Growth Factor Axis Research Articles

The impact of inactivation of the GH/IGF axis during aging on healthspan.

Several mouse lines with congenital growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis disruption have shown improved health and extended lifespan. The current study investigated how inactivating this axis, specifically during aging, impacts the healthspan. We used a tamoxifen-inducible global GH receptor (GHR) knockout mouse model starting at 12 months and followed the mice until 24 months of age (iGHRKO12-24 mice). We found sex- and tissue-specific effects, with some being pro-aging and others anti-aging. Measuring an array of cytokines in serum revealed that inactivation of the GH/IGF-1 axis at 12 months did not affect systemic inflammation during aging. On the other hand, hypothalamic inflammation was significantly reduced in iGHRKO12-24 mice, evidenced by GFAP+ (glial fibrillary acidic protein, a marker of astrocytes) and Iba-1+ (a marker for microglia). Liver RNAseq analysis indicated feminization of the male transcriptome, with significant changes in the expression of monooxygenase, sulfotransferase, and solute-carrier-transporter gene clusters. Finally, we found impaired bone morphology, more pronounced in male iGHRKO12-24 mice and correlated with GH/IGF-1 inactivation onset age. We conclude that inhibiting the GH/IGF-1 axis during aging only partially preserves the beneficial healthspan effects observed with congenital GH deficiency.

IGFBP-2 in Critical Illness: A Prognostic Marker in the Growth Hormone/Insulin-like Growth Factor Axis

Critical illness (CI) triggers complex disruptions in the growth hormone (GH)/insulin-like growth factor (IGF) axis, significantly affecting the dynamics of insulin-like growth-factor-binding proteins (IGFBPs). Among these, IGFBP-2 shows a sustained elevation during CI, which inversely correlates with serum levels of IGF-1, IGFBP-3, and the acid-labile subunit (ALS). Although IGFBP-2 does not directly interact with ALS, it may influence the availability of IGFs by competing with other IGFBPs for binding to IGF-1 and IGF-2. Research suggests that this persistent elevation of IGFBP-2 is largely driven by cytokine activity during CI, reflecting an adaptive response rather than a direct result of GH/IGF axis dysregulation. The clinical importance of IGFBP-2 is emphasized by its correlation with disease severity in conditions like sepsis and coronavirus disease 2019 (COVID-19), where its levels are markedly elevated compared to healthy controls and are similar to those observed in sepsis from various causes. Beyond its role in endocrine regulation, IGFBP-2 appears to play a part in metabolic and inflammatory pathways. Elevated IGFBP-2 levels have been linked to increased mortality and longer hospital stays, indicating its potential utility as a prognostic marker. Furthermore, measuring plasma IGFBP-2 may have other diagnostic applications, aiding in the assessment of CI when traditional biomarkers are inconclusive.

Parecoxib inhibits tumorigenesis and angiogenesis in hepatocellular carcinoma through ERK-VEGF/MMPs signaling pathway.

Parecoxib, a well-recognized nonsteroidal anti-inflammatory drug, has been reported to possess anticancer properties in various tumor types. In this work, we aimed to investigate the potential anticancer effects of parecoxib on hepatocellular carcinoma (HCC) cells. To assess the impact of parecoxib on HCC cell proliferation, we employed Cell Counting Kit-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays. Hoechst/propidium iodide (PI) double staining and flow cytometry were performed to evaluate apoptosis and cell cycle analysis. Wound healing and transwell assays were utilized to assess cell migration and invasion. Tube formation assay was employed to analyze angiogenesis. Protein levels were determined using western blotting, and mRNA expression levels were assessed using quantitative real-time polymerase chain reaction (PCR). A xenograft mouse model was used to confirm the antitumor effects of parecoxib on HCC tumors in vivo. Our data demonstrated that parecoxib effectively inhibited the proliferation of HCC cells in a dose- and time-dependent manner. In addition, parecoxib induced cell cycle arrest in the G2 phase and promoted apoptosis. Moreover, parecoxib hindered tumor migration and invasion by impeding the epithelial-mesenchymal transition process. Further investigation showed that parecoxib could significantly suppress angiogenesis through the inhibition of extracellular signal-regulated kinase (ERK)-vascular endothelial growth factor (VEGF) axis. Notably, treatment with the ERK activator phorbol myristate acetate upregulated the expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF and reversed the function of parecoxib in HCC cells. Besides, parecoxib displayed its antitumor efficacy in vivo. Collectively, our results suggest that parecoxib ameliorates HCC progression by regulating proliferation, cell cycle, apoptosis, migration, invasion, and angiogenesis through the ERK-VEGF/MMPs signaling pathway.

Mechanical loading-induced alveolar bone remodeling is suppressed in the diabetic state via the impairment of the specificity protein 1/vascular endothelial growth factor (SP1/VEGF) axis.

Orthodontic treatment involves alveolar bone remodeling in response to mechanical loading, resulting in tooth movement through traction-side bone formation and compression-side bone resorption. However, there are conflicting reports regarding alveolar bone resorption during the orthodontic treatment of patients with diabetes. Diabetes was induced in 8-week-old C56BL/6J mice using streptozotocin (STZ). Four weeks after the injection of STZ, a mechanical load was applied between the first and second molars on the right side of the upper jaw using the Waldo method with orthodontic elastics in diabetic (DM) and normal (N) mice tooth movement, gene expression, osteoclast counts, alveolar bone residual volume, and bone beam structure were evaluated. The duration until spontaneous elastic loss was significantly longer in the DM group, suggesting that tooth movement may be inhibited in the diabetic state. The number of osteoclasts at 7 days after mechanical loading and the alveolar bone resorption were both significantly lower in the DM group. The gene expression levels of vascular endothelial growth factor (VEGF), a protein related to alveolar bone remodeling, and specificity protein 1 (SP1), a transcription factor of the VEGF gene, were significantly lower in the DM group than in the N group on the compression side of mechanical loading. Mechanical loading-induced alveolar bone remodeling is suppressed in the diabetic state. Our results suggest that VEGF is a key molecule involved in impaired bone remodeling under mechanical loading in the diabetic state.

The Pattern of Gene Expression (Igf Family, Muscle Growth Regulatory Factors, and Osteogenesis-Related Genes) Involved in the Growth of Skeletal Muscle in Pikeperch (Sander lucioperca) During Ontogenesis.

The pikeperch (Sander lucioperca) is an economically important freshwater fish and a valuable food with high market acceptance. It is undergoing important changes in growth and regulatory metabolism during the ontogeny. Hence, the current study aims to investigate the mRNA expression of the growth hormone (gh)/insulin-like growth factor (igf) axis (ghr, igfI, igfbp, igfr), muscle regulatory factors (pax7, myf5, myod, myogenin, mrf, mymk, mstn), and osteogenesis-related genes (colla1a, fib1a, on, op, ostn) from hatching through day 40th post-hatching (DPH). The average total length (TL) of larvae measured at hatching was 3.6 ± 0.4 mm (67 degree days), and at the end of the experiment (40 DPH, 777 degree days), it was 27.1 ± 1.1 mm. The results showed three phases of gene expression in day 0 (egg), larval, and juvenile stages of pikeperch, which can be a progression or transition from the initial state toward the juvenile state. The expression pattern of myf5, mymk, and fib1a genes showed the highest value at day 0. The growth hormone receptor gene (ghr) and igfbp5 were raised to 1 DPH, whereas increased expression of igfI, igfII, igf1bp4, igf1rb, myod2, and mrf4 was detected at 14 DPH. The myod1, pax7, op, ostc, on, igf1ra, and col1a1a genes were highly expressed at 21 DPH and juvenile stages. According to the PLS-DA model, the most relevant VIPs are myf5 and mymk as best markers of earlier stages and igf1ra, ostc, pax7, and ghr as markers of later stages of ontogeny. Results from this study suggest that basal metabolism, growth of body cells and muscles, and bone proliferation and development can be regulated by the dynamic changes in gene expression patterns in this species. The identified genes will help to understand the basic biological process of pikeperch larvae and development, which is very important in pikeperch farming.

Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity.

Diminished signaling via insulin/insulin-like growth factor-1 (IGF-1) axis is associated with longevity in different model organisms. IGF-1 gene is highly conserved across species, with only few evolutionary changes identified in it. Despite its potential role in regulating life span, no coding variants in IGF-1 have been reported in human longevity cohorts to date. This study investigated the whole exome sequencing data from 2,487 individuals in a cohort of Ashkenazi Jewish centenarians, their offspring, and controls without familial longevity to identify functional IGF-1 coding variants. We identified two likely functional coding variants IGF-1 :p.Ile91Leu and IGF-1 :p.Ala118Thr in our longevity cohort. Notably, a centenarian specific novel variant IGF-1:p .Ile91Leu was located at the binding interface of IGF-1 - IGF-1R, whereas IGF-1 :p.Ala118Thr was significantly associated with lower circulating levels of IGF-1. We performed extended all-atom molecular dynamics simulations to evaluate the impact of Ile91Leu on stability, binding dynamics and energetics of IGF-1 bound to IGF-1R. The IGF-1 :p.Ile91Leu formed less stable interactions with IGF-1R's critical binding pocket residues and demonstrated lower binding affinity at the extracellular binding site compared to wild-type IGF-1. Our findings suggest that IGF-1 :p.Ile91Leu and IGF-1 :p.Ala118Thr variants attenuate IGF-1R activity by impairing IGF-1 binding and diminishing the circulatory levels of IGF-1, respectively. Consequently, diminished IGF-1 signaling resulting from these variants may contribute to exceptional longevity in humans.

TNFα has differential effects on the transcriptome profile of selected populations in murine cartilage

ObjectiveTo further our understanding of the role of tumor necrosis factor (TNF)α on the inflammatory response in chondrocytes. DesignWe explored the effects of TNFα on the transcriptome of epiphyseal chondrocytes from newborn C57BL/6 mice at the total and single cell (sc) resolution. ResultsGene set enrichment analysis of total RNA-Seq from TNFα-treated chondrocytes revealed enhanced response to biotic stimulus, defense and immune response and cytokine signaling and suppressed cartilage and skeletal morphogenesis and development. scRNA-Seq analyzed 14,239 ​cells and 24,320 genes and distinguished 16 ​cell clusters. The more prevalent ones were constituted by limb bud and chondrogenic cells and fibroblasts comprising ∼73 ​% of the cell population. Genes expressed by joint fibroblasts were detected in 5 clusters comprising ∼45 ​% of the cells isolated. Pseudotime trajectory finding revealed an association between fibroblast and chondrogenic clusters which was not modified by TNFα. TNFα decreased the total cells recovered by 18.5 ​% and the chondrogenic, limb bud and mesenchymal clusters by 32 ​%, 27 ​% and 7 ​%, respectively. TNFα had profound effects on the insulin-like growth factor (IGF) axis decreasing Igf1, Igf2 and Igfbp4 and inducing Igfbp3 and Igfbp5, explaining an inhibition of collagen biosynthesis, cartilage and skeletal morphogenesis. Ingenuity Pathway Analysis of scRNA-Seq data revealed that TNFα enhanced the osteoarthritis, rheumatoid arthritis, pathogen induced cytokine storm and interleukin 6 signaling pathways and suppressed fibroblast growth factor signaling. ConclusionsEpiphyseal chondrocytes are constituted by diverse cell populations distinctly regulated by TNFα to promote inflammation and suppression of matrix biosynthesis and growth.

Lessons from Klotho mouse models to understand mineral homeostasis.

Klotho, a key component of the endocrine fibroblast growth factor receptor-fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism. In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer. In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options. This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular invivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.

Exploring Vitamin D Deficiency and IGF Axis Dynamics in Colorectal Adenomas.

(1) Colorectal cancer is a major cause of cancer-related death, with colorectal adenomas (CRAs) serving as precursors. Identifying risk factors such as vitamin D deficiency and the insulin-like growth factor (IGF) axis is crucial for prevention. (2) This case-control study included 85 participants (53 CRA patients and 32 controls) who underwent colonoscopy. We measured serum vitamin D3 (cholecalciferol), calcidiol (vitamin D metabolite), calcitriol (active vitamin D metabolite), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) to explore their associations with CRA risk. (3) Results: We found that lower cholecalciferol levels were a significant risk factor for CRA (OR = 4.63, p = 0.004). Although no significant differences in calcidiol and calcitriol levels were observed between CRA patients and controls, calcidiol deficiency was common in the study population. IGF-1 levels inversely correlated with age, calcitriol, and IGFBP-3 in CRA patients. (4) This study highlights the potential of lower cholecalciferol levels to detect patients at risk of CRA when calcidiol values cannot, suggesting the importance of evaluating different vitamin D metabolites in cancer prevention research. Our findings underscore the need to further investigate the interactions between calcitriol, the active form of vitamin D, and the IGF axis in colorectal cancer development.

LIFR regulates cholesterol-driven bidirectional hepatocyte-neutrophil cross-talk to promote liver regeneration.

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-ERRα-hepatocyte growth factor axis that form bidirectional hepatocyte-neutrophil cross-talk to repair and regenerate the liver.

Insulin-like Growth Factor-1 Levels Reflect Muscle and Bone Health and Determine Complications and Mortality in Decompensated Cirrhosis

The growth hormone-insulin-like growth factor (GH-IGF-1) axis and its impairment with sarcopenia, frailty, bone health, complications, and prognosis are not well characterized in cirrhosis. We investigated the adult decompensated cirrhosis out-patients at a tertiary care institute between 2021 and 2023 for serum GH and IGF-1 levels, and associated them with sarcopenia (CT-SMI in cm2/m2), liver frailty index (LFI), osteodystrophy (DEXA), clinical decompensations (overall, ascites, encephalopathy, infection, and bleed), and survival up to 180 days. One-hundred-seventy-two patients, 95% males, aged 46.5 years (median). logIGF-1 levels were negatively associated with sarcopenia, osteodystrophy, LFI, CTP, and MELD-Na score (P<0.05 each). Patients with low IGF-1 levels had a higher incidence of complications (overall, ascites and encephalopathy) than those with intermediate, and high IGF-1 levels (P<0.05 each). Both logIGF-1 (AUC: 0.686) and MELD (AUC: 0.690) could predict 180-day mortality (P<0.05, each). Adding logIGF-1 with MELDNa further improved discriminative accuracy of MELDNa (AUC: 0.729) P<0.001. The increase in IGF-1 on follow-up was associated with better survival and fewer complications. Reduced IGF-1 levels reflect sarcopenia, frailty, and osteodystrophy in cirrhosis. Low IGF-1 are associated with severity, development of decompensations, and mortality.

Sarcopenia, frailty and growth hormone-insulin like growth factor axis among decompensated and alcohol-associated hepatitis patients

Sarcopenia, frailty and growth hormone-insulin like growth factor axis among decompensated and alcohol-associated hepatitis patients

Down-regulation of CYTL1 attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting M2 macrophage polarization via the TGF-β/CCN2 axis.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic inflammation, lung tissue fibrotic changes and impaired lung function. Pulmonary fibrosis 's pathological process is thought to be influenced by macrophage-associated phenotypes. IPF treatment requires specific targets that target macrophage polarization. Cytokine-like 1(CYTL1) is a secreted protein with multiple biological functions first discovered in CD34+ haematopoietic cells. However, its possible effects on IPF progression remain unclear. This study investigated the role of CYTL1 in IPF progression in a bleomycin-induced lung injury and fibrosis model. In bleomycin-induced mice, CYTL1 is highly expressed. Moreover, CYTL1 ablation alleviates lung injury and fibrosis in vivo. Further, downregulating CYTL1 reduces macrophage M2 polarization. Mechanically, CYTL1 regulates transforming growth factor β (TGF-β)/connective tissue growth factor (CCN2) axis and inhibition of TGF-β pathway alleviates bleomycin-induced lung injury and fibrosis. In conclusion, highly expressed CYTL1 inhibits macrophage M2 polarization by regulating TGF-β/CCN2 expression, alleviating bleomycin-induced lung injury and fibrosis. CYTL1 could, therefore, serve as a promising IPF target.

Changes in body proportions and body fat content in GH-deficient and non-GH-deficient children during the first year of growth hormone treatment.

Introduction: The growth hormone/insulin-like growth factor-1 axis (GH/IGF-1) is crucial for longitudinal bone growth and exerts several metabolic effects. It is debatable whether and how the recombinant human growth hormone (rhGH) treatment affects the trunk-limb proportions. Aim of the study: We aim to evaluate the changes in body proportions and body fat content in short children with growth hormone deficiency (GHD), children born small for gestational age (SGA), and girls with Turner syndrome (TS) during the first year of rhGH therapy. Material and methods: The data of 70 children with GHD, 40 children born SGA, and 36 girls with TS from 1998 to 2019 were analyzed. The following parameters were measured: height, body weight, sitting height, and two skinfolds on the arm above the triceps brachii and below the scapula at the beginning of rhGH therapy and after the first year of treatment. Sitting height and lower limb length were presented as percentages (%) of body height. Fat mass percentage (%FAT) was calculated using the Slaughter formula. Results: At the beginning of rhGH, TS girls had the greatest height deficit (-2.7 SDS), the highest sitting height (%), and the lowest lower limb length (%) compared to children with GHD and children born SGA. Moreover, TS girls had higher body weight SDS, BMI SDS compared to SGA children (p < 0.001), and higher %FAT compared to both GHD and SGA children (p < 0.001 for both). After the first year of rhGH therapy, a significant increase in lower limb share (%) and a decrease in %FAT were observed in all the study groups. TS girls still had significantly higher sitting height (%), shorter lower limbs (%), and higher %FAT, body weight SDS, and BMI SDS compared to children with GHD and children born SGA (p < 0.05 for all variables). Conclusions: Our results show that rhGH treatment could increase lower limb length in relation to height and reduce fat mass in treated children. Girls with TS had the largest baseline body disproportions and the highest body fat content. Despite a satisfactory reduction in height deficit, after the first year of rhGH therapy, these girls had still higher body weight SDS, BMI SDS, %FAT, the highest sitting height (%), and the lowest lower limb length (%) compared to children with GHD and born SGA.

Nutritional supplementation of breeding hens may promote embryonic development through the growth hormone-insulin like growth factor axis

The late stage of embryo development is a crucial period of metabolic changes, with rapid organ development requiring a substantial supply of nutrients. During this phase, maternal nutritional levels play a vital role in the growth, development, and metabolism of the offspring. In this study, we added 2 doses of β-carotene (βc) (120 mg/kg and 240 mg/kg) to the daily diet of Hailan Brown laying hens to investigate the impact of maternal nutritional enrichment on embryo development. Maternal nutrition supplementation significantly increased the expression of chicken embryo liver index, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and hepatocyte growth factor (HGF) in serum. At the same time, the expression of GH/growth hormone receptor (GHR), IGF-1 mRNA, and Proliferating Cell Nuclear Antigen (PCNA) protein in the liver was upregulated, indicating that maternal nutrition intervention may promote chicken embryo liver development through the GH-IGF-1 axis. Transcriptome sequencing results showed that differential genes in liver after maternal nutritional supplementation with β-carotene were enriched in pathways related to cell proliferation and metabolism. Consequently, we postulated that maternal β-carotene supplementation might operate via the GH-IGF-1 axis to regulate the expression of genes involved in growth and development, thereby promoting liver development. These results contribute to formulating more effective poultry feeding strategies to promote offspring growth and development.

Experimental Autoimmune Encephalomyelitis Influences GH-Axis in Female Rats.

Inflammation, demyelination, and axonal damage to the central nervous system (CNS) are the hallmarks of multiple sclerosis (MS) and its representative animal model, experimental autoimmune encephalomyelitis (EAE). There is scientific evidence for the involvement of growth hormone (GH) in autoimmune regulation. Previous data on the relationship between the GH/insulin like growth factor-1 (IGF-1) axis and MS/EAE are inconclusive; therefore, the aim of our study was to investigate the changes in the GH axis during acute monophasic EAE. The results show that the gene expression of Ghrh and Sst in the hypothalamus does not change, except for Npy and Agrp, while at the pituitary level the Gh, Ghrhr and Ghr genes are upregulated. Interestingly, the cell volume of somatotropic cells in the pituitary gland remains unchanged at the peak of the disease. We found elevated serum GH levels in association with low IGF-1 concentration and downregulated Ghr and Igf1r expression in the liver, indicating a condition resembling GH resistance. This is likely due to inadequate nutrient intake at the peak of the disease when inflammation in the CNS is greatest. Considering that GH secretion is finely regulated by numerous central and peripheral signals, the involvement of the GH/IGF-1 axis in MS/EAE should be thoroughly investigated for possible future therapeutic strategies, especially with a view to improving EAE disease.

Implication of Pappalysins and Stanniocalcins in the Bioavailability of IGF-I in Children With Type 1 Diabetes Mellitus.

Anomalies in the growth hormone (GH)/insulin-like growth factor (IGF) axis, are common in children with type 1 diabetes mellitus (T1DM), even in those reaching a normal or near-normal final height. However, concentrations of the IGF bioavailability regulatory factors (pappalysins [PAPP-As] and stanniocalcins [STCs]) have not been reported in children with T1DM. To determine serum concentrations of PAPP-As and STCs in children at diagnosis of T1DM and after insulin treatment and the correlation of these factors with other members of the GH/IGF axis, beta-cell insulin reserve, auxology, and nutritional status. A single-center prospective observational study including 47 patients (59.5% male), with T1DM onset at median age of 9.2 years (interquartile range: 6.3, 11.9) was performed. Blood and anthropometric data were collected at diagnosis and after 6 and 12 months of treatment. At 6 and 12 months after T1DM diagnosis, there was improvement in the metabolic control (decrease in glycated hemoglobin [HbA1c] at 12 months -3.66 [95% CI: -4.81, -2.05], P = .001), as well as in body mass index SD and height SD (not statistically significant). STC2 increased (P < .001) and PAPP-A2 decreased (P < .001) at 6 and 12 months of treatment onset (P < .001), which was concurrent with increased total IGF-I and IGF-binding protein concentrations, with no significant modification in free IGF-I concentrations. HbA1c correlated with PAPP-A2 (r = +0.41; P < .05) and STC2 (r = -0.32; P < .05). Implementation of insulin treatment after T1DM onset modifies various components of the circulating IGF system, including PAPP-A2 and STC2. How these modifications modulate linear growth remains unknown.

Gene expression analyses of GH/IGF axis in triploid crucian carp with growth heterosis.

Hybridization and polyploid breeding are the main approaches used to obtain new aquaculture varieties. Allotriploid crucian carp (3n) with rapid growth performance was generated by mating red crucian carp (RCC) with allotetraploids (4n). Fish growth is controlled by the growth hormone (GH)/insulin-like growth factor (IGF) axis. In the present study, we examined the expression characteristics of GH/IGF axis genes in hybrids F1, 4n, 3n, RCC and common carp (CC). The results showed that GHRa, GHRb, IGF1, IGF2, and IGF-1Ra were highly expressed in 3n compared with RCC and CC, whereas IGF3 was undetectable in the liver in RCC, CC and 3n. GHRa and GHRb had low expression in the 4n group. In hybrid F1, GHRa expression was low, whereas GHRb was highly expressed compared to the levels in RCC and CC. Moreover, in hybrid F1, the expression of IGF3 was higher, and the expression of IGF1 and IGF2 was lower than that in the RCC and CC, whereas the expression of IGF-1Ra was similar to that in RCC and CC. For the IGFBP genes, IGFBP1 had higher expression in 3n compared than that in RCC and CC, while other IGFBP genes were not high expressed in 3n. Among the genes detected in this study, 11 genes were nonadditively expressed in 3n, with 5 genes in the transgressive upregulation model. We proposed that the 11 nonadditive expression of GH/IGF axis genes is related to growth heterosis in 3n. This evidence provides new insights into hybridization and polyploid breeding from the perspective of hormone regulation.

MicroRNA-34a-Dependent Attenuation of Angiogenesis in Right Ventricular Failure.

The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1α-vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure. Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1α expression increased (0.12±0.01 versus 0.22±0.03, P=0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P=0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P<0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1α, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-β1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR-34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease-related RVF, RV capillarity was decreased and miR-34a increased 5-fold. In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1α-VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR-34a therapeutics in patients with at-risk RVs.

Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.

Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs). The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA). The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found. Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.