Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Objective:To explore the difference of blood pressure compliance rate in patients with continuous ambulatory peritoneal dialysis (CAPD) in the internet of things (IoT) follow-up and conventional care.Methods:CAPD patients from 3 peritoneal dialysis centers from May 2019 to October 2019 were included in this retrospective cohort study. They were divided into IoT group and conventional care group according to the way of follow-up. The difference in blood pressure compliance rate during 1 year of follow-up between the two groups was observed. The primary outcome was defined as the proportion of patients with blood pressure compliance rate≥85%.Results:A total of 75 patients were included in this study, in during 32 patients in IoT group and 43 patients in conventional care group. The comparison of baseline data between the two groups showed that the dialysis age of patients in IoT group was shorter ( P<0.01). After a median of 9(9, 12) months follow-up, the median blood pressure compliance rate was 85.2% (65.2%, 95.1%), and 25 patients (65.6%) in IoT group had met the target of blood pressure compliance rate≥85%, which was significantly higher than that in the conventional care group (17 cases, 39.5%) ( χ2=4.996, P=0.025). The cumulative probability of the target of blood pressure compliance rate≥85% was 97%, 90%, 90% and 52%, respectively in IoT group, while 95%, 86%, 55% and 34%, respectively in conventional care group after 3, 6, 9 and 12 months of follow-up, and the different between the two groups was significant (Log-rank χ2=4.774, P=0.029). Adjusted for age, sex and dialysis age, the multivariate Cox proportional risk regression model showed that serum creatinine level(for every 1 μmol/L increase, HR=1.002, 95% CI 1.000-1.003, P=0.033), follow-up mode (IoT follow-up vs conventional care, HR=0.023, 95% CI 0.003-0.210, P=0.001), follow-up times (for each additional time, HR=0.879, 95% CI 0.823-0.939, P<0.001) and the rate of weight compliance (for each increase of 1%, HR=0.964, 95% CI 0.939-0.991, P=0.008) was the independent influencing factors for the blood pressure compliance rate<85%. The results of subgroup analysis showed that patients with shorter dialysis age (<10 months) and in the centers where the nurses finished the PD follow-up work as part-time job had better blood pressure control in IoT follow-up. Conclusions:IoT follow-up is helpful to improve CAPD patients' blood pressure compliance rate. Elevated serum creatinine level at baseline is the independent risk factor associated with poor blood pressure compliance. However, IoT follow-up, more follow-up times and the elevated rate of weight compliance are the protective factors for blood pressure compliance. IoT follow-up mode is more recommended for patients with short dialysis age and for dialysis centers where most of the nurses are part-time.

Objective To investigate the effect of allicin on the development of atherosclerosis in apoE-/-mice and explore its underlying mechanism from the perspective of protein S-nitrosylation.Methods Thirty male apoE-/- mice were randomly divided into 3 groups:control group (saline,ig),low-dose group (allicin,9 mg/kg·d, ig)and high-dose group (allicin,18 mg/kg·d,ig).They were fed with high cholesterol diet for 12 weeks.The levels of plasma lipids,oxidized-LDL (ox-LDL),malondialdehyde,tumor necrosis factor-alpha and nitric oxide (NO)were measured.The atherosclerotic lesions in aortic root were evaluated after hematoxylin and eosin staining and elastica van Gieson and immunohistochemical staining,respectively.Furthermore,in vitro experiments were performed using human umbilical vein endothelial cells (HUVECs).The HUVECs were treated with allicin (10μmol/L or 20 μmol/L)for 24 hours in the presence of ox-LDL (50 μg/mL).The level of NO in supernatant was measured by a nitrate/nitrite assay. The protein S-nitrosylation of the HUVECs was detected through immunofluorescence.Results The histological analysis revealed that allicin treatment not only significantly decreased the areas of the atherosclerotic lesion (all P <0.05)but also suppressed the macrophage accumulation and smooth muscle cell proliferation in the lesion.There was no significant difference in the levels of plasma lipids between control and treated groups.However,allicin exerted obvious anti-oxidative and anti-inflammatory effects. Interestingly,the allicin treatment led to marked increase of the plasma NO level (P <0.05)and aortic protein S-nitrosylation.The experiments in vitro further proved that the allicin up-regulated the levels of NO and protein S-nitrosylation in HUVECs treated with ox-LDL (P < 0.01 ).Conclusion Allicin can inhibit the development of atherosclerosis.The mechanism is associated with the up-regulation of protein S-nitrosylation in endothelial cells, which plays an important role in anti-oxidization and anti-inflammation.

Objective To explore the molecular mechanism of blood_stasis syndrome (BSS) by studying the changes of gene expression of endothelin (ET) and constit utive nitric oxide synthase (cNOS) in vascular endothelial cells (VEC) cultured w ith BSS rabbit serum. Methods ET_1 mRNA expression and cNOS mRNA expression were analyzed by semi_quantitative reverse transcription and polymerase chain re action method. Results ET_1 mRNA expression level was increased and cNOS mRN A expression level was decreased in VEC cultured with BSS rabbit serum (Group A) as compared with VEC cultured with normal rabbit serum (Group B) or without rab bit serum (Group C) (P