Growth Factors IGF-I Research Articles

ANGIOGENIC FACTORS AS PREDICTORS OF SURVIVAL IN PATIENTS WITH BONE SARCOMAS

Introduction. Primary bone sarcomas are relatively rare neoplasms. They occur predominantly in adolescents and young adults, are characterized by an aggressive clinical course and a high metastatic potential, have a poor prognosis. In this regard, the problem of stratifying the risk of metastasis and death in order to select the optimal treatment tactics always remains relevant. The study of such markers as endostatin, vascular endothelial growth factor (VEGF), insulin-like growth factors IGF-1, IGF-2 as potentially informative predictors of survival in patients with bone sarcomas is pathogenetically determined by their involvement in the processes of tumor growth and metastasis. Aim – to analyze the relationship between pre-treatment serum levels of endostatin, VEGF, IGF-1 and IGF-2 with overall survival rates in patients with bone sarcomas. Material and methods. An analysis of overall survival rates was carried out in 134 patients with malignant bone tumors aged from 1 to 73 years (Me=27.0 years; Q1–Q3: 18.0 – 43.0 years), among them 87 men (64.9%) and 47 women (35.1%). All patients comprised 4 groups: osteosarcoma (n=58), undifferentiated pleomorphic sarcoma (n=5), Ewing sarcoma (n=29), chondrosarcoma (n=42). In all of them, before the start of specific antitumor treatment, the levels of endostatin, VEGF, IGF-1, and IGF-2 in the blood serum were determined using enzyme immunoassay. The follow-up period ranged from 1 to 229 months (Me=23.0 months; Q1–Q3: 10.0–121.0 months). To analyze overall survival, life tables and Kaplan–Meier curves were constructed. The effect of the studied serum markers on survival rates was assessed using the logrank test and Cox proportional hazards regression model. Results. During observation, death occurred in 51 patients (38.1%). In the group of deceased patients, serum levels of endostatin and IGF-2 were statistically significantly increased compared to the group of surviving patients (p 0.001 and p=0.011, respectively). Kaplan-Meier survival analysis using the logrank test revealed statistically significant differences in overall survival between the four groups of patients with different serum levels of endostatin, IGF-1 and IGF-2. The Cox regression method established the prognostic significance of endostatin as a predictor of overall survival (HR=1.012; p=0.013). Conclusion. Endostatin, IGF-1, IGF-2 can serve as predictors of overall survival of patients with bone sarcomas.

Endometrial Dysbiosis: A Possible Association with Estrobolome Alteration

Background/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women’s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including β-glucuronidase, thereby enhancing estrogen-related inflammatory states and decreasing anti-inflammatory cells. The possible connection between estrobolome impairment and gynecological diseases has been suggested in animal models. Nevertheless, in humans, coherent evidence on the estrobolome alteration and functionality of the female reproductive tract is still lacking. The objective of this study was to explore alterations in estrogen-related signaling and the putative link with endometrial dysbiosis. Methods: Women with infertility and repeated implantation failure (RIF, N = 40) were enrolled in order to explore the putative link between estrogen metabolism and endometrial dysbiosis. Endometrial biopsies were used to measure inflammatory and growth factor molecules. β-glucuronidase enzyme activity and estrogen receptor (ER) expression were also assessed. Results: Herein, increased levels of inflammatory molecules (i.e., IL-1β and HIF-1α) and decreased levels of the growth factor IGF-1 were found in the endometrial biopsies of patients presenting dysbiosis compared to eubiotic ones. β-glucuronidase activity and the expression of ERβ were significantly enhanced in patients in the dysbiosis group. Interestingly, Lactobacilli abundance was inversely related to β-glucuronidase activity and to ERβ expression, thus suggesting that an alteration of the estrogen-activating enzyme may affect the expression of ERs as well. Conclusions. Overall, these preliminary data suggested a link between endometrial dysbiosis and estrobolome impairment as possible synergistic contributing factors to women infertility and RIF.

Specific cleavage of IGFBP-4 by papp-a in nervous tissue

Astrocytes are subtypes of glial cells involved in metabolic, structural, homeostatic, and neuroprotective processes that help neurons maintain viability. Insulin-like growth factors IGF-1 and IGF-2 are known to have neuroprotective effects on neurons and glial cells through interaction with specific receptors. IGF forms a complex with IGF-binding proteins (IGFBP) in nervous tissue and is released from the complex via IGFBP proteolysis by specific proteases. It has been reported that IGFBP-2, 5 and 6 are cleaved by specific proteases in the central nervous system (CNS), followed by IGF release; however, it was unknown whether IGFBP-4 was exposed to a particular proteolysis in nervous tissue. Using neurons and astrocytes derived from human induced pluripotent stem cell lines (hiPSC), as well as rat brain-sourced primary neuron-glia cultures, we demonstrated that IGFBP-4 is specifically cleaved in nervous tissue by the Pregnancy Associated Plasma Protein A (PAPP-A) protease and that this cleavage is IGF-dependent. Our results indicate that astrocyte rather than neuron PAPP-A cleaves IGFBP-4 in nervous tissue suggesting that this may be one of the fundamental mechanisms for IGF interchange between these two types of cells.

Dynamic changes in insulin-like growth factor binding protein expression occur between embryonic and early post-hatch development in broiler chickens

Somatotropic gene expression has been altered by genetic selection, and developmental changes in insulin-like growth factor (IGF) and IGF binding protein (IGFBP) expression may contribute to rapid growth and muscle accretion in commercial broilers. The objective of this study was to evaluate changes in somatotropic axis activity between embryonic day (e) 12 and post-hatch day (d) 21. Liver and breast muscle (pectoralis major) were collected to measure gene expression, and blood was collected post-hatch to measure circulating IGFs. Liver IGF1 rose rapidly post-hatch and, in muscle, IGF1 exhibited a dynamic expression pattern. Levels decreased from e14 to e20, returned to e14 levels at d3, decreased again at d10, and stayed low thereafter. In both tissues, mRNA levels of several IGFBPs changed between embryogenesis and post-hatch. Liver IGFBP2 increased between e12 and e20, returned to e12 levels on d1, and remained low. Conversely, liver IGFBP4 expression was greater post-hatch than during embryogenesis. Expression of select IGFBPs was depressed in liver during the peri-hatch period. Liver IGFBP1, IGFBP3, IGFBP5, and IGFBP7 mRNA levels all decreased around this time and returned to embryonic levels by d3. In breast muscle, expression of both IGFBP2 and IGFBP4 was reduced after hatch. Circulating insulin-like growth factor IGF1 and IGF2 levels did not change between hatch and d21. These data suggest that post-hatch IGF effects are likely modulated by target tissue IGFR1 and IGFBP expression rather than changes in circulating hormone levels, with promotion or restriction of IGF-receptor binding regulating growth. Downregulation of several IGFBPs synthesized in the liver may facilitate the metabolic transition from utilizing yolk lipids to dietary carbohydrates. Several IGFBPs produced in breast muscle appear to have growth-promotive effects during embryogenesis but restrict growth of this tissue after hatch, as their post-hatch downregulation could facilitate local IGF signaling. These developmental gene expression patterns suggest that somatotropic hormonal signaling regulating growth and muscle accretion might be controlled through differential actions of IGFBPs and provide a basis for future functional studies.

MPs and PFOS single and combined exposure significantly alter genetic expressions of growth hormone and insulin growth factor-related biomarkers during zebrafish embryonic development

Microplastics (MPs) and perfluorooctane sulfonate (PFOS) are emerging pollutants that are ubiquitously present in the environment and can cause series of ecotoxicological effects on aquatic animals. This study examined how the expression of genes related to insulin growth factor (igf1, igf2a, igf2b, igfra, and igfrb) and growth hormone (ghrh, gh1, ghra, and ghrb) changes during the development of zebrafish embryos exposed to 8 μm polyethylene microplastics (PE-MPs) and perfluorooctane sulfonate (PFOS) individually and in combination for 72 h. Our findings revealed that both low-concentrations of MP (50 μg/L) and PFOS (0.02 μg/L) treatments could significantly activate gene expression within a short period. High concentrations of MPs (500 μg/L) and PFOS (0.1 μg/L) not only rapidly activated gene expression but also sustained high expression levels for a longer duration. During combined exposures, peak gene expression in the low concentration groups (50 μg/L MPs and 0.02 μg/L PFOS; 50 μg/L MPs and 0.1 μg/L PFOS) primarily occurred within 12 h after treatment. In the high concentration groups (500 μg/L MPs and 0.02 μg/L PFOS), peak expression was also observed within 12 h. Notably, the combined exposure groups exhibited more pronounced effects on gene expression than the individual exposure groups. The activation of gene expression was both more significant and longer-lasting in the combined exposure, indicating a synergistic regulatory effect of MPs and PFOS. Overall, our study suggests that zebrafish embryo development can be significantly impacted by exposure to MPs, PFOS, and their combination, with combined exposures having a more lasting and profound effect on gene regulation compared to single exposures.

Two pathways regulate insulin-like growth factor genes in the brain and liver of the tropical damselfish Chrysiptera cyanea: A possible role for melatonin in the actions of growth and thyroid hormones

External and internal factors are involved in controlling the growth of fishes. However, little is known about the mechanisms by which external factors trigger stimulus signals. This study explored the physiological roles of melatonin in the transcription of growth-related genes in the brain and liver of Chrysiptera cyanea, a tropical damselfish with long-day preference. In brain samples of this species collected at 4-h intervals, the transcript levels of arylalkylamine N-acetyltransferase2 (aanat2), the rate-limiting enzyme of melatonin synthesis, and growth hormone (gh) peaked at 20:00 and 00:00, respectively. Concomitantly, the transcript levels of insulin-like growth factors (igf1 and igf2) in the brain and liver were upregulated during the scotophase. Levels of iodothyronine deiodinases (dio2 and dio3), enzymes that convert thyroxine (T4) to triiodothyronine (T3) and reverse T3, respectively, increased in the brain (dio2 and dio3) and liver (dio2) during the photophase, whereas dio3 levels in the liver showed the opposite trend. Fish reared in melatonin-containing water exhibited significant increases in the transcription levels of gh and igf1 in the brain and igf1 in the liver, suggesting that growth in this fish is positively regulated by the GH/IGF pathway on a daily basis. Melatonin treatment also stimulated the transcript levels of dio2 and dio3 in the liver, but not in the brain. Fish consuming pellets containing T3, but not T4, showed significant increases in gh and igf1 in the brain and igf1 and igf2 in the liver, suggesting that the intercellular actions of the TH/IGF pathway have an impact on growth on a daily basis. In summary, IGF synthesis and action in the brain and liver undergo dual regulation by distinct hormone networks, which may also be affected by daily, seasonal, or nutritional factors.

Lactation performance, feed efficiency, and blood metabolites of dairy cows treated with recombinant bovine somatotropin: A systematic review and meta-analysis

A systematic review and meta-analysis were conducted to assess the impact of recombinant bovine somatotropin (rbST) on lactation performance, feed efficiency, and blood metabolites in dairy cows. In the systematic review, articles were selected based on the following criteria: (1) Data focusing on the influence of bovine somatotropin doses on milk production; (2) Submission of original data; (3) Articles published in journals; and (4) Articles in English or Portuguese. The analysis of variance was used with a completely randomized design and mixed models methodology. Polynomial regression was applied to significant fixed effects (rbST dose). The use of rbST resulted in increased milk yield and 4% fat-corrected milk yield, while fat, protein, and lactose contents remained unaffected. Dry matter and metabolizable energy intakes, as well as milk/feed efficiency, exhibited a linear increase, but body condition score (BCS) was negatively impacted. The administration of rbST led to higher blood concentrations of triglycerides and insulin. Cows treated with rbST showed a 23% increase in non-esterified fatty acid (NEFA) concentrations compared to non-treated cows. Additionally, growth factors IGF-1 and IGF-2 displayed a linear increase with rbST treatment. In summary, rbST administration increased milk yield and fat-corrected milk yield without affecting milk components. However, despite increasing intake, it resulted in BCS losses and alterations in blood parameters such as NEFA, IGF-1, and IGF-2.

Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an invitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Menstrual blood-derived mesenchymal stem cells combined with collagen I gel as a regenerative therapeutic strategy for degenerated disc after discectomy in rats

BackgroundAnnulus fibrosis (AF) defects have been identified as the primary cause of disc herniation relapse and subsequent disc degeneration following discectomy. Stem cell-based tissue engineering offers a promising approach for structural repair. Menstrual blood-derived mesenchymal stem cells (MenSCs), a type of adult stem cell, have gained attention as an appealing source for clinical applications due to their potential for structure regeneration, with ease of acquisition and regardless of ethical issues.MethodsThe differential potential of MenSCs cocultured with AF cells was examined by the expression of collagen I, SCX, and CD146 using immunofluorescence. Western blot and ELISA were used to examine the expression of TGF-β and IGF-I in coculture system. An AF defect animal model was established in tail disc of Sprague-Dawley rats (males, 8 weeks old). An injectable gel containing MenSCs (about 1*106/ml) was fabricated and transplanted into the AF defects immediately after the animal model establishment, to evaluate its repairment properties. Disc degeneration was assessed via magnetic resonance (MR) imaging and histological staining. Immunohistochemical analysis was performed to assess the expression of aggrecan, MMP13, TGF-β and IGF-I in discs with different treatments. Apoptosis in the discs was evaluated using TUNEL, caspase3, and caspase 8 immunofluorescence staining.ResultsCoculturing MenSCs with AF cells demonstrated ability to express collagen I and biomarkers of AF cells. Moreover, the coculture system presented upregulation of the growth factors TGF-β and IGF-I. After 12 weeks, discs treated with MenSCs gel exhibited significantly lower Pffirrmann scores (2.29 ± 0.18), compared to discs treated with MenSCs (3.43 ± 0.37, p < 0.05) or gel (3.71 ± 0.29, p < 0.01) alone. There is significant higher MR index in disc treated with MenSCs gel than that treated with MenSCs (0.51 ± 0.05 vs. 0.24 ± 0.04, p < 0.01) or gel (0.51 ± 0.05 vs. 0.26 ± 0.06, p < 0.01) alone. Additionally, MenSCs gel demonstrated preservation of the structure of degenerated discs, as indicated by histological scoring (5.43 ± 0.43 vs. 9.71 ± 1.04 in MenSCs group and 10.86 ± 0.63 in gel group, both p < 0.01), increased aggrecan expression, and decreased MMP13 expression in vivo. Furthermore, the percentage of TUNEL and caspase 3-positive cells in the disc treated with MenSCs Gel was significantly lower than those treated with gel alone and MenSCs alone. The expression of TGF-β and IGF-I was higher in discs treated with MenSCs gel or MenSCs alone than in those treated with gel alone.ConclusionMenSCs embedded in collagen I gel has the potential to preserve the disc structure and prevent disc degeneration after discectomy, which was probably attributed to the paracrine of growth factors of MenSCs.

Urine-derived stem cells genetically modified with IGF1 improve muscle regeneration.

In this study we aimed to determine the impact of human urine derived stem cells (USC) and genetically modified USC that were designed to overexpress myogenic growth factor IGF1 (USCIGF), on the regenerative capacity of cardiotoxin (CTX)-injured murine skeletal muscle. We overexpressed IGF1 in USC and investigated the alterations in myogenic capacity and regenerative function in cardiotoxin-injured muscle tissues. Compared with USC alone, USCIGF1 activated the IGF1-Akt-mTOR signaling pathway, significantly improved myogenic differentiation capacity in vitro, and enhanced the secretion of myogenic growth factors and cytokines. In addition, IGF1 overexpression increased the ability of USC to fuse with skeletal myocytes to form myotubes, regulated the pro-regenerative immune response and inflammatory cytokines, and increased myogenesis in an in vivo model of skeletal muscle injury. Overall, USC genetically modified to overexpress IGF1 significantly enhanced skeletal muscle regeneration by regulating myogenic differentiation, paracrine effects, and cell fusion, as well as by modulating immune responses in injured skeletal muscles in vivo. This study provides a novel perspective for evaluating the myogenic function of USC as a nonmyogenic cell source in skeletal myogenesis. The combination of USC and IGF1 expression has the potential to provide a novel efficient therapy for skeletal muscle injury and associated muscular defects in patients with urinary incontinence.

Handelin alleviates cachexia- and aging-induced skeletal muscle atrophy by improving protein homeostasis and inhibiting inflammation.

Handelin is a bioactive compound from Chrysanthemum indicum L. that improves motor function and muscle integrity during aging in Caenorhabditis elegans. This study aimed to further evaluate the protective effects and molecular mechanisms of handelin in a mouse muscle atrophy model induced by cachexia and aging. A tumour necrosis factor (TNF)-α-induced atrophy model was used to examine handelin activity in cultured C2C12 myotubes in vitro. Lipopolysaccharide (LPS)-treated 8-week-old model mice and 23-month-old (aged) mice were used to examine the therapeutic effects of handelin on cachexia- and aging-induced muscle atrophy, respectively, in vivo. Protein and mRNA expressions were analysed by Western blotting, ELISA and quantitative PCR, respectively. Skeletal muscle mass was measured by histological analysis. Handelin treatment resulted in an upregulation of protein levels of early (MyoD and myogenin) and late (myosin heavy chain, MyHC) differentiation markers in C2C12 myotubes (P<0.05), and enhanced mitochondrial respiratory (P<0.05). In TNF-α-induced myotube atrophy model, handelin maintained MyHC protein levels, increased insulin-like growth factor (Igf1) mRNA expression and phosphorylated protein kinase B protein levels (P<0.05). Handelin also reduced atrogin-1 expression, inhibited nuclear factor-κB activation and reduced mRNA levels of interleukin (Il)6, Il1b and chemokine ligand 1 (Cxcl1) (P<0.05). In LPS-treated mice, handelin increased body weight (P<0.05), the weight (P<0.01) and cross-sectional area (CSA) of the soleus muscle (P<0.0001) and improved motor function (P<0.05). In aged mice, handelin slightly increased the weight of the tibialis anterior muscle (P=0.06) and CSA of the tibialis anterior and gastrocnemius muscles (P<0.0001). In the tibialis anterior muscle of aged mice, handelin upregulated mRNA levels of Igf1 (P<0.01), anti-inflammatory cytokine Il10 (P<0.01), mitochondrial biogenesis genes (P<0.05) and antioxidant-related enzymes (P<0.05) and strengthened Sod and Cat enzyme activity (P<0.05). Handelin also reduced lipid peroxidation and protein carbonylation, downregulated mRNA levels of Fbxo32, Mstn, Cxcl1, Il1b and Tnf (P<0.05), and decreased IL-1β levels in serum (P<0.05). Knockdown of Hsp70 or using an Hsp70 inhibitor abolished the ameliorating effects of handelin on myotube atrophy. Handelin ameliorated cachexia- and aging-induced skeletal muscle atrophy in vitro and in vivo, by maintaining homeostasis of protein synthesis and degradation, possibly by inhibiting inflammation. Handelin is a potentially promising drug candidate for the treatment of muscle wasting.

Use of black soldier fly (Hermetia illucens) larvae meal in diets for gilthead seabream juveniles: Effects on growth-related gene expression, intermediary metabolism, digestive enzymes, and gut microbiota modulation

A study was conducted to evaluate the effects of dietary inclusion of defatted Hermetia illucens larvae meal (HM) on the expression of growth-related genes, plasma metabolites, activity of intermediary metabolism enzymes, and gut microbiota modulation in gilthead seabream (Sparus aurata) juveniles. Four experimental diets were formulated (43% crude protein, 18% crude lipids) with increasing levels of defatted HM: 0 (HM0), 15 (HM15), 30 (HM30), and 45% (HM45) replacing fishmeal (included at 34% in the control diet) at 0, 22, 60, and 100%, respectively. Fish were fed these diets for 67 days. At the end of the trial, the expression of muscle growth hormone receptors (ghr1 and ghr2), insulin-like growth factors (igf1 and igf2), cathepsins (cts-a and cts-b), and myogenic determination factor 1 (myod1) were not affected, while a downregulation of myogenic determination factor 2 (myod2) and upregulation of myostatin (mstn) was observed with HM inclusion. Plasma metabolites profile was unaffected by diet composition, except for a linear decrease trend in total lipids. A linear increase of liver alanine aminotransferase (ALT) and glutamate dehydrogenase (GDH) activity and a linear decrease of glucose 6-phosphate dehydrogenase (G6PDH), malic enzyme (ME), and (FAS) activity were observed with HM inclusion. The activity of β-hydroxy acyl-CoA dehydrogenase (HOAD) followed a quadratic trend, being higher in fish fed with diet HM15 than in the control. Likewise, amylase, trypsin, and chymotrypsin activity were higher in the posterior intestine of fish fed with diet HM15. Digesta of fish fed the HM-containing diets showed an increase in the number of operational taxonomic units, microbial richness, and diversity. Conversely, a reduction in these indexes was observed in the mucosa. Among the identified bacteria, Firmicutes represented the predominant phyla. The inclusion of HM increased the abundance of Oceanobacillus, Lederbergia, Bacillus, and Corynebacterium in the digesta while Lactobacillus and Caldalkalibacillus abundance was reduced. Overall, total FM replacement with defatted HM had no major effects on plasma metabolites and muscle growth-related genes but induced a few differences in intermediary metabolism and digestive enzymes activity. HM inclusion improved gut digesta microbiota richness and diversity, promoting the growth of potential beneficial bacteria.

32 Feeding Gilts and Sows to Maximize Their Mammary Development

Abstract The task of feeding growing replacement gilts, gestating gilts and sows to maximize their future milk yield is not easy. Yet, this is particularly important when considering the great demands made by the large litters of our current hyperprolific sow genetic lines. One aspect that needs to be considered is the effect of feeding on mammary development taking place before the onset of lactation, which is a major determinant of potential milk yield. One can only attempt to stimulate mammogenesis during periods with rapid mammary development. In swine, these periods are from three months of age until puberty, from 90 days of gestation until farrowing, and throughout lactation. Early studies showed that a 20% or 26% feed restriction from 90 days of age until puberty drastically reduces mammary parenchymal tissue mass. However, in a more recent study, sow milk yield was not altered following a 10% or 20% feed restriction, or a 25% dietary fiber addition (diluting dietary energy by 5%) from 90 days of age to breeding. This absence of effect may be due to the greater feed intake of control gilts in that recent study compared with the older studies. Such a difference in feed intake was likely brought about by genetic selection for faster growing pigs, and it appeared that feed intake of growing gilts can be reduced to 2.7 kg/day without detrimental effects on their future milk yield. During prepuberty, inclusion of the phytoestrogen genistein (2.3 g/day) in the diet increases the number of mammary parenchymal cells. During late gestation, feeding very high energy levels (10.5 Mcal ME/day) may have detrimental effects on mammary development and subsequent milk production. Furthermore, feed intake throughout gestation is important because of its effect on body condition. Gilts that are too thin (&amp;lt; 16 mm backfat thickness) in late gestation have reduced mammary development. A 40% increase in SID Lys via inclusion of additional soybean meal to the diet of gilts from days 90 to 110 of gestation increased mammary parenchymal mass by 44%. On the other hand, providing the same 40% increase in dietary SID Lys to multiparous sows during late gestation had no significant effect on mammary parenchymal mass. These findings therefore support the use of phase-feeding during gestation of gilts only. Increasing circulating concentrations of the growth factor IGF-1 during late gestation also increased mammary parenchymal mass by 22%. Current data clearly demonstrate that feeding management before lactation can be used to improve sow milk yield.

New Formulation of Platelet-Rich Plasma Enriched in Platelet and Extraplatelet Biomolecules Using Hydrogels.

Platelet-rich plasma (PRP) is an autologous biologic product used in several fields of medicine for tissue repair due to the regenerative capacity of the biomolecules of its formulation. PRP consists of a plasma with a platelet concentration higher than basal levels but with basal levels of any biomolecules present out of the platelets. Plasma contains extraplatelet biomolecules known to enhance its regenerative properties. Therefore, a PRP containing not only a higher concentration of platelets but also a higher concentration of extraplatelet biomolecules that could have a stronger regenerative performance than a standard PRP. Considering this, the aim of this work is to develop a new method to obtain PRP enriched in both platelet and extraplatelet molecules. The method is based on the absorption of the water of the plasma using hydroxyethyl acrylamide (HEAA)-based hydrogels. A plasma fraction obtained from blood, containing the basal levels of platelets and proteins, was placed in contact with the HEAA hydrogel powder to absorb half the volume of the water. The resulting plasma was characterized, and its bioactivity was analyzed in vitro. The novel PRP (nPRP) showed a platelet concentration and platelet derived growth factor (PDGF) levels similar to the standard PRP (sPRP), but the concentration of the extraplatelet growth factors IGF-1 (p < 0.0001) and HGF (p < 0.001) were significantly increased. Additionally, the cells exposed to the nPRP showed increased cell viability than those exposed to a sPRP in human dermal fibroblasts (p < 0.001) and primary chondrocytes (p < 0.01). In conclusion, this novel absorption-based method produces a PRP with novel characteristics compared to the standard PRPs, with promising in vitro results that could potentially trigger improved tissue regeneration capacity.

FEATURES OF METABOLISM AND THE POTENTIAL ROLE OF NEUROTROPHIC FACTORS OF THE BRAIN IN THE REHABILITATION PROCESS

Understanding the metabolic pathways of regulation and interaction of neurotrophic factors is interesting from the point of view of discussing neurotrophic factors as biological markers reflecting the dynamics and effectiveness of the rehabilitation process. The purpose was to analyze the features of production, metabolism, mechanisms of action of neurotrophic factors, which can explain the possibility of active involvement of the main neurotrophic factors in the rehabilitation process. The article presents an analysis of the literature on the metabolism of brain-derived neurotrophic factors (brain growth factor BDNF, neurotrophins NT-3 and NT4/5, fibroblast growth factor FGF-1 and FGF-2, nerve growth factor NGF, insulin-like growth factor IGF1, glial neurotrophic factor GDNF, ciliary neurotrophic factor CNTF). Information is given about the features of their production, the relationship between profactors and mature forms, as well as the specifics of interaction with receptors.&#x0D; Conclusion. A statistically significant drop in the levels of neurotrophic factors during the rehabilitation therapy of children with cerebral palsy using the «exohand-2» software and hardware complex reflects the active involvement of neurotrophic factors in these processes. The spectrum of biological effects of neurotrophic factors allows us to consider the entire multicomponent mechanism that occurs in the brain in the process of functional restructuring as sufficient for rehabilitation recovery.

Implications on growth performance, glucose metabolism, PI3K/AKT pathway, intestinal flora induced by dietary taurine in a high-carbohydrate diet for grass carp (Ctenopharyngodon idella).

An 8-week experiment was performed to investigate the influence on growth performance, plasma biochemistry, glucose metabolism and the insulin pathway of supplementation of dietary taurine to a high-carbohydrate diet for grass carp. In this study, fish were fed diets at one of two carbohydrate levels, 31·49 % (positive control) or 38·61 % (T00). The high-carbohydrate basal diet (T00), without taurine, was supplemented with 0·05 % (T05), 0·10 % (T10), 0·15 % (T15) or 0·20 % (T20) taurine, resulting in six isonitrogenous (30·37 %) and isolipidic (2·37 %) experimental diets. The experimental results showed that optimal taurine level improved significantly weight gain, specific growth rate (SGR), feed utilisation, reduced plasma total cholesterol levels, TAG and promoted insulin-like growth factor level. Glucokinase, pyruvate kinase and phosphoenolpyruvate carboxykinase activities showed a quadratic function model with increasing dietary taurine level, while hexokinase, fatty acid synthetase activities exhibited a positive linear trend. Optimal taurine supplementation in high-carbohydrate diet upregulated insulin receptor (Ir), insulin receptor substrate (Irs1), phosphatidylinositol 3-kinase (pi3k), protein kinase B (akt1), glycogen synthase kinase 3 β (gs3kβ) mRNA level and downregulated insulin-like growth factor (igf-1), insulin-like growth factor 1 receptor (igf-1R) and Fork head transcription factor 1 (foxo1) mRNA level. The above results suggested that optimal taurine level could improve growth performance, hepatic capacity for glycolipid metabolism and insulin sensitivity, thus enhancing the utilisation of carbohydrates in grass carp. Based on SGR, dietary optimal tributyrin taurine supplementation in grass carp was estimated to be 0·08 %.

PAPP-A-Specific IGFBP-4 Proteolysis in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

The insulin-like growth factors IGF-I and IGF-II-as well as their binding proteins (IGFBPs), which regulate their bioavailability-are involved in many pathological and physiological processes in cardiac tissue. Pregnancy-associated plasma protein A (PAPP-A) is a metalloprotease that preferentially cleaves IGFBP-4, releasing IGF and activating its biological activity. Previous studies have shown that PAPP-A-specific IGFBP-4 proteolysis is involved in the pathogenesis of cardiovascular diseases, such as ischemia, heart failure, and acute coronary syndrome. However, it remains unclear whether PAPP-A-specific IGFBP-4 proteolysis participates in human normal cardiomyocytes. Here, we report PAPP-A-specific IGFBP-4 proteolysis occurring in human cardiomyocytes derived from two independent induced pluripotent cell lines (hiPSC-CMs), detected both on the cell surface and in the cell secretome. PAPP-A was measured by fluoroimmune analysis (FIA) in a conditioned medium of hiPSC-CMs and was detected in concentrations of up to 4.3 ± 1.33 ng/mL and 3.8 ± 1.1 ng/mL. The level of PAPP-A-specific IGFBP-4 proteolysis was determined as the concentration of NT-IGFBP-4 proteolytic fragments using FIA for a proteolytic neo-epitope-specific assay. We showed that PAPP-A-specific IGFBP-4 proteolysis is IGF-dependent and inhibited by EDTA and 1,10-phenanthroline. Therefore, it may be concluded that PAPP-A-specific IGFBP-4 proteolysis functions in human normal cardiomyocytes, and hiPSC-CMs contain membrane-bound and secreted forms of proteolytically active PAPP-A.

Insulin‑like growth factor axis: A potential nanotherapy target for resistant cervical cancer tumors (Review).

Cervical cancer is among the most frequently occurring neoplasms worldwide, and it particularly affects individuals in developing countries. Factors such as the low quality of screening tests, the high incidence of locally advanced cancer stages and the intrinsic resistance of certain tumors are the main causes of failure in the treatment of this neoplasm. Due to advances in the understanding of carcinogenic mechanisms and bioengineering research, advanced biological nanomaterials have been manufactured. The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including IGF receptor 1. These receptors are activated by binding to their respective growth factor ligands, IGF-1 and IGF-2, and insulin, and play an important role in the development, maintenance, progression, survival and treatment resistance of cervical cancer. In the present review, the role of the IGF system in cervical cancer and three nanotechnological applications that use elements of this system are described, namely Trap decoys, magnetic iron oxide nanoparticles and protein nanotubes. Their use in the treatment of resistant cervical cancer tumors is also discussed.

Computational modeling of multiple myeloma interactions with resident bone marrow cells

The interaction of multiple myeloma with bone marrow resident cells plays a key role in tumor progression and the development of drug resistance. The tumor cell response involves contact-mediated and paracrine interactions. The heterogeneity of myeloma cells and bone marrow cells makes it difficult to reproduce this environment in in-vitro experiments. The use of in-silico established tools can help to understand these complex problems.In this article, we present a computational model based on the finite element method to define the interactions of multiple myeloma cells with resident bone marrow cells. This model includes cell migration, which is controlled by stress–strain equilibrium, and cell processes such as proliferation, differentiation, and apoptosis.A series of computational experiments were performed to validate the proposed model. Cell proliferation by the growth factor IGF-1 is studied for different concentrations ranging from 0–10 ng/mL.Cell motility is studied for different concentrations of VEGF and fibronectin in the range of 0–100 ng/mL. Finally, cells were simulated under a combination of IGF-1 and VEGF stimuli whose concentrations are considered to be dependent on the cancer-associated fibroblasts in the extracellular matrix.Results show a good agreement with previous in-vitro results. Multiple myeloma growth and migration are shown to correlate linearly to the IGF-1 stimuli. These stimuli are coupled with the mechanical environment, which also improves cell growth. Moreover, cell migration depends on the fiber and VEGF concentration in the extracellular matrix. Finally, our computational model shows myeloma cells trigger mesenchymal stem cells to differentiate into cancer-associated fibroblasts, in a dose-dependent manner.

Continuous exposure to alpha-glycosyl isoquercitrin from mid-gestation ameliorates polyinosinic-polycytidylic acid-disrupted hippocampal neurogenesis in rats

Polyinosinic-polycytidylic acid (PIC) provides a model of developmental neuropathy by inducing maternal immune activation. We investigated the effects of an antioxidant, alpha-glycosyl isoquercitrin (AGIQ), on PIC-induced developmental neuropathy in rats, focusing on postnatal hippocampal neurogenesis. On gestational day 15, PIC at 4 mg/kg body weight was administered to dams intravenously. AGIQ either at 0.25% or 0.5% was administered through the diet to dams from gestational day 10 until weaning on day 21 post-delivery and, thereafter, to offspring until postnatal day 77 (adult stage). At weaning, the numbers of TBR2+ cells and PCNA+ cells in the subgranular zone and reelin+ cells in the dentate gyrus hilus in offspring of dams treated with PIC only were decreased compared with untreated controls. In contrast, 0.5% AGIQ ameliorated these changes and increased the transcript levels of genes related to signaling of reelin (Reln and Vldlr), growth factors (Bdnf, Cntf, Igf1, and Igf1r), and Wnt/β-catenin (Wnt5a, Lrp6, Fzd1, and Fzd3). In adults, AGIQ increased the number of FOS+ granule cells at 0.25% and the transcript levels of NMDA-type glutamate receptor genes, Grin2a and Grin2b, at 0.25% and 0.5%, respectively. These results suggest that mid-gestation PIC treatment decreased the abundance of type-2b neural progenitor cells (NPCs) by reducing NPC proliferation in relation with suppression of reelin signaling at weaning. We suggest that AGIQ ameliorated the PIC-induced suppressed neurogenesis by enhancing reelin, growth factor, and Wnt/β-catenin signaling at weaning to rescue NPC proliferation and increased synaptic plasticity by enhancing glutamatergic signaling via NMDA-type receptors after maturation.