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At least 1,099 records · Page 61
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Evaluation of dermal wound healing activity of synthetic peptide SVVYGLR

SVVYGLR peptide (SV peptide) is a 7-amino-acid sequence with angiogenic properties that is derived from osteopontin in the extracellular matrix and promotes differentiation of fibroblasts to myofibroblast-like cells and the production of collagen type Ⅲ by cardiac fibroblasts. However, the effects of SV peptide on dermal cells and tissue are unknown. In this study, we evaluated the effects of this peptide in a rat model of dermal wound healing. The synthetic SV peptide was added to dermal fibroblasts or keratinocytes, and their cellular motility was evaluated. In an in vivo wound healing exeriment, male rats aged 8 weeks were randomly assigned to the SV peptide treatment, non-treated control, or phosphate-buffered saline (PBS) groups. Wound healing was assessed by its repair rate and histological features. Scratch assay and cell migration assays using the Chemotaxicell method showed that SV peptide significantly promoted the cell migration in both fibroblasts and keratinocytes. In contrast the proliferation potency of these cells was not affected by SV peptide. In the rat model, wound healing progressed faster in the SV peptide-treated group than in the control and PBS groups. The histopathological analyses showed that the SV peptide treatment stimulated the migration of fibroblasts to the wound area and increased the number of myofibroblasts. Immunohistochemical staining showed a marked increase of von Willebland factor-positive neomicrovessels in the SV peptide-treated group. In conclusion, SV peptide has a beneficial function to promote wound healing by stimulating granulation via stimulating angiogenesis, cell migration, and the myofibroblastic differentiation of fibroblasts. - Highlights: • The SVVYGLR peptide promoted dermal wound healing. • The SVVYGLR peptide stimulated dermal cell migration and differentiation. • The SVVYGLR peptide could be a potential therapeutic agent for treating dermal injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Androgen-responsive circular RNA circSMARCA5 is up-regulated and promotes cell proliferation in prostate cancer

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in males worldwide. Circular RNA (circRNA) is a unique class of RNA transcribed by RNA polymerase II characterized by jointing 3′ and 5′ ends together via exon or intron circularization. However, the molecular functions of circRNAs in prostate cancer have rarely been explored. In present study, we found circ-SMARCA5 was up-regulated in prostate cancer samples compared to match normal tissues. We also observed circ-SMARCA5 expression was significantly induced after DHT treatment. Functional experiments showed circ-SMARCA5 acted as an oncogene in prostate cancer by promoting cell cycle and inhibiting cell apoptosis. We thought this study provided useful information for exploring circRNAs as potential therapeutic and prognostic targets for prostate cancer. - Highlights: • To our knowledge, this is the first study to explore the molecular functions of circRNA in prostate cancer. • Our study showed that circ-SMARCA5 promoted cell proliferation and inhibited cell apoptosis in prostate cancer. • circ-SMARCA5 was for the first time reported as an androgen-responsive circRNA. • circ-SMARCA5 was for the first time reported to be up-regulated in prostate cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Effect of sodium fluoride on the sperm mitochondrial DNA in mice

Previous studies demonstrated that fluoride, as a widespread environmental pollutant, induced the reproductive toxicity at high dose. Besides the decrease of sperm characteristics like concentration, survival, and sperm motility, it was found that high fluoride induced the destructive mitochondrial ultrastructure and decreased ATP production from mitochondrial respiration. However, whether fluoride exposure can damage the mitochondrial DNA (mtDNA) of sperm is still unknown. In this study, 100 male mice were randomly divided into four groups 25 each, which were administrated with the distilled water containing 0, 25, 50 and 100 mg L{sup −1} NaF, respectively for 60 days. After exposure, sperm mtDNA copy number was measured by real-time PCR, mtDNA integrity by acridine orange (AO) staining, and nuclear DNA (nDNA) integrity through long PCR amplification, as well as MTCYB and MTATP6 mutations by PCR and direct sequencing. The results showed that 100 mg L{sup −1} NaF significantly increased sperm mtDNA copy number, and reduced nDNA integrity. There were no changes observed in mtDNA integrity, and mutations of MTCYB and MTATP6 between fluoride groups and the control group. These results indicated that along with low sperm quality, sperm mtDNA copy number is also a sensitive biomarker to reflect the sperm toxicity of fluoride. - Highlights: • NaF significantly increased sperm mtDNA copy number, and reduced nDNA integrity. • NaF did not change sperm mtDNA integrity, and mutations of MTCYB and MTATP6. • Sperm mtDNA copy number can be a potential biomarker of fluoride-induced toxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effect of eldecalcitol on articular cartilage through the regulation of transcription factor Erg in a murine model of knee osteoarthritis

Highlights: • Eldecalcitol slowed the progression of experimental osteoarthritis in mice. • This effect was observed at 4 weeks, but not at 12 weeks. • Effects were associated with increased Erg levels. • Eldecalcitol-treated cultured chondrocytes also upregulated Erg mRNA. Clinical studies have reported an association between low blood levels of 25-hydroxyvitamin D and the progression of osteoarthritis (OA), but the mechanism and effects of vitamin D signaling on articular chondrocytes and cartilage remains unclear. The purpose of this study was to investigate the effects of vitamin D on articular cartilage degeneration using eldecalcitol (ED-71), which is an active vitamin D{sub 3} analog. Eight-week old male C57BL/6NCrSlc mice were subjected to experimental surgery to induce OA and local treatments with 10 μL ED-71 (0.5 μg/mL) were administered weekly. Four and 12 weeks after surgery, joints were evaluated using histological scoring systems. In addition, gene expression was analyzed in chondrocytes that were isolated from wildtype neonatal mice, cultured, and treated with ED-71 (10{sup −8} M). Joints treated with ED-71 demonstrated slowed progression of OA at 4 weeks after surgery, but few effects were observed at 12 weeks after surgery. Ets-related gene (Erg) expression was upregulated in OA articular cartilage, and further increased by ED-71 treatment. In primary chondrocytes cultured with ED-71, the gene expression of Erg and lubricin/proteoglycan 4 significantly increased, as compared to that of cells cultured without ED-71. Local treatment with ED-71 reduced degenerative changes to the articular cartilage during the early phase of experimental OA. Regulation of Erg by ED-71 in articular cartilage could confer resistance to early osteoarthritic changes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A deficiency of the GluN2C subunit of the N-methyl-D-aspartate receptor is neuroprotective in a mouse model of ischemic stroke

Highlights: • GluN2C{sup -/-} mice have less edema, neurological deficit, and weight loss after stroke. • GluN2C{sup -/-} mice display increased neuronal integrity and decreased tauopathy. • GluN2C{sup -/-} mice display less Fyn and phosphorylation of extrasynaptic GluN2B(Y1336). • GluN2C{sup -/-} mice display increased localization of P-CREB(S133) in the nucleus. The N-methyl-D-aspartate receptor (NMDAR) ion channel plays a pivotal role in the pathology of ischemic stroke. The functional receptor consists of two GluN1 subunits (a-h) and two GluN2 subunits (A/B/C/D), the expression of which are spatially and temporally regulated in pathological and physiological conditions. While the roles of the GluN2A and GluN2B subunit in ischemic stroke have been well developed, the role of the GluN2C subunit in ischemia is not well understood. Following middle carotid artery occlusion (MCAO), GluN2C{sup -/-} male mice displayed similar volumes of infarct as wild-type (WT) mice. However, GluN2C{sup -/-} mice showed decreased cerebral edema and an enhanced rate of neurological recovery compared to WT mice. The ischemic penumbra of GluN2C{sup -/-} mice showed fewer cytoarchitectural deficits and decreased tauopathy relative to WT mice. These neuroprotective changes in GluN2C{sup -/-} mice also corresponded with decreased expression of Fyn kinase and decreased phosphorylation of GluN2B subunit at Tyr1336. Lastly, a GluN2C deficiency modified the NMDAR/pro-survival signaling axis, as shown by increased levels of nuclear CREB(P-Ser133). Thus, the GluN2C subunit enhances ischemic stroke pathology by promoting neuronal dysfunction in the penumbra region.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The Pleckstrin homology like domain family member, TDAG51, is temporally regulated during skeletal muscle regeneration

Highlights: • TDAG51 expression is low but detectable in undamaged skeletal muscle. • Muscle expression of TDAG51 increases significantly in response to damage and insulin-like growth factor 1 (IGF-1). • Mice lacking TDAG51 display reduced functional capacity and a delay in the early regenerative phases of muscle repair. • Despite early delays in regeneration, TDAG51null mice can compensate and normalize muscle repair by 10 days post injury. The capacity for skeletal muscle to repair from daily insults as well as larger injuries is a vital component to maintaining muscle health over our lifetime. Given the importance of skeletal muscle for our physical and metabolic well-being, identifying novel factors mediating the growth and repair of skeletal muscle will thus build our foundational knowledge and help lead to potential therapeutic avenues for muscle wasting disorders. To that end, we investigated the expression of T-cell death associated gene 51 (TDAG51) during skeletal muscle repair and studied the response of TDAG51 deficient (TDAG51{sup -/-}) mice to chemically-induced muscle damage. TDAG51 mRNA and protein expression within uninjured skeletal muscle is almost undetectable but, in response to chemically-induced muscle damage, protein levels increase by 5 days post-injury and remain elevated for up to 10 days of regeneration. To determine the impact of TDAG51 deletion on skeletal muscle form and function, we compared adult male TDAG51{sup -/-} mice with age-matched wild-type (WT) mice. Body and muscle mass were not different between the two groups, however, in situ muscle testing demonstrated a significant reduction in force production both before and after fatiguing contractions in TDAG51{sup -/-} mice. During the early phases of the regenerative process (5 days post-injury), TDAG51{sup -/-} muscles display a significantly larger area of degenerating muscle tissue concomitant with significantly less regenerating area compared to WT (as demonstrated by embryonic myosin heavy chain expression). Despite these early deficits in regeneration, TDAG51{sup -/-} muscles displayed no morphological deficits by 10 days post injury compared to WT mice. Taken together, the data presented herein demonstrate TDAG51 expression to be upregulated in damaged skeletal muscle and its absence attenuates the early phases of muscle regeneration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer's disease model

Highlights: • The interactions between RAGE and Aβ cause inflammatory responses and oxidative stress, and reduce cerebral blood flow. • RAGE and its ligand interactions induce a cascade related to neuronal apoptosis and inflammation. • The soluble form of RAGE (sRAGE) might suppress downregulation of the RAGE-mediated inflammatory/cell death pathway. • sRAGE-MSCs enhanced survival more effectively than MSCs in an Aβ{sub 1-42} induced rat model of AD. The main causes of Alzheimer's disease (AD) have not determined and effective treatment has not been developed yet, even though extensive researches and several clinical trials have been conducted.. Fortunately, stem cell transplantation is emerging as a potential therapeutic candidate for AD, but the success of stem cell based therapy depends on the survival of transplanted cells. Here, we generated sRAGE secreting mesenchymal stem cells (sRAGE-MSCs) and then injected these MSCs or control MSCs with amyloid beta 1–42 (Aβ{sub 1-42}) into the entorhinal cortices of male Sprague Dawley rats. The survival of transplanted cell, the number of T lymphocytes and microglia, expression of RAGE and its ligands and neuronal cell death were determined, 4 weeks after sRAGE-MSC transplantation. Transplanted sRAGE-MSCs survived longer than control MSCs and sRAGE-MSCs showed reduced level of CD4 and CD3d positive T lymphocyte. Furthermore, the number of M1 microglia in MSCs was more than that of sRAGE-MSCs as well. On the other hand, the number of M2 microglia in sRAGE-MSCs was increased compared with that of MSCs. In addition, sRAGE-MSCs decreased RAGE and RAGE ligand expressions and their interactions more effectively than those of MSCs. Finally, sRAGE-MSC transplantation protected from apoptosis and prevented decreasing numbers of neuron in Aβ{sub 1-42} treated rat brains. These observations suggest continuous sRAGE secretion from sRAGE-MSCs might appreciably improve the effectiveness of cell therapy in Aβ{sub 1-42} injected rat brains.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LOX-related collagen crosslink changes act as an initiator of bone fragility in a ZDF rats model

Highlights: • Bone mechanical loss in type 2 diabetes is mainly restricted to the post-yield behavior. • Loss of insoluble collagen in the matrix phase is the initial cause of bone mechanical loss in type 2 diabetes. • The insoluble collagen amount in bone tissue is the positive regressor of bone post-yield behavior. • The expression of Lox and lox-like family are downregulated in bone tissue in type 2 diabetes. Diabetes mellitus type 2 (DM2) results in bone abnormalities that manifest as increased bone fragility. Bone consists of two phases, the mineral phase and the matrix phase, and disorders in both are seen in DM2. However, the phase in which DM2 mediated bone fragility is initiated is still unknown. In this study, a male Zucker diabetic fatty (fa/fa) (ZDF) rat model was used to investigate the underlying mechanism initiating DM2 mediated bone fragility. The fracture surface morphology, pre- and post-yield bone mechanical behavior, insoluble collagen volume, lysyl oxidase family (LOX) enzyme levels and correlation analysis was performed to determine the relationship between insoluble collagen and post-yield behavior. Four weeks after the induction of diabetes, insoluble collagen was decreased in only the matrix phase in diabetic rats. Consistently, mechanical testing of the bone showed changes only in post-yield behavior. Diabetic rats also had decreased levels of enzymes involved in insoluble collagen formation (LOX and LOXL1 families). Correlation analysis demonstrated that insoluble collagen was a positive regressor of post-yield displacement (R = 0.894, P P < 0.001). Together, these findings suggest that bone fragility in DM2 is initiated in the matrix phase and that the LOX family may play a critical part in the pathogenesis of DM2 mediated bone fragility.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The down-regulation of cardiac contractile proteins underlies myocardial depression during sepsis and is mitigated by carbon monoxide

Highlights: • Cardiac dysfunction was associated with LPS-administered rat hearts. • Levels of myosin and actin were decreased in the hearts. • CORM mitigated these decreases as well as myocardial depression. The aim of this study is to investigate the mechanism underling cardiac dysfunction during sepsis, as well as the possible amelioration of this dysfunction by exogenous carbon monoxide (CO) administration. For this purpose, rats (six-week-old, male, Sprague-Dawley) were administered LPS (15 mg/kg body weight, i.p. 6 h) and/or CORM (30 mg/kg, i.p.). The decreased left ventricular ejection fraction (EF) observed in LPS group rats was recovered in the LSP + CORM group, confirming the protective role of CO against sepsis-induced myocardial depression. Proteomic as well as immunoblot analysis showed that the levels of myosin heavy and light chains (MHC and MLC) as well as α-cardiac actin (ACTC) were decreased in the LPS group, and these decreases were mitigated in the LSP + CORM group, suggesting that the amounts of major contractile proteins are decreased in depressed myocardium. Not only LPS-induced inflammatory cytokine (TNFα and IL-1β) production but also the decrease in myofilament proteins was mitigated by CORM. These results confirm the protective action of exogenously administered CO against myocardial depression during sepsis, and reveal a novel mechanism underling cardiac dysfunction during sepsis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Establishment and characterization of five immortalized human scalp dermal papilla cell lines

Highlights: • Five immortalized human dermal papilla cell lines are established and characterized. • Cell lines are named KNU-101, KNU-102, KNU-103, KNU-201 and KNU-202. • These cell lines maintain in vivo characteristics of dermal papilla cells. Dermal papilla (DP) regulates the growth and cycling of hair follicles. Cultured DP cells are useful for the study of their role in relation to hair growth and regeneration. However, cultivation of human DP cells is tedious and difficult. In addition, cultured DP cells possess a relatively short replicative life span, requiring immortalized human DP cell lines. We previously established an immortalized human DP cell line, SV40T-hTERT-DPC, by introducing human telomerase reverse transcriptase (hTERT) gene into the transformed cell line, SV40T-DPC. In this study, we co-transfected the simian virus 40 large T antigen (SV40T-Ag) and hTERT into DP cells from scalp hair follicles from a male with androgenetic alopecia and established five immortalized DP cell lines and named KNU-101, KNU-102, KNU-103, KNU-201 and KNU-202. We then evaluated tumorigenicity, expression of DP markers, responses to androgen, Wnt3a and BMP4, and expression of DP signature genes. These cell lines displayed early passage morphology and maintained responses to androgen, Wnt and BMP. Furthermore, these cell lines expressed DP markers and DP signature genes. KNU cell lines established in this study are potentially useful sources for hair research.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Prolyl isomerase Pin1 is required sperm production by promoting mitosis progression of spermatogonial stem cells

Highlights: • Pin1{sup −/−} mice had severe testicular atrophy. • Pin1{sup −/−} mice had less undifferentiated spermatogonia. • Pin1{sup −/−} and WT mice had similar cell counts of spermatogonial stem cells. • Pin1 promotes mitosis progression of spermatogonial stem cells. • Pin1 promotes differentiation of spermatogonial stem cell. A prolyl isomerase Pin1 deficient (Pin1{sup −/−}) male mice had severe testicular atrophy. We investigated the function of Pin1 in spermatogenesis by analyzing the Pin1{sup −/−} mice at reproductive age. Pin1{sup −/−} mice had lessαPLZF positive spermatogonia (undifferentiated spermatogonia) than wild type (WT). Nevertheless, the Pin1{sup −/−} testis contained approximately the same number of GFRα1 positive spermatogonia (SSCs in steady state) as the WT testis. Furthermore, degeneration of the spermatogenia appeared in seminiferous tubules of 10 months old Pin1{sup −/−} mouse testis, and abnormal shape GFRα1 positive spermatogonia were observed. In Pin1{sup −/−} spermatogonia, the ratio of the phospho-histone H3 positive cells (mitotic cells) in GFRα1-positive spermatogonia was higher than that of WT. These results suggest that Pin1 promotes the progression of the mitotic cell cycle of SSC in steady-state, which is required for the sperm production from SSCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CsTFL1b may regulate the flowering time and inflorescence architecture in cucumber (Cucumis sativus L.)

Highlights: • Phylogenetic analysis suggested that CsTFL1b was far from the AtTFL1 in Arabidopsis. • CsTFL1b exhibits different expression pattern from TFL1 of Arabidopsis. • CsTFL1b has conserved function in regulating flowering time. • CsTFL1b can partially rescue the terminal flower structure of tfl1-11 mutant. Cucumber is an important vegetable with indeterminate growth habit which is beneficial to its yield. In this study, we cloned the TFL1 homolog CsTFL1b in cucumber. CsTFL1b shares highly sequence similarity to TFL1 from Arabidopsis and has conservative histidine amino acid residue which is necessary for TFL1 function. However, phylogenetic analysis suggested that cucurbits TFL1s (CsTFL1b of cucumber and CmTFL1 of melon) formed a subclade which is far from the AtTFL1 in Arabidopsis or CEN in Antirrhinum. CsTFL1b was highest expressed in male flower but barely expressed in SAM which was different from TFL1 in Arabidopsis with highly transcription accumulation in SAM and CsTFL1b was located in nucleus and cytoplasm. Upon ectopic expression of CsTFL1b in Arabidopsis, the flowering time of transgenic plants was significantly delayed in both wild type and tfl1-11 mutant background but the terminal flower phenotype of tfl1-11 mutant was partially rescued. These results may underlie the discrepant function of CsTFL1b in cucumber from that in Arabidopsis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Augmented neutrophil extracellular traps formation promotes atherosclerosis development in socially defeated apoE −/− mice

Highlights: • Repeated social defeat exaggerates plaque size in apoE{sup −/−} mice. • Proportion of circulating neutrophils is significantly increased in defeated mice. • In vivo NETs formation is exaggerated within the atherosclerotic lesions in defeated mice. • DNase I treatment abrogates pro-atherogenic effect of RSD exposure. • In vitro NETs formation is exaggerated in BM PMN-MDSC from defeated mice. Depression is an independent risk factor of cardiovascular disease (CVD); however, the causal association remains undefined. We exposed mice to repeated social defeat (RSD) to precipitate depressive-like behaviors, and investigated the effects on atherosclerosis. Eight-week-old male apoE{sup −/−} mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days and fed a high-cholesterol diet (HCD) for 6 weeks. The social interaction ratio and immobility time showed dramatic social avoidance before and after HCD feeding. Defeated mice showed higher increase in atherosclerotic lesion areas in the aortic root and entire aorta than control mice. Mean blood pressure and lipid profile were equivalent in both groups. While Ly-6G- and Mac3-positive areas in the aortic root were comparable between the groups, citrullinated histone H3 (Cit-H3)- and myeloperoxidase (MPO)-positive areas, markers of neutrophil extracellular traps (NETs), were significantly increased in the defeated mice. Treatment with DNase I completely diminished the exaggerated atherosclerosis. The proportion of peripheral blood polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), but not of inflammatory monocytes, was markedly increased. Moreover, in vitro NETs formation from bone marrow (BM) PMN-MDSC was markedly augmented, accompanied by higher expression of Nox2 gene and reactive oxygen species. Our findings demonstrate that exposure to RSD promotes atherosclerosis by augmenting NETs formation within the plaque. This provides new insight into the underlying mechanism of depression-related CVD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Glycine confers neuroprotection through PTEN/AKT signal pathway in experimental intracerebral hemorrhage

Highlights: • Glycine attenuated brain injuries after rats ICH. • Glycine down-regulated PTEN in rats ICH. • The neuroprotective effect of glycine was mediated through PTEN/Akt signal pathway in experimental rat ICH. Glycine has been shown to protect against ischemic stroke through various mechanisms. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) which antagonize Akt-dependent cell survival has been linked to neuronal damage. However, whether glycine has a neuroprotective property in intracerebral hemorrhage (ICH) was unknown. This study aimed to determine the protective effect of glycine in rats ICH. Adult male Sprague-Dawley (SD) rats were subjected to left striatum infusion of autologous blood. ICH animals received glycine (0.2–3 mg/kg, icv) at 1 h after ICH with or without pre-injection of Akt Inhibitor IV (100 μM, 2 μl, icv) 0.5 h prior to glycine treatment. Our results showed that in the perihematomal area PTEN was up-regulated in the early stage after ICH. However, glycine treatment decreased PTEN protein level and increased the phosphorylation level of AKT (p-AKT) in the perihematomal area. With the administration of glycine, neuronal death was significantly reduced and Evans blue leakage was alleviated as well as the brain edema after ICH. Moreover, hematoma volume was decreased and neurobehavioral outcome was improved. Nevertheless, Akt Inhibitor IV abolished the neuroprotective effects of glycine after ICH. Together, our findings demonstrate, for the first time, the protective role of glycine on ICH rats, and suggest that the neuroprotective effect of glycine was mediated through PTEN/Akt signal pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Aerobic exercise training decreases cereblon and increases AMPK signaling in the skeletal muscle of STZ-induced diabetic rats

Highlights: • STZ-induced diabetes increased levels of CRBN protein in the skeletal muscle. • Aerobic exercise training attenuates level of CRBN protein and increases AMPK signaling in skeletal muscle. • CRBN is a regulator of exercise-mediated anti-diabetic effect. Cereblon (CRBN) has been reported as a negative regulator of adenosine monophosphate-activated protein kinase (AMPK). Aerobic exercise training has been shown to increase AMPK, which resulted in glucose regulation in skeletal muscle. However, the expression level of CRBN and its association with the physiological modulation of glucose are still unclear. Male Sprague-Dawley rats (5-week-old, n = 18) were assigned to control, streptozotocin (STZ, 65 mg/kg)-induced diabetic group, and STZ + exercise (STZ + EXE) group with six rats in each group. Rats in the STZ + EXE group exercised by treadmill running (20 m/min, 60 min, 4 times/week) for 8 weeks. Compared with the STZ group, blood glucose was significantly decreased in the STZ + EXE group. The skeletal muscle of rats in the STZ + EXE group showed a significant decrease in CRBN levels and an increase in AMPK, protein kinase B, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, fibronectin type III domain-containing protein 5, glucose transporter type 4, superoxide dismutase 1, and uncoupling protein 3 levels. These results suggest that CRBN is a potential regulator of glucose homeostasis in the skeletal muscle. Moreover, our results suggest that aerobic exercise training may provide an important physiological treatment for type 1 diabetes by decreasing CRBN and increasing AMPK signaling in skeletal muscle.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Dietary mung bean protein reduces high-fat diet-induced weight gain by modulating host bile acid metabolism in a gut microbiota-dependent manner

Highlights: • Mung bean protein intake reduces high fat diet-induced weight gain, fat accumulation, and hepatic steatosis. . • Mung bean protein intake increases plasma GLP-1 and intestinal secondary bile acids. • The anti-obesity effects occur via a mechanism that depends on the gut microbiota. The 8-globulin-rich mung bean protein (MPI) suppresses hepatic lipogenesis in rodent models and reduces fasting plasma glucose and insulin levels in obese adults. However, its effects on mitigating high fat diet (HFD)-induced obesity and the mechanism underlying these effects remain to be elucidated. Herein, we examined the metabolic phenotype, intestinal bile acid (BA) pool, and gut microbiota of conventionally raised (CONV-R) male C57BL/6 mice and germ-free (GF) mice that were randomized to receive either regular HFD or HFD containing mung bean protein isolate (MPI) instead of the dairy protein present in regular HFD. MPI intake significantly reduced HFD-induced weight gain and adipose tissue accumulation, and attenuated hepatic steatosis. Enhancement in the secretion of intestinal glucagon-like peptide-1 (GLP-1) and an enlarged cecal and fecal BA pool of dramatically elevated secondary/primary BA ratio were observed in mice that had consumed MPI. These effects were abolished in GF mice, indicating that the effects were dependent upon the presence of the microbiota. As revealed by 16S rRNA gene sequence analysis, MPI intake also elicited dramatic changes in the gut microbiome, such as an expansion of taxa belonging to the phylum Bacteroidetes along with a reduced abundance of the Firmicutes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Sterilized bifidobacteria suppressed fat accumulation and blood glucose level

Highlights: • Determined the effects of oral killed probiotics on lipid- and glucose metabolism. • Administered oral sterilized Bifidobacteria to mice on high-fat diet for four weeks. • Probiotics significantly lowered serum glucose, cholesterol, and triglycerides. • Probiotics significantly reduced lipopolysaccharides and hepatic triglycerides. • Probiotics improved glucose tolerance, insulin resistance, and gut microflora. Probiotics such as Lactobacillus and Bifidobacterium improve the balance of intestinal microflora and have various physiological functions beneficial to human health. It is not always known whether the ingested microbial cells are viable- or killed. However, even sterilized bacterial cells are functional. Bacterial cell functions are strain-specific and their modes of action are still poorly understood. The aim of this study was to elucidate the roles of sterilized bifidobacteria in obesity and lipid metabolism. To this end, mice were orally ingested sterilized bacteria. Male C57BL/6J mice aged 7 wks were raised on a high-fat diet and received oral sterilized bifidobacteria for 4 wks. Although the amount of food they ingested did not change in response to bifidobacteria administration, both weight gain and epididymal body fat mass were significantly reduced. In addition, the elevated blood glucose, triglyceride, and total cholesterol levels observed in the mice on the high-fat diet all decreased in response to bifidobacteria treatment. Hepatic triglyceride levels also decreased. Furthermore, oral glucose tolerance and insulin resistance tests indicated that sterilized bifidobacteria improved glucose tolerance and diminished insulin resistance. Sterilized bifidobacteria also decreased blood lipopolysaccharides and altered intestinal flora. The present study indicates that in mice on a high-fat diet, sterilized bifidobacteria suppressed fat accumulation, improved insulin resistance, and lowered blood glucose levels.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The long non-coding RNA PCSEAT exhibits an oncogenic property in prostate cancer and functions as a competing endogenous RNA that associates with EZH2

Highlights: • PCSEAT is specifically overexpressed in prostate cancer. • PCSEAT promotes the growth and motility of prostate cancer cells. • PCSEAT regulates EZH2 by competitively ‘sponge’ miRNA-143-3p and miRNA-24-2-5p. • PCSEAT may serve as a biomarker for EZH2 inhibitors. • PCSEAT can be transmitted via exosomes and function in recipient cell. Prostate cancer (PCa) is the most common malignancy and the leading cause of cancer deaths in males. Recent studies demonstrate that long non-coding RNAs (lncRNAs) are involved in many aspects of PCa. However, their biological roles in PCa remain imperfectly understood. Here, we characterized an lncRNA, PCa specific expression and EZH2-associated transcript (PCSEAT, annotated as PRCAT38), which is specifically overexpressed in PCa. We further demonstrated that knockdown of PCSEAT results in the reduction of PCa cell growth and motility, and overexpression of PCSEAT reverses these phenotypes. Furthermore, bioactive PCSEAT is incorporated into exosomes and transmitted to adjacent cells, thus promoting cell proliferation and motility. Mechanistically, we found that PCSEAT promotes cell proliferation, at least in part by affecting miR-143-3p- and miR-24-2-5p-mediated regulation of EZH2, suggesting that PCSEAT and EZH2 competitively ‘sponge’ miR-143-3p and miR-24-2-5p. Overall, our results reveal that PCSEAT is specifically overexpressed in PCa patients and a potential oncogene in PCa cells via mediating EZH2 activity, indicating that PCSEAT may be a potential therapeutic target in PCa.

60 APPLIED LIFE SCIENCES↗