Insulin-like Growth Factor II Research Articles

The associations of IGF2, IGF2R and IGF2BP2 gene polymorphisms with gestational diabetes mellitus: A case-control study.

To investigate the associations of Insulin-like growth factor-II (IGF2) gene, Insulin-like growth factor-II receptor (IGF2R) gene and Insulin-like growth factor-II binding protein 2 (IGF2BP2) gene polymorphisms with the susceptibility to gestational diabetes mellitus (GDM) in Chinese population. A total of 1703 pregnant women (835 GDM and 868 Non-GDM) were recruited in this case-control study. All participants underwent prenatal 75 g oral glucose tolerance test (OGTT) examinations during 24-28 gestational weeks at the Maternal and Child Health Hospital of Hubei Province from January 15, 2018 to March 31, 2019. Genotyping of candidate SNPs (IGF2 rs680, IGF2R rs416572, IGF2BP2 rs4402960, rs1470579, rs1374910, rs11705701, rs6777038, rs16860234, rs7651090) was performed on Sequenom MassARRAY platform. Logistic regression analysis was conducted to investigate the associations between candidate SNPs and risk of GDM. In addition, multifactor dimensionality reduction (MDR) method was applied to explore the effects of gene-gene interactions on GDM risk. There were significant distribution differences between GDM group and non-GDM group in age, pre-pregnancy BMI, education level and family history of diabetes (P < 0.05). After adjusted for age, pre-pregnancy BMI, education level and family history of diabetes, there were no significant associations of the candidate SNPs polymorphisms and GDM risk (P > 0.05). Furthermore, there were no gene-gene interactions on the GDM risk among the candidate SNPs (P > 0.05). However, the fasting blood glucose (FBG) levels of rs6777038 CT carriers were significantly lower than TT carriers (4.69±0.69 vs. 5.03±1.57 mmol/L, P < 0.01), and the OGTT-2h levels of rs6777038 CC and CT genotype carriers were significantly lower than TT genotype carriers (8.10±1.91 and 8.08±1.87 vs. 8.99±2.90 mmol/L, P < 0.01). IGF2 rs680, IGF2R rs416572, IGF2BP2 rs4402960, rs1470579, rs11705701, rs6777038, rs16860234, rs7651090 polymorphisms were not significantly associated with GDM risk in Wuhan, China. Further lager multicenter researches are needed to confirm these results.

Influence of polymorphisms in candidate genes on carcass and meat quality traits in rabbits.

Candidate gene is a powerful approach to study gene-trait association and offers valuable information for genetic improvement using marker-assisted selection. The current work aimed to study the polymorphisms of four single nucleotide polymorphism (SNPs) at located growth hormone (GH), insulin-like growth factor-II (IGF-II), fat mass and obesity-associated (FTO), and insulin receptor substrate-1 (IRS-1) genes, and their association with the carcass, and meat quality traits in rabbits. The SNPs were genotyped using RFLP-PCR in New Zealand White and local Baladi rabbits. The results revealed that the heterozygous genotype was the most frequent in all cases, except for the FTO SNP in LB rabbits. There was a significant effect for GH genotypes on meat lightness after slaughter and hind-part weight. While, IGF-II mutation significantly affected slaughter, hot carcass, commercial carcass, and hind-part weights. The FTO SNP was associated with cooking loss and intramuscular fat weight, and the IRS-1 SNP was significantly associated with drip loss and intramuscular fat. Specific-breed effects were obtained for IGF-II SNP on cooking loss, and for the intramuscular fat. Although the results suggested that these mutations are useful candidate genes for selection, more research for detecting more variants associated with carcass and meat quality traits in rabbits are recommended.

THU560 Serum miRNA-483 As A Diagnostic And Therapeutic Marker Of IGF-II-producing Non-islet Cell Tumor Hypoglycemia (NICTH)

Abstract Disclosure: M. Okazaki-Hada: None. M. Nagao: Grant Recipient; Self; The Foundation for Growth Science. A. Asai: None. I. Fukuda: None. L. Eliasson: None. M. Iwabu: None. Objective: Non-islet cell tumor hypoglycemia (NICTH) is known as the second major cause of spontaneous hypoglycemia next to insulinoma. Abnormal higher molecular weight forms of insulin-like growth factor II (IGF-II), so-called “big IGF-II”, are frequently detected in the sera of patients with NICTH. Thus, the disease is referred to as IGF-II-producing NICTH. We have previously reported a significant elevation of serum microRNA (miRNA)-483-5p and -3p levels in patients with IGF-II-producing NICTH. The miRNA-483 family are encoded in an intron of IGF2 gene and thus suggested to be co-expressed with IGF-II. The aim of this study was to validate the usefulness of miRNA-483 family as a diagnostic and therapeutic marker of IGF-II producing NICTH, then to examine if the IGF-II-producing tumor tissues could be the source of these circulating miRNAs Design: Serum samples from patients who had been suspected to have IGF-II-producing NICTH (n = 134) were tested. The presence of big IGF-II was confirmed by Western blotting, and miRNA-483-5p and -3p levels were evaluated by quantitative PCR. IGF-II level was also analyzed by ELISA. In addition, IGF-II, miRNA-483-5p and -3p levels were compared before and after tumor removal in serum samples from surgically treated patients with IGF-II-producing NICTH (n=21). Expression levels of miRNA-483-5p and -3p were also analyzed in the big IGF-II-expressing tumor tissues and the surrounding surgical margins (n=9). Results: Big IGF-II was detected in the sera of 91 out of 134 patients. IGF-II, miRNA-483-5p and -3p levels were significantly higher in sera with big IGF-II than in those without. The area under the receiver operating characteristic curve of miRNA-483-5p (0.85) for IGF-II-producing NICTH were higher than those of miRNA-483-3p (0.75) and IGF-II (0.75). After tumor removal, serum miRNA-483-5p level decreased (P=0.0025), but serum miRNA-483-3p and IGF-II levels did not change significantly. The expression levels of miRNA-483-5p and -3p in the tumor tissues were significantly higher than those in the surgical margins (18 and 51 times for miRNA-483-5p and -3p, respectively). Conclusion: The present study confirms that miRNA-483-5p and -3p are elevated in sera of patients with IGF-II-producing NICTH and shows that miRNA-483-5p is significantly reduced after the surgical removal of big IGF-II-producing tumors. These results highlight the usefulness of the miRNA-483 family as a diagnostic and therapeutic marker for IGF-II-producing NICTH, and strongly suggest that the tumors produce miR-483-5p and -3p in parallel with the production of big IGF-II. Presentation: Thursday, June 15, 2023

SAT141 A Case Of Non-islet Cell Tumor Hypoglycemia Which Was Ameliorated By Pazopanib Treatment

Abstract Disclosure: N. Yamamoto: None. M. Yamamoto: None. N. Kiyota: None. Y. Inaba: None. K. Kanie: None. S. Urai: None. M. Suzuki: None. Y. Sasaki: None. Y. Oi: None. Y. Tsujimoto: None. Y. Motomura: None. Y. Ohmachi: None. H. Bando: None. G. Iguchi: None. M. Nagao: None. I. Fukuda: None. H. Fukuoka: None. W. Ogawa: None. Introduction: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by insulin-like growth factor II (IGF-II) hypersecretion from the tumors. It is characterized by incompletely processed big IGF-II with potent insulin-like activity. We present a case of NICTH complicated with solitary fibrous tumor (SFT) which was ameliorated with the administration of pazopanib, a multi-targeted tyrosine kinase inhibitor. Clinical Case: A 57-year-old man went into a coma and was hospitalized. His plasma glucose levels were 26 mg/dL, and he regained consciousness after glucose administration, leading to a diagnosis of hypoglycemic coma. Moreover, a contrast-enhanced CT scan showed multiple tumors in his liver and right kidney. He was referred to our hospital for further management. After 5 hours of fasting, he had a cold sweat, and his plasma glucose levels dropped to 32 mg/dL with suppressed serum insulin levels of 0.2 U/mL. Serum 3-hydroxybutyrate levels were as low as 21 μmol/L, and plasma glucose levels increased to 83 mg/dL after glucagon administration, suggesting an agent mimicking insulin. Percutaneous liver biopsy was performed, and the tumors were diagnosed with SFT. Immunoblotting for his serum showed big IGF-II, leading to a diagnosis of NICTH, and hypoglycemia due to hypersecretion of IGF-II. Due to multiple metastases, surgery was not indicated and pazopanib was administered. Hypoglycemia during the night was prevented by glucose infusion through the central venous port, and he was discharged. Three months later, when he was re-hospitalized for thrombophlebitis of the right jugular vein, hypoglycemia did not occur even after 10 hours of fasting and CT scan showed the necrotic change of the tumor. Two weeks later of pazopanib discontinuation due to the thrombogenic adverse effect, hypoglycemia recurred accompanied by the tumor enlargement. When the anticoagulation therapy regressed the thrombosis and pazopanib was re-administered, hypoglycemia improved reproducibly and remained stable for more than 2 years although the tumor showed gradual progression. Conclusion: This is the first case in which pazopanib was effective in suppressing NICTH associated with SFT. Presentation: Saturday, June 17, 2023

Recurrent Non-islet Cell Tumor Hypoglycemia Secondary to Hepatocellular Carcinoma: Case Report and Literature Review.

Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome caused by tumors other than insulinoma that is primarily due to excessive production of insulin-like growth factor-II (IGF-II). The prevalence of NICTH is likely underestimated because of a lack of clinical recognition. A 41-year-old male with massive malignant liver tumors presented with recurrent severe hypoglycemia, weight loss, and liver cirrhosis. NICTH related to IGF-II produced by hepatocellular carcinoma was diagnosed based on clinical symptoms, biochemical tests, and elevated IGF-II/IGF-I ratio. Initial treatment with intravenous glucose and parenteral nutrition showed limited efficacy. Glucocorticoids and recombinant human growth hormone led to progressive improvement in blood glucose levels. Due to extensive tumor burden and liver failure, surgical resection was not feasible, and the patient ultimately succumbed to refractory hypoglycemia and passed away in two weeks. Early recognition and diagnosis of NICTH are crucial in patients with recurrent hypoglycemia and large tumors. Surgical resection is the preferred treatment option, but supportive care and pharmacological interventions, such as glucocorticoids and growth hormone, can help manage refractory hypoglycemia. Further research is needed to explore novel treatment options, including anti-IGF-I and -IGF-II neutralizing antibodies.

IMP3 Immunohistochemical Expression Is Related with Progression and Metastases in Xenografted and Cutaneous Melanomas

Introduction: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. Materials and Methods: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. Results: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. Conclusions: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).

Effects of age and seasonal temperatures on cortisol levels and GHR, IGF-I, and IGF-II expressions in rainbow trout (Oncorhynchus mykiss)

The growth hormone (GH)/insulin-like growth factor (IGF) endocrine axis regulates the cellular growth and organ development in related to changing environmental conditions and age. The aim of this study is to determine growth factor genes, which are biological markers of growth in muscle and liver of rainbow trout (Oncorhynchus mykiss) in different seasonal temperatures and age ranges and the reveal of the relationship between serum cortisol (COR) levels from stress parameters. No difference was found in serum COR levels between the groups with respect to temperature and age. Serum GH levels were found to be higher in the summer juvenile trout compared to the winter juvenile and adult trouts. There was no difference in liver growth hormone receptor (GHR) mRNA levels of juvenile and adult trouts in winter while insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) mRNA levels in liver and muscle tissues were found to be higher in juvenile trout compared to adults. Among trout of different ages, GHR, IGF-I and IGF-II mRNA levels in liver in summer were higher for juvenile trout compared to adults. Muscle IGF-I mRNA levels in summer were higher in adult trout compared to juveniles. IGF-II mRNA levels in liver and muscle tissues of juvenile trout showed an increase in winter compared to in summer. While the GHR and IGF-II mRNA levels in the liver tissue of adult trout were observed to higher in winter compared to summer, IGF-I mRNA levels were found to be higher in summer. GHR, IGF-I and IGF-II mRNA levels in muscle tissue of adult trout were found to be higher in summer than in winter. This study indicated that juvenile and adult rainbow trout (Oncorhynchus mykiss) are adapted to both winter and summer temperature and that GHR, IGF-I and IGF-II genes are highly expressed.

The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis.

Pulmonary fibrosis (PF) associated with systemic sclerosis (SSc) results in significant morbidity and mortality. We previously reported that insulin-like growth factor-II (IGF-II) is overexpressed in lung tissues and fibroblasts from SSc patients, and IGF-II fosters fibrosis by upregulating collagen type I, fibronectin, and TGFβ. We now show that IGF-II augments mRNA levels of profibrotic signaling molecules TGFβ2 (p ≤ 0.01) and TGFβ3 (p ≤ 0.05), collagen type III (p ≤ 0.01), and the collagen posttranslational modification enzymes P4HA2 (p ≤ 0.05), P3H2 (p ≤ 0.05), LOX (p = 0.065), LOXL2 (p ≤ 0.05), LOXL4 (p ≤ 0.05) in primary human lung fibroblasts. IGF-II increases protein levels of TGFβ2 (p ≤ 0.01), as well as COL3A1, P4HA2, P4Hβ, and LOXL4 (p ≤ 0.05). In contrast, IGF-II decreases mRNA levels of the collagen degradation enzymes cathepsin (CTS) K, CTSB, and CTSL and protein levels of CTSK (p ≤ 0.05). The SRY-box transcription factor 9 (SOX9) is overexpressed in SSc lung tissues at the mRNA (p ≤ 0.05) and protein (p ≤ 0.01) levels compared to healthy controls. IGF-II induces SOX9 in lung fibroblasts (p ≤ 0.05) via the IGF1R/IR hybrid receptor, and SOX9 regulates TGFβ2 (p ≤ 0.05), TGFβ3 (p ≤ 0.05), COL3A1 (p ≤ 0.01), and P4HA2 (p ≤ 0.001) downstream of IGF-II. Our results identify a novel IGF-II signaling axis and downstream targets that are regulated in a SOX9-dependent and -independent manner. Our findings provide novel insights on the role of IGF-II in promoting pulmonary fibrosis.

#4547 IDENTIFICATION OF GLYCOSYLATED IGF2 IN HUMAN URINARY PEPTIDOME AND ITS ASSOCIATION WITH CKD

Abstract Background and Aims Chronic kidney disease (CKD) is prevalent in 10% of world's adult population, with estimated glomerular filtration rate (eGFR) and albuminuria employed in its diagnosis. Role of protein glycosylation in causal mechanisms of CKD progression is largely unknown. Aim of this study was to identify urinary O-linked glycopeptides in association to CKD for better characterization of CKD molecular manifestations. Method Urine samples from eight CKD and two healthy subjects were analyzed by Capillary Electrophoresis-Tandem Mass Spectroscopy (CE-MS/MS) and glycopeptide analysis using Proteome Discoverer 1.4 was performed. Distribution of identified glycopeptides and correlation with Age, eGFR and Albuminuria were evaluated in 3810 datasets from the Human Urinary Proteome database using Spearman's rank correlation test and multiple linear regression analysis by statistical software R. The quantification of Insulin-like growth factor-II (IGF2) protein (7.5 kDa) was performed by enzyme-linked immunosorbent assay (ELISA) in two matched (for age, sex, no diabetes and no cardiovascular history) groups of 12 plasma samples each (eGFR &amp;lt; 30 ml/min/1.73m2 and eGFR &amp;gt; 90 ml/min/1.73m2). An open-source tool “Proteasix” was used to predict proteases involved in cleavage of the identified glycopeptides. The transcriptomics database and analysis tool “Nephroseq v4” were utilized to investigate the expression of predicted proteases in existing human transcriptomics CKD datasets. Results In total, 17 O-linked glycopeptides from 7 different proteins were identified, derived primarily from Insulin-like growth factor-II (IGF2) (n = 6). Glycosylation occurred at the surface exposed IGF2 Threonine 96 position. Further Investigation of the human proteome database containing 3810 datasets, showed that only three unglycosylated urinary peptides of IGF2 were identified, at significantly lower abundance and frequency (0-2.5% in the database) in comparison to the glycosylated forms (frequency of 23-90%). Interestingly, all identified IGF2 peptides belonged to E-domain of IGF2, i.e., 92 – 180 aa; which cleaves after undergoing O-linked glycosylation during the post-translational process yielding the “mature IGF2” (25-91 aa) protein. Results of multiple linear regression analysisa indicated that three IGF2 glycopeptides, DVStPPTVLPDNFPRYPVGKF [β(1024) = 0.08, p = 1.42*10−4], DVStPPTVLPDNFPRYPVG [β(560) = 0.01, p = 5.22*10−5] and DVStPPTVLPDNFPRYP [β(290) = 0.02, p = 1.07*10−4], exhibited positive correlation with Age and the glycopeptide tPPTVLPDNFPRYP showed strong negative association with eGFR [β(177) = -0.01, p = 4.21*10−9]. Along the same lines, the latter urinary IGF2 glycopeptide tPPTVLPDNFPRYP was found at increased [p &amp;lt; 2.2*10−16] abundance in CKD (n = 686) in comparison to healthy control (n = 229) datasets. In addition, IGF2 increased [p = 0.042] plasma levels were observed in CKD patients (eGFR &amp;lt; 30 ml/min/1.73m2 group) as supported by ELISA measurements. Protease predictions, considering also available transcriptomics data, suggest activation of cathepsin S with CKD potentially involved in the cleavage of the CKD-associated glycopeptide of IGF2. Conclusion Collectively, this study indicates that with aging and deteriorating kidney function, alterations in IGF2 proteoforms take place; which may be reflective of respective changes in the mature IGF2 protein abundance and function; as well as associated protease activity. Further, correlation analyses of the levels of the CKD-associated urinary IGF2 glycopeptide with the plasma IGF2 levels with CKD progression is planned. a Results of multiple linear regression where regression Co-efficient is β; degree of freedom is stated in (brackets); and p-value &amp;lt;0.05 was considered statistically significant

Glycosylation Analysis of Urinary Peptidome Highlights IGF2 Glycopeptides in Association with CKD

Chronic kidney disease (CKD) is prevalent in 10% of world's adult population. The role of protein glycosylation in causal mechanisms of CKD progression is largely unknown. The aim of this study was to identify urinary O-linked glycopeptides in association to CKD for better characterization of CKD molecular manifestations. Urine samples from eight CKD and two healthy subjects were analyzed by CE-MS/MS and glycopeptides were identified by a specific software followed by manual inspection of the spectra. Distribution of the identified glycopeptides and their correlation with Age, eGFR and Albuminuria were evaluated in 3810 existing datasets. In total, 17 O-linked glycopeptides from 7 different proteins were identified, derived primarily from Insulin-like growth factor-II (IGF2). Glycosylation occurred at the surface exposed IGF2 Threonine 96 position. Three glycopeptides (DVStPPTVLPDNFPRYPVGKF, DVStPPTVLPDNFPRYPVG and DVStPPTVLPDNFPRYP) exhibited positive correlation with Age. The IGF2 glycopeptide (tPPTVLPDNFPRYP) showed a strong negative association with eGFR. These results suggest that with aging and deteriorating kidney function, alterations in IGF2 proteoforms take place, which may reflect changes in mature IGF2 protein. Further experiments corroborated this hypothesis as IGF2 increased plasma levels were observed in CKD patients. Protease predictions, considering also available transcriptomics data, suggest activation of cathepsin S with CKD, meriting further investigation.

Surgical resection of a retroperitoneal liposarcoma producing insulin-like growth factor II: a case report

BackgroundTumor-produced high molecular weight insulin-like growth factor-II (big insulin-like growth factor-II) is considered to cause non-islet cell tumor hypoglycemia. This paper presents a case of surgically resected retroperitoneal liposarcoma that produced big insulin-like growth factor-II.Case presentationHere, we report the case of a 62-year-old woman who presented with an abdominal mass and hypoglycemia. Non-islet cell tumor hypoglycemia due to retroperitoneal liposarcoma was suspected. After complete resection of the tumor, the patient’s hypoglycemia improved and big insulin-like growth factor-II disappeared in the molecular weight analysis of serum insulin-like growth factor-II by western blotting. The patient had no tumor recurrence or reappearance of hypoglycemia 16 months after the operation without any adjuvant therapy.ConclusionsAlthough insulin-like growth factor-II-producing tumors are generally large and difficult to operate on, surgical resection is currently the most effective and only treatment; thus, it is essential to attempt resection aggressively.

The Effects of Four Weeks of Chiropractic Spinal Adjustments on Blood Biomarkers in Adults with Chronic Stroke: Secondary Outcomes of a Randomized Controlled Trial.

Certain blood biomarkers are associated with neural protection and neural plasticity in healthy people and individuals with prior brain injury. To date, no studies have evaluated the effects chiropractic care on serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor-II (IGF-II) and glial cell-derived neurotrophic factor (GDNF) in people with stroke. This manuscript reports pre-specified, exploratory, secondary outcomes from a previously completed parallel group randomized controlled trial. We evaluated differences between four weeks of chiropractic spinal adjustments combined with the usual physical therapy (chiro + PT) and sham chiropractic with physical therapy (sham + PT) on resting serum BDNF, IGF-II and GDNF in 63 adults with chronic stroke. Blood samples were assessed at baseline, four weeks (post-intervention), and eight weeks (follow-up). Data were analyzed using a linear multivariate mixed effects model. Within both groups there was a significant decrease in the mean log-concentration of BDNF and IGF-II at each follow-up, and significant increase log-concentration of GDNF at eight-weeks' follow-up. However, no significant between-group differences in any of the blood biomarkers at each time-point were found. Further research is required to explore which factors influence changes in serum BDNF, IGF-II and GDNF following chiropractic spinal adjustments and physical therapy.

MiR-196a enhances polymerization of neuronal microfilaments through suppressing IMP3 and upregulating IGF2 in Huntington’s disease

Huntington's disease (HD) is one of the inheritable neurodegenerative diseases, and these diseases share several similar pathological characteristics, such as abnormal neuronal morphology. miR-196a is a potential target to provide neuroprotective functions, and has been reported to enhance polymerization of neuronal microtubules in HD. While microtubules and microfilaments are two important components of the neuronal cytoskeleton, whether miR-196a improves neuronal microfilaments is still unknown. Here, we identify insulin-like growth factor 2 mRNA binding protein 3 (IMP3), and show that miR-196a directly suppresses IMP3 to increase neurite outgrowth in neurons. In addition, IMP3 disturbs neurite outgrowth invitro and invivo, and worsens the microfilament polymerization. Moreover, insulin-like growth factor-II (IGF2) is identified as the downstream target of IMP3, and miR-196a downregulates IMP3 to upregulate IGF2, which increases microfilamental filopodia numbers and activates Cdc42 to increase neurite outgrowth. Besides, miR-196a increases neurite outgrowth through IGF2 in different HD models. Finally, higher expression of IMP3 and lower expression IGF2 are observed in HD transgenic mice and patients, and increase the formation of aggregates in the HDcell model. Taken together, miR-196a enhances polymerization of neuronal microfilaments through suppressing IMP3and upregulating IGF2 in HD, supporting the neuroprotective functions of miR-196a through neuronal cytoskeleton in HD.

The growth performance, antioxidative status and muscle quality of grass carp (Ctenopharyngodon idellus) cultured in the recirculating pond aquaculture system (RPAS)

The recirculating pond aquaculture system (RPAS) consisted of culture ponds, a purification pond, inflow ditch, outflow pipe, ecological ditch, and electrically driven pump. The performance of RPAS on grass carp (Ctenopharyngodon idellus) was explored in this study. In both the RPAS and the traditional pond aquaculture system (TPAS), water quality, fish growth performance, muscle quality, and tissue biochemical properties were assessed. Pond water was exchanged every seven days in RPAS and treated using a purification system that included an ecological ditch and a purification pond with a floating bed and aquatic plant. In RPAS, nitrate‑nitrogen, ammonia‑nitrogen, and nitrite‑nitrogen concentrations were lower than in TPAS. Fish cultured in RPAS exhibited significant higher growth rate and lower feed conversion rate. A significant increase in the expression of growth-related genes of myogenin (MyoG), myofactar-5 (Myf-5), insulin-like growth factor-I gene (igf-1), insulin-like growth factor-II gene (igf-2), and growth hormone receptor gene (ghr) were found in the fish cultured in the RPAS ponds. The content of malondialdehyde in either serum or liver and hepatic protein carbonyls content declined significantly in the RPAS ponds. The activities of T-SOD and GSH in liver and GSH in serum elevated significantly in RPAS fish. Muscular histological characteristics and texture profiles did not alter between two groups. The muscular contents of aromatic amino acids of aspartic acid and glutamic acid were significantly higher in RPAS than those in TPAS. It is inferred that RPAS is beneficial to promote fish growth, decrease oxidative stress, and increase muscle umami flavor.

Immunohistochemical Expression of IMP3 in Cutaneous Basal Cell Carcinoma

Background. Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is an oncofetal protein upregulated in tumor cells during carcinogenesis. It has been linked to adverse clinical outcome in many malignancies.&#x0D; This study was aimed to evaluate an immunohistochemical expression status of IMP3 in cutaneous basal cell carcinoma (BCC) and to correlate it with the Ki-67 index values.&#x0D; Methods. Biopsy specimens from 32 cases of BCC were enrolled into this analysis. All samples were immunohistochemically stained for IMP3 (Clone 69.1) and Ki-67 antigen (Clone MIB-1).&#x0D; Results. IMP3 showed a weak expression in 11 (34.4%) cases, a moderate expression in 11 (34.4%) cases, a strong expression in 5 (15.6%) cases, and negative staining in 5 (15.6%) cases. Among seven BCCs exhibiting aggressive-growth features, all but one showed weak reactivity. In contrast, all five BCCs manifesting strong IMP3 positivity consisted of the indolent-growth histologic subtypes. BCCs with infiltrative histomorphology did not appear to have a tendency towards more striking production of IMP3. There was no significant relationship between the IMP3 expression status and the proliferation status (Ki-67 ≤ 50% vs. Ki-67 &gt; 50%) of the tumor tissue (p &gt; 0.05).&#x0D; Conclusions. The vast majority of cutaneous BCCs express IMP3, suggesting this oncoprotein is implicated in BCC carcinogenesis. However, more pronounced expression does not seem to be associated with aggressive-growth phenotype of BCC or higher proliferative activity of neoplastic cells.

Overexpression of cardiac‐specific IGF‐IIRα accelerates the development of liver dysfunction through STZ‐induced diabetic hepatocyte damage in transgenic rats

This study reports the effect of cardiac-specific insulin-like growth factor-II receptor α (IGF-IIRα) overexpression on the development of liver dysfunction in transgenic rats via STZ-induced diabetic hepatocyte damage. The cardio-hepatic syndrome comprises a number of heart and liver illnesses in which an acute or chronic disease in one organ can lead to acute or chronic disease in the other. However, the molecular mechanism involved in such a set of conditions is unclear. In this study, we developed a transgenic rat model with cardiac-specific overexpression of IGF-IIRα, which is a supplementary splicing variant of insulin-like growth factor-II receptor (IGF-IIR), expressed in pathological hearts, to investigate the relationship between late fetal gene expression in diabetic hearts and their influence on diabetic hepatopathy. STZ (55 mg/kg) was intraperitoneally delivered into IGF-IIR overexpressed transgenic (TG) and non-transgenic (NTG) animal models developed in Sprague-Dawley (SD) rats after an overnight fast. The relationship among IGF-IIRα overexpression and hepatocyte damages have been determined based on the complexity of damage in the liver. Our findings revealed that overexpression of the cardiac-specific IGF-IIRα enhances diabetes-induced morphological alterations and hepatic inflammation in the livers. The diabetic transgenic rats demonstrated the development of pathological conditions such as thick collagen fiber deposition, bridging fibrosis, and elevation of α-SMA and MMP1 related liver fibrosis mechanisms. Our data suggest that IGF-IIRα overexpression in the heart during a pathological state may worsen diabetic hepatopathy in rats.

IMP3 Expression in Thyroid Cancers and its Relationship with Prognostic Parameters

To determine the expression of IMP3 (Insulin-like growth factor-II mRNA binding protein 3), which has been reported to be associated with poor prognosis in many organ malignancies, in thyroid malignant tumors and to determine its relationship with prognostic factors such as age, gender, tumor size, and histological type of tumor.

Prognostic Value of IGF2 mRNA-Binding Protein 3 (IGF2BP3) Intratumoral Expression in Melanoma Patients at the Time of Diagnosis: Comparative Analysis of RT-qPCR Versus Immunohistochemistry

Simple SummaryAround 80% of skin cancer deaths are due to melanoma. An accurate prognosis of melanoma clinical behavior from primary tumors is important for therapeutic patient management, currently based on histopathological features. The aim of our retrospective study was to investigate the clinical significance of IGF2BP3 mRNA and protein expression in melanoma progression and to evaluate which quantification method, RT-qPCR or immunohistochemistry, provides a more reliable prognostic value of IGF2BP3 expression in primary tumors. We found that IGF2BP3 mRNA expression correlated better with clinicopathologic melanoma features than the corresponding proteins and that patients with higher IGF2BP3 mRNA levels were at more risk for earlier development of metastasis, confirming its impact on melanoma survival. Our findings support the use of IGF2BP3 mRNA levels as an independent prognostic biomarker and the implementation of its RT-qPCR analysis for routine melanoma assessment, even for the earliest stages, to improve melanoma clinical outcomes and individualized treatment.Screening for prognostic biomarkers is crucial for clinical melanoma management. Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3) has emerged as a potential melanoma diagnostic and prognostic biomarker. It is commonly tested by immunohistochemistry (IHC). Our study retrospectively examines IGF2BP3 mRNA and protein expression in primary melanomas, their correlation with clinicopathologic factors, clinical outcome, and selected miRNAs expression, and their efficiency in predicting melanoma progression and survival. RT-qPCR and IHC on IGF2BP3 expression were performed in 61 cryopreserved and 63 formalin-fixed paraffin-embedded primary melanomas, respectively, and correlated to clinicopathologic factors, distant metastasis-free survival (DMFS), and melanoma -specific survival (MSS). The correlation between RT-qPCR and IHC was significant but moderate. IGF2BP3 mRNA showed a stronger association with clinicopathologic factors (Breslow thickness, ulceration, mitosis rate, growth phase, development of metastasis, and melanoma-specific survival) than its protein counterpart. Interestingly, higher IGF2BP3 mRNA expression was detected in primary melanomas that further metastasized to distant sites and was an independent prognostic factor for the risk of unfavorable DMFS and MSS. RT-qPCR outperformed IHC in sensitivity and in predicting worse clinical outcomes. Therefore, RT-qPCR may successfully be implemented for routine IGF2BP3 assessing for the selection of melanoma patients with a higher risk of developing distant metastasis and dying of melanoma.

The socioeconomic landscape of the exposome during pregnancy.

While socioeconomic position (SEP) is consistently related to pregnancy and birth outcome disparities, relevant biological mechanisms are manifold, thus necessitating more comprehensive characterization of SEP-exposome associations during pregnancy. We implemented an exposomic approach to systematically characterize the socioeconomic landscape of prenatal exposures in a setting where social segregation was less distinct in a hypotheses-generating manner. We described the correlation structure of 134 prenatal exogenous and endogenous sources (e.g., micronutrients, hormones, immunomodulatory metabolites, environmental pollutants) collected in a diverse, population-representative, urban, high-income longitudinal mother-offspring cohort (N=1341; 2009-2011). We examined the associations between maternal, paternal, household, and areal level SEP indicators and 134 exposures using multiple regressions adjusted for precision variables, as well as potential effect measure modification by ethnicity and nativity. Finally, we generated summary SEP indices using Multiple Correspondence Analysis to further explore possible curved relationships. Individual and household SEP were associated with anthropometric/adiposity measures, folate, omega-3 fatty acids, insulin-like growth factor-II, fasting glucose, and neopterin, an inflammatory marker. We observed paternal education was more strongly and consistently related to maternal exposures than maternal education. This was most apparent amongst couples discordant on education. Analyses revealed additional non-linear associations between areal composite SEP and particulate matter. Environmental contaminants (e.g., per- and polyfluoroalkyl substances) and micronutrients (e.g., folate and copper) showed opposing associations by ethnicity and nativity, respectively. SEP-exposome relationships are complex, non-linear, and context specific. Our findings reinforce the potential role of paternal contributions and context-specific modifiers of associations, such as between ethnicity and maternal diet-related exposures. Despite weak presumed areal clustering of individual exposures in our context, our approach reinforces subtle non-linearities in areal-level exposures.

Transcytosis of tanycytes in the circumventricular organs of adult mouse brain

Tanycytes are specialized ependymal cells lining the ventricular spaces of the adult brain and thereby provide an interface between the cerebrospinal fluid (CSF) and brain parenchyma. They act as energy homeostasis, neuroendocrine regulation, and CSF-brain barrier; however, their functional significance in CSF-brain communication currently remains unknown. In the present study, we investigated the presence of tanycytic transcytosis using fluorescent tracers; a GM1 ligand, cholera toxin B (CTB), and a mannose-6-phosphate/insulin-like growth factor-Ⅱ receptor ligand, wheat germ agglutinin (WGA). Both CTB and WGA were incorporated by tanycytes and then released into brain parenchyma in the circumventricular organs such as the organum vasculosum laminae terminalis, subfornical organ, and median eminence, arcuate nucleus, and medullary central canal. Incorporated fluorescent CTB and WGA were released from tanycytes to distribute at neuronal somata. These results indicate that tanycytes of all examined brain regions possess the transport capability of macromolecules from CSF to brain neurons.