Insulin-like Growth Factor Research Articles

Circulating insulin-like growth factor-1 and the risk of multiple sclerosis: a prospective cohort study.

Circulating insulin-like growth factor 1 (IGF-1) is positively associated with the risks of certain neurological disorders, including stroke, Alzheimer's disease, and Parkinson's disease. However, the association of IGF-1 with the risk of multiple sclerosis (MS) remains unclear. A total of 348,324 participants at baseline were included from the UK biobank in this prospective study. The association of circulating IGF-1 level with MS was analyzed by Cox proportional hazard models. Further, subgroup analyses were conducted to investigate the variables influencing these associations. Among 348,324 individuals, lower circulating IGF-1 concentrations were associated with a reduced risk of MS (95 % CI, 0.5930-0.9700; P value = 0.02763). The association between lower IGF-1 levels and reduced risk of MS remains robust in older and female participants. Moreover, risk of MS appeared to be lower in IGF-1-low individuals who never smoked, currently drinking alcohol, with higher body mass index, and higher glucose concentrations. Our findings indicate that a lower concentration of serum IGF-1 was associated with a reduced risk of MS. The results provide evidence that the circulating IGF-1 may play a significant role in the pathogenesis of MS.

Hormonal symphony: The dynamic duo of IGF and EGF in gonadotropin-induced fish ovarian development and egg maturation.

Fish oocyte maturation (FOM) is a critical biological process that occurs before ovulation and is influenced by gonadotropins, particularly luteinizing hormone (LH). The release of LH stimulates the ovarian follicle to produce a maturation-inducing hormone (MIH), specifically 17α, 20β-dihydroxy-4-pregnen-3-one (17α, 20β-DP), which initiates the formation of maturation-promoting factor (MPF) through the activation of cyclin B and cdc2 kinase. Insulin-like growth factor I (IGF-I) significantly regulates ovarian functions, including steroidogenesis, by activating its membrane receptors and the tyrosine kinase pathway. IGF-I influences oocyte maturation directly via the PI3 kinase pathway, independent of steroid hormones. Additionally, epidermal growth factor (EGF) promotes cell growth and differentiation by binding to its receptor (EGFR). It is implicated in mediating human chorionic gonadotropin (hCG)-induced DNA synthesis in ovarian follicles while suppressing apoptosis. The presence of EGF in follicle cells and oocytes, along with its higher expression in oocytes, suggests it may act as a paracrine signal regulating somatic cell activity. Recent studies indicate that the activin system in follicle cells could be a target for EGF activity. The EGFR signaling pathway enhances gonadotropin-induced steroidogenesis and governs the transition of oocyte maturation stages, essential for successful fertilization. This review synthesizes current research on the roles of gonadotropins, IGFs, and EGFs in fish oocyte maturation and ovarian steroid production.

Biomimetic ECM nerve guidance conduit with dynamic 3D interconnected porous network and sustained IGF-1 delivery for enhanced peripheral nerve regeneration and immune modulation.

Recent advancements in tissue engineering have promoted the development of nerve guidance conduits (NGCs) that significantly enhance peripheral nerve injury treatment, improving outcomes and recovery rates. However, utilising tailored biomimetic three-dimensional (3D) topological porous structures combined with multiple bio-effect neurotrophic factors to create environments similar to neural tissues, regulate local immune responses, and develop a supportive microenvironment to promote peripheral nerve regeneration and repair poses significant challenges. Herein, a biomimetic extracellular matrix (ECM) NGC featuring an interconnected 3D porous network and sustained delivery of insulin-like growth factor-1 (IGF-1) is designed using multi-functional gelatine microcapsules (GMs). Nerve conduits made by blending chitosan (CS) with GMs demonstrate suitable degradation rates, reduced swelling rates, increased suture tensile strength, improved elongation at break, and 50% radial compression performance that meet clinical application requirements. In vitro cytological studies indicate that biomimetic ECM NGCs exhibit good biocompatibility, promote early survival, proliferation, and remyelination potential of Schwann cells (SCs), and support neurite outgrowth. The biomimetic ECM NGCs comprising a 3D interconnected porous network in a 10-mm sciatic nerve defect rat model sustain IGF-1 delivery, promoting early infiltration of macrophages and polarisation towards M2-type macrophages. Furthermore, observations at 12 weeks post-implantation revealed improvements in electrophysiological performance, alleviation of gastrocnemius muscle atrophy, increased peripheral nerve regeneration, and motor function restoration. Thus, biomimetic ECM NGCs offer a therapeutic strategy for peripheral nerve regeneration with promising clinical applications and transformation prospects to regulate immune microenvironments, promoting SC proliferation and differentiation with nerve axon growth.

Comparison of growth hormone therapy response according to the presence of growth hormone deficiency in children born small for gestational age with short stature in Korea: a retrospective cohort study

BackgroundThis study aimed to compare the response to growth hormone (GH) therapy according to the presence of GH deficiency (GHD) in short-stature children born small for gestational age (SGA) in Korea and to present appropriate GH dose criteria.MethodsWe evaluated 27 children born SGA with short stature and GHD (GHD group) and 23 without GHD (non-GHD group) registered in the LG Growth Study. Growth responses and changes in GH dose over a 2-year GH therapy period were compared, and the factors affecting growth response were investigated.ResultsThe standard deviation scores (SDSs) for baseline weight and body mass index (BMI) were significantly lower in boys without GHD than in boys with GHD. The SDS for insulin-like growth factor-1 (IGF-1) was lower among boys without GHD than among boys with GHD, while the SDS for insulin-like growth factor-binding protein-3 (IGFBP-3) was higher among girls without GHD than among girls with GHD; however, there was no significant difference when comparing all children with GHD to those without GHD. Regardless of the presence of GHD, the difference between chronological age and bone age decreased annually. Notably, there was significantly rapid bone age progression among patients without GHD. The findings showed differences in GH dose according to GHD starting from the 2nd year of therapy, with the non-GHD group receiving a significantly higher dose. Regarding the factors affecting growth response, younger age and bone age, higher height SDS, BMI SDS and MPH SDS were related to higher growth response (Δheight SDS and Δgrowth velocity), but there was no statistically significant correlation.ConclusionGHD is rare among children born SGA. Nonetheless, if there are any signs of decreased growth velocity or hypopituitarism, the presence of GHD should be assessed before GH therapy, and personalized therapy based on the results is required.

543 Post-translational regulation of la ribonucleoprotein domain family member 6 by insulin-like growth factor-1 modulates collagen synthesis in smooth muscle cells

543 Post-translational regulation of la ribonucleoprotein domain family member 6 by insulin-like growth factor-1 modulates collagen synthesis in smooth muscle cells

Abstract TP337: Blocking insulin-like growth factor 1 receptor in the gut abrogates IGF-1 mediated long-term neuroprotection in middle-aged female rats

Background and Purpose: Our previous studies in a rat model of ischemic stroke identified that intraperitoneal (IP), but not intracerebroventricular (ICV) administration of IGF-1 reduced stroke-induced gut leakiness and peripheral inflammation in the acute phase and attenuated stroke-induced impairment in acyclic middle-aged female rats. These data suggest that the gut may be implicated in IGF-1-mediated effects on stroke-induced cognitive impairment. To directly assess whether the effect of IGF-1 on behavioral improvement is mediated by the gut, study utilized a novel tet-inducible rAAV construct to block IGF1R specifically in the gut. Methods: Female Sprague Dawley rats (9-11 mo) were intragastrically gavaged with either recombinant rAAV construct containing IGFR-shRNA (IGFR-sh) downstream of the IESC promoter Lgr5 in a Tet-inducible system or rAAV-empty vector (Scr-sh) 4 weeks prior to experimental ischemia. Animals were subjected to endothelin-1 induced MCAo. Doxycycline was administered 4h later and IGF-1 was given ip at 4 and 24 h post-stroke. Sensorimotor function as well as peripheral inflammation (in serum samples) was assessed at 5d post-stroke and long-term cognitive impairment was evaluated after 60 days. Results: The mCherry reporter in the rAAV construct was observed in the intestinal crypt, indicating appropriate delivery of the construct. Sensorimotor function evaluated by vibrissae evoked forelimb placement task was significantly impaired in the ipsilateral paw after stroke in IGFR-Sh+IGF-1 compared to Scr-sh+IGF-1(p<0.005). IL-17 levels in serum were significantly elevated in the animals with IGFR-Sh+IGF1 compared to Scr_sh+IGF1 (p<0.004). Cognitive impairment assessed by Barnes maze showed no differences in spatial learning but revealed significant impairment in spatial recall in IGFR-sh+IGF1 group compared to SCR-sh+IGF1 animals (p<0.02). Conclusions: The present findings indicate that the beneficial effects of IGF-1 on long-term stroke recovery may be partially mediated by its effects on the gut and implicate the inflammatory cytokine IL-17a as a modifier of stroke-induced cognitive impairment. Supported by RF1NS119872 to FS and SB

Expanded biomarker analysis of an international, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

635 Background: The optimal treatment for patients (pts) with advanced HCC who progress on an ICI-containing regimen has not been defined. In pts who progressed on one prior ICI regimen, regorafenib plus pembrolizumab (rego + pembro) showed modest anti-tumor activity (primary completion analysis: overall objective response rate 7.4%, all partial responses [PR]) and an expected safety profile (NCT04696055; El-Khoueiry, ASCO 2024). We conducted additional exploratory analyses of tumor markers to gain insights into the clinical results. Methods: Overall, 95 adults with unresectable advanced HCC (C-P Class A, BCLC stage B/C, ECOG PS 0/1) received oral regorafenib 90 mg once daily 3 weeks on/1 week off plus pembrolizumab 400 mg i.v. every 6 weeks. Prior treatment: Cohort 1 = atezolizumab + bevacizumab (n=68); Cohort 2 = any other ICI alone or in combination (n=27). Biomarker analyses in subsets of pts explored potential correlations with clinical benefit (defined as tumor response or stable disease [SD] ≥ 4 months). Immune cell subtypes in blood were analyzed by flow cytometry. Tumor immune markers were assessed by immunohistochemistry. Gene expression profiling in tumor samples was by RNAseq. Results: Twenty-one pts had baseline samples for RNAseq, 7 of whom had clinical benefit (n= 3 Cohort 1 [including 1 PR], n=4 Cohort 2). Pts with clinical benefit had differential gene expression at baseline including enriched expression of genes associated with Notch, Hedgehog, fibroblast, TGF-β, and insulin-like growth factor binding protein signaling; in contrast, there was higher expression of genes associated with myeloid derived suppressor cells in pts without clinical benefit. Of note, tumor samples from pts in this study had increased Tregs and T-cell exhaustion signatures compared with pts treated with rego + pembro in a first-line study (NCT03347292).Analyses of available paired tumor samples from 4 patients (n=2 SD, n=2 progressive disease) found reductions in activated fibroblast, TGF-β, and collagen gene expression signatures from baseline to Week 6 Day 1 of treatment. Conclusions: Rego + pembro had modest activity in pts who progressed on one prior ICI-based regimen. Exploratory biomarker analyses suggest different gene expression in pts with or without clinical benefit. Clinical benefit was associated with enriched expression of genes in Notch, Hedgehog, fibroblast, and TGF-β pathways. Pre- and post-treatment biopsies showed reductions in fibroblast, TGF-β, and collagen gene expression, which are known features of HCC. In the context of the limitations of small sample size and absence of a control arm, these findings are hypothesis generating and consistent with HCC biology and regorafenib mechanism of action. Clinical trial information: NCT04696055 .

IGF2BP3 is upregulated in endometrial cancer and tightly regulates the growth of drug-resistant endometrial cancer cells via HMGA1.

Endometrial cancer (EC) is a malignant tumor with various histological subtypes and molecular phenotypes. The evaluation of drug resistance is important for cancer treatment. Progesterone resistance is the major challenge in EC. Knowledge of drug resistance in EC is important in the development of novel therapies. In this study, ten paracancerous and ten tumor tissues were collected to measure the expression of insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and high-mobility group protein 1 (HMGA1). AN3CA and Ishikawa cells were used to explore the effects of IGF2BP3 on EC. The expression levels of IGF2BP3 and HMGA1 were higher in EC tumor tissues than in paracancerous tissues. IGF2BP3 and HMGA1 are highly expressed in cisplatin-resistant EC cells. IGF2BP3 knockdown decreased the growth of cisplatin-resistant EC cells. Knockdown of IGF2BP3 decreased the level of HMGA1 protein. HMGA1 knockdown decreased the growth of cisplatin-resistant EC cells. The findings demonstrate that IGF2BP3 is upregulated in EC and closely regulates the growth of drug-resistant EC cells via HMGA1. The findings will inform the development of novel therapies for EC.

RBM47 as a potential therapeutic target for thyroid-associated ophthalmopathy.

RNA-binding motif 47 (RBM47) is a recently identified RNA-binding protein involved in early vertebrate development, immune homeostasis, and cancer development. This study examined the biological functions of RBM47 in thyroid-associated ophthalmopathy (TAO). Orbital fibroblasts (OFs) were obtained from the control (n=6) and TAO groups (n=6). Protein and gene expression in the obtained samples were investigated using immunohistochemistry, western blotting (WB), and RT-PCR. OFs with RBM47 knockdown were established using small interfering RNA. Subsequently, Oil Red O staining, WB, and RT-PCR were performed to assess adipogenesis in the OFs. The IL-1β-induced expression of proinflammatory molecules and hyaluronan (HA) was determined using enzyme-linked immunosorbent assay and RT-PCR. Moreover, TGF-β-induced fibrosis was evaluated using scratch assays, RT-PCR, and WB. RBM47 expression was markedly increased in orbital tissues and OFs obtained from individuals with TAO. RBM47 knockdown decreased adipogenesis and fibrosis in OFs, and downregulated the levels of insulin-like growth factor 1 receptor (IGF-1R), proinflammatory molecules, and HA. Furthermore, low RBM47 expression downregulated IGF-1R, which subsequently inhibited adipocyte differentiation by decreasing extracellular signal-regulated kinase signalling. These findings indicate that RBM47 may be involved in the regulation of adipogenesis, inflammation, HA production, and fibrosis, highlighting its potential of RBM47 as a therapeutic target for TAO.

IGF2BP3 curbed by miR-15c-3p restores disrupted lipid storage and progesterone secretion in chicken granulosa cells under oxidative stress through AKT-Raf1-ERK1/2 signaling pathway.

For commercial laying hens, the continuous high-intensity ovulation process leads to a significant accumulation of reactive oxygen species (ROS) in the granulosa cells, inducing oxidative stress, which accelerates ovarian aging and shortens the peak laying period. The molecular mechanisms underlying this process remain poorly understood. Therefore, we modeled the processes of oxidative stress and antioxidant in chicken granulosa cells. Small RNA sequencing revealed that miR-15c-3p expression was elevated by oxidative stress induction and attenuated by antioxidant curcumin. Functional validation with miR-15c-3p mimic and inhibitor confirmed the role of miR-15c-3p in exacerbating oxidative stress and resultant suppression of lipid droplet storage and progesterone secretion in chicken granulosa cells by targeting insulin-like growth factor 2 binding protein 3 (IGF2BP3). These regulatory effects were mediated through the sequential downstream signaling cascade of AKT-Raf1-ERK1/2. In conclusion, IGF2BP3 curbed by miR-15c-3p restores disrupted lipid storage and progesterone secretion in chicken granulosa cells under oxidative stress through AKT-Raf1-ERK1/2 signaling pathway. These findings offer new insights into the molecular mechanisms by which oxidative stress damages reproductive capacity and a theoretical basis for mitigating oxidative stress in laying hens through genetic improvement.

Iron Chelation Prevents Age-Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging.

A decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age-related sarcopenia in mice. We investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (kl/kl), an established mouse model for aging. Four weeks old Klotho -/- male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8-14 weeks (n = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods. Treatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (p < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both p < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (p = 0.019) and serum (p = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, p = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (p < 0.0001, p = 0.005), respectively, and elevated insulin-like growth factor levels (p = 0.472). This was associated with reduced DNA damage and reduced 8-hydroxy 2 deoxyguanosine in muscle and HO-1 protein (p < 0.001, p = 079), respectively. Significant weight loss (p < 0.001) and decreased water intake (p = 0.012) were observed in untreated mice compared to treatment group. Kaplan-Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (p = 0.0002). In summary, our research findings indicate that deferiprone reduced age-related sarcopenia in the muscles of Klotho-/- mice. Our finding suggests chelation of excess iron could be an effective therapy to counter sarcopenia. However, additional studies are needed to evaluate and determine the efficacy in humans.

Association of ultra-processed food-related metabolites with selected biochemical markers in the UK Biobank

BackgroundUltra-processed food (UPF) intake is positively associated with multiple adverse health outcomes. However, the underlying biological mechanisms remain unclear. Serum metabolites may elucidate these mechanisms. We investigated serum metabolites correlated with UPF and un/minimally processed food (UNPF) intake and evaluated their association with selected biochemical markers.MethodsCross-sectional study within the UK biobank, including a total of 72,817 participants with 24-hour recall dietary data and 134 nuclear magnetic resonance metabolites. UPF and UNPF intakes were evaluated using the NOVA classification, and related metabolites were identified using elastic net penalized regression. A UPF metabolomic signature was computed as a weighted sum of UPF-related metabolites, using elastic net coefficients as weights. Associations between UPF and UNPF-related metabolites, and serum C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), sex hormone-binding globulin (SHBG), and testosterone were examined using multiple quantile regression.ResultsElastic net model identified 17 and 15 metabolites uniquely related to UPF and UNPF intake, respectively. Acetoacetate, acetone, high-density lipoprotein (HDL) diameter, docosahexaenoic acid, linoleic acid, ω-3 fatty acids (FA), total lipids in large HDL cholesterol, and valine levels were decreased, but free cholesterol in extremely small very low-density lipoproteins (LDL), glutamine, glycine, glycoprotein acetyls, lactate, saturated FA, sphingomyelins, triglycerides in large LDL, and triglycerides in medium HDL levels were increased with high UPF intake. Opposite relationships were observed for UNPF intake. Heterogeneous associations were observed between UPF-related metabolites and CRP, IGF-1, SHBG, and testosterone levels. A UPF metabolomic signature was positively associated with CRP (regression coefficient per standard deviation, 1.45, 95% confidence interval, 1.385, 1.515) and negatively associated with IGF-1 (-3.16, -4.493, -1.827) and SHBG (-13.878, -15.291, -12.465).ConclusionA UPF metabolomic profile, including VLDL free cholesterol, saturated FA, triglycerides, glutamine, glycine, and glycoprotein acetyl was associated with inflammatory, insulin signalling, and reproductive biomarkers. This metabolomic profile should be explored as a potential mediators of UPF-disease associations, and as an objective marker of UPF intake.

The differential diagnosis of adrenocortical tumors: systematic review of Ki-67 and IGF2 and meta-analysis of Ki-67.

Distinguishing benign from malignant adrenocortical tumors (ACT) is not always easy, particularly for tumors with unclear malignant potential based on the histopathological features comprised of the Weiss score. Previous studies reported the potential utility of immunohistochemistry (IHC) markers to recognize malignancy, in particular the Insulin-like growth factor 2 (IGF2) and the proliferation marker, Ki-67. However, this information was not compiled before. Therefore, this review aimed to collect the evidence on the potential diagnosis utility of IGF2 and Ki-67 IHC staining. Additionally, a meta-analysis was performed to assess the Ki-67 accuracy to identify adrenocortical carcinoma. The systematic review and meta-analysis were conducted according to the PRISMA guidelines. From the 26 articles included in the systematic review, 21 articles provided individual data for IGF2 (n = 2) or for Ki-67 (n = 19), while 5 studies assessed both markers. IGF2 staining was positive in most carcinomas, in contrast to adenomas. However, the different immunostaining evaluation methods adopted among the studies impeded to perform a meta-analysis to assess IGF2 diagnostic accuracy. In contrast, for the most commonly used cut-off value of 5% stained cells, Ki-67 showed pooled specificity, sensitivity and log diagnostic odds ratio of 0.98 (95% CI 0.95 to 0.99), 0.82 (95% CI 0.65 to 0.92) and 4.26 (95% CI 3.40 to 5.12), respectively. At the 5% cut-off, Ki-67 demonstrated an excellent specificity to recognize malignant ACT. However. the moderate sensitivity observed indicates the need for further studies exploring alternative threshold values. Additionally, more studies using similar approaches are needed to assess the diagnostic accuracy of IGF2.Registration code in PROSPERO: CRD42022370389.

Uncovering the intricacies of IGF-1 in Alzheimer's disease: new insights from regulation to therapeutic targeting.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and tau tangles, leading to cognitive decline and dementia. Insulin-like Growth Factor-1 (IGF-1) is similar in structure to insulin and is crucial for cell growth, differentiation, and regulating oxidative stress, synaptic plasticity, and mitochondrial function. IGF-1 exerts its physiological effects by binding to the IGF-1 receptor (IGF-1R) and activating PI3K/Akt pathway. In addition to the physiological activities in the brain, numerous studies point to a potential protective role of the IGF-1 pathway in the pathogenesis of neurodegenerative diseases, such as AD. Interestingly, patients with AD often exhibit altered insulin and IGF-1 levels, along with an inadequate insulin response. Dysregulation of IGF-1 signaling contributes to hyperphosphorylation of tau, NFT accumulation, increased β- and γ-secretase activity, elevated Aβ production, and impaired Aβ clearance, highlighting the need to explore the role of this signaling for potential therapeutic targets of AD. This review explores the role of IGF signaling in AD pathology, highlighting IGF-1 as a promising therapeutic target due to its significant involvement in disease mechanisms. Modulating IGF-1 activity could help mitigate neurodegeneration and preserve cognitive function in AD. A comprehensive understanding of the mechanisms underlying IGF-1 dysregulation is crucial for developing targeted therapeutic strategies to address the complex and multifaceted nature of AD.

Differences in VEGF (Vascular Endothelial Growth Factor) Levels AND IGF-1 (Insulin like Growth Factor-1) in Controlled and Uncontrolled Diabetes Mellites TIP 2 Patients at Puskesmas Padang Bulan Medan City

Diabetes mellitus is a metabolic disorder characterized by an increase in blood sugar due to decreased insulin secretion by pancreatic beta cells or impaired insulin function (insulin resistance) that can lead to microvascular and macrovascular complications. The results of previous studies state that plasma levels of VEGF and IGF-1 are associated with the incidence of diabetic retinopathy and diabetic nephropathy. The examinations carried out include HbA1C using the HPLC method, measurement of VEGF and IGF-1 levels using Bioassay Technology Laboratory ELISA Human IGF-1 and VEGF. Of the 52 patients examined, it was found that 10 type 2 DM were controlled and 42 type 2 DM were uncontrolled. Uncontrolled type 2 DM had a higher VEGF level of 409 (ng/ml) than controlled 391.8 (ng/ml). IGF-1 levels of uncontrolled type 2 DM were higher at 8.8 (ng/ml) than controlled 6.6 (ng/ml). The conclusion obtained from this study is that there is no significant difference in VEGF and IGF-1 levels in controlled and uncontrolled type 2 DM. Controlled type 2 DM VEGF levels are lower than uncontrolled, while controlled IGF-1 levels are lower than uncontrolled. There was no significant difference in IGF- 1 levels with obese and non-obese patients based on Body Mass Index (BMI). IGF-1 levels of obese type 2 DM are lower than those who are not obese.

Unlocking the full potential of resistance training: a comparative analysis of low- and high-intensity effects on neurotrophic growth factors and homocysteine

ObjectiveResistance training has been demonstrated an effective approach for preventing the cognitive function decline through physiological mechanisms; however, the effect of acute resistance training at different intensities on growth factor and homocysteine levels remains unclear. This study aimed to compare the impact of resistance training at varying intensities on peripheral neurobiological factors and homocysteine levels in young adults.MethodsTwelve young male adults, predominantly engaged in various sports activities but without prior strength training experience, were recruited to participate in a randomized controlled cross-over trial. They implemented two different resistance training protocols: high intensity (HIRT, 12 repetitions at 80% 1RM) and low intensity (LIRT, 24 repetitions at 40% 1RM). Blood samples were collected at three time points: pre-training, post training, and after 30 min of rest to measure changes in serum lactate, serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), irisin, and plasma homocysteine (Hcy) levels.ResultsBoth resistance training protocols significantly increased blood lactate and perceived exertion compared to pre-training (HIRT, p < 0.01; LIRT, p < 0.01), with higher levels observed in HIRT. Acute HIRT significantly elevated serum BDNF, IGF-1, and VEGF levels post training compared to LIRT (p < 0.05), while no difference was observed in irisin levels between the two protocols at any time point. Both training protocols significantly reduced plasma Hcy levels post training (p < 0.01) and maintained lower levels than pre-training and after 30 min of rest (p < 0.05), with no significant differences between the two protocols.ConclusionsThis study demonstrates that high intensity training appears to have a greater impact on specific neurobiological factors; however, regardless of intensity, resistance training can significantly decrease plasma homocysteine.Trial registration ClinicalTrials.gov ID: NCT06114550. Date of registration 01/30/2024. https://clinicaltrials.gov/study/NCT06114550.

Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy that necessitates the identification of novel therapeutic strategies. Here, we report that intracellular levels of very long chain fatty acids (VLCFAs) control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced cell death in MM cells caused by the proteasome inhibitor, bortezomib. Conversely, inhibition of VLCFA degradation via suppression of peroxisomal acyl-CoA oxidase 1 (ACOX1) increased the cytotoxicity of bortezomib, its next-generation analog, carfilzomib, and the immunomodulatory agent lenalidomide. Furthermore, treatment with an orally available ACOX1 inhibitor cooperated with bortezomib in suppressing the growth of bortezomib-resistant MM xenografts in mice. Increased VLCFA levels caused by genetic or pharmacological inhibition of VLCFA degradation reduced the activity of two major kinases involved in MM pathogenesis, MET proto-oncogene (MET) and insulin-like growth factor 1 receptor (IGF1R). Mechanistically, inhibition of ACOX1 promoted the accumulation of VLCFA-containing cerebrosides, altered MET and IGF1R interaction with a cerebroside analog, and selectively inhibited the association of these kinases with the plasma membrane signaling platforms, importantly, without disrupting the platforms' integrity. Our study revealed a specific metabolic vulnerability of MM cells and identified a targetable axis linking VLCFA metabolism to the regulation of MET and IGF1R activity.

Gonadal miRNomes and transcriptomes in infected fish reveal sexually dimorphic patterns of the immune response.

Fish disease outbreaks caused by bacterial burdens are responsible for decreasing productivity in aquaculture. Unraveling the molecular mechanisms activated in the gonads after infections is pivotal for enhancing husbandry techniques in fish farms, ensuring disease management, and selecting the most resilience phenotype. The present study, with an important commercial species the European sea bass (Dicentrarchus labrax), an important commercial species in Europe, examined changes in the miRNome and transcriptome 48h after an intraperitoneal infection with Vibrio anguillarum. The findings indicate that following infection, testes exhibited more pronounced alterations in both the miRNome and transcriptome. Specifically, males showed approximately 26% more differentially expressed genes in testicular genes compared to females (2,624 vs. 101 DEGs). Additionally, four miRNAs (miR-183-5p, miR-191-3p, miR-451-5p, and miR-724-5p) were significantly expressed post-infection in males, while none were identified in females. Interestingly, upon deep analysis of sexual dimorphic gene modules, a larger number of miRNAs were identified in infected females targeting genes related to the immune system compared to infected males. These results suggest that fish ovaries demonstrate greater resilience in response to infections by suppressing genes related to the immune system through a post-transcriptional mechanism performed by miRNAs. In contrast, testes activate genes related to the immune system and repress genes related to cellular processes to cope with the infection. In particular, the crosstalk between the miRNome and transcriptome in infected males revealed a pivotal gene, namely, insulin-like growth factor binding protein (igfbp), acting as a gene network hub in which miR-192-3p was connected. The current study elucidated the need to comprehend the basic immune regulatory responses associated with miRNAs and gene regulation networks that depend on fish sex. The data reveal the importance of considering sex as a factor in interpreting the immune system in fish to generate efficient protocols to prevent outbreaks in fish farms.

Breed and trace mineral source influence the performance of beef heifers during periods of nutrient restriction and grazing forage at early vegetative stage.

We evaluated the effects of breed and mineral source on heifer performance during periods of nutrient restriction and grazing. On day -7, ½ Angus × ½ Nelore (ANE) and Nelore (NE) heifers (12 heifers per breed; body weight, BW = 264 ± 35kg; age = 15 ± 1 mo) were assigned to individual drylot pens to receive ad libitum Tifton 85 (Cynodon sp.) hay and white salt for 7 days. On day 0, within each breed, heifers were randomly assigned (2 × 2 factorial arrangement) to receive protein supplementation (0.20% of BW; dry matter, DM) added with sulfate (SUL) or hydroxychloride (HYD) sources of Cu, Mn, and Zn from day 0 to 49. From day 0 to 34, hay DM intake was restricted to 50% of the ad libitum intake recorded from day -7 to -1. On day 35, heifers were transferred to individual pastures to graze Tifton 85 forage at early vegetative stage until day 49. No effects of breed × mineral source × day and breed × mineral source were detected (P ≥ 0.11). Nelore heifers had greater (P ≤ 0.02) average daily gain (ADG) from day 0 to 35 and day 0 to 49 compared to ANE heifers. Cumulative diarrhea incidence, fecal pH and total days of diarrhea symptoms did not differ (P ≥ 0.19) between breeds. Nelore heifers had greater (P ≤ 0.05) serum concentrations of insulin-like growth factor 1 (IGF-1) from day 35 to 45 but had less (P ≤ 0.05) serum concentrations of cortisol and haptoglobin on day 42 and 45, respectively. Serum concentrations of urea N were greater (P ≤ 0.05) for NE vs. ANE heifers on days 0 and 42 and were less (P ≤ 0.05) for NE vs. ANE on days 38, 45 and 49. Heifers supplemented with HYD had (P ≤ 0.05) greater ADG from day 0 to 35, lower cumulative diarrhea incidence and percentage of heifers exhibiting ≥ 2 days of diarrhea from day 36 to 49, less serum concentrations of non-esterified fatty acids (NEFA) on day 35, and less serum concentrations of NEFA, cortisol and urea N on day 38 compared to SUL heifers. In summary, breed influenced serum concentrations of haptoglobin, cortisol, urea N, insulin and IGF-1, and the growth of beef heifers during nutrient restriction, but did not impact growth and incidence of diarrhea during periods of grazing forage at early vegetative stage. Regardless of breed, replacing sulfate with hydroxychloride sources of Cu, Mn, and Zn led to minimal reductions on serum concentrations of NEFA, cortisol and urea N, enhanced growth during nutrient restriction, and reduced diarrhea incidence during grazing of early vegetative forage.

Nanoparticle encapsulation enables systemic IGF-Trap delivery to inhibit intra-cerebral glioma growth.

Glioblastoma is an aggressive brain cancer with a 5-year survival rate of 5-10%. Current therapeutic options are limited, due in part to drug exclusion by the blood-brain barrier, restricting access of targeted drugs to the tumor. The receptor for the type 1 insulin-like growth factor (IGF-1R) was identified as a therapeutic target in glioblastoma. We previously reported that the intracerebral growth of glioma cells with reduced IGF-1R levels was inhibited. The objectives of this study were to evaluate the sensitivity of glioma cells to a novel IGF-axis inhibitor, the IGF-Trap, and optimize its delivery to the brain. We tested the effect of the IGF-Trap on the growth of the human glioma stem cells MES-1123 and U87 MG cells, and of murine GL261 cells in vivo, using subcutaneous and orthotopic implantation. We show that the growth of glioma cells implanted subcutaneously or orthotopically in the brain was inhibited by systemic and direct intracerebral administration of IGF-Trap, respectively, resulting in increased survival. To increase the efficiency of systemic delivery to the brain, we encapsulated the IGF-Trap in trimethyl chitosan (TRIOZAN™) nanoparticles prior to intravenous injection. We found that nanoparticle encapsulation increased the uptake and retention of the IGF-Trap in the brain and resulted in an improved therapeutic effect against intra-cerebrally growing tumors. Our results identify the IGF-Trap as a potent inhibitor of intracerebral glioma growth and show that encapsulation in nanoparticles can improve delivery of biologics such as the IGF-Trap to the brain, thereby enhancing the therapeutic response.