PRMT7 Regulates Adipogenic Differentiation of hBMSCs by Modulating IGF-1 Signaling / 生物化学与生物物理进展

ObjectiveProtein arginine methyltransferases (PRMTs) play pivotal roles in numerous cellular biological processes. However, the precise regulatory effects of PRMTs on the fate determination of mesenchymal stromal/stem cells (MSCs) remain elusive. Our previous studies have shed light on the regulatory role and molecular mechanism of PRMT5 in MSC osteogenic differentiation. This study aims to clarify the role and corresponding regulatory mechanism of PRMT7 during the adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Methods(1) Human bone marrow-derived mesenchymal stem cells (hBMSCs) were cultured in a medium that induces adipogenesis. We used qRT-PCR and Western blot to monitor changes in PRMT7 expression during adipogenic differentiation. (2) We created a cell line with PRMT7 knocked down and assessed changes in PRMT7 expression and adipogenic capacity using Oil Red O staining, qRT-PCR and Western blot. (3) We implanted hBMSCs cell lines mixed with a collagen membrane subcutaneously into nude mice and performed Oil Red O staining to observe ectopic lipogenesis in vivo. (4) A cell line overexpressing PRMT7 was generated, and we examined changes in PRMT7 expression using qRT-PCR and Western blot. We also performed Oil Red O staining and quantitative analysis after inducing the cells in lipogenic medium. Additionally, we assessed changes in PPARγ expression. (5) We investigated changes in insulin-like growth factor 1 (IGF-1) expression in both PRMT7 knockdown and overexpressing cell lines using qRT-PCR and Western blot, to understand PRMT7’s regulatory effect on IGF-1 expression. siIGF-1 was transfected into the PRMT7 knockdown cell line to inhibit IGF-1 expression, and knockdown efficiency was confirmed. Then, we induced cells from the control and knockdown groups transfected with siIGF-1 in lipogenic medium and performed Oil Red O staining and quantitative analysis. Finally, we assessed PPARγ expression to explore IGF-1’s involvement in PRMT7’s regulation of adipogenic differentiation in hBMSCs. Results(1) During the adipogenesis process of hBMSCs, the expression level of PRMT7 was significantly reduced (P<0.01). (2) The adipogenic differentiation ability of PRMT7 knockdown group was significantly stronger than that of control group (P<0.001). (3) The ectopic adipogenic differentiation ability of PRMT7 knockdown group was significantly stronger than that of control group. (4) The adipogenic differentiation ability of the PRMT7 overexpression group was significantly weaker than that of the control group (P<0.01). (5) The expression level of IGF-1 increased after PRMT7 knockdown (P<0.000 1). The expression level of IGF-1 decreased after PRMT7 overexpression (P<0.000 1), indicating that PRMT7 regulates the expression of IGF-1. After siIGF-1 transfection, the expression level of IGF-1 in all cell lines decreased significantly (P<0.001). The ability of adipogenic differentiation of knockdown group transfected with siIGF-1 was significantly reduced (P<0.01), indicating that IGF-1 affects the regulation of PRMT7 on adipogenic differentiation of hBMSCs. ConclusionIn this investigation, our findings elucidate the inhibitory role of PRMT7 in the adipogenic differentiation of hBMSCs, as demonstrated through both in vitro cell-level experiments and in vivo subcutaneous transplantation experiments conducted in nude mice. Mechanistic exploration revealed that PRMT7’s regulatory effect on the adipogenic differentiation of hBMSCs operates via modulation of IGF-1 signaling pathway. These collective findings underscore PRMT7 as a potential therapeutic target for fatty metabolic disorders, thereby offering a novel avenue for leveraging PRMT7 and hBMSCs in the therapeutic landscape of relevant diseases.

Hedysari Radix Polysaccharide Regulates Apoptosis of Smooth Muscle Cells in Gastric Antrum of Rat Model of Diabetic Gastroparesis via IGF-1/PI3K/Akt Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effects of Hedysari Radix polysaccharide on the apoptosis of gastric sinus smooth muscle cells and explore the underlying mechanism via the insulin-like growth factor-1 （IGF-1）/phosphatidylinositol 3-kinase （PI3K）/serine-threonine kinase （Akt） pathway in the rat model of diabetic gastroparesis （DGP）. MethodSixty-two Wistar male rats were randomized into a blank group （n=12） and a modelling group （n=50）. The rat model of DGP was established by small-dose multiple intraperitoneal injections of streptozotocin combined with an irregular high-fat and high-sugar diet for 4 weeks. The modeled rats were randomized into model group， mosapride citrate （1.35 mg·kg-1）， and high-， medium-， and low-dose （200， 100， and 50 mg·kg-1， respectively） Hedysari Radix polysaccharide groups. The rats were administrated with corresponding drugs by gavage， and those in the blank and model groups with equal volumes of pure water by gavage once a day for 8 consecutive weeks. The random blood glucose and body mass were measured every 2 weeks， and gastric emptying rate was calculated. Hematoxylin-eosin （HE） staining was used to observe the pathological changes of smooth muscle in gastric antrum， and terminal deoxynucleoitidyl transferase-mediated nick-end labeling （TUNEL） was employed to detect the apoptosis of smooth muscle cells in the gastric antrum. The expression of IGF-1， phosphorylated （p）-PI3K， and p-Akt in the smooth muscle of gastric sinus tissue was detected by immunohistochemistry. Western blot was employed to determine the protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax） in the smooth muscle of the gastric antrum. ResultCompared with the blank group， the model group showed elevated random blood glucose at all time points （P<0.01）， decreased body mass and gastric emptying rate （P<0.01）， increased apoptotic index of smooth muscle cells in the gastric antrum （P<0.01）， down-regulated protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， and Bcl-2， and up-regulated protein level of Bax （P<0.01）. Compared with the model group， the 8 weeks of drug administration lowered the random blood glucose， increased the body mass and gastric emptying rate （P<0.05， P<0.01）， decreased the apoptotic index of smooth muscle cells in the gastric antrum （P<0.05， P<0.01）， up-regulated the protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， and Bcl-2， and down-regulated the protein level of Bax （P<0.05， P<0.01）. Compared with the mosapride citrate group，the administration of low-dose Hedysari Radix polysaccharide for 6 and 8 weeks lowered the random blood glucose and decreased the body mass （P<0.05， P<0.01），low and medium-dose Hedysari Radix polysaccharide decreased the gastric emptying rate and the apoptotic index of smooth muscle cells in the astragaloside low-dose group decreased （P<0.05）. The protein levels of IGF-1，p-PI3K/PI3K，p-Akt/Akt and Bcl-2（low dose）were down-regulated and the protein level of Bax was up-regulated by low doses of Hedysari Radix polysaccharide （P<0.05， P<0.01）. Compared with high-dose Hedysari Radix polysaccharide， low-dose Hedysari Radix polysaccharide elevated random blood glucose and reduced body mass after 6 and 8 weeks of administration （P<0.05， P<0.01）， and the low and medium doses decreased the gastric emptying rate， increased the apoptotic index of smooth muscle cells in the gastric antrum （P<0.05， P<0.01）， down-regulated the protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， and Bcl-2， and up-regulated the protein level of Bax （P<0.05， P<0.01）. Compared with the medium-dose group，the low-dose group of Hedysari Radix polysaccharide had lower body mass，lower gastric emptying rate in rats，higher apoptotic index of smooth muscle cells in gastric sinus tissue after 6 and 8 weeks of administration （P<0.05， P<0.01）， and lower protein expression of IGF-1，p-PI3K/PI3K，p-Akt/Akt. ConclusionHedysari Radix polysaccharide protects the smooth muscle cells in gastric antrum against apoptotic injury and promotes gastric motility by activating the IGF-1/PI3K/Akt signaling pathway， as manifested by the up-regulated expression of IGF-1， p-PI3K， p-Akt， and Bcl-2 and down-regulated expression of Bax.

Effect of Yiqi Huayu Decoction Combined with Calcium Dobesilate in Treating Diabetic Kidney Disease with Qi Deficiency and Blood Stasis Syndrome and Its Effect on the Expression Levels of Vascular Endothelial Growth Factor and Insulin-like Growth Factor 1 / 广州中医药大学学报

Objective To investigate the clinical efficacy of Yiqi Huayu Decoction(mainly composed of Astragali Radix,Dioscoreae Rhizoma,Poria,fried Euryales Semen,Ecliptae Herba,Rosae Laevigatae Fructus,charred Crataegi Fructus,Ligustri Lucidi Fructus,Salviae Miltiorrhizae Radix et Rhizoma,and Leonuri Herba)combined with Calcium Dobesilate in the treatment of diabetic nephropathy(DN)with qi deficiency and blood stasis syndrome,and to observe the effect of the therapy on vascular endothelial growth factor(VEGF)and insulin-like growth factor 1(IGF-1).Methods Ninety patients with DN of qi deficiency and blood stasis type were randomly divided into an observation group and a control group,with 45 patients in each group.All patients received basic hypoglycemic therapy and treatment for controlling blood pressure and regulating lipid metabolism disorders.Moreover,the patients in the control group were given Calcium Dobesilate orally,and the patients in the observation group were given Yiqi Huayu Decoction combined with Calcium Dobesilate.The course of treatment lasted for 3 months.The changes of traditional Chinese medicine(TCM)syndrome scores,renal function parameters and serum VEGF and IGF-1 levels in the two groups of patients were observed before and after the treatment,and the clinical efficacy of the two groups was evaluated after treatment.Results(1)After 3 months of treatment,the total effective rate of the observation group was 91.11%(41/45),and that of the control group was 75.56%(34/45).The intergroup comparison(tested by chi-square test)showed that the therapeutic effect of the observation group was significantly superior to that of the control group(P＜0.05).(2)After one month and 3 months of treatment,the TCM syndrome scores of both groups were significantly lower than those before treatment(P＜0.05),and the scores after 3 months of treatment in the two groups were significantly lower than those after one month of treatment(P＜0.05).The intergroup comparison showed that the reduction of TCM syndrome scores of the observation group was significantly superior to that of the control group after one month and 3 months of treatment(P＜0.01).(3)After treatment,the levels of renal function parameters such as serum creatinine(Scr),blood urea nitrogen(BUN),and glomerular filtration rate(GFR)in the two groups of patients were significantly improved compared with those before treatment(P＜0.05),and the observation group's effect on the improvement of all renal function parameters was significantly superior to that of the control group(P＜0.01).(4)After treatment,the serum VEGF and IGF-1 levels in the two groups of patients were significantly lower than those before treatment(P＜0.05),and the observation group's effect on the decrease of serum VEGF and IGF-1 levels was significantly superior to that of the control group(P＜0.01).(5)In the course of treatment,no significant adverse reactions occurred in the two groups of patients,with a high degree of safety.Conclusion Yiqi Huayu Decoction combined with Calcium Dobesilate exerts certain therapeutic effect in treating DN patients with qi deficiency and blood stasis syndrome.The combined therapy can effectively down-regulate the serum levels of VEGF and IGF-1,significantly improve the renal function,and alleviate the clinical symptoms of the patients,with a high degree of safety.

Effects of miR-141-3p on dorsal root ganglion inflammation and lower limb pain in rats with lumbar disc herniation / 中国组织工程研究

BACKGROUND:Studies have shown that insulin-like growth factor 1/platelet-derived growth factor has an inhibitory effect on fibroblast apoptosis.miR-141-3p in bone marrow stromal cells increases with age and has a relationship with the activation of inflammatory signaling pathways,suggesting that it may be a therapeutic target for lumbar disc herniation. OBJECTIVE:To explore the effects of miR-141-3p on dorsal root ganglion inflammation and lower limb pain in rats with lumbar disc herniation by regulating insulin-like growth factor 1/platelet-derived growth factor. METHODS:Fifty male Sprague-Dawley rats,SPF level,were randomly divided into normal group,model group,miR-NC group,miR-141-3p inhibitor group and miR-141-3p mimics group,with 10 rats in each group.Except for the normal group,animal models of lumbar disc herniation were established in rats by autologous nucleus pulposus transplantation.After successful modeling,rats in the miR-NC,miR-141-3p inhibitor and miR-141-3p mimics groups were injected intrathecally with 10 μL of 20 μmol/L miR-NC,miR-141-3p inhibitor,miR-141-3p mimics,once a day for 28 days,respectively,while those in the normal and model groups were injected with the same volume of saline at the same location at the same time.Paw withdrawal thermal latency threshold was used to evaluate lower limb pain in rats.The mRNA expression of miR-141-3p in dorsal root ganglion tissue was detected by real-time fluorescence quantitative PCR,the levels of inflammatory factors in dorsal root ganglion tissue were detected by ELISA,and the expression of insulin-like growth factor 1/platelet-derived growth factor in dorsal root ganglion tissue was detected by western blot.The correlation between miR-141-3p and insulin-like growth factor 1/platelet-derived growth factor was analyzed. RESULTS AND CONCLUSION:There were no significant differences in all indexes between the miR-NC group and the model group.Paw withdrawal thermal latency threshold was significantly lower in the model group than in the normal group(P＜0.05),significantly lower in the miR-141-3p inhibitor group than the miR-NC group(P＜0.05),and significantly higher in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The mRNA expression of miR-141-3p in dorsal root ganglion tissue was significantly lower in the model group than in the normal group(P＜0.05),significantly lower in the miR-141-3p inhibitor group than in the miR-NC group(P＜0.05),and significantly higher in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The levels of tumor necrosis factor α,interleukin 1β,and interleukin 1 in dorsal root ganglion tissue were significantly higher in the model group than in the normal group(P＜0.05),significantly higher in the miR-141-3p inhibitor group than in the miR-NC group(P＜0.05),and significantly lower in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The protein expressions of insulin-like growth factor 1 and platelet-derived growth factor in dorsal root ganglion tissue were significantly lower in the model group than in the normal group(P＜0.05),significantly lower in the miR-141-3p inhibitor group than in the miR-NC group(P＜0.05),and significantly higher in the miR-141-3p mimics group than in the miR-141-3p inhibitor group(P＜0.05).The expressions of insulin-like growth factor 1 and platelet-derived growth factor showed a positive correlation with miR-141-3p(r=0.904,P＜0.001;r=0.879,P＜0.001).To conclude,miR-141-3p can significantly improve lower limb pain and inhibit inflammation in dorsal root ganglia in rats with lumbar disc herniation,and its mechanism may be related to the promotion of insulin-like growth factor 1/platelet-derived growth factor expression.

Factor de crecimiento análogo a insulina-1 y cardiotrofina-1 inducido por ejercicio y su relación con hipertrofia miocárdica en maratonistas / Cardiotrophin-1 and Insulin like growth factor induced by exercise are associated to cardiac hypertrophy in marathon runners

Antecedentes: El ejercicio de alta intensidad induce hipertrofia miocárdica necesaria para adaptar al corazón a la mayor demanda de trabajo. Se desconoce si correr una maratón induce de forma aguda factores humorales asociados al desarrollo de hipertrofia miocárdica en atletas. Objetivo: Evaluar cardiotrofina-1 (CT1) y el factor de crecimiento análogo a insulina-1 (IGF-1), conocidos inductores de hipertrofia, en maratonistas previo y justo después de correr una maratón y su relación con hipertrofia cardíaca. Métodos: Estudio prospectivo ciego simple de atletas hombres que corrieron la maratón de Santiago. Se incluyó un grupo control sedentario. En todos los sujetos se realizó un ecocardiograma transtorácico estándar. Los niveles de CT1 e IGF-1 se determinaron en plasma obtenidos antes (basal) y justo después de haber terminado (antes de 15 minutos) la maratón, usando test de ELISA. Resultados: Los atletas tenían frecuencias cardíacas menores que los controles, asociado con una mayor hipertrofia miocárdica, determinado por el grosor del septo y pared posterior del corazón, y volúmenes del ventrículo y aurícula izquierda. Los niveles basales de CT1 e IGF-1 fueron similares entre atletas y controles sedentarios. El correr la maratón aumentó los niveles de estas dos hormonas en un subgrupo de atletas. Solo los atletas que incrementaron los niveles de IGF-1, pero no de CT1, tenían volúmenes de ventrículo izquierdo y derecho más grandes que los otros atletas. Conclusiones: IGF-1 que se incrementa de forma aguda por el ejercicio, pero no CT1, estaría asociado con el aumento de los volúmenes ventriculares observado en los atletas.

Background: High intensity exercise induces the development of myocardial hypertrophy necessary to adapt the heart to the increased work demand. Whether running a marathon is associated with acutely induced humoral factors responsible for the development of myocardial hypertrophy observed in athletes is not known. Objective: To evaluate the levels of cardiotrophin-1 (CT1) and insulin-like growth factor-1 (IGF-1), known hypertrophy inducers, in marathon runners before and just after running a marathon and their relationship with cardiac hypertrophy. Methodology: Single-blind prospective study of male athletes who ran the Santiago's marathon. A sedentary control group was included. All subjects underwent a standard transthoracic echocardiogram. CT1 and IGF-1 levels were determined in plasma obtained before (basal) and just after finishing (within 15 min) the marathon using ELISA assays. Results: Athletes had lower heart rates than controls, associated with greater myocardial hypertrophy, as determined by thickness of the heart's septum and posterior wall, and left atrial and ventricular volumes. Basal CT1 and IGF-1 levels were similar between athletes and sedentary controls. Marathon running increased the levels of these two hormones in a subgroup of athletes. Only the athletes who increased IGF-1 levels, but not CT1, had larger left and right ventricular volumes. Conclusion: IGF-1 acutely increased by exercise, but not CT1, was associated with the augmented ventricular volumes observed in athletes.

Lenvatinib down-regulates IGF1R/Mek/Erk signaling pathway in the treatment of regorafenib-resistant hepatocellular carcinoma / 中华肿瘤杂志

Objective: To investigate the therapeutic effect and mechanism of lenvatinib on regorafenib-resistant hepatocellular carcinoma cells. Methods: CCK-8 and clone formation assay were used to observe the inhibitory effect of lenvatinib on the growth of hepatocellular carcinoma cells. Flow cytometry was used to detect the apoptosis of regorafenib-resistant hepatocellular carcinoma cells treated with lenvatinib. The expression levels of related proteins were detected by western blot and immunohistochemical staining. The inhibitory effect of lenvatinib on the tumor formation ability of regorafenib-resistant hepatocellular carcinoma cells in vivo was observed by subcutaneous tumor formation experiment in mice. Results: CCK-8 and clone formation assay showed that lenvatinib could inhibit the proliferation of regorafenib-resistant hepatocellular carcinoma cells. The number of clones of HepG2, SMMC7721 and regorafenib-resistant HepG2, SMMC7721 cells in lenvatinib group (120.67±11.06, 53.00±11.14, 55.00±9.54, 78.67±14.64) were all lower than those in control group (478.00±24.52, 566.00±27.87, 333.67±7.02, 210.00±12.77, all P<0.05). Flow cytometry showed that lenvatinib could promote apoptosis of regorafenib-resistant hepatocellular carcinoma cells, the apoptosis rates of HepG2, SMMC7721 and regorafenib-resistant HepG2, SMMC7721 cells in lenvatinib group [(12.30±0.70)%, (9.83±0.38)%, (15.90±1.32)%, (10.60±0.00)%] were all higher than those in control group [(7.50±0.87)%, (5.00±1.21)%, (8.10±1.61)%, (7.05±0.78)%, all P<0.05]. The apoptosis-related protein levels suggested that apoptosis was increased in the treatment of lenvatinib. The animal study showed that lenvatinib can inhibit the growth of regorafenib-resistant cells in vivo. Immunohistochemistry and western blot results showed that lenvatinib could down-regulate the abnormally activated IGF1R/Mek/Erk signaling pathway in regorafenib-resistant cells. Conclusion: Lenvatinib can reverse regorafenib resistance in hepatocellular carcinoma, possibly by down-regulating IGF1R/Mek/Erk signaling pathway.

Effects of plasma exosome⁃derived miR⁃29b⁃3p on myocardial cell inj ury in hypoxia/reoxygenation after sevoflurane postconditioning via targeting IGF1 / 安徽医科大学学报

Objective @#The purpose of this study was to investigate the effects of plasma exosome⁃derived miR⁃29b⁃3p in myocardial ischemia⁃reperfusion injury ( MIRI) rats on hypoxia/reoxygenation ( H/R) cardiomyocyte after sevoflurane (SEV) postconditioning through targeting IGF1 . @*Methods @# The GEO database was used to screen differentially expressed miRNAs in MIRI , and cardiomyocytes were treated with H/R to construct a MIRI cell model. The expression of miR⁃29b⁃3p and IGF1 in the MIRI cell model post⁃treated with SEV was intervened , and then the survival rate of cardiomyocytes was detected by MTT , apoptosis was detected by flow cytometry , and inflammatory factors (IL⁃1β and TNF⁃α ) in cardiomyocytes in each group were detected by ELISA.@*Results @#Compared with Normal group , the expression of miR⁃29b⁃3p in plasma exosomes of MIRI rats was enhanced (P < 0. 05) , and the target⁃binding relationship between miR⁃29b⁃3p and IGF1 was confirmed ( P < 0. 05) . After SEV post⁃treatment , the expression of miR⁃29b⁃3p in H/R⁃stimulated cardiomyocytes decreased , while the expression of IGF1 increased (both P < 0. 05) . Overexpression of miR⁃29b⁃3p in plasma exosomes could significantly inhibit the survival rate of H/R cells after SEV treatment , aggravate apoptosis and inflammatory response , while knockdown of miR⁃29b⁃3p showed a opposite effects (all P < 0. 05) . The rescue experimental data showed that overexpression of IGF1 could partially reverse the effects of overexpression of miR⁃29b⁃3p on H/R cell injury after SEV treatment ( all P <0. 05) .@*Conclusion @#Plasma exosome⁃derived miR⁃29b⁃3p promotes H/R cardiomyocyte injury after SEV treatment by targeting IGF1 .

The relationship between serum leptin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels and clinical parameters in primary fibromyalgia patients

SUMMARY OBJECTIVE: The aim of this study was to investigate the levels of leptin, growth hormone, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 and their relations with clinical parameters in patients with primary fibromyalgia and healthy controls. METHODS: Our study was performed on 30 female patients with primary fibromyalgia and 30 healthy controls. The levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 were measured by a two-site immunoradiometric assay. The serum level of leptin was measured by the ELISA kit. RESULTS: The serum level of leptin was significantly higher, but the serum levels of insulin-like growth factor-1 were significantly lower in patients with fibromyalgia syndrome than healthy controls (p<0.001). The leptin level was positively correlated with the Visual Analog Scale, Fibromyalgia Impact Questionnaire score, Beck Depression Inventory score, tender point count, age, and duration of disease (p<0.001), but it was negatively correlated with insulin-like growth factor-1 (p<0.001). The insulin-like growth factor-1 level was negatively correlated with age, Visual Analog Scale, Fibromyalgia Impact Questionnaire and Beck Depression Inventory scores, duration of disease, and tender point count (p<0.001). CONCLUSION: Our results indicate that high levels of serum leptin and low levels of serum insulin-like growth factor-1 may play a role in the physiopathogenesis of fibromyalgia and may be related to some symptoms.

Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.

Effect and mechanism of Zuogui Pills on neural function recovery in ischemic stroke mice based on OPN/IGF-1/mTOR / 中国中药杂志

To explore the effect and mechanism of Zuogui Pills in promoting neural tissue recovery and functional recovery in mice with ischemic stroke. Male C57BL/6J mice were randomly divided into a sham group, a model group, and low-, medium, and high-dose Zuogui Pills groups(3.5, 7, and 14 g·kg~(-1)), with 15 mice in each group. The ischemic stroke model was established using photochemical embolization. Stiker remove and irregular ladder walking behavioral tests were conducted before modeling and on days 7, 14, 21, and 28 after medication. Triphenyl tetrazolium chloride(TTC) staining was performed on day 3 after modeling, and T2-weighted imaging(T2WI) and diffusion-weighted imaging(DWI) were performed on day 28 after medication to evaluate the extent of brain injury. Hematoxylin-eosin(HE) staining was performed to observe the histology of the cerebral cortex. Axonal marker proteins myelin basic protein(MBP), growth-associated protein 43(GAP43), mammalian target of rapamycin(mTOR), and its downstream phosphorylated s6 ribosomal protein(p-S6), as well as mechanism-related proteins osteopontin(OPN) and insulin-like growth factor 1(IGF-1), were detected using immunofluorescence and Western blot. Zuogui Pills had a certain restorative effect on the neural function impairment caused by ischemic stroke in mice. TTC staining showed white infarct foci in the sensory-motor cortex area, and T2WI imaging revealed cystic necrosis in the sensory-motor cortex area. The Zuogui Pills groups showed less brain tissue damage, fewer scars, and more capillaries. The number of neuronal axons in those groups was higher than that in the model group, and neuronal activity was stronger. The expression of GAP43, OPN, IGF-1, and mTOR proteins in the Zuogui Pills groups was higher than that in the model group. In summary, Zuogui Pills can promote the recovery of neural function and axonal growth in mice with ischemic stroke, and its mechanism may be related to the activation of the OPN/IGF-1/mTOR signaling pathway.

Effect of overweight / obesity on serum immunoglobulin and IGF-1 levels in children with recurrent respiratory tract infection / 公共卫生与预防医学

Objective To explore the effect of overweight / obesity on the levels of serum immunoglobulin and IGF-1 in children with recurrent respiratory tract infection and its clinical preventive value. Methods In the study, 126 children with recurrent respiratory tract infection admitted to our hospital from January 2019 to June 2021 were included in the analysis, and the BMI standard levels of different age groups were compared to distinguish the children's body types, and then compared with the overweight/obese patients. The information of serum IGF-1 and immunoglobulin levels in infants, obese patients and normal children were analyzed and discussed, and the factors of body type, the expression of serum IGF-1 and immunoglobulin (IgG, IgA, IgM) and the relationship between repeated respiratory tract infection in children were analyzed and discussed. The association between occurrence and disease in order to guide prevention and clinical work. Statistical analysis was performed using SPSS 19.0. Results The average age of 126 children with recurrent respiratory tract infection was (5.24±2.09) years old, including 71 male children and 55 female children, 79 mild children and 47 severe children. According to the BMI standard level of age group, 39 overweight and obese children were detected in this study, 16 were thin children, and the remaining 71 children were normal. The expression levels of IGF-1 and IgG, IgA, and IgM were the lowest among the children with different disease states (P<0.05). The expression of -1, IgG, IgA, and IgM was positively correlated with the children's height, weight and BMI (all P<0.05). Conclusion The decreased expression of IGF-1, IgG, IgA and IgM was associated with the aggravation of recurrent respiratory tract infection, especially in emaciated children. It may be associated with low expression of IGF-1 and poor growth and development, low expression of IgG, IgA and IgM and poor immune level. It can actively prevent recurrent respiratory tract infection, especially severe syndrome recurrent respiratory tract infection, in children with high-risk body type, low growth and development level and immune status.

Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-I

Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2Y64A and βarr2Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

Inhibitory Effect and Mechanism of Petroleum Ether Extracts from Gastrodia elata on Aβ Protein Toxicity in Caenorhabditis Elegans / 世界科学技术-中医药现代化

Objective To explore the effect and possible mechanism of petroleum ether extract from Gastrodia elata on A amyloid β-protein deposition in Caenorhabditis elegans(C.elegans).Methods C.elegans was used as the model organism,and the experiment was divided into blank group(Control group),GEPEE 0.5 mg·mL-1 group and GEPEE 1 mg·mL-1 group.The effects of GEPEE on paralysis,life span,oxidative stress,heat stress,reactive oxygen species(ROS)level and Aβ aggregation of C.elegans were investigated,qRT-PCR was used to detect the changes of gene expression related to insulin/IGF-1 signaling pathway(IIS)in C.elegans.The main components were analyzed by high performance liquid chromatography(HPLC).Results Compared with Control group,GEPEE could significantly improve the paralysis phenotype of C.elegans(P<0.01),prolong the lifespan of C.elegans(P<0.01),enhance the motility of C.elegans(P<0.01),and increased the resistance to external oxidative stress(P<0.01),the stress ability of high temperature(P<0.01),improved the deposition of Aβ in vivo(P<0.01),decreased the ROS content in C.elegans(P<0.01),decreased the expression levels of Aβ and DAF-2(P<0.01),increased the expression levels of DAF-16 and its target genes SOD-3,GSH-Px,HSF-1 and its target gene HSP-16.2,SKN-1 and its target gene GST-4(P<0.01).Its main components were p-hydroxybenzyl alcohol and p-ethoxylbenzyl alcohol by HPLC.This study showed that GEPEE can reduce Aβ-induced toxicity in CL4176 C.elegans by reducing ROS level in vivo,increasing antioxidant level and regulating IIS pathway.Conclusion GEPEE can inhibit the toxicity of Aβ protein,and its mechanism is related to the regulation of IIS signaling pathway.

The state of Sergipe contribution to GH research: from Souza Leite to Itabaianinha syndrome

ABSTRACT In the late 19th century, José Dantas de Souza Leite, a physician born in Sergipe, published the first detailed clinical description of acromegaly under the guidance of the French neurologist Pierre Marie. In 2014, the Brazilian Society of Endocrinology and Metabolism created the "José Dantas de Souza Leite Award", which is granted every two years to a Brazilian researcher who has contributed to the development of endocrinology. In 2022, the award was given to another physician from Sergipe, Manuel Hermínio de Aguiar Oliveira, from the Federal University of Sergipe for the description of "Itabaianinha syndrome" in a cohort of individuals with isolated GH deficiency due to a homozygous inactivating mutation in the GH-releasing hormone receptor gene. This research, which was carried out over almost 30 years, was performed in partnership with Roberto Salvatori from Johns Hopkins University and in collaboration with other researchers around the world. This review article tells the story of Souza Leite, some milestones in the history of GH, and summarizes the description of Itabaianinha syndrome.

PROSTATE CANCER AND DIABETES BIOLOGY OR DETECTION BIAS

Prostate cancer and diabetes are the two highly prevalent health problems in men worldwide and have a high mortality rates but their association is quite complex and contradictory. This review reported several population based studies which tried to establish a possible association and explains the mechanism by which diabetes exhibits its effect on prostate cancer progression. It also explores the literature around the expression of various receptors and genes which enlightens the possible molecular basis of association and the effect of current antidiabetic drugs like metformin and insulin on the growth and advancement of prostate cancer in diabetic men. Masking of early tumor detection by diabetes might be the possible explanation for the reported inverse association with worse prognosis and shorter survival rate in diabetic prostate cancer patients.

Correlation of body mass index to Ghrelin and IGF-1 among children with short stature

Abstract Objective: To assess the BMI among children with Growth Hormone Deficiency (GHD) and Idiopathic Short Stature (ISS) and its correlation to ghrelin, Growth Hormone (GH), and Insulin-like Growth Factor-1 (IGF-1) levels. Methods: A cross-sectional descriptive study in which 42 patients attending the Pediatric endocrine clinic were enrolled, allocated into two groups: group I: GHD children; group II: ISS children. Ghrelin, IGF-1 and GH in both groups were measured. Results: Ghrelin was significantly higher among GHD group (p < 0.001). Overall, there was a strong negative correlation between IGF-1 and ghrelin (r = -0.977, p-value = < 0.001) while a moderate positive correlation between ghrelin and BMI (r = 0.419, p-value = 0.006). There was a weak positive non-significant correlation between IGF-1 and BMI (r = 0.276, p-value = 0.077). In GHD group, there was a weak positive non-significant correlation between ghrelin and GHmax measurement (r = 0.052, p-value = 0.824), while a weak negative non-significant correlation between both variables in ISS group (r = -0.243, p-value = 0.288). In GHD group, there was a moderate positive correlation between ghrelin and BMI (r = 0.500, p-value = 0.021), but weak negative non-significant correlation between both variables in ISS group (r = -0.255, p-value = 0.265). Conclusion: There was a negative feedback loop between ghrelin and IGF-1, whereas a positive feedback between ghrelin and BMI. BMI was more affected in the ISS group but was non-signifi-cantly correlated with ghrelin. There was no significant compensatory response of ghrelin suggesting its contribution to the pathogenesis of ISS.

Porcine Circular RNA Insulin-like Growth Factor 1 Receptor Promotes Adipocyte Differentiation / 中国生物化学与分子生物学报

Circular RNA (circRNA), as a competitive endogenous RNA (ceRNA), plays an importantrole in the regulation of cell differentiation. The purpose of this study was to identify and analyze porcinecircular RNA insulin-like growth factor 1 receptor (circIGF1R), explore its expression patterns, construct a ceRNA regulatory network related to circIGF1R, and explore the regulation of its ectopicexpression on adipogenic differentiation of mouse mesenchymal stem cells (C3H10T1 / 2) effect. Forwardand reverse PCR, Sanger sequencing, RNase R enzyme digestion tests, and qRT-PCR were used toverify that circIGF1R is a circRNA formed by the second exon of insulin-like growth factor 1 receptor(IGF1R). It was expressed in all tissues of pigs, and its expression level increased with age in adiposetissues. miRDB, TargetScan and miRWalk online software were used to predict circIGF1R target genes. RNAhybrid software was used for binding site prediction. DAVID bioinformatics functional analysissoftware was used to perform GO and KEGG enrichment analysis on candidate target genes. Cytoscapesoftware was used to construct the ceRNA network diagram. Based on the gene expression correlation andpredicted target relationship, the GO and KEGG enrichment analysis was drawn and the ceRNA networkwas constructed; the dual luciferase reporter gene test was used, and we found that circIGF1R andFABP4 can bind to ssc (Sus scrofa chromosome) -miR-133a-5p. The circIGF1R overexpression vectorwas successfully constructed and expressed in C3H10T1/ 2 cells. It was found that after overexpression ofcircIGF1R, the expression of key adipogenic regulatory factors CEBPa, CEBPß, FABP4 and PPAR? increased significantly(P<0. 01), and the number of lipid droplets increased significantly. The results ofthis study show that circIGF1R exists in pig adipose tissues, and may positively regulate the adipogenicdifferentiation of C3H10T1/ 2 cells through the ceRNA mechanism, which lays a theoretical foundation forfurther research on circIGF1R regulating the adipogenic differentiation of pig precursor intramuscularadipocytes.

LINC00649 Regulates Endoplasmic Reticulum Stress-mediated Cervical Carcinoma Cell Apoptosis via miR-424-5p/IGF1R Axis / 肿瘤防治研究

Objective To explore the effects of LINC00649/miR-424-5p/IGF1R on ERs-mediated apoptosis of cervical carcinoma (CC) cells. Methods CC-related data was obtained from GEO database, then the differentially-expressed miRNAs were analyzed. The bioinformatics database was used to predict the upstream and downstream targets of miR-424-5p. LINC00649 and IGF1R were included. Dual luciferase reporter assay was adopted to confirm the targeting relationship. qRT-PCR was used to detect the expression levels of LINC00649, miR-424-5p and IGF1R in CC tissue and cells. CCK-8 and flow cytometry were used to evaluate the proliferation and apoptosis of CC cells. Western blot was used to detect the expression of ERs-related proteins GRP78, CHOP and Caspase-12. Results Compared with paracancerous tissue and H8 cells, LINC00649 and IGF1R were up-regulated in CC tissue and cells, while miR-424-5p was down-regulated (both P < 0.05). The abnormally high expression of LINC00649 in CC was related to poor prognosis. The knockdown of LINC00649 inhibited CC cell viability and induced cell apoptosis by promoting ERs (all P < 0.05). LINC00649 upregulated the expression of IGF1R via absorbing miR-424-5p. miR-424-5p inhibitor or IGF1R overexpression partially reversed the effects of LINC00649 knockdown on CC cells (both P < 0.05). Conclusion LINC00649 could reduce cell apoptosis and improve cell viability by inhibiting the ERs process via regulating miR-424-5p/IGF1R axis in CC.

let-7b-5p suppresses the proliferation and migration of pulmonary artery smooth muscle cells via down-regulating IGF1

Abstract Objectives Some previous studies indicated that the excessive proliferation and migration of Pulmonary Artery Smooth Muscle Cells (PASMCs) could be observed in pulmonary artery intima after Pulmonary Embolism (PE) occurred. In addition, recent studies identified some miRNAs that are differentially expressed in the blood of PE patients, which might be used as a diagnostic biomarker for PE, including let-7a-5p, let-7b-5p, and miR-150-5p. Hence, the authors sought to explore the effects of let-7b-5p in PASMC proliferation and migration and the corresponding regulatory mechanism. Methods Platelet-Derived Growth Factor (PDGF) was utilized to induce the hyper-proliferation model in PASMCs. The mRNA and protein expression levels were detected by RT-qPCR and western blot, respectively. The proliferation of PASMCs was evaluated by the detection of PCNA expression, as well as CCK-8 and Edu assays. Wound healing and Transwell assays were exploited to assess the migration ability of PASMCs. The targets of let-7b-5p were predicted based on two bioinformatics online tools. Dual-luciferase and Ago2 pull-down assays were applied to confirm the interaction between let-7b-5p and IGF1. Results 40 ng/mL PDGF was selected as the optimal concentration to induce PASMCs. let-7b-5p mimics suppressed the proliferation and migration of PDGF-induced PASMCs, while let-7b-5p inhibitor led to the opposite result. In further mechanism exploration, IGF1 was predicted and confirmed as the direct target gene of let-7b-5p. The promotion role of IGF1 overexpression on the proliferation and migration of PDGF-induced PASMCs was dramatically countered by let-7b-5p mimics. Conclusion let-7b-5p prohibits the proliferation and migration of PDGF-induced PASMCs by modulating IGF1.

Investigation on the IGF-1 and lipid level in term small for gestational age infants within 24 hours postnatally / 中国新生儿科杂志

Objective:To study the insulin-like growth factors-1 (IGF-1) and lipid level of term small for gestational age (SGA) infants within 24 hours postnatally and to explore the correlation between IGF-1 and blood lipids.Methods:A prospective study was conducted on singleton term SGA and appropriate for gestational age infant (AGA) who were delivered and admitted to the neonatal ward of Guangdong Women and Children Hospital within 24 hours after birth from May 2020 to January 2021, and the infants were divided into SGA and AGA groups to compare the differences in IGF-1 and lipid levels within 24 hours after birth and to analyze the correlation between IGF-1 and lipids.Results:A total of 95 cases in the SGA group and 84 cases in the AGA group were included in the study. The proportion of infants with IGF-1 <25 ng/ml was significantly higher in SGA group (87.4%) than in the AGA group (52.4%). It was also found that the proportion of infants with IGF-1 <25 ng/ml in SGA was significantly higher than that in AGA within different gender composition groups, early-term and full-term births groups. The triglyceride (TG) level was higher in the SGA group than that in the AGA group, but the high-density lipoprotein cholesterol (HDL-C) level was lower than that in the AGA group ( P<0.05). IGF-1 level within 24 hours postnatally in SGA and AGA was positively correlated with HDL-C levels ( P<0.01) and negatively correlated with TG ( P<0.01), and HDL-C level was a predictor of IGF-1. Conclusions:Compared with term AGA, SGA term infants showed insufficient IGF-1 and HDL-C secretion and high TG within 24 hours after birth. Nutritional support for SGA should be given promptly after birth to avoid hypoglycemia and to stimulate IGF-1 secretion.