Insulin-like growth factors (IGFs) bind specifically to the IGF1 receptor on the cell surface of targeted tissues. Ligand binding to the α subunit of the receptor leads to a conformational change in ...the β subunit, resulting in the activation of receptor tyrosine kinase activity. Activated receptor phosphorylates several substrates, including insulin receptor substrates (IRSs) and Src homology collagen (SHC). Phosphotyrosine residues in these substrates are recognized by certain Src homology 2 (SH2) domain-containing signaling molecules. These include, for example, an 85 kDa regulatory subunit (p85) of phosphatidylinositol 3-kinase (PI 3-kinase), growth factor receptor-bound 2 (GRB2) and SH2-containing protein tyrosine phosphatase 2 (SHP2/Syp). These bindings lead to the activation of downstream signaling pathways, PI 3-kinase pathway and Ras-mitogen-activated protein kinase (MAP kinase) pathway. Activation of these signaling pathways is known to be required for the induction of various bioactivities of IGFs, including cell proliferation, cell differentiation and cell survival. In this review, the well-established IGF1 receptor signaling pathways required for the induction of various bioactivities of IGFs are introduced. In addition, we will discuss how IGF signals are modulated by the other extracellular stimuli or by themselves based on our studies.
The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and progression of cancer; however, therapeutics targeting it have had disappointing results in the clinic. ...As a receptor tyrosine kinase (RTK), IGF-1R is traditionally described as an ON/OFF system, with ligand stabilizing the ON state and exclusive kinase-dependent signaling activation. Newly added to the traditional model, ubiquitin-mediated receptor downregulation and degradation was originally described as a response to ligand/receptor interaction and thus inseparable from kinase signaling activation. Yet, the classical model has proven over-simplified and insufficient to explain experimental evidence accumulated over the last decade, including kinase-independent signaling, unbalanced signaling, or dissociation between signaling and receptor downregulation. Based on the recent findings that IGF-1R “borrows” components of G-protein coupled receptor (GPCR) signaling, including β-arrestins and G-protein-related kinases, we discuss the emerging paradigm for the IGF-1R as a functional RTK/GPCR hybrid, which integrates the kinase signaling with the IGF-1R canonical GPCR characteristics. The contradictions to the classical IGF-1R signaling concept as well as the design of anti-IGF-1R therapeutics treatment are considered in the light of this paradigm shift and we advocate recognition of IGF-1R as a valid target for cancer treatment.
Glycogen synthase kinase 3β (GSK3β) is a multifunctional protein kinase involved in many cellular activities including development, differentiation and diseases. GSK3β is thought to be constitutively ...activated by autophosphorylation at Tyr216 and inactivated by phosphorylation at Ser9. The GSK3β activity has previously been evaluated by inhibitory Ser9 phosphorylation, but it does not necessarily indicate the kinase activity itself. Here, we applied the Phos-tag SDS-PAGE technique to the analysis of GSK3β phosphoisotypes in cells and brains. There were three phosphoisotypes of GSK3β; double phosphorylation at Ser9 and Tyr216, single phosphorylation at Tyr216 and the nonphosphorylated isotype. Active GSK3β with phosphorylation at Tyr216 represented half or more of the total GSK3β in cultured cells. Although levels of phospho-Ser9 were increased by insulin treatment, Ser9 phosphorylation occurred only in a minor fraction of GSK3β. In mouse brains, GSK3β was principally in the active form with little Ser9 phosphorylation, and the phosphoisotypes of GSK3β changed depending on the regions of the brain, age, sex and disease conditions. These results indicate that the Phos-tag SDS-PAGE method provides a simple and appropriate measurement of active GSK3β in vivo, and the activity is regulated by the mechanism other than phosphorylation on Ser9.
Background: Over the past few years, the profile of Helicobacter pylori infection has changed in Japan. In particular, the relationship between H. pylori and gastric cancer has been demonstrated ...more clearly. Accordingly, the committee of the Japanese Society for Helicobacter Research has revised the guidelines for diagnosis and treatment of H. pylori infection in Japan.
Materials and Methods: Four meetings of guidelines preparation committee were held from July 2007 to December 2008. In the new guidelines, recommendations for treatment have been classified into five grades according to the Minds Recommendation Grades, while the level of evidence has been classified into six grades. The Japanese national health insurance system was not taken into consideration when preparing these guidelines.
Results: Helicobacter pylori eradication therapy achieved a Grade A recommendation, being useful for the treatment of gastric or duodenal ulcer, for the treatment and prevention of H. pylori‐associated diseases such as gastric cancer, and for inhibiting the spread of H. pylori infection. Levels of evidence were determined for each disease associated with H. pylori infection. For the diagnosis of H. pylori infection, measurement of H. pylori antigen in the feces was added to the tests not requiring biopsy. One week of proton‐pump inhibitor‐based triple therapy (including amoxicillin and metronidazole) was recommended as second‐line therapy after failure of first‐line eradication therapy.
Conclusion: The revised Japanese guidelines for H. pylori are based on scientific evidence and avoid the administrative restraints that applied to earlier versions.
Adequate dietary intake of amino acids is imperative for normal animal growth. Our previous work using rat hepatocarcinoma Fao cells demonstrated that growth hormone (GH) resistance, coupled with a ...concurrent reduction in insulin-like growth factor 1 (Igf1) mRNA levels, may underlie the growth retardation associated with a low-protein diet (LPD). In this study, we investigated whether FGF21 contributes to liver GH resistance in Fao rat hepatoma cells under amino acid deprivation conditions. Mice subjected to an LPD exhibited growth retardation, compromised GH signaling in the liver, and decreased blood IGF-1 levels compared with those on a control diet. To assess the potential involvement of fibroblast growth factor (FGF) 21, produced in response to amino acid deficiency, in the development of GH resistance, we examined GH signaling and Igf1 mRNA levels in Fao cells cultured in amino acid-deprived medium. Despite the inhibition of Fgf21 expression by the integrated stress response inhibitor, an inhibitor of the eukaryotic initiation factor 2-activating transcription factor 4 pathway, GH resistance persisted in response to amino acid deprivation. Additionally, the introduction of FGF21 into the control medium did not impair either GH signaling or GH-induced Igf1 transcription. These data suggest that, in Fao cells, amino acid deprivation induces GH resistance independently of FGF21 activity. By shedding light on the mechanisms behind growth retardation-associated GH resistance linked to amino acid deficiencies, our findings provide valuable insights for clinicians in formulating effective treatment strategies for individuals facing these challenges.
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•Amino acid deprivation induces growth hormone (GH) resistance in Fao cells.•Amino acid deprivation impacts GH signaling and reduces Igf1 mRNA levels.•Amino acid deprivation-induced GH resistance persists despite Fgf21 inhibition.•Introducing FGF21 does not impair GH signaling or GH-induced Igf1 transcription.•FGF21 does not influence amino acid deprivation-induced GH resistance.
This article is based on my presentation at the 9th International Congress of the Growth Hormone Research and Insulin-like Growth Factor (IGF) Societies at Seattle, USA on 17th, September 2018. In ...the article, after a general introduction to IGF research, I briefly review the IGF research being published from 2016 to 2018, focusing on what I believe represent the most interesting areas of progress. These areas include ligands of the IGF-I receptor, ligand binding to the IGF-I receptor, long-term signaling through the IGF-I receptor, intracellular organelles where IGF signals are transmitted, and novel functions of the IGFBPs. Lastly, I discuss future directions of IGF research from my point of view.
•Viral insulin-like peptides are members of the insulin/IGF superfamily.•Structural biology research showed how ligands bind to the IGF-I receptor.•IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling.•IGF signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells.
Plastic pollution has become one of the most pressing environmental issues. Recycling is a potential means of reducing plastic pollution in the environment. However, plastic fragments are still ...likely released to the aquatic environment during mechanical recycling processes. Here, we examined the plastic inputs and effluent outputs of three mechanical recycling facilities in Vietnam dealing with electronic, bottle, and household plastic waste, and we found that large quantities of microplastics (plastics <5 mm in length) are generated and released to the aquatic environment during mechanical recycling without proper treatment. Comparisons with literature data for microplastics in wastewater treatment plant effluents and surface water indicated that mechanical recycling of plastic waste is likely a major point source of microplastics pollution. Although there is a mismatch between the size of the microplastics examined in the present study and the predicted no-effect concentration reported, it is still possible that microplastics generated at facilities pose risks to the aquatic environment because there might be many plastic particulates smaller than 315 μm, as suggested by our obtained size distributions. With mechanical recycling likely to increase as we move to a circular plastics economy, greater microplastics emissions can be expected. It is therefore an urgent need to fully understand not only the scale of microplastic generation and release from plastic mechanical recycling but also the environmental risk posed by microplastics in the aquatic environment.
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•Mechanical recycling without wastewater treatment was at least a source of microplastic.•Effluent microplastic concentrations were from 1.1 × 105–2.0 × 108 MP particulates/m3.•Annual microplastic emissions from these facilities were from 0.014 to 5.8 t/year.
This review provides focused insights into the contamination status, sources, and ecological risks associated with multiple classes of antibiotics in surface water from the East and Southeast Asia ...based on publications over the period 2007 to 2020. Antibiotics are ubiquitous in surface water of these countries with concentrations ranging from <1 ng/L to hundreds μg/L and median values from 10 to 100 ng/L. Wider ranges and higher maximum concentrations of certain antibiotics were found in surface water of the East Asian countries like China and South Korea than in the Southeast Asian nations. Environmental behavior and fate of antibiotics in surface water is discussed. The reviewed occurrence of antibiotics in their sources suggests that effluent from wastewater treatment plants, wastewater from aquaculture and livestock production activities, and untreated urban sewage are principal sources of antibiotics in surface water. Ecological risks associated with antibiotic residues were estimated for aquatic organisms and the prevalence of antibiotic resistance genes and antibiotic-resistant bacteria were reviewed. Such findings underline the need for synergistic efforts from scientists, engineers, policy makers, government managers, entrepreneurs, and communities to manage and reduce the burden of antibiotics and antibiotic resistance in water bodies of East and Southeast Asian countries.
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•Antibiotic contamination status in East/Southeast Asia's surface water is reviewed.•Antibiotics are ubiquitous in surface water, especially in aquaculture and urban areas.•Antibiotic levels varied greatly from few ng/L to hundreds μg/L in surface water.•Ecological risks and prevalence of antibiotic resistance were widely observed.•Regional monitoring studies and environmental guidelines for antibiotics are needed.
RNautophagy and DNautophagy (RDA) are unconventional autophagic pathways where nucleic acids are directly transported through the lysosomal membrane, then degraded inside lysosomes. We have ...previously shown that bitopic protein LAMP2C and putative RNA transporter SIDT2, both lysosomal membrane proteins, mediate the direct transport of nucleic acids into lysosomes and that LAMP2C interacts with the nucleic acids and functions as a receptor during RDA. Because SIDT2-mediated RDA occurs in isolated lysosomes that lack LAMP2C, in this study, we tested the hypothesis that SIDT2 itself could also interact with the nucleic acids. Our results show that SIDT2 directly binds RNA and DNA through an arginine-rich motif (ARM) located within its main cytosolic domain, and disruption of this motif dramatically impairs SIDT2-mediated RNautophagic activity. We also found that SIDT2 interacts with exon 1 of HTT (huntingtin) transcript through the ARM in a CAG-dependent manner. Moreover, overexpression of SIDT2 promoted degradation of HTT mRNA and reduced the levels of polyglutamine-expanded HTT aggregates, hallmarks of Huntington disease. In addition, a comparative analysis of LAMP2C and SIDT2 functions at the cellular level revealed that the two proteins exert a synergistic effect on RNautophagic activity and that the ARMs which mediate the interactions of SIDT2 and LAMP2C with RNA are essential for the synergy. Together, our results point out the importance of nucleic acid-binding capacity of SIDT2 for its function in translocating nucleic acids through the lipid bilayer and suggests a potential application of RNautophagy activation to reduce the expression levels of disease-causing toxic proteins.
Abbreviations: ACTB/β-actin: actin beta; ARM: arginine-rich motif; CBB: Coomassie Brilliant Blue; CD: cytosolic domain; COX4I1/COX4: cytochrome c oxidase subunit 4I1; E. coli: Escherichia coli; EGFP: enhanced green fluorescent protein; EtBr: ethidium bromide; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GOLGA2/GM130: golgin A2; GST: glutathione S-transferase; HRP: horseradish peroxidase; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HTT: huntingtin; HTTex1: exon 1 of the HTT gene; LAMP2: lysosomal associated membrane protein 2; LMNA: lamin A/C; PAGE: polyacrylamide gel electrophoresis; PBS: phosphate-buffered saline; PEI: polyethyleneimine; polyQ: polyglutamine; qPCR: quantitative PCR; RAB5A: RAB5A, member RAS oncogene family; RDA: RNautophagy and DNautophagy; SCARB2/LIMP2: scavenger receptor class B member 2; SDS: sodium dodecyl sulfate; SID-1: systemic RNA interference deficient-1; SIDT2: SID1 transmembrane family member 2; WT: wild type.
Recent screening surveys have shown the presence of unknown halogenated compounds in the marine environment at comparable levels to persistent organic pollutants (POPs). However, their exposure ...levels and profiles in marine organisms and bioaccumulative potentials remain unclear. The present study performed nontarget/target screening of organohalogen compounds (OHCs) in mussel and sediment samples collected from Hiroshima Bay, Japan, in 2012 and 2018 by using integrated analyses of two-dimensional gas chromatography–high resolution time-of-flight mass spectrometry (GC×GC–HRToFMS) and magnetic sector GC–HRMS. Nontarget analysis by GC×GC–HRToFMS revealed the detection of approximately 60 OHCs including unknown mixed halogenated compounds (UHC-Br3–5Cl) with molecular formulae of C9H6Br3ClO, C9H5Br4ClO, and C9H4Br5ClO in the mussel. Interestingly, UHC-Br3–5Cl concentrations in the mussel samples, which were semi-quantified by GC–HRMS, were comparable to or higher than those of POPs at all the locations surveyed, and their geographical distribution patterns differed from those of other OHCs. These results suggest that UHC-Br3–5Cl are ubiquitous in coastal waters of Hiroshima Bay and derived from a specific source(s). The biota-sediment accumulation factors (BSAFs) of UHC-Br3–5Cl, estimated for a paired sample set of mussel (ng/g lw) and sediment (ng/g TOC), were 1 order of magnitude higher than those for POPs with similar log K ow values, indicating their high bioaccumulative potential.
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