Insulin-like Growth Factor Receptor Research Articles

Secreted decoy of insulin receptor is required for blood-brain and blood-retina barrier integrity in Drosophila

Glial cells play important roles during neurogenesis and in maintaining complex functions of the nervous system. Here, we report the characterization of a gene, Sdr, which contains a putative insulin-like growth factor receptor domain and is required to maintain critical nervous system functions in Drosophila. Sdr is expressed in glial cells during embryonic and larval stages of development, but its role in adult flies is poorly understood. As insulin signaling is important throughout the lifespan in human, we investigated the Sdr's role in adult flies. Our results demonstrate that Sdr is expressed on surface glial cells that surround the nervous system. Mutation of Sdr did not affect development but caused defects in locomotion and lifespan. Sdr mutants also showed increasingly severe defects in the blood-brain- and blood-retina-barriers as they aged. Therefore, we suggest a novel role of Sdr in maintaining the integrity of the blood-brain- and blood-retina-barriers in adult flies.

Silibinin effects on cognitive disorders: Hope or treatment?

Almost all diseases of the nervous system are related to neuroinflammation, oxidative stress, neuronal death, glia activation, and increased pro-inflammatory cytokines. Cognitive disorders are one of the common complications of nervous system diseases. The role of some plant compounds in reducing or preventing cognitive disorders has been determined. Silibinin is a plant bioflavonoid and exhibits various effects on cognitive functions. This article discusses the different mechanisms of the effect of silibinin on cognitive disorders in experimental studies. Databases, including ISI, , Google Scholar, Scopus, Medline and PubMed, were investigated from 2000 to 2021, using related keywords to find required articles. Silibinin can improve cognitive disorders by different pathways such as reducing neuroinflammation and oxidative stress, activation of reactive oxygen species- Brain-derived neurotrophic factor- Tropomyosin receptor kinase B (ROS-BDNF-TrkB) pathway in the hippocampus, an increase of dendritic spines in the brain, inhibition of hyperphosphorylation of tau protein and increasing the expression of insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R), inhibiting inflammatory responses and oxidative stress in the hippocampus and amygdala, and decrease of Homovanillic acid/Dopamine (HVA/DA) ratio and 3,4-Dihydroxyphenylacetic acid + Homovanillic acid/Dopamine (DOPAC+ HVA/DA) ratio in the prefrontal cortex and 5-hydroxyindoleacetic acid/5-hydroxytryptamine (5-HIAA/5-HT) ratio in the hippocampus. These results suggest that silibinin can be considered a therapeutic agent for the symptom reduction of cognitive disorders, and it acts by affecting various mechanisms such as inflammation, programmed cell death, and oxidative stress.

Redundant Signaling as the Predominant Mechanism for Resistance to Antibodies Targeting the Type-I Insulin-Like Growth Factor Receptor in Cells Derived from Childhood Sarcoma.

Antibodies targeting insulin-like growth factor 1 receptor (IGF-1R) induce objective responses in only 5% to 15% of children with sarcoma. Understanding the mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R-targeted antibodies. Sensitivity to the IGF-1R-targeting antibody TZ-1 was determined in rhabdomyosarcoma and Ewing sarcoma cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. The BRD4 inhibitor, JQ1, was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of receptor tyrosine kinases (RTK) was assessed. Sensitivity to TZ-1 in vivo was determined in Rh41 parental and TZ-1-resistant xenografts. Of 20 sarcoma cell lines, only Rh41 was sensitive to TZ-1. Cells intrinsically resistant to TZ-1 expressed multiple (>10) activated RTKs or a relatively less complex set of activated RTKs (∼5). TZ-1 decreased the phosphorylation of IGF-1R but had little effect on other phosphorylated RTKs in all resistant lines. TZ-1 rapidly induced activation of RTKs in Rh41 that was partially abrogated by knockdown of SOX18 and JQ1. Rh41/TZ-1 cells selected for acquired resistance to TZ-1 constitutively expressed multiple activated RTKs. TZ-1 treatment caused complete regressions in Rh41 xenografts and was significantly less effective against the Rh41/TZ-1 xenograft. Intrinsic resistance is a consequence of redundant signaling in pediatric sarcoma cell lines. Acquired resistance in Rh41 cells is associated with rapid induction of multiple RTKs, indicating a dynamic response to IGF-1R blockade and rapid development of resistance. The TZ-1 antibody had greater antitumor activity against Rh41 xenografts compared with other IGF-1R-targeted antibodies tested against this model.

Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Nutrient-sensing nanoprotoplast augments tumor accumulation and immune response with short-term starvation

Many efforts have been devoted to improve delivery efficiency of nanocarriers in tumor site. However, current strategies are mainly focusing on regulating the materials rather than the biological system. We here demonstrate that short-term starvation (STS) can enhance the cellular uptake and tumor accumulation of nanocarriers. Tumor cells can assimilate a significant amount of extracellular massive necrotic cell debris vesicles (NCDVs) and built more blood vessels after STS treatment. We thereby developed a NCDVs-mimicking nanoprotoplast using bacterial protoplast. This NCDVs-mimicking nanoprotoplast can efficiently accumulate at tumor site and inhibit type 1 or 2 insulin-like growth factor receptor (IGF-1R or IGF-2R, respectively) mediated cell proliferation by reducing IGF-1 with STS treatment and delivering inhibitors. Moreover, this nanoprotoplast can trigger the immune response and be further augmented with STS treatment. Collectively, STS treatment can not only improve the cellular uptake and tumor accumulation of NCDVs-mimicking nanoprotoplast, but also strengthen the antitumor immunity of the nanoprotoplast.

Characterization of IGF2R Molecular Expression in Canine Osteosarcoma as Part of a Novel Comparative Oncology Approach.

Progress in prognostic factors, treatments, and outcome for both canine and human osteosarcoma (OS) has been minimal over the last three decades. Surface overexpression of the cation independent mannose-6-phosphate/insulin-like growth factor receptor type 2 (IGF2R) has been proven to occur in human OS cells. Subsequently, radioimmunotherapy (RIT) targeting IGF2R has demonstrated promising preliminary results. The main aims of this study were to investigate the expression of IGF2R in spontaneously occurring canine OS cells using immunohistochemistry (IHC) on archived biopsy samples and to assess its prognostic significance. Thirty-four dogs were included in the study. All cases showed that 80-100% of OS cells stained positive for IGF2R. IGF2R overexpression alone was not shown to have prognostic significance using both visual and quantitative methods of IHC staining intensity. This study has established for the first time the consistent expression of IGF2R in spontaneously occurring canine OS. This comparative oncology approach will allow further investigation into RIT as a novel treatment modality; first in canines and then in humans with OS. In addition, further studies should be performed to assess the true prognostic significance of IGF2R overexpression.

Suppression of Insulin Receptor Substrate 1 Inhibits Breast Cancer Growth In Vitro and in Female Athymic Mice.

Targeting the type I insulin-like growth factor receptor (IGF-IR) has not been successful in breast cancer. Data suggest the highly homologous insulin receptor (IR) may be an alternate growth stimulatory pathway used by cancer cells. Since both receptors phosphorylate the insulin receptor substrate 1 (IRS-1) protein as an immediate consequence of ligand binding, disruption of both receptors could be accomplished by suppression of IRS-1. IRS-1 gene deletion by CRISPR/Cas9 editing resulted in suppression of IGF-I, insulin, and estrogen-stimulated growth in hormone-dependent MCF-7L breast cancer cells. A doxycycline-inducible IRS-1 shRNA lentiviral construct was also used to infect MCF-7L breast cancer cells. IRS-1 shRNA downregulation resulted in decreased responses to IGF-I, insulin, and estradiol in monolayer and anchorage-independent growth assays. Decreased IRS-1 levels also suppressed estradiol-stimulated gene expression and estrogen receptor binding to DNA. Xenograft growth was also inhibited by induction of IRS-1 shRNA. These data show that IRS-1 is a critical regulator of endocrine responsive breast cancer. Efforts to target this adaptor protein could have broader growth inhibitory effects and receptor targeting.

Asiatic acid in Centella asiatica extract towards morphological development in an intermittent hypoxia intrauterine embryo model and molecular prediction pathway of insulin-like growth factor-1 receptor signalling.

Hypoxia during pregnancy generates oxidative stress that alters the growth and development of the human fetus. Insulin-like growth factor-1 (IGF-1) receptors are essential for normal fetal growth. Asiatic acid in Centella asiatica (CA) has antioxidant properties to prevent growth impairment in hypoxia. This study aimed to investigate the effect of asiatic acid on the morphological development of an intermittent hypoxia (IH) zebrafish embryo model and analyze molecular docking prediction in IGF-1 receptor (IGF-1R) signaling. Embryos of zebrafish at 2 hours postfertilization (hpf) were assigned to control negative (C), IH, and combination IH and CA extract groups consisting of 1.25 (IHCA1), 2.5 (IHCA2), and 5 (IHCA3) µg/ml. Hypoxia treatment (conducted 4 hours/day) and CA extract were administered for 3 days (2-72 hpf). The parameters of body length and head length were evaluated at 3, 6, and 9 days postfertilization (dpf). The data were analyzed by a two-way analysis of variance (p < 0.05). Molecular docking was performed to explore the binding affinity of asiatic acid to IGF-1R by Molegro Virtual Docker ver.5 software. The body length and head length of embryos in the IH and treatment groups (IHCA) were shorter than those in the control group at 3 dpf (p < 0.05). However, the body length was more prolonged in the IHCA1 group, but the head length was longer in the IHCA2 group than in the IH group at 6 and 9 dpf. Molecular docking showed the reliable interaction of asiatic acid with IGF-1R signaling in an IH animal model. The administration of CA extract benefits IH through the development and growth of zebrafish embryos at a dose of 2.5-5 µg/ml. Asiatic acid has a binding affinity for IGF-1R signaling.

Elucidation of mRNA targets of miR-145-5p in diabetic kidney disease using bioinformatics analysis

Introduction: Diabetic kidney disease (DKD) is a major global cause of end-stage-kidney disease. In view of its ongoing risk of disease progression, the search for a better biomarkers and treatment led to the discovery of microRNAs which regulate gene expression post-translationally. Recently, we reported a trend of upregulation of miR-145-5p in sera of type 2 diabetic patients with macroalbuminuria in a selected Malaysian population, which concurred with previous in vivo and in vitro studies of DKD. In addition, miR-145 has been implicated as a tumour suppressor in various cancers. Methods: In this study, bioinformatics tools were utilized to predict the mRNA targets of miR-145-5p. Results: A total of 683 and 224 experimentally-validated mRNA targets of miR-145-5p were identified by Tarbase and miRTarbase, respectively. Eighty-six (86) commonly identified targets were submitted to Metascape and Enrichr for enrichment analysis. Bioinformatics analysis and literature search suggested that insulin receptor substrate 1 (IRS1) was the most promising target of miR-145-5p. Its associated Gene Ontology terms and pathways included insulin-like growth factor receptor signalling and Forkhead transcription factors (FOXO), respectively. Based on these analyses, the roles of IRS1 in DKD were proposed. Conclusion: As the kidneys are heterogenous in cell types and the mechanism of miRNA is cell-type-dependent, target prediction of miR-145-5p by bioinformatics analysis is particularly important in DKD, to improve the likelihood of a successful in vitro experimental verification in specific renal cell types. In addition, this study attempts to utilize bioinformatics studies, which is not widely done in DKD, as recently reported.

Retraction Note: Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor.

Retraction Note: Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor.

Commentary: Dysthyroid optic neuropathy: A lurking danger in thyroid eye disease.

Poonam et al., in their retrospective study, highlighted male gender, hyperthyroidism, and smoking as risk factors of developing dysthyroid optic neuropathy (DON) over four years. They highlighted the potential of recurrence of DON in patients with diabetes.[1] DON is the most dreaded complication of thyroid eye disease (TED), warranting an urgent intervention. Fortunately, the occurrence of DON is noted only in 5%–7% of TED cases.[2] The diagnosis of established DON is majorly clinical, but the diagnosis of subclinical DON may need detailed ophthalmic examination and imaging. Patients with subclinical DON may not experience a sudden diminution of vision, abnormal pupillary reflexes, and features of orbital inflammation—classical of severe TED.[2] The risk factors for clinical and subclinical DON include older age, male gender, smoking, diabetes (controlled or uncontrolled), radioisotope therapy, hyperthyroidism or Grave’s ophthalmopathy, and high level of thyroid autoantibodies.[12] The pathogenesis of DON involves mechanical, inflammatory, and vascular factors causing damage to the nerve cells and axons of the optic nerve.[2] TED patients can be classified as type I (predominantly fat enlargement) or type II disease (predominantly extraocular muscle enlargement). In type II TED, the mechanical compression of optic nerve blood supply and axonal flow at the crowded orbital apex occurs due to enlarged extraocular muscles. The reduced arterial supply to the optic nerve and sluggish outflow of the blood from the superior ophthalmic vein comprises of major vascular insults contributing to the DON.[2] Moreover, these phenomena occurring at the orbital apex do not contribute much to clinical proptosis; hence many remain underdiagnosed. In ophthalmic examination, relative afferent pupillary defect (RAPD), blue-yellow (Tritan) color deficiency, and reduced contrast sensitivity in patients of TED are sensitive parameters for detecting DON. Clinical examination of the optic disc and optic disc imaging are important for the monitoring of DON.[2] Orbital magnetic resonance imaging with or without contrast may provide sufficient details about the extraocular muscles, orbital fat, optic nerve, orbital apex, superior ophthalmic vein, and other essential orbital structures. Apparent diffusion coefficient readings from magnetic resonance imaging (MRI) may provide the activity details in the extraocular muscles. Barrett’s muscle index of >60% is considered highly sensitive and specific for DON.[3] It is calculated on coronal computed tomography (CT) or MRI at a mid-point between the posterior globe and the orbital apex. Barrett’s index includes two indices, horizontal and vertical, and the larger of the two is taken as significant. Other parameters are extraocular muscle volume/orbital volume (MV/OV) and crowding index (CI) are considered reliable indicators of DON. The 3D MRI-based volumetric analysis showed the larger extraocular muscle volume as the most relevant factor in DON.[4] Optical coherence tomography angiography (OCTA) has been used to measure retinal nerve fiber layer thickness and peripapillary capillary vessel density (whole image and radial vessel density) as DON parameters. The patients with subclinical DON have shown significantly lower vessel densities as compared to normal individuals.[25] Intravenous steroids and orbital decompression surgery remain the mainstay of treatment in DON patients. The best outcomes for DON patients are provided by combined intravenous methylprednisolone and 3-wall orbital decompression, as vision is successfully preserved in most cases with a reduction in proptosis.[6] The advent of teprotumumab, a targeted insulin-like growth factor 1 (IGF-1) receptor-based therapy, is slowly establishing itself as “medical orbital decompression” therapy. It reduces the levels of thyroid stimulating hormone (TSH) receptors and IGF-1 receptors on fibroblasts and reduces the release of pro-inflammatory cytokines like interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α) responsible for severe TED.[26] Hence, an ophthalmologist should be aware of the clinical features of subclinical DON and maintain a low threshold for aggressive treatment. For the holistic management of DON, a multidisciplinary team involving an ophthalmologist, endocrinologist, and otolaryngologist should be working in coordination to avoid blindness.

A Pro-Regenerative Environment Triggers Premalignant to Malignant Transformation of Senescent Hepatocytes.

Liver damage induces a compensatory regenerative response that can drive premalignant to malignant transformation of senescent hepatocytes.

Insulin and IGF-1 elicit robust transcriptional regulation to modulate autophagy in astrocytes

ObjectiveInsulin is a principal metabolic hormone. It regulates a plethora of metabolic pathways in peripheral tissues. The highly homologous insulin-like growth factor 1 (IGF-1), on the other hand, is important for development and growth. Recent studies have shown that insulin and IGF-1 signaling plays fundamental roles in the brain. Loss of insulin or IGF-1 receptors in astrocytes leads to altered glucose handling, mitochondrial metabolism, neurovascular coupling, and behavioral abnormalities in mice. Here, we aim to investigate molecular mechanisms by which insulin and IGF-1 signaling regulates astrocyte functions. MethodsIR-flox and IRKO primary astrocytes were treated with 100 nM insulin or IGF-1 for 6 h, and their transcriptomes were analyzed. Astrocytes with either IR deletion, IGF1R deletion or both were used to examine receptor-dependent transcriptional regulations using qPCR. Additional immunoblotting and confocal imaging studies were performed to functionally validate pathways involved in protein homeostasis. ResultsUsing next-generation RNA sequencing, we show that insulin significantly regulates the expression of over 1,200 genes involved in multiple functional processes in primary astrocytes. Insulin-like growth factor 1 (IGF-1) triggers a similar robust transcriptional regulation in astrocytes. Thus, over 50% of the differentially expressed genes are regulated by both ligands. As expected, these commonly regulated genes are highly enriched in pathways involved in lipid and cholesterol biosynthesis. Additionally, insulin and IGF-1 induce the expression of genes involved in ribosomal biogenesis, while suppressing the expression of genes involved in autophagy, indicating a common role of insulin and IGF-1 on protein homeostasis in astrocytes. Insulin-dependent suppression of autophagy genes, including p62, Ulk1/2, and several Atg genes, is blunted only when both IR and IGF1R are deleted. ConclusionsIn summary, insulin and IGF-1 potently suppress autophagy in astrocytes through transcriptional regulation. Both IR and IGF1R can elicit ligand-dependent transcriptional suppression of autophagy. These results demonstrate an important role of astrocytic insulin/IGF-1 signaling on proteostasis. Impairment of this regulation in insulin resistance and diabetes may contribute to neurological complications related to diabetes.

Leishmania kinetoplast DNA contributes to parasite burden in infected macrophages: Critical role of the cGAS-STING-TBK1 signaling pathway in macrophage parasitemia.

Leishmania parasites harbor a unique network of circular DNA known as kinetoplast DNA (kDNA). The role of kDNA in leishmania infections is poorly understood. Herein, we show that kDNA delivery to the cytosol of Leishmania major infected THP-1 macrophages provoked increased parasite loads when compared to untreated cells, hinting at the involvement of cytosolic DNA sensors in facilitating parasite evasion from the immune system. Parasite proliferation was significantly hindered in cGAS- STING- and TBK-1 knockout THP-1 macrophages when compared to wild type cells. Nanostring nCounter gene expression analysis on L. major infected wild type versus knockout cells revealed that some of the most upregulated genes including, Granulysin (GNLY), Chitotriosidase-1 (CHIT1), Sialomucin core protein 24 (CD164), SLAM Family Member 7 (SLAMF7), insulin-like growth factor receptor 2 (IGF2R) and apolipoprotein E (APOE) were identical in infected cGAS and TBK1 knockout cells, implying their involvement in parasite control. Amlexanox treatment (a TBK1 inhibitor) of L. major infected wild type cells inhibited both the percentage and the parasite load of infected THP-1 cells and delayed footpad swelling in parasite infected mice. Collectively, these results suggest that leishmania parasites might hijack the cGAS-STING-TBK1 signaling pathway to their own advantage and the TBK1 inhibitor amlexanox could be of interest as a candidate drug in treatment of cutaneous leishmaniasis.

Insulin/IGF signaling regulates presynaptic glutamate release in aversive olfactory learning.

Insulin/insulin-like growth factor (IGF) receptor signaling (IIS) supports context-dependent learning in vertebrates and invertebrates. Here, we identify cell-specific mechanisms of IIS that integrate sensory information with food context to drive synaptic plasticity and learning. In the nematode Caenorhabditis elegans, pairing food deprivation with an odor such as butanone suppresses attraction to that odor. We find that aversive olfactory learning requires the insulin receptor substrate (IRS) protein IST-1 and atypical signaling through the insulin/IGF-1 receptor DAF-2. Cell-specific knockout and rescue demonstrate that DAF-2 acts in the AWCON sensory neuron, which detects butanone, and that learning preferentially depends upon the axonally localized DAF-2c isoform. Acute food deprivation increases DAF-2 levels in AWCON post-transcriptionally through an insulin- and insulin receptor substrate-1 (ist-1)-dependent process. Aversive learning alters the synaptic output of AWCON by suppressing odor-regulated glutamate release in wild-type animals, but not in ist-1 mutants, suggesting that axonal insulin signaling regulates synaptic transmission to support aversive memory.

PSAT352 A Case Report: Unilateral Graves’ Ophthalmopathy in Euthyroid Patient

Abstract Introduction Graves’ Ophthalmopathy is an immune mediated inflammation in orbital and retroorbital tissues, occurs mainly with hyperthyroidism,10% with euthyroid and rarely with hypothyroidism, more frequently in females(1). Thyroid-stimulating hormone (TSH) receptor (TSHR) is the main auto-antigen, expressed in the thyroid gland, adipocytes and fibroblasts. It is aligned with insulin-like growth factor 1 (IGF-1) receptor. T cells activate TSHR and IGF-1 receptors and initiating a retro-orbital inflammation and accumulation of hydrophilic glycosaminoglycans (GAG)(2). Case 46 yo, Hispanic obese male with history of type 2 DM and HLD, non-smoker, non- alcoholic, no illicit drugs. Family History of DM, no allergy,Home medications: Alogliptin benzoate 25mg/day, Metformin 1000mg twice/day and atorvastatin 10mg/day. Ophthalmology checkup 2 months before; visual acuity of 20/30, B/L nasal pterygium, no Diabetic retinopathy. Normal TSH (0.56ulU/ml) 6 months before. He presented to the Emergency department with 3 days of progressive redness, puffiness, photophobia and pressure like sensations in left eye, denied palpitations, change in bowel movements, weight loss/gain, heat/cold intolerance, fever, vomiting, headache, motor weakness, sensory loss. General examination alert, orientated x3,ABP 130/60, HR 75BPM, afebrile(98.4 F), BMI 37.56kg/m2, no tremors, no thyromegaly, normal heart, lung, abdomen examinations, no edema. Left eye conjunctival injection, proptosis, decrease visual acuity 20/60 and color vision, restricted eye movements, relative afferent pupillary defect, optic Neuropathy. Right eye nasal Pterygium and normal fundus examination. Laboratory findings; normal TSH 1.4ulU/ml, FT4 1.2ng/dl, FT3121ng/dl, High TSHR antibody4.69IU/L (normal less than 1.75IU/L), Thyroid peroxidase antibody 363IU/ml (normal less than 34.9IU/ml) and Thyroid stimulating immunoglobulin 3.55 IU/L (normal less than 0.55IU/L). Normal CBC, GFR, negative C-ANCA, P-ANCA antibodies. CT orbit showed marked exophthalmoses, prominence of infraorbital fat, thickening of inferior and medial rectus muscles of left eye. He was kept on IV Solumedrol 250mg Q 6hrs for 3 days, artificial tears. Symptoms improved, was discharged on tapering oral steroid starting with prednisone 80mg daily. Follow up after 5 days reported marked improvement of symptoms with slight proptosis, no optic neuropathy. Conclusion Graves’ Ophthalmopathy can occur in euthyroid patients. Presents mainly with bilateral eye affection, few cases have unilateral eye affection. IV or oral Steroid is the Main treatment of Graves’ ophthalmopathy with local eye measures and management of thyroid disease. Other options are teprotumumab (IGF-1 receptor Inhibitor), and rituximab or orbital decompression surgery/external orbital radiation. Close follow up is recommended as orbitopathy precedes hyperthyroidism in 20%of cases(3,4). References 1-Kersten R. American Academy of Ophthalmology Section 7, Orbit, Eyelids and Lacrimal System 2004-2005: 48-56. 2-Bahn RS. Graves’ ophthalmopathy. N Engl J Med 2010; 362: 726. 3-Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med 2020; 382: 341. 4-Zang S, Ponto KA, Kahaly GJ. Clinical review: Intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011; 96: 320. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Comparative analysis of microsatellites in coding regions provides insights into the adaptability of the giant panda, polar bear and brown bear.

Short Tandem repeats (STRs) often occur within coding regions and adaptive selection could play a vital role in shaping the landscape of coding STRs. Here, we identified 849, 1282 and 1501 genes that contained 966, 1565 and 1921 STRs in the coding regions of the giant panda, polar bear and brown bear genomes, respectively. The results showed that coding STRs were subject to strong selection on STR type, motif, repetition and mode of evolution. Coding STRs were primarily found in regulatory genes. Of the three ursids studied, we found 585 differential genes in the giant panda. Gene Ontology analysis showed that the significant enrichment term (insulin-like growth factor receptor signaling pathway) exerted direct carbohydrate metabolic effects in vivo in this species. The enrichment of this pathway suggested that the giant panda's ability to absorb carbohydrates (starch) and adapt to a bamboo diet might be enhanced by variable coding STRs. We also identified 377 conserved coding STRs located in 377 genes across the three species. Kyoto Encyclopedia of Genes and Genomesenrichment analysis showed that these genes were significantly enriched in two pathway involved in key physiological processes, including cardiovascular function and energy metabolism regulation. This study provides an important resource for future studies on the regulation of rapid diet and environmental adaptation of species by coding STRs.

Direct Binding of Bovine IgG-Containing Immune Complexes to Human Monocytes and Their Putative Role in Innate Immune Training.

Bovine milk IgG (bIgG) was shown to bind to and neutralize the human respiratory synovial virus (RSV). In animal models, adding bIgG prevented experimental RSV infection and increased the number of activated T cells. This enhanced activation of RSV-specific T cells may be explained by receptor-mediated uptake and antigen presentation after binding of bIgG-RSV immune complexes (ICs) with FcγRs (primarily CD32) on human immune cells. This indirect effect of bIgG ICs on activation of RSV-specific T cells was confirmed previously in human T cell cultures. However, the direct binding of ICs to antigen-presenting cells has not been addressed. As bovine IgG can induce innate immune training, we hypothesized that this effect could be caused more efficiently by ICs. Therefore, we characterized the expression of CD16, CD32, and CD64 on (peripheral blood mononuclear cells (PBMCs), determined the optimal conditions to form ICs of bIgG with the RSV preF protein, and demonstrated the direct binding of these ICs to human CD14+ monocytes. Similarly, bIgG complexed with a murine anti-bIgG mAb also bound efficiently to the monocytes. To evaluate whether the ICs could induce innate immune training more efficiently than bIgG itself, the resulted ICs, as well as bIgG, were used in an in vitro innate immune training model. Training with the ICs containing bIgG and RSV preF protein-but not the bIgG alone-induced significantly higher TNF-α production upon LPS and R848 stimulation. However, the preF protein itself nonsignificantly increased cytokine production as well. This may be explained by its tropism to the insulin-like growth factor receptor 1 (IGFR1), as IGF has been reported to induce innate immune training. Even so, these data suggest a role for IgG-containing ICs in inducing innate immune training after re-exposure to pathogens. However, as ICs of bIgG with a mouse anti-bIgG mAb did not induce this effect, further research is needed to confirm the putative role of bIgG ICs in enhancing innate immune responses in vivo.

Nutritional Components, Biochemical Characteristics, Enzyme Activities, and Growth Differences of Five Freshwater Fish Species?

Common carp (Cyprinus carpio) is an economically important fish worldwide, with many of its species bred for consumption. However, there are few reports on the comprehensive comparative analysis of the muscle nutritional quality and stress resistance characteristics of different common carp species. In this study, after 15 months of feeding in the same environment, the nutritional components, serum biochemical indices, liver antioxidant and intestinal digestive enzyme activities, and muscle growth-related gene expression were determined in Songpu mirror carp (SPM; Cyprinus carpio Songpumirror), Heilongjiang wild carp (HLJ; Cyprinus carpio haematopirus), cold-resistant strain of purse red carp (CPR; Cyprinus carpio ‘Red purse cold-resistant’), Songhe carp (SH; Cyprinus carpio ‘Songhe’), and Songpu carp (SP; Cyprinus carpio Songpu). Muscle nutrient composition showed that HLJ had a significantly lower crude fat content and higher docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) proportion than the other four common carp species (p &lt; 0.05). The contents of lysine (Lys) and aspargine (Asp) were significantly higher in the CPR than in other species (p &lt; 0.05). Serum biochemical parameters showed that total protein (TP), total cholesterol (T-CHO), triglycerides (TG), and low-density lipoprotein (LDL) were significantly lower in SPM than in the other species (p &lt; 0.05). The results of tissue enzyme activity showed that the activities of superoxide dismutase (SOD) and catalase from Micrococcus lysodeikticus (CAT) in the liver were significantly higher, while the activities of lipase (LPS), trypsin (TRS), and α-amylase (α-AMS) in the intestine were significantly the lower in HLJ than in the other species (p &lt; 0.05). In addition, the relative expression levels of growth hormone (GH), growth hormone receptor (GHR), insulin-like growth factor 1 (IGF1), insulin-like growth factor receptor (IGF1R), and myoblast determination factor (MyoD) in SP and SH were significantly higher than those in the other species, while the relative expression of myostatin (MSTN) in HLJ was significantly higher (p &lt; 0.05). Therefore, there were significant differences in muscle nutritional quality, serum biochemical indices, liver, and intestinal enzyme activities, and muscle growth potential among the five species of common carp. This study could provide a theoretical basis for the germplasm evaluation and variety improvement of common carp.

Alterations of the expression levels of glucose, inflammation, and iron metabolism related miRNAs and their target genes in the hypothalamus of STZ-induced rat diabetes model

BackgroundThe hypothalamus of the central nervous system is implicated in the development of diabetes due to its glucose-sensing function. Dysregulation of the hypothalamic glucose-sensing neurons leads to abnormal glucose metabolism. It has been described that fractalkine (FKN) is involved in the development of hypothalamic inflammation, which may be one of the underlying causes of a diabetic condition. Moreover, iron may play a role in the pathogenesis of diabetes via the regulation of hepcidin, the iron regulatory hormone synthesis. MicroRNAs (miRNAs) are short non-coding molecules working as key regulators of gene expression, usually by inhibiting translation. Hypothalamic miRNAs are supposed to have a role in the control of energy balance by acting as regulators of hypothalamic glucose metabolism via influencing translation.MethodsUsing a miRNA array, we analysed the expression of diabetes, inflammation, and iron metabolism related miRNAs in the hypothalamus of a streptozotocin-induced rat type 1 diabetes model. Determination of the effect of miRNAs altered by STZ treatment on the target genes was carried out at protein level.ResultsWe found 18 miRNAs with altered expression levels in the hypothalamus of the STZ-treated animals, which act as the regulators of mRNAs involved in glucose metabolism, pro-inflammatory cytokine synthesis, and iron homeostasis suggesting a link between these processes in diabetes. The alterations in the expression level of these miRNAs could modify hypothalamic glucose sensing, tolerance, uptake, and phosphorylation by affecting the stability of hexokinase-2, insulin receptor, leptin receptor, glucokinase, GLUT4, insulin-like growth factor receptor 1, and phosphoenolpyruvate carboxykinase mRNA molecules. Additional miRNAs were found to be altered resulting in the elevation of FKN protein. The miRNA, mRNA, and protein analyses of the diabetic hypothalamus revealed that the iron import, export, and iron storage were all influenced by miRNAs suggesting the disturbance of hypothalamic iron homeostasis.ConclusionIt can be supposed that glucose metabolism, inflammation, and iron homeostasis of the hypothalamus are linked via the altered expression of common miRNAs as well as the increased expression of FKN, which contribute to the imbalance of energy homeostasis, the synthesis of pro-inflammatory cytokines, and the iron accumulation of the hypothalamus. The results raise the possibility that FKN could be a potential target of new therapies targeting both inflammation and iron disturbances in diabetic conditions.Graphical