Toll-like receptors (TLRs): An old family of immune receptors with a new face in cancer pathogenesis

In the dark path of tumorigenesis, the more carefully the cancer biology is studied, the more brilliant answers could be given to the countless questions about its orchestrating derivers. The identification of the correlation between Toll-like receptors (TLRs) and different processes involved in carcinogenesis was one of the single points of blinding light highlighting the interconnection between the immune system and cancer. TLRs are a wide family of single-pass membrane-spanning receptors that have developed through the evolution to recognize the structurally conserved molecules derived from microorganisms or damaged cells. But this is not everything about these receptors as they could orchestrate several downstream signalling pathways leading to the formation or suppression of cancer cells. The present review is tempted to provide a concise schematic about the biology and the characters of TLRs and also summarize the major findings of the regulatory role of TLRs and their associated signalling in the pathogenesis of human cancers

Seyyed Hassan Taqizadeh: a political biography

With the Constitutional Revolution of 1906, Iran experienced a monumental shift from rule by absolute monarchy to governance based on a constitution. The effects of this revolution were felt not only on a national level but also globally; internationally, even influencing political relationships between some of the European great powers. Revolutions are born out of theories and ideas; the study of key figures who propagated those ideas is an essential part of historiographical research.The theoretical foundation of the Constitutional Revolution of 1906 gradually developed out of an emerging discourse which reflected the changes Iran was undergoing due to increased contact with the outside world on a scale which had never been experienced before. Having begun with colonialist developments in the seventeenth century, the eighteenth century witnessed a gradual deepening of the threat to the Islamic states by European powers. As contact with the world outside the Islamic states’ territory began to be considered increasingly necessary, Islamic countries were forced to seek a solution to prevent the dominating power of Europe. New technologies gave nations the upper hand and those who lagged behind in terms of scientific and technological development were at a distinct disadvantage. These less developed countries had first to try to understand the developments before they could tackle how to stop the spread of this new threat; the threat from this new kind of power was not based on religious ideology but rather its strength originated from science. It took some time for countries such as Iran to be able to make distinctions between power derived from scientific developments and the power of religion, to accept that development was open to all peoples regardless of their religion, nationality or race. Development towards modernity was equated with European/Western science which was considered at odds with Islamic or non-European identity. This led to discord and the clergy who had been in charge of shaping their followers’ beliefs naturally had to declare their position in response to these changes. Some clergy took reactionary positions; others were more convinced that new changes were necessary for the survival of Islam in the Islamic countries whose population was predominantly Muslim. But it was not only the clergy but also politicians, writers and intellectuals among others who began to express their thoughts and ideas about what should be done in relationship to these changes. Seyyed Hassan Taqizadeh was one such man.Taqizadeh was one of the key Iranian intellectuals who played a significant role in developing and shaping the discourse of change in Iran. As such, the aim of this research has been to provide a deep and nuanced assessment of the life and career of Taqizadeh and how that helped to influence and direct the movement towards change. Taqizadeh was not the only intellectual who was engaged in the discourse of modernity or as it has been referred to in the Iranian context, “Tajaddod”. What gives Taqizadeh particular prominence, however, is the fact that, unlike others, he remained constantly on the scene, and despite many obstacles, rarely veered from his goal of steering Iran along the path towards modernity. This research uses Taqizadeh’s biography as a mirror to reflect the discourse of change in Iran and analyses his role and relationship to that discourse of change. Taqizadeh lived a long life; 91 years. His lifetime (1878-1970) connects to a long and significant period in contemporary Iranian intellectual history; he witnessed the reign of six Shahs; four of whom he had close dealings with. During Taqizadeh’s life important changes took place in Iran and throughout the wider world, including two world wars.Taqizadeh was a politician and intellectual who has left behind many works relating to history, culture and literature. Enough of his writings and records of his thoughts remain to allow his ideas and deeds to have become a living legacy for Iranian intelligentsia. In a country still largely divided over how best it should be run, Taqizadeh’s ideas have become part of the discourse of a desire to modernise the country. Taqizadeh has not always been objectively written about and there is much polemic based around his place in Iranian historiography. Some support Taqizadeh’s ideas and thoughts; for others who scorn western democracy, his ideas have been used, in contrast, to exemplify an approach which ultimately failed. For those who favour political Islam, Taqizadeh is still considered an evil representative of the corrupt West and for the more radical even an agent of the West, whose aim was to ensure the surrender of Iran to the hostile non-Islamic West.Maybe because of the controversy around him and his deeds, although there exist numerous articles and monographs based on Taqizadeh’s life, there is a paucity of published research that focuses on and highlights the importance of his life and work in the formation of a national Iranian identity and his crucial role in the narration of modernity in the Iranian context. This research endeavours to focus on details of and influences on Taqizadeh’s life that may have been previously overlooked and provide an objective and nuanced record of the legacy he has left on Iran and the journey towards modernity in that nation.This study of Taqizadeh’s life and thoughts may also go some way towards facilitating a better understanding of contemporary Iran. After experiencing two revolutions in one century, the Iran of today is overshadowed by an overriding feeling of disquiet and uncertainty about the future. Scholars and indeed some of the general public are searching for reasons that might account for and explain the current situation that the country finds itself in, particularly following the 1979 Revolution. Much discourse revolves around how the country should or should not be ruled and the best routes for its continued development; studying Taqizadeh’s life and career may help to provide some answers.Middle Eastern Studie

Toll-like receptors (TLRs) in cancer; with an extensive focus on TLR agonists and antagonists

At the forefront of the battle against pathogens or any endogenously released molecules, toll-like receptors (TLRs) play an important role as the most noble pattern recognition receptors. The ability of these receptors in distinguishing ``self'' and ``non-self'' antigens is a cornerstone in the innate immunity system; however, misregulation links inflammatory responses to the development of human cancers. It has been known for some time that aberrant expression and regulation of TLRs not only endows cancer cells an opportunity to escape from the immune system but also supports them through enhancing proliferation and angiogenesis. Over the past decades, cancer research studies have witnessed a number of preclinical and clinical breakthroughs in the field of TLR modulators and some of the agents have exceptionally performed well in advanced clinical trials. In the present review, we have provided a comprehensive review of different TLR agonists and antagonists and discuss their limitations, toxicities, and challenges to outline their future incorporation in cancer treatment strategies

c-Myc Inhibition Using 10058-F4 Increased the Sensitivity of Acute Promyelocytic Leukemia Cells to Arsenic Trioxide Via Blunting PI3K/NF-κB Axis

Backgrounds: Although ATO is widely used to treat acute promelocytic leukemia (APL), the appropriate effects of the drug as a single agent are achieved in high doses which are not clinically achievable without the risk of side effects; highlighting the necessity of its application in a combined-modality. Herein, we aimed to investigate whether c-Myc inhibition could reinforce the anti-leukemic effect of ATO, while reducing its concentration in APL cells. Methods: NB4 cells were treated with the relevant concentrations of 10058-F4 (c-Myc inhibitor) and ATO, and then the survival of the cells was evaluated using trypan blue, MTT and BrdU assays. Moreover, the mechanism of action of the agents were evaluated using Flow cytometry, qRT-PCR and western blot analysis. Results: We found that the inhibition of c-Myc using 10058-F4 could enhance the anti-leukemic effect of ATO in APL cells through reducing the phosphorylation of IκB, decreasing the expression of the anti-apoptotic genes and in turn, inducing a caspase-3-dependent apoptotic cell death. Moreover, the combination of 10058-F4 and ATO abrogated the activation of the PI3K pathway, while neither agent had significant suppressive impact on this pathway; suggesting for the first time that probably the companionship of c-Myc inhibitor may be an appealing strategy for shifting the resistance condition toward a chemo-sensitive phenotype, without the necessity to elevate the effective dose of ATO. Conclusion: Given the efficacy of 10058-F4 in adjuvanting approaches, we suggest this small molecule inhibitor as an impressing agent to be used alongside ATO in the treatment of APL. © 2020 IMS

The effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial

Objective: This study was conducted to evaluate the effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer (DFU). Methods: This randomized, double-blind, placebo-controlled trial was performed among 60 patients with grade 3 DFU according to "Wagner-Meggitt's" criteria. Participants were randomly divided into two groups (each 30 participants) and received either 50,000. IU vitamin D supplements every 2. weeks for 12. weeks (group A) or placebo (group B). Fasting blood samples were taken at study baseline and after 12-week intervention to determine related markers. Results: After 12. weeks of intervention, compared with the placebo, vitamin D supplementation resulted in a significant reduction in ulcer length (-2.1. ±. 1.1 vs. -1.1. ±. 1.1. cm, P = 0.001), width (-2.0. ±. 1.2 vs. -1.1. ±. 1.0. cm, P = 0.02) and depth (-1.0. ±. 0.5 vs. -0.5. ±. 0.5. cm, P. <. 0.001), and erythema rate (100 vs. 80, P = 0.01). In addition, in supplemented patients changes in serum insulin concentration (-3.4. ±. 9.2 vs + 2.8. ±. 9.3 μIU/mL, P = 0.01), homeostasis model of assessment-estimated insulin resistance (-1.5. ±. 4.1 vs + 1.7. ±. 5.1, P = 0.01), the quantitative insulin sensitivity check index (+. 0.006. ±. 0.02 vs. -0.006. ±. 0.02, P = 0.03) and HbA1c (-0.6. ±. 0.6 vs. -0.1. ±. 0.5, P = 0.004) were significantly different from those of patients in the placebo group. Additionally, following supplementation with vitamin D, significant reductions in serum total- (-15.8. ±. 18.9 vs + 5.3. ±. 31.8. mg/dL, P = 0.003), LDL- (-17.2. ±. 19.8 vs + 2.2. ±. 28.6. mg/dL, P = 0.003), total-/HDL-cholesterol ratio (-1.1. ±. 0.8 vs. -0.2. ±. 1.1, P = 0.001), high sensitivity C-reactive protein (hs-CRP) (-0.4. ±. 2.5 vs + 1.9. ±. 4.2. μg/mL, P = 0.01), erythrocyte sedimentation rate (ESR) (-34.7. ±. 32.4 vs. -18.0. ±. 26.6. mm/h, P = 0.03) and plasma malondialdehyde (MDA) concentrations (-0.7. ±. 0.9 vs. -0.2. ±. 0.5. μmol/L, P = 0.008) were seen compared with the placebo. Conclusions: Overall, vitamin D supplementation for 12. weeks among patients with DFU had beneficial effects on glucose homeostasis, total-, LDL-, total-/HDL-cholesterol, ESR, hs-CRP and MDA levels. In addition, vitamin D may have played an indirect role in wound healing due to its effect on improved glycemic control. © 2016 Elsevier Inc