Design,Synthesis and Molecular Docking Studies of Some Tetrahydropyrimidine Derivatives as Possible Fascin Inhibitors

Eight derivatives of tetrahydropyrimidine scaffold were designed and prepared as hybrid compounds possessing the structural features of both monastrol as an anticancer drug and nifedipine as a fascin blocking agent. All of the compounds were evaluated for their cytotoxic potency and the ability to inhibit 4T1 breast cancer cells migration. Then, they were investigated in silico for their ability to inhibit the fascin protein using molecular docking simulation. The most potent compound was 4d and the weakest one was 4a according to the in vitro cytotoxicity assay. The corresponding IC₅₀ values were 193.70 and 248.75 μm , respectively. The least cytotoxic compound ( 4a ) was one of the strongest ones in binding to the fascin binding site according to the molecular docking results. 4a and 4e inhibited the 4T1 cells migration better than other compounds. They were more potent than nifedipine in inhibiting the migration process. In silico studies proved 4h to be the most potent fascin inhibitor in terms of ΔG_bind although it was not inhibiting migration. The controversy between the in vitro and in silico results may cancel the theory of the involvement of the fascin inhibition in the migration inhibition. However, the considerable antimigratory effects of some of the synthesized compounds encourage performing further in vivo experiments to introduce novel tumor metastasis inhibitors.     

Description of a new pseudoscorpion species of the genus Amblyolpium Simon (Pseudoscorpiones: Garypinidae) from north-western Iran

A new species of pseudoscorpion, Amblyolpium atropatesi n. sp. is described and illustrated on the basis of the adult specimens extracted from soil by Berlese funnel.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:0150B850-E80D-46F5-983C-7E958FE69B87     

Collagen organization in canine myxomatous mitral valve disease: an x-ray diffraction study

Collagen fibrils, a major component of mitral valve leaflets, play an important role in defining shape and providing mechanical strength and flexibility. Histopathological studies show that collagen fibrils undergo dramatic changes in the course of myxomatous mitral valve disease in both dogs and humans. However, little is known about the detailed organization of collagen in this disease. This study was designed to analyze and compare collagen fibril organization in healthy and lesional areas of myxomatous mitral valves of dogs, using synchrotron small-angle x-ray diffraction. The orientation, density, and alignment of collagen fibrils were mapped across six different valves. The findings reveal a preferred collagen alignment in the main body of the leaflets between two commissures. Qualitative and quantitative analysis of the data showed significant differences between affected and lesion-free areas in terms of collagen content, fibril alignment, and total tissue volume. Regression analysis of the amount of collagen compared to the total tissue content at each point revealed a significant relationship between these two parameters in lesion-free but not in affected areas. This is the first time this technique has been used to map collagen fibrils in cardiac tissue; the findings have important applications to human cardiology.     

Novel strategies for inhibition of bacterial biofilm in chronic rhinosinusitis

An important role has been recently reported for bacterial biofilm in the pathophysiology of chronic diseases, such as chronic rhinosinusitis (CRS). CRS, affecting sinonasal mucosa, is a persistent inflammatory condition with a high prevalence around the world. Although the exact pathological mechanism of this disease has not been elicited yet, biofilm formation is known to lead to a more significant symptom burden and major objective clinical indicators. The high prevalence of multidrug-resistant bacteria has severely restricted the application of antibiotics in recent years. Furthermore, systemic antibiotic therapy, on top of its insufficient concentration to eradicate bacteria in the sinonasal biofilm, often causes toxicity, antibiotic resistance, and an effect on the natural microbiota, in patients. Thus, coming up with alternative therapeutic options instead of systemic antibiotic therapy is emphasized in the treatment of bacterial biofilm in CRS patients. The use of topical antibiotic therapy and antibiotic eluting sinus stents that induce higher antibiotic concentration, and decrease side effects could be helpful. Besides, recent research recognized that various natural products, nitric oxide, and bacteriophage therapy, in addition to the hindered biofilm formation, could degrade the established bacterial biofilm. However, despite these improvements, new antibacterial agents and CRS biofilm interactions are complicated and need extensive research. Finally, most studies were performed in vitro, and more preclinical animal models and human studies are required to confirm the collected data. The present review is specifically discussing potential therapeutic strategies for the treatment of bacterial biofilm in CRS patients.     

Ovarian cancer stem cell: A potential therapeutic target for overcoming multidrug resistance

The cancer stem cell (CSC) model encompasses an advantageous paradigm that in recent decades provides a better elucidation for many important biological aspects of cancer initiation, progression, metastasis, and, more important, development of multidrug resistance (MDR). Such several other hematological malignancies and solid tumors and the identification and isolation of ovarian cancer stem cells (OV-CSCs) show that ovarian cancer also follows this hierarchical model. Gaining a better insight into CSC-mediated resistance holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. Therefore, in this review, we will discuss some important mechanisms by which CSCs can escape chemotherapy, and then review the recent and growing body of evidence that supports the contribution of CSCs to MDR in ovarian cancer.     

Therapeutic potency of pharmacological adenosine receptors agonist/antagonist on cancer cell apoptosis in tumor microenvironment,current status,and perspectives

The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease.     

Immunoresolvents in asthma and allergic diseases: Review and update

Asthma and allergic diseases are inflammatory conditions developed by excessive reaction of the immune system against normally harmless environmental substances. Although acute inflammation is necessary to eradicate the damaging agents, shifting to chronic inflammation can be potentially detrimental. Essential fatty-acids-derived immunoresolvents, namely, lipoxins, resolvins, protectins, and maresins, are anti-inflammatory compounds that are believed to have protective and beneficial effects in inflammatory disorders, including asthma and allergies. Accordingly, impaired biosynthesis and defective production of immunoresolvents could be involved in the development of chronic inflammation. In this review, recent evidence on the anti-inflam]matory effects of immunoresolvents, their enzymatic biosynthesis routes, as well as their receptors are discussed.     

Herbal medicine as an auspicious therapeutic approach for the eradication of Helicobacter pylori infection: A concise review

Helicobacter pylori (H. pylori) causes gastric mucosa inflammation and gastric cancer mostly via several virulence factors. Induction of proinflammatory pathways plays a crucial role in chronic inflammation, gastric carcinoma, and H. pylori pathogenesis. Herbal medicines (HMs) are nontoxic, inexpensive, and mostly anti-inflammatory reminding meticulous emphasis on the elimination of H. pylori and gastric cancer. Several HM has exerted paramount anti-H. pylori traits. In addition, they exert anti-inflammatory effects through several cellular circuits such as inhibition of 5′-adenosine monophosphate-activated protein kinase, nuclear factor-κB, and activator protein-1 pathway activation leading to the inhibition of proinflammatory cytokines (interleukin 1α [IL-1α], IL-1β, IL-6, IL-8, IL-12, interferon γ, and tumor necrosis factor-α) expression. Furthermore, they inhibit nitrous oxide release and COX-2 and iNOS activity. The apoptosis induction in Th1 and Th17-polarized lymphocytes and M2-macrophagic polarization and STAT6 activation has also been exhibited. Thus, their exact consumable amount has not been revealed, and clinical trials are needed to achieve optimal concentration and their pharmacokinetics. In the aspect of bioavailability, solubility, absorption, and metabolism of herbal compounds, nanocarriers such as poly lactideco-glycolide-based loading and related formulations are helpful. Noticeably, combined therapies accompanied by probiotics can also be examined for better clearance of gastric mucosa. In addition, downregulation of inflammatory microRNAs (miRNAs) by HMs and upregulation of those anti-inflammatory miRNAs is proposed to protect the gastric mucosa. Thus there is anticipation that in near future HM-based formulations and proper delivery systems are possibly applicable against gastric cancer or other ailments because of H. pylori.