Including Insulin-like Growth Factor 1 Research Articles

The Influence of IGF-1, Progesterone, Androstenedione, Aromatase, and Estrogen in Successful and Unsuccessful IVF Treatments

Follicular steroidogenesis, involving proteins including insulin-like growth factor 1 (IGF-1), progesterone (P4), androstenedione, aromatase, and estrogen (E2), may influence the success of in vitro fertilization (IVF) treatments. This research aimed to 1) compare levels of these proteins in follicular fluid (FF) between subjects with successful (n=10) and unsuccessful (n=20) outcomes; 2) compare these proteins between FF and serum within each group; and 3) investigate correlations of these proteins with reproductive hormones. Classification into successful and unsuccessful groups was based on the detection of fetal heartbeat. Blood samples were collected to measure anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH) at baseline as well as IGF-1, FSH, P4, androstenedione, aromatase, and E2 in FF and serum on the day of ovum pick-up (OPU). In unsuccessful pregnancies, FF and serum IGF-1 levels and FF aromatase levels were significantly higher, whereas FF and serum androstenedione levels were significantly lower when compared to successful pregnancies ( P<0.05 all). There were no significant differences in FF E2 and P4 levels between groups; however, there was a non-significant trend towards decreased FF E2 levels in unsuccessful pregnancies. Levels of IGF-1, P4, androstenedione, and E2 were significantly higher in FF than in serum in both successful and unsuccessful groups ( P<0.01 all). The FF/serum ratios for successful and unsuccessful subjects were 2.28 and 2.06 for IGF-1, 7,920.61 and 1,919.26 for P4, 5.49 and 4.00 for androstenedione, and 193.45 and 225.60 for E2, respectively. For correlation analyses, basal AMH showed significant positive correlations with serum androstenedione in all subjects and a significant negative correlation with FF E2 in unsuccessful subjects ( P<0.05 all). Basal FSH levels were significantly negatively correlated with serum androstenedione levels in all subjects ( P<0.05). On OPU day, FF androstenedione levels showed significant positive correlations with FF and serum E2 levels in unsuccessful subjects ( P<0.05 all). Serum androstenedione levels were significantly positively correlated with FF E2 levels in successful subjects and with serum E2 levels in all and unsuccessful subjects ( P<0.01 all). FF aromatase levels had significant positive correlations with serum FSH levels in all and unsuccessful subjects ( P<0.01 all). FF E2 levels were significantly positively correlated with FF androstenedione levels in unsuccessful subjects and with serum androstenedione levels in successful subjects ( P<0.01 all). In unsuccessful pregnancies, elevated aromatase levels, despite similar or insignificantly lower FF E2 levels, could likely result from high FSH levels, potentially indicating defective FF E2 production processes that may be due to inadequate substrate availability or decreased aromatase activity. Lower androstenedione levels in unsuccessful pregnancies suggest that there may be a defect in substrate production; however, we could not determine whether there is a defect in aromatase function in these subjects. Lower FF and serum androstenedione levels in unsuccessful pregnancies might be due to poor ovarian response, as indicated by lower basal AMH and higher FSH levels observed in these subjects in our previous study, findings further supported by a positive correlation between androstenedione and basal AMH, and a negative correlation with basal FSH. The elevated IGF-1 levels in the unsuccessful group might be attributable to high FSH levels. Higher levels of IGF-1, P4, androstenedione, and E2 in FF than in serum indicate that these hormones might be primarily secreted into FF before being released into circulation. In conclusion, unsuccessful pregnancies exhibited lower FF and serum androstenedione levels, but higher FF aromatase and IGF-1 levels in both FF and serum, indicating a decreased substrate availability for E2 production in subjects with poor ovarian response. IGF-1, P4, androstenedione, and E2 were likely synthesized primarily in FF rather than serum. This research was funded by the Faculty of Medicine Siriraj Hospital Research Fund ((IO) R016433005 and Grant to support Strategic Driving Project for pushing the World University Rankings by Subject, Fiscal Year 2021 ((IO) R016421007). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Body Size Effect in Eothenomys miletus of Different Regions from Hengduan Mountain Regions: Roles of Growth Factor Contents

Background: Growth factors are active substances secreted by a variety of cells, acting as messengers to regulate cell migration, proliferation or differentiation, which had important regulatory roles in the growth of individual cells, tissues or organs. Growth factors can regulate the proliferation and differentiation ability of cells, which keep the internal environment stable and affect the body size. Methods: In order to investigate the influence of the changes of growth factors contents on body size in Eothenomys miletus from Hengduan mountain regions, E. miletus in Dali (DL), Jianchuan (JC), Lijiang (LJ), Xianggelila (XGLL) and Deqin (DQ) were collected and their 7 morphological indicators and 9 growth factors, including insulin-like growth factor1 (IGF1), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), growth hormone release inhibitory factor (GRIF), platelet-derived growth factor (PDGF), transcription elongation factor1 (TCEA1), a disintegrin and metalloprotease17 (ADAM7), branched-chain amino acid transaminase1 (BCAT1), high mobility group protein1 (HMG1) were measured. Result: The results showed that body size of E. miletus among five regions had significant differentiated, body mass, body length, forelimb length, hind limb length, tail length, IGF, bFGF, EGF, PDGF, TCEA1 contents in DL, JC and LJ were greater than those of in XGLL and DQ and the contents of GRIF, ADAM7, BCAT1 and HMG1 were also different, decreasing with the increasing of regional latitude. Moreover, the increases in the contents of growth factors lead to the increase of body size in E. miletus, which does not support Bergman's law. Regional differences in body size of E. miletus in different regions may be related to the changes in body mass, morphological indicators and the content of growth factors. Moreover, growth factors may affect the body size of E. miletus by affecting the proliferation of bone, epidermis, muscle and differentiation of cells.

Secretome from myoblasts statically loaded at low intensity promotes tenocyte proliferation via the IGF-1 receptor pathway.

Exercise is widely recognized as beneficial for tendon healing. Recently, it has been described that muscle-derived molecules secreted in response to static exercise influence tendon healing. In this study, the optimal static loading intensity for tendon healing and the composition of secretome released by myoblasts in response to different intensities of static strain were investigated. In an in vitro coculture model, myoblasts were mechanically loaded using a Flexcell Tension System. Tenocytes were seeded on transwell inserts that allowed communication between the tenocytes and myoblasts without direct contact. Proliferation and migration assays, together with RNA sequencing, were used to determine potential cellular signaling pathways. The secretome from myoblasts exposed to 2% static loading increased the proliferation and migration of the cocultured tenocytes. RNA-seq analysis revealed that this loading condition upregulated the expression of numerous genes encoding secretory proteins, including insulin-like growth factor-1 (IGF-1). Confirmation of IGF-1 expression and secretion was carried out using qPCR and enzyme-linked immunosorbt assay (ELISA), revealing a statistically significant upregulation in response to 2% static loading in comparison to both control conditions and higher loading intensities of 5% and 10%. Addition of an inhibitor of the IGF-1 receptor (PQ401) to the tenocytes significantly reduced myoblast secretome-induced tenocyte proliferation. In conclusion, IGF-1 may be an important molecule in the statically loaded myoblast secretome, which is responsible for influencing tenocytes during exercise-induced healing.

Insulin-like growth factor-1 regulates follicle selection of hens by promoting proliferation and inhibiting apoptosis of granulosa cells in prehierarchical follicles in vitro

During the reproduction stage of poultry, a single follicle is selected from a cohort of 6–8 mm small yellow follicles to initiate rapid growth and final ovulation almost daily. In the process, follicle-stimulating hormone (FSH) plays a pivotal role by interacting with intraovarian factors, including insulin-like growth Factor 1 (IGF1). The objective of this study was to analyze whether IGF1 coordinates with FSH to affect the characteristics of granulosa cells from prehierarchical follicles. After treating granulosa cells with 50 ng/mL FSH and 200 ng/mL IGF1, we detected the proliferation and apoptosis of granulosa cells using flow cytometry. The percentage of G1 phase granulosa cells was increased, and the percentage of mitotic cells and apoptotic cells was reduced under IGF1 treatment. The expression levels of the steroidogenic acute regulatory protein gene, cytochrome P450 side-chain cleavage gene and 3β-hydroxysteroid dehydrogenase gene, which are related to steroidogenic synthesis, were reduced by cotreatment with FSH and IGF1. The expression of the cell proliferation- or apoptosis-related genes cyclin dependent kinase 2, cyclin D2, B-cell leukemia/lymphoma 2, and BCL2 like 1 and the ratio of B-cell leukemia/lymphoma 2/BCL2-associated X were increased by treatment with IGF1. There was a decrease in the expression of caspase3 after treatment with FSH and IGF1. All these results showed that IGF1 reduced the expression of genes involved in progesterone synthesis, stimulated proliferation and inhibited apoptosis in granulosa cells. Thus, IGF1 may be one of the factors involved in affecting FSH responsiveness and maintaining the undifferentiated state of prehierarchical follicles before follicle selection.

Key genes affecting the progression of nasopharyngeal carcinoma identified by RNA-sequencing and bioinformatic analysis.

Background: The present work was conducted to screen the potential biomarkers affecting nasopharyngeal carcinoma (NPC) progression through RNA-sequencing (RNA-seq), bioinformatic analysis and functional experiments.Materials and Methods: Six normal samples and five NPC clinical samples were collected for RNA-seq analysis. The expression levels in both groups were determined through student’s t-test. We identified genes of P < 0.01 as the differentially expressed genes (DEGs). In addition, gene set enrichment analysis (GSEA) was conducted. Afterwards, STRING V10 database was employed to extract protein interactions among the DEGs. Later, we established a protein-protein interaction (PPI) network, and used the Cytoscape software for network visualization. qRT-PCR was conducted to verify hub genes from clinical samples. Then, the function of CXCL10 in cell proliferation, apoptosis, invasion and migration was evaluated.Results: A total of 2024 DEGs were identified, among which, 1449 were down-regulated and 575 were up-regulated. The PPI was constructed, and the hub genes including Insulin Like Growth Factor 1 (IGF1), C-X-C Motif Chemokine Ligand 10 (CXCL10), Interleukin 13 (IL13), Intercellular Adhesion Molecule 1 (ICAM1), G Protein Subunit Gamma Transducin 1 (GNGT1), Matrix Metallopeptidase 1 (MMP1), Neurexin 1 (NRXN1) and Matrix Metallopeptidase 3 (MMP3) were obtained. The expression levels of CXCL10, IGF1, MMP3, MMP1, ICAM1, and IL-13 were significantly up-regulated in tumor tissues. High expression levels of CXCL10, MMP3 and ICAM1 predicted poor prognosis of NPC patients. CXCL10 silencing suppressed NPC cell proliferation and migration.Conclusions: CXCL10 may serve as a potential key gene affecting NPC genesis and progression.

IGF-1 TMJ injections enhance mandibular growth and bone quality in juvenile rats.

Dentofacial orthopaedic treatment of mandibular hypoplasia has unpredictable skeletal outcomes. Although several biomodulators including insulin-like growth factor 1 (IGF-1) are known to contribute to chondrocyte proliferation, their efficacy in modulating mandibular growth has not been validated. The aim of this study was to determine the effect of locally delivered IGF-1 on mandibular growth and condylar bone quality/quantity in juvenile rats. Institutional vivarium using twenty-four 35-day-old male Sprague-Dawley rats. PBS or 40µg/kg (low-dose) IGF-1 or 80µg/kg (high-dose) IGF-1 was injected bilaterally into the temporomandibular joints of the rats at weekly intervals for four weeks. Cephalometric and micro-computed tomography measurements were used to determine mandibular dimensions. Bone and tissue mineral density, volume fraction and mineral content were determined, and serum IGF-1 concentrations assayed. Intra-articular administration of high-dose IGF-1 contributed to a significant 6%-12% increase in mandibular body and condylar length compared to control and low-dose IGF-1-treated animals. Additionally, IGF-1 treatment resulted in a significant decrease in the angulation of the lower incisors to mandibular plane. Condylar bone volume, bone volume fraction, mineral content and mineral density were significantly increased with high-dose IGF-1 relative to control and low-dose IGF-1 groups. Serum IGF-1 levels were similar between all groups confirming limited systemic exposure to the locally administered IGF-1. Local administration of high-dose 80µg/kg IGF-1 enhances mandibular growth and condylar bone quality and quantity in growing rats. The findings have implications for modulating mandibular growth and potentially enhancing condylar bone health and integrity.

In vitro investigation of growth factors including MGF and IGF-1 in neural stem cell activation, proliferation, and migration

Neurogenesis is mainly activated after damage in adult tissues. This destruction activates the neural stem cells (NSCs) by exiting from a quiescent state and initiating proliferation, differentiation, and migration towards the damaged area. Although studies have investigated to clarify the process of NSC biology and neurogenesis, there are still significant artifacts in understanding the primary mechanism. It is known that only a small percentage of NSC become neurons and integrate into the brain tissue after this process. The significant proportion differentiates to become either astrocytes or oligodendrocytes. Furthermore, the quiescent stem cells in the niche are mainly activated by the stimuli affect. In recent years, many studies have been conducted with varying hormones, some of which might provide neuro-stimulation effect and/or involved in the regeneration of the brain tissue and/or neuroprotection from traumatic or ischemic pathologies, including Insulin-like growth factor 1 (IGF-1), Mechano Growth Factor (MGF), Basic Fibroblast Growth Factor (FGF-2), Erythropoietin (EPO), Epidermal Growth Factor (EGF), Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF).In this study, we examined the effects of FGF-2, MGF, IGF-1, EPO, EGF, NGF, and BDNF alone or with various combinations on rat hippocampal NSC by tracking the changes in the expression of Nestin, GFAP, TUBB3, and DCX genes during 24 h (h), 72 h and 168 h time frame. The apoptosis analysis revealed that FGF-2 and FGF-2 coupled growth factors effectively protect NSCs against apoptosis, whereas MGF coupled growth factors failed in this protection. The cell cycle analysis demonstrated that these growth factors had accumulated the NSCs exit from the quiescent phase to the Mitosis phase, mostly without being long in the Synthesis Phase. Neurosphere sizes were increased with MGF, signifying MGF being effective in neural progenitor cells. The combined use of MGF with FGF-2 was more effective in postmitotic neurons than MGF alone.We have comparatively demonstrated the effect of cytokines alone and combined administration on activation, proliferation, and migration of NSCs. Although many issues are still waiting to be investigated in adult neurogenesis, neural regeneration, and adult neural stem cell biology, the results provide vital resources to the researchers that are interested in the varying effect of growth factor on NSC.

Population structure, genetic diversity, and selective signature of Chaka sheep revealed by whole genome sequencing

BackgroundChaka sheep, named after Chaka Salt Lake, are adapted to a harsh, highly saline environment. They are known for their high-grade meat quality and are a valuable genetic resource in China. Furthermore, the Chaka sheep breed has been designated a geographical symbol of agricultural products by the Chinese Ministry of Agriculture.ResultsThe genomes of 10 Chaka sheep were sequenced using next-generation sequencing, and compared to that of additional Chinese sheep breeds (Mongolian: Bayinbuluke and Tan; Tibetan: Oula sheep) to explore its population structure, genetic diversity and positive selection signatures. Principle component analysis and a neighbor-joining tree indicated that Chaka sheep significantly diverged from Bayinbuluke, Tan, and Oula sheep. Moreover, they were found to have descended from unique ancestors (K = 2 and K = 3) according to the structure analysis. The Chaka sheep genome demonstrated comparable genetic diversity from the other three breeds, as indicated by observed heterozygosity (Ho), expected heterozygosity (He), runs of homozygosity (ROH), linkage disequilibrium (LD) decay. The enrichment analysis revealed that in contrast to Mongolian or Tibetan lineage groups, the genes annotated by specific missense mutations of Chaka sheep were enriched with muscle structure development (GO:0061061) factors including insulin-like growth factor 1 (IGF1), growth differentiation factor 3 (GDF3), histone deacetylase 9 (HDAC9), transforming growth factor beta receptor 2 (TGFBR2), and calpain 3 (CAPN3), among others. A genome-wide scan using Fst and XP-CLR revealed a list of muscle-related genes, including neurofibromin 1 (NF1) and myomesin 1 (MYOM1), under potential selection in Chaka sheep compared with other breeds.ConclusionsThe comprehensive genome-wide characterization provided the fundamental footprints for breeding and management of the Chaka sheep and confirmed that they harbor unique genetic resources.

Transcriptional regulation of seven cyadox-related genes mainly activated by PI3K and NF-кB signaling pathways in PK-15 cells

Cyadox, a new antibacterial agent as the quinoxaline-1, 4-dioxides, has a good antibacterial and growth-promoting effect, and has the advantages of lower toxicity, adequate safety and faster absorption. Seven differential expressed genes (DEGs) induced by cyadox were screened in swine liver tissues, including Insulin-like Growth Factor-1 (IGF-1), Epidermal Growth Factor (EGF), Poly ADP-ribose polymerase (PARP), the Defender Against Apoptotic Death 1 (DAD1), Complement Component 3 (C3), Transketolase (TK) and cyadox-related novel gene (CRNG). To elucidate the signal mechanism that cyadox altered these genes expression, the time-effect relationship and signaling pathways related to 7 DEGs induced by cyadox were determined in Porcine Kidney-15 (PK-15) cells by RT-qPCR and the application of various signal pathway inhibitors. The phosphorylation levels of signal factors in PK-15 cells were detected by Western blot. The analyses demonstrated that, the mRNA expressions of 7 DEGs were significantly enhanced by cyadox mainly through the phosphoinositide 3-kinase (PI3K) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) signaling pathways in PK-15 cells. Furthermore, EGF might be the early response gene of cyadox to activate downstream signaling pathways and regulates the expression of other related genes or directly exerting biological effects. In brief, cyadox mainly regulates the expression of these 7 genes by PI3K and NF-кB signaling pathways to exert it's antibacterial and growth-promoting activity in PK-15 cells.

The Protective Effect of Lycopene on Prostate Growth Inhibitory Efficacy by Decreasing Insulin Growth Factor-1 in Indonesian Human Prostate Cancer Cells.

IntroductionLycopene has been discussed as a potential effector in the prevention and therapy of prostate cancer. It is red, lipophilic and naturally occurring in many fruits and vegetables, such as tomatoes. Several growth factors, including insulin-like growth factor 1 (IGF-1), play important roles in carcinogenesis and metastasis. IGF-1 is a mitogen that plays important roles in the regulation of proliferation, differentiation, and apoptosis. Binding of IGF-1 to its cognate membrane receptor activates Ras/Raf/MAP kinase signaling pathways, which regulate cell-cycle progression, cell survival, and transformation. Lycopene has its protective effect, which affects multiple IGF-1-activated signaling pathways. Lycopene stimulates apoptosis through intrinsic pathways, by stimulating the pro-apoptotic factor of the mitochondrial cavity such as the Bax/Bak protein (an apoptotic promotor). Although tomatoes are widely consumed in Indonesia, there is no research study about the effect of lycopene on prostate cancer in Indonesia. Hence, this study is conducted to measure the influence of lycopene on the level of IGF-1 in Indonesian human prostate cancer cells.Materials and MethodsProstate cancer cells were studied. In this experimental study, cells were taken from patients with Gleason score 6 and divided into 5 groups: 2 control groups and 3 treatment groups, which were given 1 µM, 2 µM and 4 µM of lycopene, respectively. Measurement of mean IGF-1 level was performed by ELISA. A comparative analysis was performed by two-way ANOVA.ResultsThe result showed that there was a significant difference in mean IGF-1 levels in the provision of various concentrations of lycopene and time of observation (p<0.05). Increased level of mean IGF-1 appeared on 2µM dose of lycopene at 48 hours observation and began to decline in 72 hours observation. This happened also on 4µM lycopene at 24 hours observation and began to decline in 48 hours observation (p<0.05).ConclusionLycopene could be administered as adjuvant therapy for prostate cancer patients to increase apoptosis, and eventually inhibit the progressivity of cancer cells.

Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.

Functional muscle hypertrophy by increased insulin-like growth factor 1 does not require dysferlin.

IntroductionDysferlin loss‐of‐function mutations cause muscular dystrophy, accompanied by impaired membrane repair and muscle weakness. Growth promoting strategies including insulin‐like growth factor 1 (IGF‐1) could provide benefit but may cause strength loss or be ineffective. The objective of this study was to determine whether locally increased IGF‐1 promotes functional muscle hypertrophy in dysferlin‐null (Dysf −/−) mice.MethodsMuscle‐specific transgenic expression and postnatal viral delivery of Igf1 were used in Dysf −/− and control mice. Increased IGF‐1 levels were confirmed by enzyme‐linked immunosorbent assay. Testing for skeletal muscle mass and function was performed in male and female mice.ResultsMuscle hypertrophy occurred in response to increased IGF‐1 in mice with and without dysferlin. Male mice showed a more robust response compared with females. Increased IGF‐1 did not cause loss of force per cross‐sectional area in Dysf −/− muscles.DiscussionWe conclude that increased local IGF‐1 promotes functional hypertrophy when dysferlin is absent and reestablishes IGF‐1 as a potential therapeutic for dysferlinopathies.

Akt Is a Molecular Target for Signal Transduction Therapy in Brain Ischemic Insult

Growth factors including insulin-like growth factor-1 (IGF-1) promote cell survival in ischemic brain injury. Stimulation of IGF-1 receptor coupled with tyrosine kinase activates phosphatidylinositol 3-kinase and subsequently, protein kinase B (Akt) in hippocampal neurons. Here we introduce a new approach of signal transduction therapy for brain damage occurring in ischemic insult. As has been shown for IGF-1, intracerebroventricular injection of sodium orthovanadate, a protein tyrosine phosphatase inhibitor, prior to ischemic insult blocked delayed neuronal death in the CA1 region. The neuroprotective effects of orthovanadate and IGF-1 were associated with an increased Akt activity in the CA1 region. We discuss here potential targets for Akt relevant to such neuroprotective activity. Our findings lead to the conclusion that Akt activity is a potential target for neuroprotective drugs in brain ischemic insult and other episodes of excitotoxic neuronal apoptosis such as seizure and Huntington’s and Parkinson’s diseases.

The effect of Lactobacillus plantarum hydrolysates promoting VEGF production on vascular growth and hair growth of C57BL/6 mice

PurposeAngiogenesis is critical in various biological processes, such as blood vessel growth, fetal differentiation, wound healing, and organ regeneration. Various growth factors have been associated with vascular regeneration, including insulin-like growth factor 1 (IGF-1), transforming growth factor-β (TGF-β), and basic fibroblast growth factor (bFGF). One of the most important mediators of vascular regeneration is vascular endothelial growth factor (VEGF). VEGF is known to increase vascular permeability, induce the proliferation of endothelial cells, and stimulate capillary formation in vivo, which are core angiogenic functions.MethodsThe hydrolysates of lactic acid bacteria were produced by hydrolyzing Lactobacillus plantarum with proteases, treated with MG-63 osteoblasts, and screened to obtain samples with an excellent VEGF production effect. These samples were applied to human dermal papilla cells (hDPC) to examine the correlation between cell growth and VEGF secretion. Furthermore, the hair growth rate was measured in hair growth experiments using C57BL/6 male mice.ResultsThe hydrolysates of the lactic acid bacteria produced in this study produced hair growth superior to the growth obtained with 5% minoxidil in hair growth experiments using C57BL/6 male mice.ConclusionsThis study aims to develop a material for application to the scalp that promotes angiogenesis in the scalp and facilitates the exchange of nutrients and wastes in the follicles to promote hair growth.

Cyadox regulates the transcription of different genes by activation of the PI3K signaling pathway in porcine primary hepatocytes.

Cyadox, a new derivative of quinoxalines, has been ascertained as an antibiotic with significant growth promoting, low poison, quick absorption, swift elimination, brief residual period, and noncumulative effect. Seven differential expressed genes, including Insulin-like Growth Factor-1 ( IGF-1), Epidermal Growth Factor ( EGF), Poly ADP-ribose polymerase ( PARP), the Defender Against Apoptotic Death 1 ( DAD1), Complement Component 3 ( C3), Transketolase ( TK) and a New gene, were induced by cyadox in swine liver tissues by messenger RNA differential display reverse transcription polymerase chain reaction (DDRT-PCR) in our laboratory. However, the signal mechanism that cyadox altered these genes expression is not completely elucidated. The signaling pathways involved in the expressions of seven genes induced by cyadox were determined in porcine primary hepatocytes by RT-qPCR and the application of various signal pathway inhibitors. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that cyadox could stimulate proliferation of porcine primary hepatocytes in a time-dependent manner. In porcine primary cultured hepatocytes, phosphoinositide 3-kinase (PI3K) and transforming growth factor-β (TGF-β) signal pathways were the main signal pathways involved in the expressions of seven genes induced by cyadox. Taken together, these results demonstrate for the first time that seven cyadox-related genes expressions in porcine primary hepatocytes treated with cyadox are mediated mainly through the PI3K signaling pathway, potentially leading to enhanced cell growth and cell immunity. EGF might be the early response gene of cyadox, and a primary regulator of the other gene expressions such as IGF-1 and DAD1, playing an important role in cell proliferation promoted by cyadox.

IGF-1-Overexpressing Mesenchymal Stem/Stromal Cells Promote Immunomodulatory and Proregenerative Effects in Chronic Experimental Chagas Disease.

Mesenchymal stem/stromal cells (MSCs) have been investigated for the treatment of diseases that affect the cardiovascular system, including Chagas disease. MSCs are able to promote their beneficial actions through the secretion of proregenerative and immunomodulatory factors, including insulin-like growth factor-1 (IGF-1), which has proregenerative actions in the heart and skeletal muscle. Here, we evaluated the therapeutic potential of IGF-1-overexpressing MSCs (MSC_IGF-1) in a mouse model of chronic Chagas disease. C57BL/6 mice were infected with Colombian strain Trypanosoma cruzi and treated with MSCs, MSC_IGF-1, or vehicle (saline) six months after infection. RT-qPCR analysis confirmed the presence of transplanted cells in both the heart and skeletal muscle tissues. Transplantation of either MSCs or MSC_IGF-1 reduced the number of inflammatory cells in the heart when compared to saline controls. Moreover, treatment with MSCs or MSC_IGF-1 significantly reduced TNF-α, but only MSC treatment reduced IFN-γ production compared to the saline group. Skeletal muscle sections of both MSC- and MSC_IGF-1-treated mice showed a reduction in fibrosis compared to saline controls. Importantly, the myofiber area was reduced in T. cruzi-infected mice, and this was recovered after treatment with MSC_IGF-1. Gene expression analysis in the skeletal muscle showed a higher expression of pro- and anti-inflammatory molecules in MSC_IGF-1-treated mice compared to MSCs alone, which significantly reduced the expression of TNF-α and IL-1β. In conclusion, our results indicate the therapeutic potential of MSC_IGF-1, with combined immunomodulatory and proregenerative actions to the cardiac and skeletal muscles.

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community.

BackgroundThe discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk‐stratification methods and may be informative regarding biological pathways contributing to disease.Methods and ResultsWe used a discovery proteomic platform that targeted high‐value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable‐adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all‐cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P‐value ranges, 9.8×10−34 to 3.6×10−2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin‐like growth factor 1 (IGF1), insulin‐like growth factor binding protein 1 (IGFBP1), insulin‐like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N‐terminal pro‐b‐type natriuretic peptide, C‐reactive protein, and leptin were associated with incident heart failure, and C‐type lectin domain family 3 member B (CLEC3B; tetranectin), N‐terminal pro‐b‐type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin‐C were associated with all‐cause mortality in a multimarker model.ConclusionsWe identified numerous protein biomarkers that predicted cardiovascular outcomes and all‐cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention.

Effect of skin graft thickness on scar development in a porcine burn model

Animal models provide a way to investigate scar therapies in a controlled environment. It is necessary to produce uniform, reproducible scars with high anatomic and biologic similarity to human scars to better evaluate the efficacy of treatment strategies and to develop new treatments. In this study, scar development and maturation were assessed in a porcine full-thickness burn model with immediate excision and split-thickness autograft coverage. Red Duroc pigs were treated with split-thickness autografts of varying thickness: 0.026in. (“thin”) or 0.058in. (“thick”). Additionally, the thin skin grafts were meshed and expanded at 1:1.5 or 1:4 to evaluate the role of skin expansion in scar formation. Overall, the burn-excise-autograft model resulted in thick, raised scars. Treatment with thick split-thickness skin grafts resulted in less contraction and reduced scarring as well as improved biomechanics. Thin skin autograft expansion at a 1:4 ratio tended to result in scars that contracted more with increased scar height compared to the 1:1.5 expansion ratio. All treatment groups showed Matrix Metalloproteinase 2 (MMP2) and Transforming Growth Factor β1 (TGF-β1) expression that increased over time and peaked 4 weeks after grafting. Burns treated with thick split-thickness grafts showed decreased expression of pro-inflammatory genes 1 week after grafting, including insulin-like growth factor 1 (IGF-1) and TGF-β1, compared to wounds treated with thin split-thickness grafts. Overall, the burn-excise-autograft model using split-thickness autograft meshed and expanded to 1:1.5 or 1:4, resulted in thick, raised scars similar in appearance and structure to human hypertrophic scars. This model can be used in future studies to study burn treatment outcomes and new therapies.

Radiotherapy-Activated Cancer-Associated Fibroblasts Promote Tumor Progression through Paracrine IGF1R Activation.

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659-70. ©2017 AACR.

Insulin-like growth factor-1 activates different catalytic subunits p110 of PI3K in a cell-type-dependent manner to induce lipogenesis-dependent epithelial-mesenchymal transition through the regulation of ADAM10 and ADAM17.

The activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is critical for the induction of epithelial-mesenchymal transition (EMT) by growth factors, including insulin-like growth factor 1 (IGF-1). The activation of intracellular lipogenesis provides proliferative and survival signals for cancer cells. In this study, we investigated the connection between lipogenesis-related EMT processes and IGF-1-mediated PI3K p110 isoform activation in primary (SW480 cells) and metastatic (SW620) colon carcinoma cells. We also examined the underlying signaling pathway that promotes fatty acid synthesis in IGF-1-activated colon cancer cells. IGF-1 stimulation upregulated the expression of lipogenic enzymes as well as the activation of Nardilysin (N-arginine dibasic convertase, NRD1) and its downstream targets, a disintegrin and metalloproteases 10 (ADAM10) and ADAM17. The upregulation of the Lyn/Syk-mediated PI3K p110δ isoform in SW480 cells and the Lyn-dependent PI3K p110α isoform in SW620 cells triggered fatty acid production and cell motility in IGF-1-activated colon cancer cells. Pharmacological inhibition with A66 (PI3K p110α specific inhibitor) and CAL-101 (PI3K p110δ specific inhibitor) efficiently inhibited EMT in colon cancer cells by blocking the NRD1/ADAM family protein signaling pathway. Gene silencing of NRD1 and ADAM family proteins attenuated the generation of intracellular fatty acid and the migratory activity of colon cancer cells. Our results suggest that the different isoforms of the PI3K p110 subunit could be therapeutic targets for primary and metastatic colon cancer and that regulation of the NRD1/ADAM signaling pathway controls lipogenesis-mediated EMT in IGF-1-stimulated colon cancer cells.