Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

In silico-based screen synergistic drug combinations from herb medicines: a case using Cistanche tubulosa.

ABSTRACT: Neuroinflammation is characterized by the elaborated inflammatory response repertoire of central nervous system tissue. The limitations of the current treatments for neuroinflammation are well-known side effects in the clinical trials of monotherapy. Drug combination therapies are promising strategies to overcome the compensatory mechanisms and off-target effects. However, discovery of synergistic drug combinations from herb medicines is rare. Encouraged by the successfully applied cases we move on to investigate the effective drug combinations based on system pharmacology among compounds from Cistanche tubulosa (SCHENK) R. WIGHT. Firstly, 63 potential bioactive compounds, the related 133 direct and indirect targets are screened out by Drug-likeness evaluation combined with drug targeting process. Secondly, Compound-Target network is built to acquire the data set for predicting drug combinations. We list the top 10 drug combinations which are employed by the algorithm Probability Ensemble Approach (PEA), and Compound-Target-Pathway network is then constructed by the 12 compounds of the combinations, targets, and pathways to unearth the corresponding pharmacological actions. Finally, an integrating pathway approach is developed to elucidate the therapeutic effects of the herb in different pathological features-relevant biological processes. Overall, the method may provide a productive avenue for developing drug combination therapeutics.

SUBMITTER: Liu J

PROVIDER: S-EPMC5703970 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Guided screen for synergistic three-drug combinations.

Project description:Combinations of three or more drugs are routinely used in various medical fields such as clinical oncology and infectious diseases to prevent resistance or to achieve synergistic therapeutic benefits. The very large number of possible high-order drug combinations presents a formidable challenge for discovering synergistic drug combinations. Here, we establish a guided screen to discover synergistic three-drug combinations. Using traditional checkerboard and recently developed diagonal methods, we experimentally measured all pairwise interactions among eight compounds in Erwinia amylovora, the causative agent of fire blight. Showing that synergy measurements of these two methods agree, we predicted synergy/antagonism scores for all possible three-drug combinations by averaging the synergy scores of pairwise interactions. We validated these predictions by experimentally measuring 35 three-drug interactions. Therefore, our guided screen for discovering three-drug synergies is (i) experimental screen of all pairwise interactions using diagonal method, (ii) averaging pairwise scores among components to predict three-drug interaction scores, (iii) experimental testing of top predictions. In our study, this strategy resulted in a five-fold reduction in screen size to find the most synergistic three-drug combinations.

| S-EPMC7347197 | biostudies-literature

Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma.

Project description:Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma associated with MYC translocation. Here, we describe drug response profiling of 42 blood cancer cell lines including 17 BL to 32 drugs targeting key cancer pathways and provide a systematic study of drug combinations in BL cell lines. Based on drug response, we identified cell line specific sensitivities, i.e. to venetoclax driven by BCL2 overexpression and partitioned subsets of BL driven by response to kinase inhibitors. In the combination screen, including BET, BTK and PI3K inhibitors, we identified synergistic combinations of PI3K and BTK inhibition with drugs targeting Akt, mTOR, BET and doxorubicin. A detailed comparison of PI3K and BTKi combinations identified subtle differences, in line with convergent pathway activity. Most synergistic combinations were identified for the BET inhibitor OTX015, which showed synergistic effects for 41% of combinations including inhibitors of PI3K/AKT/mTOR signalling. The strongest synergy was observed for the combination of the CDK 2/7/9 inhibitor SNS032 and OTX015. Our data provide a landscape of drug combination effects in BL and suggest that targeting CDK and BET could provide a novel vulnerability of BL.

| S-EPMC6089937 | biostudies-literature

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer.

Project description:Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.

| S-EPMC7765376 | biostudies-literature

Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen.

Project description:Therapeutic options for tuberculosis (TB) are limited and notoriously ineffective despite the wide variety of potent antibiotics available for treating other bacterial infections. We investigated an approach that enables an expansion of TB therapeutic strategies by using synergistic combinations of drugs. To achieve this, we devised a high-throughput synergy screen (HTSS) of chemical libraries having known pharmaceutical properties, including thousands that are clinically approved. Spectinomycin was used to test the concept that clinically available antibiotics with limited efficacy against Mycobacterium tuberculosis might be used for TB treatment when coadministered with a synergistic partner compound used as a sensitizer. Screens using Mycobacterium smegmatis revealed many compounds in our libraries that acted synergistically with spectinomycin. Among them, several families of antimicrobial compounds, including macrolides and azoles, were also synergistic against M. tuberculosis in vitro and in a macrophage model of M. tuberculosis infection. Strikingly, each sensitizer identified for synergy with spectinomycin uniquely enhanced the activities of other clinically used antibiotics, revealing a remarkable number of unexplored synergistic drug combinations. HTSS also revealed a novel activity for bromperidol, a butyrophenone used as an antipsychotic drug, which was discovered to be bactericidal and greatly enhanced the activities of several antibiotics and drug combinations against M. tuberculosis. Our results suggest that many compounds in the currently available pharmacopoeia could be readily mobilized for TB treatment, including disease caused by multi- and extensively drug-resistant strains for which there are no effective therapies.

| S-EPMC3147639 | biostudies-literature

High-throughput RNAi screen for essential genes and drug synergistic combinations in colorectal cancer.

Project description:Metastatic colorectal cancer is a leading cause of cancer death. However, current therapy options are limited to chemotherapy, with the addition of anti-EGFR antibodies for patients with RAS wild-type tumours. Novel drug targets, or drug combinations that induce a synergistic response, would be of great benefit to patients. The identification of genes that are essential for cell survival can be undertaken using functional genomics screens. Furthermore, performing such screens in the presence of a targeted agent would allow the identification of combinations that result in a synthetic lethal interaction. Here, we present a dataset containing the results of a large scale RNAi screen (815 genes) to detect essential genes as well as synergistic combinations with targeted therapeutic agents using a panel of 27 colorectal cancer cell lines. These data identify genes that are essential for colorectal cancer cell survival as well as synthetic lethal treatment combinations using novel computational approaches. Moreover, this dataset could be utilised in combination with genomic profiling to identify predictive biomarkers of response.

| S-EPMC5625556 | biostudies-literature

Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions.

Project description:Identification of effective combination therapies is critical to address the emergence of drug-resistant cancers, but direct screening of all possible drug combinations is infeasible. Here we introduce a CRISPR-based double knockout (CDKO) system that improves the efficiency of combinatorial genetic screening using an effective strategy for cloning and sequencing paired single guide RNA (sgRNA) libraries and a robust statistical scoring method for calculating genetic interactions (GIs) from CRISPR-deleted gene pairs. We applied CDKO to generate a large-scale human GI map, comprising 490,000 double-sgRNAs directed against 21,321 pairs of drug targets in K562 leukemia cells and identified synthetic lethal drug target pairs for which corresponding drugs exhibit synergistic killing. These included the BCL2L1 and MCL1 combination, which was also effective in imatinib-resistant cells. We further validated this system by identifying known and previously unidentified GIs between modifiers of ricin toxicity. This work provides an effective strategy to screen synergistic drug combinations in high-throughput and a CRISPR-based tool to dissect functional GI networks.

| S-EPMC5557292 | biostudies-literature

Inhibition of Amyloid Beta Aggregation and Deposition of Cistanche tubulosa Aqueous Extract.

Project description:Cistanche tubulosa aqueous extract (CTE) is already used as a botanical prescription drug for treating dementia in China. Our previous studies reported that phenylethanoid glycosides of CTE have anti-Alzheimer's disease (AD) activity by inhibiting amyloid β peptide (Aβ) aggregation and deposition. However, recent studies considered that the phenylethanoid glycosides may be metabolized by intestinal bacteria, because all analysis results showed that the bioavailability of phenylethanoid glycosides is extremely low. In this study we demonstrate how iron chelation plays a crucial role in the Aβ aggregation and deposition inhibition mechanism of phenylethanoid glycosides of CTE. In addition, we further proved phenylethanoid glycosides (1⁻3) could reach brain. Active CTE component and action mechanism confirmation will be a great help for product quality control and bioavailability studies in the future. At the same time, we provide a new analysis method useful in determining phenylethanoid glycosides (1⁻3) in plants, foods, blood, and tissues for chemical fingerprint and pharmacokinetic research.

| S-EPMC6412839 | biostudies-literature

Novel Synergistic Anti-Enteroviral Drug Combinations.

Project description:Background: Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved treatments for enterovirus infections. Methods: We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 (EV1) in human adenocarcinoma alveolar basal epithelial A549 cells. We also tested combinations of the most active compounds against EV1 in A549 and human immortalized retinal pigment epithelium RPE cells. Results: We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir-vemurafenib, vemurafenib-pleconaril and rupintrivir-pleconaril combinations against EV1 infection. Conclusions: Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their cocktails may have fewer side effects in vivo and, therefore, should be further explored in preclinical and clinical trials against EV1 and other enterovirus infections.

| S-EPMC9505890 | biostudies-literature

Extensive gene loss in the plastome of holoparasitic plant <i>Cistanche tubulosa</i> (Orobanchaceae).

Project description:Extensive photosynthetic gene loss and rapid evolutionary rate occur in the plastomes of parasitic plants. The holoparasitic plant Cistanche tubulosa of Orobanchaceae is an important medicinal resources that are distributed in arid areas. In this study, the complete plastome of C. tubulosa has been sequenced, assembled and analyzed. The total plastome of C. tubulosa was 75,375 bp in length, consisting of a pair of inverted repeats (IRs, 6,593 bp), a large single-copy region (LSC, 32,470 bp) and a small single-copy region (SSC, 29,719 bp). It contained 24 intact protein coding genes, nine pseudogenes, and 44 missing genes. In addition, all the protein-coding genes, which were related to photosynthesis and energy production, were pseudogenised or lost. Four rRNA genes and 24 tRNA genes were intact meanwhile five tRNA genes were missing. Phylogenetic tree indicated that C. tubulosa was closely related to C. phelypaea. Our results may improve understanding of the plastome organization, classification, and evolution of parasitic plants.

| S-EPMC7782945 | biostudies-literature

Herbal medicines in Brazil: pharmacokinetic profile and potential herb-drug interactions.

Project description:A plethora of active compounds found in herbal medicines can serve as substrate for enzymes involved in the metabolism of xenobiotics. When a medicinal plant is co-administered with a conventional drug and little or no information is known about the pharmacokinetics of the plant metabolites, there is an increased risk of potential herb-drug interactions. Moreover, genetic polymorphisms in a population may act to predispose individuals to adverse reactions. The use of herbal medicines is rapidly increasing in many countries, particularly Brazil where the vast biodiversity is a potential source of new and more affordable treatments for numerous conditions. Accordingly, the Brazilian Unified Public Health System (SUS) produced a list of 71 plant species of interest, which could be made available to the population in the near future. Physicians at SUS prescribe a number of essential drugs and should herbal medicines be added to this system the chance of herb-drug interactions further increases. A review of the effects of these medicinal plants on Phase 1 and Phase 2 metabolic mechanisms and the transporter P-glycoprotein was conducted. The results have shown that approximately half of these medicinal plants lack any pharmacokinetic data. Moreover, most of the studies carried out are in vitro. Only a few reports on herb-drug interactions with essential drugs prescribed by SUS were found, suggesting that very little attention is being given to the safety of herbal medicines. Here we have taken this information to discuss the potential interactions between herbal medicines and essential drugs prescribed to Brazilian patients whilst taking into account the most common polymorphisms present in the Brazilian population. A number of theoretical interactions are pinpointed but more pharmacokinetic studies and pharmacovigilance data are needed to ascertain their clinical significance.

| S-EPMC4087670 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data