Project description:Comparison between the multi-drug resistance Salmonella enteric serotype Newport strains from the US and the pan-susceptible strains from the UK
Project description:Tumor heterogeneity and therapy resistance are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Emerging evidence supports treatment-induced resistance to be a multifactorial process mediated by cellular plasticity involving epigenetic regulation. Here, we used a multi-omics approach to analyze in detail molecular mechanisms underlying MEK inhibitor (MEKi) resistance. Therefore, we characterized different cell stages (parental, MEKi resistant, reverted after different passages of drug withdrawal) in primary cell lines derived from a genetic PDAC mouse model, thereby minimizing inter-individual heterogeneity that could distort genome-wide analyses.
Project description:Phytophthora infestans, the causal agent of late blight disease of potatoes, is mainly controlled by the use of fungicides. Isolates that are resistant to commonly used fungicides have been reported. Also, several studies show that originally mefenoxam-sensitive isolates acquire resistance to this fungicide when exposed to sub-lethal concentrations. This phenomenon, termed ‘mefenoxam-acquired resistance’, has been observed in different Phytophthora species and seems to be unique to mefenoxam. In this study, we aimed to elucidate the molecular mechanism mediating this type of resistance as well as a possible regulatory process behind it. A combination of computational analyses and experimental approaches was used to identify differentially expressed genes with a potential association to the phenomenon. These genes were classified into seven functional groups. Most of them seem to be associated with a pleiotropic drug resistance (PDR) phenotype, typically involved in the expulsion of diverse metabolites, drugs, or other substances out of the cell. Despite the importance of RNApolI for the constitutive resistance of P. infestans to mefenoxam, our results indicate no clear interaction between this protein and the acquisition of mefenoxam resistance. Several small non-coding RNAs (ncRNAs) were found to be differentially expressed and specifically related to genes mediating the PDR phenotype, thus suggesting a possible regulatory process. We propose a model of the molecular mechanisms acting within the cell when P. infestans acquires resistance to mefenoxam after exposed to sub-lethal concentrations of the fungicide. This study provides important insights into P. infestans’ cellular and regulatory functionalities.
Project description:To combat the global burden of malaria, development of new drugs to replace or complement current therapies are urgently required. As drug resistance to existing treatments and clinical failures continue to rise, compounds targeting multiple life cycle stages and species need to be developed as a high priority. Here we show that the compound MMV1557817 is a nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end stage haemoglobin digestion in asexual parasites. Multi-stage analysis confirmed that MMV1557817 can also kill sexual stage P. falciparum, while cross-resistance studies confirmed the compound targets a mechanism of action distinct to current drug resistance mechanisms. Analysis of cross reactivity to homologous human enzymes shows the compound exhibits a high level of selectivity, whilst safety as well as druggability was confirmed in the murine model P. berghei. MMV1557817-resistant P. falciparum parasites displayed only low-level resistance (<3-fold) and exhibited a slow growth rate that was quickly outcompeted by wild type parasites. MMV1557817-resistant parasites digest significantly more haemoglobin and possess a mutation in PfA-M17 that induces partial destabilization of the PfA-M17 homohexamer, resulting in high-level resistance to specific PfA-M17 inhibition, but enhanced sensitivity to specific PfA-M1 inhibition, and importantly, these parasites were highly sensitive to artemisinin. Overall, these results confirm MMV1557817 as a potential lead compound for further drug development and highlight the potential of dual inhibition of M1 and M17 as an effective multi-species drug targeting strategy.
Project description:Background: Non-coding RNAs have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of non-coding RNA and mRNA in multi-drug resistance of colorectal cancer have not been fully elucidated.Methods: We performed RNA-sequencing to screen differentially expressed non-coding RNA and mRNA in CRC chemo-resistant and chemo-sensitive cell lines. Results: The results showed that 1779 mRNAs, 64 miRNAs, 11 circRNAs and 295 lncRNAs were common differentially expressed in two chemo-resistant cell lines.Conclusions:The results of the study may provide new theories and therapeutic targets for multi-drug resistance in colorectal cancer.
Project description:Inferring in humans biological responses to external cues such as drugs, chemicals, viruses and hormones, is an essential question in biomedicine and cannot be easily studied in humans. Thus, biomedical research has continuously relied on animal models for studying the impact of these compounds and attempted to M-^StranslateM-^T the results to humans. In this context, the Systems Biology Verification for Industrial Methodology for Process Verification in Research (SBV IMPROVER) initiative had run a Species Translation Challenge for the scientific community to explore and understand the limit of translatability from rodent to human using systems biology. Therefore, a multi-layer omics dataset was generated that comprised of phosphoproteomics, transcriptomics and cytokine data derived from normal human (NHBE) and rat (NRBE) bronchial epithelial cells exposed in parallel to more than 50 different stimuli under identical conditions. The present manuscript describes in detail the experimental settings, the generation, processing and quality control analysis of the multi-layer omics dataset. The datasets are accessible in public repositories could be leveraged for further translation studies.
Project description:Palbociclib is a specific CDK4/6 inhibitor that has been widely applied in multiple tumor types. Different from cytotoxic drugs, the anticancer mechanism of palbociclib mainly depends on cell cycle inhibition. Therefore, the resistance mechanism is different. For clinical cancer patients, drug resistance is inevitable for almost all cancer therapies including palbociclib. We have trained palbociclib resistance cell lines in vitro to monitor the clinical situation and applied LC-MS-based proteomic and glycoproteomic technology to deeply understand the underly mechanism behind the resistance. As a result, the resistant cells mainly relied on an alternative metabolic pathway to keep proliferation based on proteomic analysis. Metabolic processes related to carbohydrates, lipids, DNA, cellular proteins, glucose, and amino acids were observed to be upregulated. Most dramatically, the protein expression of COX-1 and NDUFB8 have been detected to be significantly overexpressed. When a COX-1 inhibitor was hired to combine with palbociclib, a synergistic effect could be obtained, suggesting the altered COX-1 involved metabolic pathway is the major reason for the acquired palbociclib resistance. Additionally, through glycoproteomic analysis, the global glycosylation was found to be elevated in the palbociclib-resistant cells. Moreover, the integration of glycoproteomic data allowed us to detect a lot more proteins that have been glycosylated with low abundance, these proteins were normally overwhelmed by those highly abundant proteins during regular proteomic LC-MS detection. These low abundant glycoproteins are mainly involved in the cellular biology process of cell migration, regulation of chemotaxis, as well as glycoprotein metabolic process which offered us a great more detail on the roles the alternated glycan modification played during drug resistance. The high efficiency of the integrated proteomic and N-glycoproteomic workflow in discovering drug resistance mechanisms paves the new way for drug development. With a clear understanding of the resistance mechanism, new drug targets and drug combinations could be designed to resensitize the resistant tumors.