scholarly journals Identification of Casiopeina II-gly secondary targets through a systems pharmacology approach

2018 ◽  
Author(s):  
Guillermo de Anda-Jáuregui ◽  
Jesús Espinal-Enríquez ◽  
Junguk Hur ◽  
Sergio Antonio Alcalá-Corona ◽  
Lena Ruiz-Azuara ◽  
...  
Keyword(s):  
Immune Responses ◽  
Network Theory ◽  
Metabolic Pathways ◽  
Chemotherapeutic Agents ◽  
Biological Pathways ◽  
Systems Pharmacology ◽  
Novel Approach ◽  
Pathway Crosstalk ◽  
Hela Cell Lines

AbstractCasiopeinas are a group of copper-based compounds designed to be used as less toxic, more efficient chemotherapeutic agents. In this study, we analyzed the in vitro effects of Casiopeina Il-gly on the expression of canonical biological pathways. Using microarray data from HeLa cell lines treated with Casiopeina II-gly, we identified biological pathways that are perturbed after treatment. We present a novel approach integrating pathway analysis and network theory: The Pathway Crosstalk Network. We constructed a network with deregulated pathways, featuring links between those pathways that crosstalk with each other. We identified modules grouping deregulated pathways that are functionally related. Through this approach, we were able to identify three features of Casiopeina treatment: a) Perturbation of signaling pathways, related to induction of apoptosis; b) perturbation of metabolic pathways, and c) activation of immune responses. These findings can be useful to drive new experimental exploration on their role in adverse effects and efficacy of Casiopeinas.

scholarly journals A Novel Approach to Drug Delivery for Hepatities C Virus (HCV) for High Immune Responses

2008 ◽  
Vol 2 (2) ◽  
Author(s):  
W. T. Chen ◽  
C. Zhang
Keyword(s):  
Immune Responses ◽  
High Strength ◽  
Azomethine Ylides ◽  
Enzyme Linked Immunosorbent Assay ◽  
Large Animal ◽  
Testing Environment ◽  
Large Animal Models ◽  
Novel Approach ◽  
Large Animals

Hepatities C Virus (HCV) is a significant health problem worldwide due to the lack of effective vaccines. HCV plasmid DNA (pDNA) vaccine represents a promising means to induce a Th1-biased cell-mediated response which tends to be associated with HCV clearance. However, the immune responses induced by naked pDNA vaccine in large animals as well as in humans are usually too weak to show sufficient protection against new infections. Therefore, it is interesting to look for new ways to deliver HCV pDNA vaccine. In this research, carbon nanotube (CNT) is used as a carrier to deliver the pDNA vaccine of HCV to induce high immune responses, because CNT has some excellent properties such as high strength and good biocompatibility. One of the key approaches to make this idea work is to treat CNT so that it can bind with HCV pDNA with good stability. An approach called 1, 3-dipolar cycloaddition of azomethine ylides was modified. We analyzed the complex of f-CNTs combined with pDNA vaccines expressing HCV E2 protein by using Enzyme-linked immunospot (ELISPOT) or Enzyme-linked immunosorbent assay (ELISA) assay in vitro. The result showed that the CNT approach can induce stronger protective immune responses than the needle delivery of naked pDNA vaccine. We have also found an optimal way to treat CNT in light of the highest immune response in the same testing environment. The success of this research will warrant testing HCV vaccine in large animal models and human clinical trials.

scholarly journals The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiao Gao ◽  
Qingwei Wang ◽  
Ying Wang ◽  
Jiang Liu ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Chemotherapy Resistance ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Serine Phosphorylation ◽  
Cancer Cell Growth ◽  
Rich Domain ◽  
Novel Approach ◽  
Growth Inhibitory

Abstract A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53−/− and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.

scholarly journals Activation of Tyrosine Metabolism in CD13+ Cancer Stem Cells Drives Relapse in Hepatocellular Carcinoma

2020 ◽  
Vol 52 (2) ◽  
pp. 604-621 ◽  
Author(s):  
Li Sun ◽  
Lin Zhang ◽  
Jun Chen ◽  
Chaoqun Li ◽  
Hongqin Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Metabolic Pathways ◽  
Isotope Labeling ◽  
Chemotherapeutic Agents ◽  
Protein Levels ◽  
Huh7 Cells ◽  
Tyrosine Metabolism

PurposeCancer stem cells (CSCs) are naturally resistant to chemotherapy, explaining why tumor relapse frequently occurs after initial regression upon administration of chemotherapeutic agents in most cases. A CSC population characterized by CD13 expression has been identified in hepatocellular carcinoma (HCC). In the current study, we aimed to clarify the molecular mechanism by which it escapes conventional therapies. Materials and MethodsHere, we used flow cytometry to examine the percentage of CD13<sup>+</sup> CSCs in HepG2 and HuH7 cells after chemotherapy. Using in vitro isotope labeling technique, we compared metabolic pathways between CD13<sup>+</sup> and CD13<sup>–</sup> subpopulations. Using co-immunoprecipitation and western blotting, we determined the target expressions in protein levels under different conditions. We also performed immunohistochemistry to detect the target proteins under different conditions. Animal models were constructed to verify the potential role of tyrosine metabolism in post-chemotherapeutic relapse in vivo.ResultsWe observed that quiescent CD13<sup>+</sup> CSCs are enriched after chemotherapy in HCCs, and serve as a reservoir for recurrence. Mechanistically, CD13<sup>+</sup> CSCs were dependent on aerobic metabolism of tyrosine rather than glucose as energy source. Tyrosine metabolism also generated nuclear acetyl-CoA to acetylate and stabilize Foxd3, thereby allowing CD13<sup>+</sup> CSCs cells to sustain quiescence and resistance to chemotherapeutic agents.ConclusionThese findings encourage further exploration of eliminating CD13<sup>+</sup> cells by targeting specific metabolic pathways to prevent recurrence in HCCs.

scholarly journals Fabrication of Core Crosslinked Polymeric Micelles as Nanocarriers for Doxorubicin Delivery: Self-Assembly, In Situ Diselenide Metathesis and Redox-Responsive Drug Release

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 580
Author(s):  
Yihenew Simegniew Birhan ◽  
Haile Fentahun Darge ◽  
Endiries Yibru Hanurry ◽  
Abegaz Tizazu Andrgie ◽  
Tefera Worku Mekonnen ◽  
...  
Keyword(s):  
Colloidal Stability ◽  
Polymeric Micelles ◽  
Mdck Cells ◽  
Chemotherapeutic Agents ◽  
Burst Release ◽  
Cytotoxicity Test ◽  
Hela Cell Lines ◽  
Redox Responsive ◽  
Crosslinked Micelles

Polymeric micelles (PMs) have been used to improve the poor aqueous solubility, slow absorption and non-selective biodistribution of chemotherapeutic agents (CAs), albeit, they suffer from disassembly and premature release of payloads in the bloodstream. To alleviate the thermodynamic instability of PMs, different core crosslinking approaches were employed. Herein, we synthesized the poly(ethylene oxide)-b-poly((2-aminoethyl)diselanyl)ethyl l-aspartamide)-b-polycaprolactone (mPEG-P(LA-DSeDEA)-PCL) copolymer which self-assembled into monodispersed nanoscale, 156.57 ± 4.42 nm, core crosslinked micelles (CCMs) through visible light-induced diselenide metathesis reaction between the pendant selenocystamine moieties. The CCMs demonstrated desirable doxorubicin (DOX)-loading content (7.31%) and encapsulation efficiency (42.73%). Both blank and DOX-loaded CCMs (DOX@CCMs) established appreciable colloidal stability in the presence of bovine serum albumin (BSA). The DOX@CCMs showed redox-responsive drug releasing behavior when treated with 5 and 10 mM reduced glutathione (GSH) and 0.1% H2O2. Unlike the DOX-loaded non-crosslinked micelles (DOX@NCMs) which exhibited initial burst release, DOX@CCMs demonstrated a sustained release profile in vitro where 71.7% of the encapsulated DOX was released within 72 h. In addition, the in vitro fluorescent microscope images and flow cytometry analysis confirmed the efficient cellular internalization of DOX@CCMs. The in vitro cytotoxicity test on HaCaT, MDCK, and HeLa cell lines reiterated the cytocompatibility (≥82% cell viability) of the mPEG-P(LA-DSeDEA)-PCL copolymer and DOX@CCMs selectively inhibit the viabilities of 48.85% of HeLa cells as compared to 15.75% of HaCaT and 7.85% of MDCK cells at a maximum dose of 10 µg/mL. Overall, all these appealing attributes make CCMs desirable as nanocarriers for the delivery and controlled release of DOX in tumor cells.

scholarly journals Doxorubicin-Loaded PLGA Nanoparticles for Cancer Therapy: Molecular Weight Effect of PLGA in Doxorubicin Release for Controlling Immunogenic Cell Death

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1165
Author(s):  
Yongwhan Choi ◽  
Hong Yeol Yoon ◽  
Jeongrae Kim ◽  
Suah Yang ◽  
Jaewan Lee ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Cell Death ◽  
Immune Responses ◽  
Release Kinetics ◽  
Plga Nanoparticles ◽  
Chemotherapeutic Agents ◽  
Immunogenic Cell Death ◽  
Tumor Site ◽  
Living Body

Direct local delivery of immunogenic cell death (ICD) inducers to a tumor site is an attractive approach for leading ICD effectively, due to enabling the concentrated delivery of ICD inducers to the tumor site. Herein, we prepared doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using different molecular weight PLGA (7000 g/mol and 12,000 g/mol), showing different drug release kinetics. The different release kinetics of DOX might differently stimulate a tumor cell-specific immune response by releasing damage-associated molecular patterns (DAMPs), resulting in showing a different antitumor response in the living body. DOX-PLGA7K NPs showed faster DOX release kinetics than DOX-PLGA12K NPs in the physiological condition. DOX-PLGA7K NPs and DOX-PLGA12K NPs were successfully taken up by the CT-26 tumor cells, subsequently showing different DOX localization times at the nucleus. Released DOX successfully lead to cytotoxicity and HMGB1 release in vitro. Although the DOX-PLGA7K NPs and DOX-PLGA12K NPs showed different sustained DOX release kinetics in vitro, tumor growth of the CT-26 tumor was similarly inhibited for 28 days post-direct tumor injection. Furthermore, the immunological memory effect was successfully established by the ICD-based tumor-specific immune responses, including DC maturation and tumor infiltration of cytotoxic T lymphocytes (CTLs). We expect that the controlled release of ICD-inducible chemotherapeutic agents, using different types of nanomedicines, can provide potential in precision cancer immunotherapy by controlling the tumor-specific immune responses, thus improving the therapeutic efficacy.

scholarly journals RNA Encoding the MPT83 Antigen Induces Protective Immune Responses against Mycobacterium tuberculosis Infection

2004 ◽  
Vol 72 (11) ◽  
pp. 6324-6329 ◽  
Author(s):  
Tian Xue ◽  
Evangelos Stavropoulos ◽  
Min Yang ◽  
Silvia Ragno ◽  
Martin Vordermeier ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Significant Protection ◽  
Mycobacterium Tuberculosis Infection ◽  
Immunization Strategies ◽  
Novel Approach ◽  
T Cell Immune Responses ◽  
Cellular Immune ◽  
Dna Vectors

ABSTRACT We have previously demonstrated that vaccination of mice with plasmid DNA vectors expressing immunodominant mycobacterial genes induced cellular immune responses and significant protection against challenge with Mycobacterium tuberculosis. We demonstrate here, using in vitro-synthesized RNA, that vaccination with DNA or RNA constructs expressing the M. tuberculosis MPT83 antigen are capable of inducing specific humoral and T-cell immune responses and confer modest but significant protection against M. tuberculosis challenge in mice. This is the first report of protective immunity conferred against intracellular bacteria by an RNA vaccine. This novel approach avoids some of the drawbacks of DNA vaccines and illustrates the potential for developing new antimycobacterial immunization strategies.

Effect of black seeds (Nigella sativa) volatile oil on the cervical cancer: In vitro study, on Hela cell lines

2019 ◽  
Vol 7 (4) ◽  
pp. 91-96
Author(s):  
Isra'a Al-sobhi ◽  
◽  
Rawan Al-Ghabban ◽  
Soad Shaker Ali ◽  
Jehan Al-Amri ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Hela Cell ◽  
Cell Lines ◽  
Nigella Sativa ◽  
In Vitro Study ◽  
Volatile Oil ◽  
Vitro Study ◽  
Hela Cell Lines ◽  
Black Seeds

New Mechanistic Insight on the PIM-1 Kinase Inhibitor AZD1208 Using Multidrug Resistant Human Erythroleukemia Cell Lines and Molecular Docking Simulations

2019 ◽  
Vol 19 (11) ◽  
pp. 914-926 ◽  
Author(s):  
Maiara Bernardes Marques ◽  
Michael González-Durruthy ◽  
Bruna Félix da Silva Nornberg ◽  
Bruno Rodrigues Oliveira ◽  
Daniela Volcan Almeida ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Site ◽  
Cell Lines ◽  
Chemotherapeutic Agents ◽  
Atp Binding ◽  
Human Leukemia ◽  
Atp Binding Site ◽  
Mechanistic Insight ◽  
Multiple Drugs

Background:PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype.Objective:In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR).Materials and Methods:In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR).Results:Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments.Conclusion:Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.

In silico approach for designing a novel recombinant fusion protein as a Candidate Vaccine against HPV

2020 ◽  
Vol 17 ◽  
Author(s):  
Mohsen Sisakht ◽  
Amir Mahmoodzadeh ◽  
Mohammadsaeid Zahedi ◽  
Davood Rostamzadeh ◽  
Amin Moradi Hasan-Abad ◽  
...  
Keyword(s):  
Immune Responses ◽  
Fusion Protein ◽  
In Silico ◽  
Precancerous Lesions ◽  
Candidate Vaccine ◽  
T Cell Epitopes ◽  
Binding Interaction ◽  
Hpv16 E6 ◽  
E7 Proteins

Background: Human papillomavirus (HPV) is the main biological agent causing sexually transmitted diseases (STDs), including precancerous lesions and several types of prevalent cancers. To date, numerous types of vaccines are designed to prevent high-risk HPV. However, their prophylactic effect is not the same and does not clear previous infections. Therefore, there is an urgent need for developing therapeutic vaccines that trigger cell-mediated immune responses for the treatment of HPV. The HPV16 E6 and E7 proteins are ideal targets for vaccine therapy against HPV. Fusion protein vaccines, which include both immunogenic interest protein and an adjuvant for augmenting the immunogenicity effects, are theoretically capable of guarantee the power of the immune system against HPV. Method: A vaccine construct, including HPV16 E6/E7 proteins along with a heat shock protein GP96 (E6/E7-NTGP96 construct), was designed using in silico methods. By the aid of the SWISS-MODEL server, the optimal 3D model of the designed vaccine was selected, followed by physicochemical and molecular parameters were performed using bioinformatics tools. Docking studies were done to evaluate the binding interaction of the vaccine. Allergenicity, immunogenicity, B, and T cell epitopes of the designed construct were predicted. Results: Immunological and structural computational results illustrated that our designed construct is potentially proper for stimulation of cellular and humoral immune responses against HPV. Conclusion: Computational studies showed that the E6/E7-NTGP96 construct is a promising candidate vaccine that needs further in vitro and in vivo evaluations.

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