Indomethacin-Enhanced Anticancer Effect of Arsenic Trioxide in A549 Cell Line: Involvement of Apoptosis and Phospho-ERK and p38 MAPK Pathways

Background. Focusing on novel drug combinations that target different pathways especially apoptosis and MAPK could be a rationaleforcombinationtherapyinsuccessfultreatmentoflungcancer.Concurrentuseofcyclooxygenase(COX)inhibitorswith arsenictrioxide(ATO)mightbeapossibletreatmentoption.Methods.CytotoxicityofATO,dexamethasone(Dex),celecoxib(Cel), andIndomethacin(Indo)individuallyorincombinationwasdeterminedat24,48,and72hrsinA549lungcancercells.TheCOX-2 gene and protein expression, MAPK pathway proteins, and caspase-3 activity were studied for the most cytotoxic combinations. Results. The IC 50s of ATO and Indo were 68.

Antioxidant Activity of Iranian Echium amoenum Fisch & C.A. Mey Flower Decoction in Humans: A cross-sectional Before/After Clinical Trial

Medicinal plants are recognized as sources of natural antioxidants that can protect from biological system oxidative stress. The present cross-sectional before/after clinical trial was carried out to investigate the antioxidant properties of the decoction of the flowers of Echium amoenum Fisch & C.A. Mey in humans. A group of 38 healthy subjects was invited to use the E. amoenum (7 mg kg(−1)) twice daily for 14 days. Blood samples before and after entering the study were measured for lipid peroxidation level (LPO), total antioxidant capacity (TAC) and total thiol (SH) molecules. A significant reduction of blood LPO (24.65 ± 11.3 versus 19.05 ± 9.7, P = 0.029) was observed after 14 days of E. amoenum consumption. Blood TAC (1.46 ± 0.51 versus 1.70 ± 0.36, P = 0.018) and total thiol molecules (0.49 ± 0.11 versus 0.56 ± 0.12, P = 0.001) increased after 14 days of E. amoenum consumption. In conclusion, this antioxidative stress potential of E. amoenum may be due to its bioactive antioxidant components, especially rosmarinic acid and flavonoids. In recent years the importance of oxidative stress in the pathophysiology of many human disorders has been confirmed, thus use of this plant as a dietary supplement is highly recommended

Cyclooxygenase inhibitors combined with deuterium-enriched water augment cytotoxicity in A549 lung cancer cell line via activation of apoptosis and MAPK pathways

Objective(s): Combination chemotherapy is a rational strategy to increase patient response and tolerability and to decrease adverse effects and drug resistance. Recently, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to be associated with reduction in occurrence of a variety of cancers including lung cancer. On the other hand, growing evidences suggest that deuterium-enriched water (DEW, D2O) and deuterium-depleted water (DDW) play a role both in treatment and prevention of cancers. In the present study, we examined the effects of DEW and DDW in combination with two NSAIDs, celecoxib and indomethacin, on A549 human non-small lung cancer cell to identify novel treatment options. Materials and Methods: The cytotoxicity of celecoxib or indomethacin, alone and in combination with DDW and DEW was determined. The COX-2, MAPK pathway proteins, the anti-apoptotic Bcl2 and pro-apoptotic Bax proteins and caspase-3 activity were studied for cytotoxic combinations.Results: Co-administration of selective and non-selective COX-2 inhibitors with DEW led to a remarkable increase in cytotoxicity and apoptosis of A549 cells. These events were associated with activation of p38 and JNK MAPKs and decreasing pro-survival proteins Bcl-2, COX-2 and ERK1/2. Furthermore, the combination therapy activated caspase-3, and the apoptosis mediator, and disabled poly ADP-ribose polymerase (PARP), the key DNA repair enzyme, by cleaving it.  Conclusion: The combination of DEW with NSAIDs might be effective against lung cancer cells by influence on principal cell signalling pathways, and this has a potential to become a candidate for chemotherapy

Losartan enhances the suppressive effect of pirfenidone on the bleomycin-induced epithelial-mesenchymal transition and oxidative stress in A549 cell line

Objective(s): Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. Despite the promising anti-fibrotic effect, the toleration of pirfenidone (PFD) by the patients in full dose is low. Combination therapy is a method for enhancing the therapeutic efficiency of PFD and decreasing its dose. Therefore, the present study evaluated the effect of a combination of losartan (LOS) and PFD on oxidative stress parameters and the epithelial-mesenchymal transition (EMT) process induced by bleomycin (BLM) in human lung adenocarcinoma A549 cells. Materials and Methods: The non-toxic concentrations of BLM, LOS, and PFD were assessed by the MTT assay. Malondialdehyde (MDA) and anti-oxidant enzyme activity including catalase (CAT) and superoxide dismutase (SOD) were assessed after co-treatment. Migration and western blot assays were used to evaluate EMT in BLM-exposed A549 after single or combined treatments. Results: The combination treatment exhibited a remarkable decrease in cellular migration compared with both single and BLM-exposed groups. Furthermore, the combination treatment significantly improved cellular anti-oxidant markers compared with the BLM-treated group. Moreover, combined therapy markedly increased epithelial markers while decreasing mesenchymal markers. Conclusion: This in vitro study revealed that the combination of PFD with LOS might be more protective in pulmonary fibrosis (PF) than single therapy because of its greater efficacy in regulating the EMT process and oxidative stress. The current results might offer a promising therapeutic strategy for the future clinical therapy of lung fibrosis

INVESTIGATION THE ROLE OF MEPXH1 (HIS139ARG) POLYMORPHISM ON NUMBER OF EXACERBATIONS AND DISEASE SEVERITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN A SMOKER POPULATION

The purpose of this study was to examine investigation the role of mEPXH1 (His139Arg) polymorphisms on number of exacerbations and disease severity in chronic obstructive pulmonary disease in a smoker population. Chronic obstructive pulmonary disease (COPD) has become the fourth most common single cause of morbidity, and its prevalence is increasing worldwide. It is a syndrome composed of chronic bronchitis, small airways disease (bronchiolitis), and emphysema, in varying proportions between affected individuals. The study was performed cohort and prospectively. The population consist of 213 patients with COPD disease. Genotyping of mEPXH1 was performed using multiplex PCR. Data analysis included, Pearson’s r correlations, regression analysis, ANOVA analyses, Tukey, test for comparison and SPSS software (package of Spss / pc + + ver18). The results showed that there is not relationship between polymorphisms of mEPXH1 and number of exacerbations. According the results, there is not significant relationship between polymorphisms of mEPXH1 and disease severity. Also there is not significant relationship between mEPXH1 and disease in COPD patients on basis parameters of spirometery and oxidative stress in COPD patients

Effect of EGF and FGF on the expansion properties of human umbilical cord mesenchymal cells

Mesenchymal stem cells have been increasingly introduced to have great potential in regenerative medicine, immunotherapy, and gene therapy due to their unique properties of self-renewal and differentiation into multiple cell lineages. Studies have shown that these properties may be limited and changed by senescence-associated growth arrest under different culture conditions. This study aimed to present the ability of some growth factors on human umbilical cord mesenchymal (hUCM) cells expansion and telomerase activity. To optimize hUCM cell growth, epidermal growth factor (EGF) and fibroblast growth factor (FGF) were utilized in culture media, and the ability of these growth factors on the expression of the telomerase reverse transcriptase (TERT) gene and cell cycle phases was investigated. TERT mRNA expression increased in the hUCM cells treated by EGF and FGF. So, the untreated hUCM cells expressed 30.49 ± 7.15% of TERT, while EGF-treated cells expressed 51.82 ± 12.96% and FGF-treated cells expressed 33.77 ± 11.55% of TERT. Exposure of hUCM cells to EGF or FGF also promoted the progression of cells from G1 to S phase of the cell cycle and induced them to decrease the number of cells entering the G2/M phase. Our study showed that EGF and, to a lesser extent, FGF amplify the proliferation and expansion of hUCM cells

Effect of EGF and FGF on the expansion properties of human umbilical cord mesenchymal cells

Mesenchymal stem cells have been increasingly introduced to have great potential in regenerative medicine, immunotherapy, and gene therapy due to their unique properties of self-renewal and differentiation into multiple cell lineages. Studies have shown that these properties may be limited and changed by senescence-associated growth arrest under different culture conditions. This study aimed to present the ability of some growth factors on human umbilical cord mesenchymal (hUCM) cells expansion and telomerase activity. To optimize hUCM cell growth, epidermal growth factor (EGF) and fibroblast growth factor (FGF) were utilized in culture media, and the ability of these growth factors on the expression of the telomerase reverse transcriptase (TERT) gene and cell cycle phases was investigated. TERT mRNA expression increased in the hUCM cells treated by EGF and FGF. So, the untreated hUCM cells expressed 30.49±7.15% of TERT, while EGF-treated cells expressed 51.82±12.96% and FGFtreated cells expressed 33.77±11.55% of TERT. Exposure of hUCM cells to EGF or FGF also promoted the progression of cells from G1 to S phase of the cell cycle and induced them to decrease the number of cells entering the G2/M phase. Our study showed that EGF and, to a lesser extent, FGF amplify the proliferation and expansion of hUCM cells

Autophagy modulators : mechanistic aspects and drug delivery systems

Funding: this work was supported by a grant from NMRC-CIRG to CTY. APK was supported by grants from National Medical Research Council of Singapore, NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative to Cancer Science Institute of Singapore, National University of Singapore. R.M. acknowledges financial supports of Kerman University of Medical Sciences.Autophagy modulation is considered to be a promising programmed cell death mechanism to prevent and cure a great number of disorders and diseases. The crucial step in designing an effective therapeutic approach is to understand the correct and accurate causes of diseases and to understand whether autophagy plays a cytoprotective or cytotoxic/cytostatic role in the progression and prevention of disease. This knowledge will help scientists find approaches to manipulate tumor and pathologic cells in order to enhance cellular sensitivity to therapeutics and treat them. Although some conventional therapeutics suffer from poor solubility, bioavailability and controlled release mechanisms, it appears that novel nanoplatforms overcome these obstacles and have led to the design of a theranostic-controlled drug release system with high solubility and active targeting and stimuli-responsive potentials. In this review, we discuss autophagy modulators-related signaling pathways and some of the drug delivery strategies that have been applied to the field of therapeutic application of autophagy modulators. Moreover, we describe how therapeutics will target various steps of the autophagic machinery. Furthermore, nano drug delivery platforms for autophagy targeting and co-delivery of autophagy modulators with chemotherapeutics/siRNA, are also discusse

Early and late preventive effect of Nigella sativa on the bleomycin-induced pulmonary fibrosis in rats: An experimental study

Objective: Pulmonary fibhrosis is a disease of the connective tissues in the respiratory system. Nigella sativa has been used for the treatment of pulmonary diseases like asthma. This study investigated the early and late preventive effect of methanolic extract of N. sativa on a bleomycin- induced pulmonary fibrosis model. Materials and Methods: This study was carried out using 52 rats. Pulmonary fibrosis was induced by a single endotracheal injection of bleomycin (5 mg/kg). Extract of N. sativa (500 mg/kg per day) or methylprednisolone succinate (4 mg/kg per day) was injected intraperitoneally in two periods (i.e. days 1-14 as early preventive group and days 15-28 days as late preventive group). The lung tissues were histologically examined at the end of each period and inspected for the amount of hydroxyproline and biomarkers of oxidative stress. Results: The pulmonary inflammation and fibrosis were significantly decreased in groups treated with methylprednisolone and N. sativa extract compared to bleomycin group in both early and late prevention groups (

Anticholinesterase, antioxidant, and neuroprotective effects of Tripleurospermum disciforme and Dracocephalum multicaule

Background: Nowadays, owing to medicinal plants as a candidate to obtain promising new medicinal agents, there is a renewed interest in the use of these natural sources for drug development. Objective: In the present study, we aimed to assess the anticholinesterase, antioxidant, and neuropotective effects of Tripleurospermum disciforme and Dracocephalum multicaule extracts. Materials and Methods: Methanolic extract of the plants was prepared by maceration method. Anticholinesterase effect of different concentrations of the plants was studied by colorimetric method and antioxidant activity was evaluated using diphenypicrylhydrazil (DPPH) assay. Protective effect of the extracts against amyloid β (Aβ)-induced toxicity in PC12 cells was determined by MTT (3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) method. Results: Both T. disciforme and D. multicaule extracts could inhibit acetylcholinesterase (AChE) in a dose-dependent manner. The highest inhibition occurred at 5 μg/ml (71.18 ± 4.9 and 79.06 ± 3.1% inhibition respectively by T. disciforme and D. multicaule) in comparison to tacrine (86.37 ± 3.24%). The greatest DPPH inhibition of T. disciforme and D. multicaule was shown at 800 μg/ml (89.04 ± 3.9 and 78.5 ± 3.7%, respectively). None of tested extracts induced protection against βA toxicity in PC12 cell. Conclusion: Although the results indicated anticholinesterase and antioxidant of the T. disciforme and D. multicaule, further specific studies and scientific validity are needed