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1.
Int J Mol Sci ; 22(23)2021 Nov 25.
Article in English | MEDLINE | ID: covidwho-1559503

ABSTRACT

Cancer is one of the most important health problems of our population, and one of the common anticancer treatments is chemotherapy. The disadvantages of chemotherapy are related to the drug's toxic effects, which act on cancer cells and the healthy part of the body. The solution of the problem is drug encapsulation and drug targeting. The present study aimed to develop a novel method of preparing multifunctional 5-Fluorouracil (5-FU) nanocarriers and their in vitro characterization. 5-FU polyaminoacid-based core@shell nanocarriers were formed by encapsulation drug-loaded nanocores with polyaminoacids multilayer shell via layer-by-layer method. The size of prepared nanocarriers ranged between 80-200 nm. Biocompatibility of our nanocarriers as well as activity of the encapsulated drug were confirmed by MTT tests. Moreover, the ability to the real-time observation of developed nanocarriers and drug accumulation inside the target was confirmed by fluorine magnetic resonance imaging (19F-MRI).


Subject(s)
Amino Acids/chemistry , Drug Carriers/administration & dosage , Drug Carriers/chemical synthesis , Fluorouracil/pharmacology , Mammary Neoplasms, Experimental/drug therapy , Nanoparticles/administration & dosage , Animals , Antimetabolites, Antineoplastic/chemistry , Antimetabolites, Antineoplastic/pharmacology , Female , Fluorouracil/chemistry , Mammary Neoplasms, Experimental/pathology , Nanoparticles/chemistry , Tumor Cells, Cultured
2.
Sci Rep ; 11(1): 17263, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1550348

ABSTRACT

Dexamethasone (Dex) is a highly insoluble front-line drug used in cancer therapy. Data from clinical trials indicates that the pharmacokinetics of Dex vary considerably between patients and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Non-toxic, fully biodegradable Dex loaded nanovectors (NV) were formulated, via simple direct hydration within 10 min, as a vehicle to extend exposure and distribution in vivo. Dex-NV were just as effective as the free drug against primary human leukemia cells in vitro and in vivo. Importantly, high levels of DMSO solvent were not required in the NV formulations. Broad distribution of NV was seen rapidly following inoculation into mice. NV accumulated in major organs, including bone marrow and brain, known sanctuary sites for ALL. The study describes a non-toxic, more easily scalable system for improving Dex solubility for use in cancer and can be applied to other medical conditions associated with inflammation.


Subject(s)
Dexamethasone/administration & dosage , Drug Delivery Systems/methods , Nanostructures/chemistry , Polymers/chemistry , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Xenograft Model Antitumor Assays/methods , Animals , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/chemistry , Antineoplastic Agents, Hormonal/pharmacokinetics , Child , Dexamethasone/chemistry , Dexamethasone/pharmacokinetics , Drug Liberation , Humans , Kaplan-Meier Estimate , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Treatment Outcome , Tumor Cells, Cultured , Young Adult
3.
J Cancer Res Clin Oncol ; 148(3): 599-608, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1527467

ABSTRACT

INTRODUCTION: Cathepsin L (CTSL) is a kind of the SARS-entry-associated CoV-2's proteases, which plays a key role in the virus's entry into the cell and subsequent infection. We investigated the association between the expression level of CTSL and overall survival in Glioblastoma multiforme (GBM) patients, to better understand the possible route and risks of new coronavirus infection for patients with GBM. METHODS: The expression level of CTSL in GBM was analyzed using TCGA and CGGA databases. The relationship between CTSL and immune infiltration levels was analyzed by means of the TIMER database. The impact of CTSL inhibitors on GBM biological activity was tested. RESULTS: The findings revealed that GBM tissues had higher CTSL expression levels than that of normal brain tissues, which was associated with a significantly lower survival rate in GBM patients. Meanwhile, the expression level of CTSL negatively correlated with purity, B cell and CD8+ T cell in GBM. CTSL inhibitor significantly reduced growth and induced mitochondrial apoptosis. CONCLUSION: According to the findings, CTSL acts as an independent prognostic factor and can be considered as promising therapeutic target for GBM.


Subject(s)
Biomarkers, Tumor/metabolism , COVID-19/pathology , Cathepsin L/metabolism , Dipeptides/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/pathology , Apoptosis , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/virology , Case-Control Studies , Cell Proliferation , Female , Glioblastoma/drug therapy , Glioblastoma/enzymology , Humans , Male , Middle Aged , Prognosis , SARS-CoV-2/physiology , Survival Rate , Tumor Cells, Cultured
4.
J Med Chem ; 65(4): 2940-2955, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1475245

ABSTRACT

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Binding Sites/drug effects , COVID-19/metabolism , Coronavirus Papain-Like Proteases/isolation & purification , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Pandemics , Surface Plasmon Resonance , Tumor Cells, Cultured
5.
Molecules ; 25(19)2020 Oct 08.
Article in English | MEDLINE | ID: covidwho-1125723

ABSTRACT

The major groups of antioxidant compounds (isoflavonoids, xanthones, hydroxycinnamic acids) in the rhizome methanol extracts of four Ukrainian Iris sp. (Iris pallida, Iris hungarica, Iris sibirica, and Iris variegata) were qualitatively and quantitatively analyzed using HPLC-DAD and UPLC-MS/MS. Gallic acid, caffeic acid, mangiferin, tectoridin, irigenin, iristectorigenin B, irisolidone, 5,6-dihydroxy-7,8,3',5'-tetramethoxyisoflavone, irisolidone-7-O-ß-d-glucopyranoside, germanaism B, and nigricin were recognized by comparing their UV/MS spectra, chromatographic retention time (tR) with those of standard reference compounds. I. hungarica and I. variegata showed the highest total amount of phenolic compounds. Germanaism B was the most abundant component in the rhizomes of I. variegata (7.089 ± 0.032 mg/g) and I. hungarica (6.285 ± 0.030 mg/g). The compound analyses showed good calibration curve linearity (r2 > 0.999) and low detection and quantifications limit. These results validated the method for its use in the simultaneous quantitative evaluation of phenolic compounds in the studied Iris sp. I. hungarica and I. variegata rhizomes exhibited antioxidant activity, as demonstrated by the HPLC-ABTS system and NRF2 expression assay and anti-inflammatory activity on respiratory burst in human neutrophils. Moreover, the extracts showed anti-allergic and cytotoxic effects against cancer cells. Anti-coronavirus 229E and lipid formation activities were also evaluated. In summary, potent antioxidant marker compounds were identified in the examined Iris sp.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Antiviral Agents/pharmacology , Iris Plant/chemistry , Plant Extracts/pharmacology , Coronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Humans , NF-E2-Related Factor 2/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Tumor Cells, Cultured
6.
Vet Pathol ; 57(4): 467-471, 2020 07.
Article in English | MEDLINE | ID: covidwho-175692

ABSTRACT

Discovered in 2003 at the Royal Veterinary College, London, canine respiratory coronavirus (CRCoV) is a betacoronavirus of dogs and major cause of canine infectious respiratory disease complex. Generally causing mild clinical signs of persistent cough and nasal discharge, the virus is highly infectious and is most prevalent in rehoming shelters worldwide where dogs are often closely housed and infections endemic. As the world grapples with the current COVID-19 pandemic, the scientific community is searching for a greater understanding of a novel virus infecting humans. Similar to other betacoronaviruses, SARS-CoV-2 appears to have crossed the species barrier, most likely from bats, clearly reinforcing the One Health concept. Veterinary pathologists are familiar with coronavirus infections in animals, and now more than ever this knowledge and understanding, based on many years of veterinary research, could provide valuable answers for our medical colleagues. Here I review the early research on CRCoV where seroprevalence, early immune response, and pathogenesis are some of the same key questions being asked by scientists globally during the current SARS-CoV-2 pandemic.


Subject(s)
Betacoronavirus , Coronavirus Infections/veterinary , Disease Models, Animal , Dog Diseases/virology , Animals , Antibodies, Viral/blood , Betacoronavirus/classification , Betacoronavirus/growth & development , Betacoronavirus/immunology , Chiroptera/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Coronavirus OC43, Human/classification , Coronavirus, Bovine/classification , Dog Diseases/epidemiology , Dogs , Prevalence , Tumor Cells, Cultured
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