Insight into Shenqi Jiangtang Granule on the improved insulin sensitivity by integrating in silico and in vivo approaches.

ETHNOPHARMACOLOGICAL RELEVANCE: Presently, insulin resistance has been a growing concern that urgently needs to be addressed, because it not only places patients at risk of developing type 2 diabetes mellitus but also results in metabolic syndrome and different aspects of cardiovascular diseases. Shenqi Jiangtang Granule (SJG) is a classic traditional Chinese medicine (TCM) prescription that is widely used to treat diabetes mellitus and its complications in clinical practice. While studies have revealed that SJG with multi-ingredients and multi-targets characteristics possesses potential anti-insulin resistance pharmacological properties, its mechanisms of action and molecular targets for the treatment of insulin resistance are still obscure, which prompt us to conduct an in-depth research. AIM OF THE STUDY: This study was purposed to uncover the pharmacological mechanism of SJG against insulin resistance through integrating network pharmacology and experimental validation. MATERIALS AND METHODS: The putative ingredients of SJG and its related targets were discerned from the TCMSP database. Subsequently, insulin resistance-associated targets were retrieved from GeneCard, OMIM, and GEO database. Compound-target, protein-protein interaction (PPI), and compound-target-pathway networks were established using Cytoscape software. GO and KEGG pathway analyses were performed to identify possible enrichment of genes with specific biological themes. Molecular docking was used to verify the correlation between the main active ingredients and hub targets. Optimal docking conformation was further analyzed by molecular dynamics (MD) simulation. Finally, the potential molecular mechanisms of SJG acting on insulin resistance, as predicted by the network pharmacology analyses, were validated experimentally in insulin-resistant rat model. RESULTS: 136 active compounds, 211 corresponding targets in addition to 1463 disease-related targets were collected, of which 94 intersection targets were obtained. 29 key targets including AKT1, VEGFA, IL-6, CASP3, and PTGS2 were identified through PPI network analysis. Hub module of PPI network was closely associated with inflammation. GO and KEGG analyses also revealed that inflammation-related pathways may be a central factor for SJG to modulate insulin resistance. Molecular docking test showed a good binding potency between primary active ingredients and core targets, and the binding mode of optimal docking conformation was stable in MD simulation. A rat model of insulin resistance was successfully induced by chronic high-fat diet (HFD) consumption. Through a series of in vivo studies, including HEC, ITT, and HOMA-IR measurement, it was revealed that SJG exhibited a beneficial effect on ameliorating insulin resistance, as demonstrated by a significant increase of GIR and a significant decrease of AUCITT and HOMA-IR index value. Further molecular biological analysis showed that SJG can decrease the mRNA expression level and serum concentration of inflammatory cytokines (TNF-α, IL-6, and IL-1ß), along with suppressing the p-NFκB protein overexpression, indicating its anti-inflammatory activity. Also, it can contribute to the reversal of the impaired hepatic insulin signaling pathway, as evidenced by up-regulated protein expression of p-Akt and GLUT2. CONCLUSIONS: Through in silico and in vivo approaches, the present study not only provides a unique insight into the possible mechanism of SJG in insulin resistance after successfully filtering out associated key target genes and signaling pathways, but also suggests a novel promising therapeutic strategy for curing insulin resistance.

Logistic regression analysis of factors influencing the effectiveness of intensive sound masking therapy in patients with tinnitus.

OBJECTIVES: To investigate factors influencing the effectiveness of intensive sound masking therapy on tinnitus using logistic regression analysis. DESIGN: The study used a retrospective cross-section analysis. PARTICIPANTS: 102 patients with tinnitus were recruited at the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, China. INTERVENTION: Intensive sound masking therapy was used as an intervention approach for patients with tinnitus. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants underwent audiological investigations and tinnitus pitch and loudness matching measurements, followed by intensive sound masking therapy. The Tinnitus Handicap Inventory (THI) was used as the outcome measure pre and post treatment. Multivariate logistic regression was performed to investigate the association of demographic and audiological factors with effective therapy. RESULTS: According to the THI score changes pre and post sound masking intervention, 51 participants were categorised into an effective group, the remaining 51 participants were placed in a non-effective group. Those in the effective group were significantly younger than those in the non-effective group (P=0.012). Significantly more participants had flat audiogram configurations in the effective group (P=0.04). Multivariable logistic regression analysis showed that age (OR=0.96, 95% CI 0.93 to 0.99, P=0.007), audiometric configuration (P=0.027) and THI score pre treatment (OR=1.04, 95% CI 1.02 to 1.07, P<0.001) were significantly associated with therapeutic effectiveness. Further analysis showed that patients with flat audiometric configurations were 5.45 times more likely to respond to intervention than those with high-frequency steeply sloping audiograms (OR=5.45, 95% CI 1.67 to 17.86, P=0.005). CONCLUSION: Audiometric configuration, age and THI scores appear to be predictive of the effectiveness of sound masking treatment. Gender, tinnitus characteristics and hearing threshold measures do not seem to be related to treatment effectiveness. A further randomised control study is needed to provide evidence of the effectiveness of prognostic factors in tinnitus interventions.

Visual cortex activation decrement following cochlear implantation in prelingual deafened children.

OBJECTIVE: Visual take-over of the auditory cortex in prelingual deaf children has been widely reported. However, there have been few studies on visual cortex plasticity after cochlear implantation (CI). In this study, we investigated the hypothesis that extrinsic auditory stimulation following CI in prelingual deafened children can induce visual cortex plasticity. METHOD: Visual evoked potentials (VEPs) were recorded in 37 CI children (4 groups with different use times) and 8 control subjects, in response to sound and nonsound stimuli. Latency and amplitude were analyzed for the P1, N1 and P2 components on the Oz electrode. Comparisons of VEP were conducted between the sound and nonsound stimuli and among different groups in order to view evidence of visual cortex reorganization. RESULTS: The latency of the P2 component was significantly longer at the occipital site (Oz) in CI 0M than those in the other four groups. After the effect of age was excluded, a significant negative correlation was found between CI usage and P2 latency of nonsound stimuli. Occipital P1N1 latency and P1 amplitude were not affected by group or stimulus category. However, the N1 and P2 amplitudes were significantly larger in response to a sound stimulus than to a nonsound stimulus. CONCLUSION: Our findings suggest that P2 latency develops with CI usage and may be a biomarker of visual cortex plasticity.