Insulin Growth Factor Research Articles

Approach to the patient with controlled acromegaly and acromegalic arthropathy: clinical diagnosis and management.

Following the description of an illustrative case of a 70-year-old female patient with longstanding active acromegaly and invalidating, progressive joint complaints, current insights regarding diagnosis, treatment, and long-term management of acromegalic arthropathy are summarized. Since clinical trials on this topic are lacking, the reported recommendations are based on extensive clinical and research experience with this clinical entity, and on established diagnostics and interventions in patients with other rheumatic diseases. The cornerstones of the management of acromegalic arthropathy remains normalization of growth hormone and insulin growth factor-1 levels. However, patients with severe or progressive acromegalic arthropathy require a multidisciplinary approach to determine adequate diagnostics and treatment options. Because of the high prevalence and invalidating character of acromegalic arthropathy, developing evidence-based effective prevention and treatment strategies, preferably by international collaboration within rare disease networks, e.g., Endo-ERN, is a clear unmet need.

Effect of a Physical Exercise Intervention on Physical Function Parameters and Blood Analytical Changes in Lung Cancer Survivors: A Feasibility Study.

Background: Lung cancer carries a high burden of systemic symptoms, including in survivors, leading to a reduced quality of life (QoL). We assessed whether a 12-week multicomponent supervised exercise programme, including muscular strength and aerobic training, was beneficial in patients who had undergone surgery for early non-small cell lung cancer (NSCLC) in terms of physical performance, QoL, and metabolic and nutritional analytical parameters. Methods: Physical performance was measured by gait speed, handgrip strength, 30 s sit-to-stand (30s-STS) test repetitions, distance covered in the 6 min walk test (6MWT), and the Short Physical Performance Battery (SPPB) score. QoL was assessed with the EORTC-QLQ-C30 questionnaire. Blood glucose, cholesterol, triglycerides, total proteins, albumin, pre-albumin, creatinine, c-reactive protein, insulin-growth factor 1 (IGF-1), and the haemoglobin and hematocrit percentages were measured before and after the intervention in order to observe any beneficial effects related to metabolic markers. Results: After the intervention, the mean scores for the 6MWT (p < 0.001), STS (p < 0.001), 6MWT (p < 0.01), and SPPB (p < 0.01) had significantly improved. However, handgrip strength and nutritional analytical were unchanged. The EORTC-QLQ-C30 functions and symptoms significantly improved after the intervention (p < 0.05 and p < 0.01, respectively). A significant decrease in cholesterol, triglycerides, and IGF-1 and a significant increase in pre-albumin in blood was also observed post-intervention (p < 0.05). Conclusions: This supervised, community-based 12-week multicomponent was feasible (adherence rate 70.35%) and provided benefits not only to physical performance but also to the quality of life of patients with NSCLC.

Conquering Insulin Network Dysfunctions in Alzheimer's Disease: Where Are We Today?

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration.

Fluoxetine and Sertraline Inhibit Height Growth and Growth Hormone Signaling During Puberty.

The aim of this study was to examine the effect of fluoxetine and sertraline on height growth and insulin-like growth factor-1 (IGF-1) during puberty. In this 6-month cohort study, electronic medical records were used to identify 8- to 15-year-old participants, within 1 month of starting fluoxetine (n = 39) or sertraline (n = 27), and sexual maturation stages 2 to 4 were confirmed. Conditions that interfere with height growth led to exclusion. Participants underwent anthropometric assessments and phlebotomy. Healthy, unmedicated children (n = 36) also provided anthropometric data. After the baseline height Z-score, sex, Tanner stage, daily selective serotonin reuptake inhibitor (SSRI) dose, and time were accounted for, the interaction effect of dose by time was inversely associated with height Z-score in SSRI-treated participants (β = -0.18; 95% confidence interval [CI]: -0.35, -0.02). Sertraline and fluoxetine did not differ in their effect on height growth. Compared with being unmedicated, SSRI treatment was associated with a smaller growth in height (time × dose 2-way interaction effect β = -1.30; 95% CI: -2.52, -0.09). The interaction effect of dose by time was significant for body mass index Z-score (β = 0.35; 95% CI: 0.06, 0.64) but not weight Z-score (β = 0.24; 95% CI: -0.01, 0.49). Body mass index Z-score increased more with sertraline compared with fluoxetine (time × dose × SSRI type 3-way interaction effect P < 0.05). SSRI dose was inversely associated with IGF-1 (β = -63.5; 95% CI: -112.2, -14.7) but not insulin growth factor binding protein-3 concentration (β = -207.3; 95% CI: -536.2, 121.5). Fluoxetine and sertraline reduce height gain and IGF-1 concentration, in a dose-dependent manner. Longer-term studies are necessary.

6367 Growth gone Awry: A Rare Case of Acromegaly in a 16-Year-Old Female with Panhypopituitarism Secondary to Craniopharyngioma on Low Doses of Growth Hormone with Low IGF-1 levels

Abstract Disclosure: L.M. Ayala Castro: None. J. Ye Tay: None. A. Diaz: None. This report highlights a rare case of a 16-year-old female with panhypopituitarism due to craniopharyngioma, where GH replacement therapy triggered acromegaly features despite having low IGF-1 levels. Background: Craniopharyngiomas are the most common tumors causing acquired pituitary deficiencies in children. Various mechanisms contribute to acromegaly, and hypersensitivity to hormonal treatment in this benign tumor emerges as a plausible avenue for investigation. Case Presentation: A 16-year-old female diagnosed with craniopharyngioma at age 5 developed secondary panhypopituitarism. Baseline hormonal profiles indicated markedly reduced levels of IGF-1 and insulin growth factor–binding protein 3 (IGF-BP3). Despite the established condition, GH treatment was initiated at age 8 for potential growth and development benefits. Before commencing GH therapy, a bone age assessment revealed normal skeletal development. However, GH replacement therapy led to an unexpectedly robust response, resulting in physical changes consistent with acromegaly. Paradoxically, laboratory evaluations showed low IGF-1 levels. Imaging studies, including pituitary MRI, ruled out new abnormalities or tumors. As the patient approached peak adult height at 16, having been on adult GH therapy since age 13, a decision was made to discontinue GH replacement therapy and address acromegaly symptoms. Frequent follow-up visits were planned to assess growth velocity, monitor hormonal levels, and evaluate potential adverse effects. Discussion: This case demonstrates an unusual sensitivity to exogenous GH, resulting in an exaggerated response contrary to expected IGF-1 elevation. Atypical IGF-1 levels may suggest alterations in liver physiology, GH receptor signaling pathways (e.g., Laron Syndrome), or downstream defects in IGF-1 synthesis. Further research is crucial to elucidate the underlying mechanisms. Conclusion: Only 3 cases of acromegaly as a side effect of GH replacement therapy have been reported in the literature. We report a further case that underscores the complexity of managing hormonal imbalances, especially in unique patient populations with panhypopituitarism secondary to craniopharyngioma. The unexpected response to GH treatment emphasizes the need for individualized approaches and vigilant monitoring.

Regionalized cell and gene signatures govern esophageal epithelial homeostasis.

Regionalized disease prevalence is a common feature of the gastrointestinal tract. Herein, we employed regionally resolved Smart-seq3 single-cell sequencing, generating a comprehensive cell atlas of the adult mouse esophagus. Characterizing the esophageal axis, we identify non-uniform distribution of epithelial basal cells, fibroblasts, and immune cells. In addition, we demonstrate a position-dependent, but cell subpopulation-independent, transcriptional signature, collectively generating a regionalized esophageal landscape. Combining invivo models with organoid co-cultures, we demonstrate that proximal and distal basal progenitor cell states are functionally distinct. We find that proximal fibroblasts are more permissive for organoid growth compared with distal fibroblasts and that the immune cell profile is regionalized in two dimensions, where proximal-distal and epithelial-stromal gradients impact epithelial maintenance. Finally, we predict and verify how WNT, BMP, insulin growth factor (IGF), and neuregulin (NRG) signaling are differentially engaged along the esophageal axis. We establish a cellular and transcriptional framework for understanding esophageal regionalization, providing a functional basis for epithelial disease susceptibility.

Exogenous Insulin Effect on the Initiation of Breast Cancer in Type 2 Diabetes Mellitus Patients

Background: Growing evidence has indicated that women with type 2 diabetes mellitus are at an increased risk of developing breast cancer. However, as a major adjuvant treatment, the influence of hormone therapy such as exogenous insulin on type 2 diabetes mellitus in primary breast-cancer remains controversial. Objective: To explore the relationship between different types of hypoglycemic medications for diabetes and the factors that may contribute to the initiation of breast cancer. Methods: The study included 80 blood samples taken from 80 females recruited from Ibn Al-Bitar Center for Cardiac Surgery Hospital in Baghdad, Iraq, between November 2022 and February 2023. They were within the age range of 40 to 70 years. They were divided into three groups according to the treatment strategy and duration of disease as follows: Group 1: (20) patients who take insulin only, Group 2: (20) patients who take metformin with insulin, and G 3: (40) patients on metformin only for less than one year. An enzymatic oxidation technique was used to test the following biochemical parameters for all research groups: Total cholesterol, triglycerides, fasting blood glucose, and high-density lipoprotein cholesterol. Using the Friedewald formula, the very low-density lipoprotein cholesterol and low-density lipoprotein cholesterol were determined. Using an enzymatic process, Insulin levels and Insulin like growth factor-1(IGF-1), Estrogen receptor alpha (ERα) levels, and breast cancer susceptibility protein 1 (BRCA1) were measured with an enzyme-linked immunosorbent assay (ELISA). Glycated hemoglobin (HbA1c) level was measured with a sandwich immunodetection method. Finally, The Homeostasis Model Assessment for insulin resistance (HOMA-IR) was calculated according to the specific formula. Results: The values for HbA1C%, FBS, and lipid profile showed non-significant differences when compared between study groups. While BRCA-1, estrogen receptor alpha (ERα), insulin, insulin growth factor IGF-1, and HOMA IR All showed significant differences among all groups. Conclusion: Taking metformin only for less than one year seemed to contribute to higher levels of BRCA-1.

C1q/MASP Complexes-Hybrid Complexes of Classical and Lectin Pathway Proteins Are Found in the Circulation.

Complement pathways, traditionally regarded as separate entities invitro, are increasingly noted for cross-communication and bypass mechanisms. Among these, the MBL/ficolin/CL-associated serine protease (MASP)-3, a component of lectin pathway pattern recognition molecules, has shown the ability to process critical substrates such as pro-factor D and insulin growth factor binding protein-5. Given shared features between lectin pathway pattern recognition molecules and C1q from the classical pathway, we hypothesized that C1q might be a viable invivo binding partner for the MASPs. We used microscale thermophoresis, ELISA, and immunoprecipitation assays to detect C1q/MASP complexes and functionally assessed the complexes through enzymatic cleavage assays. C1q/MASP-3 complexes were detected in human serum and correlated well with MASP-3 serum levels in healthy individuals. The binding affinity between MASP-3 and C1q invitro was in the nanomolar range, and the interaction was calcium-dependent, as demonstrated by their dissociation in the presence of EDTA. Furthermore, most of the circulating C1q-bound MASP-3 was activated. Based on immunoprecipitation, also C1q/MASP-2 complexes appeared to be present in serum. Finally, C1q/MASP-2 and C1q/MASP-3 invitro complexes were able to cleave C4 and pro-factor D, respectively. Our study reveals the existence of C1q/MASP complexes in the circulation of healthy individuals, and both C1q/MASP-2 and C1q/MASP-3 complexes display proteolytic activity. Hence, this study uncovers a crosstalk route between complement pathways not previously described.

Rate of body weight gain during early gestation in F0 beef heifers has effects that extend multigenerationally to the F2 fetuses.

Our aim was to investigate the effects of maternal (F0) body weight (BW) gain during the first 84 d of gestation on body composition, ovarian reserve, and hormonal and metabolic parameters of breeding-age F1 heifers, as well as the body weight and morphometry of F2 fetuses. The study also evaluated the effect of maternal body weight gain (F0) on the mRNA relative abundance of the small intestine of both F1 heifers and F2 fetuses. Crossbred Angus heifers (F0; n = 100) were managed to gain 0.20kg/d (low gain [LG], n = 50) or 0.75kg/d (moderate gain [MG], n = 50) for the first 84 d of gestation. Subsequently, F0 dams were managed on a common forage-based diet for the rest of gestation until the weaning of the F1 offspring. At 15 months of age a subset of F1 heifers was randomly selected for the current experiment (n = 8 LG and n = 8 MG). Heifers were bred via artificial insemination (AI; d 0), then harvested on d 84 of gestation. On d -10, 42, and 84, BW was recorded, and blood was collected and analyzed for concentrations of glucose, non-esterified fatty acids, progesterone, insulin, and insulin-like growth factor-1. Weight of F1 carcasses, organs, gravid uteri, and F2 fetuses and organs were recorded at harvest. Visible follicles were counted on F1 ovaries at harvest, and histology was used to count microscopic follicles. Liver and jejunal samples from F1 heifers were collected to measure tissue oxygen consumption and jejunal samples from F1 heifers and F2 fetuses were collected for mRNA relative abundance analysis. Body weight of F1 heifers from MG dams tended to be 12kg greater (P = 0.06) than for F1 heifers from LG dams. Concentrations of glucose were greater (P = 0.03) in F1 heifers from the MG group, with no differences in other blood metabolites or follicular populations (P ≥ 0.16). Interestingly, mammary glands were heavier (P = 0.05) and placentas and body depth tended to be heavier and greater, respectively (P ≤ 0.10), for F2 fetuses from F0 LG heifers. Oxygen consumption in the liver and jejunum, as well as mRNA relative abundance in the jejunum of F1 heifers, were not affected by F0 rate of gain (P ≥ 0.16). However, the NDUFC1, SDHA, UQCR1, and PPARG genes were upregulated (P ≤ 0.05) in the jejunum of F2 fetuses from the LG group. In conclusion, BW gain of F0 heifers during early gestation exerts subtle effects on pre-breeding BW and blood metabolites in F1 offspring, with impacts present in F2 placenta, mammary gland, and intestine.

Teprotumumab for the Treatment of Thyroid Eye Disease: Why Should We Keep Our Eyes "Wide Open"?-A Clinical and Pharmacovigilance Point of View.

Objectives: Thyroid eye disease (TED) treatment has been recently revolutionized with the approval of teprotumumab, a targeted insulin growth factor 1 receptor (IGF1R) inhibitor. To date, teprotumumab is the only FDA-approved drug for treating TED. In this article, we would like to temper the current enthusiasm around IGF1R inhibitors. Methods: critical review of the literature by independent academic practitioners. Results: several questions should be raised. First, "how an orphan drug has become a blockbuster with annual sales exceeding $1 billion?" Teprotumumab infusions are expensive, costing about USD 45,000 for one infusion and USD 360,000 for eight infusions in a 75 kg patient. Teprotumumab approval was based on two randomized clinical trials investigating active (clinical activity score ≥ 4) TED patients. Despite this, teprotumumab was approved by the FDA for "the treatment of TED" without distinguishing between active and inactive forms. The second question is as follows: "how can a new drug, compared only to a placebo, become the new standard without being compared to historically established gold standard medical or surgical treatments?" Teprotumumab has never been compared to other medical treatments in active TED nor to surgery in chronic TED. Up to 75% of patients may experience proptosis regression after treatment discontinuation. Finally, ototoxicity has emerged as a potentially devastating side effect requiring frequent monitoring. Investigation into the long-term side effects, especially in women of childbearing age, is also warranted. Conclusions: Teprotumumab is undoubtedly a major treatment option in TED. However, before prescribing a drug, practitioners should assess its benefit/risk ratio based on the following: (i) evidence-based medicine; (ii) their empirical experience; (iii) the cost/benefit analysis; (iv) the long-term outcomes and safety profile.

Dysregulated mTOR networks in experimental sporadic Alzheimer's disease.

Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD. This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration. Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules. Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL pY1135/1136-IGF-1R, Akt, PTEN, pS380-PTEN, pS2448-mTOR, p70S6K, pT412-p70S6K, p/T-pT412-p70S6K, p/T-Rictor, and p/T-Raptor. Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.

Markers of Metabolic Abnormalities in Vitiligo Patients.

While vitiligo is primarily caused by melanocyte deficiency or dysfunction, recent studies have revealed a notable prevalence of metabolic syndrome (MetS) among patients with vitiligo. This suggests shared pathogenic features between the two conditions. Individuals with vitiligo often exhibit variations in triglyceride levels, cholesterol, and blood pressure, which are also affected in MetS. Given the similarities in their underlying mechanisms, genetic factors, pro-inflammatory signalling pathways, and increased oxidative stress, this study aims to highlight the common traits between vitiligo and metabolic systemic disorders. Serum analyses confirmed increased low-density lipoprotein (LDL) levels in patients with vitiligo, compared to physiological values. In addition, we reported significant decreases in folate and vitamin D (Vit D) levels. Oxidative stress is one of the underlying causes of the development of metabolic syndromes and is related to the advancement of skin diseases. This study found high levels of inflammatory cytokines, such as interleukin-6 (IL-6) and chemokine 10 (CXCL10), which are markers of inflammation and disease progression. The accumulation of insulin growth factor binding proteins 5 (IGFBP5) and advanced glycation end products (AGEs) entailed in atherosclerosis and diabetes onset, respectively, were also disclosed in vitiligo. In addition, the blood-associated activity of the antioxidant enzymes catalase (Cat) and superoxide dismutase (SOD) was impaired. Moreover, the plasma fatty acid (FAs) profile analysis showed an alteration in composition and specific estimated activities of FAs biosynthetic enzymes resembling MetS development, resulting in an imbalance towards pro-inflammatory n6-series FAs. These results revealed a systemic metabolic alteration in vitiligo patients that could be considered a new target for developing a more effective therapeutic approach.

Circulating proteomic profiles in women with morbid obesity compared to normal-weight women

In this study, we aimed to evaluate circulating proteomic levels in women with morbid obesity (MO) compared to normal-weight (NW) women. Moreover, we have compared the proteomic profile between women with metabolically healthy (MH) MO and those with type 2 diabetes mellitus (T2DM). The study included 66 normal-weight (NW) women and 129 women with MO (54 MH and 75 with T2DM). Blood samples were processed for proteomics, involving protein extraction, quantification, digestion with peptide labelling and Nano (liquid chromatography (LC)-(Orbitrap) coupled to mass/mass spectrometry (MS/MS) analysis. Statistical analyses were performed. We identified 257 proteins. Women with MO showed significantly increased levels of 35 proteins and decreased levels of 45 proteins compared to NW women. Enrichment analysis of metabolic pathways revealed significant findings. Women with MO have an altered proteomic profile compared to normal-weight women, involving proteins significantly related to chylomicron assembly, complement cascade, clotting pathways and the insulin growth factor system. Regarding women with MO and T2DM compared to MHMO women, the proteomic profile shows alterations in mostly the same pathways associated with obesity. These findings confirmed in previous reports can help us better understand the pathophysiology of obesity and associated diseases. SignificanceWomen with morbid obesity (MO) exhibit substantial proteomic alterations compared to normal-weight (NW) women, involving 80 proteins. These alterations are linked to significant metabolic pathways, including chylomicron assembly, complement cascade, clotting pathways and the insulin growth factor system. Additionally, women with MO and type 2 diabetes mellitus (T2DM) compared to metabolically healthy MO women share similar proteomic changes than the first comparison. These findings enhance our understanding of the pathophysiology of obesity and associated diseases, offering potential targets for therapeutic intervention.

Date palm: a potential nutraceutical and phytomedicine in most frequent aging associated diseases

AbstractSenescence, often known as ageing, is a condition of decline that shows itself as a decrease in fertility and survival at older ages. Ageing theory suggests that ageing evolves as a function of life history optimization or because of mutation pressure, depending on the degree of externally imposed mortality and shocks to fertility. An important key factor to many aging-related disorders (ARDs), such as hypertension, myocardial infarction, atherosclerosis, osteoporosis, cancer, and neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, is ageing, a process influenced by countless biological and genetic pathways. While there have been significant advancements in therapeutics for age-related disorders, nutritional therapy, encasing various products from natural sources is recommended for durable and fruitful treatment. Numerous health advantages of the date palm, Phoenix dactylifera, have been well-documented. These include antioxidant, anti-inflammatory, cardioprotective, and neuroprotective activity. Phytochemical analysis of date palm demonstrates a lot of beneficial nutraceuticals that can ameliorate ARDs like polyphenols, phytosterols, carotenoids, flavonoids, terpenoids, fatty acids, carbohydrates, vitamins, and amino acids etc. The major signaling and molecular pathways by which these phytoconstituents exert their anti-ageing effects include terminating inflammation by blocking the release in of IL-6, TNF-α and clearance of Aβ plaques for neurodegenerative diseases; blocking ACE-II and HMG-CoA for cardio-protection; regulating RANK, p38MAPK-Runx2 pathways, and insulin-growth factor-1 (IGF-1) for osteoporosis. However, research on the benefits of date palm is still lacking. The purpose of this review is to shed light on the various biological activities of date palm in ARDs and to explore its remedial mechanisms.

Plasma miRNAs across the Alzheimer's disease continuum: Relationship to central biomarkers.

MicroRNAs (miRNAs) play important roles in gene expression regulation and Alzheimer's disease (AD) pathogenesis. We investigated the association between baseline plasma miRNAs and central AD biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N=803): amyloid, tau, and neurodegeneration (A/T/N). Differentially expressed miRNAs and their targets were identified, followed by pathway enrichment analysis. Machine learning approaches were applied to investigate the role of miRNAs as blood biomarkers. We identified nine, two, and eight miRNAs significantly associated with A/T/N positivity, respectively. We identified 271 genes targeted by amyloid-related miRNAs with estrogen signaling receptor-mediated signaling among the enriched pathways. Additionally, 220 genes targeted by neurodegeneration-related miRNAs showed enrichment in pathways including the insulin growth factor 1 pathway. The classification performance of demographic information for A/T/N positivity was increased up to 9% with the inclusion of miRNAs. Plasma miRNAs were associated with central A/T/N biomarkers, highlighting their potential as blood biomarkers. We performed association analysis of microRNAs (miRNAs) with amyloid/tau/neurodegeneration (A/T/N) biomarker positivity. We identified dysregulated miRNAs for A/T/N biomarker positivity. We identified Alzheimer's disease biomarker-specific/common pathways related to miRNAs. miRNAs improved the classification for A/T/N positivity by up to 9%. Our study highlights the potential of miRNAs as blood biomarkers.

IGF 1, BDNF, and NGF mediate the neuro-modulatory role of stem cells in acrylamide-induced hippocampal toxic changes in rats.

Acrylamide (ACR), a common industrial chemical, is a strong neurotoxic material. The hippocampus is a brain area of interest mostly affected by Alzheimer's disease. Mesenchymal stem cells (MSCs) usefulness in various neurological diseases including Alzheimer's is being debated. In this work, the authors aim to explore the role of MSCs in ACR-induced hippocampal neurodegeneration and elucidate the mediating mechanism. For this purpose, ten rats served as control, another ten were injected ACR (i.p. 50 mg/kg/day for 2 weeks), and the last ten rats were injected ACR in addition to MSCs (i.p. 1 × 10⁷ MSCs single injection). ACR induced neurodegenerative histopathological hippocampal changes and adversely altered hippocampal oxidative stress markers SOD, MDA, and GSH. ACR had induced hippocampal demyelination as detected by silver staining. ACR significantly (P < 0.05) up-regulated the ELISA hippocampal TNF-alpha and IL-6 and produced microglial & astrocyte activation (as tracked by Iba1 & GFAP immunohistochemistry respectively). ACR significantly reduced hippocampal PCR gene expression of IGF 1 (insulin growth factor-1), BDNF (brain-derived neurotrophic factor), and NGF (nerve growth factor). MSCs administration had mitigated all the previous deleterious changes. Acrylamide caused detrimental effects on the hippocampus and demonstrably altered the hippocampal architecture. Bone marrow mesenchymal stem cells offered a promising therapeutic role against these neurotoxic effects of acrylamide, presumably through modulation of IGF 1, BDNF, and NGF gene expressions.

PSIX-12 Influence of obesity on satiety hormones, serum metabolome, and fecal microbiome in adult dogs

Abstract The objective of this study was to investigate the difference between lean and obese dogs in terms of their satiety hormones, serum metabolome, and fecal microbiome. Mixed-breed lean (n = 30; 17 male and 13 female; 4.0 ± 2.5 yr of age; 24.6 ± 6.3% body fat) and obese (n = 30; 19 male and 11 female; 7.3 ± 2.1 yr of age; 46.9 ± 3.9% body fat) adult dogs were used in this study. Blood samples were collected to measure satiety hormones and serum metabolome, and fresh fecal samples were collected for microbiome analysis. It was hypothesized that obese dogs had altered metabolism and gut microbiome compared with lean dogs. Data were analyzed using MIXED procedure of SAS, using body type as the fixed effect and dog as the random effect. Results showed that obese dogs had greater (P &amp;lt; 0.05) serum leptin, insulin, and insulin-like growth factor-1 (IGF-1) concentrations, but reduced (P &amp;lt; 0.05) gastric inhibitory peptide (GIP) than lean dogs. Serum concentrations of all essential amino acids except for threonine in obese dogs were greater (P &amp;lt; 0.05) than in lean dogs. Obese dogs also had greater (P &amp;lt; 0.05) concentrations of serum N-Lactoyl amino acids and dipeptides except for prolylglycine than their lean counterparts. Additionally, concentrations of serum long-chain saturated and monounsaturated fatty acids were less (P &amp;lt; 0.05; only for myristate, pentadecanoate, and non-adecanoate) or similar in obese dogs compared with lean dogs. Serum oxidative stress makers, such as oxidized glutathione, cysteine-glutathione, and 4-hydroxynonenal, were greater (P &amp;lt; 0.05) in obese dogs than lean dogs. Furthermore, obese dogs had less (P &amp;lt; 0.05) fecal Firmicutes, but greater (P &amp;lt; 0.05) fecal Bacteroidetes and Fusobacteria, compared with lean dogs. There were no differences (P &amp;gt; 0.10) in fecal microbiome alpha diversity, such as Chao1 and Shannon index, between lean and obese dogs. In conclusion, obese dogs had differential body metabolism and gut microbiome compared with lean dogs.

The Use of Kidney Biomarkers, Nephrin and KIM-1, for the Detection of Early Glomerular and Tubular Damage in Patients with Acromegaly: A Case-Control Pilot Study.

Acromegaly is a rare disorder caused by excessive growth hormone (GH) secreted from a pituitary tumor. High levels of GH and insulin growth factor-1 can lead to renal hypertrophy, as well as to diabetes mellitus and hypertension, which negatively impact kidney function. It is believed that high GH may also be involved in the onset of diabetic nephropathy, the main cause of end-stage kidney disease in developed countries. This case-control study was conducted on 23 acromegalic patients and on a control group represented by 21 healthy subjects. The following parameters were determined for all the subjects: serum creatinine, serum urea, estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (UACR), nephrin and kidney injury molecule 1 (KIM-1). Patients with acromegaly showed higher levels of UACR and lower levels of eGFR as compared to healthy subjects. No significant correlations were found between clinical or biochemical parameters associated with acromegaly and nephrin or KIM-1. There was no glomerular or proximal tubular damage at the time of the study, as proven by the normal levels of the biomarkers nephrin and KIM-1. Studies including more patients with uncontrolled disease are needed to clarify the utility of nephrin and KIM-1 for the detection of early kidney involvement in acromegalic patients.

Tryptophan regulates the expression of IGFBP1 in bovine endometrial epithelial cells in vitro via the TDO2-AHR pathway

BackgroundThis study aimed to identify the roles of L-tryptophan (Trp) and its rate-limiting enzymes on the receptivity of bovine endometrial epithelial cells. Real-time PCR was conducted to analyze the differential expression of genes between different groups of bovine endometrial epithelial cells. Western blot was performed to detect Cyclooxygenase-2 (COX2) expression after treatment with Trp or kynurenine (the main metabolites of Trp). The kynurenine assay was used to examine if Trp or prostaglandin E2 (PGE2) can increase the production of kynurenine in the bovine endometrial epithelial cells.ResultsTrp significantly stimulates insulin growth factor binding protein 1 (IGFBP1) expression, a common endometrial marker of conceptus elongation and uterus receptivity for ruminants. When bovine endometrial epithelial cells are treated with Trp, tryptophan hydroxylase-1 remains unchanged, but tryptophan 2,3-dioxygenase 2 (TDO2) is significantly increased, suggesting tryptophan is mainly metabolized through the kynurenine pathway. Kynurenine significantly stimulates IGFBP1 expression. Furthermore, Trp and kynurenine significantly increase the expression of aryl hydrocarbon receptor (AHR). CH223191, an AHR inhibitor, abrogates the induction of Trp and kynurenine on IGFBP1. PGE2 significantly induces the expression of TDO2, AHR, and IGFBP1.ConclusionsThe regulation between Trp / kynurenine and PGE2 may be crucial for the receptivity of the bovine uterus.

Fluorescent tagging of endogenous IRS2 with an auxin-dependent degron to assess dynamic intracellular localization and function

Insulin Receptor Substrate 2 (IRS2) is a signaling adaptor protein for the insulin (IR) and Insulin-like Growth Factor-1 (IGF-1R) receptors. In breast cancer, IRS2 contributes to both initiation of primary tumor growth and establishment of secondary metastases through regulation of cancer stem cell (CSC) function and invasion. However, how IRS2 mediates its diverse functions is not well understood. We used CRISPR/Cas9-mediated gene editing to modify endogenous IRS2 to study the expression, localization, and function of this adaptor protein. A cassette containing an auxin inducible degradation (AID) sequence, 3X-FLAG tag and mNeon-green was introduced at the N-terminus of the IRS2 gene to provide rapid and reversible control of IRS2 protein degradation and analysis of endogenous IRS2 expression and localization. Live fluorescence imaging of these cells revealed that IRS2 shuttles between the cytoplasm and nucleus in response to growth regulatory signals in a PI3K-dependent manner. Inhibition of nuclear export or deletion of a putative nuclear export sequence in the C-terminal tail promotes nuclear retention of IRS2, implicating nuclear export in the mechanism by which IRS2 intracellular localization is regulated. Moreover, the acute induction of IRS2 degradation reduces tumor cell invasion, demonstrating the potential for therapeutic targeting of this adaptor protein. Our data highlight the value of our model of endogenously tagged IRS2 as a tool to study IRS2 localization and function.