• Humans
• Human Growth Hormone/therapeutic use
• Randomized Controlled Trials as Topic
• Fatty Liver/drug therapy
• Treatment Outcome
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/complications
• Biomarkers/blood
• gamma-Glutamyltransferase/blood
• Liver/metabolism

• DNA damage repair
• Insulin like growth factor 1(IGF1)
• Lipid metabolism
• Liver fibrosis
• Oxidative stress

• Humans
• Insulin-Like Growth Factor I/metabolism
• Receptor, IGF Type 1/metabolism
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Animals
• Signal Transduction
• DNA Damage
• DNA Repair
• Oxidative Stress
• Liver/metabolism
• Liver/pathology
• Lipid Metabolism

• growth hormone
• insulin-like growth factor-1
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis

• Adult
• Aged
• Carcinoma, Hepatocellular
• Cross-Sectional Studies
• Diabetes Mellitus, Type 2
• Female
• Human Growth Hormone
• Humans
• Insulin-Like Growth Factor I
• Lipids
• Liver Cirrhosis/etiology
• Liver Cirrhosis/pathology
• Liver Neoplasms
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease
• Obesity/complications
• Overweight/complications
• Young Adult

• R01 DK095792 NIDDK NIH HHS
• UL1 TR002541 NCATS NIH HHS
• K24 HL092902 NHLBI NIH HHS
• UL1 TR001102 NCATS NIH HHS
• UL1 TR000170 NCATS NIH HHS
• K24 DK109940 NIDDK NIH HHS
• K23 DK113220 NIDDK NIH HHS
• T32 DK007028 NIDDK NIH HHS
• K23 DK115903 NIDDK NIH HHS
• K23 DK113252 NIDDK NIH HHS
• National Institutes of Health
• Doris Duke Charitable Foundation
• Harvard Clinical and Translational Science Center
• National Center for Advancing Translational Sciences

The outbreak of Coronavirus Disease 2019 (COVID-19) has been increasing rapidly. This disease causes an increase in proinflammatory cytokine production that leads to cytokine storm or cytokine release syndrome (CRS). Autologous activated platelet-rich plasma (aaPRP) contains various types of growth factors and anti-inflammatory cytokines that may have the potential to suppress CRS. This study of phase I/II trial was aimed to evaluate the safety and efficacy of aaPRP to treat severe COVID-19 patients.

A total of 10 severe COVID-19 patients from Koja Regional Public Hospital (Koja RPH) were admitted to the intensive care unit (ICU). All patients received aaPRP administration three times. Primary outcomes involving the duration of hospitalization, oxygen needs, time of recovery, and mortality were observed. Secondary outcomes involving C-reactive protein (CRP), neutrophil, lymphocyte, and lymphocyte-to-CRP (LCR) and neutrophil-lymphocyte ratio (NLR) were analyzed.

All patients were transferred to the ICU with a median duration of 9 days. All patients received oxygen at enrollment and nine of ten patients recovered from the ICU and transferred to the ward room. There was one patient who passed away in the ICU due to heart failure. The results of secondary outcomes showed that CRP value and lymphocytes counts were significantly decreased while neutrophils, LCR, and NLR were slightly increased after aaPRP administration.

Our results of the phase I/II trial demonstrated that the use of aaPRP in severe COVID-19 patients was safe and not associated with serious adverse events, which showed that aaPRP was a promising adjunctive therapy for severe COVID-19 patients.

• Nonalcoholic fatty liver disease (NAFLD)
• glucose
• human immunodeficiency virus
• insulin-like growth factor-1
• insulin-like growth factor–binding proteins
• nonalcoholic steatohepatitis (NASH)

• Adult
• Blood Glucose/metabolism
• Double-Blind Method
• Female
• Follow-Up Studies
• Gonadotropin-Releasing Hormone/analogs & derivatives
• Growth Hormone-Releasing Hormone/analogs & derivatives
• Growth Hormone-Releasing Hormone/therapeutic use
• HIV
• HIV Infections/blood
• HIV Infections/complications
• HIV Infections/drug therapy
• HIV Infections/metabolism
• Humans
• Insulin-Like Growth Factor Binding Proteins/blood
• Insulin-Like Growth Factor Binding Proteins/genetics
• Insulin-Like Growth Factor I/genetics
• Insulin-Like Growth Factor I/metabolism
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Severity of Illness Index

• P30 DK040561 NIDDK NIH HHS
• KL2 TR002542 NCATS NIH HHS
• UL1 TR002541 NCATS NIH HHS
• U01 AI115711 NIAID NIH HHS
• U19 AI082630 NIAID NIH HHS
• K23 HD100266 NICHD NIH HHS
• R01 DK108370 NIDDK NIH HHS
• R01 AI136715 NIAID NIH HHS
• UL1 TR001102 NCATS NIH HHS
• R01 DK114144 NIDDK NIH HHS
• National Institutes of Health
• National Institute of Allergy and Infectious Diseases
• National Cancer Institute

• Alcohol consumption
• Fetal growth restriction
• IGF-1
• Oxidative stress
• Placenta

• Cobb E
• Hubbard F15
• IGF1
• IGFBP2
• SNP
• TGFß3
• chicken
• growth
• meat

• Aging
• Central nervous system
• Dopamine
• Estrogens
• IGF-1
• Parkinson’s disease

• Brain
• Dopamine
• Female
• Humans
• Insulin-Like Growth Factor I
• Neurons
• Parkinson Disease

• Atherosclerosis
• Cardiovascular disease
• Cardiovascular system
• IGF1
• Metabolic syndrome

• IGF-1
• RT-qPCR
• gene ontology
• microarrays
• neuroprotection
• neurotrophic factors

Nonalcoholic fatty liver disease is one of the major complications of obesity, occurring already in pediatric age. Insulin like growth factor-I has been proposed as a potential therapeutic agent for its beneficial effect in experimental liver fibrosis. The aim of this work was to investigate the expression of insulin-like growth factor-I and its receptor in the liver of children with biopsy-proven nonalcoholic fatty liver disease and relate it to liver histological features.

45 obese children and adolescents (14 females and 31 males) with nonalcoholic fatty liver disease were included. Insulin like growth factor-I and its receptor expression was evaluated in liver tissue by immunofluorescence and qPCR.

The expression of insulin like growth factor-I and its receptor were significantly related to fibrosis and were higher in children with stage 3 fibrosis compared to stage 1 and 2 (p<0.001 and p = 0.007 respectively). mRNA of insulin like growth factor-I receptor was higher in more advanced stages of fibrosis (p<0.001). Furthermore, the expression of insulin like growth factor-I and its receptor in hepatic stellate cells, the cell type mostly involved in fibrosis progression, was significantly increased in stage 3 fibrosis compared to stage 1 (p = 0.01 and p = 0.008 respectively).

We demonstrated for the first time that insulin like growth factor-I and its receptor are upregulated in children with nonalcoholic fatty liver disease. These findings give a new hint for the potential therapeutic use of insulin like growth factor-I in pediatric nonalcoholic fatty liver disease complicated by liver fibrosis.

• Adolescent
• Biopsy
• Child
• Cohort Studies
• Disease Progression
• Female
• Gene Expression
• Humans
• Insulin-Like Growth Factor I/genetics
• Insulin-Like Growth Factor I/metabolism
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/complications
• Liver Cirrhosis/genetics
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Male
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Pediatric Obesity/complications
• Pediatric Obesity/genetics
• Pediatric Obesity/metabolism
• Pediatric Obesity/pathology
• Receptor, IGF Type 1/genetics
• Receptor, IGF Type 1/metabolism

Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2) act in response to growth hormone (GH). Other IGF family components include at least six binding proteins (IGFBP1 to 6), manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R). The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth), and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD), lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC) stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma). Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.

• cirrhosis
• hepatocellular carcinoma
• insulin-like growth factor system
• liver
• nonalcoholic fatty liver disease

• Cellular protection
• Free radicals
• IGF-1
• Mitochondria
• Oxidative damage

• Animals
• Apoptosis/genetics
• Hormone Replacement Therapy
• Insulin-Like Growth Factor I/deficiency
• Insulin-Like Growth Factor I/genetics
• Insulin-Like Growth Factor I/therapeutic use
• Liver/metabolism
• Loss of Heterozygosity
• Male
• Mice
• Mice, Transgenic
• Mitochondria, Liver/metabolism
• Mitochondria, Liver/pathology
• Mitochondrial Diseases/drug therapy
• Mitochondrial Diseases/genetics
• Oxidative Stress/genetics
• Treatment Outcome

Cell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl₄)-induced liver damage compared to healthy controls (Wt Igf^+/+). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1^+/−).

Three groups of 25 ± 5-week-old healthy male mice (Wt Igf^+/+) were included in the protocol: untreated controls (Wt). Controls that received CCl₄ (Wt + CCl₄) and Wt + CCl₄ were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl₄ + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1^+/−) groups were studied: untreated Hz, Hz + CCl₄, and Hz + CCl₄ + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM.

An altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl₄ + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl₄. Moreover, there was a correlation between MDA levels and the histological damage score (Pearson’s r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma.

IGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series (healthy and IGF-1-deficient mice) with acute liver damage, suggesting that low doses of IGF-1, in acute liver damage, could be a feasible therapeutic option.

The online version of this article (doi:10.1186/s12967-017-1198-4) contains supplementary material, which is available to authorized users.

• Acute liver damage
• Fibrogenesis
• Hepatoprotection
• IGF-1
• Oxidative damage

• Acute liver damage
• Fibrogenesis
• GH/IGF-1 axis
• IGF-1
• Mitochondrial protection
• Non-alcoholic fatty liver disease
• Oxidative damage
• Steatosis

The mechanisms responsible for the development of nonalcoholic fatty liver disease (NAFLD) and progression to nonalcoholic steatohepatitis (NASH) are incompletely understood. Growing evidence suggests that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may have roles in the development and progression of NAFLD. We hypothesized that lower serum IGF-1 levels would be associated with increased liver fat accumulation, inflammation, and fibrosis in a group of meticulously phenotyped obese subjects with liver biopsies.

A retrospective, cross-sectional study was performed at Massachusetts General Hospital, Boston, MA, USA and St. Mary's Hospital, Richmond, VA, USA. Liver biopsies were performed in 142 subjects during NAFLD work-up or bariatric surgery and were graded by a single, blinded pathologist. Main outcome measures included liver histology and serum IGF-1.

Mean age was 52±10 years and body mass index (BMI) was 43±9 kg/m². Mean serum IGF-1 was lower in subjects with lobular inflammation (112±47 vs. 136±57 ng/ml, P=0.01), hepatocyte ballooning (115±48 vs. 135±57 ng/ml, P=0.05), higher fibrosis stage (stage 2–4 vs. 0–1; 96±40 vs. 125±51 ng/ml, P=0.005), and NASH (109±45 vs. 136±57 ng/ml, P=0.002). All results remained significant after controlling for age, BMI, and a diagnosis of diabetes, and all but hepatocyte ballooning (trend, P=0.06) remained significant after excluding individuals with cirrhosis. Steatosis was not significantly associated with mean serum IGF-1 levels.

Low serum IGF-1 levels are associated with increased histologic severity of NAFLD when rigorously controlled for age, BMI, the presence of diabetes, and after the exclusion of subjects with cirrhosis. Further investigation is warranted to determine the differential effects of GH and IGF-1 on the development and progression of NAFLD, which could further elucidate pathophysiology and identify therapeutic targets.

• Cytoskeleton
• Extracellular matrix
• Gene expression
• Hepatocytes
• IGF-1
• Tight junctions

Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs’ activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs in vitro and in vivo. Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis.

• Aminaphtone (PubChem CID: 84621)
• Cytokines
• Endothelial cells
• Endothelin-1
• Gene expression profiling
• Inflammation

• Cell Line
• Cytokines/genetics
• Cytokines/metabolism
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Gene Expression Profiling
• Humans
• Immunomodulation/drug effects
• Interleukin-1beta/pharmacology
• para-Aminobenzoates/pharmacology

• lipid metabolism
• insulin resistance
• dyslipidemia
• aging
• oxidative stress
• gh/igf-i axis
• obesity
• mitochondrial dysfunction
• cellular protection

• Animals
• Carbohydrate Metabolism
• Humans
• Insulin Resistance
• Insulin-Like Growth Factor I/metabolism
• Lipid Metabolism
• Metabolic Syndrome/metabolism
• Models, Biological

• Amino Acid Sequence
• Animals
• Ascorbic Acid/pharmacology
• Blotting, Western
• Cloning, Molecular
• DNA, Complementary/genetics
• Gene Expression Profiling
• Gene Expression Regulation, Enzymologic/drug effects
• Gene Expression Regulation, Enzymologic/genetics
• Gene Expression Regulation, Enzymologic/physiology
• Molecular Sequence Data
• Oligonucleotides/genetics
• Phylogeny
• Porifera/enzymology
• Porifera/metabolism
• Prolyl Hydroxylases/genetics
• Protein Subunits/genetics
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

Bone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone.

Several proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice, Igf^+/+, n = 10), heterozygous Igf^+/- group with partial IGF-I deficiency (Hz, n = 10), and heterozygous Igf^+/- mice treated with IGF-I for 10 days (Hz + IGF-I, n = 10).

Data in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity.

Low doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor.

• laron syndrome
• liver cirrhosis
• aging
• oxidative stress
• gh/igf-i axis
• mitochondrial dysfunction
• cellular protection
• growth
• cancer protection

• Animals
• Disease
• Growth and Development
• Humans
• Insulin-Like Growth Factor I/chemistry
• Insulin-Like Growth Factor I/deficiency
• Insulin-Like Growth Factor I/metabolism
• Organ Specificity

AIM: To compare rifaximin and insulin-like growth factor (IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.

METHODS: Rats with CCl₄-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups: Cirrhosis; Cirrhosis + IGF-1; Cirrhosis + rifaximin; Controls; Controls + IGF-1; and Controls + rifaximin. An oral glutamine-challenge test was performed, and plasma and cerebral ammonia, glucose, bilirubin, transaminases, endotoxemia, brain water content and ileocecal cultures were measured and liver histology was assessed.

RESULTS: Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups, and improved some liver function parameters (bilirubin, alanine aminotransferase and aspartate aminotransferase). These effects were associated with a significant reduction in cerebral water content. Blood and cerebral ammonia levels, and area-under-the-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals. By contrast, IGF-1 administration failed to improve most alterations observed in cirrhosis.

CONCLUSION: By reducing gut bacterial overgrowth, only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema, alterations associated with hepatic encephalopathy.

• Hyperammonemia
• Low-grade brain edema
• Hepatic encephalopathy
• Rifaximin
• Insulin-like growth factor 1
• Cirrhosis

AIM: To characterize the mitochondrial dysfunction in experimental cirrhosis and to study whether insulin-like growth factor-I(IGF-I) therapy (4 wk) is able to induce beneficial effects on damaged mitochondria leading to cellular protection.

METHODS: Wistar rats were divided into three groups: Control group, untreated cirrhotic rats and cirrhotic rats treated with IGF-Itreatment (2 &mgr;g/100 g bw/d). Mitochondrial function was analyzed by flow cytometry in isolated hepatic mitochondria, caspase 3 activation was assessed by Western blot and apoptosis by TUNEL in the three experimental groups.

RESULTS: Untreated cirrhotic rats showed a mitochondrial dysfunction characterized by a significant reduction of mitochondrial membrane potential (in status 4 and 3); an increase of intramitochondrial reactive oxigen species (ROS) generation and a significant reduction of ATPase activity. IGF-Itherapy normalized mitochondrial function by increasing the membrane potential and ATPase activity and reducing the intramitochondrial free radical production. Activity of the electron transport complexes Iand III was increased in both cirrhotic groups. In addition, untreated cirrhotic rats showed an increase of caspase 3 activation and apoptosis. IGF-Itherapy reduced the expression of the active peptide of caspase 3 and resulted in reduced apoptosis.

CONCLUSION: These results show that IGF-Iexerts a mitochondrial protection in experimental cirrhosis leading to reduced apoptosis and increased ATP production.

• Insulin-like growth factor-I
• Cirrhosis
• Mitochondrial protection
• Caspases
• Apoptosis
• Oxidative damage

• Adenosine Triphosphatases/metabolism
• Aging/drug effects
• Animals
• Antioxidants/metabolism
• Caspases/metabolism
• Cytoprotection/drug effects
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Electron Transport Complex IV/metabolism
• Hepatocytes/drug effects
• Insulin-Like Growth Factor I/pharmacology
• Male
• Matrix Metalloproteinases/metabolism
• Mitochondria, Liver/drug effects
• Mitochondria, Liver/metabolism
• Mitochondria, Liver/physiology
• Oxidative Stress/drug effects
• Oxygen Consumption/drug effects
• Proton Pumps/metabolism
• Rats
• Rats, Wistar

• Animals
• Capillaria
• Colorimetry
• Enoplida Infections/blood
• Female
• Hydroxyproline/analysis
• Liver/chemistry
• Liver Cirrhosis, Experimental/blood
• Male
• Rats
• Rats, Wistar
• Reproducibility of Results

• Animals
• Female
• Gene Expression
• Genetic Therapy/methods
• Genetic Vectors/administration & dosage
• Humans
• Injections
• Insulin-Like Growth Factor Binding Protein 3/genetics
• Insulin-Like Growth Factor Binding Protein 3/metabolism
• Insulin-Like Growth Factor I/genetics
• Insulin-Like Growth Factor I/metabolism
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis, Experimental/metabolism
• Liver Cirrhosis, Experimental/pathology
• Liver Cirrhosis, Experimental/prevention & control
• Luciferases/genetics
• Male
• Mice
• Mice, Inbred BALB C
• Rats
• Rats, Wistar
• Simian virus 40/genetics
• Transduction, Genetic/methods
• Transgenes

N/A

• N/A

• Amino Acid Sequence
• Animals
• Fibrosis/prevention & control
• Insulin-Like Growth Factor I/antagonists & inhibitors
• Insulin-Like Growth Factor I/physiology
• Kidney/pathology
• Male
• Nephrectomy
• Oligopeptides/chemical synthesis
• Oligopeptides/pharmacology
• Rats
• Rats, Wistar

• Base Sequence
• Binding Sites
• Chromatin Immunoprecipitation
• DNA/genetics
• DNA Primers/chemistry
• DNA-Binding Proteins/chemistry
• Down-Regulation
• Gene Expression Regulation
• HeLa Cells
• Humans
• Luciferases/metabolism
• Models, Genetic
• Molecular Sequence Data
• Plasmids/metabolism
• Procollagen-Proline Dioxygenase/biosynthesis
• Procollagen-Proline Dioxygenase/chemistry
• Procollagen-Proline Dioxygenase/genetics
• Promoter Regions, Genetic
• RNA, Messenger/metabolism
• RNA, Small Interfering/metabolism
• Response Elements
• Smoking
• Transcription Factors/metabolism
• Transcription, Genetic
• Transfection
• Transforming Growth Factor beta/metabolism
• Transforming Growth Factor beta1
• Up-Regulation

• R01 HL066053 NHLBI NIH HHS
• K08 HL080085-02 NHLBI NIH HHS
• K08 HL080085 NHLBI NIH HHS
• HL066053 NHLBI NIH HHS
• HL71608 NHLBI NIH HHS
• R01 HL071608 NHLBI NIH HHS

The exogenous administration of Insulin-like Growth Factor-I (IGF-I) induces hepatoprotective and antifibrogenic actions in experimental liver cirrhosis. To better understand the possible pathways behind the beneficial effect of IGF-I, the aim of this work was to investigate severe parameters involved in oxidative damage in hepatic tissue from cirrhotic animals treated with IGF-I (2 μg. 100 g^-1. day^-1). Iron and copper play an important role in oxidative mechanisms, producing the deleterious hydroxyl radical (*OH) that peroxides lipid membranes and damages DNA. Myeloperoxidase (MPO) and nitric oxide (NO) are known sources of free radicals and induce reduction of ferritin-Fe³⁺ into free Fe²⁺, contributing to oxidative damage.

Liver cirrhosis was induced by CCl₄ inhalation in Wistar male rats for 30 weeks. Healthy controls were studied in parallel (n = 10). Fe and Cu were assessed by atomic absoption spectrometry and iron content was also evaluated by Perls' staining. MPO was measured by ELISA and transferrin and ferritin by immunoturbidimetry. iNOS expression was studied by immuno-histochemistry.

Liver cirrhosis was histologically proven and ascites was observed in all cirrhotic rats. Compared to controls untreated cirrhotic rats showed increased hepatic levels of iron, ferritin, transferrin (p < 0.01), copper, MPO and iNOS expression (p < 0.01). However, IGF-treatment induced a significant reduction of all these parameters (p < 0.05).

the hepatoprotective and antifibrogenic effects of IGF-I in cirrhosis are associated with a diminution of the hepatic contents of several factors all of them involved in oxidative damage.

AIM: To investigate the relationship between insulin-like growth factor-I, -II (IGF-I and IGF-II), IGF-binding protein 3 (IGFBP-3) and Child-Pugh score in patients with liver cirrhosis, and to search for potential clinical markers of liver function.

METHODS: Forty-four patients with advanced liver cirrhosis of viral origin were divided into 3 groups according to severity of cirrhosis (Child-Pugh score) and 38 healthy subjects served as controls. Serum levels of IGF-I, IGF-II and IGFBP-3 were measured by immunoradiometric assay.

RESULTS: Serum IGF-I, IGF-II and IGFBP-3 levels were significantly lower in patients with cirrhosis than in controls, and serum concentrations of IGF-I, IGF-II and IGFBP-3 were associated with the severity of liver dysfunction, and dropped sharply during the progression of liver failure. Among these 3 parameters, serum IGF-II was the most sensitive and effective indicator for liver dysfunction. Concentrations of IGF-I < 30 ng/mL, IGF-II < 200 ng/mL and IGFBP-3 < 6 ng/mL implied a negative prognosis for patients with liver cirrhosis.

CONCLUSION: Serum IGF-I, IGF-II and IGFBP-3 may provide a new dimension in the assessment of liver dysfunction. Combined detection of serum IGF-I, IGF-II and IGFBP-3 with Child-Pugh score is more effective in predicting prognosis than Child-Pugh score alone.

• Adult
• Aged
• Aged, 80 and over
• Biomarkers
• Biopsy
• Female
• Humans
• Insulin-Like Growth Factor Binding Protein 3/blood
• Insulin-Like Growth Factor I/metabolism
• Insulin-Like Growth Factor II/metabolism
• Liver Cirrhosis/blood
• Liver Cirrhosis/pathology
• Male
• Middle Aged
• Predictive Value of Tests
• Prognosis

• Adult
• Aged
• Alleles
• Case-Control Studies
• Collagen Type I/genetics
• Collagen Type I, alpha 1 Chain
• Female
• Gene Frequency
• Genome
• Humans
• Hungary
• Insulin-Like Growth Factor I/genetics
• Insulin-Like Growth Factor I/therapeutic use
• Liver Cirrhosis, Biliary/complications
• Liver Cirrhosis, Biliary/genetics
• Microsatellite Repeats
• Middle Aged
• Osteoporosis/etiology
• Osteoporosis/genetics
• Polymerase Chain Reaction/methods
• Polymorphism, Genetic
• Statistics, Nonparametric

• Animals
• Apoptosis/drug effects
• Caspases/metabolism
• Cell Cycle/drug effects
• Cell Division/drug effects
• DNA/biosynthesis
• Hepatocytes/cytology
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• In Vitro Techniques
• Insulin-Like Growth Factor I/pharmacology
• Mitogen-Activated Protein Kinases/antagonists & inhibitors
• Mitogen-Activated Protein Kinases/genetics
• Mitogen-Activated Protein Kinases/metabolism
• Oligonucleotides, Antisense/genetics
• Oligonucleotides, Antisense/pharmacology
• Phosphorylation
• Rats
• Rats, Wistar
• Receptor, IGF Type 1/metabolism
• fas Receptor/metabolism

AIM: To evaluate respectively the effects of portaazygous disconnection (PAD), mesocaval shunt (MCS) and distal splenocaval shunt (DSCS) on the portasytemic shunting (PSS), hepatic function (HF), hepatic mitochondrial respiratory function (HMRF) and its ultrastructure, anti-oxidation ability (HAOA) and lipoperoxide (LPO), so as to provide theoretical basis to select a suitable operation.

METHODS: Using the cirrhotic portal hypertensive model induced by CCl₄/ethanol in Wristar rats, we investigated PSS, HF, HMRF and its HAOA and LPO during three wks after MCS, DSCS and PAD.

RESULTS: After MCS, the PSS were further increased, HF, HMRF and HAOA were significantly decreased, and LPO increased. Hepatic mitochondrial ultrastructure showed severely damaged. Only a little improvement was found on the third wk. After DSCS and PAD, above mentioned indexes were less influenced, and they were restored a little more quickly in DSCS groups than that in PAD groups. During the first postoperative wk, the PAD group showed the highest mortality.

CONCLUSION: DSCS may be a desirable operation among the three kinds of operation.

• N/A

• Animals
• Antioxidants/metabolism
• Carbon Tetrachloride
• Insulin-Like Growth Factor I/pharmacology
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Male
• Rats
• Rats, Wistar

• Animals
• Immunohistochemistry
• Insulin-Like Growth Factor I/antagonists & inhibitors
• Insulin-Like Growth Factor I/metabolism
• Interleukin-10/pharmacology
• Liver Cirrhosis, Experimental/metabolism
• Male
• Rats
• Rats, Sprague-Dawley
• Receptor, IGF Type 1/antagonists & inhibitors
• Receptor, IGF Type 1/metabolism

• Albumins/metabolism
• Cytokines/physiology
• Humans
• Insulin-Like Growth Factor I/physiology
• Leptin/physiology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/physiopathology
• Muscle Proteins/biosynthesis
• Muscle Proteins/metabolism
• Muscle, Skeletal/metabolism
• Muscular Atrophy/metabolism
• Myofibrils/metabolism