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Bioengineering & Translational Medicine May 2019The treatment of metastatic cancer is a great challenging issue throughout the world. Conventional chemotherapy can kill the cancer cells and, whereas, would exacerbate...
The treatment of metastatic cancer is a great challenging issue throughout the world. Conventional chemotherapy can kill the cancer cells and, whereas, would exacerbate the metastasis and induce drug resistance. Here, a new combinatorial treatment strategy of metastatic cancer was probed via subsequentially dosing dual nanomedicines, marimastat-loaded thermosensitive liposomes (MATT-LTSLs) and paclitaxel nanocrystals (PTX-Ns), via intravenous and intratumoral injection. First, the metastasis was blocked and cancer cells were locked in the tumor microenvironment (TME) by delivering the matrix metalloproteinase (MMP) inhibitor, MATT, to the tumor with LTSLs, downregulating the MMPs by threefold and reducing the degradation of the extracellular matrix. And then, the "locked" cancer cells were efficiently killed via intratumoral injection of the other cytotoxic nanomedicine, PTX-Ns, along with no metastasis and 100% inhibition of tumor growth. This work highlights the importance of the TME's integrity in the chemotherapy duration. We believe this is a generalized strategy for cancer treatment and has potential guidance for the clinical administration.
PubMed: 31249880
DOI: 10.1002/btm2.10130 -
Journal of Computational Biology : a... Oct 2019This study aimed to explore crucial genes that contribute to the development of rheumatoid arthritis (RA). Three GSE77298, GSE55457, and GSE55235 data sets were used to...
This study aimed to explore crucial genes that contribute to the development of rheumatoid arthritis (RA). Three GSE77298, GSE55457, and GSE55235 data sets were used to analyze the differentially expressed genes (DEGs) between RA synovial membrane tissue samples and normal synovial membrane tissue samples. Then, the functional enrichment analysis and protein-protein interactions (PPIs) construction were performed for DEGs. Subsequently, submodule analysis and regulatory network that contained transcription factors (TFs), microRNAs, and their targets were conducted. Finally, small-molecule drugs related to the DEGs were predicted. A total of 173 upregulated and 54 downregulated DEGs identified in at least 2 of 3 data sets. , , , , and were both highlighted in the PPI and submodule networks. In addition, miR-101, TF, , and had high degree in the regulatory network, and regulation pairs of miR-101- and TF- were obtained. Drugs such as alemtuzumab and marimastat were negatively related to expression of the DEGs and might be useful drugs for RA treatment. In addition, most DEGs were involved in innate immune response (e.g., , , , , and ) and phagosome pathway (e.g., ). We suggested that miR-101 that regulated , TF that regulated , as well as as and might contribute to the RA pathogenesis. In addition, anti-inflammatory agent alemtuzumab and matrix metalloproteinase inhibitor marimastat might be useful drugs for RA treatment through functioning on their target genes.
Topics: Arthritis, Rheumatoid; Cartilage; Dual Specificity Phosphatase 1; Gene Expression Profiling; Gene Ontology; Gene Regulatory Networks; Humans; MicroRNAs; Protein Interaction Maps; Synovial Membrane; Transcriptome; Up-Regulation
PubMed: 31246497
DOI: 10.1089/cmb.2019.0021 -
Toxins Jun 2019Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also... (Review)
Review
Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also suffer through disabilities and long-term health consequences. The only treatment for SBE, antivenom, has a number of major associated problems, not least, adverse reactions and limited availability. This emphasises the necessity for urgent improvements to the management of this disease. Administration of antivenom is too frequently based on symptomatology, which results in wasting crucial time. The majority of SBE-affected regions rely on broad-spectrum polyvalent antivenoms that have a low content of case-specific efficacious immunoglobulins. Research into small molecular therapeutics such as varespladib/methyl-varespladib (PLA inhibitors) and batimastat/marimastat (metalloprotease inhibitors) suggest that such adjunctive treatments could be hugely beneficial to victims. Progress into toxin-specific monoclonal antibodies as well as alternative binding scaffolds such as aptamers hold much promise for future treatment strategies. SBE is not implicit during snakebite, due to venom metering. Thus, the delay between bite and symptom presentation is critical and when symptoms appear it may often already be too late to effectively treat SBE. The development of reliable diagnostical tools could therefore initiate a paradigm shift in the treatment of SBE. While the complete eradication of SBE is an impossibility, mitigation is in the pipeline, with new treatments and diagnostics rapidly emerging. Here we critically review the urgent necessity for the development of diagnostic tools and improved therapeutics to mitigate the deaths and disabilities caused by SBE.
Topics: Animals; Antivenins; Humans; Reptilian Proteins; Snake Bites; Snake Venoms
PubMed: 31226842
DOI: 10.3390/toxins11060363 -
Cell Proliferation Jul 2019Mycobacterium tuberculosis (Mtb) leads to approximately 1.5 million human deaths every year. In pulmonary tuberculosis (TB), Mtb must drive host tissue destruction to... (Review)
Review
Mycobacterium tuberculosis (Mtb) leads to approximately 1.5 million human deaths every year. In pulmonary tuberculosis (TB), Mtb must drive host tissue destruction to cause pulmonary cavitation and dissemination in the tissues. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading all components of pulmonary extracellular matrix (ECM). It is well established that Mtb infection leads to upregulation of MMPs and also causes disturbance in the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thus altering the extracellular matrix deposition. In TB, secretion of MMPs is mainly regulated by NF-κB, p38 and MAPK signalling pathways. In addition, recent studies have demonstrated the immunomodulatory roles of MMPs in Mtb pathogenesis. Researchers have proposed a new regimen of improved TB treatment by inhibition of MMP activity to hinder matrix destruction and to minimize the TB-associated morbidity and mortality. The proposed regimen involves adjunctive use of MMP inhibitors such as doxycycline, marimastat and other related drugs along with front-line anti-TB drugs to reduce granuloma formation and bacterial load. These findings implicate the possible addition of economical and well-tolerated MMP inhibitors to current multidrug regimens as an attractive mean to increase the drug potency. Here, we will summarize the recent advancements regarding expression of MMPs in TB, their immunomodulatory role, as well as their potential as therapeutic targets to control the deadly disease.
Topics: Animals; Extracellular Matrix; Humans; Lung; Matrix Metalloproteinases; Mycobacterium tuberculosis; Signal Transduction; Tuberculosis, Pulmonary
PubMed: 31199047
DOI: 10.1111/cpr.12649 -
Analytical Chemistry Apr 2019Performing quantitative high throughput screening (qHTS) is in urgent need in current chemical, biological, and medical research. In this work, we developed an automated...
Performing quantitative high throughput screening (qHTS) is in urgent need in current chemical, biological, and medical research. In this work, we developed an automated microfluidic dilution and large-scale screening system in the nanoliter range, by combining the droplet-based microfluidic robot technique with a novel unilateral Taylor-Aris dispersion-based dilution approach. The unilateral dispersion approach utilizes multiphase microfluidic design to generate a concentration gradient with fast gradient generation time, low sample/reagent consumption, and high operation efficiency over the widely used bilateral Taylor-Aris dispersion approach adopted in previous dilution systems. The present system is capable of automatically generating a large and tunable range of concentration gradients covering ca. 6 orders of magnitude in droplet arrays and achieving qHTS of a large number of different samples. We applied the microfluidic droplet system in miniaturized enzyme kinetic assay in 8-nL droplets and high-throughput quantitative screening of enzyme inhibitors with a library of 102 compounds. Only 9.8 μL of enzyme solution was consumed in 2448 droplet assays containing 102 compounds and 24 concentrations, representing an approximate 1600-fold reduction compared with multiwell plate-based assays. In the screening, dose-response curves of each tested compound were established and 4 hits (CP-471474, ilomastat, batimastat, and marimastat) were screened to have inhibitory activity to matrix metallopeptidase-9 (MMP-9), which demonstrated that the present system has the potential to provide a miniaturized qHTS platform for drug discovery.
PubMed: 30813716
DOI: 10.1021/acs.analchem.8b04564 -
Biological Chemistry May 2019ADAM8 as a membrane-anchored metalloproteinase-disintegrin is upregulated under pathological conditions such as inflammation and cancer. As active sheddase, ADAM8 can...
ADAM8 as a membrane-anchored metalloproteinase-disintegrin is upregulated under pathological conditions such as inflammation and cancer. As active sheddase, ADAM8 can cleave several membrane proteins, among them the low-affinity receptor FcεRII CD23. Hydroxamate-based inhibitors are routinely used to define relevant proteinases involved in ectodomain shedding of membrane proteins. However, for ADAM proteinases, common hydroxamates have variable profiles in their inhibition properties, commonly known for ADAM proteinases 9, 10 and 17. Here, we determined the inhibitor profile of human ADAM8 for eight ADAM/MMP inhibitors by in vitro assays using recombinant ADAM8 as well as the in vivo inhibition in cell-based assays using HEK293 cells to monitor the release of soluble CD23 by ADAM8. ADAM8 activity is inhibited by BB94 (Batimastat), GW280264, FC387 and FC143 (two ADAM17 inhibitors), made weaker by GM6001, TAPI2 and BB2516 (Marimastat), while no inhibition was observed for GI254023, an ADAM10 specific inhibitor. Modeling of inhibitor FC143 bound to the catalytic sites of ADAM8 and ADAM17 reveals similar geometries in the pharmacophoric regions of both proteinases, which is different in ADAM10 due to replacement in the S1 position of T300 (ADAM8) and T347 (ADAM17) by V327 (ADAM10). We conclude that ADAM8 inhibitors require maximum selectivity over ADAM17 to achieve specific ADAM8 inhibition.
Topics: ADAM Proteins; HEK293 Cells; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Membrane Proteins; Substrate Specificity
PubMed: 30738011
DOI: 10.1515/hsz-2018-0396 -
Journal of Translational Medicine Oct 2018Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat using traditional chemotherapy, an approach which has been effective in other types...
BACKGROUND
Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat using traditional chemotherapy, an approach which has been effective in other types of cancer. Most chemotherapeutics cause DNA damage leading to cell death. Recent discoveries have highlighted a potential role for the p53 tumor suppressor in this disease. Given the pivotal role of p53 in the DNA damage response, here we investigated the predictive power of the p53 interactome model for MPM patients' stratification.
METHODS
We used bioinformatics approaches including omics type analysis of data from MPM cells and from MPM patients in order to predict which pathways are crucial for patients' survival. Analysis of the PKT206 model of the p53 network was validated by microarrays from the Mero-14 MPM cell line and RNA-seq data from 71 MPM patients, whilst statistical analysis was used to identify the deregulated pathways and predict therapeutic schemes by linking the affected pathway with the patients' clinical state.
RESULTS
In silico simulations demonstrated successful predictions ranging from 52 to 85% depending on the drug, algorithm or sample used for validation. Clinical outcomes of individual patients stratified in three groups and simulation comparisons identified 30 genes that correlated with survival. In patients carrying wild-type p53 either treated or not treated with chemotherapy, FEN1 and MMP2 exhibited the highest inverse correlation, whereas in untreated patients bearing mutated p53, SIAH1 negatively correlated with survival. Numerous repositioned and experimental drugs targeting FEN1 and MMP2 were identified and selected drugs tested. Epinephrine and myricetin, which target FEN1, have shown cytotoxic effect on Mero-14 cells whereas marimastat and batimastat, which target MMP2 demonstrated a modest but significant inhibitory effect on MPM cell migration. Finally, 8 genes displayed correlation with disease stage, which may have diagnostic implications.
CONCLUSIONS
Clinical decisions related to MPM personalized therapy based on individual patients' genetic profile and previous chemotherapeutic treatment could be reached using computational tools and the predictions reported in this study upon further testing in animal models.
Topics: Cell Line, Tumor; Cell Survival; Deoxycytidine; Etoposide; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Models, Biological; Neoplasm Staging; Pleural Neoplasms; Proportional Hazards Models; Transcriptome; Tumor Suppressor Protein p53; Wound Healing; Gemcitabine
PubMed: 30316293
DOI: 10.1186/s12967-018-1650-0 -
Tropical Medicine and Infectious Disease Apr 2018With the inclusion of snakebite envenoming on the World Health Organization's list of Neglected Tropical Diseases, an incentive has been established to promote research... (Review)
Review
With the inclusion of snakebite envenoming on the World Health Organization's list of Neglected Tropical Diseases, an incentive has been established to promote research and development effort in novel snakebite antivenom therapies. Various technological approaches are being pursued by different research groups, including the use of small molecule inhibitors against enzymatic toxins as well as peptide- and oligonucleotide-based aptamers and antibody-based biotherapeutics against both enzymatic and non-enzymatic toxins. In this article, the most recent advances in these fields are presented, and the advantages, disadvantages, and feasibility of using different toxin-neutralizing molecules are reviewed. Particular focus within small molecules is directed towards the inhibitors varespladib, batimastat, and marimastat, while in the field of antibody-based therapies, novel recombinant polyclonal plantivenom technology is discussed.
PubMed: 30274438
DOI: 10.3390/tropicalmed3020042 -
Oncotarget Aug 2018Matrix metalloproteinases (MMPs) may play a critical role in metastatic cancers, yet multiple human clinical trials targeting MMPs have surprisingly failed. Cancer cell...
Matrix metalloproteinases (MMPs) may play a critical role in metastatic cancers, yet multiple human clinical trials targeting MMPs have surprisingly failed. Cancer cell density changes dramatically during the early growth of a primary tumor and during the early seeding steps of secondary tumors and has been implicated in playing an important role in regulating metastasis and drug resistance. This study reveals that the expression of MMPs is tightly regulated by local tumor cell density through the synergistic signaling mechanism of Interleukin 6 (IL-6) and Interleukin 8 (IL-8) via the JAK2/STAT3 complex. Local tumor cell density also plays a role in the responsiveness of cells to matrix metalloproteinases inhibitors (MMPI), such as Batimastat, Marimastat, Bryostatin I, and Cipemastat, where different migratory phenotypes are observed in low and high cell density conditions. Cell density-dependent MMP regulation can be directly targeted by the simultaneous inhibition of IL-6 and IL-8 receptors via Tocilizumab and Reparixin to significantly decrease the expression of MMPs in mouse xenograft models and decrease effective metastasis. This study reveals a new strategy to decrease MMP expression through pharmacological intervention of the cognate receptors of IL-6 and IL-8 to decrease metastatic capacity of tumor cells.
PubMed: 30220965
DOI: 10.18632/oncotarget.25863 -
The Journal of Parasitology Aug 2018In the course of a structure based drug discovery program the known anticancer candidate marimastat was uncovered as a potent inhibitor of an enzyme in nematode cuticle...
In the course of a structure based drug discovery program the known anticancer candidate marimastat was uncovered as a potent inhibitor of an enzyme in nematode cuticle biogenesis. It was shown to kill Caenorhabditis elegans, and the sheep parasites Haemonchus contortus and Teladorsagia circumcinta via an entirely novel nematode-specific pathway, specifically by inhibiting cuticle-remodelling enzymes that the parasites require for the developmentally essential moulting process. This discovery prompted an investigation of the compound's effect on Heligmosomoides polygyrus parasites in a mouse model of helminth infection. Mice were administered the drug via oral gavage daily from day of infection for a period of 2 wk. A second group received the drug via intra-peritoneal implantation of an osmotic minipump for 4 wk. Control groups were administered identical volumes of water by oral gavage in both cases. Counts of H. polygyrus faecal egg and larval load showed that marimastat effected a consistent and significant reduction in egg laying, and a consistent but minor reduction in adult worm load when administered every day, starting on the first day of infection. However, the drug failed to have any significant effect on egg counts or worm burdens when administered to mice with established infections. Therefore, marimastat does not appear to show promise as an anthelmintic in gastrointestinal nematode infections, although other metalloproteases such as batimastat may prove more effective.
PubMed: 30085900
DOI: 10.1645/18-33