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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 361 records · Page 20
All sourcesNASA NTRSDOE OSTI
DOE OSTI2013

Boron neutron capture therapy (BNCT) for liver metastasis in an experimental model: dose–response at five-week follow-up based on retrospective dose assessment in individual rats

Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. Employing an experimental model of liver metastases in rats, we recently demonstrated that BNCT mediated by boronophenylalanine (BPA-BNCT) at 13 Gy prescribed to tumor is therapeutically useful at 3-week follow-up. The aim of the present study was to evaluate dose–response at 5-week follow-up, based on retrospective dose assessment in individual rats. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA-BNCT (n = 19), Beam only (n = 8) and Sham (n = 7) (matched manipulation, no treatment). For each rat, neutron flux was measured in situ and boron content was measured in a pre-irradiation blood sample for retrospective individual dose assessment. For statistical analysis (ANOVA), individual data for the BPA-BNCT group were pooled according to absorbed tumor dose, BPA-BNCT I: 4.5–8.9 Gy and BPA-BNCT II: 9.2–16 Gy. At 5 weeks post-irradiation, the tumor surface area post-treatment/pre-treatment ratio was 12.2 +/- 6.6 for Sham, 7.8 +/- 4.1 for Beam only, 4.4 +/- 5.6 for BPA-BNCT I and 0.45 +/- 0.20 for BPA-BNCT II; tumor nodule weight was 750 +/- 480 mg for Sham, 960 +/- 620 mg for Beam only, 380 +/- 720 mg for BPA-BNCT I and 7.3 +/- 5.9 mg for BPA-BNCT II. The BPA-BNCT II group exhibited statistically significant tumor control with no contributory liver toxicity. Potential threshold doses for tumor response and significant tumor control were established at 6.1 and 9.2 Gy, respectively.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2019

Regulation of Proliferative Processes in Rat Adrenal Cortex by Transcriptional Factor PRH under Conditions of Developmental Exposure to Endocrine Disruptor DDT

The effects of endocrine disrupters of transcriptional control of morphogenesis are poorly studied. Changes in the expression of transcriptional factor PRH and proliferation of adrenal cortical cells were analyzed in pubertal and postpubertal rats exposed prenatally and postnatally to low doses of endocrine disrupter DDT. In rats exposed to DDT, the expression of PRH and proliferation of adrenal cortical cells differed from those in control rats. Association between these parameters was weakened in the zona glomerulosa and zona reticularis and was absent in the zona fasciculata. These findings suggest that exposure to DDT in pre- and postnatal periods impairs the regulation of proliferative processes by transcriptional factor PRH in all zones of rat adrenal cortex, which can be a mechanism of the disruptive action of DDT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Combined Effects of Hypokinesia and Ambient Temperature on Heart Remodeling in Normotensive and Hypertensive Rats

We studied the effect of hypokinesia combined with cold exposure on morphological parameters of the heart in Wistar-Kyoto rats and rats with spontaneous genetically determined hypertension (SHR). The pathological processes developing in the heart of white laboratory rats significantly affected cardiac function and manifested in the deterioration of the morphological structure of the heart: reduction of heart weight, thinning of the free wall of the left ventricle. These changes indicate transition to a lower energy level of functioning. At the same time, hypertrophy of the right free wall develops in both rat lines. Combined effect of hypokinesia and cold is probably a factor indirectly promoting the development of pulmonary heart.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Enhanced Therapeutic Potency of Nanoemulsified Garlic Oil Blend Towards Renal Abnormalities in Pre-diabetic Rats

The therapeutic potency of ultrasonic nanoemulsified garlic oil blend using a non-ionic surfactant (Tween 80) was assessed on pre-diabetic Wistar rats with microalbuminuria. The pre-diabetic condition was induced in male albino Wistar rats by supplementing high-fat diet. The prolonged period of the pre-diabetic state caused renal dysfunctioning, which was indicated by microalbuminuria. Treatment of pre-diabetic rats with nanoemulsified garlic oil blend significantly ameliorated the lipid profile (p < 0.001), urinary albumin (p < 0.01), microprotein (p < 0.001), urinary triglycerides (p < 0.01), serum triglycerides (p < 0.01), serum albumin (p < 0.05), and protein levels (p < 0.01) in comparison to treatment of pre-diabetic rats with garlic oil blend or atorvastatin. Similarly, histopathological investigations indicated a remarkable attenuation in the mesangial expansion and proliferation, glomerular and tubular basement membrane thickening, and the tubular lipid deposits on administering nanoemulsified garlic oil blend than garlic oil blend or atorvastatin. Moreover, nanoemulsified garlic oil blend significantly promoted renal podocin gene expression by 3.98-fold (p < 0.001) and attenuated increased urinary podocin level by 2.92-fold (p < 0.01). Thus, our study affirms that the efficacy of garlic oil blend was augmented upon nanoemulsification, which substantially ameliorated the renal abnormalities observed in the pre-diabetic condition than garlic oil blend or atorvastatin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Rubidium-82 PET imaging is feasible in a rat myocardial infarction model

Background: Small-animal myocardial infarct models are frequently used in the assessment of new cardioprotective strategies. A validated quantification of perfusion using a non-cyclotron-dependent PET tracer would be of importance in monitoring response to therapy. We tested whether myocardial PET perfusion imaging is feasible with Rubidium-82 ({sup 82}Rb) in a small-animal scanner using a rat myocardial infarct model. Methods: 18 Sprague-Dawley rats underwent permanent coronary artery ligation (infarct group), and 11 rats underwent ischemia-reperfusion (reperfusion group) procedure. {sup 82}Rb-PET and magnetic resonance imaging (MRI) were conducted before and after the intervention. Perfusion was compared to both left ventricle ejection fraction (LVEF) and infarct size assessed by MRI. Results: Follow-up global {sup 82}Rb-uptake correlated significantly with infarct size (infarct group: r = −0.81, P < 0.001 and reperfusion group: r = −0.61, P = 0.04). Only {sup 82}Rb-uptake in the infarct group correlated with LVEF. At follow-up, a higher segmental {sup 82}Rb-uptake in the infarct group was associated with better wall motion (β = 0.034, CI [0.028;0.039], P < 0.001, R{sup 2} = 0.30), and inversely associated with scar transmurality (β = −2.4 [−2.6; −2.2], P < 0.001, R{sup 2} = 0.59). The associations were similar for the reperfusion group. Conclusion: {sup 82}Rb-PET is feasible in small animal scanners despite the long positron range and enables fast and time-efficient myocardial perfusion imaging in rat models.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Role of bone marrow cells in the development of pancreatic fibrosis in a rat model of pancreatitis induced by a choline-deficient/ethionine-supplemented diet

Highlights: Black-Right-Pointing-Pointer BMC-derived PSCs play a role in a rat CDE diet-induced pancreatitis model. Black-Right-Pointing-Pointer BMC-derived PSCs contribute mainly to the early stage of pancreatic fibrosis. Black-Right-Pointing-Pointer BMC-derived activated PSCs can produce PDGF and TGF {beta}1. -- Abstract: Bone marrow cell (BMC)-derived myofibroblast-like cells have been reported in various organs, including the pancreas. However, the contribution of these cells to pancreatic fibrosis has not been fully discussed. The present study examined the possible involvement of pancreatic stellate cells (PSCs) originating from BMCs in the development of pancreatic fibrosis in a clinically relevant rat model of acute pancreatitis induced by a choline-deficient/ethionine-supplemented (CDE) diet. BMCs from female transgenic mice ubiquitously expressing green fluorescent protein (GFP) were transplanted into lethally irradiated male rats. Once chimerism was established, acute pancreatitis was induced by a CDE diet. Chronological changes in the number of PSCs originating from the donor BMCs were examined using double immunofluorescence for GFP and markers for PSCs, such as desmin and alpha smooth muscle actin ({alpha}SMA), 1, 3 and 8 weeks after the initiation of CDE feeding. We also used immunohistochemical staining to evaluate whether the PSCs from the BMCs produce growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF) {beta}1. The percentage of BMC-derived activated PSCs increased significantly, peaking after 1 week of CDE treatment (accounting for 23.3 {+-} 0.9% of the total population of activated PSCs) and then decreasing. These cells produced both PDGF and TGF{beta}1 during the early stage of pancreatic fibrosis. Our results suggest that PSCs originating from BMCs contribute mainly to the early stage of pancreatic injury, at least in part, by producing growth factors in a rat CDE diet-induced pancreatitis model.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

L-Arginine ameliorates cardiac left ventricular oxidative stress by upregulating eNOS and Nrf2 target genes in alloxan-induced hyperglycemic rats

Highlights: Black-Right-Pointing-Pointer L-Arginine treatment reduced the metabolic disturbances in diabetic animals. Black-Right-Pointing-Pointer Antioxidant marker proteins were found high in myocardium by L-arginine treatment. Black-Right-Pointing-Pointer Elevated antioxidant status, mediates the reduced TBA-reactivity in left ventricle. Black-Right-Pointing-Pointer L-Arginine treatment enhanced the Nrf2 and eNOS signaling in left ventricle. Black-Right-Pointing-Pointer Improved cell survival signaling by arginine, offers a novel tactic for targeting. -- Abstract: Hyperglycemia is independently related with excessive morbidity and mortality in cardiovascular disorders. L-Arginine-nitric oxide (NO) pathway and the involvement of NO in modulating nuclear factor-E2-related factor-2 (Nrf2) signaling were well established. In the present study we investigated, whether L-arginine supplementation would improve the myocardial antioxidant defense under hyperglycemia through activation of Nrf2 signaling. Diabetes was induced by alloxan monohydrate (90 mg kg{sup -1} body weight) in rats. Both non-diabetic and diabetic group of rats were divided into three subgroups and they were administered either with L-arginine (2.25%) or L-NAME (0.01%) in drinking water for 12 days. Results showed that L-arginine treatment reduced the metabolic disturbances in diabetic rats. Antioxidant enzymes and glutathione levels were found to be increased in heart left ventricles, thereby reduction of lipid peroxidation by L-arginine treatment. Heart histopathological analysis further validates the reversal of typical diabetic characteristics consisting of alterations in myofibers and myofibrillary degeneration. qRT-PCR studies revealed that L-arginine treatment upregulated the transcription of Akt and downregulated NF-{kappa}B. Notably, transcription of eNOS and Nrf2 target genes was also upregulated, which were accompanied by enhanced expression of Nrf2 in left ventricular tissue from diabetic and control rats. Under these findings, we suggest that targeting of eNOS and Nrf2 signaling by L-arginine supplementation could be used as a potential treatment method to alleviate the late diabetic complications.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

Highlights: Black-Right-Pointing-Pointer We investigated mechanisms of mitochondrial regulation in rat hepatocytes. Black-Right-Pointing-Pointer Tetradecylthioacetic acid (TTA) was employed to activate mitochondrial oxidation. Black-Right-Pointing-Pointer Mitochondrial biogenesis and respiration were induced. Black-Right-Pointing-Pointer It was confirmed that PPAR target genes were induced. Black-Right-Pointing-Pointer The mechanism involved activation mTOR. -- Abstract: The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPAR{alpha}-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Characterization of rat serum amyloid A4 (SAA4): A novel member of the SAA superfamily

Highlights: • The full length rat SAA4 (rSAA4) mRNA was characterized by rapid amplification of cDNA ends. • rSAA4 mRNA has 1830 bases including a GA dinucleotide tandem repeat in the 5′UTR. • Three consecutive C/EBP promoter elements are crucial for transcription of rSAA4. • rSAA4 is abundantly expressed in the liver on mRNA and protein level. - Abstract: The serum amyloid A (SAA) family of proteins is encoded by multiple genes, which display allelic variation and a high degree of homology in mammals. The SAA1/2 genes code for non-glycosylated acute-phase SAA1/2 proteins, that may increase up to 1000-fold during inflammation. The SAA4 gene, well characterized in humans (hSAA4) and mice (mSaa4) codes for a SAA4 protein that is glycosylated only in humans. We here report on a previously uncharacterized SAA4 gene (rSAA4) and its product in Rattus norvegicus, the only mammalian species known not to express acute-phase SAA. The exon/intron organization of rSAA4 is similar to that reported for hSAA4 and mSaa4. By performing 5′- and 3′RACE, we identified a 1830-bases containing rSAA4 mRNA (including a GA-dinucleotide tandem repeat). Highest rSAA4 mRNA expression was detected in rat liver. In McA-RH7777 rat hepatoma cells, rSAA4 transcription was significantly upregulated in response to LPS and IL-6 while IL-1α/β and TNFα were without effect. Luciferase assays with promoter-truncation constructs identified three proximal C/EBP-elements that mediate expression of rSAA4 in McA-RH7777 cells. In line with sequence prediction a 14-kDa non-glycosylated SAA4 protein is abundantly expressed in rat liver. Fluorescence microscopy revealed predominant localization of rSAA4-GFP-tagged fusion protein in the ER.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

High fat diet promotes achievement of peak bone mass in young rats

Highlights: • High fat diet helps in achieving peak bone mass at younger age. • Shifting from high fat to normal diet normalizes obese parameters. • Bone parameters are sustained even after withdrawal of high fat diet. - Abstract: The relationship between obesity and bone is complex. Epidemiological studies demonstrate positive as well as negative correlation between obesity and bone health. In the present study, we investigated the impact of high fat diet-induced obesity on peak bone mass. After 9 months of feeding young rats with high fat diet, we observed obesity phenotype in rats with increased body weight, fat mass, serum triglycerides and cholesterol. There were significant increases in serum total alkaline phosphatase, bone mineral density and bone mineral content. By micro-computed tomography (μ-CT), we observed a trend of better trabecular bones with respect to their microarchitecture and geometry. This indicated that high fat diet helps in achieving peak bone mass and microstructure at younger age. We subsequently shifted rats from high fat diet to normal diet for 6 months and evaluated bone/obesity parameters. It was observed that after shifting rats from high fat diet to normal diet, fat mass, serum triglycerides and cholesterol were significantly decreased. Interestingly, the gain in bone mineral density, bone mineral content and trabecular bone parameters by HFD was retained even after body weight and obesity were normalized. These results suggest that fat rich diet during growth could accelerate achievement of peak bone mass that is sustainable even after withdrawal of high fat diet.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats

Objective: Obesity-induced vascular dysfunction is related to chronic low-grade systemic inflammation. Recent studies indicate that NLRP3, a multiprotein complex formed by NOD-like receptor (NLR) family members, is a key component mediating internal sterile inflammation, but the role in obesity-related vascular dysfunction is largely unknown. In the present study, we investigate whether NLRP3 activation is involved in vascular inflammation in obese Otsuka Long-Evans Tokushima Fatty rats (OLETF). Methods and results: Male OLETF with their control Long-Evans Tokushima Otsuka rats (LETO) were studied at 3 and 12 months of age. Aortic relaxation in response to acetylcholine decreased gradually with age in both strains, with early and persistent endothelium dysfunction in obese OLETF compared with age-matched LETO controls. These changes are associated with parallel changes of aortic endothelial nitric oxide synthase (eNOS) content, macrophage accumulation and intimal thickening. NLRP3 increased in OLETF rats compared to LETO. Consistent with inflammasome activation, the conversion of procaspase-1 to cleaved and activated forms as well as IL-1β markedly increased in OLETF rats. Additionally, we observed increased expression of dynamin-related protein-1 (Drp1) and decreased fusion-relative protein optic atropy-1(OPA1). Altered mitochondrial dynamics was associated with elevated oxidative stress level in OLETF aortas. Conclusions: These results demonstrate that obesity seems to accelerate endothelial dysfunction in OLETFs via the activation of NLRP3 and mitochondrial dysfunction. - Highlights: • NLRP3 is involved in obesity-induced vascular dysfunction. • Impaired mitochondrial dynamics may have been linked to mitochondrial defect and inflammasome activation. • Obesity seems to accelerate vascular dysfunction via NLRP3 activation and mitochondrial dysfunction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Treatment of Parkinson's disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles

Parkinson's disease (PD) is a very common neurological disorder. However, effective therapy is lacking. Although the blood-brain-barrier (BBB) protects the brain, it prevents the delivery of about 90% of drugs and nucleotides into the brain, thereby hindering the development of gene therapy for PD. Magnetic resonance imaging (MRI)-guided focused ultrasound delivery of microbubbles enhances the delivery of gene therapy vectors across the BBB and improves transfection efficiency. In the present study, we delivered nuclear factor E2-related factor 2 (Nrf2, NFE2L2) contained in nanomicrobubbles into the substantia nigra of PD rats by MRI-guided focused ultrasound, and we examined the effect of Nrf2 over-expression in this animal model of PD. The rat model of PD was established by injecting 6-OHDA in the right substantia nigra stereotactically. Plasmids (pDC315 or pDC315/Nrf2) were loaded onto nanomicrobubbles, and then injected through the tail vein with the assistance of MRI-guided focused ultrasound. MRI-guided focused ultrasound delivery of nanomicrobubbles increased gene transfection efficiency. Furthermore, Nrf2 gene transfection reduced reactive oxygen species levels, thereby protecting neurons in the target region. - Highlights: • MRI-guided focused ultrasound enhances gene transfection into the brain of rats. • Increased Nrf2 expression protects neurons in the rat model of PD. • Nrf2 protects neurons in PD by inhibiting ROS production.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effect of dexmedetomidine on rats with convulsive status epilepticus and association with activation of cholinergic anti-inflammatory pathway

Convulsive status epilepticus (CSE) is a neurological disease with contraction and extension of limbs, leading to damage of hippocampus and cognition. This study aimed to explore the effects of dexmedetomidine (DEX) on the cognitive function and neuroinflammation in CSE rats. All rats were divided into control group, CSE group and DEX group. Morris water maze test was used to measure cognitive function. Acute hippocampal slices were made to detect long-term potentiation (LTP). Immunohistochemistry was used to determine the expression of α7-nicotinic acetylcholine receptor (α7-nAChR) and interleukin-1β (IL-1β). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of IL-1β, tumor necrosis factor-α (TNF-α), S-100β and brain-derived neurotrophic factor (BDNF). Our results showed that DEX improved the memory damage caused by CSE. DEX reduced seizure severity and increased the amplitudes and sustainable time of LTP, and also inhibited the hippocampal expression of α7-nAChR and IL-1β in CSE rats. DEX treatment decreased serum IL-1β, TNF-α and S-100β levels and increased BDNF levels. The effects of DEX on seizure severity and LTP could be simulated by nicotine or attenuated by concurrent α-bungarotoxin (α-BGT) treatment. In conclusions, DEX significantly improved spatial cognitive dysfunction, reduced seizure severity and increased LTP in CSE rats. Improvements by DEX were closely related to enhancement of cholinergic anti-inflammatory pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Secretion of GLP-1 but not GIP is potently stimulated by luminal d-Allulose (d-Psicose) in rats

Highlights: • Oral gavage of allulose potently and sustainably induced GLP-1 secretion in rats. • Allulose stimulated GLP-1 but not affect GIP secretion, in contrast to glucose. • Allulose exerts GLP-1-releasing effect in the intestinal lumen. Glucagon-like peptide 1 (GLP-1), an incretin gastrointestinal hormone, is secreted when stimulated by nutrients including metabolizable sugars such as glucose and fructose. d-Allulose (allulose), also known as d-psicose, is a C-3 isomer of d-fructose and a rare sugar with anti-diabetic or anti-obese effects in animal models. In the present study, we examined whether an oral administration of allulose could stimulate GLP-1 secretion in rats, and investigated the underlying mechanisms. Oral, but not intraperitoneal, administration of allulose (0.5–2.0 g/kg body weight) elevated plasma GLP-1 levels for more than 2 h in a dose-dependent manner. The effects of allulose on GLP-1 secretion were higher than that of dextrin, fructose, or glucose. In addition, oral allulose increased total and active GLP-1, but not glucose-dependent insulinotropic polypeptide (GIP), levels in the portal vein. In anesthetized rats equipped with a portal catheter, luminal (duodenum and ileum) administration of allulose increased portal GLP-1 levels, indicating the luminal effect of allulose. Allulose-induced GLP-1 secretion was abolished in the presence of xanthohumol (a glucose/fructose transport inhibitor), but not in the presence of inhibitors of the sodium-dependent glucose cotransporter 1 or the sweet taste receptor. These results demonstrate a potent and lasting effect of orally administered allulose on GLP-1 secretion in rats, without affecting GIP secretion. The potent and selective GLP-1-releasing effect of allulose holds promise for the prevention and treatment of glucose intolerance through promoting endogenous GLP-1 secretion.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hypothalamic AMPK-induced autophagy ameliorates hypercatabolism in septic rats by regulating POMC expression

Highlights: • Sepsis decreases hypothalamic AMPK-autophagy and increases POMC. • Hypercatabolism is associated with hypothalamic autophagy and POMC. • Central activation of AMPK-autophagy ameliorates elevated POMC during sepsis. • Central activation of AMPK-autophagy ameliorates hypercatabolism during sepsis. Hypercatabolism plays a critical role in the pathogenesis of post-critical care debility in critical patients. Central nervous system may exerte a critical role in the regulation of hypercatabolism. However, little is known about the exact mechanisms of the central role. Here, we reported that actived hypothalamic AMP-activated protein kinase (AMPK)-induced autophagy modulated the expression of POMC to ameliorate hypercatabolism in septic rats. Firstly, rats were i.c.v. injected with the lentiviral vector containing shRNA against POMC. Two weeks after injections, rats were intraperitoneally injected with LPS or saline. Twenty-four hours later, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism markers and neuropeptides expression were detected. Then, rats were injected with AICAR or saline into third ventricle and promptly intraperitoneally injected with LPS or saline. Twenty-four hours after infection, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism, hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that sepsis would decrease the level of hypothalamic autophagy accompany with the alterations of POMC expression and hypercatabolism. Knocking out hypothalamus POMC expression could significantly ameliorate hypercatabolism. Moreover, Central activation of AMPK-induced autophagy pathway via third ventricle injection of AICAR, an AMPK activator, could efficiently ameliorate hypercatabolism as well as attenuate the elevated POMC expression rather than other neuropeptides. Taken together, these results suggested that hypothalamic AMPK-autophagy pathway as a regulatory pathway for POMC expression was essential for hypercatabolism during sepsis. And hypothalamic AMPK-autophagy activation could attenuate the POMC expression to ameliorate hypercatabolism. Pharmaceuticals with the ability of activating hypothalamic AMPK-autophagy pathway may be a therapeutic potential for hypercatabolism in septic patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Canstatin modulates L-type calcium channel activity in rat ventricular cardiomyocytes

Excessive increase of cytosolic Ca{sup 2+} through the activation of L-type Ca{sup 2+} channels (LTCCs) via β adrenergic receptor induces apoptosis of cardiomyocytes. Canstatin, a cleaved fragment of collagen type IV α2 chain, is abundantly expressed in normal heart tissue. We previously reported that canstatin inhibits β adrenergic receptor-stimulated apoptosis in cardiomyoblasts. Here, we tested the hypothesis that canstatin regulates LTCCs activity in ventricular cardiomyocytes. Collagen type IV α2 chain (COL4A2) small interfering (si) RNA (for canstatin suppression) or control siRNA was injected via jugular vein in Wistar rats. Two days after the injection, electrocardiogram (ECG) was recorded and the left ventricular tissue was isolated using Langendorff apparatus. Immunofluorescence staining was performed to clarify the distribution of canstatin in cardiomyocytes. The knockdown efficiency was confirmed by Western blotting. The L-type Ca{sup 2+} channel current (I{sub CaL}) of ventricular cardiomyocyte was measured by a whole-cell patch clamp technique. In immunofluorescence staining, colocalization of canstatin and α{sub v} integrin was observed in the isolated ventricular cardiomyocytes. The I{sub CaL} of ventricular cardiomyocyte isolated from COL4A2 siRNA-injected rats was significantly enhanced compared with control siRNA-injected rats. Recombinant canstatin (250 ng/ml) significantly reversed it. ECG analysis showed that QT interval tended to be shortened and amplitude of T wave was significantly increased in the COL4A2 siRNA-injected rats. In summary, we for the first time clarified that suppressing canstatin expression increases the basal I{sub CaL} in ventricular cardiomyocytes. It is proposed that canstatin might play a role in the stabilization of cardiac function through the modulation of LTCC activity in cardiomyocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

GAPDH-targeted therapy – A new approach for secondary damage after traumatic brain injury on rats

Highlights: • Exogenous GAPDH interact with SH-SY5Y cells and penetrate them. • Exogenous GAPDH induce death of SH-SY5Y cells. • Hydrocortysone-21-hemisuccinate reduced cytotoxic effect of exogenous GAPDH. • Hydrocortisone derivative rescue motor function of rats after traumatic brain injure. Massive neuronal death caused by a neurodegenerative pathology or damage due to ischaemia or traumatic brain injury leads to the appearance of cytosolic proteins in the extracellular space. We found that one of the most abundant cellular polypeptides, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), appearing in the medium of dying cells or body fluids is able to form aggregates that are cytotoxic to adjacent cells. Since we previously showed that the hydrocortisone derivative RX624 can inhibit the ability of GAPDH to transport the enzyme complex with polyglutamine and reduce the cytotoxicity of the complex, we explored the effects of GAPDH on SH-SY5Y neuroblastoma cells. We found that the latter treated with particular forms of GAPDH molecules die with a high efficiency, suggesting that the exogenous enzyme does kill adjacent cells. RX624 prevented the interaction of exogenous GAPDH with the cell membrane and reduced the level of death by more than 10%. We also demonstrated the efficiency of RX624 treatment in a rat model of traumatic brain injury. The chemical blocked the formation of GAPDH aggregates in the brain, inhibited the cytotoxic effects of cerebrospinal fluid and rescued the motor function of injured rats. Importantly, RX624 treatment of rats had a similar effect as the intracranial injection of anti-GAPDH antibodies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Plasma exosomes regulate systemic blood pressure in rats

Highlights: • Roles of exosomes on regulation of essential hypertension remain to be determined. • Plasma exosomes modulated systemic blood pressure in normotensive and hypertensive rats. • Plasma exosomes modestly changed structure and function of cardiovascular tissues. • Present findings indicate exosomes are potential target for treatment of essential hypertension. Exosomes, the smallest extracellular vesicle, contain various molecules and mediate cell-cell communication. A number of studies demonstrate exosomes are involved in important physiological and pathological processes. Moreover, microRNA (miRNA) regulating hypertension development through the suppression of certain translation was recently reported. However, roles of exosomes containing various molecules including miRNA on development of essential hypertension have not been examined. We tested the hypothesis that plasma exosomes regulate systemic blood pressure in normotensive and spontaneously hypertensive rats (SHR). Normotensive Wistar Kyoto rats (WKY) and SHR (5-10-week-old) were intraperitoneally administrated with exosomes derived from plasma in WKY or SHR weekly for 6 weeks. Exosomes were isolated by an ultracentrifuge method. SHR-derived exosomes significantly increased systolic blood pressure in WKY, while WKY-derived exosomes decreased it in SHR. In WKY, SHR-derived exosomes induced modest structural changes of thoracic aorta, such as wall thickening and decreased abundance of collagen, which were similar to the changes observed in SHR. On the contrary, WKY-derived exosomes tended to reverse the changes in SHR. WKY-derived exosomes significantly suppressed the increased prostaglandin F{sub 2α}-induced contraction of mesenteric arterial smooth muscle in SHR. In addition, wet weight and perivascular fibrosis of left ventricles in WKY were significantly increased by SHR-derived exosomes, while the fibrosis but not ventricular weight was significantly decreased by WKY-derived exosomes in SHR. We for the first time demonstrated that plasma exosomes can modulate systemic blood pressure as well as structure and function of cardiovascular tissues in both normotensive and hypertensive rats.

60 APPLIED LIFE SCIENCES↗