Drug repositioning based on network-specific core genes identifies potential drugs for the treatment of autism spectrum disorder in children.

Identification of exact causative genes is important for in silico drug repositioning based on drug-gene-disease relationships. However, the complex polygenic etiology of the autism spectrum disorder (ASD) is a challenge in the identification of etiological genes. The network-based core gene identification method can effectively use the interactions between genes and accurately identify the pathogenic genes of ASD. We developed a novel network-based drug repositioning framework that contains three steps: network-specific core gene (NCG) identification, potential therapeutic drug repositioning, and candidate drug validation. First, through the analysis of transcriptome data for 178 brain tissues, gene network analysis identified 365 NCGs in 18 coexpression modules that were significantly correlated with ASD. Second, we evaluated two proposed drug repositioning methods. In one novel approach (dtGSEA), we used the NCGs to probe drug-gene interaction data and identified 35 candidate drugs. In another approach, we compared NCG expression patterns with drug-induced transcriptome data from the Connectivity Map database and found 46 candidate drugs. Third, we validated the candidate drugs using an in-house mental diseases and compounds knowledge graph (MCKG) that contained 7509 compounds, 505 mental diseases, and 123,890 edges. We found a total of 42 candidate drugs that were associated with mental illness, among which 10 drugs (baclofen, sulpiride, estradiol, entinostat, everolimus, fluvoxamine, curcumin, calcitriol, metronidazole, and zinc) were postulated to be associated with ASD. This study proposes a powerful network-based drug repositioning framework and also provides candidate drugs as well as potential drug targets for the subsequent development of ASD therapeutic drugs.

Bushen Qiangji Granule () medicated serum inhibits osteogenic differentiation of fibroblasts in ankylosing spondylitis by inhibiting the BMP/Smads signal pathway in vitro.

OBJECTIVE: To explore the mechanism of Bushen Qiangji Granule (, BSQJ) in restraining the osteogenic differentiation of ankylosing spondylitis (AS) fifibroblasts. METHODS: Hip joint capsules were obtained from AS patients (n=10) receiving total hip replacement and healthy hip joint capsules from patients with hip fracture (n=10) receiving surgery as a control. Finite fifibroblast lines were established from these tissue samples to observe the effect of BSQJ on suppressing osteogenic differentiation of fifibroblasts. The expression of osteogenic marker gene corebinding factor a1 (Cbfa1) and Smad family proteins were examined by Western blot and real-time quantitative polymerase chain reaction (qPCR). RESULTS: The mRNA expression level of Cbfa1 was significantly higher in AS fibroblasts than that in normal fibroblasts and the expression of pSmad1, pSmad5, Smad4 and Cbfa1 in AS fibroblasts was also higher, demonstrating the activation of the BMP/Smads signal pathway in AS fifibroblasts. BSQJ-medicated serum not only restrained the mRNA and protein expression levels of Cbfa1 and inhibited protein expression level of Smad4 but also decreased the expression quantities of pSmad1 and pSmad5. CONCLUSIONS: BSQJ can inhibit osteogenic differentiation of AS fifibroblasts in vitro by suppressing the activation of the BMP/Smads signal pathway. This may be the important molecular mechanism of BSQJ in regulating AS ossifification.

Elemene, the essential oil of Curcuma wenyujin, inhibits osteogenic differentiation in ankylosing spondylitis.

OBJECTIVE: To explore the effects of Elemene, the essential oil of Curcuma wenyujin, on Bone morphogenetic protein/drosophila mothers against decapentaplegic proteins (BMP/SMADs) signal pathway in ankylosing spondylitis (AS) fibroblasts. METHODS: Hip joint capsules were obtained from AS patients (n=10) receiving total hip replacement. Healthy hip joint capsules from patients with hip fracture (n=10) receiving surgery were included as a control. Primary fibroblast cell lines were established from these tissue samples. Fibroblasts were incubated with Elemene for 48 hours. The protein expression was detected by Western blot. The mRNA expression was detected by real-time fluorescent quantitative polymerase chain reaction (PCR). RESULTS: The results showed that the expression of proteins including SMAD1, pSMAD1, SMAD4 and Runt-related transcription factor 2 (RUNX2), and mRNA of RUNX2, which were over-expressed in AS fibroblasts were decreased in the AS fibroblasts cultured in medium with Elemene. CONCLUSIONS: Ele could have a hand in anti-osteogenic differentiation of AS fibroblasts by inhibiting the BMP/SMADs signal pathway and subsequently blocking expression of ossification marker genes RUNX2 that initiate the osteogenic differentiation.

Application of molecular imaging technologies in antitumor drug development and therapy.

Molecular imaging enables noninvasive characterization, quantification and visualization of biological and pathological processes in vivo at cellular and molecular level. It plays an important role in drug discovery and development. The skillful use of molecular imaging can provide unique insights into disease processes, which greatly aid in identifications of target. Importantly, molecular imaging is widely applied in the pharmacodynamics study to provide earlier endpoints during the preclinical drug development process, since it can be applied to monitor the effects of treatment in vivo with the use of biomarkers. Herein, we reviewed the application of molecular imaging technologies in antitumor drug development process ranging from identification of targets to evaluation of therapeutic effect.

[Clinical observation of cognitive impairment after traumatic brain injury treated with acupuncture and cognitive training].

OBJECTIVE: To observe the clinical efficacy on cognitive impairment after traumatic brain injury (TBD treated with acupuncture and cognitive training. METHODS: Sixty patients were randomized into an observation group and a control group, 30 cases in each one, and 5 cases of them were dropped out due to the earlier discharge. Finally, there were 28 cases in the observation group and 27 cases in the control group. In the control group, the cognitive training and conventional treatment were applied. In the observation group, on the basis of the treatment as the control group, acupuncture was applied to Baihui (GV 20), Fengchi (GB 20), Geshu (BL 17) and Fenglong (ST 40), once a day, for 4 weeks totally. The mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were adopted to evaluate the cognitive function in the patients of post-TBI cognitive impairment. RESULTS: (1) After treatment, the total score in MMSE and the score of each item were increased significantly as compared with those before treatment in the two groups (all P<0. 05). Except for the score of immediate recall, the score in MMSE and the score of each of the other items were increased significantly in the observation group as compared with those in the control group after treatment (all P<0. 05). (2)After treatment, the total score in MoCA and the score of each item were increased significantly as compared with those before treatment in the two groups (all P<. 05). Except for the score of nomenclature item, the total score in MoCA and the score of each of the other items were increased significantly in the observation group as compared with those in the control group after treatment (all P<0. 05). CONCLUSION: Both the simple cognitive training and the combined therapy of acupuncture and cognitive training improve MMSE and MoCA scores and relieve the cognitive impairment induced by TBI. But the combined therapy achieves the much better efficacy.

Functional electrical stimulation early after stroke improves lower limb motor function and ability in activities of daily living.

BACKGROUND: Functional electrical stimulation (FES) to patients early after stroke has been proved to improve walking ability. The effects on abilities in activities of daily living (ADL) are not clear. OBJECTIVE: To investigate the effectiveness of FES in improving lower limb function and ability in ADL of early stroke patients. METHODS: Thirty-seven stroke patients were randomly allocated to standard rehabilitation (SR) group (n = 18), and FES group with FES and SR (n = 19). SR included 60 minutes each for physiotherapy and occupational therapy. FES was delivered for 30 min to induce ankle dorsiflexion and eversion. Treatments were 5 days per week for 3 weeks. Evaluations including the composite spasticity scale (CSS), lower-extremity subscale of Fugl-Myer Assessment (FMA), postural assessment scale for stroke patients (PASS), Berg Balance Scale (BBS), and modified Barthel Index (MBI) assessed before treatment, after 2 and 3 week treatment respectively. RESULTS: After 2 week treatment, FES group showed a significant reduction of CSS and improvements of FMA, MBI and PASS. After 3 week treatment, FES group showed a further reduction of CSS and also improvement of FMA, MBI and BBS as well. CONCLUSIONS: FES on the paretic lower limbs early after stroke improved the mobility and ability in ADL.