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1.
Drug Dev Res ; 84(3): 433-457, 2023 05.
Article in English | MEDLINE | ID: mdl-36779381

ABSTRACT

A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor-2 (VEGFR-2) with an IC50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR-2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51-fold increment in total apoptotic level in leukemia cell line HL-60(TB) and a 6.91-fold increase in the caspase-3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 µg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram-negative DNA gyrase with IC50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR-2 active site and compounds 3a-c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties.


Subject(s)
Antineoplastic Agents , DNA Gyrase , Anti-Bacterial Agents/chemistry , Antineoplastic Agents/chemistry , Cell Proliferation , Coumarins/pharmacology , DNA Gyrase/metabolism , DNA Gyrase/pharmacology , Drug Design , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor Receptor-2/metabolism , Humans
2.
Appl Biochem Biotechnol ; 194(11): 5196-5219, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35715546

ABSTRACT

Doxorubicin (DOX) is a chemotherapeutic agent that can disrupt testicular function leading to male infertility. This study examined the protective role of natural flavone, acacetin (ACA), and a protease of Bacillus cereus bacteria (B. cereus) as well as the potential role of miR-155/SIRT1/FOXO1 network in DOX-induced testicular injury. Twenty-four male Wistar rats were randomly allocated into four groups and treated as follows: Control, DOX (1 mg/kg, i.p) every other day for 21 days with a total dose equal to 10 mg/kg throughout the experiment, and pre-treated groups that received ACA (5 mg/kg/day, p.o) or B. cereus protease (36 mg/kg/day, p.o) for a week prior to DOX administration. DOX challenge reduced the testis weight coefficient, serum testosterone, and testicular 17ß-hydroxysteroid dehydrogenase (17ß-HSD). DOX caused a significant increase in testicular oxidative stress, inflammatory, and apoptotic markers. Aberrant testicular miR-34c, a germ-specific miRNA, and miR-155 expressions were observed, along with decreased protein expression of sirtuin1 (SIRT1) dependent forkhead box 1 (FOXO1) acetylation which induces apoptosis. Besides, abnormal histopathological architecture and a marked reduction in the testicular expression of proliferating cell nuclear antigen (PCNA) were observed. ACA or protease administration significantly improved the histopathological and immunohistochemical pictures compared with DOX alone and renovated testicular functions. Interestingly, treatment with protease was more significant than treatment with ACA in ameliorating DOX-induced testicular injury. Taken together, this study reveals the prophylactic role of these two regimens on male fertility by exhibiting antioxidant, anti-inflammatory, and anti-apoptotic effects against DOX-elicited testicular damage, possibly via modulating miR-155/SIRT1/FOXO1 network.


Subject(s)
Flavones , MicroRNAs , Testis , Animals , Male , Rats , Antibiotics, Antineoplastic/pharmacology , Antioxidants/metabolism , Apoptosis , Bacillus cereus/genetics , Doxorubicin/toxicity , Flavones/pharmacology , MicroRNAs/genetics , MicroRNAs/metabolism , Oxidative Stress , Peptide Hydrolases/metabolism , Proliferating Cell Nuclear Antigen/metabolism , Rats, Wistar , Sirtuin 1/genetics , Sirtuin 1/metabolism , Testis/drug effects , Testis/physiopathology , Testosterone/metabolism
3.
Asian Pac J Cancer Prev ; 21(2): 355-361, 2020 Feb 01.
Article in English | MEDLINE | ID: mdl-32102511

ABSTRACT

OBJECTIVES: Searching for sensitive, minimally invasive biomarkers that represent tumor-associated changes in the peripheral blood might enable the early diagnosis of breast cancer (BC) and monitoring of tumor progression. METHODS: Herein, we investigated the association of some circulating biomarkers with the risk of metastasis. In the current study, 115 BC patients which were subdivided into two groups: nonmetastatic breast cancer patients (NMBC) (n=83) and metastatic breast cancer patients (MBC) (n=32), and 79 apparently healthy controls were recruited. Serum protein levels of lysosomal protein transmembrane 4 beta (LAPTM4B), receptor activator of nuclear factor-kappa b (NF-Kb) ligand (RANKL), osteoprotegerin (OPG), vitamin D (VIT D), chitinase-3-like protein 1 (also known as YKL-40), and sirtuin 1 (SIRT1) were assessed in blood samples using ELISA technique. RESULTS: The results showed that RANKL and OPG had the highest diagnostic potential for MBC detection, with area under the curve values of 0.97 and 0.94, respectively. Moreover, logistic regression analysis showed that RANKL had the highest differentiation power in the discrimination of MBC from NMBC. CONCLUSION: The study highlighted that measuring RANKL and OPG may be helpful in the early detection of metastasis in Egyptian patients with BC.


Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/secondary , Carcinoma, Lobular/secondary , Osteoprotegerin/blood , RANK Ligand/blood , Adult , Aged , Breast Neoplasms/blood , Breast Neoplasms/epidemiology , Carcinoma, Ductal, Breast/blood , Carcinoma, Ductal, Breast/epidemiology , Carcinoma, Lobular/blood , Carcinoma, Lobular/epidemiology , Case-Control Studies , Egypt/epidemiology , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Invasiveness , Prognosis , ROC Curve , Young Adult
4.
Int J Nanomedicine ; 12: 7015-7023, 2017.
Article in English | MEDLINE | ID: mdl-29026298

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease treated by nonsteroidal anti-inflammatory drugs (NSAIDs) including lornoxicam (LX). Nanocarriers have been used to increase the efficacy and reduce the side effects of various drugs. The objective of the present study was to compare the therapeutic efficacy of systemic administration of lornoxicam-loaded nanomicellar formula (LX-NM) with that of free LX. MATERIALS AND METHODS: The LX-loaded mixed polymeric nanomicellar formula was prepared by direct equilibrium technique. Two rat models were used in the study: carrageenan-induced acute edema and Freund's complete adjuvant (FCA)-induced chronic arthritis. RESULTS: The inhibitory effect of LX-NM on carrageenan-induced edema was higher than free LX for the same dose (1.3 mg/kg, i.p.). LX-NM (0.325 mg/kg, i.p.) produced effects comparable to that of diclofenac, which served as a standard. In the FCA model, daily treatment with LX-NM (0.325 mg/kg, i.p.) starting on day 14 significantly reduced the percentage of edema and increased weight growth. However, the same dose of LX failed to confer any significant change. Additionally, LX-NM significantly attenuated the rise of tumor necrosis factor-α (TNF-α), interleukin-1ß, prostaglandin E2, nuclear factor-κß, malondialdehyde and nitric oxide serum levels. In contrast, LX failed to show any significant reduction in elevated serum biomarkers except for TNF-α. CONCLUSION: LX-NM is an alternative delivery system that is simply prepared at low costs. It showed a superior therapeutic efficacy against RA compared to free LX. Thus, LX-NM can be considered as a promising candidate for treatment of RA and similar inflammatory disorders.


Subject(s)
Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Micelles , Nanoparticles/chemistry , Piroxicam/analogs & derivatives , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Arthritis, Experimental/blood , Arthritis, Experimental/complications , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/pathology , Biomarkers/blood , Carrageenan , Chronic Disease , Dinoprostone/blood , Disease Models, Animal , Edema/blood , Edema/complications , Edema/drug therapy , Edema/pathology , Freund's Adjuvant , Interleukin-1beta/blood , Male , Nanoparticles/ultrastructure , Piroxicam/pharmacology , Piroxicam/therapeutic use , Polymers/chemistry , Rats, Wistar , Thiobarbituric Acid Reactive Substances/metabolism , Tumor Necrosis Factor-alpha/blood
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