bluuebunny/crossref_metadata_2025 huggingface dataset:
Electroacupuncture and Moxibustion Hinder the Progression of Renal Disease by Modulating Systemic and Renal Renin‐Angiotensin System (RAS)
Authors: Naves Marcelo Andery , Paterno Josne Carla , Jara Zaira palomino , Fernandes Fernanda Barrinha , Casarini Dulce Elena , Sales Elizabeth Oliveira , de Paulo Castro Teixeira Vicente
Published: June 2021

INTRODUCTION AND AIMS

Systemic and renal RAS are pivotal for the development and maintenance of renal disease. Traditional Chinese Medicine (TCM) is increasingly recognized as an effective therapy in several fields of medicine. Among its therapeutic strategies are eletroacupuncture (EA) and moxibustion (MO). We investigate the effects of EA and MO on RAS in an experimental model of hypertensive and progressive renal disease.

METHODS

Male wistar rats were submitted to 5/6 nephrectomy (5/6 nx) and studied along eight weeks. There were threee groups: 5/6 nx (NX), 5/6 nx and sham EA (NX‐AS); 5/6 nx and EA‐MO session real acupuncture points (NX‐AM). We evaluated 24h‐proteinuria, plasma and renal Ang I, Ang II and Ang1–7 and plasma renin activity.

RESULTS

Groups
Ang I (ng/mL)
Ang II (ng/mL)
Ang 1–7 (ng/mL)
Renin Activity

NX
50 ± 13.5ψ
58.7 ± 19.9ψ
4 ± 2.1
22.9 ± 7.2

NX‐AS
25 ± 6.6
22.5 ± 6.2
5 ± 1.3
40.1 ± 0.9

NX‐AM
88 ±21.6#
32 ± 9.1#
15.8 ± 7.2*
29.8 ± 4.6*

(p=<0,05) vs NX and NX‐AS;

(p=<0,05) vs NXAS;

(p=<0,05) vs NX‐AS and NX‐AM

CONCLUSIONS

EA‐MO modulated RAS leading to higher production of systemic and renal Ang1–7. Since A1–7 is protective against endothelial dysfunction and has vasodilatory and antifibrotic effects, our findings suggest that it could be contribute to the improvement of the progression of renal disease in this model.
Nephrovascular interactions in a mathematical model of rat renal autoregulation
Authors: Sgouralis Ioannis , Layton Anita
Published: June 2021

We have developed a mathematical model of a nephrovascular tree in the rat kidney to study the interactions among the myogenic response and tubuloglomerular feedback (TGF). The model consists of coupled branches, each representing an afferent arteriole, glomerular filtration, and a short loop of Henle. Afferent arterioles are modeled by chains of vascular smooth muscles that are myogenically active and electrically coupled. The loop of Henle models predict tubular fluid and Cl− transport. Both the myogenic response and TGF, activated by hydrostatic pressure variations and distal Cl− concentration, respectively, operate by affecting the associated afferent arteriole membrane potential that leads to alterations in the vascular tone. Under basal conditions, each nephrovascular branch independently develops two distinct oscillations: a fast one (~165 mHz) arising from spontaneous activity of the myogenic mechanism, and a slow one (~30 mHz) mediated by TGF. The electrical and hemodynamical coupling of the various branches, together with heterodyning, yields oscillations in flow patterns of increased spectral complexity. This research was supported in part by NIH grant DK‐89066.
Sex‐specific actions of the Prostaglandin E type 4 (EP4) receptor to attenuate salt sensitivity and hypertension
Authors: Herrera Marcela , Koller Beverly , Coffman Thomas M
Published: June 2021

Prostaglandin E2 (PGE2) is the major prostanoid produced by the kidney, mediating its actions via four distinct E‐prostanoid receptor isoforms: EP1‐EP4. The EP4 receptor (EP4R) induces closure of the ductus arteriosus (DA) and triggers macula densa stimulation of renin, but can also induce vasodilation. Thus, the net impact of the EP4R on BP regulation is not clear. Deletion of EP4R causes post‐natal lethality due to failure of DA closure. Therefore, conditional deletion of the EP4R was carried out by crossing EP4flox/flox mice with a mouse line bearing a Cre‐recombinase transgene with tamoxifen‐inducible expression in all tissues. After 2 weeks of tamoxifen induction, efficient excision of the EP4R was documented in kidney, aorta and spleen. Using radiotelemetry in male mice, we found that EP4R deletion increased resting BP by 5±1mm Hg (p<0.001), caused an exaggerated response to high salt feeding (118±1 vs. 108±1mmHg; p<0.001), and enhanced the severity of angiotensin II‐dependent hypertension (149±1 vs. 133±1mmHg; p<0.001). These BP differences were not apparent in female mice. We conclude that the actions of PGE2 to attenuate salt‐sensitivity and hypertension are mediated by EP4Rs. However, their impact on blood pressure differs between sexes.

Source of research support: K99HL109167 (to MH) and R01 DK069896 (to TMC).
Weight‐loss surgery rapidly alleviates platelet hyperactivity in morbid obesity
Authors: Dobrydneva Yuliya , Periasamy Monica , Butcher Matthew , Galkina Elena , Kuhn Norine , Lieb David , Fontana Mark , Wohlgemuth Steven , Nadler Jerry
Published: June 2021

Morbid obesity is accompanied by platelet hyperactivity, leading to thrombotic events such as myocardial infarction and stroke. Platelets are pivotal for development of thrombosis. Bariatric surgery is the most effective intervention to reduce thrombotic events and alleviate type II diabetes in morbidly obese. However, effect of bariatric surgery on platelet function is largely unknown. In this pilot study we compared the short‐term effects of Roux‐en‐ Y Gastric Bypass (RY) and Lap Banding (LB) on prothrombotic monocyte‐platelet aggregates (MPA) that reflect platelet activation in vivo. MPA were measured in whole blood by flow cytometry pre‐ and post‐surgically at 1 and 3 months. In morbidly obese patients, MPA are drastically elevated compared to non‐obese controls. Both RY and LB decreased MPA in blood (unstimulated and stimulated with ADP). However RY alleviated platelet hyperactivity more rapidly (at 1 month post‐op) and more profoundly compared to LB. Bariatric surgery decreased MPA more profoundly in diabetics than in non‐diabetics. There is no correlation between BMI and decreased platelet activation after RY, but there is strong correlation after LB. Decreased MPA also correlates with decreased IL‐6 post‐surgically. Thus gastric bypass is more efficacious than gastric banding to reduce platelet hyperactivity in morbid obesity leading to a reduction in thrombotic events.
Effect of high‐fat diet (HFD) on resistance artery function in normal pregnant rats
Authors: Spradley Frank T. , Palei Ana C. , Granger Joey P.
Published: June 2021

Despite clinical evidence that obesity is the leading attributable risk for preeclampsia (PE) in developed countries, the mechanisms whereby metabolic factors increase the risk for PE are unclear. The purpose of this study was to examine the effects of HFD on resistance artery endothelial function in normal pregnant rats. Twelve‐week‐old Sprague‐Dawley rats were fed a normal diet (ND; 13% fat kcal; N=5–8) or HFD (40% fat kcal; N=9–11). At 21 weeks old, timed‐pregnant rats were generated. At gestational day 19, wire myography showed in third‐order mesenteric arteries that sensitivity (logEC50) of endothelial‐dependent relaxation to acetylcholine (ACh) was greater in HFD (−7.9 ± 0.3M) vs. ND (−6.7 ± 0.3M) (P<0.05). In the HFD group, treatment of artery rings with the non‐selective nitric oxide synthase inhibitor L‐NAME reduced sensitivity to ACh (logEC50 of −6.6 ± 0.2M, P<0.05 vs. untreated rings), whereas in the ND group, L‐NAME did not alter the ACh response (−6.6 ± 0.3M) vs. untreated rings. Endothelial‐independent relaxation to Na nitroprusside was similar (logEC50: ND: −6.5 ± 0.4M vs. HFD: −7.0 ± 0.2M). These data suggest that normal pregnancy protects against HFD‐induced endothelial dysfunction. However, this protective pathway may be targeted in PE by factors released from the ischemic placenta that are known to promote the hypertension and endothelial dysfunction of this disease. HL105324, HL51971
Acute kidney injury following orthopedic trauma in obese Zucker rats
Authors: Mittwede Peter , Xiang Lusha , Clemmer John , Lu Silu , Gowdey Andrew , Hester Robert
Published: June 2021

An increased incidence of multiple organ failure occurs following trauma in obesity, but the extent and mechanism of exacerbated damage to specific organs is not understood. The kidney, in particular, is susceptible to organ failure. We hypothesized that there would be impairment in renal function following trauma in obesity. Lean (LZ) and obese (OZ) Zucker rats (11–13 wk, n=6 per group) were used. Orthopedic trauma was mimicked with bilateral hind limb soft tissue injury, followed by an injection of crushed bone components to the area. Twenty‐four hours after trauma, glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure (BP), and urine albumin measurements were taken. RPF was similar in all groups. LZ and OZ exhibited similar basal BP (122 ± 3 vs. 125 ± 5 mmHg, respectively) and GFR (1.51 ± .15 vs. 1.70 ± .13 ml/min/g). Trauma resulted in a significantly decreased BP (108 ± 3 mmHg) and GFR (0.89 ± .07 ml/min/g) in OZ with no changes in LZ (115 ± 3 mmHg, 1.40 ± .20 ml/min/g). As compared to pre‐trauma values, urine albumin excretion was significantly increased in the twenty hours following trauma in OZ (.63 ± .30 vs. 1.60 ± .51 mg), but not in LZ (.27 ± .05 vs. .51 ± .12 mg). These results show that in our model of orthopedic trauma, acute kidney injury occurs in obese but not in lean rats. This model will allow us to elucidate the mechanisms of trauma‐induced renal damage in obesity.

Supported by NIH HL‐51971, HL‐89581, AHA‐12SDG12050525
Autonomic Reflexes May Contribute to the Symptomatology of Mal de Debarquement Syndrome
Authors: Wilson Thad E. , LePorte Andrew D. , Toma Kumika , Thomas James S. , Clark Brian C.
Published: June 2021

Mal de debarquement syndrome (MdDS) is the phantom perception of self‐motion triggered by a passive motion event such as sea or air travel. To test the hypothesis that autonomic reflexes are altered in MdDS, head‐down rotation (HDR) was used to test vestibular reflexes and 60° head‐up tilt (HUT) was used to test combined baroreceptor and vestibular reflexes in 9 female MdDS patients and 9 age‐ and sex‐matched controls. Heart rate (HR, ECG), arterial blood pressure (ABP, finger photoplethysmography), and cardiac output (CO), stroke volume and systemic vascular resistance (SVR) were calculated (Modelflow) in 6 min bins for steady‐state and dynamic (FFT) analysis during baseline, perturbation (HDR or HUT), and recovery. HDR decreased stroke volume and CO in both groups, but SVR increased in MdDS. No changes in the ABP power spectrum were observed during HDR. HUT increased mean ABP, HR, and SVR while decreasing pulse pressure, stroke volume, and CO in both groups. Increases in mean ABP and SVR in MdDS were augmented compared to controls. HUT increased the ABP low frequency spectral power and R‐to‐R interval low frequency/high frequency ratios in both groups. These pilot data identified exaggerated vascular resistances to a postural change in MdDS possibly due to increased sympathetic reflex gain. Thus, altered autonomic reflexes appear to be a part of MdDS symptomatology.

Funding: MdDS Balance Disorder Foundation
Shp2 signaling in Pomc neurons is important for leptin's actions on blood pressure, energy balance and glucose homeostasis.
Authors: do Carmo Jussara Marcia , da Silva Alexandre A. , Sessums Price O. , Ebaad Sabira H. , Hall John E.
Published: June 2021

Previous studies showed that Src homology‐2 tyrosine phosphatase (Shp2) is an important regulator of body weight homeostasis. We examined if deletion of Shp2 in proopiomelanocortin (Pomc) neurons attenuate the chronic cardiovascular and metabolic responses to leptin. Mice with Shp2 deleted in Pomc neurons (Shp2/Pomc‐Cre, n=7) and control mice (Shp2flox/flox, n=9) were implanted with telemetry probes for measurement of 24‐hr mean arterial pressure (MAP) and venous catheters for leptin infusion. After a 5‐day baseline period, mice received leptin infusion (2 μg/kg/day, iv) for 7 days. Shp2/Pomc‐Cre mice were slightly heavier (34±1 vs 31±1 g), but consumed the same amount of food (3.9±0.3 vs 3.8±0.2 g) compared to control mice. Leptin infusion reduced food intake by 30% and raised MAP by 5 mmHg in control mice, whereas Shp2/Pomc‐Cre mice exhibited attenuated responses on food intake (~18%) and MAP (2 mmHg). Leptin infusion decreased insulin and glucose levels in control mice (12±1 to 6±1 μU/ml and 142±12 to 81±8 mg/100 ml) while no changes were observed in Shp2/Pomc‐Cre mice. Leptin also increased energy expenditure by 16% in control mice and only 7% in Shp2/Pomc‐cre mice. These results indicate that Shp2 signaling in Pomc neurons is important in mediating the long‐term appetite and blood pressure actions of leptin and for the ability of leptin to reduce insulin and glucose levels. (NHLBI‐PO1HL51971/ AHA SDG5680016)
Microglia Display Distinct Sex‐dependent Gene Expression Profiles in The Postnatal and Adult CNS
Authors: Nikodemova Maria , Crain Jessica , Watters Jyoti J
Published: June 2021

Microglial activation is associated with all CNS disorders, many of which are sexually dimorphic or age‐dependent. However, little is known about whether microglia are sexually dimorphic, or how their basal gene expression is altered with age in the healthy CNS. Analysis of microglia from the brains of 3 day‐ to 12 month‐old male and female C57Bl/6 mice revealed distinct gene expression profiles during postnatal development that are significantly different from adulthood. In addition, we found a 2‐fold higher density of microglia/mg tissue in the postnatal brain than in the adult brain. Postnatal microglia are characterized by high iNOS, TNFα and arginase‐1 mRNA levels, whereas adult microglia (2–4 months) are characterized by low pro‐inflammatory cytokine expression that was increased at 12 months of age. Although the microglial phenotype appears to change with age, microglia in the healthy brain were not committed to an M1 or M2 phenotype at any time. We found sexual dimorphisms in microglia in the absence of sex differences in estrogen receptor expression, and only at P3 when females had higher expression of inflammatory cytokines than males. Since basal gene expression may prime microglial responsiveness to physiological or pathological events, the same stimulus may induce different sex‐and age‐dependent microglial activities, and thereby contribute to altered CNS vulnerability at specific ages.
Pro‐atherogenic blood flow and shear patterns acutely induce the release of CD62E+ and CD31+/CD42b− endothelial microparticles in humans
Authors: Jenkins Nathan T , Padilla Jaume , Boyle Leryn , Credeur Daniel P , Laughlin M. Harold , Fadel Paul J
Published: June 2021

A large body of evidence links decreased and/or oscillatory blood flow and shear to the development of a pro‐atherogenic vascular endothelial phenotype. However, additional human studies are needed to provide more definitive support for this link, as most of the available data come from in vitro experiments and rodent models. To address this, a 220 mmHg occlusion cuff was placed on the forearm of 10 men to induce a localized region of proatherogenic blood flow and shear patterns in the proximal vasculature for 20 min. We hypothesized that this maneuver would induce endothelial activation and apoptosis, as indicated by increases in local concentrations of CD62E+ and CD31+/CD42− bendothelial microparticles (EMPs), respectively. Distal cuff occlusion induced reductions in mean blood flow, mean shear and antegrade shear, and increases in retrograde flow, retrograde shear, and oscillatory shear stress. Relative to baseline, CD62E+ EMPs increased by ~3 fold at 10 min and ~4 fold at 20 min in the experimental arm (P < 0.05). CD31+/CD42b− EMP concentrations were elevated by ~9 fold at the 20 min time point (P < 0.05). There were no changes in EMPs in the contralateral arm, exposed to normal resting blood flow. These data support the hypothesis that pro‐atherogenic blood flow and shear patterns acutely induce endothelial activation and apoptosis in humans.

Grants: T32‐AR048523, R01‐HL093167, AHA 11POST5080002.
Oxidative stress level mediates the inotropic effects of alcohol on the heart
Authors: AlRubaiee Mustafa , Umoh Nsini , Jeffress Miara , Walker Robin , Cousins Valerie , Haddad Georges E
Published: June 2021

Alcohol has deleterious as well as beneficial cardiac effects depending on the exposure level, length and frequency. Binge drinking can be associated with significant cardiac dysfunction depending on the amount of alcohol consumption. Thus, the objective of this study is to evaluate the role of acute alcohol‐induced oxidative stress in altering cardiac function in vivo. Anesthetized adult rats were infused with (% w/v) low (LA: 0.023%), moderate (MA: 0.115%) or high (HA: 0.461%) alcohol levels through the jugular vein while measuring the pressure‐‐volume loop with a conductance catheter apically inserted in the left ventricle. Isolated cardiocytes were used for oxidative stress assays. LA increases ESPVR at a maintained EDV and SV and reduced oxidative stress, whereas MA and HA did not affect ESPVR but increased EDV, SV and oxidative stress. Furthermore, LA reduced stroke work and PVA whereas MA and HA increased these energy parameters. Interestingly, MA and HA increased cardiac compliance. We conclude that acute MA or HA increases cardiac compliance with oxidative stress at an elevated energy cost, whereas LA has the opposite effect. This seemingly compensatory compliance response could be outweighed by cardiac overwork in chronic alcohol leading to dilated alcoholic cardiomyopathy.

This work was supported in part by grants NIH/NIAAA/1R15AAA019816–01A1 and 2G12 RR003048 RCMI/NCRR/NIH.
Sex Differences in Aortic Endothelial Function of Streptozotocin‐induced Diabetic Rats: A Possible Role of Superoxide Production
Authors: Han Xiaoyuan , Zhang Rui , Anderson Leigh , Rahimian Roshanak
Published: June 2021

Little is known of the interaction between diabetes and gender in the vasculature. This study was designed to investigate 1) whether there were gender differences in rat aortic endothelium‐dependent vasodilation (EDV) in streptozotocin (STZ, 60 mg/kg, iv)‐induced diabetic rats at early stage of the disease (1 wk), and 2) the potential role of superoxide in diabetes‐induced vascular dysfunction. EDV to acetylcholine (ACh; 10−8 to 10−5 M) was measured in aortic rings precontracted with phenylephrine (2 μM) before and after pretreatment with MnTMPyP (10 mM), a superoxide scavenger. In addition, the level of endothelial nitric oxide synthase (eNOS) and NADPH oxidase (Nox, a potent sources of superoxide) 1, 2 and 4 mRNA expression were determined using real‐time RT‐PCR. ACh‐induced relaxations were significantly impaired in aortic rings from both male and female diabetic rats. However, the extent of impairment was significantly greater in diabetic females than diabetic males. Preincubation with MnTMPyP increased EDV only in diabetic female group. Accordingly, our data showed that in females, the level of Nox4 mRNA expression was substantially enhanced, whereas the level of eNOS mRNA expression was decreased at 1 wk after the induction of diabetes. These data suggest that the predisposition of female rat aorta to vascular injury in diabetes is possibly due to the superoxide production (supported by NIH/NIDCR).
Anti‐parstatin promotes angiogenesis and ameliorates left ventricular dysfunction during pressure overload
Authors: Givvimani Srikanth , Narayanan Nithya , Pushpakumar Sathnur Basappa , Tyagi Suresh C.
Published: June 2021

Parstatin, novel protease activated receptor‐1 (PAR‐1) derived peptide is a potent inhibitor of angiogenesis. We and others have reported that imbalance between angiogenic growth factors and anti‐angiogenic factors results in transition from compensatory cardiac hypertrophy to heart failure in a pressure overload condition. Though cardioprotective role of parstatin was shown previously in ischemic cardiac injury, its role in pressure overload cardiac injury is yet to unveil. We hypothesize that supplementing anti‐parstatin antibody during pressure overload condition augments angiogenesis and ameliorate left ventricular dysfunction and heart failure. To verify this, we created ascending aortic banding in mice to mimic pressure overload condition and then treated mice with anti‐parstatin antibody. Left ventricular function was assessed by echocardiography and pressure‐volume loop study. Angiogenic growth factors and anti‐angiogenic factors along with MMP‐2,‐9 were evaluated by western blot and immunohistochemistry.

Results

our results showed an improved left ventricular function in anti‐parstatin treated aortic banding hearts compared to their corresponding wild type controls. Expression of angiogenic growth factor, VEGF, MMP‐2 and CD31 expression was increased in treated aortic banding hearts compared to their corresponding wild type controls. Our results suggest that treating pressure overload mice with anti‐parstatin antibody augments angiogenesis and ameliorates left ventricular dysfunction.
HDACs are O‐GlcNAc modified and OGT O‐GlcNAcylation is decreased with acute exercise
Authors: Medford Heidi M , Marsh Susan A
Published: June 2021

Chronic exercise promotes beneficial morphological and physiological cardiac changes, termed physiological cardiac hypertrophy. Class I HDACs 1–3,8 promote, while class II HDACs 4–7,9,10 inhibit hypertrophy in pressure‐overloaded hearts. HDAC signaling in hypertrophy occurs in complex with transcriptional co‐repressors mSin3A and REST. The post‐translational attachment of O‐GlcNAc by OGT to serine and threonine residues of proteins confers acute cardioprotection, and OGT is known to complex with REST transcriptional co‐repressor mSin3A. We hypothesized that chromatin modifying proteins would be O‐GlcNAcylated and that this would be altered in mouse hearts by acute exercise. 15 or 30 minutes of treadmill running did not elicit changes in cardiac fractions of O‐GlcNAc, OGT, OGA, HDACs 1–5, REST, and mSin3A. Independent of exercise, we found HDACs 2–5 and mSin3A in cytosol as well as nuclear fractions; HDAC2 and mSin3A were predominantly nuclear. Cytosolic protein O‐GlcNAcylation was lower in exercised hearts after 15min but higher in nuclear fractions after 15min and 30min. Immunoprecipitation showed decreased OGT O‐GlcNAcylation and decreased association of OGT with REST in response to exercise, independent of time. HDACs 1,2,4,5 were O‐GlcNAcylated, with no effect of exercise or time. We are first to demonstrate HDAC O‐GlcNAcylation and the OGT/REST interaction. This is a significant finding as it links the putatively pathological REST/mSin3A/HDAC complex to OGT and O‐GlcNAc in exercise‐induced cardiac hypertrophy.
Effect of VPAC2 agonist on improving cardiac output in pulmonary hypertension
Authors: Mizuno Yusuke , Koga Motokazu , Kashiwagi Shizuka , Watanabe Itaru , Goto Takahisa
Published: June 2021

Pulmonary hypertension (PH) is associated with significant perioperative risk for major complications, including cardiac arrest and death. Vasoactive intestinal peptide (VIP) and its related peptide PACAP are known to have vasodilatory and protective effects in several organs and VIP has been expected to be promising treatment option for PH. However, still little is known about the role of VIP/PACAP signaling in PH. Previously we presented that decreased expression of VIP and PACAP were associated with increased their receptors VPAC1, VPAC2, and PAC1 in monocrotaline‐induced PH. These data raised the question that altered expression of the receptors could increase vasodilatory response of pulmonary artery to VIP/PACAP and may contribute to improving cardiac performance in PH To answer the question, we investigated effect of administration of VIP/PACAP agonists on pulmonary/systemic pressure, the vascular resistances and cardiac output in monocrotaline‐induced PH. VPAC2 but not VPAC1, PAC1agonist decreased pulmonary arterial pressure and its vascular resistance and improved cardiac output, almost as same as prostacyclin in the PH rats, while not affecting pulmonary circulation in normal rats. Therefore, increased VPAC2 expression may be involved in enhanced vasodilatory responses and contribute to improved cardiac output. VPAC2 agonist may be a promising treatment for PH.
Proteomic analysis of the cAMP/protein kinase A (PKA) signaling pathway identifies PKA as a regulator of cellular response to oxidative stress
Authors: McCann Thalia , Wilderman Andrea S. , Guo Yurong , Taylor Susan S. , Insel Paul A.
Published: June 2021

The second messenger cAMP, acting through PKA, induces apoptosis in certain lymphoma and leukemia cells. This apoptotic response facilitated the isolation of a cAMP‐resistant, clonal variant of wild‐type (WT) murine S49 cells; these cAMP‐resistant cells lack PKA activity (kin‐cells) and expression of the PKA catalytic subunit. As an approach to identify “new” actions of cAMP/PKA, we used a quantitative proteomic (iTRAQ) method and compared the protein expression profiles of WT and kin‐ S49 cells under “basal” conditions. We identified 19 proteins with altered (12 higher, 7 lower) basal expression in kin‐ cells. Among the proteins with higher basal expression in kin‐ cells are the antioxidants glutathione reductase (Gsr) and thioredoxin1 (Txn1). Consistent with this increase in antioxidant expression, we found that, compared to WT cells, kin‐ cells have increased resistance to oxidative stress (150 μM H2O2 for 16 hr), measured as cell viability and lipid peroxidation (the production of malondialdehyde). cAMP/PKA thus inhibits the basal expression of two important antioxidants. The loss of PKA function in kin‐cells may help protect these (and perhaps other) T cells from oxidative damage. More generally, these data reveal the ability of a global proteomic approach to identify new features of cAMP/PKA signaling and regulation in mammalian cells. (Supported by HHMI [SST] and NIH Grants [SST and PAI]).
Metabolic effects of polydextrose, lactitol and Bacteroides thetaiotaomicron in rats fed with high‐fat diet
Authors: Herzig Karl‐Heinz , Olli Kaisa , Madetoja Mari , Tiihonen Kirsti
Published: June 2021

Polydextrose (PDX) and lactitol enhance satiety and influence postprandial glucose and lipid levels. Furthermore, low levels of Bacteroidetes are associated with increased BMI. We investigated the supplementation of PDX, lactitol and Bacteroides thetaiotaomicron on metabolic parameter in rats on high‐fat diet. Hundred male rats were fed a high fat (42%) diet for two weeks. Rats, allocated into four groups, were administered orally 2 ml saline containing B. thetaiotaomicron (1010bacteria/day) with or without addition of PDX or lactitol (2 g/day), or saline alone for 8 days. Postprandial blood samples were collected at 0, 1, 3, 5 and 8 h for the determination of triglycerides (TG), glucose, insulin, gastrointestinal peptides and caecal material collected. B. thetaiotaomicron supplementation alone did not have any significant effect on body weight gain, but when administered together with lactitol or PDX, there was a significant decline in mean body weight. TG were decreased by the combination of B. thetaiotaomicron and lactitol or B. thetaiotaomicron and PDX. Plasma insulin levels were lower in all test groups. Caecal branched SCFAs and SCFAs were significantly decreased in both lactitol and PDX‐treated groups, while there were no significant changes in these parameters in rats receiving B. thetaiotaomicron alone. Both lactitol and PDX in combination with B. thetaiotaomicron significantly decreased the dry matter, while heat values were increased in the B. thetaiotaomicron‐fed rats.

Conclusion

Our results suggest that B. thetaiotaomicron has only minor effects on body weight, whereas polydextrose and lactitol may be useful in weight management and attenuating post‐prandial TG.
Angiotensin II Stimulates Renin Synthesis and Secretion in Mouse Collecting Duct M‐1 cells via a PKC alpha‐mediated cAMP Stimulation Mechanism
Authors: LIU LIU , Lara Lucienne S. , Gonzalez Alexis A , Bourgeois Camille RT , Seth Dale M. , Prieto Minolfa C.
Published: June 2021

To test the hypothesis that Ang II stimulates renin synthesis and secretion in collecting duct (CD) cells via activation of PKC and subsequent stimulation of cAMP/PKA/CREB pathway, we treated mouse cortical CD (M‐1) cells with Ang II (10−7M). Ang II treatment for 6‐h increased intracellular renin gene expression and renin content in culture media (Ang II: 31±4 vs. 19±4 ng Ang I/hr/ml; p<0.05). Likewise, this treatment increased intracellular cAMP levels by 1 min (148±32 pmol/mg protein) which reached a peak at 30 min (290±27 vs. 44±0 pmol/mg protein; p<0.05). The adenlyate cyclase activator, forskolin and the analogue of cAMP, dibutyryl‐cAMP both significantly increased renin gene expression. These responses were followed by increases in pCREB levels and prevented by PKA inhibition with H89 or PKI. PKC inhibition either with calphostin C or a PKCα dominant negative prevented the augmentation of intracellular levels of cAMP, pCREB and renin mRNA in Ang II‐treated M‐1 cells. Ang II stimulates renin synthesis and secretion in M‐1 cells via PKCα‐mediated cAMP accumulation and PKA/CREB activation. By this mechanism distal tubular renin may contribute to local Ang II generation, thus to activation of sodium reabsorption.
Effects of chronic swim stress on endocrine and cardiac function in angiotensin AT1a receptor knockout mice
Authors: Almahroug Najat Khalifa , Alhajoj Ahmed , Alghamri Mahmod , Morris Mariana , Pohlman Roberta L
Published: June 2021

Stress increases circulating angiotensin II (AngII) which contributes to stimulation of adrenal Ang type 1 receptors (AT1R), mediating stress‐induced hormone release. The goal was to assess the influence of chronic swim stress on adrenal and cardiac function in AT1aR knockout mice. Adult male AT1R knockout (KO) and wild type (WT) mice (n=6) were used; groups were exercise (KO and WT) and sedentary (KO and WT). Exercise paradigm was swimming, 1 hour 3d/wk for 7 weeks. Urine and plasma corticosterone (CORT) were measured by RIA. Cardiac function was assessed by echocardiography (Echo). Results showed that plasma CORT was lower in chronic exercise as compared to sedentary groups (3 fold decrease). Urinary CORT was used to show the dynamic response to exercise stress. The stimulatory change was 10 fold higher in WTEX as compared to 5 fold in KOEX. Echo showed a higher ejection fraction (EF%) in KOEX (75%) vs. WTEX (55%). Assessment of mitral valve function showed a higher A‐wave velocity in KOEX as compared to WTEX. Ang AT1aR deficient mice showed improved cardiac response and reduced adrenal stress response to chronic exercise.
The Neuroprotective Effect of Cerebrolysin Against Type 1 Diabetes‐Induced Dementia In Rats
Authors: Nassar Noha N , Georgy Gehan S. , Mansour Hanaa A. , Abdallah Dalaal M
Published: June 2021

Cognitive decline and increased dementia are associated with diabetes. This work aimed to evaluate the potential neuroprotective effect of cerebrolysin (CBL) in modulating hippocampal alterations associated with streptozotocin (STZ) hyperglycemic complications. To this end, male Sprague Dawley rats were divided into (i) control (ii) CBL control (4 weeks) (iii) STZ diabetic control, and (iv) STZ + CBL (4 weeks). Diabetes was confirmed by hyperglycemia and elevated glycated haemoglobin (HbA1c) % level, which were associated by weight loss, elevation in serum tumor necrosis factor (TNF)‐α and decreased serum insulin like growth factor (IGF)‐1 levels. Furthermore, STZ caused learning and memory impairment that corroborated degenerative changes and neuronal loss in the hippocampus. Behavioral deficit was associated by changes in several neurotransmitter molecules. Moreover, diabetic rats showed an increase in hippocampal nitric oxide as well as thiobarbituric acid derivatives levels, however non‐protein thiols decreased. Though CBL did not affect STZ‐induced hyperglycemia, it partly improved body weight and HbA1c %. Such effects were associated by enhancement in both learning and memory as well as apparent normal cellularity in CA1and CA3 areas. CBL amended serum TNF‐α, IGF‐1, glutamate (GLU), serotonin (5‐HT) as well as oxidative biomarkers In conclusion, CBL possesses neuroprotection against diabetes‐associated cerebral neurodegeneration and cognitive decline via anti‐inflammatory and antioxidant effects as well as modulating hippocampal GLU and 5‐HT.
A new potent and specific 5‐HT2C receptor agonist with preclinical anti‐psychotic and anti‐obesity properties
Authors: Canal Clint , Morgan Drake , Kondabolu Krishnakanth , Rowland Neil , Booth Ray
Published: June 2021

Development of serotonin 2C (5‐HT2C) receptor agonists for treatment of neuropsychiatric disorders including schizophrenia, substance abuse, and eating disorders is challenging due to ~75% sequence similarity and identical Gαq‐mediated signaling among the 5‐HT2 family. Essentially all reported selective 5‐HT2C receptor agonists (including FDA‐approved Belviq®) also activate 5‐HT2A and/or 5‐HT2B receptors at physiologically relevant doses, potentially causing hallucinations and/or cardiopulmonary toxicity in humans, respectively. Herein is described a novel, potent and efficacious 5‐HT2C receptor partial agonist, m80‐PAT (Ki = 7.2 (2.2) nM; EC50 = 16.6 (3.20) nM; Emax (relative to 5‐HT) = 84.4 (5.0) % for human 5‐HT2C receptor‐mediated PLC signaling), that does not activate 5‐HT2A or 5‐HT2B receptors. m80‐PAT is highly effective in preclinical C57Bl/6 mouse psychoses models, reducing the 2,5‐dimethoxy‐4‐iodoamphetamine (DOI)‐elicited head‐twitch response, and MK‐801 and amphetamine induced hyperlocomotion. Significantly, m80‐PAT does not alter locomotor activity on its own, nor in combination with DOI, and also decreases consumption of highly palatable food. m80‐PAT holds promise as an effective compound to treat drug‐induced psychoses without liability for weight gain, hallucinations, heart disease, or motoric abnormalities.
Cytotoxic Effects of Manganese in Human Prostate Carcinoma DU145 Cells
Authors: Idikuda Vinaykumar , Lai Maria , Pfau Jean , Bhushan Alok , Leung Solomon , Lai james
Published: June 2021

Manganese (Mn) is a micro‐nutrient essential for maintaining the normal functions of many enzymes and other proteins in mammalian cells and tissues. However, Mn is toxic when taken in excess. Our previous studies have shown that Mn induces cell death in human neural tumor cells by altering, in part, their energy metabolism leading to necrosis. To investigate the hypothesis that Mn generally exerts toxicity in cancer cells by inducing them to undergo apoptosis and/or necrosis, this study aims to determine the effects of Mn on human prostate carcinoma DU145 cells. Our results demonstrate that at pathophysiological levels Mn induced dose‐related decrease in survival of DU145 cells concomitant with alterations in their cellular morphology. Results from flow cytometry analysis and lactate dehydrogenase release assays obtained with DU145 cells treated with MnCl2 for 48 hours revealed that at lower treatment levels, Mn induced mainly apoptosis whereas at higher levels, it induced mainly necrosis in DU145 cells. Studies are ongoing to determine the signaling mechanisms underlying the Mn‐mediated effects. Thus, our findings may assume pathophysiological significance of Mn toxicity in prostate cancer and may have implications in cancer chemotherapy.
Developing methods to enhancing cell engraftment in a genetically engineered mouse model
Authors: Hsu Yu Chen , Kao Chung‐Yang , Tsai Ming‐Shian , Yu I‐Shing , Chen Chun‐Yu , Lin Chien‐Yu , Lee Fang‐Jen , Wu Yao‐Ming , Lin Shu‐Wha
Published: June 2021

Cell/stem cell transplantation would be a promising approach for the treatment of genetic liver diseases and end‐stage liver diseases. Since a significant hurdle is the poor engraftment efficiency in the host liver, developing methods to enhance cell engraftment is important for cell/stem cell therapy. We have generated a genetically engineered mouse (GEM) line with narrowed sinusoidal diameters, which is also associated with the cancer cells preferentially colonized in the mouse liver as a result of retention of tumor cells. In the current study, we used the primary hepatocytes from R26R‐GR mice, a double‐fluorescent‐reporter knockin mouse line that could be used as a reporter system for investigation of cell therapy conditioning. We shown the donor cell engraftment can be improved in this GEM line. After the equivalent number of the primary hepatocytes was transplanted, the efficiency of cell engraftment was significantly greater in the GEM than that in WT mice at all the time points. We demonstrated that the R26R‐GR mouse could be a good tool to trace the donor cells in the research for cell/stem cell therapy, and that the donor cells could enhance engraftment in our GEM line. We suggest that this strategy may be applicable to improve cell/stem cell therapy in the near future.
Effects of binge drinking on brain blood flow
Authors: Serrador Jorge M , Tosto Jenna , Tzeng Shieak
Published: June 2021

Ethanol intoxication, especially binge drinking is a major risk factor for both ischaemic and haemorrhagic stroke. Compared with non–binge drinkers, the risk of stroke doubles within one hour of consuming alcohol even after adjusting for average alcohol consumption, age, and gender. Despite these epidemiological associations the mechanisms have yet to be defined. We tested the hypothesis that binge drinking impairs cerebrovascular reactivity to blood pressure and carbon dioxide.

Eight subjects were recruited to undergo a binge drinking protocol wherein ethanol (0.8 g/kg) were consumed within one hour (~6 standard drinks for an 80 kg subject). Heart rate, blood pressure, middle cerebral artery blood velocity, and end‐tidal PCO2 were measured during cerebrovascular reactivity testing at baseline and at peak intoxication. To assess regulation of cerebral blood flow subjects performed a sit to stand maneuver.

During the protocol breath alcohol concentration increased to ~0.053±0.010 %Alcohol. Peak breath alcohol concentration was associated with a significant increase in mean arterial pressure (81±9.2 vs. 86±10 mmHg) and attenuated blood pressure decrease when standing (−19±1 vs. −17±1 mmHg). In contract there was a reduction in the Autoregulatory index (4.4±0.4 vs 3.5±0.5, p=0.004) associated with a greater decrease in cerebral blood flow (−11±2 vs. −15±2 %). However, CO2 reactivity remained unchanged.

These pilot data suggest that binge drinking impairs the regulation of cerebral blood flow against transient reductions in blood pressure but does not alter vascular reactivity to CO2. Future work is needed to determine how long this impairment persists.
Enhanced apoptosis may lead to fewer nephrons in Japanese quail subjected to reduced nutrition during development
Authors: Nishimura Hiroko , Nishi Yuko , Nameta Masaaki , Kidokoro Kengo , Satoh Minoru , Yamaguchi Ken'ichi , Shimada Toshio , Kashihara Naoki
Published: June 2021

Inadequate fuel supply during the perinatal period may trigger structural alterations in humans and experimental animals, leading to increased vulnerability to chronic diseases in later life. Using a unique avian model of Coturnix japonica, we noted that partial egg‐white withdrawal (EwW) before the start of incubation impaired nephrogenesis, resulting in smaller birth weight, fewer nephrons, and glomerular injury. The present study aims to determine whether the lower number of nephrons in EwW quail is due to delayed nephrogenesis or enhanced apoptosis of nephrons. We found that 9–10% of EwW embryos had larger nephrogenic zones on embryonic day 15 (E15), while apoptosis measured by the Tunel method (In situ Apoptosis Detection Kit) was also higher than in control (CT). In EwW embryos, mesonephros still remains on E15, suggesting delayed maturation of nephrons. Apoptosis decreases after birth in both groups. Plasma Glucocorticoid (GC, ng/ml), a stress hormone, was significantly (P < 0.01) higher at neonatal day 4 (D4) in EwW (28.4 ± 3.3, n = 7) than in CT (11.0 ± 3.8, n = 8) quail. GC decreased at D18 in both groups. These results suggest that although nephrogenic activity is high in low‐nutrition quail during the perinatal period, enhanced apoptosis may result in lowering the number of mature nephrons. (Grant‐in‐Aid from Japan Ministry for Education 21390307)
Short‐and long‐term fructose feeding alters exercise capacity of rats
Authors: Sun Angela , Kertowidjojo Elizabeth , Song Su , Hintze Thomas H
Published: June 2021

To test the hypothesis that high‐fructose (HF) consumption alters exercise capacity, rats were fed a normal, or a HF (60%) diet for 3, 6, 10 and 30 days, and run on a treadmill. Surprisingly, running distance/work was significantly increased in rats fed HF for 3 (HF‐3D) and 6 days, but was decreased in rats of HF‐30D. Shear stressinduced vasodilation (SSID) in plantaris muscle arterioles of HF‐3D rats was significantly greater than that of controls. L‐NAME abolished the difference in SSID between two groups, suggesting an increased NO‐mediated SSID in HF‐3D rats. Upregulation of phospho‐eNOS (p‐eNOS) in skeletal muscles of HF‐3D compared to controls suggests an enhanced eNOS sensitivity to shear stress. However, SSID was significantly reduced in vessels of HF‐30D rats that were hypertensive, showing a weaker inhibitory effect of L‐NAME on the responses and downregulation of phospho‐eNOS. There was an impaired NO‐dependent regulation of myocardial oxygen consumption in HF‐30D rats, which was partially reversed by apocynin. Thus, short‐term HF feeding enhances exercise capacity of rats, due to an increased endothelial sensitivity to shear stress, which promotes tissue perfusion and oxygen utilization. Long‐term HF feeding initiates endothelial dysfunction in a superoxide‐dependent manner, which restrict exercise capacity of rats. (This work was supported by NIH HL‐43023).
TOLERANCE TO NITROGLYCERIN IS DUE TO eNOS UNCOUPLING.
Authors: de Rezende Dias Vania Braghini , Silva Bruno Rodrigues , Grando Marcella Daruge , Bendhack Lusiane Maria
Published: June 2021

The mechanisms underlying the tolerance induced by nitroglycerin (NTG) and the contribution of endothelial cells (EC) remain unclear. In this regard, NTG could activate eNOS acting as a signal amplifier pathway eNOS phosphorylation in the residue Ser1177. We have verified that the endothelium modulates the vasodilatation induced by NTG in rat aorta and the in vitro tolerance was induced after 5 minutes incubation with NTG (EC100). This study aimed to investigate the effects of (i) addition of NOS cofactor BH4, (ii) the expression of eNOS and (iii) phosphorylation of Ser1177on eNOS NTG‐induced relaxation during tolerance. Incubation with the NOS cofactor BH4 reversed the potency of NTG‐induced tolerance (pD2 from 7.63 ± 0.08 to 8.27: ± 0.07) and efficacy (from 54.7±3.6% to 94.5±2.5% P<0.001). No changes were observed in the phosphorylation of Ser1177, the activation site of eNOS when compared with control (0.225±0.030 vs 0.159±0.0270, n= 7/group). Therefore, our results suggest that NTG‐induced aorta tolerance in a short‐time may involve eNOS uncoupling, but not phosphorylation of Ser1177. Supported by FAPESP and CNPq.
Long‐Term Exposure of Obesity Induced by Unsaturated High‐Fat Diet promotes Cardiac Dysfunction and Increase of Myocardial Collagen
Authors: Leopoldo Andre , Leopoldo Ana Paula Lima , Sugizaki Mário , Nascimento André , Campos Dijon , da Silva Danielle , Padovani Carlos , Cicogna Antonio
Published: June 2021

Several experimental models have shown that obesity leads to cardiac dysfunction as well as alterations in myocardial collagen. The purpose was to test the hypothesis: the increased time of exposure to obesity intensifies the cardiac dysfunction; the functional impairment in vivo and in vitro is enhanced by time due to increased levels of myocardial collagen. Thirty‐day‐old male Wistar rats were assigned to one of two groups (n=110 each): control (C) and obese (Ob). The C group was fed a standard diet and Ob group was fed cycles of four high‐fat diets for 15, 30 and 45 weeks. The obesity was defined by adiposity index and cardiac remodeling by structural and functional analysis. Obesity promoted comorbities after 15, 30 and 45 weeks, nevertheless, did not alter the systolic blood pressure. The echocardiographic analysis showed that the time of exposure to obesity promoted LV hypertrophy, but not promotes changes on interstitial collagen. Cardiac function in vivo showed that obesity led to an increased in indexes fractional shortening after 30 weeks. The time of exposure to obesity influenced only echocardiographic systolic parameters, but did not modify cardiac function in vitro. In conclusion, the time of exposure to obesity not enhances myocardial dysfunction and reduces the ability of filling and ejection of heart. The accumulation of collagen in Ob groups does not cause damage of cardiac function in vivo and in vitro.
Hormone status does not alter noradrenergic sympathetic neurotransmitter involvement during local skin warming in young human females
Authors: Collins Ann Belton , Carter Stephen J , Del Pozzi Andrew T , Hodges Gary J
Published: June 2021

Previously, we reported that norepinephrine, and not neuropeptide Y (NPY), modulates basal vascular tone and contributes to the overall vasodilator response in young human females. Female reproductive hormones have been shown to alter vascular responses to NPY. We investigated the effects of female hormone status on sympathetic neurotransmitter contribution to cutaneous vasodilation in young females. Young females voluntarily taking oral contraceptives were tested during the high‐ and low‐hormone phases. Microdialysis fibers, local heaters, and laser‐Doppler probes were placed on the forearms and treated as follows: untreated control (CT), propranolol and yohimbine (YP) to antagonize a‐ and ß‐receptors, BIBP to antagonize Y1‐receptors, and bretylium toyslate to block the presynaptic release of sympathetic neurotransmitters. Sites were heated from 33 to 42 °C. YP treatment resulted in increased basal CVC at rest (P < 0.05) and reduction of peak CVC during warming (P < 0.05) compared to CT in both high‐ and low‐hormone groups. BIBP showed no effect on CVC (P >; 0.05) during either phase. These data suggest that hormone status does not alter noradrenergic sympathetic neurotransmitter involvement during rest conditions or local warming of the skin. Supported by The University of Alabama.
Do Humans With a Patent Foramen Ovale Have a Higher Core Body Temperature During Rest, Exercise and Post‐Exercise?
Authors: Davis James , Ng Chi‐Yan A , Hill Sierra D , Lovering Andrew T
Published: June 2021

Approximately 25–40% of the population has a patent foramen ovale (PFO). We have shown that people with a PFO (PFO+) have decreased pulmonary gas efficiency at rest due to a widened AaDO2. We have also shown that during maximal exercise, PFO+ subjects exhibited a lower SaO2 than subjects without a PFO (PFO−), which was caused by an increased esophageal temperature (Tesoph), resulting in a right shift in the oxyhemoglobin dissociation curve. It is unknown if this was coincidental or if PFO+ subjects have a higher Tesoph Therefore, the purpose of this study was to determine if PFO+ subjects have a higher Tesoph than PFO− subjects during rest, exercise and post‐exercise. Six males (3 PFO−: age ‐ 23 ± 1 yrs, height – 177.0 ± 7.4 cm, weight – 79.0 ± 5.9 kg, BSA ‐ 1.97 ± 0.11 m2; 3 PFO+: age ‐ 24 ± 4 yrs, height – 177.0 ± 2.9 cm, weight – 82.5 ± 4.7 kg, BSA 2.01 ± 0.05 m2) completed exercise bouts on two separate days. On day 1, subjects completed a VO2MAX test; during day 2 they completed an exercise bout with four 2:30 min. stages at 25, 50, 75 and 90% of the maximum workload achieved during the VO2MAX test. We measured Tesoph, rectal temperature (Trectal) and intestinal temperature (Tpill). There were no temperature differences detected between groups for any exercise protocols. These data suggest that there is no difference in Tesoph between PFO+ and PFO− subjects.