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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.
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Objective:To investigate the role of a disintegrin and metalloprotease 12 (ADAM12) gene in chondrocyte injury in patients with Kashin-Beck disease (KBD) and its impact on genes related to insulin-like growth factor binding protein (IGFBP).Methods:Articular cartilage samples were obtained from 5 patients with KBD and 5 control subjects admitted to Honghui Hospital Affiliated to Xi'an Jiaotong University. Chondrocytes were extracted and cultured in vitro. Quantitative real-time PCR (qRT-PCR) and Western blotting were used to detect the expression levels of ADAM12 mRNA and protein in chondrocytes of patients with KBD and control subjects, respectively. Subsequently, ADAM12 gene overexpression was performed using lentivirus in chondrocytes of patients with KBD. MTT assay was used to detect changes in cell viability after ADAM12 gene overexpression, and qRT-PCR was used to detect the mRNA expression levels of chondrocyte differentiation related genes SRY-box transcription factor 9 (SOX9) and type Ⅱ collagen (COLⅡ), apoptosis-related gene B-cell lymphoma/leukaemia-2-associated X protein (BAX), and anabolic related genes IGFBP3 and IGFBP5. Results:The expression levels of ADAM12 mRNA and protein in chondrocytes of patients with KBD (0.57 ± 0.05, 0.81 ± 0.07) were significantly lower than those of control subjects (1.00 ± 0.00, 1.00 ± 0.00), and the differences were statistically significant ( t = - 24.50, - 3.61, P < 0.05). The results of MTT assay showed that the cell viability of chondrocytes in ADAM12 overexpression group (1.09 ± 0.05) was higher than that in empty vector control group (1.00 ± 0.08), and the difference was statistically significant ( t = 4.12, P = 0.031). The results of qRT-PCR showed that compared with empty vector control group, the mRNA expression levels of IGFBP3 (2.35 ± 0.79 vs 0.96 ± 0.25), IGFBP5 (2.13 ± 0.30 vs 0.98 ± 0.34), SOX9 (2.92 ± 0.51 vs 0.94 ± 0.36) and COLⅡ (6.45 ± 2.81 vs 0.87 ± 0.19) in ADAM12 overexpression group were significantly increased, and the differences were statistically significant ( t = 3.19, 5.16, 6.27, 4.10, P < 0.05); while the expression level of BAX mRNA (0.31 ± 0.06 vs 1.02 ± 0.22) was significantly decreased, and the difference was statistically significant ( t = - 11.16, P < 0.001). Conclusion:The ADAM12 gene may have a role in inhibiting apoptosis and promoting differentiation in chondrocyte injury in patients with KBD, and its overexpression can increase expression of IGFBP3 and IGFBP5.
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@#Type 2 diabetes mellitus(T2DM)was a chronic,non-communicable disease with a combination of multiple genetic and environmental factors,of which the main characteristics included insufficient insulin secretion and insulin resistance.Insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2/IMP2),an important insulin secretion-related protein in human body,is mainly expressed in tissues and cells such as pancreas,fat and intestine.It has been confirmed that IGF2BP2 can down-regulate the expression of IGF2 and the function damage of the related islet β cell is an important cause of T2DM and vascular complications.Therefore,IGF2BP2 gene can be used as an important predictor for diabetes mellitus risk.This paper reviews the correlation between IGF2BP2 gene and T2DM.
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ObjectiveTo investigate the pharmacodynamic characteristics and explore the molecular mechanism of Honghua oral liquid （HOL） in relieving neuropathic pain （NP）. MethodHealthy male SD rats were randomly assigned into sham group， model group， low-， medium-， high-dose （0.5， 1.0， 2.0 mL·kg-1·d-1， respectively） HOL groups， and a positive drug （pregabalin， 25 mg·kg-1·d-1） group， with 6 rats in each group. Spinal nerve ligation （SNL） of L5 was conducted in other groups except the sham group. Drug administration was performed 3 days after the SNL surgery for 2 consecutive weeks， and samples were collected after the end of the administration. During the treatment period， the mechanical pain threshold and cold pain threshold were determined to measure the pain-relieving effect of HOL. Transcriptome sequencing was performed on hippocampal tissue samples from the sham， model， and high-dose HOL groups， and differentially expressed genes between the sham group and the model group as well as the model group and HOL high-dose group were obtained. After pathway enrichment analysis， we selected the targets which were closely related to neuroinflammation for validation， and predicted the specific binding sites of the major active components in HOL with the targets through molecular docking. In addition， the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-10 （IL-10） were determined by enzyme-linked immunosorbent assay （ELISA） to evaluate the effect of HOL on neuroinflammation in NP rats. ResultCompared with the sham group， SNL decreased the mechanical pain threshold and cold pain threshold （P<0.05）. Compared with the model group， HOL recovered the mechanical pain threshold and cold pain threshold （P<0.05）. The transcriptome data showed that 376 differentially expressed genes （DEGs） were identified between the model group and the sham group， including 124 upregulated genes and 252 downregulated genes， and 194 DEGs between the model group and the high-dose HOL group， including 33 upregulated genes and 161 downregulated genes. Among them， insulin-like growth factor 1（IGF1）， matrix metallopeptidase-2 （MMP-2）， matrix metallopeptidase-14 （MMP-14）， erb-B2 receptor tyrosine kinase 2 （ERBB2）， and integrin subunit alpha 5 （ITGA5） associated with NP were selected for further validation. The Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） results showed that compared with the sham group， the modeling up-gurelated the mRNA levels of the above five molecules in the hippocampus （P<0.01）. Compared with model group， HOL down-regulated the mRNA levels of these molecules （P<0.01）. The molecular docking results showed that the main active components of safflower， hydroxysafflor yellow A， kaempferol， and quercetin， formed stable hydrogen bonds with the amino acid residues of IGF1， MMP-2， MMP-14， ERBB2， and ITGA5. The enzyme-linked immunosorbent assay（ELISA） results showed that compared with those in the sham group， the serum levels of TNF-α and IL-10 were out of balance in the model rats （P<0.01）. Compared with the model group， HOL lowered the level of the pro-inflammatory cytokine TNF-α （P<0.01） and elevated that of the anti-inflammatory cytokine IL-10 （P<0.05）. ConclusionHOL exerts analgesic effect on SNL rats by inhibiting neuroinflammation.
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Teprotumumab-trbw,a monoclonal antibody that acts on the insulin growth factor-Ⅰ receptor, was approved in 2020 for the treatment of thyroid-associated ophthalmopathy, but little is known about it in China. It is hoped to provide guidance for clinical use through the review of its molecular structure, pharmacokinetics, therapeutic mechanism, clinical research and safety. It inhibits immune inflammation by blocking thyroid-stimulating hormone receptor /insulin growth factor-Ⅰ receptor crosstalk signaling, so as to reduce the production of hyaluronic acid and inflammatory factors in response. It can also promote the apoptosis of retro-orbital fibroblasts/adipocytes and inhibit the expression of genes related to the synthesis of thyroid hormones, thereby significantly improving the clinical symptoms such as exophthalmos and diplopia. The common adverse reactions of Teprotumumab-trbw are muscle spasm, hyperglycemia, hearing loss and so on. Teprotumumab-trbw is effective and durable in the treatment of thyroid-associated ophthalmopathy, and patients with secondary treatment can also benefit from it, which provides a new way and hope for the treatment of thyroid-associated ophthalmopathy.
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Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease associated with thyroid dysfunction that can significantly impact quality of life, result in visual impairment and facial disfigurement. Traditional treatments are often unsatisfactory. Studies have shown that teprotumumab, a human monoclonal antibody that can inhibit insulin-like growth factor 1 receptor(IGF-1R), has become an emerging targeted drug for TAO. Although the drug has proven to be effective and relatively safe in the treatment of TAO, adverse reactions are worthy of attention of ophthalmologists with the continuous promotion of clinical application, including hearing impairment, hyperglycemia, diarrhea, muscle spasms, infusion reactions, cognitive decline, thyroid suppression, alopecia, nausea and fatigue. Teprotumumab was generally well tolerated, with most adverse events being mild or moderate in severity. This paper aims to review the adverse reactions and precautions of teprotumumab in the treatment of TAO.
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ObjectiveTo investigate the inhibitory effects and mechanism of the compound Phyllanthus urinaria Ⅱ （CPU Ⅱ）on the growth of transplanted hepatocellular carcinoma Hep3B2.1-7 （Short for Hep3R） cells in nude mice. MethodAfter the establishment of a xenograft model of hepatocellular carcinoma Hep3B cells in mice， the model mice were randomly divided into a model group， a high-dose CPU Ⅱ group （57.5 g·kg-1）， a low-dose CPU Ⅱ group （28.75 g·kg-1）， and a 5-fluorouracil （5-FU） group （0.025 g·kg-1）， with eight mice in each group. The mice in the high- and low-dose CPU Ⅱ groups were treated with drugs by gavage， once per day， and those in the model group were treated with the same volume of normal saline. The mice in the 5-FU group were treated by 5-FU by intraperitoneal injection， once every other day. After 28 days of administration， mice were sacrificed， and transplanted tumors were collected. Immunohistochemistry （IHC） was used to detect the expression of proliferating cell nuclear antigen （PCNA） of tumor tissues. Terminal-deoxynucleotidyl transferase-mediated nick end labeling （TUNEL） was used to detect cell apoptosis of tumor tissues. The mRNA expression of miR-122 and insulin-like growth factor 1 receptor （IGF-1R） in tumor tissues was detected by Real-time quantitative PCR （Real-time PCR）. The protein expression of CCAAT/enhancer-binding protein α （C/EBPα）， hepatocyte nuclear factor-4α （HNF-4α）， and IGF-1R in tumor tissues was detected by Western blot. ResultThe tumor suppression rates of the high- and low-dose CPU Ⅱ groups and the 5-FU group were 74.90%， 63.62%， and 64.15%， respectively. Compared with the model group， the CPU Ⅱ groups and the 5-FU group showed reduced weight （P<0.01） and volume of tumors （P<0.01）， decreased PCNA positive cells， shallow staining， increased apoptosis cells of transplanted tumor tissues （P<0.05， P<0.01）， increased expression of mRNA expression of miR-122 （P<0.01）， down-regulated mRNA expression of IGF-1R （P<0.01）， and up-regulated protein expression of C/EBPα and HNF-4α in nude mouse transplanted tumor tissues （P<0.01）. The expression of IGF-1R protein in the high-dose CPU Ⅱ group was down-regulated （P<0.05）. Compared with the low-dose CPU Ⅱ group， the high-dose CPU Ⅱ group showed increased apoptotic cells （P<0.01）， up-regulated mRNA expression of miR-122 （P<0.01）， and increased expression of C/EBPα and HNF-4α proteins （P<0.01）. ConclusionCPU Ⅱ has an obvious inhibitory effect on the growth of transplanted hepatocellular carcinoma Hep3B cells in nude mice. The mechanism of action is related to enhancing the expression of transcription factors HNF-4α and C/EBPα， thereby promoting the expression of miR-122 and inhibiting the expression of its target gene IGF-1R.
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Objective:To evaluate the relationship between hippocampal miR-3065-5p and insulin-like growth factor-1/phosphatidylinositol 3-kinase/protein kinase B(IGF-1/PI3K/Akt)signaling pathway in a mouse model of perioperative neurocognitive disorder (PND).Methods:Eighty clean-grade healthy male C75BL/6 mice, aged 12-14 weeks, weighing 20-30 g, were divided them into 4 groups ( n=20 each) using the random number table method: control group (C group), PND group, miR-3065-5p agonist group (Ag group) and miR-3065-5p agonist negative control group (Ag-NC group). PND model was prepared by internal fixation of tibial fracture under anesthesia with 1.5% isoflurane. Two days before developing the model, miR-3065-5p agomir 2 μl was injected into the lateral ventricle in Ag group, miR-3065-5p agomir negative control 2 μl was injected into the lateral ventricle in Ag-NC group. Morris water maze test and open field test were performed at 7 days after surgery. The mice were sacrificed after the end of test, and hippocampal tissues were obtained for determination of the expression of miR-3065-5p, IGF-1 mRNA and Bcl-2 mRNA (by quantitative real-time polymerase chain reaction) and expression of IGF-1, phosphorylated Akt (p-Akt), phosphorylated glycogen synthase kinase-3β (p-GSK3β) and Bcl-2 (by Western blot). Results:There was no significant difference in each parameter in the open field test among the four groups ( P>0.05). Compared with group C, the postoperative escape latency was significantly prolonged, the percentage of time of stay at the target quadrant was decreased, the number of crossing the original platform was reduced, the expression of miR-3065-5p was up-regulated, and the expression of IGF-1 mRNA, Bcl-2 mRNA, IGF-1, p-Akt, p-GSK3β and Bcl-2 was down-regulated in the other three groups ( P<0.05). Compared with PND group and Ag-NC group, the postoperative escape latency was significantly prolonged, the percentage of time of stay at the target quadrant was decreased, the number of crossing the original platform was reduced, the expression of miR-3065-5p was up-regulated, and the expression of IGF-1 mRNA, Bcl-2 mRNA, IGF-1, p-Akt, p-GSK3β and Bcl-2 was down-regulated in Ag group ( P<0.05). Conclusions:Up-regulation of miR-3065-5p can inhibit the activation of IGF-1/PI3K/Akt signaling pathway, which might be one of the mechanisms of PND developed in mice.
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Abstract Objective: To determine the prevalence of vitamin A deficiency (VAD) and serum concentrations of retinol, correlating them with IGF-1 concentrations in preschoolers with DS. Methods: Cross-sectional study was conducted on 47 children with DS aged 24 to 72 months, in Ribeirão Preto, Brazil. VAD was determined by the relative dose-response (RDR) test. Retinol serum concentration ≤ 0.70 μmol/L and IGF-1 serum concentration below the 3rd percentile for sex and age were considered to represent deficiency. C-reactive protein (CRP) was determined at the beginning of the study. Weight, height, and information about fever and/or diarrhea were obtained at the beginning of the study. Results: VAD prevalence was 25.5% (12/47), and 74.5% (35/47) of the children had deficient retinol before the intervention. CRP was not associated with VAD. Mean IGF-1 were 103.5 ng/mL (SD = 913) for the group with VAD and 116.3 ng/mL (SD = 54.9) for the group with no VAD (p-value = 0.85); 8.5% (4/47) of the children showed deficient IGF-1, but without VAD. No association was observed between VAD and IGF-1 deficiency. A moderate positive correlation was observed between pre-intervention retinol and IGF-1 (ρ = 0.37; p-value = 0.01). Conclusion: a high prevalence of VAD and deficient retinol was observed and there was a positive correlation between serum retinol and IGF-1.
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Humans , Child, Preschool , Child , Vitamin A Deficiency/epidemiology , Insulin-Like Growth Factor I/analysis , Down Syndrome , Vitamin A , Brazil/epidemiology , Prevalence , Cross-Sectional StudiesABSTRACT
Objective:To investigate the effect of milk on sebum secretion in golden hamsters, and to explore its possible mechanism of action.Methods:Eighteen golden hamsters were randomly and equally divided into 3 groups: blank control group receiving no intervention, whole-milk group gavaged with whole milk, and skimmed-milk group gavaged with skimmed milk. The gavage feeding was performed at a dose of 2.5 ml twice a day for 4 consecutive weeks. The maximum transverse diameter and maximum longitudinal diameter of bilateral sebaceous gland spots were measured on days 0, 7, 14, 21 and 28 after the start of intervention, and the area of sebaceous gland spots was calculated; at 24 hours after the last gavage, bilateral sebaceous gland spot tissues were resected, and subjected to immunohistochemical study to determine the expression of insulin-like growth factor-1 (IGF-1) /sterol regulatory element-binding protein-1 (SREBP-1) /acetyl-coenzyme A carboxylase (ACC-1) signaling pathway in sebaceous gland spots. Statistical analysis was carried out by using repeated measures analysis of variance, one-way analysis of variance for independent groups, Kruskal-Wallis H test, and least significant difference- t test for multiple comparisons. Results:Repeated measures analysis of variance showed that there was no significant difference in the area of sebaceous gland spots of golden hamsters among the 3 groups ( F= 0.96, P= 0.417) . The IGF-1 expression was significantly higher in the skimmed-milk group (0.39 ± 0.03) than in the blank control group (0.35 ± 0.03, t= 2.62, P= 0.021) and whole-milk group (0.33 ± 0.02, t= 3.82, P= 0.002) ; compared with the blank control group (0.36 ± 0.02) , the skimmed-milk group showed significantly increased SREBP-1 expression (0.42 ± 0.04, t= 2.64, P= 0.021) ; the ACC-1 expression was significantly higher in the skimmed-milk group (0.40 ± 0.03) and whole-milk group (0.40 ± 0.05) than in the blank control group (0.34 ± 0.03; t= 2.39, 2.47, P= 0.031, 0.026, respectively) . Conclusion:Milk may promote sebum secretion in golden hamsters through the IGF-1/SREBP-1/ACC-1 signaling pathway.
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Objective:To analyzed clinical characteristics of pituitary growth hormone(GH) adenomas patients with different responses to oral glucose inhibitory GH test.Methods:The clinical data of 50 patients with pituitary GH adenomas newly diagnosed with complete test data and case data in the Department of Endocrinology of Chinese PLA General Hospital was retrospectively analyzed from 2016 to 2021. The cases were divided into two groups according to the cutoff point of GH elevating to 50% of basaline during oral glucose test: abnormal elevation group(A group, n=16) and non-elevation group(B group, n=34). The clinical features, biochemistry, iconography, and immunohistochemistry of the two groups were analyzed. Results:The serum total cholesterol(TC)[(3.9±0.8) vs (4.6±0.9)mmol/L], 120 minutes insulin after glucose loading [11.2(4.4, 25.0) vs 92.0(10.8, 311.8)mU/L], long [1.0(0.4, 2.1) vs 1.5(0.5, 7.3) cm] and short[0.6(0.3, 1.3) vs 1.0(0.5, 5.8)cm] diameters of adenomas in A group were less than those in B group(all P<0.05) while insulin-like growth factor Ⅰ(IGF-Ⅰ) level was higher [(908.2±233.7) vs (743.1±273.1) ng/mL, P<0.05]. There were no significant differences in sex, age, disease course, clinical features, random GH, homeostasis model assessment of insulin resistance index(HOMA-IR), pituitary adenoma site, and invasive properties between the two groups. The immunohistochemical positive rates of ACTH(33% vs 0%) and prolactin(100% vs 28.6%)in A group were higher than those in B group( P<0.05). Conclusion:Pituitary GH adenomas patients with a paradoxical GH response pattern display lower serum TC and 120 minutes insulin levels as well as higher IGF-Ⅰ concentration and proportion of pituitary microadenomas. " Pure" growth hormone tumors may represent entities of a particular class of diseases in acromegaly.
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Sepsis is an important cause of acute kidney injury (AKI). About 60% of sepsis patients will develop AKI. At present, the standard of clinical diagnosis of AKI is still based on the changes in serum creatinine and urine volume. Because of its lag in time, it may lead to delay in treatment and increase the mortality. To find a new biomarker similar to "troponin" for the diagnosis of AKI, and to achieve the early diagnosis and prevention of AKI, is of great significance to reduce the mortality of AKI. In recent years, it has been found that tissue inhibitors of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) can be used for early diagnosis of sepsis associated-acute kidney injury (SA-AKI). They also have important values in risk stratification, prognosis judgment, intervention and other aspects of SA-AKI. In this paper, the research progress of the application of TIMP-2 and IGFBP7 in SA-AKI is reviewed.
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OBJECTIVES@#To study the serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in children with autism spectrum disorder (ASD) and their association with the core symptoms of ASD.@*METHODS@#A total of 150 ASD children aged 2-7 years (ASD group) and 165 healthy children matched for age and sex (control group) who were recruited at the outpatient service of Chongqing Health Center for Women and Children were enrolled as subjects. Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) were used to evaluate the core symptoms of the ASD children. Chemiluminescence was used to measure the serum levels of IGF-1 and IGFBP-3 in both groups.@*RESULTS@#The ASD group had a significantly lower serum level of IGF-1 than the control group (P<0.05). The children with severe ASD had significantly lower serum levels of IGF-1 and IGFBP-3 than those with mild-to-moderate ASD (P<0.001). For the children aged 2-3 years, the ASD group had a significantly lower serum level of IGF-1 than the control group (P<0.05). Boys had a significantly lower serum level of IGF-1 than girls in both ASD and control groups (P<0.05). The serum levels of IGF-1 and IGFBP-3 were negatively correlated with the total score of CARS (r=-0.32 and -0.40 respectively, P<0.001).@*CONCLUSIONS@#The reduction in serum IGF-1 level in early childhood may be associated with the development of ASD, and the serum levels of IGF-1 and IGFBP-3 are associated with the core symptoms of ASD children.
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Child , Child, Preschool , Female , Humans , Male , Autism Spectrum Disorder , Autistic Disorder , Insulin-Like Growth Factor Binding Protein 3 , Insulin-Like Growth Factor IABSTRACT
Background Diabetes is a major threat to public health across the world. Studies have shown that exposure to p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) is closely related to the occurrence of type 2 diabetes mellitus. However, the relevant molecular mechanism is not clear. Objective To investigate the effects of p,p'-DDE on H19 differentially methylated region (DMR) methylation and insulin secretion of rat insulinoma cells (INS-1 cells). Methods INS-1 cells were cultured with different concentrations (0, 3.125, 6.25, 12.5, 25, 50, and 75 µmol·L−1) of p,p'-DDE for 24 h, and the viability of INS-1 cells was detected by CCK-8 method. INS-1 cells were exposed to 0, 12.5, 25, and 50 µmol·L−1 p,p'-DDE for 24 h in subsequent experiments. The methylation levels of 24 CpG sites in H19 DMR were analyzed by bisulfite genomic sequencing. The expression levels of insulin-like growth factor 2 (IGF2) mRNA were detected by real-time quantitative PCR. The expression levels of IGF2 and insulin-like growth factor-1 receptor (IGF1R) proteins were detected by Western blotting. The insulin secretion function of INS-1 cells was determined by glucose-stimulatedinsulin secretion test (5 and 25 mmol·L−1 glucose, respectively). Results Compared with the control group, the viability of INS-1 cells increased significantly after treatment with 12.5 µmol·L−1 p,p'-DDE; however, it was significantly inhibited after treatment with 50 or 75 µmol·L−1 p,p'-DDE (P<0.01); therefore, 50 µmol·L−1 was chosen as the maximum concentration of exposure for subsequent experiments. The 25 µmol·L−1 p,p'-DDE treatment decreased the methylation levels of CpG18 and CpG22-CpG24 sites in H19 DMR, and the 50 µmol·L−1 p,p'-DDE treatment decreased the methylation levels of CpG10-CpG24 sites (P<0.05 or P<0.05). Multiple concentrations (12.5, 25, and 50 µmol·L−1) of p,p'-DDE down-regulated the mRNA and protein relative expression levels of IGF2 and the protein relative expression levels of IGF1R. The transcription level of IGF2 decreased to 67.8%, 68.6%, and 62.5% of the control group, the protein level of IGF2 decreased to 73.3%, 79.5%, and 80.9% of the control group, and the protein level of IGF1R decreased to 54.8%, 25.6%, and 12.9% of the control group, respectively (P<0.01). In the high glucose context, p,p'-DDE at selected concentrations inhibited the insulin secretion levels to 85.0%, 58.6%, and 49.5% of the control group, respectively (P<0.01). Conclusion p,p'-DDE could down-regulate methylation level of H19 DMR, interfere the IGF2/IGF1R signaling pathway, and inhibit insulin secretion of islet cells.
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Objective:To explore the predictive value of serum tissue inhibitor of metalloproteinases-2(TIMP-2), insulin-like growth factor-binding protein-7 (IGFBP-7), angiopoietin-2 (Ang-2) and laboratory examination indicators in patients with sepsis associated acute kidney injury (SAKI).Methods:Present study included 69 patients with sepsis, who were admitted to the emergency department of Peking University Third Hospital from April 2017 to August 2018. Within 72 hours of admission, 28 cases developed SAKI. General clinical features including sequential organ failure assessment (SOFA), acute physiological and chronic health status score Ⅱ (APACHE Ⅱ) and laboratory examination indicators including white blood cells (WBC), neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), D-dimer, fibrinogen (Fib), urea, uric acid (UA) were analyzed and serum samples were obtained to detect the levels of biomarkers TIMP-2, IGFBP-7, and Ang-2. Multivariate logistic regression analysis was performed to determine independent risk factors of SAKI, and the receiver operating characteristic (ROC) area under the curve (AUC) was used to assess the early predictive value of biomarkers and laboratory examination indicators for SAKI.Results:Compared with the non-SAKI group, patients in the SAKI group had higher SOFA score, higher incidence of septic shock, higher NLR, PCT, CRP, D-dimer, and UA levels (all P<0.05). The levels of TIMP-2, IGFBP-7, TIMP-2×IGFBP-7 and Ang-2 in the SAKI group were 23.5 (17.3, 30.3)ng/ml, (185.6±47.2)ng/ml, 3.98(2.89, 6.00) (ng/ml) 2/1 000, 1 953 (950, 2 239) pg/ml respectively, which were significantly higher than those in the non-SAKI group (16.4[13.5, 22.4] ng/ml, [139.4±34.7]ng/ml, 2.28[1.57, 4.03](ng/ml) 2/1 000, 576[334, 1 076] pg/ml, respectively, all P<0.05). Logistic regression analysis showed that IGFBP-7 ( OR=1.039, 95%CI 1.000-1.079, P<0.05) and SOFA ( OR=1.521, 95%CI 1.144-2.022, P<0.05) are independent risk factors of SAKI. ROC curve analysis showed that the AUC of IGFBP-7 and SOFA scores for early prediction of SAKI was 0.805 (sensitivity 78.6%,specificity 78.3%), 0.832 (sensitivity 67.9%,specificity 82.9%) respectively. Combined both biomarkers, the AUC increased to 0.893 (sensitivity 82.1%, specificity 87.8%), the diagnostic performance was superior to IGFBP-7 or SOFA alone ( P<0.05). Conclusion:Elevated IGFBP-7 and SOFA are independent risk factors for sepsis associated acute kidney injury, and combined assessment with IGFBP-7 and SOFA can increase the diagnostic performance on the early detection of high-risk patients with SAKI.
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Objective:To investigate the effects of vagus nerve stimulation on postoperative cognitive dysfunction and the role of hippocampal insulin growth factor 1 signaling pathway in aged mice.Methods:Seventy-five clean-grade C57 mice of both sexes, aged 21-23 months, weighing 28-34 g, were divided into 5 groups ( n=15 each) using a random number table method: sham operation group (group S), operation group (group O), operation + vagus nerve stimulation group (group O+ V), operation + IGF-1 siRNA group (group O+ I) and operation + vagus nerve stimulation + IGF-1 siRNA group (group O+ V+ I). Group O underwent exploratory laparotomy.Group O+ V received a 30-min electrical stimulation of the vagus nerve (intensity 0.5 mA, frequency 20 Hz, time 30 s, 6 times, interval 5 min) after the end of exploratory laparotomy.Group O+ I underwent exploratory laparotomy and inhaled IGF-1 siRNA solution 10 μl intranasally at 24 h before surgery and 24 and 48 h after surgery.Group O+ V+ I underwent electrical vagus nerve stimulation after exploratory laparotomy and inhaled IGF-1 siRNA solution 10 μl intranasally at 24 h before surgery and 24 and 48 h after surgery.Morris water maze tests were performed on 14-18 days after operation.On day 7 after operation, the mice were sacrificed and the hippocampus was obtained for determination of the expression of Bax, ionized calcium-binding adapter molecule 1 (Iba-1), insulin-like growth factor 1 (IGF-1), insulin-like growth factor 1 receptor (IGF1R), phosphorylated IGF1R (p-IGF1R), interleukin-1beta (IL-1β) and activated caspase-3 by Western blot. Results:Compared with group S, the escape latency was significantly prolonged on days 16-18 after operation, the frequency of crossing the platform was reduced, the time spent in the target quadrant was shortened, the expression of IGF-1 and p-IGF1R was down-regulated, and the expression of Iba-1, IL-1β, activated caspase-3 and Bax was up-regulated in group O ( P<0.05). Compared with group O, the escape latency was significantly shortened on days 16-18 after operation, the frequency of crossing the platform was increased, the time spent in the target quadrant was prolonged, the expression of IGF-1 and p-IGF1R was up-regulated, and the expression of Iba-1, IL-1β, activated caspase-3 and Bax was down-regulated in group O+ V ( P<0.05), and no significant change was found in the parameters mentioned above in group O+ I ( P>0.05). Compared with group O+ V, the escape latency was significantly prolonged on days 16-18 after operation, the frequency of crossing the platform was reduced, the time spent in the target quadrant was shortened, the expression of IGF-1 and p-IGF1R was down-regulated, and the expression of Iba-1, IL-1β, activated caspase-3 and Bax was up-regulated in group O+ V+ I ( P<0.05). There was no significant difference in the expression of IGF1R among the four groups ( P>0.05). Conclusions:Vagus nerve stimulation can reduce postoperative cognitive dysfunction, and the mechanism is related to activation of IGF-1 signaling pathway and reduction of hippocampal neuroinflammation and neuronal apoptosis in aged mice.
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Klotho is a gene associated with aging, the transmembrane protein encoded by this gene is highly expressed in the kidney, and is also expressed in tissues such as the brain, parathyroid and pituitary glands. The extracellular domain of Klotho can also be cleaved and shed to form soluble Klotho, which acts as a circulating hormone and can be detected in blood, cerebrospinal fluid, and urine. More and more studies have shown that Klotho protein plays an important role in the complex regulation of growth hormone (GH)-insulin-like growth factor 1(IGF1) axis. The interaction between Klotho protein and GH-IGF1 axis is bidirectional, which regulates each other, and then regulates the normal linear growth of children. In addition, Klotho protein can also affect the growth and development of fetus and newborn through different ways, and its mechanism is not very clear.
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Objective:To investigate the effects of chronic stress during pregnancy on depressive behavior and DNA methylation of insulin-like growth factor-2 ( IGF-2 )/long non-coding RNA ( lncRNA ) H19 in hippocampus of female offspring rats.Methods:A total of 32 SPF female SD rats were divided into model group and control group according to the random number table. The rats in the model group were treated with chronic unpredictable mild stress (CUMS) to establish the depression model, and the rats in the control group were fed normally.On the 7th day of stress stimulation, all female rats mated with male rats. One day before stress stimulation and 1, 7, 14, 21, 28 days after stress stimulation, blood samples were collected from the inner canthus vein of the rats to determine the plasma corticosterone concentration. Eight female pups were randomly selected from each group on postnatal day 28(PND28) and postnatal day 42 (PND42). Plasma corticosterone concentration was measured after angular vein blood collection. At PND42, the depression-like behavior of female pups in the two groups was measured by sucrose preference test, tail suspension test and forced swimming test. The expression of IGF-2/H19 and related transferases in hippocampus of offspring rats was detected by RT-PCR and Western blot. Methyl target technology was used to capture and sequence 19 CpG sites of IGF-2 differentially methylated region(DMR) fragment 2, 8 CpG sites in H19 imprinting control region (ICR) fragment 1 and 15 CpG sites in H19-ICR fragment 2, and calculate the methylation level of each CpG site. SPSS 26.0 was used for statistical analysis of relevant data by repeated measurement ANOVA, t test and non-parametric test. Results:(1) The data of plasma corticosterone content of the two groups of female rats at different times were analyzed by repeated measurement variance.The results showed that the the interaction effect between time and group was not significant ( F=2.997, P=0.066), and the main effect of time was significant ( F=4.44, P=0.010). The main effect of group was significant ( F=41.40, P=0.001). According to the independent effect analysis of factors between groups, on the 14th, 21st, and 28th days of stress, the plasma corticosterone concentration of the model group was higher than that of the control group (all P<0.001). (2) In the sucrose preference test, the total liquid consumption (11.10(10.38, 11.58) mL, 13.55(12.00, 15.77) mL, Z=-3.055, P=0.002), 1% sucrose water consumption ((5.50±1.30) mL, (8.56±2.04) mL, t=-3.582, P=0.003) and 1% sucrose preference percentage ( (51.35±8.69) %, (62.11±8.05) %, t=-2.576, P=0.022) of female pups in the model group were significantly lower than those in the control group. (3) The duration of immobility in tail suspension test ((126.95±39.89) s, (54.30±25.00) s, t=4.375, P=0.001) and forced swimming test ((7.97±6.66) s, (1.85±2.12) s, t=2.478, P=0.037) of female offspring in the model group were longer than those in the control group. (4) The expression of IGF-2 mRNA ((0.46±0.24), (1.00±0.00), t=3.821, P=0.019) and H19 mRNA ((0.60±0.25), (1.00±0.00), t=3.574, P=0.007) in hippocampus of female pups in the model group were lower than those of control group. The relative expression of IGF-2 protein in female offspring of model group was lower than that in control group ((0.77±0.04), (1.00±0.00), t=9.876, P=0.01). The relative expression of CCTC-binding factor (CTCF) mRNA ((1.29±0.12), (1.00±0.00), t=-4.850, P=0.003) and protein ((1.90±0.28), (1.00±0.00), t=-5.513, P=0.005) were higher than those in the control group. (5) The methylation levels of three CpG sites in the IGF-2 DMR region of female offspring in the model group were lower than those in the control group ( t=-3.21, -3.00, -3.34, all P<0.05), located at chr1215831028, chr1215831055 and chr1215831205, respectively. The methylation level of IGF-2 DMR fragment was lower than that of the control group ( t=-3.453, P=0.048). The relative expression levels of DNMT3A mRNA ( t=5.102, P=0.002), DNMT3A ( t=10.213, P<0.001) and DNMT3B ( t=4.169, P=0.014) in female offspring of the model group were lower than those in the control group. Conclusion:Chronic stress during pregnancy causes depression and despair in female offspring mice, and the mechanism may be related to the decrease of methylation level of imprinted gene IGF-2 DMR caused by the decrease of methyltransferase expression.
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Objective:To investigate the efficacy of floating acupuncture therapy in the treatment of chronic refractory pressure ulcers and its effects on serum levels of superoxide dismutase, malondialdehyde and insulin-like growth factor-1.Methods:A total of 60 patients with chronic refractory pressure ulcers who received treatment in The Second Hospital of Jiaxing from October 2019 to October 2021 were included in this study. They were randomly divided into observation and control groups, with 30 patients in each group. The patients in the control group were given routine treatment, while the patients in the observation group were given floating acupuncture therapy based on routine treatment. Clinical efficacy, wound healing rate after 7, 14 and 21 days of treatment, the time of emerging granulation tissue, the time of shedding rotten meat, and the time of wound healing, changes in serum levels of superoxide dismutase, malondialdehyde and insulin-like growth factor-1 after 21 days of treatment relative to those before treatment were compared between the two groups.Results:Total response rate in the observation group was significantly higher than that in the control group [90.0% (27/30) vs. 66.7% (20/30), χ2 = 4.81, P < 0.05]. Wound healing rate after 7, 14 and 21 days of treatment in the observation group was significantly higher than that in the control group ( t = -5.45, -7.77, -7.51, all P < 0.001). The time of emerging granulation tissue, the time of shedding rotten meat, and the time of wound healing in the observation group were significantly shorter than those in the control group ( t = 5.69, 9.26, 8.91, all P < 0.001). After 21 days of treatment, serum levels of superoxide dismutase, malondialdehyde and insulin-like growth factor-1 in the observation group were (96.52 ± 10.43) U/mL, (4.32 ± 0.78) μmol/L, (43.52 ± 8.29) μg/L, respectively, which were significantly different from (83.76 ± 6.81) U/mL, (5.48 ± 0.92) μmol/L, (36.78 ± 9.18) ng/mL, in the control group ( t = 5.61, 5.27, 2.98, all P < 0.05). Conclusion:Floating acupuncture therapy is effective in the treatment of refractory pressure ulcer. It can accelerate wound healing, increase serum superoxide dismutase and insulin-like growth factor-1 levels, and decrease serum malondialdehyde level.
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Objective:To investigate the correlation between serum insulin-like growth factor 1 (IGF-1), thyroid stimulating hormone (TSH), degree of insulin resistance and thyroid nodule imaging reporting and data system (TI-RADS) grading in patients with type 2 diabetes mellitus (T2DM).Methods:The clinical data of 120 patients with T2DM from February 2020 to November 2021 in Kunshan Hospital of Integrated Traditional Chinese and Western Medicine were retrospectively analyzed. Among them, 56 patients had no thyroid nodules (non-thyroid nodule group), all patients were TI-RADS grade 1; 64 patients had thyroid nodules (thyroid nodule group), including 7 cases of TI-RADS grade 2, 12 cases of TI-RADS grade 3, 20 cases of TI-RADS grade 4, and 25 cases of TI-RADS grade 5. The levels of IGF-1 and TSH were measured by automated biochemical analyzer, the homeostatic model assessment insulin resistance index (HOMA-IR) was calculated. Spearman method was used for correlation analysis; multivariate Logistic regression was used to analyze the independent risk factors of TI-RADS grading in patients with T2DM combined with thyroid nodules; the receiver operating characteristic (ROC) curve was drawn to analyze the efficacy of IGF-1, TSH and HOMA-IR in predicting TI-RADS grading in patients with T2DM combined with thyroid nodules.Results:The IGF-1, TSH and HOMA-IR in thyroid nodule group were significantly higher than those in non-thyroid nodule group: (185.35 ± 45.08) ng/L vs. (168.36 ± 30.25) ng/L, (2.98 ± 0.85) mU/L vs. (2.69 ± 0.35) mU/L and 3.25 ± 0.75 vs. 2.95 ± 0.44, and there were statistical differences ( P<0.05 or <0.01). In patients with T2DM combined with thyroid nodules, with the increase of TI-RADS classification, the IGF-1, TSH and HOMA-IR gradually increased, and there were statistical differences ( P<0.05). Spearman correlation analysis result showed that the levels of IGF-1, TSH and HOMA-IR were positive correlation with TI-RADS grading ( r = 0.918, 0.906 and 0.920; P<0.05). Multivariate Logistic regression analysis result showed that the IGF-1, TSH and HOMA-IR were independent risk factors for TI-RADS grading in patients with T2DM combined with thyroid nodule ( OR = 1.684, 1.044 and 1.851; 95% CI 0.674 to 6.665, 0.032 to 0.055 and 1.212 to 2.298; P<0.01 or <0.05). ROC curve analysis result show that the area under the curve of IGF-1, TSH and HOMA-IR for predicting the TI-RADS grading patients with T2DM combined with thyroid nodule were 0.946, 0.983 and 0.975, with all sensitivity of 100.00%, and specificity of 82.14%, 91.07% and 89.29%. Conclusions:There is a correlation between IGF-1, TSH, HOMA-IR and TI-RADS grading in patients with T2DM combined with thyroid nodule, which has some guiding value for clinical monitoring of thyroid nodule changes.