Acamprosate has no effect on NMDA-induced toxicity but reduces toxicity induced by spermidine or by changing the medium in organotypic hippocampal slice cultures from rat

BACKGROUND: It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor-mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA receptor subunits. These effects on NMDA receptors imply that the drug may have neurotoxic or neuroprotective actions under different conditions, and these studies were undertaken to evaluate this possibility in hippocampal neuronal cultures. METHODS: Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in medium for 28 days. The effects of acamprosate (100 microM) alone or on neurotoxic challenges induced by either 50 microM NMDA or 100 microM spermidine were studied. Neurotoxicity was assessed by uptake of propidium iodide 24 hr after challenge. Calcium entry was measured by uptake of 45Ca2+ into the culture during the challenge. RESULTS: Acamprosate produced no neurotoxicity in these cultures after acute or subchronic exposure. In contrast, the presence of acamprosate significantly reduced "basal" propidium iodide uptake caused by the medium change procedure; similar effects were obtained with dizocilpine (MK-801; 30 microM) and, to a lesser extent, with ifenprodil (50 microM). Acamprosate did not significantly potentiate or inhibit NMDA-induced neurotoxicity, but the presence of acamprosate significantly reduced spermidine-induced neurotoxicity. CONCLUSION: No evidence was obtained that the putative agonist or coagonist effects of acamprosate on the NMDA receptor are able to cause neurotoxicity. Similarly, no evidence for inhibitory effects of acamprosate on NMDA-induced toxicity was observed under any of these conditions. However, acamprosate significantly inhibited the toxicity associated with changing medium and the toxicity induced by spermidine in these hippocampal cultures. The mechanism is unknown but is compatible with previously reported inhibition of polyamine-mediated effects.     

Chronic exposure to schistosome eggs reduces serum cholesterol but has no effect on atherosclerotic lesion development

Previous studies have shown that people infected with schistosomiasis have lower levels of serum cholesterol than uninfected controls. To better understand the impact of this parasitic infection on serum cholesterol levels and on atherosclerotic lesion development induced by hypercholesterolemia, apolipoprotein E (ApoE)-deficient mice were chronically exposed to the eggs of Schistosoma mansoni over a period of 16 weeks. Total serum cholesterol and low-density lipoprotein (LDL) were reduced in egg-exposed ApoE-deficient mice fed a diet high in cholesterol compared to unexposed controls. However, exposure to eggs had no effect on atherosclerotic lesion size or progression in ApoE-deficient mice. Macrophages isolated from egg-exposed mice had an enhanced ability to take up LDL but not acetylated LDL (acLDL). This study suggests that schistosome eggs alone may alter serum lipid profiles through enhancing LDL uptake by macrophages, but these changes do not ultimately affect atherosclerotic lesion development.     

Increased but imbalanced expression of VEGF and its receptors has no positive effect on angiogenesis in systemic sclerosis skin

OBJECTIVE: To investigate the expression of vascular endothelial growth factor (VEGF) and its vascular and lymphatic receptors in skin in systemic sclerosis (SSc) compared to systemic lupus erythematosus (SLE), Raynaud's phenomenon (RP) and normal healthy control skin. METHODS: Staining was performed using rabbit anti-human antibodies in DAKO TechMate Horizon staining robot programmed for the biotin-streptavidin protocol. RESULTS: VEGF was sporadically and weakly expressed in normal skin, but in spite of vascular damage in diseased skin, VEGF expression was only slightly upregulated. In contrast, its vascular receptors VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1), were clearly upregulated. Finally, the lymphatic VEGFR-3 (Flt-4) receptor was also upregulated in diseased skin and ectopically expressed also in blood vessels. Negative staining and positive sample controls confirmed the specificity of the staining. CONCLUSION: The imbalanced expression of VEGF and its vascular receptors suggest that the compensatory efforts to angiogenesis fail in SSc, in part due to insufficient local production of VEGF, which was low compared to VEGFR expression. This is compatible with the recent observations on the lack of alpha V beta 3+ newly formed blood vessels in SSc skin. Since microvascular angiogenic stimuli normally induce first VEGF and then VEGFR, these findings also suggest that the angiogenic cascade is turned on, but there is a defect in the finalization of its effects. Normalization of angiogenic cascade in SSc could provide a future therapeutic target.     

槲皮素在机械性创伤导致大鼠心脏继发性损伤中的保护作用

目的 观察槲皮素对机械性创伤（MT）造成大鼠继发性心肌细胞及心脏功能损伤的保护效果,同时探究其作用机制。 方法 实验分为在体实验和离体实验。将120只成年雄性SD大鼠按随机数字表法分为4组,分别为正常组、创伤组、创伤+槲皮素和创伤+溶剂组。先后应用小动物定量创伤仪制备大鼠MT模型;经右颈总动脉向左心室内插管,记录左心室舒缩压力变化,检测大鼠心功能,初步研究槲皮素对心脏的保护作用;通过MTT比色法检测槲皮素对创伤诱导的H9c2细胞存活率的影响,确定槲皮素对心脏的保护效果;在槲皮素的保护机制研究中,TUNEL染色后计算心肌细胞凋亡指数,以评估心肌细胞的凋亡状况;通过酶标仪检测H9c2细胞在加入槲皮素前后产生活性氧(ROS)自由基的量的变化;激光共聚焦显微镜下观察测定经Fluo-4AM标记的心肌细胞内Ca2+的浓度变化,从而初步探讨槲皮素发挥保护作用的机制。结果 ①心功能指标LVDP、+dP/dtmax 、-dP/dtmax显示,创伤组、创伤+溶剂组与正常组比较均明显下降,而创伤+槲皮素组较创伤组升高（P<0.01）。②MTT检测发现,在一定的浓度范围内,槲皮素对H9c2细胞没有细胞毒性作用,并且可明显阻碍创伤血清对H9c2细胞的损伤。③MT后通过对正常组、创伤组、创伤+槲皮素组和创伤+溶剂组心肌细胞凋亡指数的检测,发现创伤+槲皮素组与创伤组比较凋亡指数明显降低(P<0.01)。④通过对H9c2细胞内ROS的检测,发现槲皮素能够减低MT后细胞内ROS的产生。⑤通过对心肌细胞内钙浓度变化的检测,发现MT后Ca2+浓度上升,给予一定浓度槲皮素后Ca2+浓度下降。结论 在一定的浓度范围内,槲皮素能够降低MT后产生的ROS自由基,抑制Ca2+内流,继而降低心肌细胞凋亡,改善MT后心脏功能,发挥心脏保护作用。     

Oral administration of inducible nitric oxide synthase inhibitors reduces nitric oxide synthesis but has no effect on the severity of experimental colitis

BACKGROUND: Increased concentrations of nitrate and nitrite (the breakdown products of nitric oxide) in the serum and faeces of patients with inflammatory bowel disease (IBD) suggests that increased synthesis of nitric oxide occurs in IBD. The aim of this study was to assess aminoguanidine (AMG), a selective inhibitor of inducible nitric oxide synthase, with regard to its effectiveness as a nitric oxide inhibitor and as a modulator of inflammation in trinitrobenzene sulfonic acid (TNBS)-induced colitis. MATERIALS AND METHODS: Colitis was induced in Wistar rats. Selective (AMG) and non-selective (1-nitroso-arginine methyl ester (1-NAME)) inhibitors of nitric oxide synthase were given in the drinking water. Colonic citrulline and arginine concentrations were assessed using high-performance liquid chromatography. The severity of colitis was assessed by a macroscopic scoring system. RESULTS: Both 1-NAME and AMG successfully reduced nitric oxide synthesis. There was no evidence of substrate depletion in the colonic wall. Neither of the agents reduced the severity of colonic inflammation. CONCLUSIONS: Oral administration of nitric oxide synthase inhibitors reduced nitric oxide synthesis in the colonic wall. This study does not provide evidence to support a role for nitric oxide in the pathogenesis of colonic inflammation in TNBS colitis.     

gamma-tocopherol, but not alpha-tocopherol, potently inhibits neointimal formation induced by vascular injury in insulin resistant rats

Insulin resistance may enhance the neointima formation via increased oxidative stress. However, clinical trials investigating the benefit of antioxidant therapy with alpha-tocopherol showed negative results. Recent studies showed that chemical characteristics of gamma-tocopherol are distinct from those of alpha-tocopherol. We hypothesized that gamma-tocopherol is superior to alpha-tocopherol in preventing the neointima growth after arterial injury in insulin resistance. Male rats were fed with standard chow or a high fructose diet for induction of insulin resistance. Thereafter, the left carotid artery was injured with a balloon catheter. After 2 weeks, the carotid arteries were harvested and histomorphometrically analyzed. The neointima-media ratio of the injured artery was significantly greater in insulin resistance group (n=8, 1.33+/-0.12) than in normal group (n=10, 0.76+/-0.11, p<0.01). gamma-Tocopherol (100 mg/kg/day) reduced the ratio (n=5, 0.55+/-0.21, p<0.01 vs. insulin resistance group), while alpha-tocopherol was without effect (n=7, 1.08+/-0.14). The quantification of plasma phosphatidylcholine hydroperoxide, an indicator of systemic oxidative stress, and dihydroethidium fluorescence staining of the carotid artery, an indicator of the local superoxide production, showed that oxidative stress in the systemic circulation and local arterial tissue was increased in insulin resistance. Both tocopherols decreased plasma phosphatidylcholine hydroperoxide, but failed to suppress the superoxide production in the carotid arteries. Increased 3-nitrotyrosine in neointima by insulin resistance was greatly reduced only by gamma-tocopherol. In conclusion, gamma-tocopherol, but not alpha-tocopherol, reduces the neointima proliferation in insulin resistance, independently of its effects on superoxide production. The beneficial effect may be related with its inhibitory effects on nitrosative stress.     

Substituting enzymatically interesterified butter for native butter has no effect on lipemia or lipoproteinemia in Man

The aim of this study was to determine whether substituting enzymatically interesterified butter for native butter in the usual diet affects lipid and lipoprotein levels in man. Parameters studied were serum total cholesterol, LDL-cholesterol, HDL-cholesterol, free cholesterol, phospholipids, triglycerides, apoA1 and apoB and the fatty acid composition of serum triglycerides, free fatty acids, phospholipids and cholesterol esters. Subjects were healthy volunteers and a controlled design was used. The only mathematically significant difference found when interesterified butter was substituted for butter was an about 7% lower fraction of oleic acid in the serum cholesterol esters (p = 0.005). In contrast to an earlier study where chemically interesterified butter fat was substituted for native butter, no indications are found in this study that replacing native butter by enzymatically interesterified butter, in amounts normally consumed, may have any beneficial effect on health.     

Fenofibrate increases the L-arginine:ADMA ratio by increase of L-arginine concentration but has no effect on ADMA concentration

Asymmetric dimethylarginine (ADMA), a guanidino-substituted analogue of L-arginine, is a potent endogenous competitive inhibitor of the endothelial nitric oxide synthase and therefore a potentially atherogenic amino acid. Hyperlipidemia and hyperhomocysteinemia have both been reported to be associated with elevated ADMA concentrations. Therefore, we investigated the influence of micronized fenofibrate (200 mg/day, 6 week treatment) on the L-arginine:ADMA ratio in 25 hypertriglyceridemic men. ADMA was neither associated to serum triglycerides, serum cholesterol, LDL-cholesterol or HDL-cholesterol or plasma total homocysteine at baseline. Treatment with fenofibrate did not alter plasma ADMA level, in contrast to serum triglycerides which were significantly lowered and plasma total homocysteine which was significantly increased. In addition, serum L-arginine levels significantly increased, leading to a higher L-arginine:ADMA ratio after treatment. The null effect of fenofibrate on plasma ADMA levels is in line with reported effects of other lipid-lowering agents (HMG-CoA-reductase inhibitors), but fenofibrate treatment elevated the plasma L-arginine:ADMA ratio, suggesting an improvement of endogenous NO formation and endothelial function. The results do not support the view that in vivo ADMA metabolism itself is directly influenced by cholesterol or homocysteine.     

血红素加氧酶-1基因转染对内毒素诱导的ECV304细胞氧化损伤的影响

目的 探讨血红素加氧酶-1( HO-1)基因转染对脂多糖诱导的ECV304细胞氧化损伤的影响.方法 利用逆转录病毒介导的基因转染技术将HO-1基因转染人人脐静脉内皮细胞(ECV304),应用RT-PCR和Western印迹技术检测转染细胞HO-1 mRNA和蛋白表达水平.未转染和转染HO-1基因的ECV304细胞分别培养于含或不含脂多糖(5 mg/L)的DMEM培养基24h后,检测细胞脂质过氧化产物丙二醛(MDA)含量和乳酸脱氢酶(LDH)释放率.结果 HO-1基因和蛋白在转染的ECV304细胞的表达量显著升高.与ECV304细胞相比,转染HO-1基因的ECV304细胞MDA含量和LDH释放率均下降(P＜0.05);应用HO-1抑制剂锌原卟啉共孵育后,转染细胞的MDA含量和LDH释放率增高.结论 HO-1的基因转染可增强ECV304细胞对抗脂多糖氧化损伤的能力.     

p53基因在亚砷酸钠致人胚胎肺成纤维细胞凋亡中的作用

目的 探讨p53、Bax、bcl-2基因在亚砷酸钠(NaAs02)致人胚胎肺成纤维细胞(HELF)凋亡中的作用.方法 分别取转染了p53质粒HELF细胞(p53组)、转染了PC质粒的HELF细胞(PC组)、常规培养的HELF细胞(正常组),在6孔板中培养48 h后,分别加入0、3、9、15 mmoL/L NaAsO2溶液,培养24 h后,用real-time PCR法检测p53、Bax、bcl-2 mRNA基因表达水平,采用免疫组织化学SABC法检测p53、Bax、bcl-2基因蛋白表达水平;用流式细胞仪检测细胞凋亡情况.结果 p53组细胞p53基因mRNA表达水平(0.51±0.29)低于PC组及正常组[(1.32±0.26),(1.00±0.20),P均<0.05],p53组p53基因蛋白表达水平[(4.10±1.20)%]低于PC组和正常组[(8.00±1.63)%、(7.90±1.79)%,P均<0.05];p53组、PC组、正常组在染砷0、3、9、15 mmol/L时,细胞凋亡率[(0.57±0.28)%、(22.91±4.86)%、(40.05±3.93)%、(44.87±3.58)%,(0.65±0.24)%、(14.09±3.49)%、(20.31±3.66)%、(32.42±3.63)%,(0.56±0.25)%、(12.14±3.70)%、(19.61±3.63)%、(30.43±2.83)%]、Bax mRNA表达水平[(12.73±3.96)、(25.12±6.42)、(104.96±26.77)、(154.04±3052),(14.63±3.57)、(36.75±3.67)、(272.26±66.11)、(846.12±243.36),(14.75±5.65)、(37.22±11.27)、(278.51±37.42)、(861.67±369.29)]、Bax蛋白表达水平[(15.07±0.83)%、(23.79±3.99)%、(3851±158)%、(53.86±124)%,(15.43±1.45)%、(36.11±1.37)%、(56.86±1.97)%、(76.09±2.01)%,(15.20±1.03)%、(35.25±1.09)%、(55.56±2.17)%、(74.48±2.85)%]均随着染毒剂量的增加而增高(P均<0.05),而bcl-2 mRNA表达水平[(443.00±244.47)、(156.79±53.18)、(62.13±13.66)、(23.10±6.44),(420.55±110.77)、(48.15±10.02)、(14.91±6.53)、(7.54±2.62),(577.75±123.22)、(49.68±10.11)、(12.41±1.28)、(7.22±1.89)]、bcl-2蛋白表达水平[(47.20±3.77)%、(41.80±2.94)%、(36.00±2.36)%、(29.00±2.91)%,(45.90±4.15)%、(35.70±2.77)%、(29.80±2.78)%、(24.80±2.66)%,(46.70±3.47)%、(36.20±2.90)%、(30.10±3.21)%、(25.10±2.28)%]均随着染毒剂量的增加而降低(P均<0.05);在染砷3、9、15 mmol/L时,p53组的细胞凋亡率、bcl-2 mRNA表达水平、bcl-2蛋白表达水平均高于同一染砷剂量的正常组和PC组(P均<0.05),而Bax mRNA表达水平、Bax基因蛋白表达水平均低于同一染砷剂量的正常组和PC组(P均<0.05).结论 p53基因减少了NaAsO2致HELF的凋亡,可能是通过改变部分凋亡途径实现.     

p53基因在亚砷酸钠致人胚胎肺成纤维细胞凋亡中的作用

Objective To investigate the p53,Bax,bcl-2 gene in NaAsO2-induced human embryonic lung fibroblasts(HELF)apoptosis.Methods HELF was divided into HELF cells transfected with p53 plasmid(p53 group),HELF cells transfected with PC plasmid(PC group)and normal cultured HELF cells(normal group).The mRNA expression of p53,Bax and bcl-2 gene was detected by real-time PCR,the protein expression of p53,Bax and bcl-2 was assessed by immunohistochemical SABC and the cell apoptosis of HELF was detected by flow cytometry(FCM),in a 6-well plate and cultured for 48 hours,which was exposed to different doses(0,3,9,15mmol/L)NaAsO2 for 24 hours.Results The p53 gene mRNA expression level of p53 group(0.51±0.29)was lower than that of the normal group and PC group [ (1.00 ± 0.20), (1.32 ± 0.26), all P < 0.05 ]. The p53 protein expression level of p53 group(4.10 ± 1.20) was lower than the PC group and normal group[ (8.00 ± 1.63), (7.90 ± 1.79), allP < 0.05]. In p53 group, PC group, normal group exposed to 0,3,9,15 mmol/L NaAsO2 doses, the apoptotic rate [(0.57 ± 0.28)%, (22.91 ± 4.86)%, (40.05 ± 3.93)%, (44.87 ± 3.58)%; (0.65 ± 0.24)%, (14.09 ± 3.49)%,(20.31 ± 3.66)%, (32.42 ± 3.63)%; (0.56 ± 0.25)%, (12.14 ± 3.70)%, (19.61 ± 3.63)%, (30.43 ± 2.83)%], Bax mRNA expression level[(12.73 ± 3.96), (25.12 ± 6.42), (104.96 ± 26.77), (154.04 ± 30.52); (14.63 ± 3.57),(36.75 ± 3.67), (272.26 ± 66.11), (846.12 ± 243.36); (14.75 ± 5.65), (37.22 ± 11.27), (278.51 ± 37.42),(861.67 ± 369.29) ], Bax protein expression level [ ( 15.07 ± 0.83 ) %, ( 23.79 ± 3.99 ) %, (38.51 ± 1.58 ) %, (53.86 ±1.74)%;(15.43 ± 1.45)%,(36.11 ± 1.37)%, (56.86 ± 1.97)%, (76.09 ± 2.01)%; (15.20 ± 1.03)%,(35.25 ±1.09)%, (55.56 ± 2.17)%, (74.48 ± 2.85)% ] was respectively increased in a dose-dependent manner with the increased concentration of NaAsO2(all P < 0.05). The bel-2 mRNA expression level [ (443.00 ± 244.47), (156.79 ±53.18), (62.13 ± 13.66), (23.10 ± 6.44); (420.55 ± 110.77), (48.15 ± 10.02), (14.91 ± 6.53), (7.54 ± 2.62);(577.75 ± 123.22), (49.68 ± 10.11), (12.41 ± 1.28), (7.22 ± 1.89)], bcl-2 protein expression level[(47.20 ±3.77)%, (41.80 ± 2.94)%, (36.00 ± 2.36)%, (29.00 ± 2.91)%; (45.90 ± 4.15)%, (35.70 ± 2.77)%, (29.80 ±2.78)%, (24.80 ± 2.66)% ; (46.70 ± 3.47)%, (36.20 ± 2.90)%, (30.10 ± 3.21)%, (25.10 ± 2.28)% ] wasdecreased in a dose-dependent manner with the increased concentration of NaAsO2(all P < 0.05 ). In 3,9,15 mmol/L NaAsO2, apoptotic rate of p53 group, mRNA expression of bcl-2, protein expression of bcl-2 was higher than that ofnormal group and PC group, respectively (all P < 0.05), but mRNA expression of Bax, protein expression of Bax was respeetivelylower than that normal group and the PC group(P < 0.05 ). Conclusion p53 gene reduced the apoptosis induced by NaAsO2 in HELF, possibly by changing the apoptosis pathway.     

p53基因在亚砷酸钠致人胚胎肺成纤维细胞凋亡中的作用

Objective To investigate the p53,Bax,bcl-2 gene in NaAsO2-induced human embryonic lung fibroblasts(HELF)apoptosis.Methods HELF was divided into HELF cells transfected with p53 plasmid(p53 group),HELF cells transfected with PC plasmid(PC group)and normal cultured HELF cells(normal group).The mRNA expression of p53,Bax and bcl-2 gene was detected by real-time PCR,the protein expression of p53,Bax and bcl-2 was assessed by immunohistochemical SABC and the cell apoptosis of HELF was detected by flow cytometry(FCM),in a 6-well plate and cultured for 48 hours,which was exposed to different doses(0,3,9,15mmol/L)NaAsO2 for 24 hours.Results The p53 gene mRNA expression level of p53 group(0.51±0.29)was lower than that of the normal group and PC group [ (1.00 ± 0.20), (1.32 ± 0.26), all P < 0.05 ]. The p53 protein expression level of p53 group(4.10 ± 1.20) was lower than the PC group and normal group[ (8.00 ± 1.63), (7.90 ± 1.79), allP < 0.05]. In p53 group, PC group, normal group exposed to 0,3,9,15 mmol/L NaAsO2 doses, the apoptotic rate [(0.57 ± 0.28)%, (22.91 ± 4.86)%, (40.05 ± 3.93)%, (44.87 ± 3.58)%; (0.65 ± 0.24)%, (14.09 ± 3.49)%,(20.31 ± 3.66)%, (32.42 ± 3.63)%; (0.56 ± 0.25)%, (12.14 ± 3.70)%, (19.61 ± 3.63)%, (30.43 ± 2.83)%], Bax mRNA expression level[(12.73 ± 3.96), (25.12 ± 6.42), (104.96 ± 26.77), (154.04 ± 30.52); (14.63 ± 3.57),(36.75 ± 3.67), (272.26 ± 66.11), (846.12 ± 243.36); (14.75 ± 5.65), (37.22 ± 11.27), (278.51 ± 37.42),(861.67 ± 369.29) ], Bax protein expression level [ ( 15.07 ± 0.83 ) %, ( 23.79 ± 3.99 ) %, (38.51 ± 1.58 ) %, (53.86 ±1.74)%;(15.43 ± 1.45)%,(36.11 ± 1.37)%, (56.86 ± 1.97)%, (76.09 ± 2.01)%; (15.20 ± 1.03)%,(35.25 ±1.09)%, (55.56 ± 2.17)%, (74.48 ± 2.85)% ] was respectively increased in a dose-dependent manner with the increased concentration of NaAsO2(all P < 0.05). The bel-2 mRNA expression level [ (443.00 ± 244.47), (156.79 ±53.18), (62.13 ± 13.66), (23.10 ± 6.44); (420.55 ± 110.77), (48.15 ± 10.02), (14.91 ± 6.53), (7.54 ± 2.62);(577.75 ± 123.22), (49.68 ± 10.11), (12.41 ± 1.28), (7.22 ± 1.89)], bcl-2 protein expression level[(47.20 ±3.77)%, (41.80 ± 2.94)%, (36.00 ± 2.36)%, (29.00 ± 2.91)%; (45.90 ± 4.15)%, (35.70 ± 2.77)%, (29.80 ±2.78)%, (24.80 ± 2.66)% ; (46.70 ± 3.47)%, (36.20 ± 2.90)%, (30.10 ± 3.21)%, (25.10 ± 2.28)% ] wasdecreased in a dose-dependent manner with the increased concentration of NaAsO2(all P < 0.05 ). In 3,9,15 mmol/L NaAsO2, apoptotic rate of p53 group, mRNA expression of bcl-2, protein expression of bcl-2 was higher than that ofnormal group and PC group, respectively (all P < 0.05), but mRNA expression of Bax, protein expression of Bax was respeetivelylower than that normal group and the PC group(P < 0.05 ). Conclusion p53 gene reduced the apoptosis induced by NaAsO2 in HELF, possibly by changing the apoptosis pathway.     

Dietary fish oil modestly attenuates the effect of age on diastolic function but has no effect on memory or brain inflammation in aged rats

Fish oil (FO) mediates a number of cardioprotective benefits in patients with cardiovascular disease. In the absence of cardiovascular disease, however, the effects of FO on cardiac structure and function are not clear. In addition, it is not known if an effective dosing strategy for attenuating age-related cardiac dysfunction is also effective at limiting cognitive dysfunction. Therefore, we determined if 4 months of FO supplementation in aged rats would lessen age-related cardiac dysfunction while concomitantly preventing the cognitive decline that is normally observed in this population. The results indicate that FO initiated late in life modifies diastolic function in a small but positive way by attenuating the age-related increases in filling pressure, posterior wall thickness, and interstitial collagen without mitigating age-related deficits in memory or increases in brain inflammation. These data raise the possibility that FO supplementation for purposes of cardiac and brain protection may need to occur earlier in the life span.     

Insulin-like growth factor I has a direct effect on glucose and protein metabolism, but no effect on lipid metabolism in type 1 diabetes

There is evidence of a metabolic role for IGF-I in type 1 diabetes, but it is unclear whether IGF-I acts indirectly by reducing GH secretion or has direct effects. Using stable isotopes we have investigated, on three separate occasions, the effect of a pulse of recombinant human GH, a sc injection of recombinant human IGF-I, and a placebo on glucose, lipid, and protein metabolism in subjects with type 1 diabetes during a basal insulin infusion and a hyperinsulinemic euglycemic clamp. Endogenous GH secretion was suppressed with octreotide. IGF-I reduced the hepatic glucose production rate (Ra), increased peripheral glucose uptake, and reduced protein breakdown during the basal insulin infusion (P < 0.05, P < 0.005, and P < 0.05, respectively, vs. placebo) and the hyperinsulinemic euglycemic clamp (P < 0.05, P < 0.005, and P < 0.05, respectively, vs. placebo). IGF-I had no effect on glycerol Ra, an index of lipolysis. GH increased glucose and glycerol Ra during the basal insulin infusion (P < 0.005 vs. placebo study), but the effects were no different from placebo during the clamp. In conclusion, IGF-I had a direct effect on glucose and protein metabolism, which was maintained during the hyperinsulinemic euglycemic clamp. This suggests that IGF-I acts in concert with insulin and may have an important role in maintaining glucose homeostasis and protein metabolism in type 1 diabetes.