Reduction In Insulin-like Growth Factor Research Articles

Growth hormone resistance induced by amino acid deprivation in fao cells is independent of FGF21

Adequate dietary intake of amino acids is imperative for normal animal growth. Our previous work using rat hepatocarcinoma Fao cells demonstrated that growth hormone (GH) resistance, coupled with a concurrent reduction in insulin-like growth factor 1 (Igf1) mRNA levels, may underlie the growth retardation associated with a low-protein diet (LPD). In this study, we investigated whether FGF21 contributes to liver GH resistance in Fao rat hepatoma cells under amino acid deprivation conditions. Mice subjected to an LPD exhibited growth retardation, compromised GH signaling in the liver, and decreased blood IGF-1 levels compared with those on a control diet. To assess the potential involvement of fibroblast growth factor (FGF) 21, produced in response to amino acid deficiency, in the development of GH resistance, we examined GH signaling and Igf1 mRNA levels in Fao cells cultured in amino acid-deprived medium. Despite the inhibition of Fgf21 expression by the integrated stress response inhibitor, an inhibitor of the eukaryotic initiation factor 2-activating transcription factor 4 pathway, GH resistance persisted in response to amino acid deprivation. Additionally, the introduction of FGF21 into the control medium did not impair either GH signaling or GH-induced Igf1 transcription. These data suggest that, in Fao cells, amino acid deprivation induces GH resistance independently of FGF21 activity. By shedding light on the mechanisms behind growth retardation-associated GH resistance linked to amino acid deficiencies, our findings provide valuable insights for clinicians in formulating effective treatment strategies for individuals facing these challenges.

The causal effects of genetically predicted alcohol consumption on endometrial cancer risk from a Mendelian randomization study

Endometrial cancer (EC) is a common gynecological tumor in females with an increasing incidence over the past few decades. Alcohol consumption has been linked to the occurrence of various cancers; However, epidemiological studies have shown inconsistent associations between alcohol consumption and EC risk. In order to avoid the influence of potential confounding factors and reverse causality in traditional epidemiological studies, we used a method based on genetic principles-Mendelian randomization (MR) analysis to test whether there is a causal relationship between alcohol consumption and EC. MR analysis was conducted using publicly available summary-level data from genome-wide association studies (GWAS). Fifty-seven single nucleotide polymorphisms (SNPs) were extracted as instrumental variables for alcohol exposure from the GWAS and Sequencing Consortium of Alcohol and Nicotine GWAS summary data involving 941,287 participants of European ancestry. SNPs for EC were obtained from the Endometrial Cancer Association Consortium, the Endometrial Cancer Epidemiology Consortium, and the UK Biobank, involving 121,885 European participants. The inverse variance weighted (IVW) method was used as the primary method to estimate the causal effect, and the MR-Egger regression and weighted median method were used as supplementary methods. Sensitivity analyses were conducted using the Mendelian Randomization Pleiotropy RESidual Sum and Outlier global test, MR-Egger intercept test, and leave-one-out analysis to evaluate the impact of pleiotropy on causal estimates. An increase of 1 standard deviation of genetically predicted log-transformed alcoholic drinks per day was associated with a 43% reduction in EC risk [odds ratio (OR) = 0.57, 95% confidence interval (CI) 0.41–0.79, P < 0.001]. Subgroup analysis of EC revealed that alcohol consumption was a protective factor for endometrioid endometrial cancer (EEC) (OR = 0.56, 95% CI 0.38–0.83, P = 0.004) but not for non-endometrioid endometrial cancer (NEC) (OR = 1.36, 95% CI 0.40–4.66, P = 0.626). The MR-Egger regression and weighted median method yielded consistent causal effects with the IVW method. The consistent results of sensitivity analyses indicated the reliability of our causal estimates. Additionally, alcohol consumption was associated with decreased human chorionic gonadotropin (HCG) and insulin-like growth factor 1 (IGF1) levels. This MR study suggests that genetically predicted alcohol consumption is a protective factor for EC, particularly for EEC, and this protective effect may be mediated through the reduction of HCG and IGF1.

Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro

PurposeHypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro.MethodsC2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated.ResultsThe combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells.ConclusionsOur results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

SARM1 promotes the neuroinflammation and demyelination through IGFBP2/NF-κB pathway in experimental autoimmune encephalomyelitis mice.

Multiple sclerosis (MS) is an autoimmune disease, and its typical characteristics are neuroinflammation and the demyelination of neurons in the central nervous system (CNS). Sterile alpha and TIR motif containing 1 (SARM1) is an essential factor mediating axonal degeneration and SARM1 deletion reduces the neuroinflammation in spinal cord injury. This study aimed to explore the roles of SARM1 and its underlying mechanisms in MS. Experimental autoimmune encephalomyelitis (EAE, a model of MS) model was established. Immunostaining, western blot, electron microscope, and HE staining were used to examine the pathological manifestations such as inflammation, demyelination, and neuronal death in SARM1f/f EAE mice and SARM1Nestin -CKO EAE mice. In addition, RNA-seq, real-time PCR and double-immunostaining were used to examine the underlying mechanism of SARM1 in EAE mice. SARM1 was upregulated in neurons of the spinal cords of EAE mice. SARM1 knockout in CNS ameliorated EAE with less neuroinflammation, demyelination, and dead neurons. Mechanically, SARM1 knockout resulted in the reduction of insulin-like growth factor (IGF)-binding protein 2 (IGFBP2) in neurons of EAE mice, which might inhibit the neuroinflammation through inhibiting NF-κB signaling. Finally, activation of NF-κB partially aggravated the neuroinflammation and demyelination deficits of SARM1Nestin -CKO EAE mice. These results identified the unknown role of SARM1 in the promotion of neuroinflammation and demyelination and revealed a novel drug target pathway of SARM1/IGFBP2/NF-κB for MS.

Unexpected role for IGF-1 in starvation: Maintenance of blood glucose

Wild-type (WT) mice maintain viable levels of blood glucose even when adipose stores are depleted by 6 d of 60% calorie restriction followed by a 23-h fast (hereafter designated as "starved" mice). Survival depends on ghrelin, an octanoylated peptide hormone. Mice that lack ghrelin suffer lethal hypoglycemia when subjected to the same starvation regimen. Ghrelin is known to stimulate secretion of growth hormone (GH), which in turn stimulates secretion of IGF-1 (insulin-like growth factor-1). In the current study, we found that starved ghrelin-deficient mice had a 90% reduction in plasma IGF-1 when compared with starved WT mice. Injection of IGF-1 in starved ghrelin-deficient mice caused a twofold increase in glucose production and raised blood glucose to levels seen in starved WT mice. Increased glucose production was accompanied by increases in plasma glycerol, fatty acids and ketone bodies, and hepatic triglycerides. All of these increases were abolished when the mice were treated with atglistatin, an inhibitor of adipose tissue triglyceride lipase. We conclude that IGF-1 stimulates adipose tissue lipolysis in starved mice and that this lipolysis supplies energy and substrates that restore hepatic gluconeogenesis. This action of IGF-1 in starved mice is in contrast to its known action in inhibiting adipose tissue lipase in fed mice. Surprisingly, the ghrelin-dependent maintenance of plasma IGF-1 in starved mice was not mediated by GH. Direct injection of GH into starved ghrelin-deficient mice failed to increase plasma IGF-1. These data call attention to an unsuspected role of IGF-1 in the adaptation to starvation.

Replacement of prolonged-acting octreotide with lanreotide autogel 120 mg in patients with Acromegaly in real clinical practice

Introduction. In the cases of neurosurgery failure in acromegaly treatment, drug therapy with somatostatin analogues (SSA) octreotide or lanreotide is indicated. The effectiveness of SSA is limited by the presence of resistance, there is an opinion that in some cases it can be overcome by replacing one drug with another.Aim. Own experience analysis of transferring acromegaly patients from therapy with long-acting octreotide to lanreotide autogel 120 mg.Materials and methods. The case histories of acromegaly patients who were recommended to replace long-acting octreotide therapy with lanreotide therapy 120 mg were analyzed. GH and insulin-like growth factor-1 (IGF-1) dynamics was evaluated at least 6 months after the replacement of the drug. The target value for GH was considered to be less than 2.5 micrograms/l, for IGF-1 – an excess of no more than 30% of the upper normal limit.Results. 24 patients were transferred to lanreotide therapy 120 mg. Of the 19 patients with insufficient reduction of GH and IGF-1 on prolonged-acting octreotide therapy at a dose of 40 mg every 28 days (OCT40) the prescription of lanreotide 120 mg every 28 days (LAN120) led to the target values of both GH and IGF-1 in 4 (21%) cases. These patients had no more than a twofold excess of IGF-1, and the level of GH was less than 2.5 mcg/l on the background of OCT 40 therapy. In 6 (32%) patients, IGF-1 levels normalized or decreased, but GH remained outside the target values. In 9 (47%) cases, the replacement of the SSA did not lead to a significant positive dynamics in the levels of GH and IGF-1. The effects of lanreotide therapy 120 mg in another five patients initially treated with octreotide 20 mg are also described.Conclusions. Replacement of OCT4 with LAN120 may be effective in some patients with acromegaly. A slight increase in the level of IGF-1 together with the target values of GH before replacing the SSA may be the predictor of success.

Cabergoline treatment in cats with diabetes mellitus and hypersomatotropism.

The aim of this study was to evaluate the safety and efficacy of cabergoline to control hypersomatotropism (HST) and diabetes mellitus (DM) in cats. This was a prospective cohort study. Twenty-three cats with HST and concurrent DM were enrolled. Cats received a dose of 10 μg/kg cabergoline q48h PO for 6 months. Serum insulin-like growth factor 1 (IGF-1) and fructosamine concentrations, insulin dose and Insulin Resistance Index (IRI) were measured at the time of diagnosis of HST and at the start of cabergoline treatment (t0), and 3 months (t1) and 6 months (t2) during cabergoline treatment. A decrease and normalization of serum IGF-1 concentration was observed in 35% and 26% of cats, respectively. Median IGF-1 (t0: 1350 ng/ml [range 832-1501]; t1: 1284 ng/ml [range 365-1501]; t2: 1240 ng/ml [range 263-1501]; P = 0.016) decreased significantly. Twelve cats underwent diagnostic imaging of the pituitary area. The median pituitary height at t0 of cats that experienced an IGF-1 reduction (n = 5/12) was significantly lower compared with those that did not experience an IGF-1 reduction (n = 7/12) (3.2 mm [range 3.1-3.7] vs 6 mm [range 3.5-9.5]; P = 0.011). Median fructosamine (t0: 628 µmol/l [range 400-963]; t1: 404 µmol/l [range 249-780]; t2: 400 µmol/l [range 260-815]; P <0.0001), insulin dose (t0: 1.3 IU/kg [range 0.5-4.6]; t0: 0.5 IU/kg [range 0-2.3]; t2: 0.4 IU/kg [range 0-2.1]; P <0.0001) and IRI (t0: 800 µmolIU/kgl [range 257-2700]; t1: 300 µmolIU/kgl [range 0-1498]; t2: 250 µmolIU/kgl [range 0-1498]; P <0.0001) decreased significantly during cabergoline treatment. Eight cats achieved diabetic remission between months 1 and 6 of cabergoline treatment (median time to achieve remission: 3 months [range 1-6]). Three cats experienced asymptomatic hypoglycemia. Cabergoline was effective in normalizing IGF-1 concentration in 26% of cats. Cabergoline improved diabetes control and was associated with remission of DM in 35% of cases. Cabergoline could be a treatment option for cats with HST and DM, especially in those cases with a relatively small pituitary tumor.

Postoperative GH and Degree of Reduction in IGF-1 Predicts Postoperative Hormonal Remission in Acromegaly.

PurposeDetermine predictive factors for long-term remission of acromegaly after transsphenoidal resection of growth hormone (GH)-secreting pituitary adenomas.MethodsWe identified 94 patients who had undergone transsphenoidal resection of GH-secreting pituitary adenomas for treatment of acromegaly at the USC Pituitary Center from 1999-2019 to determine the predictive value of postoperative endocrine lab values.ResultsPatients underwent direct endoscopic endonasal (60%), microscopic transsphenoidal (38%), and extended endoscopic approaches (2%). The cohort was 63% female and 37% male, with average age of 48.9 years. Patients presented with acral enlargement (72, 77%), macroglossia (40, 43%), excessive sweating (39, 42%), prognathism (38, 40%) and frontal bossing (35, 37%). Seventy-five (80%) were macroadenomas and 19 (20%) were microadenomas. Cavernous sinus invasion was present in 45%. Available immunohistochemical data demonstrated GH staining in 88 (94%) and prolactin in 44 (47%). Available postoperative MRI demonstrated gross total resection in 63% of patients and subtotal resection in 37%. Most patients (66%) exhibited hormonal remission at 12 weeks postoperatively. Receiver operating characteristic (ROC) curves demonstrated postoperative day 1 (POD1) GH levels ≥1.55ng/mL predicted failure to remit from surgical resection alone (59% specificity, 75% sensitivity). A second ROC curve showed decrease in corrected insulin-like growth factor-1 (IGF-1) levels of at least 37% prognosticated biochemical control (90% sensitivity, 80% specificity).ConclusionPOD1 GH and short-term postoperative IGF-1 levels can be used to successfully predict immediate and long-term hormonal remission respectively. A POD1 GH cutoff can identify patients likely to require adjuvant therapy to emphasize clinical follow-up.

Characteristics and treatment responsiveness of patients with acromegaly and a paradoxical GH increase to oral glucose load.

We aimed to investigate the clinical, biochemical, histological and radiological characteristics as well as the response to somatostatin analogs (SSA) in a large cohort of acromegaly patients with a paradoxical GH response (PR) to oral glucose tolerance test (OGTT). Retrospective study. Of 110 patients with acromegaly included in our study, 30 (PR+; 27%) had a paradoxical GH increase of more than 25% relative to basal GH levels during OGTT. At diagnosis, PR+ patients were older than PR- patients (52 ± 16 years vs 44 ± 14 years, P < 0.05) and had smaller pituitary tumors (40% microadenomas vs 19%, P < 0.05), which were less often invasive (17% vs 35%, P < 0.05), overall more secreting (insulin-like growth factor-1 (IGF-1)/tumoral surface: 2.35 ULN/cm2 (0.28-9.06) vs 1.08 (0.17-7.87), P = 0.011), and more often hypointense on T2-weighted MRI (92% vs 48%, P = 0.001). While the rate of remission after surgery was similar in the two groups (69%), a better response to SSA treatment was observed in PR+ patients, either before (IGF-1 reduction of > 50% after 3-6 months in 77% vs 49%, P = 0.023) or after surgery (normalization of IGF-1 in 100% vs 44%, P = 0.011). Our study demonstrates that in acromegaly, a paradoxical GH increase during OGTT is associated with particular features of somatotroph adenomas and with a better prognosis in terms of response to SSA.

Effects of Behavioral Weight Loss and Metformin on IGFs in Cancer Survivors: A Randomized Trial.

Higher levels of insulin-like growth factor-1 (IGF-1) are associated with increased risk of cancers and higher mortality. Therapies that reduce IGF-1 have considerable appeal as means to prevent recurrence. Randomized, 3-parallel-arm controlled clinical trial. Cancer survivors with overweight or obesity were randomized to (1) self-directed weight loss (comparison), (2) coach-directed weight loss, or (3) metformin treatment. Main outcomes were changes in IGF-1 and IGF-1:IGFBP3 molar ratio at 6 months. The trial duration was 12 months. Of the 121 randomized participants, 79% were women, 46% were African Americans, and the mean age was 60 years. At baseline, the average body mass index was 35 kg/m2; mean IGF-1 was 72.9 (SD, 21.7) ng/mL; and mean IGF1:IGFBP3 molar ratio was 0.17 (SD, 0.05). At 6 months, weight changes were -1.0% (P = 0.07), -4.2% (P < 0.0001), and -2.8% (P < 0.0001) in self-directed, coach-directed, and metformin groups, respectively. Compared with the self-directed group, participants in metformin had significant decreases on IGF-1 (mean difference in change: -5.50 ng/mL, P = 0.02) and IGF1:IGFBP3 molar ratio (mean difference in change: -0.0119, P = 0.011) at 3 months. The significant decrease of IGF-1 remained in participants with obesity at 6 months (mean difference in change: -7.2 ng/mL; 95% CI: -13.3 to -1.1), but not in participants with overweight (P for interaction = 0.045). There were no significant differences in changes between the coach-directed and self-directed groups. There were no differences in outcomes at 12 months. In cancer survivors with obesity, metformin may have a short-term effect on IGF-1 reduction that wanes over time.

Effects of caloric restriction on immunosurveillance, microbiota and cancer cell phenotype: Possible implications for cancer treatment.

Fasting, caloric restriction and foods or compounds mimicking the biological effects of caloric restriction, known as caloric restriction mimetics, have been associated with a lower risk of age-related diseases, including cardiovascular diseases, cancer and cognitive decline, and a longer lifespan. Reduced calorie intake has been shown to stimulate cancer immunosurveillance, reducing the migration of immunosuppressive regulatory T cells towards the tumor bulk. Autophagy stimulation via reduction of lysine acetylation, increased sensitivity to chemo- and immunotherapy, along with a reduction of insulin-like growth factor 1 and reactive oxygen species have been described as some of the major effects triggered by caloric restriction. Fasting and caloric restriction have also been shown to beneficially influence gut microbiota composition, modify host metabolism, reduce total cholesterol and triglyceride levels, lower diastolic blood pressure and elevate morning cortisol level, with beneficial modulatory effects on cardiopulmonary fitness, body fat and weight, fatigue and weakness, and general quality of life. Moreover, caloric restriction may reduce the carcinogenic and metastatic potential of cancer stem cells, which are generally considered responsible of tumor formation and relapse. Here, we reviewed in vitro and in vivo studies describing the effects of fasting, caloric restriction and some caloric restriction mimetics on immunosurveillance, gut microbiota, metabolism, and cancer stem cell growth, highlighting the molecular and cellular mechanisms underlying these effects. Additionally, studies on caloric restriction interventions in cancer patients or cancer risk subjects are discussed. Considering the promising effects associated with caloric restriction and caloric restriction mimetics, we think that controlled-randomized large clinical trials are warranted to evaluate the inclusion of these non-pharmacological approaches in clinical practice.

Inhibition of mitochondria ATP synthase suppresses prostate cancer growth through reduced insulin-like growth factor-1 secretion by prostate stromal cells.

Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.

Activation of Uterine Smad3 Pathway Is Crucial for Embryo Implantation.

Embryo implantation is a complicated physiological process tightly regulated by multiple biological molecules including growth factors. Transforming growth factor-betas (TGF-βs) and their most specific signal transduction factors, Smads, are expressed in the endometrium during the window of implantation. Recent researches indicated that Smad dependent TGF-β signaling may play an important role in the process of embryo implantation. In this study, we measured the expression of TGF-β1, TGF-β receptor type I (TβRI), Smad3 and p-Smad3 in the endometrium of mice and observed their elevation on day 4, 5 and 6 of pseudopregnancy. Then we administrated a specific Smad3 inhibitor (Sis3) into the uterine cavity of mice on day 3 of pregnancy. The results showed a reduction in insulin-like growth factor-1 (IGFBP-1) expression and the decreased number of implanted embryo after the administration. In addition, Sis3 was found to reduce the IGFBP-1 secretion in decidualized endometrial stromal cells. Taken all together, our findings demonstrated that TGF-β/Smad3 signaling is involved in the process of embryo implantation.

Prognostic Significance of IGF-1 Signalling Pathway in Patients With Advanced Non-small Cell Lung Cancer.

Insulin-like growth factor 1 (IGF-1)-mediated molecular pathway has been implicated in non-small cell lung cancer (NSCLC) pathogenesis and progression. We aimed to evaluate serum levels of IGF-1, IGF-2 and IGF-binding protein 3 (IGF-BP3) before and after standard treatment in patients with advanced NSCLC and their prognostic and predictive correlations. Seventy-three patients were prospectively included. Analysis and quantification of circulating levels of IGF1, IGF2, IGFBP3 were performed by total ELISA in peripheral blood samples at baseline and 3 months post-treatment. The median values of IGF-1 and IGF-1/IGF-BP3 ratios (125.82 vs. 133.4 ng/ml, p=0.087 and 0.01006 vs. 0.01252, p=0.011) were both decreased after treatment. Importantly, the post-treatment value of the ratio was significantly reduced only among responders to treatment (0.01044 from 0.01255, p=0.02). Reduction of IGF-1/IGF-BP3 ratio was statistically significant only among patients with NSCLC who responded to first-line treatment. If validated in larger cohorts, IGF-1/IGFBP3 might be a useful predictive tool for response to chemotherapy in NSCLC.

The Middle-Aged Bone Marrow Microenvironment Drives Hematopoietic Stem Cell Aging through Altered Production of Insulin-like Growth Factor-1 (IGF1)

Globally, lifespan continues to increase. A growing challenge is how to maintain a healthy aging population. In hematopoiesis, healthspan is limited by a decline in regenerative capacity and overproduction of myeloid cell types at the expense of lymphoid cell types. These alterations contribute to decreased immune function, poor response to vaccination and increased susceptibility to myeloid neoplasms. Methods to extend hematopoietic healthspan are unclear, in part due to our relatively poor understanding of the factors controlling aging.To address this gap in knowledge, we utilized mouse models to examine at what age did impaired regenerative capacity and myeloid-biased hematopoiesis begin to occur. We find that these phenotypes become significant by 9-12 months of age, representing middle age in mice. Through reciprocal transplantation studies of purified long-term hematopoietic stem cells (LT-HSCs) between young and middle-aged mice, we find that the middle-aged bone marrow (BM) microenvironment is sufficient to cause impaired regenerative capacity and myeloid-biased hematopoiesis from young LT-HSCs. These studies clearly implicate components of the BM microenvironment at middle age as causing hematopoietic aging.To uncover the factors altered in the middle-aged BM microenvironment that cause hematopoietic stem and progenitor cell aging, we utilized single cell RNA-Seq and ELISA analysis. Together, these identified a reduction in Insulin-Like Growth Factor-1 (IGF1) in the BM microenvironment as the top candidate regulator of hematopoietic stem and progenitor cell aging. Expression of the receptor for IGF1, IGF1R, was dynamically altered on hematopoietic stem and progenitor cell populations with aging, suggesting that these respond to altered local levels of IGF1. In vitro colony-forming unit studies demonstrate that stimulating hematopoietic stem and progenitor cells isolated from middle-aged mice with exogenous IGF-1 ligand resulted in a dose-dependent suppression of myeloid cell overproduction, rescuing the aging phenotype. Finally, direct restoration of IGF1 levels in the BM microenvironment by short-term intrafemoral injection, at middle age, suppressed myeloid cell overproduction and restored B cell production in the BM and peripheral blood.In summary, this study reveals a novel role for IGF1 in hematopoietic aging. We show that decline in local levels of IGF1 in the BM microenvironment at middle age cause hematopoietic aging. In addition, we demonstrate that short-term restoration of IGF1 at middle age can rescue hematopoietic aging. IGF1 thus represents an attractive candidate molecule to restore hematopoietic regenerative capacity and balanced lineage cell production to extend hematopoietic healthspan into older age. DisclosuresNo relevant conflicts of interest to declare.

Sporadic amyotrophic lateral sclerosis (SALS) - skeletal muscle response to cerebrospinal fluid from SALS patients in a rat model.

ABSTRACTSkeletal muscle atrophy is the most prominent feature of amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease of motor neurons. However, the contribution of skeletal muscle to disease progression remains elusive. Our previous studies have shown that intrathecal injection of cerebrospinal fluid from sporadic ALS patients (ALS-CSF) induces several degenerative changes in motor neurons and glia of neonatal rats. Here, we describe various pathologic events in the rat extensor digitorum longus muscle following intrathecal injection of ALS-CSF. Adenosine triphosphatase staining and electron microscopic (EM) analysis revealed significant atrophy and grouping of type 2 fibres in ALS-CSF-injected rats. Profound neuromuscular junction (NMJ) damage, such as fragmentation accompanied by denervation, were revealed by α-bungarotoxin immunostaining. Altered expression of key NMJ proteins, rapsyn and calpain, was also observed by immunoblotting. In addition, EM analysis showed sarcolemmal folding, Z-line streaming, structural alterations of mitochondria and dilated sarcoplasmic reticulum. The expression of trophic factors was affected, with significant downregulation of vascular endothelial growth factor (VEGF), marginal reduction in insulin-like growth factor-1 (IGF-1), and upregulation of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). However, motor neurons might be unable to harness the enhanced levels of BDNF and GDNF, owing to impaired NMJs. We propose that ALS-CSF triggers motor neuronal degeneration, resulting in pathological changes in the skeletal muscle. Muscle damage further aggravates the motor neuronal pathology, because of the interdependency between them. This sets in a vicious cycle, leading to rapid and progressive loss of motor neurons, which could explain the relentless course of ALS.This article has an associated First Person interview with the first author of the paper.

Potential utility of aldose reductase-deficient Schwann cells IKARS1 for the study of axonal degeneration and regeneration.

Potential utility of aldose reductase-deficient Schwann cells IKARS1 for the study of axonal degeneration and regeneration.

Рівень інсуліноподібного фактору росту-1 та гідроген сульфіду у щурів з неалкогольною жировою хворобою печінки, асоційованою з гіпергомоцистеїнемією

Introduction. Evolution of nonalcoholic fatty liver disease (NAFLD) is often accompanied by increased levels of homocysteine, on the other hand hyperhomocysteinemia (HHC) is considered as an independent factor for steatosis and fibrosis of the liver. An important role in regulating of liver functional state has IGF-1 and gas mediator – hydrogen sulfide (H2S), but their role in the pathogenesis NAFLD associated with HHC, is not certain.The aim of the study – to investigate level of insulin-like growth factor-1 (IGF-1) in blood and concentration of H2S in the liver of rats with NAFLD induced by high fat diet (HFD) and its combination with HHC.Methods of the research. The experiment was performed on 56 white male rats. Animals were divided into 4 groups. Group 1 and group 2 received standard diet, group 3 and group 4 received HFD for 60 days. Rats from groups 2 and 4 were injected іntragastrically daily by thiolakton homocysteine in the dose of 100 mg/kg. After experiment the levels of homocysteine and IGF-1 in serum and H2S content in the liver of rats were determined.Results and Discussion. Homocysteine thiolactone or HFD and especially their combination causes a reduction of IGF-1 in serum and H2S content in the liver of rats. Rats with NAFLD associated with HHC had levels of H2S and IGF-1 significantly lower (respectively 22.6 % and 32.2 %) than that of rats with purely NAFLD. The level of homocysteine is inversely correlated with the level of IGF-1 in blood and the level of H2S in the liver (r= -0.68, -0.73, р&lt;0.01). Formation of deficit аntifibrotic mediators (IGF-1 and H2S) may be a factor in the progression NAFLD associated with HHC.Conclusions. 60-day use of HFD or homocysteine thiolactone causes reduction of IGF-1 in serum and H2S content in the liver, but the most significant shortage of mediators is as result of the combination HFD with HHC.

Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction.

Growth deficits are common in cystic fibrosis (CF), but their cause is complex, with contributions from exocrine pancreatic insufficiency, pulmonary complications, gastrointestinal obstructions, and endocrine abnormalities. The CF mouse model displays similar growth impairment despite exocrine pancreatic function and in the absence of chronic pulmonary infection. The high incidence of intestinal obstruction in the CF mouse has been suggested to significantly contribute to the observed growth deficits. Previous studies by our group have shown that restoration of the cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium prevents intestinal obstruction but does not improve growth. In this study, we further investigate growth deficits in CF and gut-corrected CF mice by assessing insulin-like growth factor 1 (IGF-1). IGF-1 levels were significantly decreased in CF and gut-corrected CF adult mice compared to wildtype littermates and were highly correlated with weight. Interestingly, perinatal IGF-1 levels were not significantly different between CF and wildtype littermates, even though growth deficits in CF mice could be detected late in gestation. Since CFTR has been suggested to play a role in water and nutrient exchange in the placenta through its interaction with aquaporins, we analyzed placental aquaporin expression in late-gestation CF and control littermates. While significant differences were observed in Aquaporin 9 expression in CF placentas in late gestation, there was no evidence of placental fluid exchange differences between CF and control littermates. The results from this study indicate that decreased IGF-1 levels are highly correlated with growth in CF mice, independent of CF intestinal obstruction. However, the perinatal growth deficits that are observed in CF mice are not due to decreased IGF-1 levels or differences in placenta-mediated fluid exchange. Further investigation is necessary to understand the etiology of early growth deficits in CF, as growth has been shown to be a significant factor in disease outcomes.

Changes in Acid Labile Subunit (ALS) and Insulin-Like Growth Factor 1 (IGF-1) Concentration in Hyperthyroidism before and After Medical Treatment: A Prospective Controlled Study

Background:The relationship of altered thyroid status with GH and components of insulin-like Growth factor (IGF-1) axis is complex and not fully understood. We aimed to evaluate changes in Acid labile subunit (ALS) and IGF-1 in hyperthyroidism, before and after normalization of thyroid status. Methods:Thirty-four hyperthyroid patients matched with 36 normal controls were studied. The patients and controls were assessed at baseline and the patients were followed up prospectively and re-assessed after 6 months of treatment with antithyroid drug (ATD) (carbimazole). On each occasion, blood was collected for measurement of ALS, IGF-1, glucose, insulin, intact proinsulin and thyroid function. Results: Pre-treatment levels of ALS (p=0.012) and IGF-1 (p=0.007) were significantly lower in patients than controls. Five to 10 weeks post-treatment with ATD, all patients were restored to euthyroidism. ALS and IGF-1 levels increased significantly to similar levels of controls after 6 months of ATD. Within the patients, ALS (p=0.049) and IGF-1 (p=0.001) correlated inversely with free T3, whereas, only IGF-1 (p=0.005) correlated inversely with free T4. Conclusion:These results demonstrate that untreated hyperthyroidism is associated with reduction in ALS and IGF-1. Due to the fact that ALS and IGF-1 were related inversely with thyroid status and their concentrations were normalized with euthyroidism, it would be possible to consider their reductions as helpful markers of altered thyroid status, namely hyperthyroidism.