Objective: To explore susceptibility genes for autism spectrum disorders (ASD). Methods: Whole-exome sequencing was carried out for 60 family trios affected with sporadic ASD. Genetic variants discovered in over 10% of the patients were selected for genotype-phenotype correlation and pathway enrichment analysis using Phenolyzer software and metascape database. Combining gene-phenotypic scores, pathway-related genes associated with neural and neurite triggering were screened for the candidates. Results: A total of 170 common variants were found to be associated with the ASD phenotype. Among these, there was only one high-confidence gene [SHANK2 (0.8146)] and four medium-confidence genes [ERBB2 (0.1322), LAMC3 (0.1117), PPFIA4 (0.1059), DISC1 (0.1002)]. Twenty-pathways and four biological processes were found to be statistically significant by pathway enrichment analysis, which included neuron projection morphogenesis (GO: 0048812), regulation of neuroblast proliferation (GO: 1902692), modulation of excitatory postsynaptic potential (GO: 0098815), and dendrite morphogenesis (GO: 0048813). Twenty-one genes were found to be closely associated with neurological and neurite triggering, among which only SHANK2, ERBB2, and DISC1 had above-medium confidence correlation scores with the ASD phenotypes. Conclusion Abnormal neuron projection morphogenesis (GO: 0048812) may be closely related to the occurrence of ASD. SHANK2, ERBB2, and DISC1 are susceptibility genes for ASD.

Purpose To investigate the expression of CYP4 A11 and CYP4 A22 in triple-negative breast carcinoma (TNBC) and its relationship with clinicopathological features and M2 tumor-associated macrophages (TAMs). Methods 72 cases of TNBC with clinical and pathological data were collected. The expression of CYP4 A11 and CYP4 A22 in the carcinoma cells and the expression of CD68 and CD163 of the TAMs were detected by immunohistochemically and analyzed with image processing software. The relationship between the expressions of CYP4 A11 and CYP4 A22 with clinicopathologic features and its correlation of the M2 state of TAMs was studied. Results Both the immunohistochemically staining scores of CYP4 A11 and CYP4 A22 were higher in cancer tissues than that in breast tissues (P<0.001, P<0.001). The higher expression of CYP4 A11 was associated with tumor diameter increase (P<0.001), lymph node metastasis (P<0.001), higher clinical stage (P<0.001) and higher Ki-67 index (P=0.011). Both the positive rates of CD68 and CD163 in the high expression group of CYP4 A11 were higher than those in the low expression group of CYP4 A11 (P=0.021, P<0.001). The higher expression of CYP4 A22 was associated with lymph node metastasis (P<0.001), higher clinical stage (P=0.006), higher recurrence rate (P<0.001), and higher Ki-67 index (P=0.040).The positive rates of CD163 in the high expression group of CYP4 A22 was higher than that in the low expression group of CYP4 A22 (P<0.001). Conclusion Both the expression of CYP4 A11 and CYP4 A22 may be associated with M2 polarization state of TAMs, high proliferative activity and lymph node metastasis in the TNBC.

Two sesquiterpenes were isolated from the agarwood originating from Gyrinops salicifolia with various chromatographic techniques, and their structures were determined as 12-hydroxy-dihydrocyperolone(1) and(rel)-4β,5β,7β-eremophil-9-en-12,8α-olide(2), through a combined analysis of physicochemical properties and spectroscopic evidence. Compound 1 was a new compound. Compound 2 showed cytotoxicities against K562 and BEL-7401 cell lines, with IC_(50) values of(17.85±0.04) and(21.82±0.07) mg·L~(-1), respectively [taxol as positive control, with IC_(50) values of(1.97±0.11) and(6.31±0.08) mg·L~(-1)].
Antineoplastic Agents, Phytogenic ; isolation & purification ; pharmacology ; Cell Line, Tumor ; Humans ; Molecular Structure ; Phytochemicals ; isolation & purification ; pharmacology ; Sesquiterpenes ; isolation & purification ; pharmacology ; Thymelaeaceae ; chemistry ; Wood ; chemistry

OBJECTIVE: To follow up the participants of the randomized clinical trial "Efficacy and Safety of Niaoduqing Particles () for Delaying Moderate-to-Severe Renal Dysfunction", and assess the long-term effects of Niaoduqing Particles on delaying the progression of renal dysfunction. METHODS: Participants, who had previously been randomly assigned to receive Niaoduqing Particles or placebo for 24 weeks (146 cases in each group), were invited to follow-up and all were administered Niaoduqing Particles 5 g thrice daily and 10 g before bedtime for 24 weeks. The primary endpoints were changes in baseline serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) after completion of the open-label treatment period. RESULTS: After the double-blind period, the median (interquartile range) changes in Scr were 1.1 (-13.0-24.1) and 11.7 (-2.6-42.9) μmol/L for the Niaoduqing Particle and placebo groups, respectively (P=0.008), and the median changes in eGFRs were-0.2 (-4.3-2.7) and-2.21 (-5.7-0.8) mL•min•1.73 m, respectively (P=0.016). There were significant differences in the double-blind period changes in renal function between groups. After the open-label period, the median changes in Scr were 9.0 (-10.0-41.9) and 17.5 (-6.0-50.0) μmol/L for the Niaoduqing Particle and placebo groups according to baseline grouping, respectively (P=0.214), and the median changes in eGFRs were-2.3 (-6.4-1.9) and-3.7 (-7.5-1.1) mL•min•1.73 m, respectively (P=0.134). There were no statistical differences in the open-label period changes in renal function between groups. The eGFR reduction of participants who accepted Niaoduqing Particle treatment for 48 weeks was projected to 2.5 mL•min•1.73 m per year. CONCLUSION Niaoduqing Particles appear to have long-term efficacy for patients with moderate-to-severe renal dysfunction. Although there was no statistical difference, the early use of Niaoduqing Paticles seems to ameliorate the worsening of renal function. (Trial registration No. ChiCTR-TRC-12002448).
Adult ; Disease Progression ; Double-Blind Method ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Follow-Up Studies ; Glomerular Filtration Rate ; drug effects ; Humans ; Kidney Diseases ; drug therapy ; physiopathology ; Male ; Middle Aged ; Outcome Assessment (Health Care)

Mixed linked leukemia 4 (MLL4) is a specific methyltransferase of histone 3 position lysine 4 (H3K4). It is also one of the important members of COMPASS/Set1-like protein complex. Both MLL4 protein itself and its mediated H3K4 methylation modification can cause changes in chromatin structure and function, thus regulating gene transcription and expression. With the studies of MLL4 protein in recent years, the roles of MLL4 gene, MLL4 protein and protein complex in the development of tissues and organs, tumor diseases and other physiological and pathophysiological processes have been gradually revealed. In this paper, the research progress of MLL4 gene, MLL4 protein characteristics, biological function and its effect on disease were reviewed, in order to further understand the effect of histone methyltransferase on gene expression regulation, as well as its non-enzyme dependent function. This paper may provide new ideas for the prevention, diagnosis and treatment of related diseases.
DNA-Binding Proteins ; physiology ; Histone-Lysine N-Methyltransferase ; physiology ; Histones ; chemistry ; Humans ; Methylation

Objective: To explore the safety, feasibility and advantages of Da Vinci robot "3+ 2" mode in radical gastrectomy. Methods: Clinical data of 30 patients received radical gastrectomy at our department under the "3+ 2" mode of Da Vinci robot from Jan. 2018 to Oct. 2018 were retrospectively analyzed. 30 patients who received classical robot mode in the same period were randomly selected as control group. Results: Compared with the control group, the observation group had a shorter operative time (174±16)min vs.(197±19)min, t=-3.275, P<0.01) , a lower operation costs[(22 794±3 660)yuan vs.(29 307±3 220)yuan, t=-3.316, P<0.01; and inhospital costs (70 910±6 399)yuan vs.(78 180±6 636)yuan), t=-7.316, P<0.01]. Conclusion The "3+ 2" mode of Da Vinci robot in radical gastrectomy is beneficial to enhance the exposure of the surgical field, improve the cooperation of assistants, reduce the costs of surgery, shorten the operative time and the learning curves. In addition, it has similar clinical efficacy to radical gastrectomy under the classical robot mode.

Objective: In order to evaluate the therapeutic effects and safety of denosumab and bisphosphonates in glucocorticoid induced osteoporosis patients. Methods: Standard studies were obtained by searching CNKI, CBM, VIP, Wanfang, Pubmed, Embase and Cochrane databases. Results: Three RCTs with 869 patients were included in this study. It showed that the mean changes of lumbar spine, total hip and femoral neck bone mineral density (BMD) for patients in denosumab group were increased by 2.47%, 1.43% and 1.07% respectively compared to those of bisphosphonates group.There was no statistically significant difference between patients receiving denosumab and those receiving bisphosphonate in terms of adverse events and serious adverse events. Conclusions Denosumab has an effective increase for lumbar spine, total hip and femoral neck bone mineral density, and the safety of both is similar.

Objective: Study on the mechanism of Tongfengning in reducing serum uric acid from the perspective of renal urate transporter. Method: The human renal tubular epithelial cells(HK-2)was randomly divided into normal group, model group, Tongfengning low, medium and high dose group (7.65,15.3,30.6 g·kg^-1) and benzbromarone group (50 μmo1·L^-1),different culture media were given for intervention.HK-2 and cell supernatant were collected after 24 h of intervention. The expressions of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1(OAT1), organic anion transporter 3(OAT3), and ATP-binding cassette superfamily G member 2 (ABCG2) protein and mRNA were detected in HK-2 of all groups by Western blot and Real-time PCR. Result: Compared with normal group, the expression of URAT1, GLUT9 protein and mRNA was significantly increased(P<0.01), while the expression of ABCG2 protein and mRNA was significantly decreased in model group (P<0.01). Compared with model group, the expression of URAT1, GLUT9 protein and mRNA in each dose of Tongfengning group and benzbromarone group were decreased (P<0.01), and each doses of Tongfengning group was superior to the benzbromarone group. The expression of ABCG2 protein and mRNA was increased in each dose of Tongfengning group (P<0.01). Compared with Tongfengning medium dose group, the expression of URAT1,GLUT9 protein and mRNA increased, while the expression of ABCG2 protein and mRNA decreased in the low and Tongfengning high dose groups (P<0.01). OAT1 and OAT3 were not expressed in all groups. Conclusion: Tongfengning can regulate the reabsorption and secretion of uric acid in renal tubules, promote the excretion of uric acid in kidney and reduce the level of serum uric acid by down-regulating the expression of URAT1, GLUT9 protein and mRNA in HK-2 and up-regulating the expression of ABCG2 protein and mRNA. It is suggested that the regulation of renal uric acid transporter protein may be one of the specific mechanisms of Tongfengning to reduce serum uric acid by promoting dampness and turbid removal. OAT1, OAT3 protein and mRNA were not expressed in HK-2 cultured in vitro.

Objective: To research the effect of traditional Chinese medicine compound Chaijie Yiganxian (CJYGX) on the hepatic fibrosis in rats and explore the mechanism. Method: Totally 60 SD rats were randomly divided into normal group, model group, positive group (Biejia Jianwan), and low, medium and high-dose CJYGX groups. Except for the normal group, the remaining five groups were involved in establishing the hepatic fibrosis model through the intraperitoneal injection of thioacetamide (TAA). Fourth weeks after modeling, the positive group was given Biejiajian pill (1 g·kg^-1·d^-1), and high, medium and low-dose CJYGX groups were given CJYGX(7.96, 3.98, 1.99 g·kg^-1·d^-1), respectively. The model group was given normal saline once a day for 5 weeks. 24 h after the last intragastric administration with chloral hydrate, the rats were anesthetized slightly. Serum and liver tissues were collected. The liver wet weight was weighed electronically, and the liver index was calculated. Liver function indexes[alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP)] and serum markers[laminin (LN), hyaluronidase (HA), Ⅳ collagen (CⅣ), procollagen Ⅲ (PCⅢ)] of hepatic fibrosis were detected by enzyme linked immunosorbent assay (ELISA). The degree of hepatic fibrosis by Masson stain, mRNA expressions of transforming growth factor-β₁ (TGF-β₁), Smad2, Smad3, Smad4, Smad7 were detected by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR), and protein expression levels of platelet derived growth factor (PDGF), TGF-β₁ and α-smooth muscle actin (α-SMA) were detected by immunohistochemical or Western blot. Result: Compared with the blank group, the model group liver index was significantly increased; the contents of ALP, AST and ALT were significantly increased; the liver fibrosis indexes LN, HA, Ⅳ-C, PCⅢ and HYP were significantly increased; the degree of liver fibrosis was significantly increased in Masson tissue; the mRNA expressions of TGF-β₁, Smad2, Smad3, Smad4 were significantly increased; and the Smad7 mRNA expression was significantly decreased. The protein expressions of TGF-β₁, PDGF and α-SMA increased significantly (P<0.01). Compared with model group, different doses of CJYGX can reduce the concentrations of ALP, AST, ALT, and the hepatic fibrosis indexes (LN and HA, Ⅳ-C, PCⅢ) and HYP also were significantly lower. Masson staining show that CJYGX can significantly reduce the degree of hepatic fibrosis. Real-time PCR show that CJYGX can significantly down-regulate mRNA expressions of TGF-β₁, Smad2, Smad3, Smad4 and up-regulate mRNA expression of Smad7.Immunohistochemical and Western blot analysis show that, compared with model group, CJYGX could significantly reduce the protein expressions of TGF-β₁, PDGF and α-SMA (P<0.05, P<0.01). Conclusion: Traditional Chinese medicine compound CJYGX may protect TAA-induced hepatic fibrosis injury by interfering with TGF-β₁/Smad signaling pathway.

AIM:To observe the effect of central prostaglandin E2(PGE2) on sympathetic activation in chronic heart failure (CHF) and to explore the underlying mechanism. METHODS:Male SD rats were subjected to coronary ar-tery ligation to induce heart failure (HF), and the intracerebroventricular infusion was performed by osmotic pump continu-ously. The rats in sham group and HF group were given artificial cerebrospinal fluid (0. 25 μL/h). The rats in HF plus treatment group was given celecoxib (CLB; 20 mg/h). After 4 weeks, the levels of PGE2 in cerebrospinal fluid ( CSF), the sympathetic nerve excitability and cardiac function were measured, and the changes of corticotropin-hormone releasing hormone ( CRH)-containing neurons activation and neurotransmitter contents in the hypothalamic paraventricular nucleus ( PVN) were also determined. RESULTS:Compared with the sham-operated rats, the HF rats had raised level of PGE2 in CSF, up-regulated renal sympathetic nerve activity and plasma norepinephrine, increased left ventricular end diastolic pres-sure, lung-to-body weight and right ventricular-to-body weight ratios, and decreased maximal increase and decreased rate of left ventricular pressure (P<0.05). In addition, the number of CRH positive neurons in PVN and the level of plasma ad-renocorticotropic hormone were higher in HF rats than those in sham-operated rats (P<0.05). After administration of CLB into the lateral ventricle of HF rats, the contents of PGE2 in CSF were significantly reduced, the number of activation CRH neurons in PVN was decreased, the excitability of sympathetic nerves was down-regulated and cardiac function was im-proved (P<0.05). Compared with the sham-operated rats, the content of glutamic acid in PVN of HF rats was increased, the content of γ-aminobutyric acid and the number of glutamate decarboxylase 67-positive neurons were decreased ( P<0.05). After the CLB was given, the above indexes were reversed (P<0.05). CONCLUSION:These findings indicate that in CHF, the increased central PGE2 may activate CRH-containing PVN neurons and contribute to the augmented sym-pathetic drive possibly by modulating the neurotransmitters within the PVN.