Increased Liver Protein Research Articles

Chia (Salvia hispanica L.) oil supplementation ameliorates liver oxidative stress in high-fat diet-fed mice through PPAR-γ and Nrf2 upregulation

This study aimed to evaluate the hepatic antioxidant activity of a high-fat diet supplemented with chia oil in mice. Forty animals were divided into Control (C, n = 10), Control + 1.5 % chia oil (CC, n = 10), High fat (HF, n = 10), and High fat + 1.5 % chia oil (HFC, n = 10) groups. Chia oil reduced serum triacylglycerol in the HF group (p < 0.05). Chia oil promotes lower hepatic concentrations of F2-isoprostane (8-epi PGF2α) and thiobarbituric acid (TBARs) than HF. Chia oil increased liver protein expression and activity of superoxide dismutase 1 and 2 (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx). It also upregulated the expression of PPAR-γ and NRF2, a master transcription factor involved in the antioxidant response in the liver, compared to their counterparts. The results reveal that chia oil improves the metabolic and antioxidant systems in the liver of high-fat diet-fed mice.

Effect of Genistein Supplementation on Exercise-Induced Inflammation and Oxidative Stress in Mice Liver and Skeletal Muscle.

Background and objectives: The purpose of this study was to investigate the influences of oral high-dose genistein (GE) administration on exercise-induced oxidative stress, inflammatory response and tissue damage. Materials and Methods: Thirty-two mice were randomly divided into control group (Con; sedentary/0.5% CMC-Na), GE administrated group (GE; sedentary/GE dosed), exercise group (Ex; exercise/0.5% CMC-Na), or GE administrated plus exercise group (GE + Ex; exercise/GE dosed), mice in the GE and GE + Ex group were given GE orally at the dose of 200 mg/kg weight. Results: Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, liver interleukin (IL)-6, IL-1β, superoxide dismutase 1 (SOD1), catalase (CAT), hemeoxygenase-1 (HO-1) gene expression levels and skeletal muscle IL-6, nuclear factor erythroid 2-related factor (Nrf2), and HO-1 gene expression levels increased immediately after exhaustive exercise. GE supplementation increased liver protein carbonyl concentrations. On the other hand, GE supplementation significantly decreased SOD1, CAT gene expression levels in the liver and Nrf2, and HO-1 gene expression levels in the skeletal muscles. Conclusions: Acute exercise induced organ damage, inflammation, and oxidative stress in skeletal muscles and the liver. However, a single dose of GE supplementation before exercise did not lead to favorable antioxidant and anti-inflammatory effects in this study.

Enhanced nitric oxide-mediated autophagy contributes to the hepatoprotective effects of ischemic preconditioning during ischemia and reperfusion

Ischemic preconditioning (IPC) protects against liver ischemia/reperfusion (I/R) injury. Autophagy is an essential cytoprotective system that is rapidly activated by multiple stressors. Nitric oxide (NO) acts as an inducer of IPC. We examined the impact of autophagy in liver IPC and its regulation by NO. Male C57BL/6 mice were subjected to 60 min of hepatic ischemia followed by 6 h of reperfusion. IPC was achieved for 10 min of ischemia followed by 10 min of reperfusion prior to sustained ischemia. Nω-Nitro-l-arginine methyl ester (L-NAME, 15 mg/kg, i.v., all NOS inhibitor) and aminoguanidine (AG, 10 mg/kg, i.v., iNOS inhibitor) were injected 10 min before IPC. SB203580 (10 mg/kg, i.p., p38 inhibitor) was injected 30 min before IPC. I/R increased serum alanine aminotransferase activity. IPC attenuated this increase, which was abolished by L-NAME, but not AG. Microtubule-associated protein-1 light chain 3-II levels increased and p62 protein levels decreased after I/R; these changes were augmented by IPC and abolished by L-NAME. I/R increased liver protein expression of autophagy-related protein (Atg)12-Atg5 complex and lysosome-associated membrane protein-2. IPC augmented the expression of these proteins, which were abolished by L-NAME, but not AG. IPC also augmented the level of phosphorylated p38 MAPK induced by I/R and this phosphorylation was abolished by L-NAME. Our findings suggest that IPC-mediated NO protects against I/R-induced liver injury by enhancing autophagic flux.

Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice.

Sepsis induces an acute inflammatory response in the liver, which can lead to organ failure and death. Given the anti-inflammatory effects of exercise, we hypothesized that habitual physical activity could protect against acute sepsis-induced liver inflammation via mechanisms, including heat shock protein (HSP) 70/72. Male C57BL/6J mice (n = 80, ∼8 wk of age) engaged in physical activity via voluntary wheel running (VWR) or cage control (SED) for 10 wk. To induce sepsis, we injected (2 mg/kg ip) LPS or sterile saline (SAL), and liver was harvested 6 or 12 h later. VWR attenuated increases in body and epididymal adipose tissue mass, improved glucose tolerance, and increased liver protein content of PEPCK (P < 0.05). VWR attenuated increases in LPS-induced IL-6 signaling and mRNA expression of other inflammatory markers (TNF-α, chemokine C-C motif ligand 2, inducible nitric oxide synthase, IL-10, IL-1β) in the liver; however, this was not reflected at the whole body level, as systemic markers of inflammation were similar between SED and VWR. Insulin tolerance was greater in VWR compared with SED at 6 but not 12 h after LPS. The protective effect of VWR occurred in parallel with increases in the liver protein content of HSP70/72, a molecular chaperone that can protect against inflammatory challenges. This study provides novel evidence that physical activity protects against the inflammatory cascade induced by LPS in the liver and that these effects may be mediated via HSP70/72.

Metabolic Effects of CX3CR1 Deficiency in Diet-Induced Obese Mice.

The fractalkine (CX3CL1-CX3CR1) chemokine system is associated with obesity-related inflammation and type 2 diabetes, but data on effects of Cx3cr1 deficiency on metabolic pathways is contradictory. We examined male C57BL/6 Cx3cr1-/- mice on chow and high-fat diet to determine the metabolic effects of Cx3cr1 deficiency. We found no difference in body weight and fat content or feeding and energy expenditure between Cx3cr1-/- and WT mice. Cx3cr1-/- mice had reduced glucose intolerance assessed by intraperitoneal glucose tolerance tests at chow and high-fat fed states, though there was no difference in glucose-stimulated insulin values. Cx3cr1-/- mice also had improved insulin sensitivity at hyperinsulinemic-euglycemic clamp, with higher glucose infusion rate, rate of disposal, and hepatic glucose production suppression compared to WT mice. Enhanced insulin signaling in response to acute intravenous insulin injection was demonstrated in Cx3cr1-/- by increased liver protein levels of phosphorylated AKT and GSK3β proteins. There were no differences in adipose tissue macrophage populations, circulating inflammatory monocytes, adipokines, lipids, or inflammatory markers. In conclusion, we demonstrate a moderate and reproducible protective effect of Cx3cr1 deficiency on glucose intolerance and insulin resistance.

Modification of hepatic iron metabolism induced by pravastatin during obstructive cholestasis in rats

Aims To evaluate iron biochemistry and contributing liver mechanisms during obstructive cholestasis and pravastatin treatment in rats. Main methods A rat model of cholestasis induced by bile duct ligation (BDL) was used for the study. The detection of iron and the expression of relevant molecules were performed one week after surgery in the control, and cholestatic animals after treatment with either saline or pravastatin (1 mg/kg/day). Key findings Saline-administered BDL rats showed, in comparison to sham-operated animals, a significant increase in plasma iron concentration, increased liver protein content of heme oxygenase-1 (HO-1) and a decline in the expression of hepcidin. Ferroportin 1 expression was increased with a simultaneous reduction in intrahepatic iron concentration. The administration of pravastatin to BDL animals attenuated proliferation changes in liver parenchyma, prevented HO-1 induction, restored hepatic mRNA hepcidin expression to control levels and induced the expression of ferritin, transferrin receptors (TfR1/2) and divalent metal transporter-1. This was accompanied by an increased content of intrahepatic iron when compared to the BDL animals, and a reduction of hyperbilirubinemia. Significance Cholestasis-induced increase in plasma and decrease in hepatic iron levels were associated with up-regulation of liver HO-1 and ferroportin 1. Pravastatin alleviated cholestatic liver impairment and raised liver iron content by modulation of heme catabolism and an increase of hepatic iron uptake and storage capacity.

Anti‐oxidation activities of CordyMax in an oxidative stress model: A mechanism of its anti‐aging property

Cordyceps sinensis (Cs) is traditionally believed as an anti‐aging herb. CordyMax (CM), a mycelia fermentation product of Cs, has shown the benefits of lifespan extension, anti‐fatigue and improving glucose‐lipid‐energy metabolisms. We further tested the antioxidant function of CM in mice, the mechanism of its anti‐aging effect. Mice were randomized into 5 groups, receiving vehicle or CM at a dose of 0.5, 1.0 or 1.5 g/kg for 60 days by gavage. They were given a single dose of 11 Gry 60Co γ‐radiation on Day 60 and sacrificed on Day 64. Compared to non‐radiation controls, γ‐radiation reduced plasma glutathione (GSH) &amp; the thiol groups, liver catalase (CAT) &amp; SOD, GSH‐peroxidase (GSH‐Px), GSH‐reductase (GSH‐Rd), and increased liver protein carbonyl groups. Compared to radiation controls, 60 days of oral CM increased plasma thiol groups by 21–25% in the 3 dose groups, and liver CAT by 15–16% (all p&lt;0.01). Oral CM at a dose of 0.5 or 1.0g/kg increased GSH‐Px by 15% (p=0.01). CM therapy (1.0 or 1.5g/kg) reduced liver protein carbonyl groups by 9–14% (p=0.04, &lt;0.01) and 8‐OHdG by 26–34% (p&lt;0.01); and increased plasma GSH by 26–27% (p=0.02, 0.03), liver GSH‐Rd by 10–11% (p=0.02) and liver SOD by 6–9% (p&lt;0.05). In conclusion, oral CM improves antioxidant capacity in mice with radiation‐induced oxidative injure, supporting in general the anti‐aging activity of CM.

Effects of propylthiouracil, methimazole and thyroidectomy on liver and plasma proteins: differential response to thyroxine.

Differential effects of propylthiouracil (PTU), methimazole (MMI) and thyroidectomy (Tx) on liver and plasma proteins have been studied in rats, some of which have been simultaneously treated with L-thyroxine (T4). Although the absolute liver weights were lower in all hypothyroid groups, the relative liver weights (g/100 g) were significantly higher in PTU and MMI groups, while in Tx group they were lower. T4 administration raised the absolute liver weights in all groups, even though there was no significant difference between relative weights in PTU and MMI groups. In Tx group, however, the relative weight was restored to control level. One of the constituents responsible for the increased relative liver weight was liver protein. The increased liver protein concentration (mg/g) was, however, not reflected in the synthesis rate which was uniformly low in all groups inspite of T4 therapy. Plasma albumin concentration was raised in hypothyroid rats which did not respond to T4 therapy. On the other hand, increased total plasma protein level was restored to normal. Relative 14C-glycine incorporation into albumin, fibrinogen, seromucoids and total proteins was reduced from 14 to 30%, 5.2 to 19% and 13 to 23% of control in PTU, MMI and Tx groups, respectively. Of these, only MMI and Tx groups appeared to be responsive to T4 therapy. Of all the protein fractions, fibrinogen synthesis was least affected by various treatments. To some extent these observations may be explained on the basis of altered general endocrine status and specific extra-thyroidal effects, rather than on the basis of thyroid status alone.

Increased liver protein and mRNA expression of natural killer cell-enhancing factor B (NKEF-B) in ayu ( Plecoglossus altivelis) after Aeromonas hydrophila infection

Natural killer cell-enhancing factor (NKEF) may mediate cellular responses to proinflammatory molecules. The liver proteins of Aeromonas hydrophila-infected ayu ( Plecoglossus altivelis) and healthy control fish were analyzed by 2DE. A protein, which increased significantly in diseased fish, was identified as NKEF-B by MALDI-TOF-MS. A full-length cDNA clone of this protein was subsequently isolated. It contains 1092 bp with an open reading frame of 591 bp, coding for 197 amino acids with MW 21.9 kDa and p I 6.38, values similar to those determined by 2DE. Ayu NKEF-B had highest similarity (93.1% amino acid identity) to those of carp and zebrafish. Phylogenetic analysis showed that ayu NKEF-B falls into the fish NKEF-B cluster and is most closely related to that of carp and zebrafish. It was determined that ayu NKEF-B mRNA expression was significantly increased in many tissues at the early stage of bacterial infection. In conclusion, the increased NKEF-B mRNA and protein expression in ayu were closely associated with A. hydrophila infection.

Insulin stimulates muscle protein synthesis in neonates during endotoxemia despite repression of translation initiation

Skeletal muscle protein synthesis is reduced in neonatal pigs in response to endotoxemia. To examine the role of insulin in this response, neonatal pigs were infused with endotoxin (LPS, 0 and 10 mug.kg(-1).h(-1)), whereas glucose and amino acids were maintained at fasting levels and insulin was clamped at fasting or fed (2 or 10 muU/ml) levels. Fractional rates of protein synthesis and translational control mechanisms were examined in longissimus dorsi muscle and liver. In the presence of fasting insulin, LPS reduced muscle protein synthesis (-29%), and increasing insulin to fed levels accelerated muscle protein synthesis in both groups (controls, +44%; LPS, +64%). LPS, but not insulin, increased liver protein synthesis by +28%. In muscle of fasting neonatal pigs, LPS reduced 4E-BP1 phosphorylation and eIF4E to eIF4G binding. In muscle of controls, but not LPS pigs, raising insulin to fed levels increased 4E-BP1 and S6K1 phosphorylation and eIF4E to eIF4G binding. In muscle and liver, neither LPS nor insulin altered eIF2B activity. eEF2 phosphorylation decreased in response to insulin in both LPS and control animals. The results suggest that, in endotoxemic neonatal animals, the response of protein synthesis to insulin is maintained despite suppression of mTOR-dependent translation initiation and eIF4E availability for eIF4F assembly. Maintenance of an anabolic response to the feeding-induced rise in insulin likely exerts a protective effect for the neonate to the catabolic processes induced by sepsis.

Chronic iron overload enhances inducible nitric oxide synthase expression in rat liver

Iron is an essential micronutrient promoting oxidative stress in the liver of overloaded animals and human, which may trigger the expression of redox-sensitive genes. We have tested the hypothesis that chronic iron overload (CIO) enhances inducible nitric oxide synthase (iNOS) expression in rat liver by extracellular signal-regulated kinase (ERK1/2) and NF-kappaB activation. CIO (diet enriched with 3%(wt/wt) carbonyl-iron for 12 weeks) increased liver protein carbonylation and decreased reduced glutathione (GSH) content and the GSH/GSSG ratio after 6 weeks, parameters that are normalized after 8-12 weeks of treatment. These changes are paralleled by higher phosphorylated-ERK1/2 to non-phosphorylated-ERK1/2 ratios at 6 and 8 weeks, increased NF-kappaB DNA binding to the iNOS gene promoter at 8-12 weeks, and higher iNOS mRNA expression and activity at 8 and 12 weeks. It is concluded that CIO triggers liver oxidative stress at early times, with upregulation of iNOS expression involving the ERK/NF-kappaB pathway at later times, a finding that may represent a hepatoprotective mechanism against CIO toxicity in addition to the recovery of GSH homeostasis.

Translational control of protein synthesis in muscle and liver of growth hormone-treated pigs.

GH treatment increases protein deposition and the efficiency of dietary protein used for growth. To identify the mechanisms that regulate tissue protein synthesis in response to exogenous GH treatment, fully fed, growing swine were treated with GH for 7 d. Fasted and fed pigs were infused with [1-(13)C]leucine to determine protein synthesis rates, and translation initiation factor activity levels were measured in skeletal muscle and liver. Feeding increased protein synthesis and translational efficiency in both muscle and liver of control and GH-treated pigs, and this was associated with increased 4E-BP1 and S6 kinase 1 phosphorylation, decreased association of eukaryotic initiation factor (eIF) 4E with 4E-BP1, and increased association of eIF4E with eIF4G. GH increased muscle protein synthesis and translational efficiency in fed pigs. GH increased liver protein synthesis of fasted and fed pigs in association with increased ribosome number. In muscle, but not liver, GH increased eIF2B activity and 4E-BP1 phosphorylation in both the fasted and fed state and increased the association of eIF4E with eIF4G in the fed state. We conclude that GH increases muscle protein synthesis in the fed state, in part, via mechanisms that enhance the binding of mRNA and methionyl-tRNA to the 40S ribosomal subunit, whereas GH increases liver protein synthesis in the fasted and fed states by increasing ribosome number. The results further indicate that the GH-induced protein synthetic response is dependent upon nutritional state and is tissue specific.

Effect of growth hormone on muscle and liver protein synthesis in septic rats receiving glutamine-enriched parenteral nutrition.

Administration of recombinant human growth hormone (rhGH) to critically ill adults in an attempt to attenuate catabolism was associated with increased morbidity and mortality. Possible explanations included inhibition of glutamine release from skeletal muscle and consequent restriction of splanchnic glutamine supply. In this study, we examined the effects of rhGH on plasma glutamine levels and on muscle and liver glutamine concentrations and protein synthesis rates in sepsis. We investigated the possibility that administration of supplemental glutamine might ameliorate any adverse effects of rhGH. Prospective study in rats rendered septic by cecal ligation and puncture. University hospital laboratory. A total of 78 male Wistar rats in six groups. Animals received 6-hr tail vein infusions, commencing 18 hrs after cecal ligation and puncture, of either (a) 0.9% sodium chloride, (b) a standard parenteral nutrition (PN) solution without glutamine, or (c) an isocaloric, isonitrogenous PN solution with glutamine. PN groups received 400 microg rhGH or equivolume 0.9% sodium chloride vehicle in a divided subcutaneous and intravenous dose at PN commencement. Sacrifice was at the end of the infusion period. A further group was unoperated and uninfused and killed at 24 hrs as baseline controls. Glutamine concentrations were measured by fluorometry. Protein synthesis in muscle and liver was measured by a "flooding-dose" technique employing L-[4-H]phenylalanine. Plasma glutamine was increased after cecal ligation and puncture except in the saline and glutamine with rhGH animals. Muscle glutamine was reduced after cecal ligation and puncture and was significantly lower in animals receiving standard PN with rhGH vs. saline alone. Liver glutamine was increased in animals receiving saline and those receiving standard PN with rhGH. PN, with or without glutamine, increased muscle protein synthesis, and the administration of rhGH tended to further increase this effect. Neither PN, glutamine, nor rhGH had an effect on the increased liver protein synthesis characteristic of sepsis. In sepsis, increased muscle protein synthesis with PN and rhGH administration is not associated with increased muscle glutamine levels. Administration of rhGH does not result in reduced liver glutamine levels or rates of hepatic protein synthesis. PN containing glutamine was no more efficacious than standard PN at increasing muscle protein synthesis.

Pulse Protein Feeding Pattern Restores Stimulation of Muscle Protein Synthesis during the Feeding Period in Old Rats

Muscle loss during aging could be related to a lower sensitivity of muscle protein synthesis to feeding. To overcome this decrease without increasing protein intake, we proposed to modulate the daily protein feeding pattern. We showed that consuming 80% of dietary proteins at noon (pulse pattern) improved nitrogen balance in elderly women. The present study was undertaken in rats to determine which tissues are the targets of the pulse pattern and what mechanisms are involved. Male Sprague-Dawley 11- and 23-mo-old rats (n = 32 per age) were fed 4 isoproteic (18% protein) meals/d for 10 d. Then half of the rats at each age were switched to a 11/66/11/11% repartition of daily proteins (pulse pattern) for 21 d. On d 21, rats were injected with a flooding dose of L-(13)C-valine (50 atom% excess, 150 micromol/100 g body) and protein synthesis rates were measured in liver, small intestine and gastrocnemius muscle in either the postabsorptive or the fed state. Epitrochlearis muscle degradation rates and plasma amino acid concentrations were measured at the same times. The pulse pattern had the following effects: 1) it significantly increased liver protein synthesis response to feeding and postprandial plasma amino acid concentrations at both ages; 2) it restored a significant response to feeding of gastrocnemius muscle protein synthesis in old rats; and 3) it had no effect in small intestine or on muscle breakdown. Thus, using a pulse pattern could be useful in preventing the age-related loss of muscle by increasing feeding-induced stimulation of muscle protein synthesis.

Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat

We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations. Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later. A group of non-operated animals were killed at the time of surgery. Protein synthesis was determined using a flooding dose of L-[4-(3)H] phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay. Protein synthesis in gastrocnemius muscle fell in all groups. Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation. After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals. CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation. Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals. Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP. Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation. In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation. In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations. Plasma glutamine concentrations are initially maintained, but fall later. In liver, protein synthesis is increased, while glutamine concentrations are preserved. These results support a peripheral-to-splanchnic glutamine flux in sepsis.

Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat

We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations. Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later. A group of non-operated animals were killed at the time of surgery. Protein synthesis was determined using a flooding dose of l-[4-3H] phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay. Protein synthesis in gastrocnemius muscle fell in all groups. Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation. After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals. CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation. Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals. Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP. Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation. In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation. In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations. Plasma glutamine concentrations are initially maintained, but fall later. In liver, protein synthesis is increased, while glutamine concentrations are preserved. These results support a peripheral-to-splanchnic glutamine flux in sepsis.

O.23 Increased liver protein synthesis after a caseinprotein meal in comparison to a soy protein meal

O.23 Increased liver protein synthesis after a caseinprotein meal in comparison to a soy protein meal

Effect of Human Growth Hormone on Human Pancreatic Carcinoma Growth, Protein, and Cell Cycle Kinetics

The role of human growth hormone (hGH) as a nutritional adjunct for cancer patients is controversial because of its potential mitogenic effects on tumor growth. No studies to date have examined the effect of hGH on human tumor responsein vivo. In Vitro:Athymic mice were injected (s.c.) daily with hGH (GH,n= 14) or saline (CTL,n= 14). On Day 10, serum was collected and added to human pancreatic carcinoma cells in culture.In Vivo:Athymic mice were inoculated (s.c.) with human pancreatic carcinoma cells. On Day 14, mice were randomized to receive daily either hGH (GH,n= 14) or saline (CTL,n= 12). On Day 29, animals received [3H]phenylalanine for tissue protein fractional synthetic rate (FSR) measurement. Tumors were excised and cell cycle kinetics analyzed. Data are expressed as mean ± SEM. Statistical analysis was performed by unpairedttest and/or ANOVA where appropriate.In Vitro:Serum from GH-treated animals had elevated IGF-1 levels (287 ± 34 ng/ml vs 157 ± 53 ng/ml,P< 0.001) and significantly stimulated cell growth (No. cells × 103/well) compared with CTL serum (925 ± 31 vs 747 ± 38,P< 0.001).In Vivo:Serum from GH-treated animals had elevated IGF-1 levels (287 ± 34 ng/ml vs 157 ± 53 ng/ml,P< 0.001) and significantly stimulated cell growth (No. cells × 103/well) compared with CTL serum (925 ± 31 vs 747 ± 38,P< 0.001).In Vivo:Growth hormone had no significant effect on tumor growth rate (mm3/day) (1.45 ± 0.47 CTL vs 1.57 ± 0.66 GH), final tumor weight (mg) (0.19 ± 0.15 CTL vs 0.17 ± 0.06 GH), DNA Index (1.5 ± 0.1 CTL vs 1.5 ± 0.1 GH), percent S phase (20.3 ± 3.3 CTL vs 22.1 ± 3.0 GH), or tumor FSR (%/day) (51.1 ± 17.8 CTL vs 70.2 ± 61.1 GH). Growth hormone significantly elevated serum IGF-1 levels (ng/ml) (176 ± 48 CTL vs 222 ± 53 GH,P< 0.005) and liver FSR (%/day) (62.8 ± 17.8 CTL vs 79.7 ± 12.7 GH,P< 0.005). Serum of GH-treated mice increased human pancreatic cell growthin vitro. In vivo,GH administration raised serum IGF-1 levels and increased liver protein FSR, without tumor growth, cell cycle kinetics, or protein FSR.

Pentoxifylline decreases body weight loss and muscle protein wasting characteristics of sepsis.

Sepsis induces metabolic disorders that include loss of body weight, muscle wasting, and acute-phase protein synthesis in liver. Cytokines are generally recognized as active mediators of these disorders, and the implication of tumor necrosis factor (TNF) has been frequently discussed in the recent past. However, the identity of the active agent in alterations of protein metabolism is still controversial. To improve our understanding of the role of cytokines in mediating muscle wasting observed in sepsis, we investigated muscle and liver protein metabolism in the following three groups of rats: infected control rats (INF-C); infected rats pretreated with pentoxifylline (PTX-INF), which is a potent inhibitor of TNF secretion; and pair-fed rats for the PTX-INF group pretreated with pentoxifylline. Pentoxifylline nearly completely suppressed TNF secretion but did not influence the transient fall in rectal temperature, the decreased hematocrit, and the increased liver protein mass and synthesis observed in INF-C rats. Pentoxifylline decreased the anorexia, the loss of body weight and muscle protein observed in INF-C animals, and partially prevented the decrease in muscle protein synthesis induced by infection. The overall data indicate that pentoxifylline is an effective agent in mitigating the characteristic muscle protein wasting induced by sepsis and confirm the limited role of TNF in the mediation of the acute-phase protein synthesis. Our results suggest a probable implication of TNF in the regulation of protein balance in muscle but do not allow discarding possible implication of other mediators that would be inhibited by pentoxifylline.

Bioactivity of neolignans from fructus Schizandrae.

Fructus Schizandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. During past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glycogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schizandrae have an inducing effect on hepatic microsomal drug-metabolizing enzyme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in China as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From natural Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.