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Unlike adult mammals, the hearts of neonatal mice possess the ability to completely regenerate from myocardial infarction (MI). This observation has sparked vast interest in deciphering the potentially lifesaving and morbidity-reducing mechanisms involved in neonatal cardiac regeneration. In mice, the regenerative potential is lost within the first week of life and coincides with a reduction of Insulin-like growth factor 1 receptor (Igf1r) expression in the heart. Igf1r is a well-known regulator of cardiomyocyte maturation and proliferation in neonatal mice. To test the role of Igf1r as a pivotal factor in cardiac regeneration, we knocked down (KD) Igf1r specifically in cardiomyocytes using recombinant adeno-associated virus (rAAV) delivery and troponin T promotor driven shRNAmirs. Cardiomyocyte specific Igf1r KD versus control mice were subjected to experimental MI by permanent ligation of the left anterior descending artery (LAD). Cardiac functional and morphological data were analyzed over a 21-day period. Neonatal Igf1r KD mice showed reduced systolic cardiac function and increased fibrotic cardiac remodeling 21 days post injury. This cardiac phenotype was associated with reduced cardiomyocyte nuclei mitosis and decreased AKT and ERK phosphorylation in Igf1r KD, compared to control neonatal mouse hearts. Our in vivo murine data show that Igf1r KD shifts neonatal cardiac regeneration to a more adult-like scarring phenotype, identifying cardiomyocyte-specific Igf1r signaling as a crucial component of neonatal cardiac regeneration. [ABSTRACT FROM AUTHOR]

Abstract Unlike adult mammals, the hearts of neonatal mice possess the ability to completely regenerate from myocardial infarction (MI). This observation has sparked vast interest in deciphering the potentially lifesaving and morbidity-reducing mechanisms involved in neonatal cardiac regeneration. In mice, the regenerative potential is lost within the first week of life and coincides with a reduction of Insulin-like growth factor 1 receptor (Igf1r) expression in the heart. Igf1r is a well-known regulator of cardiomyocyte maturation and proliferation in neonatal mice. To test the role of Igf1r as a pivotal factor in cardiac regeneration, we knocked down (KD) Igf1r specifically in cardiomyocytes using recombinant adeno-associated virus (rAAV) delivery and troponin T promotor driven shRNAmirs. Cardiomyocyte specific Igf1r KD versus control mice were subjected to experimental MI by permanent ligation of the left anterior descending artery (LAD). Cardiac functional and morphological data were analyzed over a 21-day period. Neonatal Igf1r KD mice showed reduced systolic cardiac function and increased fibrotic cardiac remodeling 21 days post injury. This cardiac phenotype was associated with reduced cardiomyocyte nuclei mitosis and decreased AKT and ERK phosphorylation in Igf1r KD, compared to control neonatal mouse hearts. Our in vivo murine data show that Igf1r KD shifts neonatal cardiac regeneration to a more adult-like scarring phenotype, identifying cardiomyocyte-specific Igf1r signaling as a crucial component of neonatal cardiac regeneration.

Background: To overcome organ shortage during transplantation, interspecies organ generation via blastocyst complementation has been proposed, although not yet in evolutionarily distant species. To establish high levels of chimerism, low chimerism is required early in development, followed by high chimerism, to effectively complement the organ niche. Very few human cells are expected to contribute to chimerism in heterologous animals. Previous studies had demonstrated increased donor chimerism in both intra- and interspecies chimeras in rodents, using insulin-like growth factor 1 receptor (Igf1r) knockout (KO) mice; deletion of the Igf1r gene in the mouse host embryo created a cell-competitive niche. The current study aimed to generate IGF1R–KO pigs and evaluate whether they have the same phenotype as Igf1r-KO mice. Methods: To generate IGF1R–KO pigs, genome-editing molecules were injected into the cytoplasm of pig zygotes. The fetuses were evaluated at 104 days of gestation. Results: IGF1R–KO pigs were generated successfully. Their phenotypes were almost identical to those of Igf1r-KO mice, including small lungs and enlarged endodermal organs in fetuses, and they were highly reproducible. Conclusions: Pigs may allow the generation of organs using blastocyst complementation with developmentally-compatible xenogeneic pluripotent stem cells over a large evolutionary distance.

Objective This study aimed to investigate the effect of Dapagliflozin on the hypertrophy and apoptosis of cardiomyocytes induced by angiotensin II (Ang II). Methods Primary rat neonatal cardiomyocytes were isolated, cultured and randomly divided into 4 groups: control group, Ang II group, dapagliflozin group 1 (0.5 μmol/L, and dapagliflozin group 2 (2 μmol/L). α-actin staining was used to detect cell area. qPCR was applied to detect embryonic gene transcription. Tunel staining was adopted to detect cell apoptosis level. The caspase3 kit was used to detect caspase3 activity and western blotting was used to detect classical signal molecules. Results The cell surface area of the Ang II group was significantly larger than that of the control group (P < 0.05). The cell surface area of the dapagliflozin group 1 and the dapagliflozin group 2 was significantly lower than that of the Ang II group (P < 0.05). The results of qPCR showed that the fetal gene transcription of Ang II group was significantly higher than that of the control group (P < 0.05); the fetal gene transcription of dapagliflozin group 1 and dapagliflozin group 2 was lower than that of Ang II group (P < 0.05). Tunel staining showed that the number of apoptosis in the Ang II group was higher than that in the control group (P < 0.05); the number of apoptosis in the dapagliflozin group 1 and the Dapagliflozin group 2 was lower than that in the Ang II group (P < 0.05). The cas-pase3 activity of the cells in the Ang II group was higher than that of the control group (P < 0.05) but lower in dapagliflozin group 1 and the dapagliflozin group 2 (P < 0.05). The results of Western blotting showed that the activation of insulin-like growth factor 1 receptor (IGF1R) and Akt in the Ang II group was lower than that in the control group (P < 0.05) but increased in the dapagliflozin group 1 and 2 cells (P < 0.05). Conclusion Dapagliflozin could directly act on cardiomyocytes to protect them from Ang II -induced damage. [ABSTRACT FROM AUTHOR]

Hyperglycemia induces chronic stresses, such as oxidative stress and endoplasmic reticulum (ER) stress, which can result in β -cell dysfunction and development of Type 2 Diabetes Mellitus (T2DM). Ginsenoside Rk1 is a minor ginsenoside isolated from Ginseng. It has been shown to exert anti-cancer, anti-inflammatory, anti-oxidant, and neuroprotective effects; however, its effects on pancreatic cells in T2DM have never been studied. This study aims to examine the novel effects of Ginsenoside Rk1 on ER stress-induced apoptosis in a pancreatic β -cell line MIN6 and HFD-induced diabetic pancreas, and their underlying mechanisms. We demonstrated that Ginsenoside Rk1 alleviated ER stress-induced apoptosis in MIN6 cells, which was accomplished by directly targeting and activating insulin-like growth factor 1 receptor (IGF-1R), thus activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Bcl-2-associated agonist of cell death (Bad)-B-cell lymphoma-2 (Bcl-2) pathway. This pathway was also confirmed in an HFD-induced diabetic pancreas. Meanwhile, the use of the IGF-1R inhibitor PQ401 abolished this anti-apoptotic effect, confirming the role of IGF-1R in mediating anti-apoptosis effects exerted by Ginsenoside Rk1. Besides, Ginsenoside Rk1 reduced pancreas weights and increased pancreatic insulin contents, suggesting that it could protect the pancreas from HFD-induced diabetes. Taken together, our study provided novel protective effects of Ginsenoside Rk1 on ER stress-induced β -cell apoptosis and HFD-induced diabetic pancreases, as well as its direct target with IGF-1R, indicating that Ginsenoside Rk1 could be a potential drug for the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health concern, with lung cancer consistently leading as one of the most common malignancies. Genetic aberrations involving receptor tyrosine kinases (RTKs) are known to be associated with cancer initiation and development, but RTK involvement in smoking-associated lung cancer cases is not well understood. The Insulin-like Growth Factor 1 Receptor (IGF-1R) is a receptor that plays a critical role in lung cancer development. Its signaling pathway affects the growth and survival of cancer cells, and high expression is linked to poor prognosis and resistance to treatment. Several reports have shown that by activating IGF-1R, tobacco smoke-related carcinogens promote lung cancer and chemotherapy resistance. However, the relationship between IGF-1R and cancer is complex and can vary depending on the type of cancer. Ongoing investigations are focused on developing therapeutic strategies to target IGF-1R and overcome chemotherapy resistance. Overall, this review explores the intricate connections between tobacco smoke-specific carcinogens and the IGF-1R pathway in lung carcinogenesis. This review further highlights the challenges in using IGF-1R inhibitors as targeted therapy for lung cancer due to structural similarities with insulin receptors. Overcoming these obstacles may require a comprehensive approach combining IGF-1R inhibition with other selective agents for successful cancer treatment. [ABSTRACT FROM AUTHOR]

Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease associated with thyroid dysfunction that can significantly impact quality of life, result in visual impairment and facial disfigurement. Traditional treatments are often unsatisfactory. Studies have shown that teprotumumab, a human monoclonal antibody that can inhibit insulin-like growth factor 1 receptor(IGF-1R), has become an emerging targeted drug for TAO. Although the drug has proven to be effective and relatively safe in the treatment of TAO, adverse reactions are worthy of attention of ophthalmologists with the continuous promotion of clinical application, including hearing impairment, hyperglycemia, diarrhea, muscle spasms, infusion reactions, cognitive decline, thyroid suppression, alopecia, nausea and fatigue. Teprotumumab was generally well tolerated, with most adverse events being mild or moderate in severity. This paper aims to review the adverse reactions and precautions of teprotumumab in the treatment of TAO.

Aberrant protein glycosylation is a hallmark of cancer, but few drugs targeting cancer glycobiomarkers are currently available. Here, we showed that a lectibody consisting of the high-mannose glycan-binding lectin Avaren and human immunoglobulin G1 (IgG1) Fc (AvFc) selectively recognizes a range of cell lines derived from lung, breast, colon, and blood cancers at nanomolar concentrations. Binding of AvFc to the non-small cell lung cancer (NSCLC) cell lines A549 and H460 was characterized in detail. Co-immunoprecipitation proteomics analysis revealed that epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) are among the lectibody's common targets in these cells. AvFc blocked the activation of EGFR and IGF1R by their respective ligands in A549 cells and inhibited the migration of A549 and H460 cells upon stimulation with EGF and IGF1. Furthermore, AvFc induced potent Fc-mediated cytotoxic effects and significantly restricted A549 and H460 tumor growth in severe combined immunodeficiency (SCID) mice. Immunohistochemistry analysis of primary lung tissues from NSCLC patients demonstrated that AvFc preferentially binds to tumors over adjacent non-tumor tissues. Our findings provide evidence that increased abundance of high-mannose glycans in the glycocalyx of cancer cells can be a druggable target, and AvFc may provide a new tool to probe and target this tumor-associated glycobiomarker.

AIM: To explore the beneficial effects and underlying mechanisms of linsitinib (OSI-906) on angiotensin II (Ang II) -induced cardiac hypertrophy in mice. METHODS: Thirty C57BL/6J mice were randomly divided into 3 groups (10 mice each group): control group, model (Ang II)group, and Ang II+OSI-906 group. Myocardial hypertrophy mouse model was constructed by treating with Ang II(2 mg* *kg_1 *d_1) with the subcutaneous injection for 2 weeks, and the Ang II+OSI-906 group was given OSI-906(50 mg/kg) by gastric irrigation on this basis. Using hematoxylin-eosin (HE)staining, the pathological changes of heart tissue of mice were evaluated. Using RT-qPCR, the related mRNA levels of heart tissues of mice were detected. The protein expressions of the AMPK/SIRT3 signaling pathway were detected using Western blot assay. The indicators of oxidative stress, including malondialdehyde(MDA), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were detected by ELISA kits. RESULTS: Compared with model group, the cardiac mass indexes(HW/BW and HW/TL) were significantly decreased in Ang Il-treated mice with OSI-906-treatment (PVO. 05). Moreover, OSI-906-treatment showed the similar alterations on the pathological changes of heart tissues. The mRNA levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP), and the inflammatory cytokines of tumor necrosis factor-a(TNF-ot), interleukin lp(IL-Ip) and interleukin 6(IL-6) were all significantly down-regulated in the heart tissues of mice in Ang II+OSI-906 group (PV0. 05). Furthermore, the level of MDA was significantly decreased(PVO.01), but the levels of SOD, CAT and GSH-Px were increased (P<0. 05). The phosphorylation of AMP-activated protein kinase (p-AMPK)and silent information regulator 3 (SIRT3) were up-regulated (P<0. 05). Consistently, the mRNA expressions of ANP, BNP and myosin heavy chain (p-MHC) were significantly increased in primary neonatal mice cardiomyocytes treated with Compound C, a blocker of AMPK signaling. CONCLUSION: OSI-906 significantly inhibited Ang Il-induced myocardial inflammation and oxidative stress in mice, and may play a cardioprotective role through the AMPK/SIRT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) denotes a heterogeneous category of cancers occurring within the bone marrow that are initiated by the unrestricted proliferation of haematopoietic stem cells. Various factors effectuate the dysregulation of AML cell proliferation; for instance, the upregulation of insulin-like growth factor 1 receptor (IGF1R) within AML cells influences their proliferation. However, there is a current dearth of research assessing the association between IGF1R and prognostic risk as well as its potential as an AML immunotherapeutic. This study aims to elucidate the role of IGF1R in AML progression and evaluate its prognostic value. To this end, RNA-sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database was analysed to compare IGF1R expression between AML and normal tissues. Moreover, a Kaplan–Meier survival analysis was performed to determine whether IGF1R expression correlates with patient overall survival (OS). TCGA data revealed upregulated IGF1R expression in the peripheral blood of AML patients compared to that in healthy individuals. Meanwhile, IGF1R expression positively correlates with patient OS. Additionally, elevated IGF1R expression promotes NK cell expansion and enhances its functional activation, thereby inhibiting AML cell proliferation. Collectively, these findings highlight the clinical potential of IGF1R in the effective treatment of AML through the activation of NK cell proliferation and function and suggest that it may represent a potential predictive marker of AML prognosis. [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health concern, with lung cancer consistently leading as one of the most common malignancies. Genetic aberrations involving receptor tyrosine kinases (RTKs) are known to be associated with cancer initiation and development, but RTK involvement in smoking-associated lung cancer cases is not well understood. The Insulin-like Growth Factor 1 Receptor (IGF-1R) is a receptor that plays a critical role in lung cancer development. Its signaling pathway affects the growth and survival of cancer cells, and high expression is linked to poor prognosis and resistance to treatment. Several reports have shown that by activating IGF-1R, tobacco smoke-related carcinogens promote lung cancer and chemotherapy resistance. However, the relationship between IGF-1R and cancer is complex and can vary depending on the type of cancer. Ongoing investigations are focused on developing therapeutic strategies to target IGF-1R and overcome chemotherapy resistance. Overall, this review explores the intricate connections between tobacco smoke-specific carcinogens and the IGF-1R pathway in lung carcinogenesis. This review further highlights the challenges in using IGF-1R inhibitors as targeted therapy for lung cancer due to structural similarities with insulin receptors. Overcoming these obstacles may require a comprehensive approach combining IGF-1R inhibition with other selective agents for successful cancer treatment.

Background The renin‐angiotensin system plays a crucial role in the development of heart failure, and Ang II (angiotensin II) acts as the critical effector of the renin‐angiotensin system in regulating cardiac fibrosis. However, the mechanisms of cardiac fibrosis are complex and still not fully understood. IGF1R (insulin‐like growth factor 1 receptor) has multiple functions in maintaining cardiovascular homeostasis, and low‐dose IGF1 treatment is effective in relieving Ang II–induced cardiac fibrosis. Here, we aimed to investigate the molecular mechanism of IGF1R in Ang II–induced cardiac fibrosis. Methods and Results Using primary mouse cardiac microvascular endothelial cells and fibroblasts, in vitro experiments were performed. Using C57BL/6J mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated 9 (Cas9)‐mediated IGF1R heterozygous knockout (Igf1r+/−) mice, cardiac fibrosis mouse models were induced by Ang II for 2 weeks. The expression of IGF1R was examined by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot. Mice heart histologic changes were evaluated using Masson and picro sirius red staining. Fibrotic markers and signal molecules indicating the function of the Akt (protein kinase B)/ERK (extracellular signal‐regulated kinase)/nuclear factor‐κB pathway were detected using quantitative reverse transcription polymerase chain reaction and Western blot. RNA sequencing was used to explore IGF1R‐mediated target genes in the hearts of mice, and the association of IGF1R and G‐protein–coupled receptor kinase 5 was identified by coimmunoprecipitation. More important, blocking IGF1R signaling significantly suppressed endothelial‐mesenchymal transition in primary mouse cardiac microvascular endothelial cells and mice in response to transforming growth factor‐β1 or Ang II, respectively. Deficiency or inhibition of IGF1R signaling remarkably attenuated Ang II–induced cardiac fibrosis in primary mouse cardiac fibroblasts and mice. We further observed that the patients with heart failure exhibited higher blood levels of IGF1 and IGF1R than healthy individuals. Moreover, Ang II treatment significantly increased cardiac IGF1R in wild type mice but led to a slight downregulation in Igf1r+/− mice. Interestingly, IGF1R deficiency significantly alleviated cardiac fibrosis in Ang II–treated mice. Mechanistically, the phosphorylation level of Akt and ERK was upregulated in Ang II–treated mice, whereas blocking IGF1R signaling in mice inhibited these changes of Akt and ERK phosphorylation. Concurrently, phosphorylated p65 of nuclear factor‐κB exhibited similar alterations in the corresponding group of mice. Intriguingly, IGF1R directly interacted with G‐protein–coupled receptor kinase 5, and this association decreased ≈50% in Igf1r+/− mice. In addition, Grk5 deletion downregulated expression of the Akt/ERK/nuclear factor‐κB signaling pathway in primary mouse cardiac fibroblasts. Conclusions IGF1R signaling deficiency alleviates Ang II–induced cardiac fibrosis, at least partially through inhibiting endothelial‐mesenchymal transition via the Akt/ERK/nuclear factor‐κB pathway. Interestingly, G‐protein–coupled receptor kinase 5 associates with IGF1R signaling directly, and it concurrently acts as an IGF1R downstream effector. This study suggests the promising potential of IGF1R as a therapeutic target for cardiac fibrosis.

The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.

Cell surface proteins carrying N-glycans play important roles in inter- and intracellular processes including cell adhesion, development, and cellular recognition. Dysregulation of the glycosylation machinery has been implicated in various diseases, and investigation of global differential cell surface proteome effects due to the loss of N-glycosylation will provide comprehensive insights into their pathogenesis. Cell surface proteins isolated from Parent Pro–5 CHO cells (W5 cells), two CHO mutants with loss of N-glycosylation function derived from Pro–5 CHO (Lec1 and Lec4 cells), were subjected to proteome analysis via high-resolution LCMS. We identified 44 and 43 differentially expressed membrane proteins in Lec1 and Lec4 cells, respectively, as compared to W5 cells. The defective N-glycosylation mutants showed increased abundance of integrin subunits in Lec1 and Lec4 cells at the cell surface. We also found significantly reduced levels of IGF-1R (Insulin like growth factor-1 receptor); a receptor tyrosine kinase; and the GTPase activating protein IQGAP1 (IQ motif-containing GTPase activating protein), a highly conserved cytoplasmic scaffold protein) in Lec1 and Lec4 cells. In silico docking studies showed that the IQ domain of IQGAP1 interacts with the kinase domain of IGF-1R. The integrin signaling and insulin growth factor receptor signaling were also enriched according to GSEA analysis and pathway analysis of differentially expressed proteins. Significant reductions of phosphorylation of ERK1 and ERK2 in Lec1 and Lec4 cells were observed upon IGF-1R ligand (IGF-1 LR3) stimulation. IGF-1 LR3, known as Long arginine3-IGF-1, is a synthetic protein and lengthened analog of insulin-like growth factor 1. The work suggests a novel mechanism for the activation of IGF-1 dependent ERK signaling in CHO cells, wherein IQGAP1 plausibly functions as an IGF-1R-associated scaffold protein. Appropriate glycosylation by the enzymes MGAT1 and MGAT5 is thus essential for processing of cell surface receptor IGF-1R, a potential binding partner in IQGAP1 and ERK signaling, the integral components of the IGF pathway. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of IGF1R β subunit mutants sb-IGF1R and ma-IGF1R on the biological behavior of osteosarcoma 143B cells. Methods We designed and constructed sb-IGF1R and ma-IGF1R fragments. They were cloned into adenovirus AdEasy shuttle plasmid, to obtain Ad-sbIGF1R and Ad-maIGF1R. We observed the proliferation, migration and apoptosis of the osteosarcoma cells transfected with Ad-sbIGF1R, Ad-maIGF1R and Ad-IGF1R. The Ad-sbIGF1R, Ad-maIGF1R and Ad-GFP nude mouse models were constructed to evaluate the tumor growth in vitro. Results By plasmid PCR, IGF-1R β subunit mutant was overexpressed in osteosarcoma cells. Ad-sbIGF1R and Ad-maIGF1R significantly inhibited the proliferation and migration of osteosarcoma cells, and promoted cell apoptosis, and inhibited tumor growth in subcutaneous tumor-bearing nude mouse models. Conclusion IGF1R β subunit mutants inhibit the proliferation and migration of osteosarcoma cells and induce cell apoptosis.

Wei Tang,1,&ast; Qian Lv,1,&ast; Xiao Huang,2,&ast; Yuzhen Li,2 JunJie Zou,1 Jiaoyang Zheng,1 Liangliang Sun,1 Yi Bao,1 Haiyan Chen,1 Tuo Li,1 Bei Zhang,1 Song Xue,1 Yan Song,1 Xingxing Zhang,1 Xiangfang Chen,1 Jiping Cai,2 Yongquan Shi1 1Department of Endocrinology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, People’s Republic of China; 2Department of Ophthalmology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangfang Chen; Yongquan Shi, Department of Endocrinology, Second Affiliated Hospital of Naval Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai, 200003, People’s Republic of China, Email chenxiangfang@smmu.edu.cn; young.stone@smmu.edu.cnObjective: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease that involves the remodeling of orbit and periorbital tissues. Thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) may stimulate the activation of autoimmunity in TAO, but the exact mechanism is unclear. We investigated whether IGF-1R/TSHR modulation in TAO may involve microRNA regulation.Methods: We conducted microarray analysis using RNA from the orbital connective tissue samples of 3 healthy and 3 patients with TAO. The involvement of differentially regulated microRNA in IGF-1R/TSHR modulation in TAO was evaluated in orbital fibroblasts (OFs) and female BALB/c mice.Results: Using hierarchical cluster analysis, we identified that miR-143 was downregulated in TAO. The expression levels of miR-143 in OFs were significantly reduced under IL-1B stimulation. However, OF proliferation and inflammatory responses decreased when miR-143 is overexpressed. In contrast, the suppression of miR-143 increased levels of inflammatory markers (IL-6, IL-8, MCP1) and hyaluronan accumulation. Moreover, overexpression of miR-143 significantly lowers levels of IGF-1R and TSHR. A luciferase assay indicated that miR-143 targets the 3′-UTR of IGF-1R. Increases in the expression of IGF-1R increased the expression of the inflammasome marker NLRP3 and apoptotic marker cleaved caspase-1; however, miR-143 overexpression decreased levels of IGF-1R, TSHR, NLRP3, cleaved caspase 1, IL-1B, and IL-18. In a mouse model of TAO, overexpression of miR-143 significantly reduced levels of IGF-1R and attenuated the adipogenesis associated with TAO.Conclusion: We found that miR-143 directly targets IGF-1R to alleviate the inflammatory response in TAO by indirectly decreasing levels of TSHR and inactivating NLRP3.Keywords: thyroid-associated ophthalmopathy, miR-143, thyroid-stimulating hormone receptor, insulin-like growth factor 1 receptor, NLRP3

Background and Aims: This review aims to summarize current and emerging therapies for treatment of thyroid eye disease (TED), in the light of novel understanding of pathogenetic mechanisms, leading to new treatment options and clinical trials.Methods: We reviewed and analyzed peer-reviewed literature reporting recent translational studies and clinical trials in the treatment of TED. Searches were made at www.pubmed.gov with keywords "thyroid eye disease," "Graves' ophthalmopathy," "thyroid orbitopathy," and "Graves' orbitopathy."Results: Surgery is reserved for rehabilitation in chronic TED or for emergent compressive optic neuropathy. Oral and intravenous glucocorticoid therapy has been used for decades with variable efficacy in acute TED, but results may be temporary and side effects significant. Nonsteroidal oral immunosuppressive agents offer modest benefit in TED. Several immunomodulatory monoclonal antibodies, including rituximab and tocilizumab, have shown efficacy for inactivating TED. Recently, teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) inhibitor, has demonstrated significant improvement in proptosis, clinical activity score, diplopia, and quality of life in patients with active TED, with good tolerability. Newly proposed TED therapies, currently in preclinical and clinical trial phases, include thyroid-stimulating hormone (TSH) receptor inhibitory drugs, RVT-1401, local anti-vascular endothelial growth factor therapy, IGF-1R drugs delivered subcutaneously and orally, and desensitization to the TSH receptor with modified TSH receptor peptides.Conclusion: New, albeit incomplete, understanding of the molecular mechanisms of TED has led to new promising therapies and offered improved outcomes in TED patients. Their full role and their relationship to classical immune suppression should be clarified over the next few years. [ABSTRACT FROM AUTHOR]

Background: To overcome organ shortage during transplantation, interspecies organ generation via blastocyst complementation has been proposed, although not yet in evolutionarily distant species. To establish high levels of chimerism, low chimerism is required early in development, followed by high chimerism, to effectively complement the organ niche. Very few human cells are expected to contribute to chimerism in heterologous animals. Previous studies had demonstrated increased donor chimerism in both intra- and interspecies chimeras in rodents, using insulin-like growth factor 1 receptor ( Igf1r ) knockout (KO) mice; deletion of the Igf1r gene in the mouse host embryo created a cell-competitive niche. The current study aimed to generate IGF1R- KO pigs and evaluate whether they have the same phenotype as Igf1r -KO mice., Methods: To generate IGF1R- KO pigs, genome-editing molecules were injected into the cytoplasm of pig zygotes. The fetuses were evaluated at 104 days of gestation., Results: IGF1R -KO pigs were generated successfully. Their phenotypes were almost identical to those of Igf1r -KO mice, including small lungs and enlarged endodermal organs in fetuses, and they were highly reproducible., Conclusions: Pigs may allow the generation of organs using blastocyst complementation with developmentally-compatible xenogeneic pluripotent stem cells over a large evolutionary distance., Competing Interests: H.Nagashima is a founder and shareholder of PorMedTec Co., Ltd. These associations do not alter the authors' adherence to the journal's policies on sharing data and materials. The other authors declare that they have no conflicts of interest., (© 2024 The Author(s).)

The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.

As cannabis use during pregnancy increases, it is important to understand its effects on the developing fetus. Particularly, the long-term effects of its psychoactive component, delta-9-tetrahydrocannabinol (THC), on the offspring's reproductive health are not fully understood. This study examined the impact of gestational THC exposure on the miRNA profile in adult rat ovaries and the possible consequences on ovarian health. Prenatal THC exposure resulted in the differential expression of 12 out of 420 evaluated miRNAs. From the differentially expressed miRNAs, miR-122-5p, which is highly conserved among species, was the only upregulated target and had the greatest fold change. The upregulation of miR-122-5p and the downregulation of its target insulin-like growth factor 1 receptor (Igf1r) were confirmed by RT-qPCR. Prenatally THC-exposed ovaries had decreased IGF-1R-positive follicular cells and increased follicular apoptosis. Furthermore, THC decreased Igf1r expression in ovarian explants and granulosa cells after 48 h. As decreased IGF-1R has been associated with diminished ovarian health and fertility, we propose that these THC-induced changes may partially explain the altered ovarian follicle dynamics observed in THC-exposed offspring. Taken together, our data suggests that prenatal THC exposure may impact key pathways in the developing ovary, which could lead to subfertility or premature reproductive senescence. [ABSTRACT FROM AUTHOR]

Purpose: To screen the hypoglycemic active ingredients of Coptidis rhizoma, and study their targets as well as signal pathways via network pharmacology. Methods: Fifty-nine ingredients of Coptidis rhizoma were screened. Their targets were confirmed by comparing with the hypoglycemic targets in DrugBank databases. The relationship between ingredients and targets was revealed through String database. The ingredient-target-passageway network was constructed. Coptidis rhizoma was soaked in boiling water and concentrated. Rat models were rendered diabetic by the administration of streptozotocin (STZ) intraperitoneal injection. The hyperglycemic rats received Coptidis rhizoma extract (0.40 g/kg, once a day by gavage). Results: After four weeks of treatment, the blood glucose levels (BG) of all treated hyperglycemic rats decreased (p < 0.05). Twenty-four hypoglycemic active compounds were obtained after screening the extract of Coptidis rhizome via network pharmacology. These active compounds activated 13 targets, including D (2) dopamine receptor (DRD2), Insulin-like growth factor 1 receptor (IGF1R), 5- hydroxytryptamine receptor 2C (HTR2C), 5-hydroxytryptamine receptor 3A (HTR3A) and sodiumdependent noradrenaline transporter (SLC6A2). These targets were involved in 141 pathways, e.g., cAMP signaling pathway, chemokine signaling pathway, Rap1 signaling pathway, estrogen signaling pathway, and apelin signaling pathway. Conclusion: Coptidis rhizoma contains several active compounds that exhibit good hypoglycemic effects. Thus, there is a need for human studies on the hypoglycemic effects of Coptidis rhizome extract [ABSTRACT FROM AUTHOR]

Background: Peritoneal fibrosis (PF) is caused by epithelial-mesenchymal transdifferentiation (EMT) in the peritoneum under high glucose (HG) conditions. The study aimed to explored the role of Insulin-like growth factor 1 receptor (IGF-1R) in the regulation of EMT in human peritoneal mesothelial cells (HPMCs). Methods: We used HG peritoneal dialysis fluid (PDF) to induce in vivo PF in mice, and treated HPMCs with HG in vitro to stimulate EMT. Results: In the mice, the higher the glucose concentration in the dialysate, the more obvious the peritoneal tissue thickening and the more that collagen was deposited. The in vitro study indicated that the expression of IGF-1R, α-SMA, vimentin was upregulated, while the expression of occludin, ZO-1, and E-cadherin was downregulated in HPMCs under HG and IGF-1R overexpression conditions. Conversely, the expression of IGF-1R, α-SMA, and vimentin was downregulated, while the expression of occludin, ZO-1, and E-cadherin was upregulated in IGF-1R-underexpressed HPMCs under HG conditions. The cell migration abilities were increased, while the cell adhesion abilities were reduced in HPMCs under HG and IGF-1R overexpression conditions. In contrast, cell migration abilities were reduced, while cell adhesion abilities were increased in IGF-1Runderexpressed HPMCs under HG conditions. Conclusions: Targeting at IGF-1R may provide novel insights into the prevention and treatment of PF. [ABSTRACT FROM AUTHOR]

Crosstalk between cancer-associated fibroblasts (CAFs) and tumour cells plays a critical role in multiple cancers, including hepatocellular carcinoma (HCC). CAFs contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. However, effect and mechanism of CAF-mediated promotion of hepatocellular carcinoma cells are still unclear. In study, we demonstrated CAFs promoted the proliferation and inhibited the apoptosis of HCC cells by secreting interleukin-6 (IL-6), which induced autocrine insulin-like growth factor-1 (IGF-1) in HCC. IGF-1 promoted the progression and chemoresistance of HCC. IGF-1 receptor (IGF-1R) inhibitor NT157 abrogated the effect of CAF-derived IL-6 and autocrine IGF-1 on HCC. Mechanistic studies revealed that NT157 decreased IL-6-induced IGF-1 expression by inhibiting STAT3 phosphorylation and led to IRS-1 degradation, which mediated the proliferation of tumour by activating AKT signalling in ERK-dependent manner. Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours. Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib. • In the coculture system, CAFs derived IL-6, which can promote the progression of HCC by inducing autocrine IGF-1 in HCC. • NT157 enhanced the activation of the ERKMAPK pathway and blocked IGF-1/IRS1/AKT signalling by IRS1/2. • CAFs led to the resistance of HCC to sorafenib through IL-6 and IGF-1. • Synergy of CAFs was seen between NT157 and sorafenib in the treatment of HCC, most likely due to p-ERK inhibition. • NT157 may be a potential drug for reversing sorafenib resistance by inhibiting IGF1R/AKT signalling in HCC. [ABSTRACT FROM AUTHOR]

The aim of this review was to describe all of the mutations in the growth hormone receptor (GHR) and insulin-like growth factor-1 receptor (IGF1R) genes that have been discovered so far, and their possible impact on final body height, as well as their relationship with catch-up growth in children born small for gestational age (SGA). Mutations in the GHR gene were found to cause a body height below −2 SD, from the mean for sex and age, whereas the mutations in the IGF1R gene were associated with low body height and intrauterine growth restriction (IUGR), and with being born SGA. After birth, when the child's growth is not restricted by the intrauterine environment, the infant may develop its developmental potential and experience catch-up growth, which makes it possible to catch up with peers born appropriate for gestational age (AGA). Despite this, catch-up growth does not apply to all, but only to about 85% of SGA children, and its mechanism is unknown. It is possible that SGA children who did not experience catch-up growth are carriers of mutations in the GHR and/or IGF1R genes [ABSTRACT FROM AUTHOR]

Thyroid eye disease (TED) is an autoimmune disorder that manifests in the orbit. In TED, the connective tissue behind the eye becomes inflamed and remodels with increased fat accumulation and/or increased muscle and scar tissue. As orbital tissue expands, patients develop edema, exophthalmos, diplopia, and optic neuropathy. In severe cases vision loss may occur secondary to corneal scarring from exposure or optic nerve compression. Currently there is no cure for TED, and treatments are limited. A major breakthrough in TED therapy occurred with the FDA approval of teprotumumab, a monoclonal insulin-like growth factor 1 receptor (IGF1R) blocking antibody. Yet, teprotumumab therapy has limitations, including cost, infusion method of drug delivery, variable response, and relapse. We describe approaches to target orbital fibroblasts and the complex pathophysiology that underlies tissue remodeling and inflammation driving TED. Further advances in the elucidation of the mechanisms of TED may lead to prophylaxis based upon early biomarkers as well as lead to more convenient, less expensive therapies. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of IGF1R β subunit mutants sb-IGF1R and ma-IGF1R on the biological behavior of osteosarcoma 143B cells. Methods We designed and constructed sb-IGF1R and ma-IGF1R fragments. They were cloned into adenovirus AdEasy shuttle plasmid, to obtain Ad-sbIGF1R and Ad-maIGF1R. We observed the proliferation, migration and apoptosis of the osteosarcoma cells transfected with Ad-sbIGF1R, Ad-maIGF1R and Ad-IGF1R. The Ad-sbIGF1R, Ad-maIGF1R and Ad-GFP nude mouse models were constructed to evaluate the tumor growth in vitro. Results By plasmid PCR, IGF-1R β subunit mutant was overexpressed in osteosarcoma cells. Ad-sbIGF1R and Ad-maIGF1R significantly inhibited the proliferation and migration of osteosarcoma cells, and promoted cell apoptosis, and inhibited tumor growth in subcutaneous tumor-bearing nude mouse models. Conclusion IGF1R β subunit mutants inhibit the proliferation and migration of osteosarcoma cells and induce cell apoptosis. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 receptor (IGF-1R) is expressed in malignant and normal breast tissue, and its intermittent activation by multiple IGF-1 signaling pathways leads to neoplasm cell proliferation, impaired apoptosis, increased survival, and resistance to cytotoxic therapeutic agents. Therefore, simultaneous suppression of the receptor and its cognate ligand would be a powerful promising strategy inhibiting malignant phenotypes of breast cancer cells. In the present study, Methoxypoly(ethylene glycol) - Poly(caprolactone) was hybridized with Dimethyldioctadecylammonium bromide (DDAB) cationic lipid (mPEG-PCL-DDAB) nanoparticles (NPs) and used as a carrier for simultaneous delivery of lycopene and insulin-like growth factor 1 receptor-specific lycopene encapsulated-mPEG-PCL-DDAB nanoparticle/siRNA to MCF-7 breast cancer cells. Then, the antitumor effects of this construct were evaluated in vitro. The results demonstrated that the synthesized mPEG-PCL-DDAB nanoparticle had suitable physicochemical properties. The use of mPEG-PCL-DDAB nanoparticle-loaded anti-insulin-like growth factor 1 receptor-siRNA and lycopene dramatically induced the process of apoptosis and arrested cell cycle in the MCF-7 tumor cell lines. In general, the findings of this study demonstrated the potency of mPEG-PCL-DDAB nanoparticles for dual delivery of siRNA, and lycopene in breast cancer cell lines followed the induction of apoptosis. [ABSTRACT FROM AUTHOR]

4-Vinylcyclohexene diepoxide (VCD) is a potentially hazardous industrial chemical that may enter a goat's body in various ways during industrial breeding. Ovarian granulosa cells (GCs) play a critical role in supporting follicle development and hormone synthesis. However, there are few studies on the effect of VCD on goat ovarian GCs. In this study, goat ovarian GCs were isolated and treated with VCD. The results showed that treatment with VCD increased the proportion of S phase and G2/M cells, but decreased the proportion of G1 phase. VCD treatment significantly inhibited the expression of cyclin A and cyclin-dependent kinase 2 (CDK2). But the expression levels of p21 and p27 were increased. VCD could induce an apparent increase in the proportion of apoptosis and the level of cleaved caspase 3. Treatment with VCD significantly reduced the progesterone and estrogen concentration in the medium in which goat ovarian GCs were cultured. Correspondingly, the expression level of steroidogenic acute regulatory protein (STAR) was significantly downregulated. Treatment with 0.25 and 0.5 mM VCD, the protein expression level of insulin-like growth factor 1 receptor (IGF1R) and Akt were significantly decreased. Moreover, treatment with 0.25 mM VCD significantly inhibited the phosphorylation of Akt. In conclusion, VCD exposure had cytotoxic effects such as decreased cell viability, disordered cell cycle, increased apoptosis, and interference with steroid hormone synthesis on goat GCs. These cytotoxic effects of VCD on goat GCs may be due to the downregulation of IGF1R and the inhibition of IGF1R/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Activation of the insulin-like growth factor 1 receptor (IGF-1R)-mediated Janus kinase (JAK)1/2-Stat3 pathway contributes to hepatocarcinogenesis. Specifically, a previous study showed that IGF-1R inhibition downregulated Midkine expression in hepatocellular carcinoma (HCC). Aims: The present study investigated the role of IGF-1R-JAK1/2-Stat3 and Midkine signaling in HCC, in addition to the molecular link between the IGF-1R-Stat3 pathway and Midkine. Methods: The expression levels of IGF-1R, Stat3, and Midkine were measured using reverse transcription-quantitative PCR, following which the association of IGF-1R with Stat3 and Midkine expression was evaluated in HCC. The molecular link between the IGF-1R-Stat3 pathway and Midkine was then investigated in vitro before the effect of IGF-1R-Stat3 and Midkine signaling on HCC growth and invasion was studied in vitro and in vivo. Results: IGF-1R, Stat3, and Midkine mRNA overexpressions were all found in HCC, where the levels of Stat3 and Midkine mRNA correlated positively with those of IGF-1R. In addition, Midkine mRNA level also correlated positively with Stat3 mRNA expression in HCC tissues. IGF-1R promoted Stat3 activation, which in turn led to the upregulation of Midkine expression in Huh7 cells. Similarly, Midkine also promoted Stat3 activation through potentiating JAK1/2 phosphorylation. Persistent activation of this Stat3-Midkine-Stat3 positive feedback signal loop promoted HCC growth and invasion, the inhibition of which resulted in significant antitumor activities both in vitro and in vivo. Conclusions: Constitutive activation of the IGF-1R-mediated Stat3-Midkine-Stat3 positive feedback loop is present in HCC, the inhibition of which can serve as a potential therapeutic intervention strategy for HCC. [ABSTRACT FROM AUTHOR]

Androgenetic alopecia (AGA) is the most common pattern of hair loss resulting from the effects of androgen on hair follicles. MicroRNAs (miRs) serve imperative roles in the regulation of many biological processes of hair follicles. However, the exact molecular mechanism of AGA remains to be elucidated. In the present study, we found miR‐122, which is mainly recognized as a tumor suppressor, was highly overexpressed in the bulb of balding hair follicles in comparison with nonbalding ones in AGA. Moreover, miR‐122 induces apoptosis of human dermal papilla cells (hDPCs) with miR‐122 mimics in vitro, and the expression of insulin‐like growth factor 1 receptor (IGF1R) in hDPCs was reduced following upregulation of miR‐122. Mechanistically, dual‐luciferase reporter assay confirmed that miR‐122 directly targeted the 3′‐untranslated region of IGF1R. These findings suggested that upregulation of miR‐122 induces apoptosis, potentially via the repression of IGF1R in hDPCs of AGA, providing a novel insight into the potential pathological mechanism of miR‐122 in AGA DPCs. [ABSTRACT FROM AUTHOR]

Tao Geng, Zhi-Yuan Song, Jing-Xian Xing, Bing-Xun Wang, Shi-Peng Dai, Ze-Sheng Xu Department of Cardiovascular Disease, Cangzhou Central Hospital of Tianjin Medical University, Cangzhou, Hebei Province, People’s Republic of ChinaCorrespondence: Ze-Sheng XuDepartment of Cardiovascular Disease, Cangzhou Central Hospital of Tianjin Medical University, No. 16, Xinhua West Road, Cangzhou, Hebei Province, People’s Republic of ChinaTel +86-15003172868Email xutuqian848141@163.comPurpose: Myocardial ischemia-reperfusion injury primarily causes myocardial infarction (MI), which is manifested by cell death. Angiogenesis is essential for repair and regeneration in cardiac tissue after MI. In this study, we aimed to investigate the effect of exosomes derived from the serum of MI patients in angiogenesis and its related mechanism.Patients and Methods: Exosomes, isolated from serum, were collected from MI (MI-exosome) and control (Con-exosome) patients. After coculturing with human umbilical vein endothelial cells, MI-exosome promoted cell proliferation, migration, and tube formation.Results: The results revealed that the production and release of MI-exosome were associated with cardiomyocytes. Moreover, microarray assays demonstrated that miRNA-143 was significantly decreased in MI-exosome. Meanwhile, the overexpression and knockdown of miRNA-143 could inhibit and enhance angiogenesis, respectively. Furthermore, the effect of exosomal miRNA-143 on angiogenesis was mediated by its targeting gene, insulin-like growth factor 1 receptor (IGF-IR), and was associated with the production of nitric oxide (NO).Conclusion: Taken together, exosomes derived from the serum of patients with MI promoted angiogenesis through the IGF-IR/NO signaling pathway. The results provide novel understanding of the function of exosomes in MI.Keywords: myocardial ischemia, exosome, miRNA-143, insulin-like growth factor 1 receptor, angiogenesis

Background: Periampullary cancer (PC) is a global medical burden. Less than 5% of patients experience an overall survival of 5 years or more. The study aims to analyze the importance of epidermal growth factor receptor (EGFR)/insulin-like growth factor 1 receptor (IGF1R)–beta-catenin (β-catenin)–CD44 pathway in the development of periampullary cancer of Indian patients. Subjects and Methods: Expression profile of EGFR, IGF1R, β-catenin, and CD44 was verified by immunohistochemical analysis in primary tumor samples (N = 14) and respective adjacent normal tissues. Results: In periampullary carcinoma patients, a high level of EGFR expression was seen in 64% of the samples along with co-expression of IGF1R in 77.8% of samples. Furthermore, the high expression of EGFR and IGF1R significantly correlated with the increased expression of β-catenin along with CD44 expression of the tumors. Conclusion: The EGFR/IGF1R–β-catenin–CD44 pathway seems to be important in the development of PC with clinical importance.

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. There has been no effective medication to prevent proptosis in thyroid eye disease until 2020 when the anti-insulin-like growth factor 1 receptor (anti-IGF-1R) antibody, Teprotumumab, was approved by the US Food and Drug Administration, sparking increased interest in immune-based drug development. This study aims to review the newly developed drug therapy as well as conventional treatment for TED. Treatment of TED has traditionally been high-dose steroids and orbital radiotherapy, but recently there has been a paradigm shift in the treatment of TED in the United States with the introduction of the therapeutic agent teprotumumab, which dramatically reduces proptosis. However, concerns remain about the development of hearing impairment as a potentially fatal complication and long-term safety. Recently, several clinical trials are underway to assess the efficacy and safety of novel drugs targeting mammalian target of rapamycin complex 1, interleukin-6, fragment crystallizable receptor, and IGF-1R in treating TED. With the explosive increase in interest from academia and pharmaceutical companies in TED, there is anticipation for the development of drugs that are equivalent or superior to teprotumumab while being safer.

Insulin-like growth factor 1 receptor (IGF1R) is a cell surface receptor, belonging to the tyrosine kinase receptor superfamily. IGF1R plays a role not only in normal cell development but also in malignant transformation, which has become a candidate therapeutic target for the treatment of human cancer. This study aimed to explore insertions and deletions (indels) in IGF1R gene and investigate their association with growth traits in four Chinese cattle breeds (Xianan cattle, Jinnan cattle, Qinchuan cattle and Nanyang cattle). The current paper identified a 28-bp indel by polymerase chain reaction within IGF1R gene. The analysis showed that there was a significant correlation between the locus and the hucklebone width of Nanyang cattle in four periods, in which it was highly correlated at 6, 12 and 18 months. At the age of 6 months, it was also significantly correlated with body height, body weight and body length. Association analysis showed that the locus in Jinnan cattle was extremely significantly correlated with body slanting length and body weight, and significantly correlated with chest circumference. There was no significant correlation between this locus and growth traits of Xianan cattle and Qinchuan cattle. The detected indel in the IGF1R gene was significantly associated with growth traits in Jinnan and Nanyang cattle, and could be used as a molecular marker for growth trait selection. [ABSTRACT FROM AUTHOR]

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In aging hypertensive conditions, deterioration of insulin‐like growth factor 1 receptor (IGF1R) cause a pathological impact on hypertensive hearts with an increased Ang II level. Recovering these adverse conditions through transplanted adipose‐derived stem cells is a challenging approach. Moreover, Danggui, a Traditional Chinese medicine (TCM), is used for the treatment of cardioprotective effects. In this study, to evaluate whether the combined effect of MSCs and TCM can recover the cardiac function in late‐stage hypertension rats. We observed that lower dose of Danggui crude extract treatment showed an increased level of cell viability with maintained stemness properties and growth rate in rat adipose‐derived stem cells (rADSCs). Further, we cocultured the H9c2 cells with rADSCs and the results revealed that Danggui‐treated MSCs enhanced the IGF1R expression and attenuated the hypertrophy in H9c2 cells against Ang II challenge by immunoblot and rhodamine‐phalloidin staining. In addition, Danggui crude extract was also quantified and characterized by HPLC and LC–MS analysis. Furthermore, the in vivo study was performed by considering 11 months old rats (n = 7). Importantly, the oral administration of Danggui crude extract with stem cells intravenous injection in SHR‐D‐ADSCs group showed a combination effect to augment the cardiac function through enhancement of ejection fraction, fractional shortening, contractility function in the late‐stage hypertension conditions. We have also observed a decreased apoptosis rate in the heart tissue of SHR‐D‐ADSCs group. Taken together, these results indicate that the combinatorial effects of Danggui crude extract and stem cell therapy enhanced cardiac function in late‐stage SHR rats. [ABSTRACT FROM AUTHOR]

Objective To construct a recombinant eukaryotic expression plasmid encoding insulin-like growth factor 1 receptor(IGF-1R) α subunit gene. Methods The primers were designed and synthesized according to the coding sequence of human IGF-1R α subunit gene in GeneBank. The total RNA was extracted from thyroid tissues in patients with Graves' disease by one-step TRIzol method and reversely transcribed into cDNA, which was then taken as the template. After purification, the IGF-1R alpha subunit coding gene was amplified by PCR and ligated through topological cloning with pcDNA 3. 1D/V5-His-TOPO vector to construct IGF-1R α-pcDNA™3. 1D/V5-His-TOPO eukaryotic expression plasmid. The recombinant plasmid was transformed into E. coli by heat shock method, and the positive clones were screened in the medium containing ampicillin. The eukaryotic expression plasmid of IGF-1R α-pcDNA™3. 1D/ V5-His-TOPO was extracted by alkaline lysis and identified by PCR, restriction enzyme digestion(Hind III, BamH I and ScaI) and DNA sequence analysis. Results The total RNA in thyroid tissues of patients with Graves' disease was pure and complete (OD260/OD280: 1. 8-2. 0). A total of 2 679 bp fragment of target gene was amplified by reverse transcription and PCR. Three positive clone colonies were selected to extract plasmids, and the target fragments were amplified by PCR. The digested products of corresponding length were obtained after single enzyme digestion and double enzyme digestion, which proved that the recombinant plasmids contained IGF-1Rα subunit gene sequence. Further sequencing and sequence alignment analysis showed that the IGF-1Rα subunit gene sequence in the recombinant plasmid was completely consistent with the published sequence of NCBI, and the connection with the vector interface was correct. The translation and reading frame of IGF-1R α subunit gene was correct. Conclusion The recombinant eukaryotic expression plasmid IGF-1R αpcDNA™3. 1D/V5-His-TOPO was successfully constructed and identified. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to investigate whether single nucleotide polymorphisms (SNPs) at the +3179G/A insulin-like growth factor 1 receptor (IGF-1R) locus were associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) genetic susceptibility and also explore age and sex distribution of the rs2229765 in healthy adults. Patients and methods: This cross-sectional study was conducted between September 2012 and October 2014. Seventy patients with RA (7 males, 63 females; mean age: 54±1 years; range, 32 to 78 years) and 56 with AS (44 males, 12 females; mean age: 38±9 years; range, 22 to 57 years) were genotyped using polymerase chain reaction-restriction fragment length polymorphism method. The genotype and allele frequencies of the rs2229765 polymorphism in both patient groups were compared to those in 308 healthy donors (141 males, 167 females; mean age: 35±19 years; range, 18 to 75 years) who were further subjected to analysis of sex- and age-related genetic variation. Results: We identified the homozygous genotype AA (22.9% vs. 14.1%; odds ratio [OR]=2.33, p=0.034) and A-allele (47.9% vs. 37.5%; OR=1.53, p=0.032) associated with increased risk for RA, but not AS. The same genotype AA was non-significantly more common in healthy males than females, and the frequency of the A-allele was markedly higher in younger males (46% vs. 40%; p=0.039). The overall percentage of healthy carriers of the AA gene variant was 18%. Conclusion: We primarily present an inverse effect of the +3179G/A IGF-1R polymorphism on disease susceptibility to RA and AS, confirming the distinctly different immune pathways involved in the pathogenesis of both inflammatory arthritides. In addition, we could also show trends regarding age- and sex-specific patterns of the rs2229765 genotype distribution in the general population. [ABSTRACT FROM AUTHOR]

Abstract Background Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease (AD), while how to initiate early cognitive stimulation is unclear. Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing, we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period. Methods After conception, maternal AD transgenic mice (3 × Tg AD) were exposed to gestational environment enrichment (GEE) until the day of delivery. The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age. Western blotting, immunohistochemistry, real-time PCR, immunoprecipitation, chromatin immunoprecipitation (ChIP) assay, electrophysiology, Golgi staining, activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7–10-month-old adult offspring. Results We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7–10-m-old AD offspring. The beneficial effects of GEE were accompanied by global histone hyperacetylation, including those at bdnf promoter-binding regions, with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus. GEE increased insulin-like growth factor 1 (IGF1) and activated its receptor (IGF1R), which phosphorylates Ca2+/calmodulin-dependent kinase IV (CaMKIV) at tyrosine sites and triggers its nuclear translocation, subsequently upregulating histone acetyltransferase (HAT) and BDNF transcription. The upregulation of IGF1 mimicked the effects of GEE, while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation. Conclusions These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.

Lili Lv,1 Xiaodong Wang,2 Tonghui Ma31Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, Jilin 130000, People’s Republic of China; 2Department of Digestive Endoscopy, The Second Hospital of Jilin University, Changchun, Jilin 130000, People’s Republic of China; 3Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130000, People’s Republic of ChinaPurpose: Recent studies have identified microRNA-944 (miR-944) as a cancer-related miRNA, but its expression and precise functions in hepatocellular carcinoma (HCC) remain unknown.Patients and methods: miR-944 expression in HCC tissues and cell lines were detected by RT-qPCR. A series of functional assays were utilized to examine the influence of miR-944 on the malignant phenotypes of HCC cells in vitro and in vivo. More importantly, the associated mechanisms underlying the activity of miR-944 in HCC cells were investigated using bioinformatics, luciferase reporter assays, RT-qPCR, and western blot analysis.Results: In this study, we report for the first time, a significant downregulation of miR-944 in HCC tissues and cell lines and the correlation between its downregulation and malignant clinical parameters, including Edmondson-Steiner grade, TNM stage, and venous infiltration. Low miR-944 expression predicted poorer overall survival rate and disease-free survival rate in patients with HCC. Functionally, exogenous miR-944 expression attenuated cell proliferation, clone formation, metastasis, and epithelial-mesenchymal transition and increased apoptosis in HCC, whereas miR-944 knockdown produced the opposite results. In addition, ectopic miR-944 expression hindered HCC tumor growth in vivo. Mechanistically, insulin-like growth factor 1 receptor (IGF-1R) was demonstrated to be the direct target gene of miR-944 in HCC cells. Furthermore, the expression level of miR-944 was inversely correlated with IGF-1R expression in HCC tissues. Rescue experiments showed that IGF-1R was at least partially responsible for the effects of miR-944 on the malignant phenotypes of HCC cells. In addition, the PI3K/Akt pathway was notably deactivated, both in vitro and in vivo, upon miR-944 upregulation.Conclusion: This study provides the first evidence that miR-944 directly targets IGF-1R and inhibits the aggressiveness of HCC, in vitro and in vivo, by decreasing PI3K/Akt signaling. Hence, targeting miR-944 may open a new avenue for the treatment of patients with HCC.Keywords: hepatocellular carcinoma, microRNA-944, insulin-like growth factor 1 receptor, PI3K/Akt pathway, epithelial-mesenchymal transition

Glucose hypometabolism is observed in epilepsy and promotes epileptogenesis. Glucose hypometabolism in epilepsy may be attributed to decreased neuronal glucose uptake, but its molecular mechanism remains unclear. Zinc‐α2‐glycoprotein (ZAG) is related to glucose metabolism and is reported to suppress seizures. The anti‐epileptic effect of ZAG may be attributed to its regulation of neuronal glucose metabolism. This study explored the effect of ZAG on neuronal glucose uptake and its molecular mechanism via insulin‐like growth factor 1 receptor (IGF1R)‐regulated glucose transporter 3 (GLUT‐3) expression. The ZAG level was modulated by lentivirus in primary culture neurons. Neuronal seizure models were induced by Mg2+‐free artificial cerebrospinal fluid. We assessed neuronal glucose uptake by the 2‐NBDG method and Glucose Uptake Colorimetric Assay Kit. IGF1R was activated by IGF1 and blocked by AXL1717. The expression and distribution of IGF1R and GLUT‐3, together with IGF1R phosphorylation, were measured by western blot. The binding between ZAG and IGF1R was determined by coimmunoprecipitation. Neuronal glucose uptake and GLUT‐3 expression were significantly decreased by seizure or ZAG knockdown, whereas ZAG over‐expression or IGF1 treatment reversed this decrease. The effect of ZAG on neuronal glucose uptake and GLUT‐3 expression was blocked by AXL1717. ZAG increased IGF1R distribution and phosphorylation possibly by binding. Additionally, IGF1R increased GLUT‐3 activity by increasing GLUT‐3 expression. In epilepsy/seizure, neuronal glucose uptake suppression may be attributed to a decrease in ZAG, which suppresses neuronal GLUT‐3 expression by regulating the activity of IGF1R. ZAG, IGF1R, and GLUT‐3 may be novel potential therapeutic targets of glucose hypometabolism in epilepsy and seizures. [ABSTRACT FROM AUTHOR]

Objective: To study the effects of carotid artery stenting (CAS) and carotid endarterectomy (CEA) on cerebral blood flow, serum miR-145 and insulin-like growth factor 1 receptor (IGF1R) in treatment of severe internal carotid artery stenosis. Methods: The clinical data of 100 patients with severe carotid stenosis admitted to our hospital from January 2018 to December 2019 were retrospectively analyzed, they were divided into A group and B group according to different operative methods, 50 cases in each group, the A group was given CAS treatment, and the B group received CEA treatment. The perioperative conditions, cerebral blood flow, serum miR-145, IGF1R, Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA) were compared between the two groups, and the postoperative complications, restenosis rate and mortality rate were compared. Results:There was no significant difference in operation time, intraoperative blood loss, postoperative mechanical ventilation time, ICU stay time and hospitalization time between the two groups(P＞0.05); at postoperative 30 days, there were no significant differences in the relative time to peak (RTTP), relative mean transit time (rmtt), relative cerebral blood volume (rCBV), relative cerebral blood flow (rcbe), serum miR-145, IGF1R, MMSE scale and MOCA scale scores between the two groups(P＞0.05); within postoperative 30 days, there was no significant difference in bradycardia, myocardial enzyme spectrum increased, hyperperfusion syndrome, local hematoma and acute carotid artery occlusion between the two groups(P＞0.05); the incidence of stroke and hypotension in A group were significantly higher than that in B group, the incidence of hypertension in the B group was significantly higher than that in A group (P＜0.05); at postoperative1 year, there was no significant difference in mortality and restenosis rate between the two groups (P＞0.05). Conclusion: CAS and CEA have similar effects in the treatment of patients with severe internal carotid artery stenosis, they are can effectively improve cerebral blood flow, regulate the expression of serum miR-145 and IGF1R, and promote the recovery of cognitive function. However, the incidence of stroke and hypotension after CAS is higher, and the incidence of hypertension after CEA is higher. [ABSTRACT FROM AUTHOR]

Skeletal loading and unloading has a pronounced impact on bone remodeling, a process also regulated by insulin-like growth factor 1 (IGF-1) signaling. Skeletal unloading leads to resistance to the anabolic effect of IGF-1, while reloading after unloading restores responsiveness to IGF-1. However, a direct study of the importance of IGF-1 signaling in the skeletal response to mechanical loading remains to be tested. In this study, we assessed the skeletal response of osteoblast-specific Igf-1 receptor deficient (Igf-1r-/- ) mice to unloading and reloading. The mice were hindlimb unloaded for 14 days and then reloaded for 16 days. Igf-1r-/- mice displayed smaller cortical bone and diminished periosteal and endosteal bone formation at baseline. Periosteal and endosteal bone formation decreased with unloading in Igf-1r+/+ mice. However, the recovery of periosteal bone formation with reloading was completely inhibited in Igf-1r-/- mice, although reloading-induced endosteal bone formation was not hampered. These changes in bone formation resulted in the abolishment of the expected increase in total cross-sectional area with reloading in Igf-1r-/- mice compared to the control mice. These results suggest that the Igf-1r in mature osteoblasts has a critical role in periosteal bone formation in the skeletal response to mechanical loading.

Objective To observe the expression of insulin-like growth factor 1 receptor antisense imprinted long non-coding RNA（IRAIN）in the esophageal squamous cell carcinoma（ESCC）tissues and to explore the relationship be⁃ tween the promoter methylation status of IRAIN and the clinicopathological features. Methods In 63 ESCC patients who underwent surgical resection，tumor tissues and adjacent normal tissues were taken during the operation，and the expres⁃ sion and promoter methylation status of IRAIN were detected by QPCR and MSP methods, respectively. The relationships between the promoter methylation status of IRAIN and the relative expression of IRAIN and the clinicopathological charac⁃ teristics of patients were analyzed. Results The relative expression of IRAIN in the ESCC tissues was lower than that in the adjacent normal tissues 68. 25%（43/63）vs. 30. 16%（19/63)，P<0. 05］. The relative expression of IRAIN and the high expression rate of IRAIN in ESCC tissues with methylated IRAIN gene promoter were lower than those in non-methyl⁃ ated ESCC tissues（all P<0. 05). The promoter methylation status of IRAIN gene in the ESCC tissues was related to the maximal tumor diameter, TNM stage，and lymph node metastasis（all P<0. 05）. Conclusions In ESCC tissues，the ex⁃ pression of IRAIN decreases，while the promoter methylation rate of IRAIN gene increases. The down-regulation of IRAIN may be related to the promoter methylation status of IRAIN gene，and the promoter methylation rate of IRAIN gene may be related to the tumor metastasis. [ABSTRACT FROM AUTHOR]

Diabetes has been reported to modulate the airway smooth muscle reactivity and lead to attenuation of allergic inflammatory response in the lungs. In this study, we aimed to study the effect of insulin on cell activation and airway responsiveness in patients with diabetes mellitus (DM). The airway contraction in rat model groups including a non‐DM group, a non‐DM+INDUCTION group, a DM+INDUCTION group and a DM+INDUCTION+INSULIN group was measured to observe the effect of insulin on airway responsiveness. Radioenzymatic assay was conducted to measure the levels of histamine, and ELISA assay was conducted to measure bronchial levels of interleukin (IL)‐1b, tumour necrosis factor (TNF)‐a, cytokine‐induced neutrophil chemoattractant (CINC)‐1, P‐selectin and β‐hexosaminidase. The tension in the main and intrapulmonary bronchi of DM+INDUCTION rats was lower than that of the non‐DM+INDUCTION rats, whereas the treatment of insulin partly restored the normal airway responsiveness to OA in DM rats. The release of histamine was remarkably suppressed in DM+INDUCTION rats but was recovered by the insulin treatment. Also, OA significantly increased the levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in non‐DM rats, whereas insulin treatment in DM+INDUCTION rats partly restored the normal levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in DM rats. Moreover, the expression of IR and IGF1R was evidently suppressed in DM rats, with the methylation of both IR and IGF1R promoters was aggravated in DM rats. Therefore, we demonstrated that DM‐induced hypermethylation inhibited mast cell activation and airway responsiveness, which could be reversed by insulin treatment. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of berberine on the proliferation, cell cycle progression and apoptosis of esophageal cancer cells and related mechanism. Methods MTT assay was used to evaluate the effects of berberine on cell viability. Propidium iodide staining was used to detect cell cycle progression. Annexin V-FITC/PI staining assay was used to measure cell apoptosis, and Western blot analysis was performed to determine the phosphorylation of insulin-like growth factor 1 receptor (IGF-1R) as well as the two major downstream signaling molecules AKT and p42/44MAPK(ERK). Results In vitro, berberine inhibited the proliferation of four esophageal cancer cell lines in a concentration-dependent manner. Moreover, the IC50 values of berberine against different esophageal cancer cells were negatively correlated with the expression level of IGF-1R. The distribution of KYSE450 cells cycle was arrested in G2/M phase. Berberine dose-dependently induced the cell apoptosis, and the apoptosis ratio of KYSE450 cells with high IGF-1R level was significantly higher than that of KYSE150 cells with low IGF-1R level after berberine treatment at the same concentration. Berberine dose-dependently inhibited the phosphorylation of IGF-1R and blocked AKT and ERK activation. Conclusion Berberine could inhibit cell proliferation, cell cycle arrest and induce cell apoptosis of esophageal cancer via inactivation of IGF-1R as well as the downstream molecules AKT and ERK.

Background: In the current society, infertility related to age has become a social problem. The in vitro fertilization (IVF) success rate in women with poor ovarian response (POR) is very low. Dandelion extract T-1 (DE-T1) is an effective component of the extract from the leaves and stems of Taraxacum officinale, which is one of the medicines used in some patients with POR, but its molecular mechanism remains unclear. Methods: Following IVF, ovarian granulosa cells (GCs) of sixty patients were extracted and divided into normal ovarian response (NOR) and POR groups. GCs were cultured in a dose-dependent and time-dependent manner with DE-T1, proliferation of GCs was determined by Cell Counting Kit-8 assay, and mRNA levels of insulin-like growth factor 1 receptor (IGF-1R), luteotropic hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), LHR, and CYP19A1 (aromatase) were determined by quantitative polymerase chain reaction. Progesterone and estradiol (E2) concentrations were determined by enzyme-linked immunosorbent assay. Results: The cell viability gradually increased with the progressive increase in the DE-T1 concentration. Compared with the control group (without DE-T1), the mRNA expressions of FSHR, LHR, IGF-1R, and CYP19A1 were upregulated after the addition of DE-T1, especially in the 2.5% DE-T1 group (P < 0.01). The expression of IGF-1R was upregulated approximately 25 times (24.97 ± 4.02 times) in the POR group with 2.5% DE-T1. E2 and progesterone levels increased with the increasing DE-T1 concentration. There were highly significant differences in the E2 and progesterone secretion between the NOR and POR groups (P < 0.01). Conclusion: DE-T1 may promote steroid hormone synthesis by promoting GC proliferation and upregulating GC receptor expression, thereby improving ovarian endocrine function.

To study the: (1) function of micro (mi)R-223 on H2O2-induced H9C2 cells; (2) relationship between miR-223 and insulin-like growth factor 1 receptor (IGF-1R); and (3) role of miR-223 on the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. H9C2 cells were selected to establish the H2O2-injury model. Overexpression/low expression of miR-223 in H9C2 cells was constructed, respectively. Flow cytometry and western blotting were applied to measure the apoptosis, cell activity, and expression of related proteins. Dual-luciferase reporter gene assays (DLRGAs) were applied to test if miR-223 targeted IGF-1R. Overexpression/low expression of IGF-1R was constructed to test if miR-223 regulated IGF-1R expression negatively. Increases in miR-223 expression were observed in H2O2-induced H9C2 cells. miR-223 absence improved H2O2-induced H9C2-cell apoptosis accompanied by an increase in B-cell lymphoma (Bcl)-2 expression and decrease in expression of Bax and cleaved caspase-3 (P < 0.05). miR-223 silencing increased expression of IGF-1R, p-PI3K, and p-AKT in H2O2-induced H9C2 cells (P < 0.05). miR-223 overexpression aggravated H2O2-induced H9C2-cell apoptosis and reduced expression of the proteins of IGF-1R, p-PI3K, and p-AKT. DLRGAs showed IGF-1R to be a downstream gene of miR-223. IGF-1R silencing significantly inhibited expression of p-PI3K and p-AKT proteins (P < 0.05). miR-223 negatively regulated IGF-1R expression for H9C2-cell apoptosis and the PI3K/AKT pathway. miR-223 absence can ameliorate H2O2-induced cardiomyocyte apoptosis by targeting IGF-1R to regulate PI3K/AKT activity. [ABSTRACT FROM AUTHOR]