Inzulinu podobný růstový faktor 2 patří, spolu s několika dalšími inzulinu podobnými peptidy, do evolučně konzervované rodiny signalizačních molekul, které jsou nezbytné pro normální buněčnou proliferaci a vývoj mozku. Dřívější studie se zaměřovaly převážně na jeho úlohu v embryonálním vývoji a kancerogenezi. V posledních letech byly odhaleny nové poznatky týkající se role inzulinu podobného růstového faktoru 2 v centrální nervové soustavě, zejména jeho význam pro učení, konsolidaci paměti a zlepšení kognitivních funkcí. I přes stále ne zcela prozkoumanou fyziologickou roli inzulinu podobného růstového faktoru 2 se v našem článku snažíme podrobněji popsat a vysvětlit jeho známé funkce a diskutovat jeho potenciální využití, včetně možné aplikace v léčbě neurodegenerativních onemocnění.

Insulin-like growth factor 2 (IGF2), along with several other insulin-like peptides, belongs to an evolutionarily conserved family of signalling molecules essential for normal cell proliferation and brain development. Previous studies have mainly focused on its role in embryonic development and carcinogenesis. In recent years, new insights revealed the role of IGF2 in the central nervous system, particularly its importance in learning, memory consolidation and enhancement. Despite the still not fully explored physiological role of IGF2, in this article we aim to describe and explain its known functions in more detail and discuss its potential uses, including its possible application in the treatment of neurodegenerative diseases.

• MeSH
• exprese genu genetika   MeSH
• insulinu podobný růstový faktor II * fyziologie   genetika   metabolismus   ultrastruktura   MeSH
• inzulin fyziologie   MeSH
• karcinogeneze genetika   metabolismus   MeSH
• kognice fyziologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci etiologie   genetika   klasifikace   MeSH
• receptor IGF typ 2 fyziologie   metabolismus   ultrastruktura   MeSH
• receptor inzulinu fyziologie   genetika   ultrastruktura   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Parasitic nematodes transition between dramatically different free-living and parasitic stages, with correctly timed development and migration crucial to successful completion of their lifecycle. However little is known of the mechanisms controlling these transitions. microRNAs (miRNAs) negatively regulate gene expression post-transcriptionally and regulate development of diverse organisms. Here we used microarrays to determine the expression profile of miRNAs through development and in gut tissue of the pathogenic nematode Haemonchus contortus. Two miRNAs, mir-228 and mir-235, were enriched in infective L3 larvae, an arrested stage analogous to Caenorhabditis elegans dauer larvae. We hypothesized that these miRNAs may suppress development and maintain arrest. Consistent with this, inhibitors of these miRNAs promoted H. contortus development from L3 to L4 stage, while genetic deletion of C. elegans homologous miRNAs reduced dauer arrest. Epistasis studies with C. elegans daf-2 mutants showed that mir-228 and mir-235 synergise with FOXO transcription factor DAF-16 in the insulin signaling pathway. Target prediction suggests that these miRNAs suppress metabolic and transcription factor activity required for development. Our results provide novel insight into the expression and functions of specific miRNAs in regulating nematode development and identify miRNAs and their target genes as potential therapeutic targets to limit parasite survival within the host.

• MeSH
• Caenorhabditis elegans genetika   MeSH
• cholesteny farmakologie   MeSH
• delece genu MeSH
• druhová specificita MeSH
• genová ontologie MeSH
• Haemonchus účinky léků   genetika   růst a vývoj   MeSH
• larva MeSH
• messenger RNA genetika   metabolismus   MeSH
• mikro RNA biosyntéza   genetika   MeSH
• proteiny Caenorhabditis elegans genetika   MeSH
• receptor inzulinu genetika   MeSH
• RNA helmintů biosyntéza   genetika   MeSH
• vývojová regulace genové exprese účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Annona and ginger have prominent uses in traditional medicine; their therapeutic properties have not been sufficiently explored. The ameliorative effect of Annona or ginger extracts on hyperglycaemia associated with oxidative stress, inflammation, and apoptosis in experimentally induced diabetes was addressed. Type 1 diabetes in male rats was induced by a single injection of streptozotocin (STZ; 40 mg/kg, i.p.), then Annona (100 mg/kg) or ginger (200 mg/kg) extracts were orally administered daily for 30 days. The Annona and ginger extracts ameliorated hyperglycaemia, insulin level, glycosylated haemoglobin (HbA1c) and insulin resistance (HOMA-IR) levels in the diabetic rats. The treatments significantly ameliorated liver function enzymes and total proteins; this was confirmed by histopathological examination of liver sections. Annona and ginger extracts significantly reduced elevated malondialdehyde (MDA) and restored activity of antioxidant enzymes in the liver such as glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) and the hepatic content of reduced glutathione (GSH). The oxidative stressdependent inflammation was regulated by both Annona and ginger extracts, which was indicated by down-regulation of TNF-α, NF-κB, pro-apoptotic proteins Bax, p53, and anti-apoptotic protein Bcl-2. Moreover, the expression of insulin receptor (INSR) and glucose transporter 2 (GLUT2) genes was markedly regulated by both these extracts. The results suggest that Annona and ginger extracts ameliorate the hepatic damage resulting from diabetes by advocating antioxidants and modulating apoptotic mediator proteins in the liver of diabetic rats. In conclusion, Annona and ginger extracts have a potential therapeutic effect in the treatment of diabetes and its complications.

• MeSH
• Annona chemie   MeSH
• antioxidancia metabolismus   MeSH
• apoptóza účinky léků   MeSH
• biologické markery krev   MeSH
• experimentální diabetes mellitus krev   farmakoterapie   enzymologie   MeSH
• glykovaný hemoglobin metabolismus   MeSH
• inzulin krev   MeSH
• inzulinová rezistence MeSH
• jaterní testy MeSH
• játra účinky léků   patofyziologie   MeSH
• krevní glukóza metabolismus   MeSH
• malondialdehyd metabolismus   MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• přenašeč glukosy typ 2 genetika   metabolismus   MeSH
• protein X asociovaný s bcl-2 metabolismus   MeSH
• receptor inzulinu genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• rostlinné extrakty farmakologie   terapeutické užití   MeSH
• TNF-alfa metabolismus   MeSH
• zázvor lékařský chemie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Information on how insulin and insulin-like growth factors 1 and 2 (IGF-1 and -2) activate insulin receptors (IR-A and -B) and the IGF-1 receptor (IGF-1R) is crucial for understanding the difference in the biological activities of these peptide hormones. Cryo-EM studies have revealed that insulin uses its binding sites 1 and 2 to interact with IR-A and have identified several critical residues in binding site 2. However, mutagenesis studies suggest that Ile-A10, Ser-A12, Leu-A13, and Glu-A17 also belong to insulin's site 2. Here, to resolve this discrepancy, we mutated these insulin residues and the equivalent residues in IGFs. Our findings revealed that equivalent mutations in the hormones can result in differential biological effects and that these effects can be receptor-specific. We noted that the insulin positions A10 and A17 are important for its binding to IR-A and IR-B and IGF-1R and that A13 is important only for IR-A and IR-B binding. The IGF-1/IGF-2 positions 51/50 and 54/53 did not appear to play critical roles in receptor binding, but mutations at IGF-1 position 58 and IGF-2 position 57 affected the binding. We propose that IGF-1 Glu-58 interacts with IGF-1R Arg-704 and belongs to IGF-1 site 1, a finding supported by the NMR structure of the less active Asp-58-IGF-1 variant. Computational analyses indicated that the aforementioned mutations can affect internal insulin dynamics and inhibit adoption of a receptor-bound conformation, important for binding to receptor site 1. We provide a molecular model and alternative hypotheses for how the mutated insulin residues affect activity.

• MeSH
• insulinu podobný růstový faktor I chemie   genetika   MeSH
• insulinu podobný růstový faktor II chemie   genetika   MeSH
• inzulin analogy a deriváty   chemická syntéza   chemie   genetika   MeSH
• lidé MeSH
• mnohočetné abnormality genetika   MeSH
• mutace genetika   MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• poruchy růstu genetika   MeSH
• proteinové domény genetika   MeSH
• receptor IGF typ 1 chemie   genetika   MeSH
• receptor inzulinu chemie   genetika   MeSH
• sekvence aminokyselin genetika   MeSH
• vazba proteinů genetika   MeSH
• vazebná místa genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase-type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared [d-HisB24, GlyB31, TyrB32]-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of [d-HisB24, GlyB31, TyrB32]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-HisB24, GlyB31, TyrB32]-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.

• MeSH
• insulinu podobný růstový faktor I chemie   genetika   metabolismus   MeSH
• inzulin agonisté   metabolismus   MeSH
• kinetika MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• receptor inzulinu chemie   genetika   metabolismus   MeSH
• receptory somatomedinů chemie   genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions with insulin becoming a key regulator of metabolism, whereas insulin-like growth factors (IGF)-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin receptor isoforms A and B (IR-A and IR-B) and insulin-like growth factor type I receptor (IGF-1R). Identification of structural determinants in IGFs and insulin that trigger their specific signaling pathways is of increasing importance in designing receptor-specific analogs with potential therapeutic applications. Here, we developed a straightforward protocol for production of recombinant IGF-II and prepared six IGF-II analogs with IGF-I-like mutations. All modified molecules exhibit significantly reduced affinity toward IR-A, particularly the analogs with a Pro-Gln insertion in the C-domain. Moreover, one of the analogs has enhanced binding affinity for IGF-1R due to a synergistic effect of the Pro-Gln insertion and S29N point mutation. Consequently, this analog has almost a 10-fold higher IGF-1R/IR-A binding specificity in comparison with native IGF-II. The established IGF-II purification protocol allowed for cost-effective isotope labeling required for a detailed NMR structural characterization of IGF-II analogs that revealed a link between the altered binding behavior of selected analogs and conformational rearrangement of their C-domains.

• MeSH
• CD antigeny chemie   genetika   metabolismus   MeSH
• insulinu podobný růstový faktor II chemie   genetika   metabolismus   MeSH
• lidé MeSH
• missense mutace MeSH
• protein - isoformy chemie   genetika   metabolismus   MeSH
• proteinové domény MeSH
• receptor IGF typ 1 chemie   genetika   metabolismus   MeSH
• receptor inzulinu chemie   genetika   metabolismus   MeSH
• rekombinantní proteiny chemie   genetika   metabolismus   MeSH
• substituce aminokyselin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Despite the recent first structural insight into the insulin-insulin receptor complex, the role of the C terminus of the B-chain of insulin in this assembly remains unresolved. Previous studies have suggested that this part of insulin must rearrange to reveal amino acids crucial for interaction with the receptor. The role of the invariant Phe(B24), one of the key residues of the hormone, in this process remains unclear. For example, the B24 site functionally tolerates substitutions to D-amino acids but not to L-amino acids. Here, we prepared and characterized a series of B24-modified insulin analogues, also determining the structures of [D-HisB24]-insulin and [HisB24]-insulin. The inactive [HisB24]-insulin molecule is remarkably rigid due to a tight accommodation of the L-His side chain in the B24 binding pocket that results in the stronger tethering of B25-B28 residues to the protein core. In contrast, the highly active [D-HisB24]-insulin is more flexible, and the reverse chirality of the B24C(α) atom swayed the D-His(B24) side chain into the solvent. Furthermore, the pocket vacated by Phe(B24) is filled by Phe(B25), which mimics the Phe(B24) side and main chains. The B25→B24 downshift results in a subsequent downshift of Tyr(B26) into the B25 site and the departure of B26-B30 residues away from the insulin core. Our data indicate the importance of the aromatic L-amino acid at the B24 site and the structural invariance/integrity of this position for an effective binding of insulin to its receptor. Moreover, they also suggest limited, B25-B30 only, unfolding of the C terminus of the B-chain upon insulin activation.

• MeSH
• inzulin chemie   genetika   metabolismus   MeSH
• lidé MeSH
• receptor inzulinu chemie   genetika   metabolismus   MeSH
• sekundární struktura proteinů MeSH
• vazba proteinů fyziologie   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The pathogenesis of myotonic dystrophy type 2 includes the sequestration of MBNL proteins by expanded CCUG transcripts, which leads to an abnormal splicing of their target pre-mRNAs. We have found CCUG(exp) RNA transcripts of the ZNF9 gene associated with the formation of ribonuclear foci in human skeletal muscle and some non-muscle tissues present in muscle biopsies and skin excisions from myotonic dystrophy type 2 patients. Using RNA-FISH and immunofluorescence-FISH methods in combination with a high-resolution confocal microscopy, we demonstrate a different frequency of nuclei containing the CCUG(exp) foci, a different expression pattern of MBNL1 protein and a different sequestration of MBNL1 by CCUG(exp) repeats in skeletal muscle, vascular smooth muscle and endothelia, Schwann cells, adipocytes, and ectodermal derivatives. The level of CCUG(exp) transcription in epidermal and hair sheath cells is lower compared with that in other tissues examined. We suppose that non-muscle tissues of myotonic dystrophy type 2 patients might be affected by a similar molecular mechanism as the skeletal muscle, as suggested by our observation of an aberrant insulin receptor splicing in myotonic dystrophy type 2 adipocytes.

• MeSH
• aktiny metabolismus   MeSH
• analýza rozptylu MeSH
• antigeny CD34 metabolismus   MeSH
• endotel metabolismus   patologie   MeSH
• konfokální mikroskopie MeSH
• kosterní svaly metabolismus   MeSH
• kůže metabolismus   patologie   MeSH
• lidé MeSH
• myotonické poruchy diagnóza   genetika   metabolismus   patologie   MeSH
• neurofilamentové proteiny metabolismus   MeSH
• proteiny S100 metabolismus   MeSH
• proteiny vázající RNA genetika   metabolismus   MeSH
• receptor inzulinu genetika   MeSH
• repetitivní sekvence nukleových kyselin genetika   MeSH
• RNA metabolismus   MeSH
• sestřih RNA genetika   MeSH
• transport proteinů fyziologie   MeSH
• tukové buňky metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• adipogeneze genetika   MeSH
• adipokiny genetika   MeSH
• celogenomová asociační studie MeSH
• energetický metabolismus genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• hypothalamus MeSH
• index tělesné hmotnosti MeSH
• lidé MeSH
• mitochondrie MeSH
• modely u zvířat MeSH
• obezita * etiologie   genetika   vrozené   MeSH
• polymorfismus genetický MeSH
• pozorovací studie jako téma MeSH
• receptor inzulinu genetika   MeSH
• tuková tkáň MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• klinické zkoušky MeSH

Western lifestyle leading to obesity and type 2 diabetes has been associated with increased risk of colorectal cancer (CRC). Diet and related factors may affect the risk by modifying plasma insulin levels. Thus, the inter-individual variation in insulin signaling may play a plausible role in the development of CRC. We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. We studied the association of five single nucleotide polymorphisms (SNPs) with the risk of CRC using a hospital-based case-control design with 712 cases and 748 controls from the Czech Republic. The INSR A-603G promoter SNP, which is located within a known Sp1-binding site, was associated with the risk of CRC, with carriers of the G allele having a decreased risk (odds ratios (OR) 0.71, 95% confidence interval (CI) 0.54-0.93). Carrying the variant allele of the IRS1 Gly972Arg SNP further decreased the risk among the INSR-603G allele carriers (OR 0.28, 95% CI 0.11-0.70). SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. In conclusion, genetic variation in the insulin signaling pathway genes may affect the risk of CRC.

• MeSH
• CD antigeny * genetika   metabolismus   MeSH
• dospělí MeSH
• fosfoproteiny genetika   MeSH
• genetická predispozice k nemoci MeSH
• inzulin genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * fyziologie   MeSH
• karcinom * genetika   MeSH
• kolorektální nádory * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• promotorové oblasti (genetika) * MeSH
• proteiny insulinového receptorového substrátu MeSH
• receptor inzulinu * genetika   metabolismus   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce * genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH