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1.
Saudi Pharm J ; 30(2): 138-149, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35528855

RESUMO

Melanoma is an aggressive skin cancer with a high rate of metastasis to other organs. Recent studies specified the overexpression of V-domain Ig suppressor of T-cell activation (VISTA) and Aryl Hydrocarbon Receptor (AHR) in melanoma. Metformin shows anti-tumor activities in several cancer types. However, the mechanism is unclear. This study aims to investigate the inhibitory effect of metformin on VISTA via AHR in melanoma cells (CHL-1, B16) and animal models. VISTA and AHR levels were assessed by qPCR, Western blot, immunofluorescence microscope, flow cytometry, and immunohistochemistry. Here, metformin significantly decreased VISTA and AHR levels in vitro and in vivo. Furthermore, metformin inhibited all AHR-regulated genes. VISTA levels were dramatically inhibited by AHR modulations using shRNA and αNF, confirming the central role of AHR in VISTA. Finally, melanoma cells were xenografted in C57BL/6 and nude mice. Metformin significantly reduced the tumor volume and growth rate. Likewise, VISTA and AHR-regulated protein levels were suppressed in both models. These findings demonstrate for the first time that VISTA is suppressed by metformin and identified a new regulatory mechanism through AHR. The data suggest that metformin could be a new potential therapeutic strategy to treat melanoma patients combined with targeted immune checkpoint inhibitors.

2.
Chem Res Toxicol ; 33(7): 1719-1728, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32370496

RESUMO

Gefitinib (GEF) is a selective inhibitor of the epidermal growth factor receptor (EGFR) used to treat non-small cell lung cancer. Yet, few cases of cardiotoxicity have been reported. However, the role of the PTEN/Akt/FoxO3a pathway, which mediates GEF anticancer activity, in GEF cardiotoxicity remains unclear. For this purpose, in vitro H9c2 cells and in vivo rat cardiomyocytes were utilized as study models. Treatment of H9c2 cells and Sprague-Dawley rats with GEF significantly induced the expression of hypertrophic and apoptotic markers at mRNA and protein levels with an increased plasma level of troponin. This was accompanied by induction of autophagy and mitochondrial dysfunction in H9c2 cells. Inhibition of cardiac EGFR activity and Akt cellular content of in vitro and in vivo rat cardiomyocytes by GEF increased PTEN and FoxO3a gene expression and cellular content. Importantly, treatment of H9c2 cells with PI3K/Akt inhibitor increased PTEN and FoxO3a mRNA expression associated with potentiation of GEF cardiotoxicity. In addition, by using LC-MS/MS, we showed that GEF is metabolized in the rat heart microsomes into one cyanide- and two methoxylamine-adduct reactive metabolites, where their formation was entirely blocked by CYP1A1 inhibitor, α-naphthoflavone. The current study concludes that GEF induces cardiotoxicity through modulating the expression and function of the cardiac PTEN/AKT/FoxO3a pathway and the formation of CYP1A1-mediated reactive metabolites.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/metabolismo , Receptores ErbB/antagonistas & inibidores , Proteína Forkhead Box O3/metabolismo , Gefitinibe/efeitos adversos , PTEN Fosfo-Hidrolase/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Cardiotoxicidade/genética , Linhagem Celular , Receptores ErbB/metabolismo , Proteína Forkhead Box O3/genética , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microssomos/metabolismo , Miocárdio/metabolismo , PTEN Fosfo-Hidrolase/genética , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
3.
Toxicol Mech Methods ; 29(2): 119-127, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30273082

RESUMO

Although a plethora of studies have examined tobacco smoke-cancer disease association, the involvement of cellular genetic toxicity remains unclear. Therefore, the present study provides molecular evidence for a pathway involved in the DNA damage induced by long-term cigarette and waterpipe smoke in human subjects. The study population consisted of 45 subjects who were divided into three groups; healthy nonsmokers group, cigarette smokers group, and waterpipe smokers group. A questionnaire and consent form was distributed and signed by all participants. Total RNA was extracted from the blood using PAXgene Blood RNA Kit and mRNA expression levels of target genes were quantified by RT-PCR. Our results showed that 80% of the participants smoke 20-39 cigarettes/day, whereas 12% smoke more than 40 cigarettes/day. With regard to waterpipe smoke, the majority (46%) smoke more than 5 times/week. Both cigarette and waterpipe smokers showed increased the plasma levels 8-hydroxy-2'-deoxyguanosine (8-OHdG), of DNA damage marker. In addition, the mRNA expression levels of DNA repair genes (OGG1 and XRCC1) were significantly inhibited in both cigarette and waterpipe smokers groups by 30% and 60%, respectively. This was associated with a marked decrease (50%) in the expression of detoxifying genes (NQO1 and GSTA1) with an increase in CYP1A1 mRNA expression, a cancer-activating gene. Both cigarette and waterpipe smokers increased in the plasma concentrations of several toxic heavy metals such as Cd (130%), Pb (47%), and Ni (30%). In conclusion: the present findings clearly explore the genotoxic effect of cigarette and waterpipe smoking on human DNA.


Assuntos
Fumar Cigarros/efeitos adversos , Dano ao DNA , Exposição por Inalação/efeitos adversos , Estresse Oxidativo , Fumaça/efeitos adversos , Fumantes , Fumar Cachimbo de Água/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Fumar Cigarros/sangue , Fumar Cigarros/genética , Citocromo P-450 CYP1A1/sangue , Citocromo P-450 CYP1A1/genética , DNA Glicosilases/sangue , DNA Glicosilases/genética , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Feminino , Regulação Enzimológica da Expressão Gênica , Glutationa Transferase/sangue , Glutationa Transferase/genética , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/sangue , NAD(P)H Desidrogenase (Quinona)/genética , Medição de Risco , Fatores de Tempo , Transcriptoma , Fumar Cachimbo de Água/sangue , Fumar Cachimbo de Água/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/sangue , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto Jovem
4.
Saudi Pharm J ; 27(5): 682-693, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31297023

RESUMO

A new series of 5,5-diphenylhydantoin derivatives containing benzylidene or isatin (4-19) was synthesized. Their anticancer activity against HeLa, a cervical cancer cell line, A549, a lung cancer cell line, and MDA-MB-231, a breast cancer cell line, was evaluated. Compounds 13, 16, 17 and 18 exhibited potent anticancer activity with average IC50 values against the tested cell lines of 109, 59, 81 and 113 µM, respectively. Compound 16 showed potent EGFR and VEGFR2 inhibitory activity with IC50 values of 6.17 and 0.09 µM, respectively. In addition, compound 16 induced caspase-dependent apoptosis and reactive oxygen species (ROS) production at 5 and 10 µM. Moreover, a molecular docking simulation was performed for compound 16 and sunitinib to predict the protein-ligand interactions with the active site of VEGFR2.

5.
Saudi Pharm J ; 26(7): 1035-1043, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30416360

RESUMO

Gold complex bis(diethyldithiocarbamato-gold(I)) bis(diphenylphosphino) methane (BDG-I) is cytotoxic toward different cancer cell lines. We compared the cytotoxic effect of BDG-I with that of cisplatin in the A549 lung cancer cell line. Additionally, we investigated the molecular mechanism underlying the toxic effect of BDG-I toward the A549 cell line and the identification of cancer-related miRNAs likely to be involved in killing the lung cancer cells. Further, X-ray crystallographic data of the compound were acquired. Using microarray, global miRNA expression profiling in BDG-I-treated A549 cells revealed 64 upregulated and 86 downregulated miRNAs, which targeted 4689 and 2498 genes, respectively. Biological network connectivity of the miRNAs was significantly higher for the upregulated miRNAs than for the downregulated miRNAs. Two of the 10 most upregulated miRNAs (hsa-mir-20a-5p and hsa-mir-15b-5p) were associated with lung cancer. AmiGo2 server and Panther pathway analyses indicated significant enrichment in transcription regulation of miRNA target genes that promote intrinsic kinase-mediated signaling, TGF-ß, and GnRH signaling pathways, as well as oxidative stress responses. BDG-I crystal structure X-ray diffraction studies revealed gold-gold intramolecular interaction [Au…Au = 3.1198 (3) Å] for a single independent molecule, reported to be responsible for its activity against cancer. Our present study sheds light on the development of novel gold complex with favorable anti-cancer therapeutic functionality.

6.
J Pharm Bioallied Sci ; 16(Suppl 1): S564-S566, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38595415

RESUMO

Background: Tooth extraction often results in bone loss in the alveolar ridge, which can complicate subsequent dental implant placement. Alveolar ridge preservation (ARP) techniques, such as bone grafting, aim to mitigate this bone loss. Platelet-rich plasma (PRP) has been proposed as an adjunct to bone grafting in ARP to enhance bone regeneration. Materials and Methods: A total of 60 patients requiring tooth extraction and ARP were included in this randomized controlled trial. Patients were divided into two groups: Group A received bone grafting alone, while Group B received bone grafting with PRP. Clinical and radiographic assessments were performed at baseline and 6-month postsurgery. Bone density and height were measured using arbitrary values. Results: At the 6-month follow-up, Group B demonstrated a statistically significant increase in bone density (P < 0.05) and bone height (P < 0.05) compared to Group A. The arbitrary values for bone density in Group B increased by 15% and bone height increased by 10% compared to baseline measurements. Group A showed minimal improvement. Conclusion: The incorporation of PRP as an adjunct to bone grafting in ARP following tooth extraction significantly enhances bone density and height, suggesting its efficacy in preserving the alveolar ridge.

7.
Health Sci Rep ; 7(4): e2036, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38650719

RESUMO

Background: Diabetes has evolved into a worldwide public health issue. One of the most serious complications of diabetes is diabetic foot ulcer (DFU), which frequently creates a significant financial strain on patients and lowers their quality of life. Up until now, there has been no curative therapy for DFU, only symptomatic relief or an interruption in the disease's progression. Recent studies have focused attention on mesenchymal stem cells (MSCs), which provide innovative and potential treatment candidates for several illnesses as they can differentiate into various cell types. They are mostly extracted from the placenta, adipose tissue, umbilical cord (UC), and bone marrow (BM). Regardless of their origin, they show comparable features and small deviations. Our goal is to investigate MSCs' therapeutic effects, application obstacles, and patient benefit strategies for DFU therapy. Methodology: A comprehensive search was conducted using specific keywords relating to DFU, MSCs, and connected topics in the databases of Medline, Scopus, Web of Science, and PubMed. The main focus of the selection criteria was on English-language literature that explored the relationship between DFU, MSCs, and related factors. Results and Discussion: Numerous studies are being conducted and have demonstrated that MSCs can induce re-epithelialization and angiogenesis, decrease inflammation, contribute to immunological modulation, and subsequently promote DFU healing, making them a promising approach to treating DFU. This review article provides a general snapshot of DFU (including clinical presentation, risk factors and etiopathogenesis, and conventional treatment) and discusses the clinical progress of MSCs in the management of DFU, taking into consideration the side effects and challenges during the application of MSCs and how to overcome these challenges to achieve maximum benefits. Conclusion: The incorporation of MSCs in the management of DFU highlights their potential as a feasible therapeutic strategy. Establishing a comprehensive understanding of the complex relationship between DFU pathophysiology, MSC therapies, and related obstacles is essential for optimizing therapy outcomes and maximizing patient benefits.

8.
AMB Express ; 14(1): 17, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38329626

RESUMO

The genus Enterobacter belongs to the ESKAPE group, which includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. This group is characterized by the development of resistance to various antibiotics. In recent years, Enterobacter cloacae (E. cloacae) has emerged as a clinically important pathogen responsible for a wide range of healthcare-associated illnesses. Identifying Enterobacter species can be challenging due to their similar phenotypic characteristics. The emergence of multidrug-resistant E. cloacae is also a significant problem in healthcare settings. Therefore, our study aimed to identify and differentiate E. cloacae using Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) as a fast and precise proteomic analytical technique. We also tested hospital-acquired E. cloacae isolates that produce Extended-spectrum beta-lactamases (ESBL) against commonly used antibiotics for treating urinary tract infections (UTIs). We used a total of 189 E. cloacae isolates from 2300 urine samples of patients with UTIs in our investigation. We employed culturing techniques, as well as the BD Phoenix™ automated identification system (Becton, Dickinson) and Analytical Profile Index (API) system for the biochemical identification of E. cloacae isolates. We used the MALDI Biotyper (MBT) device for peptide mass fingerprinting analysis of all isolates. We utilized the single peak intensities and Principal Component Analysis (PCA) created by MBT Compass software to discriminate and cluster the E. cloacae isolates. Additionally, we evaluated the sensitivity and resistance of ESBL-E. cloacae isolates using the Kirby Bauer method. Out of the 189 E. cloacae isolates, the BD Phoenix system correctly identified 180 (95.24%) isolates, while the API system correctly identified 165 (87.30%) isolates. However, the MBT accurately identified 185 (98.95%) isolates with a score of 2.00 or higher. PCA positively discriminated the identified E. cloacae isolates into one group, and prominent peaks were noticed between 4230 mass-to-charge ratio (m/z) and 8500 m/z. The ESBL-E. cloacae isolates exhibited a higher degree of resistance to ampicillin, amoxicillin-clavulanate, cephalothin, cefuroxime, and cefoxitin. Several isolates were susceptible to carbapenems (meropenem, imipenem, and ertapenem); however, potential future resistance against carbapenems should be taken into consideration. In conclusion, MALDI-TOF MS is a powerful and precise technology that can be routinely used to recognize and differentiate various pathogens in clinical samples. Additionally, the growing antimicrobial resistance of this bacterium may pose a significant risk to human health.

9.
Environ Sci Pollut Res Int ; 29(43): 64959-64970, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35482242

RESUMO

Lead (Pb) is one of the most frequent hazardous air contaminants, where the lungs are particularly vulnerable to its toxicity. However, the Pb distribution and its impact on lung inflammation/apoptosis and particularly the involvement of nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways in Pb-induced lung toxicity have not yet been fully investigated. Adult male Wistar albino rats were exposed to Pb nitrate 25, 50, and 100 mg/kg b.w. orally for 3 days. The histopathological changes of several rat organs were analyzed using hematoxylin and eosin staining. The concentrations of Pb ion in different organ tissues were quantified using inductive coupled plasma mass spectrometry, while gas chromatography-mass spectrometry was used to identify organic compounds. The changes in the mRNA and protein expression levels of inflammatory and apoptotic genes in response to Pb exposure were quantified by using RT-PCR and Western blot analyses, respectively. Treatment of rats with Pb for three consecutive days significantly increased the accumulation of Pb in lung tissues causing severe interstitial inflammation. Pb treatment also increased the percentage of lung apoptotic cells and modulated apoptotic genes (Bc2, p53, and TGF-α), inflammatory markers (IL-4, IL-10, TNF-α), and oxidative stress biomarkers (iNOS, CYP1A1, EphX) in rat lung tissues. These effects were associated with a significant increase in organic compounds, such as 3-nitrotyrosine and myeloperoxidase, and some inorganic elements, such as selenium. Importantly, the Pb-induced lung inflammation and apoptosis were associated with a proportional increase in the expression of NF-κB and AhR mRNAs and proteins. These findings clearly show that Pb induces severe inflammation and apoptosis in rat lungs and suggest that NF-κB and AhR may play a role in Pb-induced lung toxicity.


Assuntos
Apoptose , Pneumonia , Receptores de Hidrocarboneto Arílico , Animais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Chumbo/farmacologia , Pulmão , Masculino , NF-kappa B/metabolismo , Nitratos/farmacologia , Pneumonia/metabolismo , Ratos , Ratos Wistar , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais
10.
Saudi J Biol Sci ; 28(8): 4201-4209, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34354400

RESUMO

Cigarettes and other tobacco products are used to obtain nicotine that is responsible for their stimulating effects. However, a lot of other organic and inorganic chemicals are also released along with nicotine. Cadmium (Cd) is one of the several heavy metals that are health hazards and is one of the inorganic elements released in tobacco smoke. The in-vitro investigation focused on exploring the effects of nicotine hydrogen tartrate (NHT) and cadmium (Cd) and their toxic interactions in the A549 cell line. In cell viability assay NHT exhibited its IC50 at 11.71 mM concentration, and the IC50 of Cd was found to be 83 µM after a 24 h exposure. Toxic effects of NHT (5 mM and 10 mM), Cd (50 µM and 100 µM), and their combination were also investigated by flowcytometry. The investigation included apoptotic and necrotic events, the effect on different cell cycle phases, and generation of reactive oxygen species by NHT, Cd, and their combination of different concentrations. Data reveal evident toxic effects of NHT, Cd, and NHT + Cd. It also indicates that the toxic interaction of NHT and Cd is not additive and appears to be minimal when compared with NHT or Cd exposures alone.

11.
Saudi J Biol Sci ; 28(12): 7396-7403, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34867043

RESUMO

Metformin (MET) is a clinically used anti-hyperglycemic agent that shows activities against chemically-induced animal models of cancer. A study from our laboratory showed that MET protectes against 7, 12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis in vitro human non-cancerous epithelial breast cells (MCF10A) via activation of the aryl hydrocarbon receptor (AhR). However, it is unclear whether MET can prevent the initiation of breast carcinogenesis in an in vivo rat model of AhR-induced breast carcinogenesis. Therefore, the main aims of this study are to examine the effect of MET on protecting against rat breast carcinogenesis induced by DMBA and to explore whether this effect is medicated through the AhR pathway. In this study, treatment of female rats with DMBA initiated breast carcinogenesis though inhibiting apoptosis and tumor suppressor genes while inducing oxidative DNA damage and cell cycle proliferative markers. This effect was associated with activation of AhR and its downstream target genes; cytochrome P4501A1 (CYP1A1) and CYP1B1. Importantly, MET treatment protected against DMBA-induced breast carcinogenesis by restoring DMBA effects on apoptosis, tumor suppressor genes, DNA damage, and cell proliferation. Mechanistically using in vitro human breast cancer MCF-7 cells, MET inhibited breast cancer stem cells spheroids formation and development by DMBA, which was accompanied by a proportional inhibition in CYP1A1 gene expression. In conclusion, the study reports evidence that MET is an effective chemopreventive therapy for breast cancer by inhibiting the activation of CYP1A1/CYP1B1 pathway in vivo rat model.

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