• Endocrine regulation
• Hormones
• Obesity
• Pituitary
• Prostate
• Prostate cancer

• Humans
• Male
• Prostate/physiology
• Prostate/metabolism
• Pituitary Gland/physiology
• Pituitary Gland/metabolism
• Pituitary Gland/cytology
• Animals
• Pituitary Hormones/metabolism
• Pituitary Hormones/physiology
• Prostatic Diseases/metabolism
• Prostatic Diseases/physiopathology
• Prostatic Neoplasms/metabolism

• Universidad de Córdoba

• Chronic liver disease
• Musculoskeletal disorder
• Osteoporosis
• Osteosarcopenia
• Sarcopenia

• Humans
• Liver Diseases/complications
• Liver Diseases/physiopathology
• Sarcopenia/physiopathology
• Sarcopenia/complications
• Chronic Disease
• Muscle Weakness/physiopathology
• Osteoporosis/etiology
• Bone Diseases/physiopathology
• Bone Diseases/complications

• child pugh class
• hepatic encephalopathy
• hepatocellular carcinoma
• hypoglycemia
• liver cirrhosis

• acute liver failure
• ferroptosis
• insulin-like growth factor-1
• iron loading
• mesenchymal stem cell

• Humans
• Mice
• Animals
• Hepcidins/adverse effects
• Hepcidins/metabolism
• Ferroptosis
• Liver Failure, Acute/therapy
• Liver Failure, Acute/chemically induced
• Liver Failure, Acute/pathology
• Mesenchymal Stem Cells/metabolism
• Umbilical Cord
• Mesenchymal Stem Cell Transplantation/methods
• Insulin-Like Growth Factor I/metabolism

• All-cause mortality.
• End-stage liver diseases
• Liver transplantation
• Perioperative stroke
• Triglyceride-glucose index

• Male
• Humans
• Female
• Liver Transplantation/adverse effects
• Retrospective Studies
• Liver
• Hospital Mortality
• Glucose
• Insulin Resistance
• Triglycerides
• Blood Glucose
• Risk Factors
• Biomarkers

• No. 2023WW501 "Five and five" project of the Third Affiliated Hospital of Sun Yat-Sen University
• No. 2023B110006 Science and Technology Planning Project of Guangdong Province - Regional Innovation Capacity and Support System Construction
• “Five and five” project of the Third Affiliated Hospital of Sun Yat-Sen University

• cirrhosis
• decompensation
• insulin-like growth factor 1
• liver functional reserve
• prognosis

• Animals
• Mice
• Cytokines
• Inflammation
• Liver Cirrhosis
• Macrophages

• R01 GM049039 NIGMS NIH HHS

• Cell therapy
• Cirrhosis
• Genetic engineering
• Liver disease
• Stem cells

The chronic liver diseases will slowly develop into liver fibrosis, cirrhosis, and even liver cancer if no proper control is performed with high efficiency. Up to now, the most effective treatment for end-stage liver diseases is liver transplantation. However, liver transplantation has the problems of donor deficiency, low matching rate, surgical complications, high cost, and immune rejection. These problems indicate that novel therapeutic strategies are urgently required. Mesenchymal stem cells (MSCs) are somatic stem cells with multidirectional differentiation potential and self-renewal ability. MSCs can secrete a large number of cytokines, chemokines, immunomodulatory molecules, and hepatotrophic factors, as well as produce extracellular vesicles. They alleviate liver diseases by differentiating to hepatocyte-like cells, immunomodulation, homing to the injured site, regulating cell ferroptosis, regulating cell autophagy, paracrine effects, and MSC-mitochondrial transfer. In this review, we focus on the main resources of MSCs, underlying therapeutic mechanisms, clinical applications, and efforts made to improve MSC-based cell therapy efficiency.

• MS-based proteomics
• clinical proteomics
• liver disease
• liver fibrosis
• tissue proteome atlas

• Humans
• Liver/metabolism
• Liver Cirrhosis/metabolism
• Non-alcoholic Fatty Liver Disease/metabolism
• Proteome/metabolism
• Proteomics

• Novo Nordisk Fonden (NNF)
• EC | H2020 | H2020 Priority Excellent Science | H2020 Research Infrastructures (INFRA)

Background: Congenital portosystemic shunts (CPSS) are rare vascular anomalies resulting in communications between the portal venous system and the systemic venous circulation, affecting an estimated 30,000 to 50,000 live births. CPSS can present at any age as a multi-system disease of variable severity mimicking both common and rare pediatric conditions. Case presentations: Case A: A vascular malformation was identified in the liver of a 10-year-old girl with tall stature, advanced somatic maturation, insulin resistance with hyperinsulinemia, hyperandrogenemia and transient hematuria. Work-up also suggested elevated pulmonary pressures. Case B: A young girl with trisomy 8 mosaicism with a history of neonatal hypoglycemia, transient neonatal cholestasis and tall stature presented newly increased aminotransferase levels at 6 years of age. Case C: A 3-year-old boy with speech delay, tall stature and abdominal pain underwent abdominal ultrasound (US) showing multiple liver nodules, diagnosed as liver hemangiomas by hepatic magnetic resonance imaging (MRI). Management and outcome: After identification of a venous malformation on liver Doppler US, all three patients were referred to a specialized liver center for further work-up within 12 to 18 months from diagnosis. Angio-computed tomography (CT) scan confirmed the presence of either an intrahepatic or extrahepatic CPSS with multiples liver nodules. All three had a hyperintense signal in the globus pallidus on T1 weighted cerebral MRI. Right heart catheterization confirmed pulmonary hypertension in cases A and C. Shunts were closed either using an endovascular or surgical approach. Liver nodules were either surgically removed if there was a risk of malignant degeneration or closely monitored by serial imaging when benign. Conclusion: These cases illustrate most of the common chief complaints and manifestations of CPSS. Liver Doppler US is the key to diagnosis. Considering portosystemic shunts in the diagnostic work-up of a patient with unexplained endocrine, liver, gastro-intestinal, cardiovascular, hematological, renal or neurocognitive disorder is important as prompt referral to a specialized center may significantly impact patient outcome.

• Abernethy malformation
• congenital portosystemic shunt
• hepatopulmonary syndrome
• liver nodules
• pulmonary arterial hypertension
• tall stature

Background and Aims: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) remains a serious entity with high mortality. Growth hormone (GH) is related to the liver metabolism and regeneration. The present study aimed to explore the changes and prognostic efficacy of GH on the outcome of HBV-ACLF.

Methods: A prospective cohort of 124 patients and a cross-sectional cohort of 142 subjects were enrolled. GH and insulin-like growth factor-1(IGF-1) were detected by ELISA. Thirty-day survival was collected and the association between GH and the 30-day mortality of HBV-ACLF was analyzed.

Results: The mean age of the whole prospective cohort was 46.61 ± 12.71 years, and 19 (15.3%) patients were female. The median (IQR) of GH levels in non-survivors were 1106.55 (674.25, 1922.4) pg/ml, which were significantly lower than in survivors (p < 0.001). In the cross-sectional cohort, GH level was significantly higher in liver cirrhosis - acute decompensation (LC-AD) group than liver cirrhosis (LC) group (p < 0.001) while IGF-1 decreased significantly in LC, LC-AD, ACLF groups than health control (HC) and chronic Hepatitis B (CHB) groups (p < 0.001). The area under the receiver operating characteristic curve (AUROC) of GH for predicting 30-day mortality was 0.793. We built a new prognostic model, namely MELD-GH, which showed better predictive efficacy than Child-Pugh, MELD, CLIF-SOFA, and CLIF-C ACLF scores.

Conclusions: Low GH predicted the poor outcome of HBV-ACLF patients. GH and IGF-1 levels were differently distributed among HC, CHB, LC, LC-AD, and ACLF patients. MELD-GH had better predictive accuracy when compared to Child-Pugh, MELD, CLIF-SOFA, and CLIF-C ACLF scores.

• acute-on-chronic liver failure
• growth hormone
• hepatitis B
• mortality
• prognostic model

• Estrogen
• Growth hormone
• Hypothalamus-pituitary axis
• Lactation
• Prolactin

• Animals
• Female
• Hormones/metabolism
• Humans
• Hypothalamo-Hypophyseal System/physiology
• Lactation/physiology
• Models, Biological

• breast cancer
• gene expression
• insulin-like growth factor 1
• prognosis
• recurrence

• Adult
• Aged
• Aged, 80 and over
• Brazil/epidemiology
• Breast Neoplasms/blood
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Breast Neoplasms/therapy
• Case-Control Studies
• Cell Differentiation
• Cell Proliferation
• Cross-Sectional Studies
• Female
• Gene Expression/genetics
• Humans
• Insulin-Like Growth Factor I/genetics
• Lymph Nodes/pathology
• Lymphatic Metastasis
• Middle Aged
• Neoplasm Grading/methods
• Neoplasm Recurrence, Local/genetics
• RNA, Messenger/genetics

• Child-Turcotte-Pugh score
• Insulin-like growth factor 1
• Liver cirrhosis
• Model for end-stage liver disease

• euthyroidism
• free thyroxine
• hyperthyroidism
• igf-1
• logtsh
• thyroid-stimulating hormone

• Adult
• Body Mass Index
• Female
• Graves Disease/blood
• Humans
• Hyperthyroidism/blood
• Insulin-Like Growth Factor I/analysis
• Linear Models
• Male
• Middle Aged
• Prospective Studies
• Taiwan
• Thyrotropin/analysis
• Thyrotropin/blood
• Thyroxine/analysis
• Thyroxine/blood

• IGF-1
• liver injury
• miR-214
• sevoflurane

• Animals
• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/metabolism
• Chemical and Drug Induced Liver Injury/metabolism
• Down-Regulation/drug effects
• Insulin-Like Growth Factor I/metabolism
• Liver/drug effects
• Liver/metabolism
• Male
• MicroRNAs/metabolism
• RNA, Messenger/metabolism
• Rats
• Rats, Sprague-Dawley
• Receptor, IGF Type 1/metabolism
• Sevoflurane/pharmacology
• Up-Regulation/drug effects

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

• IGF-1
• IGFBP-1
• NAFLD
• NASH
• fibrosis

Insulin-like growth factor I (IGF-I) has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE) was shown to be induced by elevated intracranial dopamine (DA). The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS) was found in neurons. Ribosomal S6 protein kinase (RSK) phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2). In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95–nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95–nNOS interactions in MHE.

• ERK1/2/RSK pathway
• PSD95–nNOS interaction
• dopamine
• insulin-like growth factor I
• minimal hepatic encephalopathy

• Anti-Müllerian hormone
• Antiviral therapy
• HBV
• HCV
• Sustained viral response

• Cell therapy
• Liver fibrosis
• Mesenchymal stem cells

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

• Breast cancer
• Genetic polymorphism
• IGF-1
• Status menopausal
• qPCR

We have previously reported that persons co-infected with HIV and hepatitis C virus (HCV) had liver disease stages similar to HIV-uninfected individuals who were approximately 10 years older. Insulin-like growth factor 1(IGF-1) levels have long been known to decline with advancing age in humans and non-humans alike. We examined whether HIV infection affects the expected decline in IGF-1 in persons with chronic hepatitis C virus (HCV) infection and if that alteration in IGF-1 decline contributes to the link between HIV, aging, and liver disease progression.

A total of 553 individuals with HCV infection were studied from the AIDS Linked to the Intravenous Experience (ALIVE) cohort for whom more than 10 years of follow-up was available. Serum IGF-1 levels were determined by ELISA and evaluated according to baseline characteristics and over time by HIV status and liver disease progression. Linear regression with generalized estimating equations was used to determine whether IGF-1 decline over time was independently associated with liver disease progression.

Baseline IGF-1 levels were strongly associated with age (P < 0.0001) but not with gender or HIV infection. Levels of IGF-1 declined at a rate of -1.75 ng/mL each year in HCV mono-infected individuals and at a rate of -1.23 ng/mL each year in HIV/HCV co-infected individuals (P < 0.05). In a multivariable linear regression model, progression of liver fibrosis was associated with HIV infection and age, as well as with a slower rate of IGF-1 decline (P = 0.001); however, the rate of IGF-1 decline did not alter the strength of the associations between HIV, liver disease, and age.

The normal decline in IGF-1 levels with age was attenuated in HIV/HCV co-infected individuals compared to those with HCV mono-infection, and slower IGF-1 decline was independently associated with liver disease progression.

• Fibrosis
• HIV-1
• Hepatitis C
• IGF-1
• Liver

Obesity is a major health problem that courses with severe comorbidities and a drastic impairment of homeostasis and function of several organs, including the prostate gland (PG). The endocrine–metabolic regulatory axis comprising growth hormone (GH), insulin and IGF1, which is drastically altered under extreme metabolic conditions such as obesity, also plays relevant roles in the development, modulation and homeostasis of the PG. However, its implication in the pathophysiological interplay between obesity and prostate function is still to be elucidated. To explore this association, we used a high fat–diet obese mouse model, as well as in vitro primary cultures of normal‐mouse PG cells and human prostate cancer cell lines. This approach revealed that most of the components of the GH/insulin/IGF1 regulatory axis are present in PGs, where their expression pattern is altered under obesity conditions and after an acute insulin treatment (e.g. Igfbp3), which might have some pathophysiological implications. Moreover, our results demonstrate, for the first time, that the PG becomes severely insulin resistant under diet‐induced obesity in mice. Finally, use of in vitro approaches served to confirm and expand the conception that insulin and IGF1 play a direct, relevant role in the control of normal and pathological PG cell function. Altogether, these results uncover a fine, germane crosstalk between the endocrine–metabolic status and the development and homeostasis of the PG, wherein key components of the GH, insulin and IGF1 axes could play a relevant pathophysiological role.

• IGF1
• insulin
• obesity
• prostate
• prostate cancer

• apoptosis
• insulin-like growth factor 1
• isoflurane
• liver injury
• necrosis

• endocrine dysfunction
• hormone
• liver transplantation

• Acute decompensation
• Acute-on-chronic liver failure
• Insulin-like growth factor binding protein 3
• Liver cirrhosis
• Prognosis

Studies have established a relationship between hypothalamic-pituitary dysfunction and the onset of liver damage, which may occasionally progress to cirrhosis. Patients with hypopituitarism can develop a metabolic syndrome-like phenotype. Insulin resistance is the main pathophysiological axis of metabolic syndrome and is the causal factor in the development of nonalcoholic fatty liver disease (NAFLD). We present the case of a young patient with liver cirrhosis of unknown aetiology that was finally attributed to panhypopituitarism.

• AKT
• FoxO3a
• GSK-3β
• IGF-1
• IGF-1R
• Liver cirrhosis

Hepatic fibrosis and cirrhosis cause strong human suffering and necessitate a monetary burden worldwide. Therefore, there is an urgent need for the development of therapies. Pre-clinical animal models are indispensable in the drug discovery and development of new anti-fibrotic compounds and are immensely valuable for understanding and proofing the mode of their proposed action. In fibrosis research, inbreed mice and rats are by far the most used species for testing drug efficacy. During the last decades, several hundred or even a thousand different drugs that reproducibly evolve beneficial effects on liver health in respective disease models were identified. However, there are only a few compounds (e.g., GR-MD-02, GM-CT-01) that were translated from bench to bedside. In contrast, the large number of drugs successfully tested in animal studies is repeatedly tested over and over engender findings with similar or identical outcome. This circumstance undermines the 3R (Replacement, Refinement, Reduction) principle of Russell and Burch that was introduced to minimize the suffering of laboratory animals. This ethical framework, however, represents the basis of the new animal welfare regulations in the member states of the European Union. Consequently, the legal authorities in the different countries are halted to foreclose testing of drugs in animals that were successfully tested before. This review provides a synopsis on anti-fibrotic compounds that were tested in classical rodent models. Their mode of action, potential sources and the observed beneficial effects on liver health are discussed. This review attempts to provide a reference compilation for all those involved in the testing of drugs or in the design of new clinical trials targeting hepatic fibrosis.

• 3R principle
• animal experimentation
• clinical trials
• collagen
• hepatic fibrosis
• therapy
• translational medicine
• α-smooth muscle actin

• hepatocellular carcinoma
• insulin resistance
• insulin signalling

• IGF-I
• chronic liver disease
• growth hormone

• Acyl ghrelin
• Deacylation
• Liver failure
• Liver transplantation

• Biomarkers/blood
• Biomarkers/metabolism
• Female
• Graft Survival
• Human Growth Hormone/blood
• Humans
• Insulin-Like Growth Factor I/metabolism
• Liver Transplantation/adverse effects
• Male
• Middle Aged
• Patient Outcome Assessment
• Postoperative Period
• Risk Factors
• Time Factors
• Tissue Donors

Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines.

We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings.

Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.

• fasting
• gene expression
• insulin-like growth factor-1 (igf-1)
• insulin-like growth factor-binding protein 2 (igfbp-2)
• liver
• peroxisome-proliferator-activated receptor α (pparα)
• g6pc, glucose-6-phosphatase catalytic subunit
• hek, human embryonic kidney
• igf, insulin-like growth factor
• igf-1r, insulin-like growth factor-1 receptor
• igfbp, insulin-like growth factor-binding protein
• mtor, mammalian target of rapamycin
• pck1, phosphoenolpyruvate carboxykinase 1
• ppar, peroxisome-proliferator-activated receptor
• ppre, peroxisome-proliferator-responsive element
• qpcr, quantitative pcr
• s6k, s6 kinase
• wt, wild-type

• Animals
• Cells, Cultured
• Fasting/metabolism
• Gene Expression Regulation/drug effects
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Insulin-Like Growth Factor Binding Protein 2/genetics
• Insulin-Like Growth Factor I/metabolism
• Liver/drug effects
• Liver/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PPAR alpha/deficiency
• PPAR alpha/genetics
• PPAR gamma/agonists
• Peroxisome Proliferators/pharmacology
• Phosphorylation
• Proto-Oncogene Proteins c-akt/metabolism
• Pyrimidines/pharmacology
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Rosiglitazone
• Signal Transduction
• Thiazolidinediones/pharmacology
• Up-Regulation/drug effects

• ros
• igf-1
• cancer
• apoptosis
• bile acids

• ATP Binding Cassette Transporter, Subfamily B/genetics
• Animals
• Bile Acids and Salts/metabolism
• Cholestasis/complications
• Growth Hormone/metabolism
• Hepatocytes/physiology
• Homeostasis
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• Liver Neoplasms, Experimental/etiology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Reactive Oxygen Species/metabolism
• Receptors, Somatotropin/genetics
• Up-Regulation
• ATP-Binding Cassette Sub-Family B Member 4