Synthesis, characterization and biological evaluation of some 2-arylbenzoxazole acetic acid derivatives as potential anticancer agents

A series of 2-arylbenzoxazole compounds possessing a cytotoxic activity as potential anticancer agents has been synthesised. Oxidative coupling of benzaldehyde with o-aminophenol utilizing lead tetraacetate approach has been used to realize the synthesis of compounds 1-11. The cytotoxicity of 1-11 have been screened against breast cancer cell line MCF-7 and human colon cancer cell line HCT-116 utilizing doxorubicin as reference drug. Among these compounds, 2-(3-benzyloxyphenyl)benzoxazole-5-acetic acid 5 and 2-(4-methoxyphenyl)benzoxazol-5-acetic acid 10, are found to be promising cytotoxic compounds against MCF-7 cell line. In addition, this study shows that the presence of acetic acid group at position 5 of benzoxazole nucleus enhances the activity. Moreover, it is noticed that the presence of oxygen atom directly linked to the phenyl substituent improves activity. The results offer a new benzoxazole based template to design and develop novel antineoplastic agents.

Synthesis, characterization and biological evaluation of some 2-arylbenzoxazole acetic acid derivatives as potential anticancer agents

1496-1501A series of 2-arylbenzoxazole compounds possessing a cytotoxic activity as potential anticancer agents has been synthesised. Oxidative coupling of benzaldehyde with o-aminophenol utilizing lead tetraacetate approach has been used to realize the synthesis of compounds 1-11. The cytotoxicity of 1-11 have been screened against breast cancer cell line MCF-7 and human colon cancer cell line HCT-116 utilizing doxorubicin as reference drug. Among these compounds, 2-(3-benzyloxyphenyl)benzoxazole-5-acetic acid 5 and 2-(4-methoxyphenyl)benzoxazol-5-acetic acid 10, are found to be promising cytotoxic compounds against MCF-7 cell line. In addition, this study shows that the presence of acetic acid group at position 5 of benzoxazole nucleus enhances the activity. Moreover, it is noticed that the presence of oxygen atom directly linked to the phenyl substituent improves activity. The results offer a new benzoxazole based template to design and develop novel antineoplastic agents

Immunomodulatory effects of tigecycline in Balb/c mice

Tigecycline is a glycylcycline antibiotic approved by the FDA for the treatment of complicated infections. Despite its effectiveness, the FDA announced a warning of increasing mortality associated with its use. There is, however, no clear explanation for this side effect. Previous reports found a possible effect of tigecycline on leukocyte proliferation and proinflammatory cytokine release. We therefore investigated the effect of tigecycline on the immune components and response in Balb/c mice in vivo and in vitro. It was found that tigecycline enhanced lymphocyte proliferation and significantly increased cellular infiltration within the footpad, as based on DTH testing, but reduced the hemagglutination titer. In splenocyte cultures, tigecycline suppressed splenocyte proliferation with IC50 3–5 mol L–1, significantly increased IL-2 secretion and reduced IL-17 secretion in a dose dependent mode. In conclusion, tigecycline is safe at therapeutic and sub-therapeutic doses, but it could still have an immunomodulatory effect at higher doses. Use of higher doses of tigecycline requires further investigation

Human toll - like receptor 9 (hTLR9) expression and function in haematological and non-haematological malignancies

This thesis addresses the expression and function of human TLR9 in haematological and non-haematological tumour cells. I have shown that most B linage tumour cell lines expressed TLR9, with the exception of myeloma cell lines U266, Karpas 707H and the EBV-lymphoblastoid HMy2 cell line, whereas all non-haematological cell lines tested were negative or very weakly positive. TLR9 positive B-cells/B-cell lines, responded to CpG-ODN activation by activating intracellular signalling pathways, cytokine release, surface marker upregulation and cellular proliferation, whereas TLR9 negative cells did not.;Data on the ability of pre-treatment with low doses of CpG-ODN to induce a refractory state (tolerance) on Burkitt's lymphoma BJAB cells indicates that low doses of CpG-ODN tolerised NF-kappaB activation and, to some extent, cellular proliferation and surface marker upregulation. Moreover, reactivating NF-kappaB on BJAB cells after being tolerised with low dose of CpG-ODN is time dependent with the tolerising effect lasting up to two weeks after a single dose of CpG-ODN.;Finally, inhibiting the signalling pathways (ERK, p38MAPK, PI3K/AKTand NF-kappaB) with selective inhibitors U0126, SB203580, LY294002 and Curcumin respectively, has shown different effects on basal and CpG-ODN activated surface marker expression, cellular proliferation and cytokine release. Furthermore, different signalling pathways mediate different functional effects of CpG-ODN/TLR9 activation, and suggest that ERK and p38 MAPK pathways are involved in CpG-ODN mediated NF-kappaB activation. This work should shed a new light on the mechanisms of action of CpG activation on TLR5 signalling in immune and non-immune cells and on its immunotherapeutic use in the treatment of cancer

Academic stress-induced changes in Th1- and Th2-cytokine response

Psychological stress stimulates physiological responses releasing catecholamines and corticoids, which act via corresponding receptors on immune cells, producing a shift in the cytokine balance. These responses are variable depending on the nature of stressors. The effect of the academic stress on the production of the Th1-cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6 and IL-8) and Th2-cytokines (IL-1ra, IL-4, IL-5 and IL-10) on 35 medical/health sciences students after completing their questionnaires was investigated. Blood samples were taken at three stages; baseline stage at the beginning, midterm and final academic examination stages. Plasma cortisol and cytokines were measured during the three stages. The last two stages were compared with the baseline non-stress period. Results of the stress induced during the final examination stage were the highest with a significant increase in cortisol release, IL-4, IL-5 and IL-1ra release with a shift in Th1:Th2 cytokines balance towards Th2. Whereby, the midterm stage did not show significant reduction in Th1-cytokines except for TNF-α, with an increase in IFN-γ level that was reduced in the third stage. Th2 cytokine, IL-1ra, had positive correlations with Th1 cytokines; IL-2 and IFN-γ in the second stage and IL-6 cytokine in the third stage. Cortisol was positively correlated with IL-8 in the last stage and heart rates had negative correlation with IL-10 in the first and last stages. Findings of this study indicate that exam stress down-regulates Th1 with a selective up-regulation of Th2-cytokines. In conclusion, Cortisol might have a role in suppressing the release of Th1- mediated cellular immune response which could increase the vulnerability among the students to infectious diseases. Keywords: Academic stress, Cortisol, Th1-cytokines, Th2-cytokines, Medical/health sciences student

A threshold level of TLR9 mRNA predicts cellular responsiveness to CpG-ODN in haematological and non-haematological tumour cell lines

The human toll like receptor 9 (TLR9) detects differences between microbial and host DNA, based on unmethylated deoxycytidyl deoxyguanosine dinucleotide (CpG) motifs, leading to activation of both innate and adaptive immune mechanisms. The synthetic TLR9 agonist, CpG-ODN, can substitute for microbial DNA in these responses, and is in clinical trials as an immunomodulatory agent in diseases as diverse as infections, cancer and allergic disorders. Human TLR9 is expressed on cells of haematopoietic origin (principally plasmacytoid dendritic cells and B cells), but has also been described as being expressed on a number of other cell types. In order to clarify the expression and function of TLR9 in a range of cells of both haematopoietic and non-haematopoietic origin, we investigated the level of expression of TLR9 mRNA, and the ability of the cells to respond to CpG-ODN by upregulation of cell surface markers, cytokine production, cellular proliferation and activation of NFκB. Our data show that the cellular response to CpG-ODN depended on a threshold level of expression of TLR9. TLR9 was widely expressed amongst B cell tumours (with the exception of myeloma cell lines), but we did not find either threshold levels of expression of TLR9 or responses to CpG-ODN in several myeloma or myeloid tumour cell lines or any non-haematological tumour cell lines tested in our study. TLR9-positive cells varied significantly in their responses to CpG-ODN, and the level of TLR9 expression beyond the threshold did not correlate with the magnitude of the response to CpG-ODN. Finally, CpG-ODN induced NFκB activation and increased cellular proliferation in Hek293 cells that had been stably transfected with hTLR9, but did not affect the expression of surface markers or synthesis of IL-6, IL-10 or TNF-α. Thus both haematological and non-haematological cells expressing appropriate levels of TLR9 respond to CpG-ODN, but the nature of the TLR9-mediated response is dependent on cell type

Immunomodulatory Effects of Tigecycline in Balb/C Mice

Tigecycline is a glycylcycline antibiotic approved by the FDA for the treatment of complicated infections. Despite its effectiveness, the FDA announced a warning of increasing mortality associated with its use. There is, however, no clear explanation for this side effect. Previous reports found a possible effect of tigecycline on leukocyte proliferation and proinflammatory cytokine release. We t herefore i nvestigated the effect of tigecycline on the immune components and response in Balb/c mice in vivo and in vitro. It was found that tigecycline enhanced lymphocyte proliferation and significantly increased cellular infiltration within the footpad, as based on DTH testing, but reduced the hemagglutination titer. In splenocyte cultures, tigecycline suppressed splenocyte proliferation with IC50 3-5 mmol L-1, significantly increased IL-2 secretion and reduced IL-17 secretion in a dose dependent mode. In conclusion, tigecycline is safe at therapeutic and sub-therapeutic doses, but it could still have an immunomodulatory effect at higher doses. Use of higher doses of tigecycline requires further investigation

Attitude towards hpv vaccination and the intention to get vaccinated among female university students in health schools in jordan

Cervical cancer is a leading cause of morbidity and mortality in women worldwide. The availability of prophylactic vaccines for high-risk types of human papillomavirus (HPV) infection represents an important advancement in the prevention of cervical cancer. In Jordan, the availability of the HPV vaccination is restricted to individuals who are willing to pay. The aim of the current study was to evaluate the willingness and attitude of female university students in health schools/faculties in Jordan to get HPV vaccination and their knowledge about the virus. A self-administered online questionnaire was distributed in October 2021, which comprised 27 items to evaluate HPV knowledge, history of HPV vaccination, intentions to get the HPV vaccine, and the reason(s) behind vaccine refusal for those who rejected vaccination. The study sample comprised 836 participants: medical students (39.7%), pharmacy students (26.0%), dental students (21.2%), and nursing students (13.2%). Only 524 participants had heard of HPV prior to the study (62.7%), of which 48.7% knew about the availability of HPV vaccines. The lowest level of HPV knowledge was observed among nursing students. Only 19/524 students reported a history of HPV vaccination (3.6%). The overall willingness to receive HPV vaccination if provided freely was 75.0%, while only 16.0% were willing to pay for the vaccine. The most common reason for HPV vaccine rejection was the perceived low risk to get HPV infection. Significantly higher intentions to get HPV vaccination were found among older participants and medical students. The embrace of vaccine conspiracy beliefs was associated with a significantly less willingness to get the HPV vaccination (p < 0.001). Dependence on the internet/social media as the source of HPV knowledge was associated with a significantly lower intention to get HPV vaccination (p = 0.002). The coverage of the HPV vaccination among female university students in health schools in Jordan appeared extremely low; however, three-fourths of the students who had heard of HPV were willing to receive the HPV vaccination if provided freely. Complacency appeared as a major factor for HPV vaccine rejection. Increasing the levels of knowledge and awareness of HPV infection and its association with cervical cancer through reliable sources is recommended. This can be helpful for the individual benefit of the students besides the potentially positive role they can play in community education. Countering vaccine conspiracy beliefs with proper education and awareness programs can be helpful to appraise the role of HPV vaccines in cancer prevention

Phenolic contents and antioxidant activity of barhi date palm (Phoenix dactylifera L.) kernels extracts

Consumption of foods rich in phytochemicals with potential antioxidant properties can reduce the risk of various degenerative diseases such as cancer, atherosclerosis, diabetes, and aging. Several plant materials have been studied as sources of potentially safe natural antioxidants such as vegetables, fruits, cereals, barks, roots, spices and herbs. However, relatively less information is available on the antioxidant potentials of food processing products and agro-industrial wastes which are usually discarded in huge quantities. Some studies reported that the peel and kernel fractions of some fruits have been found to possess higher antioxidant activity than the pulp fraction based on their ferric reducing/antioxidant power (FRAP) values. Accordingly, the search for new natural antioxidants in wastes such as peels, brans and kernels has taken a very high attention in the last decade. The kernels obtained after date processing constitute a very cheap source for the extraction of antioxidant phenols, which makes them suitable for the preparation of dietary supplements, or in the production of phytochemicals, providing an important economic advantage through increase the utilization of date kernels while also additive value will be added to the residue. The aim of this research was, therefore, to investigate the effect of different extraction solvents on the phenolic content and antioxidant activity of Barhi date palm kernels (DPK). The solvent systems used were methanol, ethanol, acetone and distilled water. The antioxidant activity of the Barhi DPK was evaluated using ferric-reducing antioxidant power assay (FRAP), 1,1-diphenyl-2-picrylhydrazyl free radical-scavenging capacity (DPPH), 2,2- azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) and total phenolic compounds (TPC)

Synthesis, Crystal Study, and Anti-Proliferative Activity of Some 2-Benzimidazolylthioacetophenones towards Triple-Negative Breast Cancer MDA-MB-468 Cells as Apoptosis-Inducing Agents

On account of its poor prognosis and deficiency of therapeutic stratifications, triple negative breast cancer continues to form the causative platform of an incommensurate number of breast cancer deaths. Aiming at the development of potent anticancer agents as a continuum of our previous efforts, a novel series of 2-((benzimidazol-2-yl)thio)-1-arylethan-1-ones 5a–w was synthesized and evaluated for its anti-proliferative activity towards triple negative breast cancer (TNBC) MDA-MB-468 cells. Compound 5k was the most active analog against MDA-MB-468 (IC50 = 19.90 ± 1.37 µM), with 2.1-fold increased activity compared to 5-fluorouracil (IC50 = 41.26 ± 3.77 µM). Compound 5k was able to induce apoptosis in MDA-MB-468, as evidenced by the marked boosting in the percentage of florecsein isothiocyanate annexin V (Annexin V–FITC)-positive apoptotic cells (upper right (UR) + lower right (LR)) by 2.8-fold in comparison to control accompanied by significant increase in the proportion of cells at pre-G1 (the first gap phase) by 8.13-fold in the cell-cycle analysis. Moreover, a quantitative structure activity relationship (QSAR) model was established to investigate the structural requirements orchestrating the anti-proliferative activity. Finally, we established a theoretical kinetic study