC = flux/mean arterial pressure) was reached, 15 mM L‐NAME (nonselective NOS inhibitor) was perfused at all sites to directly quantify NO‐dependent vasodilation. Data were expressed as a percentage of maximum vasodilation (%CVCmax; 28 mM sodium nitroprusside). NO‐dependent vasodilation was greater following dairy cheese ingestion compared to the same amount of Na in pretzels (560 mg Na: 57±6 vs. 43±4%; p=0.004, 1120 mg Na: 55±5 vs. 46±5%; p=0.04) or soy cheese (57±6 vs. 44±6%; p=0.002). NO‐dependent vasodilation was not different among the control site, the arginase‐inhibited site, or the iNOS‐inhibited site for any of the five dietary treatments (all p>0.05). These results suggest that Na ingestion in dairy cheese is associated with greater NO bioavailability compared to ingestion of an equal amount of Na from non‐dairy sources but that this difference is not mediated by arginase‐ or iNOS‐dependent mechanisms. Rather, macronutrients in dairy cheese likely prevent acute Na‐induced microvascular dysfunction through previously demonstrated antioxidant properties.Support or Funding InformationSupported by Dairy Management Inc. and T32GM108563
The Ketogenic Diet Alters Endocrine Regulation of Energy Metabolism in Ultra‐Endurance Athletes
Authors: Miller Vincent J , Hyde Parker N , Dickerson Ryan , LaFountain Richard A , Maresh Carl M , Kraemer William J , Volek Jeff S 
Published: November 2023

PurposeThe ketogenic diet induces a profound shift in energy metabolism from carbohydrate oxidation towards fat oxidation, both at rest and during exercise. We compared endocrine regulators of energy metabolism in keto‐adapted and non‐keto‐adapted ultra‐endurance athletes before, during, and after aerobic exercise to better understand the role of endocrine function in adaptation to a ketogenic diet (keto‐adaptation).MethodsTwenty elite ultra‐endurance athletes (male, age 33.5 ± 6.4 yr, BMI 22.1 ± 1.5 kg/m2, VO2max 64.5 ± 4.9 mL/kg/min) who habitually consumed a high‐carbohydrate (HC, 59:14:25 % carbohydrate:protein:fat) or very‐low carbohydrate (LC, 10:19:70) diet for at least 6 months ran on a treadmill for 180 min at 64% of VO2max. Glucagon, cortisol, and leptin were measured from serum collected before exercise (BL); 60 and 120 min after initiation of exercise (RUN60, RUN120); and 0, 60, and 120 min after completion of exercise (IP, P60, P120). After BL and IP, participants consumed a shake with macronutrient ratios similar to their habitual diet (5 kcal/kg body mass, HC: 50:36:14, LC: 5:81:14 % carbohydrate:protein:fat). Glucagon, cortisol, and leptin were further analyzed for correlations with non‐esterified fatty acids (NEFA), glycerol, β‐hydroxybutyrate, total ketones, insulin, glucose, and muscle glycogen.ResultsGlucagon increased with exercise (p<0.0001) and was significantly higher in keto‐adapted athletes at all time points except IP and P120 (p<0.05). Cortisol also increased with exercise (p<0.0001) and was significantly higher in keto‐adapted athletes at RUN60 (p<0.05). Leptin decreased with exercise (p<0.0001), but without any significant effect of diet. Glucagon and, to a lesser extent, cortisol positively correlated with markers of increased fat oxidation (β‐hydroxybutyrate, total ketones, NEFA, and glycerol, p<0.05) and negatively correlated with markers of increased carbohydrate metabolism (glucose, insulin, and lactate, p<0.05). Glucagon's correlations with β‐hydroxybutyrate and total ketones were persistent, occurring at all time points except BL (p<0.01). Glucagon and cortisol also positively correlated with each other at P120 (p<0.005). Muscle glycogen content negatively correlated with glucagon at IP (p<0.05) and positively correlated with leptin at P120 (p<0.05).ConclusionIn elite ultra‐endurance athletes, a long‐term ketogenic diet is associated with higher glucagon levels before, during, and after aerobic exercise. This is in conjunction with a more than two‐fold higher rate of peak fat oxidation, indicating glucagon may have an important role in keto‐adaptation. The similar but less persistent patterns of cortisol suggest these two hormones may contribute to keto‐adaptation in a coordinated manner.Support or Funding InformationSupport for this work was provided by Quest Nutrition and The Robert C. and Veronica Atkins Foundation.
Dietary Vitamin A Intake Affects the Body Mass Gain and Hepatic Gene Expression in Rats fed a High‐Fat Diet
Authors: Kuang Heqian , Li Yang , Eastep Jennifer , Chen Guoxun 
Published: November 2023

IntroductionVitamin A (VA) plays a role in variety of physiological functions from development to metabolic homeostasis. Feeding of a high‐fat (HF) diet has been shown to cause the development of metabolic diseases such as obesity and fatty liver. The purpose of our study is to determine whether in a HF diet setting, VA status affects and the protein expression levels of hepatic genes involved in glucose, fatty acid metabolism, and insulin signaling pathways.MethodsSprague Dawley (SD) rats after weaning were fed an isocaloric HF‐VA sufficient (HF‐VAS) or HF‐VA deficient (HF‐VAD) diet for 8 weeks. Their body mass and food intake were recorded weekly. At the end of feeding, tissue samples were weighted and collected for analysis. The protein levels in liver samples were determined via immunoblotting.ResultsFrom week 6, body mass of HF‐VAD rats was significantly lower than that of HF‐VAS ones. On the other hand, the total food intake was similar between HF‐VAD and HF‐VAS groups. The liver mass and epididymal fat mass of HF‐VAD group were significant lower than that of HF‐VAS group. The hepatic expression level of cytochrome P450 26A1 protein in HF‐VAS group is higher than that in HF‐VAD group, suggesting reduced retinoic acid production. For glucose metabolism, the expression levels of glucokinase and phosphoenoylpyruvate carboxykinase in HF‐VAS group were higher than the level in HF‐VAD group. For fatty acid biosynthesis, the expression levels of acetyl‐CoA carboxylase (ACC), phosphor‐ACC, fatty acid synthase, and ATP citrate lyase were similar in two groups. The levels of insulin receptor β‐subunit and insulin receptor substrate (IRS) 1 were increased in HF‐VAD rats, while the expression level of IRS 2 were decreased in HF‐VAD rats. The expression level of mitogen‐activated protein kinase of HF‐VAD group was higher than that of HF‐VAS group. The expression levels of protein kinase C ζ, ι, δ, mammalian target of rapamycin, AMP‐activated protein kinase α and β, and protein kinase B were similar between HF‐VAD and HF‐VAS groups. The HF‐VAD rats had higher levels of glycogen synthase kinase 3α (GSK‐3α) and lower GSK‐3β expression levels, but not glycogen synthase, than the HF‐VAS rats did.ConclusionsVA status reduced the body mass gain in rats fed a HF diet. In a HF setting, VA status still can alter the expression levels of genes for glucose metabolism and insulin signaling pathways. These and our previous results indicate that VA status and its metabolism affect the hepatic expression levels of insulin‐regulated genes in both normal and HF dietary conditions. More studies are needed to determine the underlying mechanisms for these changes.
Diet and Exercise Training Improve Insulin‐Glucose Metabolism and Sympathetic Hyperactivation in Obstructive Sleep Apnea and Metabolic Syndrome
Authors: Cepeda Felipe X. , Rodrigues Sara , Dutra‐Marques Akothirene C.B. , Carvalho Jefferson C. , Toschi‐Dias Edgar , Rondon Maria Urbana P.B. , Alves Maria Janieire N.N. , Lorenzi‐Filho Geraldo , Trombetta Ivani C. 
Published: November 2023

Obstructive sleep apnea (OSA) impairs insulin‐glucose metabolism and muscle sympathetic nervous activity (MSNA). Metabolic syndrome (MetS) frequently is common in OSA patients, exacerbating these alterations. In this context, the effect of hypocaloric diet and exercise training (D+ET) in patients with OSA+MetS is not clear. We tested the hypotheses that: 1) D+ET would improve insulin‐glucose metabolism and MSNA; and 2) The reduction in MSNA is associated with the improvement insulin‐glucose metabolism. Never treated OSA patients (apnea‐hypopnea index‐AHI>15 events/h by polysomnography, PSG) and MetS (ATP‐III), were divided into: Control (C, n=10, 46±2y) and D+ET (n=11, 55±3y). D (−500kcal/day) and ET (40min, 3times/week of cycle exercise for 4‐months). We evaluated MSNA (microneurography) and HOMA‐IR and QUICK by fasting insulin/glucose. Both groups were similar in MetS risk factors, PSG parameters, MSNA and fasting insulin/glucose at pre‐intervention. Compared with C, D+ET improved VO2 peak, body weight, waist circumference, systolic and diastolic blood pressure, AHI (P<0,05). D+ET decreased MSNA (31±2 vs. 25±2 bursts/min, P=0.01), fasting insulin (13±1.3 vs. 9±1.0 μUI/mL, P=0.02), HOMA‐IR (3.4±0.4 vs. 2.2±0.3, P=0.03) and increased QUICK (0.32±0.01 vs. 0.35±0.01, P=0.02). No changes were found in C group. Further analysis showed a significant association between change in fasting insulin (R=0.49, P=0.03), in HOMA‐IR (R=0.54, P=0.02) and in QUICK (R=−0.55, P=0.02) with the change in MSNA. D+ET improved insulin‐glucose metabolism and MSNA in patients with OSA+MetS. The effect of D+ET in insulin‐glucose metabolism, can be a candidate to explain, at least in part, the improvement in sympathetic activity.Support or Funding InformationFundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) #2011/17533‐6, #2015/17533‐6 and #2016/16831‐7
Neutral Sphingomyelinase: structure and function
Authors: Hannun Yusuf 
Published: November 2023

Sphingolipid metabolism constitutes a network of connected bioactive metabolites that include sphingosine, sphingosine 1‐phosphate, ceramide, ceramide 1‐phosphate, and several others. A compendium of enzymes control the metabolism, regulation, and interconversion of these molecules. These enzymes show very specific sub cellular localization, distinct mechanisms of regulation, and specific cellular functions. Sphingomyelinases (SMases) are positioned at the apex of regulated hydrolytic pathways involved in the regulation of ceramide formation and function. There are three families of SMases distinguished the pH optimum of their action, and the neutral SMases include the largest number of members of which nSMase2 is the best studied. nSMase2 is activated by multiple extracellular agents, including cytokines, ROS, and specific chemotherapeutic agents. Basic mechanistic and structural results will be presented based on the recent crystal structure of the enzyme. Results will be discussed on the regulation of this enzyme by doxorubicin, and a role for the enzyme in the DNA damage response. The yeast counterpart of this enzyme, Isc1p also defines a novel pathway involved in the DNA damage response that recapitulates the functions of the mammalian enzyme. Together, these results define novel and compartment specific functions of neutral sphingomyelinases in the DNA damage response.Support or Funding InformationNational Institutes of Health R37GM043825
Mild Whole Body Heating Decreases Muscle Sympathetic Nerve Activity in Middle Aged and Older Individuals
Authors: Cui Jian , Gao Zhaohui , Blaha Cheryl , Sinoway Lawrence I. 
Published: November 2023

A number of reports suggest that whole body heat stress (i.e. increase in core temperature (Tcore) > 0.5 °C) induces a significant increase in muscle sympathetic nerve activity (MSNA) in young and older individuals. However, the effects of mild whole body heating (MWBH) on MSNA have not been specifically examined. A prior report from this laboratory suggests that MSNA is lower in the summer than it is in the winter. In this study, we hypothesized that MWBH would decrease the resting MSNA in middle aged and older individuals. MSNA from a peroneal nerve, ECG and heart rate (HR), blood pressure (BP), Tcore with telemetry temperature pill, mean skin temperature (Tsk), forearm skin blood flow (SkBF) and sweat rate (SR) were measured throughout the study in 8 male healthy subjects (59.6 ± 2.4 years, 177 ± 3 cm, 88 ± 6 kg). After the normothermic (Tsk at ~34 °C) data collection, passive whole body heating was applied via water‐perfused suits with ~46 °C water. After Tsk reached ~36 °C, the water temperature was slightly decreased. The MWBH data were collected during a period (1522 ± 61 sec) with Tsk > 36 °C and the peak increase in Tcore < 0.35 °C. Cardiac output was measured with echocardiography during baseline and MWBH. During a separate visit, a time control trial (non‐heating trial) was performed when the Tsk was controlled at ~34 °C throughout the study. The data were collected during the same time windows as those in the heating trial. Over the MWBH period, the averaged Tsk was 36.8 ± 0.3 °C, and the averaged increase in Tcore was 0.09 ± 0.05 °C. From normothermic baseline, SkBF (100 to 174 ± 31%) and cutaneous vascular conductance (CVC, 100 to 190 ± 43%) increased. Systolic BP (117.5 ± 1.3 to 113.5 ± 2.2 mmHg) did not significantly change, while diastolic BP (75.3 ± 1.9 to 70.7 ± 2.5 mmHg) and mean BP (89.4 ± 1.3 to 85.0 ± 2.3 mmHg, both P < 0.05) fell. MSNA burst rate (38.9 ± 3.0 to 28.9 ± 3.4 bursts/min), burst incidence (60.4 ± 4.5 to 42.4 ± 5.2 bursts/100 beats) and total activity (847 ± 47 to 583 ± 66 units/min, all P < 0.05) decreased, while HR (64.7 ± 2.9 to 69.1 ± 3.0 beats/min) increased. Cardiac output increased (P < 0.05). In the non‐heating time control trial, none of these variables changed. These data suggest that the MWBH may decrease resting MSNA and BP in middle aged and older individuals. Further studies are necessary to examine the mechanisms.Support or Funding InformationSupported by American Heart Association Grant 15GRNT24480051 (Cui), National Institutes of Health Grants P01 HL096570 (Sinoway) and UL1 TR000127 (Sinoway).