• animal model
• fruit fly
• insulin resistance
• metabolic disorder

• SNAIL2
• cancer stem cells
• epithelial-mesenchymal transition
• pancreatic cancer
• tumor spheroid

• Animals
• Antineoplastic Agents/therapeutic use
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Cell Line
• Cell Line, Tumor
• Drug Resistance, Neoplasm/genetics
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Insulin-Like Growth Factor Binding Protein 2/genetics
• Insulin-Like Growth Factor Binding Protein 2/metabolism
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• RNA Interference
• Snail Family Transcription Factors/genetics
• Snail Family Transcription Factors/metabolism
• Xenograft Model Antitumor Assays/methods
• Mice

• 17K09460 Grants-in-Aid KAKENHI from the Ministry of Education, Culture, Sports, Science, and Technology
• Sumitomo Dainippon Pharma Inc.

• Hu sheep
• curved hair
• dermal papilla cell
• insulin-like growth factor binding protein-5
• pregnancy-associated plasma protein A2

• Animals
• Cell Proliferation/genetics
• Gene Expression Profiling
• Hair Follicle/growth & development
• Hair Follicle/metabolism
• Insulin-Like Growth Factor Binding Protein 5/genetics
• Pregnancy-Associated Plasma Protein-A/genetics
• Sheep/genetics
• Sheep/growth & development
• Sheep, Domestic/genetics

• Acute kidney injury
• Cystatin C
• Liver cirrhosis
• NAG
• NGAL

Neuromuscular junction (NMJ) research is vital to advance the understanding of neuromuscular patho‐physiology and development of novel therapies for diseases associated with NM dysfunction. In vivo, the micro‐environment surrounding the NMJ has a significant impact on NMJ formation and maintenance via neurotrophic and differentiation factors that are secreted as a result of cross‐talk between muscle fibers and motor neurons. Recently we showed the formation of functional NMJs in vitro in a co‐culture of immortalized human myoblasts and motor neurons from rat‐embryo spinal‐cord explants, using a culture medium free from serum and neurotrophic or growth factors. The aim of this study was to assess how functional NMJs were established in this co‐culture devoid of exogenous neural growth factors. To investigate this, an ELISA‐based microarray was used to compare the composition of soluble endogenously secreted growth factors in this co‐culture with an a‐neural muscle culture. The levels of seven neurotrophic factors brain‐derived neurotrophic factor (BDNF), glial‐cell‐line‐derived neurotrophic factor (GDNF), insulin‐like growth factor‐binding protein‐3 (IGFBP‐3), insulin‐like growth factor‐1 (IGF‐1), neurotrophin‐3 (NT‐3), neurotrophin‐4 (NT‐4), and vascular endothelial growth factor (VEGF) were higher (p < 0.05) in the supernatant of NMJ culture compared to those in the supernatant of the a‐neural muscle culture. This indicates that the cross‐talk between muscle and motor neurons promotes the secretion of soluble growth factors contributing to the local microenvironment thereby providing a favourable regenerative niche for NMJs formation and maturation.

• cross-talk
• motor neurons
• muscle
• neural growth factors
• neuromuscular junction (NMJ)

• Differentiation
• embryonic stem cells
• fibroblast
• growth factor
• photoreceptor
• taurin and Retinoic Acid (RA).

A number of studies performed on rodents suggest that insulin-like growth factor 2 (IGF-2) or its analogs may possibly be used for treating some conditions like Alzheimer’s disease, Huntington’s disease, autistic spectrum disorders or aging-related cognitive impairment. Still, for translational research a comparative knowledge about the function of IGF-2 and related molecules in model organisms (rats and mice) and humans is necessary. There is a number of important differences in IGF-2 signaling between species. In the present review we emphasize species-specific patterns of IGF-2 expression in rodents, humans and some other mammals, using, among other sources, publicly available transcriptomic data. We provide a detailed description of Igf2 mRNA expression regulation and pre-pro-IGF-2 protein processing in different species. We also summarize the function of IGF-binding proteins. We describe three different receptors able to bind IGF-2 and discuss the role of IGF-2 signaling in learning and memory, as well as in neuroprotection. We hope that comprehensive understanding of similarities and differences in IGF-2 signaling between model organisms and humans will be useful for development of more effective medicines targeting IGF-2 receptors.

• CNS
• IGF-binding proteins
• IGF1R
• IGF2R/CI-M6P
• insulin receptor
• insulin-like growth factor 2
• learning and memory
• neuroprotection
• species-specific gene expression

• Alzheimer Disease/metabolism
• Animals
• Gene Expression Regulation
• Humans
• Insulin-Like Growth Factor II/biosynthesis
• Memory
• Mice
• Neuroprotective Agents/metabolism
• Protein Processing, Post-Translational
• Rats
• Receptor, IGF Type 2/metabolism
• Signal Transduction

Insulin-like growth factor-1 (IGF-1) is the principal mediator of growth hormone (GH), plays a crucial role in promoting cell growth and differentiation in childhood and continues to have an anabolic effect in adults. IGF-1 is part of a wide network of growth factors, receptors and binding proteins involved in mediating cellular proliferation, differentiation and apoptosis. Bioavailability of IGF-1 is affected by insulin-like growth factor binding proteins (IGFBPs) which bind IGF-1 in circulation with an affinity equal to or greater than that of the IGF-1 receptor (IGF-1R). The six IGFBPs serve as carrier proteins and bind approximately 98% of all circulating IGF-1. Other proteins known to bind IGF-1 include ten IGFBP-related proteins (IGFBP-rPs), albeit with lower affinities than the IGFBPs. IGF-1 expression levels vary in a number of clinical conditions suggesting it has the potential to provide crucial information as to the state of an individual’s health. IGF-1 is also a popular doping agent in sport and has featured in many high-profile doping cases in recent years. However, the existence of IGFBPs significantly reduces the levels of immunoreactive IGF-1 in samples, requiring multiple pre-treatment steps that reduce reproducibility and complicates interpretation of IGF-1 assay results. Here we provide an overview of the IGF network of growth factors, their receptors and the entirety of the extended family of IGFBPs, IGFBP-rPs, E peptides as well as recombinant IGF-1 and their derivatives. We also discuss issues related to the detection and quantification of bioavailable IGF-1.

• ALS
• IGF
• IGF-1R
• IGF-2R
• IGFBP
• IGFBP-rP
• IGFBPL1
• doping
• insulin
• insulin-like growth factor

• Animals
• Apoptosis
• Biomarkers/metabolism
• Cell Differentiation
• Cell Proliferation
• Doping in Sports
• Growth Hormone/metabolism
• Humans
• Insulin/metabolism
• Insulin-Like Growth Factor I/metabolism
• Intercellular Signaling Peptides and Proteins/metabolism
• Mice
• Neoplasms/metabolism
• Peptides/chemistry
• Performance-Enhancing Substances/pharmacology
• Protein Binding
• Receptor, IGF Type 1/metabolism
• Recombinant Proteins/chemistry
• Substance Abuse Detection/methods

The insulin signaling (IIS) pathway plays an important role in the metabolism, growth, development, reproduction, and longevity of an organism. As a key member of the IIS pathway, insulin-like growth factor binding proteins (IGFBPs) are widely distributed a family in invertebrates and vertebrates that are critical in various aspects of physiology. As an important mariculture species, the growth of Pacific white shrimp, Litopenaeus vannamei, is one of the most concerning characteristics in this area of study. In this study, we identified three IGFBP genes in the genome of L. vannamei and analyzed their gene structures, phylogenetics, and expression profiles. LvIGFBP1 was found to contain three domains (the insulin growth factor binding (IB) domain, the Kazal-type serine proteinase inhibitor (Kazal) domain, and the immunoglobulin C-2 (IGc2) domain), while LvIGFBP2 and LvIGFBP3 only contained a single IB domain. LvIGFBP1 exhibited high expression in most tissues and different developmental stages, while LvIGFBP2 and LvIGFBP3 were only slightly expressed in hemocytes. The RNA interference of LvIGFBP1 resulted in a significantly smaller increment of body weight than that of control groups. These results will improve our understanding of the conservative structure and function of IGFBPs and show potential applications for the growth of shrimp.

• Litopenaeus vannamei
• gene expression
• gene structures
• growth
• insulin growth factor binding proteins

• Amino Acid Sequence
• Animals
• Gene Expression
• Insulin/metabolism
• Insulin-Like Growth Factor Binding Proteins/chemistry
• Insulin-Like Growth Factor Binding Proteins/genetics
• Insulin-Like Growth Factor Binding Proteins/metabolism
• Penaeidae/classification
• Penaeidae/genetics
• Penaeidae/metabolism
• Phylogeny
• Protein Conformation
• Sequence Analysis, DNA
• Signal Transduction
• Structure-Activity Relationship
• Transcriptome

Nuclear import is considered as one of the major limitations for non-viral gene delivery systems and the incorporation of nuclear localization signals (NLS) that mediate nuclear intake can be used as a strategy to enhance internalization of exogenous DNA.

In this work, human-derived endogenous NLS peptides based on insulin growth factor binding proteins (IGFBP), namely IGFBP-3 and IGFBP-5, were tested for their ability to improve nuclear translocation of genetic material by non-viral vectors. Several strategies were tested to determine their effect on chitosan mediated transfection efficiency: co-administration with polyplexes, co-complexation at the time of polyplex formation, and covalent ligation to chitosan. Our results show that co-complexation and covalent ligation of the NLS peptide derived from IGFBP-3 to chitosan polyplexes yields a 2-fold increase in transfection efficiency, which was not observed for NLS peptide derived from IGFBP-5.

These results indicate that the integration of IGFBP-NLS-3 peptides into polyplexes has potential as a strategy to enhance the efficiency of non-viral vectors.

• HEK293T cells
• IGFBP
• chitosan
• gene therapy
• nuclear localization signals

• Biomarkers
• Haemodynamics
• Heart failure
• Heart transplantation
• Metabolism
• Pulmonary hypertension

• Biomarkers
• Case-Control Studies
• Heart Failure/surgery
• Heart Transplantation
• Hemodynamics
• Humans
• Insulin-Like Growth Factor Binding Proteins/blood
• Receptor for Advanced Glycation End Products

• Actelion Pharmaceuticals Sweden AB
• Avtal om läkarutbildning och forskning

• Crassostrea gigas
• GSK-3β
• IGF-1
• RUNX2
• growth performance
• osteogenesis

Insulin-like growth factor binding proteins (IGFBPs) are secreted proteins that play an important role in IGF regulation of growth and development of vertebrate and invertebrates. In this study, the IGFBP7 gene was cloned and characterized from mantle tissues of H. discus hannai, and designated as Hdh IGFBP7. The full-length cDNA sequence transcribed from the Hdh IGFBP7 gene was 1519-bp long with an open reading frame of 720-bp corresponding to a putative polypeptide of 239 amino acids. The molecular mass of its mature protein was approximately 23.44 KDa with an estimated isoelectric point (pI) of 5.35, and it shared significant homology with IGFBP7 gene of H. madaka. Hdh IGFBP7 has a characteristic IGFBP N-terminal domain (22–89 aa), a kazal-type serine proteinase inhibitor domain (77–128), and an immunoglobulin-like C2 domain (144–223). Furthermore, twelve cysteine residues and a signature motif of IGFBPs (XCGCCXXC) were found in its N-terminal domain. Phylogenetic analysis revealed that Hdh IGFBP7 was aligned with IGFBP7 of H. madaka. Tissue distribution analysis showed that the mRNA of Hdh IGFBP7 was expressed in all examined tissues, with the highest expression level observed in the mantle and gill tissues. The expression level of Hdh IGFBP7 mRNA was relatively higher at the juvenile stage during its metamorphosis period. In situ hybridization showed that Hdh IGFBP7 transcript was expressed in epithelial cells of the dorsal mantle pallial and mucus cells of the branchial epithelium in gill. These results provide basic information for future studies on the role of IGFBP7 in IGF regulation of shell growth, development and metamorphosis of abalone.

• Haliotis discus hannai
• IGFBP7
• in situ hybridization
• mRNA expression
• metamorphosis

• Amino Acid Sequence/genetics
• Animal Shells/metabolism
• Animals
• Base Sequence/genetics
• Cloning, Molecular/methods
• DNA, Complementary/genetics
• Gastropoda/genetics
• Gene Expression Regulation/genetics
• Insulin-Like Growth Factor Binding Proteins/genetics
• Insulin-Like Growth Factor Binding Proteins/metabolism
• Metamorphosis, Biological/genetics
• Mollusca/genetics
• Open Reading Frames/genetics
• Phylogeny
• RNA, Messenger/genetics
• Sequence Alignment/methods

• Haliotis discus hannai
• IGFBP-5
• in situ hybridization
• mRNA expression
• neural ganglia

Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF–GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.

• glucose regulated protein (GRP) 94
• insulin-like growth factor
• obligate chaperone

• CD44
• IGFBP-3
• humanin
• hyaluronan
• kinetics
• peptide

• A549 Cells
• Disulfides/chemistry
• Disulfides/metabolism
• Glycosylation
• Humans
• Hyaluronan Receptors/chemistry
• Hyaluronan Receptors/metabolism
• Hyaluronic Acid/chemistry
• Hyaluronic Acid/metabolism
• Insulin-Like Growth Factor Binding Protein 3/chemistry
• Insulin-Like Growth Factor Binding Protein 3/metabolism
• Intracellular Signaling Peptides and Proteins/chemistry
• Intracellular Signaling Peptides and Proteins/metabolism

• R15 GM131222 NIGMS NIH HHS

Giant freshwater prawns (Macrobrachium rosenbergii) are commonly found throughout the world. The size of the male giant freshwater prawn is much larger than that of the female. Therefore, understanding the molecular mechanism that underlies the sexual differentiation of M. rosenbergii is of both commercial and scientific importance. Insulin-like androgenic gland hormone (IAG) plays a key role in the differentiation of sex in M. rosenbergii. Although IAG has been investigated, the regulatory relationship between IAG and its binding protein partner, the insulin-like androgenic gland hormone-binding protein (IAGBP), has not been studied in M. rosenbergii. Here, we cloned and characterized the IAGBP from M. rosenbergii (Mr-IAGBP) for the very first time. Transcriptomic analysis showed that Mr-IAGBP mRNA was detected in a wide array of tissues with the highest expression found in the androgenic gland. The importance of IAG in male development was further demonstrated by an increase in IAG transcripts during the development of the androgenic gland and Mr-IAG was only highly transcribed in the androgenic gland of M. rosenbergii. Interestingly, we found that the Mr-IAG gene expression started during the 20th-day larva after hatching stage (LH20), followed (20th-day post-larval stage, PL20) by a gradual elevation of Mr-IAGBP levels. The levels of both genes peaked at the adult stage. The relationship between Mr-IAGBP and Mr-IAG was further analyzed using RNA interference. The injection of Mr-IAGBP double-stranded RNA (dsRNA) significantly reduced the transcription of Mr-IAG, while the amount of Mr-IAGBP mRNA and the translation of IAGBP protein was significantly reduced by the injection of Mr-IAG dsRNA. These results revealed that IAGBP is involved in IAG signaling. Furthermore, our data supports the hypothesis that (IAG and IAGBP)-IAG receptor signaling schemes exist in M. rosenbergii. Our results will provide important information for the further study of determining the sex of M. rosenbergii.

• Macrobrachium rosenbergii
• RNA interference
• insulin-like androgenic gland hormone (IAG)
• insulin-like androgenic gland hormone-binding protein (IAGBP)

• Anthropometric measurements
• Auxology
• Child
• Growth hormone therapy
• Height
• Short stature
• Growth

Insulin-like growth factor binding protein-3 (IGFBP-3) is a p53 tumor suppressor-regulated protein and a major carrier for IGFs in circulation. Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer. Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer. Over the past two decades, a wealth of evidence has revealed both tumor suppressing and tumor promoting effects of IGF/IGF-IR-independent actions of IGFBP-3 depending upon cell types, post-translational modifications, and assay methods. However, IGFBP-3′s anti-tumor function has been well accepted due to identification of functional IGFBP-3-interacting proteins, putative receptors, or crosstalk with other signaling cascades. This review mainly focuses on transmembrane protein 219 (TMEM219), which represents a novel IGFBP-3 receptor mediating antitumor effect of IGFBP-3. Furthermore, this review delineates the potential underlying mechanisms involved and the subsequent biological significance, emphasizing the clinical significance of the IGFBP-3/TMEM219 axis in assessing both the diagnosis and the prognosis of cancer as well as the therapeutic potential of TMEM219 agonists for cancer treatment.

• IGF system
• IGFBP-3
• IGFBP-3R
• TMEM219
• agonists
• anti-metastatic
• anti-tumor
• mAb therapy

• Amino Acid Sequence
• Animals
• Humans
• Insulin-Like Growth Factor Binding Protein 3/chemistry
• Insulin-Like Growth Factor Binding Protein 3/metabolism
• Neoplasm Metastasis
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Receptors, Cell Surface/metabolism
• Signal Transduction
• Survival Analysis

• R21 CA216685 NCI NIH HHS

• binding proteins
• cancer
• cross-talk
• growth factors
• insulin
• mechanism

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

• cow
• endometrium
• involution
• rumen-protected glucose

• fasting
• growth
• immunoassay
• insulin-like growth factor binding protein-1a
• salmon

• bariatric surgery
• diabetes
• insulin-like growth factor binding protein 7
• metabolic syndrome
• obesity
• protein−protein interactions
• proteomics
• tandem mass tagging

• IGF-1
• Imp-L2
• cross-linking
• diazirine ring
• mass spectrometry

• MR/K000179/1 Medical Research Council
• MR/R009066/1 Medical Research Council

To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells’ mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants’ enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.

• IGF signaling
• cell biology
• hair cell
• mitochondria
• neuroscience
• oxidative stress
• pregnancy associated plasma protein a
• zebrafish

• Cancer
• Insulin-like growth factor
• Growth hormone

• EGF
• IGF-1
• PI3K signaling pathway
• cyadox
• porcine primary hepatocytes

• PCOS
• iTRAQ
• inflammation
• insulin resistance
• non-depleted serum
• proteomics

• Serradigitus gertschi
• proteome
• scorpion
• transcriptome
• venom

• Animals
• Arthropod Proteins/analysis
• Calcium Channel Blockers/analysis
• Calcium Channel Blockers/chemistry
• Female
• Gene Expression Profiling
• Hyaluronoglucosaminidase/analysis
• Hyaluronoglucosaminidase/chemistry
• Male
• Peptide Hydrolases/analysis
• Peptide Hydrolases/chemistry
• Peptides/analysis
• Peptides/chemistry
• Phospholipases A2/analysis
• Phospholipases A2/chemistry
• Potassium Channel Blockers/analysis
• Potassium Channel Blockers/chemistry
• Proteome
• Proteomics
• Scorpion Venoms/chemistry
• Scorpions
• Sodium Channel Blockers/analysis
• Sodium Channel Blockers/chemistry

Fever is a fundamental response to infection and a hallmark of inflammatory disease, which has been conserved and shaped through millions of years of natural selection. Although fever is able to stimulate both innate and adaptive immune responses, the very nature of all the molecular thermosensors, the timing and the detailed mechanisms translating a physical trigger into a fundamental biological response are incompletely understood. Here we discuss the consequence of hyperthermic stress in dendritic cells (DCs), and how the sole physical input is sensed as an alert stimulus triggering a complex transition in a very narrow temporal window. Importantly, we review recent findings demonstrating the significant and specific changes discovered in gene expression and in the metabolic phenotype associated with hyperthermia in DCs. Furthermore, we discuss the results that support a model based on a thermally induced autocrine signalling, which rewires and sets a metabolism checkpoint linked to immune activation of dendritic cells. Importantly, in this context, we highlight the novel regulatory functions discovered for IGFBP‐6 protein: induction of chemotaxis; capacity to increase oxidative burst and degranulation of neutrophils, ability to induce metabolic changes in DCs. Finally, we discuss the role of IGFBP‐6 in autoimmune disease and how novel mechanistic insights could lead to exploit thermal stress‐related mechanisms in the context of cancer therapy.

• T cells
• cancer microenvironment
• dendritic cells
• fever
• immune system
• inflammation
• mitochondrial metabolism
• neutrophils

Skeletal muscle comprises 30–40% of the total body mass and plays a central role in energy homeostasis in the body. The deregulation of energy homeostasis is a common underlying characteristic of metabolic syndrome. Over the past decades, peroxisome proliferator-activated receptors (PPARs) have been shown to play critical regulatory roles in skeletal muscle. The three family members of PPAR have overlapping roles that contribute to the myriad of processes in skeletal muscle. This review aims to provide an overview of the functions of different PPAR members in energy homeostasis as well as during skeletal muscle metabolic disorders, with a particular focus on human and relevant mouse model studies.

• aging
• insulin resistance
• lipid metabolism
• muscle regeneration
• peroxisome proliferator-activated receptor
• physical exercise
• skeletal muscle
• type 2 diabetes

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

• Haplotype
• LD
• PRE1
• Promoter activity
• SNP

Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease that almost exclusively affects women. LAM cells migrate to the lungs, where they cause cystic destruction of lung parenchyma. Mutations in TSC1 or TSC2 lead to the activation of the mammalian target of rapamycin complex-1, a kinase that regulates growth factor-dependent protein translation, cell growth, and metabolism. Insulin-like growth factor binding protein 2 (IGFBP2) binds insulin, IGF1 and IGF2 in circulation, thereby modulating cell survival, migration, and invasion in neoplasms. In this study, we identified that IGFBP2 primarily localized in the nucleus of TSC2-null LAM patient-derived cells in vitro and in vivo. We also showed that nuclear accumulation of IGFBP2 is closely associated with estrogen receptor alpha (ERa) expression. Furthermore, estrogen treatment induced IGFBP2 nuclear translocation in TSC2-null LAM patient-derived cells. Importantly, depletion of IGFBP2 by siRNA reduced cell proliferation, enhanced apoptosis, and decreased migration and invasion of TSC2-null LAM patient-derived cells. More interestingly, depletion of IGFBP2 markedly decreased the phosphorylation of MAPK in LAM patient-derived TSC2-null cells. Collectively, these results suggest that IGFBP2 plays an important role in promoting tumorigenesis, through estrogen and ERalpha signaling pathway. Thus, targeting IGFBP2 may serve as a potential therapeutic strategy for women with LAM and other female gender specific neoplasms.

• ERα
• IGFBP2
• estrogen
• lymphangioleiomyomatosis
• nuclear localization

• IGFBP-7
• Wnt/β-Catenin
• differentiation
• oligodendrocytes

• IGFBPs
• autoimmune diseases
• biomarkers
• metabolism
• therapeutic targets

• comparative biology
• gene family evolution
• genome duplication
• insulin-like growth factor binding protein
• physiology
• teleost fish

• animal welfare
• biomarker
• insulin-like growth factor
• metabolism
• pig shipment
• stress hormones

• ILP2)
• alanine scanning
• binding interaction
• decapod
• electrostatics
• hotspot residue
• insulin-like androgenic gland peptide (IAG)
• insulin-like growth factor binding protein (IGFBP)
• insulin-like peptides (ILP1
• molecular modelling

• IGF-I
• Liver cirrhosis
• ascites
• portal hypertension

• Aged
• Cohort Studies
• Enzyme-Linked Immunosorbent Assay
• Humans
• Hypertension, Portal
• Insulin-Like Growth Factor I/analysis
• Kaplan-Meier Estimate
• Liver Cirrhosis/blood
• Liver Cirrhosis/mortality
• Middle Aged
• Prognosis
• Survival Analysis

• IGF-1
• anorexia nervosa
• eating disorders
• saliva
• serum

• brain
• diabetes
• insulin and IGF1 receptors

• Animals
• Antigens, CD/metabolism
• Brain/metabolism
• Humans
• Receptor, IGF Type 1/metabolism
• Receptor, Insulin/metabolism
• Signal Transduction