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BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with complex pathogenesis. Currently, the pathogenesis of ASD is not fully understood. Moreover, current treatments do not effectively alleviate the primary symptoms of ASD social disorder (SCDA). Jiawei Yinhuo Tang (JWYHT) is an improved version of the classic prescription Yinhuo Tang. Although this medication has been shown to improve social behavior in ASD patients, the mechanism by which it works remains unknown. METHODS: In this study, network pharmacology bioinformatics analysis was used to identify the key targets, biological functions, and signal pathways of JWYHT in SCDA. Then, molecular docking and molecular dynamic simulation were used to validate the activity and stability of the active ingredient and the target protein during the binding process. RESULTS: The analysis identified 157 key targets and 9 core targets of JWYHT (including proto-oncogene (FOS), caspase 3 (CASP3), mitogen-activated protein kinase-3 (MAPK3), interleukin-6 (IL6), mitogen-activated protein kinase-1 (MAPK1), tumor necrosis factor (TNF), mitogen-activated protein kinase-8 (MAPK8), AKT serine/threonine kinase 1 (AKT1), and 5-hydroxytryptamine receptor 1B (5HT1B)) in SCDA. In addition, the Kyoto Encyclopedia of Gene and Genome results, as well as the staggering network analyses, revealed 20 biological processes and 20 signal pathways targeted by JWYHT in SCDA. Finally, molecular docking analysis was used to determine the binding activity of the main active components of JWYHT to the key targets. The binding activity and stability of methyl arachidonate and MAPK8 were demonstrated using molecular dynamics simulation. CONCLUSION: This study demonstrates that JWYHT regulates neuronal development, synaptic transmission, intestinal and cerebral inflammatory response, and other processes in SCDA.
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Objective:To explore the value of octreotide suppression test(OST) in predicting the efficacy of somatostatin receptor ligands(SRLs) in the treatment of active acromegaly.Methods:The clinical data of 76 patients with active acromegaly from 2011 to 2020 was retrospectively analyzed. OST was carried out as follows: After an overnight fasting and baseline sampling of growth hormone(GH), 100 μg octreotide was subcutaneously injected, and sampling for GH was obtained every 2 hours for 8 hours. All patients were treated with SRLs for at least 3 months. A good GH response is defined as a post-treatment random GH<1 μg/L or >80% fall compared with the baseline GH. A good insulin-like growth factor Ⅰ(IGF-Ⅰ) response is defined as IGF-Ⅰ<1.3 upper limit of normal(ULN) or >50% reduction compared with the baseline. If both GH and IGF-Ⅰ fulfill the criteria of a good response, it is defined as a good GH and IGF-Ⅰ response.Results:The baseline level of GH during OST was 15.00(6.38, 34.20) μg/L, the median time to reach the nadir GH was(3.65±1.65) hours, and the nadir GH level was 1.47(0.50, 4.19) μg/L. The median GH suppression rate was 89.12%(72.71%, 95.09%). When the cutoff value of GH suppression rate in predicting a good GH response was 89.32%, the area under the curve(AUC) was 0.74, with a sensitivity of 81.80% and specificity of 66.00%. When the cutoff value of GH suppression rate in predicting a good IGF-Ⅰ response was 93.14%, the AUC was 0.64, with a sensitivity of 50.00% and specificity of 75.60%. When the GH suppression rate was 90.71%, the AUC was 0.78, with the sensitivity of 83.30% and specificity of 70.00% in predicting a good GH and IGF-Ⅰ response. Compared with GH/IGF-Ⅰ non-responders, GH/IGF-Ⅰ responders displayed lower nadir GH during OST, higher GH suppression rate and IGF-Ⅰ reduction rate, and lower ratio of IGF-1 to ULN( P<0.05). Conclusion:GH suppression rate during the OST is a valuable predictor to evaluate the efficacy of SRLs in patients with acromegaly, with the highest sensitivity and specificity when the cutoff value is 90.71%.
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Objective:Cushing′s disease(CD) is caused by the pituitary adrenocorticotroph hormone(ACTH) secreting adenomas, leading to increased serum cortisol levels and various abnormal metabolic processes. Untreated CD is linked to high mortality, thus it is critical to elucidate its pathogenesis. This study aims to explore the pathogenesis of pituitary ACTH adenomas using whole-genome sequencing analysis.Methods:Fresh tumor tissues and peripheral blood samples were collected in 9 confirmed cases of pituitary ACTH adenomas who underwent surgery. Whole genome sequencing was then performed, followed by analysis and verification of single nucleotide mutations, copy number variation(CNV) and chromosome structure variations.Results:Somatic USP8 mutations(p.Ser718del, p. Ser718Pro, p. Pro720Arg, p. Pro720Gln) were found in 5 patients, with a rate of 55.6%; CNV of USP8 was detected in 1 patient; TP53(p.Cys135Tyr), NF1(p.Val1049Glufs*11) and KMT2C(c.3323+ 1G>A) mutations were identified in 1 patient harboring wild-type USP8. CNV analysis showed a loss of heterozygosity in multiple chromosomes in a wild-type USP8 patient. Structural variations were found in 2 with unknown significance. No germline gene mutations were detected in this study.Conclusion:Somatic USP8 mutations, increased copy number of USP8, variations of tumor-related genes such as TP53 and extensive somatic CNV all contribute to pathogenesis of CD. Chromosomal structure variations may suggest high-risk pituitary ACTH adenomas, and call for frequent follow-up and aggressive treatment.
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Objective:To report the clinical characteristics, diagnosis, and treatment of 2 cases of X-linked acrogigantism(X-LAG).Methods:The clinical information of two patients were retrospectively reported, and peripheral blood DNA was collected for copy number variations detection.Results:Both patients had onset at age of two, with common clinical characteristics including linear growth acceleration, mild facial coarsening, enlargement of hands and feet, increased appetite, and snoring, etc. The heights Z scores of the two patients before treatment were + 6.86 and + 6.53, respectively. Growth hormone(GH) glucose inhibition test showed that GH nadir values were over 1 ng/mL and insulin-like growth factor-Ⅰ(IGF-Ⅰ) were 586.0 ng/mL and 1 042.0 ng/mL, respectively. Patient 1 received three cycles of octreotide microspheres therapy followed by surgery, and achieved clinical and biochemical remission. Patient 2 had lanreotide for 5.5 years but failed biochemical remission. Microduplication of Xq26.3, which contained pathogenic gene G-protein coupled receptor 101(GPR101), was found in germline DNA of two patients through copy number variation detection, leading to the diagnosis of X-LAG.Conclusion:It should be cautious of X-LAG when children below 2 years old presents symptoms such as overgrowth and so on. Medication combined with surgery is effective.
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The aim of this study was to assess the effects of orlistat or metformin treatment on lipid and glucose metabolism, and gonadal function in obese/overweight women with polycystic ovary syndrome (PCOS). A total of 39 patients diagnosed with PCOS were randomly (digital table method) divided into orlistat treatment group (20 cases) and metformin treatment group (19 cases). Compared with those before, treatment with either orlistat or metformin significantly reduced body weight, body mass index (BMI), hip circumferences, and serum insulin levels of the PCOS patients both at the end of 3 months and 6 months ( P<0.05). No significant differences could be viewed between orlistat and metformin treated subjects. Moreover, orlistat treatment significantly lowered the levels of low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and homeostasis model assessment-insulin resistance (HOMA-IR) ( P<0.05), while there were no significant changes in above parameters with metformin treatment. The improvement of menstrual cycle was observed after 6-month treatment in both groups ( P<0.05). However, changes in polycystic ovarian morphology by ultrasound were only observed in orlistat treated group. In conclusion, orlistat is comparable with metformin in weight loss and improvement of insulin resistance and menstrual cycle, and is superior to metformin in improvement of lipid metabolism in overweight/obese PCOS patients.
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To compare changes in platelet related parameters in obese patients before and after sleeve gastrectomy (SG), we retrospectively analyzed the clinical data of 31 obese patients who underwent SG in Peking Union Medical College Hospital from December 2012 to September 2020. Results showed that compared with those before surgery, platelet count (PLT) decreased significantly at 2-12 weeks of follow-up ( P=0.009), while platelet distribution width (PDW), mean platelet volume (MPV), and large platelet ratio (P-LCR) increased significantly at the same periods of follow-up after operation ( P<0.001). However, the levels of PDW, MPV, and P-LCR began to decrease at 16-55 weeks when compared with those at 2-12 weeks of follow-up ( P<0.01). PLT was positively correlated with white blood cells and neutrophils at 2-12 weeks of follow-up and positively correlated with high sensitivity C-reactive protein at 16-55 weeks of follow-up after operation ( P<0.05).
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Objective This article reported the clinical characteristics and gene mutations of two pseudoachondroplasia cases, and made a literature review in order to improve clinicians' understanding of the disease. Methods Clinical features of two patients who were short stature accompanied with skeletal deformities were summarized, and they accepted whole exome sequencing. We also reviewed literature to summarize the clinical characteristics and known gene research progress of all reported Chinese pseudoachondroplasia cases. Results The two patients' clinical characteristics were short limbdwarfism with skeletal deformity. Genetic results showed that there were two heterozygous mutations in the cartilage oligomeric matrix protein (COMP) gene of the two patients, c.14171419delGAC and c.1552G>A, respectively. Up to March 2019, a total of 58 cases of pseudoachondroplasia have been reported in China. The median height of these patients is-5.03 SDS. The clinical features include abnormal gait, short limbs, short fingers/toes, scoliosis, bracelet sign, ankle sign and other skeletal deformities. COMP is the pathogenic gene and mutations mainly located in calmodulin-like domains. The hotspot mutation is c. 14171419delGAC. Conclusions Pseudoachondroplasia is a kind of rare genetic disease characterized by short stature and skeletal deformities. The clinical and genetic characteristics of the disease were summarized, which may improve the early diagnosis rate.
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Objective@#This article reported the clinical characteristics and gene mutations of two pseudoachondroplasia cases, and made a literature review in order to improve clinicians′ understanding of the disease.@*Methods@#Clinical features of two patients who were short stature accompanied with skeletal deformities were summarized, and they accepted whole exome sequencing. We also reviewed literature to summarize the clinical characteristics and known gene research progress of all reported Chinese pseudoachondroplasia cases.@*Results@#The two patients′ clinical characteristics were short limbdwarfism with skeletal deformity. Genetic results showed that there were two heterozygous mutations in the cartilage oligomeric matrix protein (COMP) gene of the two patients, c. 1417_1419delGAC and c. 1552G>A, respectively. Up to March 2019, a total of 58 cases of pseudoachondroplasia have been reported in China. The median height of these patients is -5.03 SDS. The clinical features include abnormal gait, short limbs, short fingers/toes, scoliosis, bracelet sign, ankle sign and other skeletal deformities. COMP is the pathogenic gene and mutations mainly located in calmodulin-like domains. The hotspot mutation is c. 1417_1419delGAC.@*Conclusions@#Pseudoachondroplasia is a kind of rare genetic disease characterized by short stature and skeletal deformities. The clinical and genetic characteristics of the disease were summarized, which may improve the early diagnosis rate.
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Objective To evaluate the effects of a traditional Chinese medicine Rubia cordifolia L.aqueous extract (RCAE) on body weight, fat mass and parameters of glucose and lipid metabolism in high fat diet (HFD)-induced obese rats and its mechanism.Methods pGL3-Enhancer-PPARγ2 (625 bp)-Luc plasmid, a luciferase reportergene expression plasmid containing PPARγ2 promoter was constructed and stably transfected 3T3-L1 preadipocytes were established.PPARγ2 promoter`s activities in these cells were detected after administration with different concentration (0.1 mg/L~1 000 mg/L) of RCAE or with 100 mg/L RCAE for different action time.PPARγ2 mRNA expression in human adipocytes were detected after administration with 100 mg/L RCAE.Meanwhile, HFD-induced obese rats were administrated with low or high dose RCAE to investigate the effects of RCAE on serum glucose, lipid and insulin levels, body weight, visceral fat mass and so on.Results 10 mg/L RCAE could increase luciferase expression in 3T3-L1 cells to 1.43 folds of that in control group (P<0.01) and it reached 3.24 folds of that in control group when the concentration of RCAE was 1000 mg/L (P<0.01).With the administration with 100 mg/L RCAE, the luciferase activity of 3T3-L1 cells peaked at 28 h where it was 2.72 folds of that in control group (P<0.01), and the expression of PPARγ2 mRNA in human adipocytes increased to 2.27 folds of that in control group (P<0.01).Compared with HFD group, low dose RCAE significantly reduced the fasting insulin level, HOMA-IR and visceral fat mass (P<0.05).Conclusions Low dose RCAE significantly reduces the visceral fat mass and ameliorates insulin resistance in HFD-induced obese rats.The potential mechanism may be explained by the stimulation of PPARγ2 promoter activities and the increased expression of PPARγ2 gene.
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Objective To clarify the possible gene mutations in luteinizing hormone(LH) receptor gene in a boy with LH independent precocious puberty and probe the mechanism the of diseases caused by LH receptor activating mutations. Methods ( 1 ) Describe the clinical manifestations and laboratory data in a 5-year-old boy with LH independent precocious puberty. (2) Peripheral leukocytes were collected from the proband, his parents and other 20 normal puberty developed males. PCR and direct DNA sequence of 11 exons in LH receptors gene were conducted. Results (1) The proband was diagnosed to have LH independent precocious puberty according to the clinical symptoms and the laboratory tests. (2) A germ-line heterozygous point mutation in the 11 exon of LH receptor gene was found in the proband and his mother:c1193 T→C leading to amino acid change with M398T, which causes consecutively an activation of the LH receptor. (3) Other nucleotide changes in the proband and other normal males include c935 A→ G (N312S) and c1065 T→C(same sense mutation). Conclusions (1) A germ-line heterozygous point mutation in the LH receptor gene with M398T leads to consecutively activation of the LH receptor and LH independent precocious puberty. (2) The same point mutation does not have any influence on the puberty development, menstruation and productive functions of the proband's mother. (3) The LH receptor gene has possible polymorphism in the Han ethnic population.
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OBJECTIVE@#To explore the mechanism of formaldehyde inducing ovarian toxicity in female rats by observing the effect of formaldehyde on the expression of Fas and caspase-8 mRNA, and the activity of caspase-3 and caspase-8 of ovary tissues in female rats.@*METHODS@#Forty female Sprague-Dawley(SD) rats were randomly divided into a control group and 3 formaldehyde groups at different concentrations. The rats in the formaldehyde groups were intraperitoneally injected different doses of formaldehyde (20.0,2.0 and 0.2 mg/kg) continuously for 14 days.After 14 days, all rats were sacrificed and their ovaries were collected for detecting the expression of Fas and caspase-8 mRNA with RT-PCR, the protein expression of Fas with Western blot, and the activities of caspase-8 and caspase-3 with spectrophotometric method.@*RESULTS@#Compared with the control group, the expression of Fas mRNA and its protein and caspase-8 mRNA and the activity of caspase-8 and caspase-3 of ovary tissues in the rats treated with formaldehyde significantly increased with dose (P<0.05).@*CONCLUSION@#The increase of Fas gene expression and the activity of caspase-8 and caspase-3 may be the important mechanism of ovarian toxicity induced by formaldehyde in female rats.
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Animais , Feminino , Ratos , Apoptose , Genética , Caspase 3 , Genética , Metabolismo , Caspase 8 , Genética , Metabolismo , Poluentes Ambientais , Toxicidade , Formaldeído , Toxicidade , Ovário , Metabolismo , Patologia , RNA Mensageiro , Genética , Metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Receptor fas , Genética , MetabolismoRESUMO
Objective:To study the effect of interleukin-11(IL-11),ciliary neurotropic factor (CNTF) and transforming growth factor-β (TGF-β) on the hGH gene promoter activity in rat pituitary MtT/S cells and the interaction with pituitary-specific transcription factor Pit-1.Methods:Stable transformed MtT/S cell line which contains hGH gene promoter -484-30 bp and luciferase reporter gene firstly established,then the concentration of GH in the medium and lysate of MtT/S cells and luciferase activities in MtT/S cells were measured after treatment these cells with the above cytokines,the effects of cytokines on secretion and synthesis of GH,and the promoter activity of the hGH gene were observed.Results:The results showed that IL-11(20 nmol/L),CNTF(10 nmol/L) and TGF-β(5 nmol/L) regulated secretion and synthesis of GH,and the luciferase expression in stable transformed MtT/S cells.IL-11 and CNTF had the stimulatory effect,whereas TGF-β had the inhibitory effect.Neither overexpression of Pit-1 nor inhibiting Pit-1 expression affected the regulatory role of these cytokines.Conclusion:IL-11,CNTF and TGF-β regulate the GH production in pituitary MtT/S cell line by regulating the hGH gene promoter activity.Pit-1 may not be involved in these actions.
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Objective To compare the clinical efficacy and safety of domestic orlistat and imported orlistat in Chinese overweight and obese patients. Methods In a randomized, double-blinded and positive-controlled study, 228 adults (BMI 24-< 40 kg/m~2) evaluated at seven research centers were randomized to receive domestic orlistat or imported orlistat 120 mg 3 times a day with an energy-controlled diet for 24 weeks. Results After 24 weeks, domestic orlistat treated patients got significant weight-loss (5.0±3.7) kg, which was comparable with that of imported orlistat treated patients (4.5±3.5) kg (P=0.3922).Compared with the findings before treatment, there was significant decrease of systolic blood pressure (4.4±11.5)mm Hg (1 mm Hg=0.133 kPa) and serum levels of TC (0.54±0.79) mmol/L and LDL-C (0.32±0.64) mmol/L in the domestic orlistat treated group(compared with levels of baseline, P< 0. 0001). There was no significant difference between the two groups in the changes of blood pressure and lipid levels. Both groups had similar adverse event profiles, most of which were mild and transient gastrointestinal events. There were no serious adverse events in beth groups. Conclusions Domestic orlistat combined with a light low-energy diet promoted significant weight loss, which was comparable with that of imported orlistat after 24 weeks of treatment. There was also improvement in blood pressure and serum levels of TC and LDL-C. Domestic orlistat was as effective and safe as imported orlistat in the treatment of obesity.
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Objective To establish a method of primary culture of human preadipocyte in a serum-free medium. Methods Collangenase digestion was used to dispart preadipocyte.The cells were identified by microscopy stained by oil red O and determination of the activity of Glycerol-3-phosphate dehydronase(G-3-PDH). Results The primary cultured human preadipocyte proliferated in the aserum-free medium successfully.In the differential serum-free medium the cells turned to be round on the 4 th day.The adipose drops began to cumulate in the cells,and to the most quantity until the 21 st day.Conclusion The human preadipocyte can be primarily cultured and induced to differentiate in serum-free medium,which is the base for researching the effects of hormones and factors to the proliferation and differentiation of preadipocyte.
