Network pharmacology-based exploration of therapeutic mechanism of Liu-Yu-Tang in atypical antipsychotic drug-induced metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is prevalent in patients receiving atypical antipsychotic drugs (AADs), but there are few effective interventions. The Traditional Chinese herbal decoction Liu-Yu-Tang (LYT) has achieved clinical improvement for AAD-induced MetS, but its pharmacological mechanism remains unclear. METHOD: A network pharmacology-based method was utilized in this study. First, the TCMSP and SwissTargetPrediction database were used to acquire plasma-absorbed components and putative targets of LYT, respectively. Second, an interaction network between shared targets of LYT and MetS was constructed using STRING online tool. Topological analyses were performed to extract hub gene targets. Finally, we did a pathway analysis of gene targets using the Kyoto Encyclopedia of Genes and Genomes (KEGG) to find biological pathways of LYT. RESULTS: We obtained 655 putative targets of LYT, 434 known targets of AADs, and 1577 MetS-related gene targets. There are 232 shared targets between LYT and MetS. Interaction network construction and topological analysis yielded 60 hub targets, of which 18 were major hub targets, among which IL-6, IL-8, TNF, PI3K, MAPK, and NF-κB (RELA) are the most important in LYT's treatment of AAD-induced MetS. Pathway enrichment analysis revealed a statistically high significance of the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis and the insulin resistance pathway. CONCLUSIONS: LYT may control activities of the pro-inflammatory cytokines IL-6, IL-8, TNF and the important signal transduction molecules PI3K, MAPKs, and NF-κB (RELA), regulating metabolic disturbance-related pathways like the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis, and the insulin resistance pathway, generating therapeutic effects for AAD-induced MetS.

SNX29, a new susceptibility gene shared with major mental disorders in Han Chinese population.

OBJECTIVES: Environmental and genetic factors play important roles in the development of schizophrenia (SCZ), bipolar disorder (BPD) or major depressive disorder (MDD). Some risk loci are identified with shared genetic effects on major psychiatric disorders. To investigate whether SNX29 gene played a significant role in these psychiatric disorders in the Han Chinese population. METHODS: We focussed on 11 single-nucleotide polymorphisms (SNPs) harbouring SNX29 gene and carried out case-control studies in patients with SCZ (n = 1248), BPD (n = 1344), or MDD (n = 1056), and 1248 healthy controls (HC) recruited from the Han Chinese population. We constructed weighted gene co-expression network analysis (WGCNA) and extracted significant modules by R package. RESULTS: We found that rs3743592 was significantly associated with MDD and rs6498263 with BPD in both allele and genotype distributions. Before correction, rs3743592 showed allelic and genotypic significance with SCZ, rs6498263 showed allelic significance with SCZ. WGCNA identified top 10 modules of co-expressed genes. Gene Ontology (GO) and pathway analysis were used to examine the functions of SNX29, which revealed that SNX29 was involved in the regulation of a number of biological processes, such as TGF-beta, ErbB, and Wnt signalling pathway, etc. CONCLUSIONS: Our results supported common risk factors in SNX29 might share among these three mental disorders in the Han Chinese population.

The New NNRTI ACC007 Combined with Lamivudine and Tenofovir Disoproxil Fumarate Show Synergy Anti-HIV Activity In Vitro.

BACKGROUND: Acquired immunodeficiency syndrome can hardly be cured currently and people with human immunodeficiency virus (HIV) need lifelong treatment that may result in the emergence of drug resistance which leads to failed treatment. Thus, the development of new anti- HIV drugs and new treatment regimens are necessary. OBJECTIVE: The aim of this study is to analyze the combined anti-HIV activity of tenofovir disoproxil fumarate, lamivudine and ACC007, a new non-nucleoside reverse transcriptase inhibitor. METHODS: The antiviral activity of tenofovir disoproxil fumarate, lamivudine and ACC007 alone or in combination against different HIV-1 strains was determined by the detection of HIV-1 p24 level through enzyme-linked immunosorbent assay. RESULT: ACC007 showed EC50 of nanomolar range (from 3.03 nM to 252.59 nM) against all HIV-1 strains used in this study except the HIV-1A17, with EC50 of 1.57 µM. The combined antiviral activity of ACC007, lamivudine and tenofovir disoproxil fumarate showed synergy antiviral activity against all HIV-1 strains used in this study. The three-drug combination showed moderate synergism against HIV-1A17, HIV-14755-5, HIV-1K103N and HIV-1V106M, with a combination index value ranging from 0.71 to 0.87, and showed synergism against the other HIV-1 strains with combination index value from 0.35 to 0.67. The combination with ACC007 significantly increases the dose reduction index value of lamivudine and tenofovir disoproxil fumarate, compared with two-drug combination. CONCLUSION: ACC007 exhibits potent antiviral activity alone or with 3TC and TDF, and exerts synergistic effect against all HIV strains used in our investigation in vitro.

Patient health questionnaire-15 (PHQ-15) to distinguish bipolar II disorder from major depressive disorder.

A sequential-recruited clinical trial has been conducted to assess capacity of Patient Health Questionnaire-15 (PHQ-15) in distinguishing bipolar II disorder from major depressive disorder. A total of 73 patients (49 BD-II depression patients) filled sociodemographic characteristics, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 Questionnaire (GAD-7), and PHQ-15. Sum score of PHQ-15 showed statistically significant difference in the two groups (t-test, P = 0.027). The area under the curve was 0.663 (P = 0.025), and the specificity was 0.75 at sum score of 13. Patients with BD-II depression has more somatic symptoms than MDD, and PHQ-15 might be used for identification.

Network pharmacology-based identification for therapeutic mechanism of Ling-Gui-Zhu-Gan decoction in the metabolic syndrome induced by antipsychotic drugs.

BACKGROUND: The metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. METHODS: A network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of "edge betweenness" of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. RESULTS: This approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. CONCLUSIONS: LGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.

14-Formyl-15-aryloxy/methoxymatrine and 14-Aryloxymethylidenyl-matrine Derivatives as Anti-HIV-1 Agents.

BACKGROUND: The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has always been a global health threat and leading cause of deaths. However, due to the emergence of drug-resistant HIV, an inevitable consequence of increasing use of antiretroviral drugs posed a major threat to antiretroviral therapy success. OBJECTIVE: The discovery of anti-HIV-1 agents will be used for the effective treatment of HIV/AIDS. METHOD: In continuation of our program aimed to discover anti-HIV-1 agents, twelve matrine derivatives, such as 14-formyl-15-aryloxy/methoxymatrines (3a-j) and 14-aryloxymethylidenylmatrines (3k,l), were semi-prepared from matrine, and evaluated against HIV-1 IIIB replication in acutely infected C8166 cells in vitro. RESULTS: Among them, compound 3j showed the most potent anti-HIV-1 activity with EC50 and therapeutic index (TI) values of 1.79 µg/mL, and 98.2, respectively. CONCLUSION: It has been demonstrated that the positions of methyl on the phenyl ring and 14- formylmatrine-15-oxy on the naphthyl ring were very important for the activity. It will lay the foundation for further structural modification and application of matrines as HIV-1 inhibitors.

[The anti-HIV-1 activities of benzophenones non-nucleoside reverse transcriptase inhibitors in vitro].

To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC(50) greater than 200 µg·m L(-1). DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1(IIIB,) HIV-1(74V,) HIV-1(RF/V82F/184V,) HIV-1(NL4-3) (gp41(36G)N42S,) HIV-1(KM018,) HIV-1(TC-1) and HIV-1(Wan.) However, NNRTIs drug-resistant strain HIV-1(A17) showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.