Synthesis,antitumor activity and molecular docking study of some novel 3-benzyl-4(3H)quinazolinone analogues

A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI₅₀ (10.47, 7.24 and 14.12?µM. respectively), and are nearly 1.5–3.0-fold more potent compared with the positive control 5-FU with mean GI₅₀, 22.60?µM. On the other hand, compounds 6 and 10 yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9 showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032.     

Potassium-induced alleviation of salinity stress in <Emphasis Type="Italic">Brassica campestris</Emphasis> L.

Salinity is an important abiotic factor that adversely affects major agricultural soils of the world and hence limits crop productivity. An optimum mineral-nutrient status of plants plays critical role in determining plant tolerance to various stresses. A pot experiment was conducted on mustard (Brassica campestris L.) to study the protective role of added potassium (K, 40 mg kg⁻¹ soil) against salinity-stress (0, 40 and 80 mM NaCl)-induced changes in plant growth, photosynthetic traits, ion accumulation, oxidative stress, enzymatic antioxidants and non-enzymatic antioxidants at 30 days after sowing. Increasing NaCl levels decreased the growth, photosynthetic traits and the leaf ascorbate and glutathione content but increased the leaf ion accumulation and oxidative stress, and the activity of antioxidant enzymes. In contrast, K-nutrition improved plant growth, photosynthetic traits, activity of antioxidant enzymes and the ascorbate and glutathione content, and reduced ion accumulation and oxidative stress traits in the leaves, more appreciably at 40 mM than at 80 mM NaCl. The study illustrates the physiological and biochemical basis of K-nutrition-induced NaCl tolerance in mustard as a means to achieving increased crop productivity in a sustainable way.     

Induction of IL-10 and TGFβ from CD4+CD25+FoxP3+ T Cells Correlates with Parasite Load in Indian Kala-azar Patients Infected with Leishmania donovani

Background

Visceral leishmaniasis (VL) is distinguished by a complex interplay of immune response and parasite multiplication inside host cells. However, the direct association between different immunological correlates and parasite numbers remains largely unknown.

Methodology/Principal Findings

We examined the plasma levels of different disease promoting/protective as well as Th17 cytokines and found IL-10, TGFβ and IL-17 to be significantly correlated with parasite load in VL patients (r = 0.52, 0.53 and 0.51 for IL-10, TGFβ and IL-17, respectively). We then extended our investigation to a more antigen-specific response and found leishmanial antigen stimulated levels of both IL-10 and TGFβ to be significantly associated with parasite load (r = 0.71 and 0.72 for IL-10 and TGFβ respectively). In addition to cytokines we also looked for different cellular subtypes that could contribute to cytokine secretion and parasite persistence. Our observations manifested an association between different Treg cell markers and disease progression as absolute numbers of CD4⁺CD25⁺ (r = 0.55), CD4⁺CD25^hi (r = 0.61) as well as percentages of CD4⁺CD25⁺FoxP3⁺ T cells (r = 0.68) all correlated with parasite load. Encouraged by these results, we investigated a link between these immunological components and interestingly found both CD4⁺CD25⁺ and CD4⁺CD25⁺FoxP3⁺ Treg cells to secrete significantly (p<0.05) higher amounts of not only IL-10 but also TGFβ in comparison to corresponding CD25^- T cells.

Conclusions/Significance

Our findings shed some light on source(s) of TGFβ and suggest an association between these disease promoting cytokines and Treg cells with parasite load during active disease. Moreover, the direct evidence of CD4⁺CD25⁺FoxP3⁺ Treg cells as a source of IL-10 and TGFβ during active VL could open new avenues for immunotherapy towards cure of this potentially fatal disease.     

Regulation of autophagy by polyphenols: Paving the road for treatment of neurodegeneration

In the present paper, we will discuss on the importance of autophagy in the central nervous system, and outline the relation between autophagic pathways and the pathogenesis of neurodegenerative disorders. The potential therapeutic benefits of naturally occurring phytochemicals as pharmacological modulators of autophagy will also be addressed. Our findings provide renewed insight on the molecular modes of protection by polyphenols, which is likely to be at least in part mediated not only by their potent antioxidant and anti-inflammatory effects, but also through modulation of autophagic processes to remove the aberrant protein aggregates.     

Effects of Modafinil on Clonic Seizure Threshold Induced by Pentylenetetrazole in Mice: Involvement of Glutamate,Nitric oxide,GABA, and Serotonin Pathways

Epilepsy is the third most common chronic brain disorder. Modafinil is an awakening agent approved for narcolepsy. In addition to its clinical uses some reports revealed that modafinil was associated with some alterations in seizure threshold. The purpose of this study was to clarify the effect of acute administration of modafinil in clonic seizure threshold (CST) induced by pentylenetetrazole in mice and the involvement of glutamate, nitric oxide, gamma amino butyric acid (GABA), and serotonin systems in this feature. Modafinil at 80 and 150 mg/kg showed anti- and pro-convulsant effects respectively and expressed maximum anti- and pro-convulsant activities at 30 min after injection. Both modulatory effects were blunted by pretreatment of l-NAME [nonspecific nitric oxide synthase (NOS) inhibitor; 10 mg/kg, i.p.], 7-nitroindazole (a neuronal NOS inhibitor; 40 mg/kg, i.p.), and aminoguanidine (an inducible NOS inhibitor; 50 mg/kg, i.p.). Injection of the NOS precursor l-arginine (60 mg/kg, i.p.) before modafinil did not change the anti-convulsant effect, while thoroughly reversed the pro-convulsant one. Our experiments displayed that administration of diazepam (a GABA_A receptor agonist; 0.02 mg/kg, i.p.) and MK-801 (a NMDA receptor antagonist; 0.05 mg/kg, i.p.) before different doses of modafinil significantly increased CST. Finally, pretreatment of citalopram (a selective serotonin reuptake inhibitor; 0.1 mg/kg, i.p.) did not modify the convulsant activities of modafinil. Therefore, nitric oxide system may mediate anti-convulsant activity, while glutamate, nitric oxide, and GABA pathways may involve in pro-convulsant property. Serotonin receptors have no role on convulsant effects of modafinil.     

Assessment of Heavy Metals and Metalloids in Solanum tuberosum and Pisum sativum Irrigated with Urban Wastewater in the Suburbs of Sargodha City,Pakistan

Dietary exposure to heavy metals (viz., Ni, As, Fe, Cr, Mn, Co, Mo, Cu, Zn, Se, Cd, and Pb) has been recognized as a potential hazard to human health. This study investigates the level of contamination at two different sites in Pakistan, one irrigated with canal water (Site-I) and the other with urban wastewater (Site-II). At Site-II, irrigation with wastewater resulted in a significant increase in heavy metals and metalloids in soil and a subsequent build-up in two vegetables selected for study (Solanum tuberosum [potato] and Pisum sativum [pea]). Results showed that mean concentrations of heavy metals and metalloids in soil at Site-I were lower than those of Site-II. Mean concentrations of As and Cd in soil at both sites and for both vegetables were found above maximum permissible levels, while for both vegetables As at both sites and Cd, Mo, and Pb exceeded the suggested maximum levels for vegetables. High levels of some metals in the soils and vegetables could be due to unnecessary use of fertilizers and disposable water for irrigating the soils and the environmental cues prevalent in the areas, such as presence of ions that may bind the metals, often play an important role in uptake.     

Synthesis,development, characterization and effectiveness of bovine pure platelet gel‐collagen‐polydioxanone bioactive graft on tendon healing

Bovine platelet gel (BPG) is an accessible and cost‐effective source of growth factors which may have a value in tendon regenerative medicine. We produced a collagen implant (CI) as a tendon proper, covered it with polydioxanone (PDS) sheath to simulate paratenon and finally embedded the BPG as an active source of growth factor within the bioimplant to test whether BPG would be able to accelerate and enhance tendon regeneration and repair. After in vitro characterization of the bioactive grafts, the grafts were implanted in rabbit large tendon defect model. Untreated tendons and tendons treated with either CI or CI‐PDS were served as controls for the CI‐PDS‐BPG. The animals were investigated clinically, ultrasonographically and haematologically for 120 days. After euthanasia, dry matter content, water uptake and delivery characteristics and also gross morphological, histopathological and scanning electron microscopic features of the healing tendons were assessed. In vitro, the activated platelets in the scaffold, released their growth factors significantly more than the controls. BPG also increased cell viability, and enhanced cellular differentiation, maturation and proliferation inside the CI‐PDS compared with the controls. In vivo, the BPG modulated inflammation, increased quality and rate of fibroplasia and produced a remodelled tendon that had significantly higher collagen content and superior collagen fibril and fibre differentiation than controls. Treatment also significantly improved tendon water uptake and delivery characteristics, animals’ serum PDGF level, CI‐PDS biocompatibility and biodegradability and reduced peritendinous adhesions, muscle fibrosis and atrophy. BPG was effective on tendon healing and CI‐PDS‐BPG may be a valuable bioscaffold in tendon reconstructive surgery.