EDITOR’S CHOICE – Inhibitory Effects of 1,4-disubstituted Thiosemicarbazide Derivatives on Streptococcus mutans and Streptococcus sanguinis Mono-species Biofilms

Journal: Letters in Drug Design & Discovery

Author(s): Malgorzata Miazga-Karska, Maciej Wos, Agnieszka A. Kaczor, Anna Pachuta-Stec, Grazyna Ginalska, Monika Pitucha*

Graphical Abstract:



Background: Bacterial biofilms are a cause of a number of infections and are associated with specific drug resistance. In particular, dental biofilm can consist of up to 100 bacterial species and may result in the diseases in the teeth and the surrounding tissues, including dental caries and periodontal diseases. Moreover, pathogens from the dental biofilm can migrate to other organs and lead to systemic diseases. Thus, it is important to search for inhibitors of dental biofilm formation. The series of 1,4-disubstitued thiosemicarbazide derivatives were evaluated for their ability to inhibit mono-species Streptococcus mutans or Streptococcus sanguinis biofilm formation.

Methods: The Minimum Biofilm Inhibitory Concentration (MBIC) is defined as the lowest concentration of an antimicrobial agent required to inhibit the formation of biofilm. MBIC was determined spectrophotometrically. Molecular docking was performed using Glide from the Schrödinger suite of software. The grid file was generated indicating acarbose as a reference ligand. The compounds were modeled using LigPrep protocol from the Schrödinger suite of software. Molecular docking was performed using the SP (standard precision) protocol of Glide. Molecular dynamics studies of ligand-receptor complexes was performed using Desmond v.

Results: The series of 1,4-disubstituted thiosemicarbazide derivatives were synthesized and investigated for their ability to inhibit S. mutans or S. sanguinis biofilm. The most active compounds caused inhibition of S. sanguinis and S. mutans biofilm formation in the concentration of 7.81 µg/ml- 62.5 µg/ml. We showed, that growth of S. mutans and S. sanguinis biofilm was faster and higher in presence of sucrose. Additionally it was harder to inhibit the growth of biofilm in BHIbroth with the presence of sucrose, than the biofilm growing in BHI without sucrose. It seems that colonization by tested caries bacteria depends on sucrose content in medium. Based on above in vitro anti-biofilm data, we postulated that the mechanism of antibacterial activity of the investigated compounds might be connected with the inhibition of mono-species bacteria biofilm formation. In order to demonstrate that the investigated compounds may inhibit the enzyme glucansucrase and thus, biofilm formation, we performed molecular docking and molecular dynamics of the studied compounds to glucansucrase crystal structure. The obtained results reveal that the thiosemicarbazide derivatives can be used as potential inhibitors of dental biofilm formation, acting possibly through inhibition of glucansucrase.

Conclusion: In this study we showed that some of tested thiosemicarbazide derivatives can be used as potential inhibitors for mono-species cultures of S. mutans or S. sanguinis biofilm. The possible blocking mechanism of mono-species biofilm formation was proposed via molecular modelling technique. The data suggested that this mechanism may involve the glucansucrase inhibition as it was demonstrated that tested derivatives occupy the same binding pocket in this enzyme as acarbose, commonly known inhibitor of glucosylotransferases. Therefore, it is possible that tested derivatives could be used in prevention of dental caries.

Read more here: http://www.eurekaselect.com/156376/article



EDITOR’S CHOICE – Cytomegalovirus Infection: The Neurodevelopmental Peptide Signatures

Journal: Current Drug Discovery Technologies

Author(s): Guglielmo Lucchese, Darja Kanduc*

Graphical Abstract:



Background and Objective: HCMV infection may cause neurodevelopmental disorders, including intellectual disability, hearing loss, cortical malformations, and calcifications. Theorizing about the still unknown molecular basis of HCMV-related diseases, this study analyzes the peptide sharing between HCMV, strains AD169 and Merlin, and human proteins, searching for shared sequences that might lead to crossreactive autoimmune injuries in the brain during immune responses following HCMV infection.

Method: HCMV proteins were analyzed for peptides shared with the human proteome using the Pir Peptide Match resource.

Result: Numerous HCMV peptides (ranging from 9 to 13 mer in length) are disseminated through hundreds of human proteins. The peptide sharing mostly involves crucial neurodevelopmental antigens such as PITX3, implicated in the differentiation of meso-diencephalic dopaminergic neurons; SIX3, which controls proper anterioposterior patterning of the diencephalon and formation of the rostral diencephalon during forebrain development; and ZIC2, which plays a fundamental role in the early stage of organogenesis of the central nervous system.

Conclusion: This study describes a HCMV vs human peptide overlap that may represent a crossreactive platform linking the pathologic sequelae of HCMV infection to the immune anti-HCMV response. The data could inform development of effective and safe immune therapeutic/preventive approaches against HCMV infections.

Read more here: http://www.eurekaselect.com/155272/article


EDITOR’S CHOICE – Regulation of the Unfolded Protein Response in Disease

Journal: Current Immunology Reviews

Author(s): Samuel Lara-Reyna, Thomas Scambler, Jonathan Holbrook, Heledd H. Jarosz-Griffiths, Daniel Peckham, Michael F. McDermott

Graphical Abstract:



Background: The Unfolded Protein Response (UPR) is a well conserved mechanism that mammalian cells use to cope with stress and infections. This mechanism is exquisitely regulated at several levels, including post-transcriptional modifications by microRNAs. These small non-coding RNAs are mainly involved in the degradation of mRNA, thereby blocking protein translation. The finely balanced interplay between the UPR and microRNAs is altered in several disorders, contributing to both disease aetiology and pathology.

Methods: We review and explore alterations in the UPR and microRNAs in several inflammatory conditions, including bone, lung, and neurodegenerative diseases. We also evaluate the impact of these alterations on the disruption of cellular homeostasis and suggest possible therapeutic options to restore this balance.

Results: Several components of the UPR, including IRE1, ATF6, and PERK, are clearly dysregulated in inflammatory bone, lung, and neurodegenerative diseases, contributing to the inflammatory process in these disorders. XBP1s, which is downstream of IRE1, is shown to be dysregulated in several diseases, and significantly contributes to the inflammatory process. MicroRNAs show unique dysregulated signatures in each individual tissue and disorder, suggesting that these small transcripts may regulate different pathways in a cell-dependent manner. Finally, there are functional connections between these dysregulated microRNAs and the UPR, which may underlie important pathological aspects of these disorders.

Conclusion: It is evident that microRNAs regulate several components of the UPR and that these small non-coding RNAs, or other molecules that restore the UPR balance, may represent possible therapeutic options to normalise intracellular homeostasis.

Read more here: http://www.eurekaselect.com/160374/article


EDITOR’S CHOICE – An Efficient Gram Scale Synthesis of Aryl Iodides from Aryl Diazofluoroborates in Water under Mild Conditions

Journal: Letters in Organic Chemistry

Author(s): Somnath S. Gholap

Graphical Abstract:


Transition metal-free synthesis of synthetically valuable aryl iodides from aryl diazofluroborates in water under mild conditions has been described. Majority of synthesized aryl iodides are obtained in quantitative yields (>99 %) under present reaction conditions. The structural effects due to the substituents present on aryl diazofluoroborates did not show any satisfactory effect on the yields of the aryl iodides. Hence, the methodology presented here was found to be adventitious for the quantitative production of synthetically valuable aryl iodides.


Read more here: http://www.eurekaselect.com/155407/article


EDITOR’S CHOICE – Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells

Journal: Current Cancer Drug Targets

Author(s): Tiantian Zhang, Dennis H. Kordish, Yogesh R. Suryawanshi, Rob R. Eversole, Steven Kohler,Charles D. Mackenzie, Karim Essani*.

Graphical Abstract:



Background: Oncolytic viruses (OVs), which preferentially infect cancer cells and induce host anti-tumor immune responses, have emerged as an effective melanoma therapy. Tanapoxvirus (TANV), which possesses a large genome and causes mild self-limiting disease in humans, is potentially an ideal OV candidate. Interleukin-2 (IL-2), a T-cell growth factor, plays a critical role in activating T cells, natural killer (NK) cells and macrophages in both the innate and adaptive immune system.

Objective: We aimed to develop a recombinant TANV expressing mouse IL-2 (TANVΔ66R/mIL- 2), replacing the viral thymidine kinase (TK) gene (66R) with the mouse (m) mIL-2 transgene resulting in TANVΔ66R/mIL-2.

Methods: Human melanoma tumors were induced in female athymic nude mice by injecting SKMEL- 3 cells subcutaneously. Mice were treated with an intratumoral injection of viruses when the tumor volumes reached 45 ± 4.5 mm3.

Results: In cell culture, expression of IL-2 attenuated virus replication of not only TANVΔ66R/ mIL-2, but also TANVGFP. It was demonstrated that IL-2 inhibited virus replication through intracellular components and without activating the interferon-signaling pathway. Introduction of mIL-2 into TANV remarkably increased its anti-tumor activity, resulting in a more significant regression than with wild-type (wt) TANV and TANVΔ66R. Histopathological studies showed that extensive cell degeneration with a significantly increased peri-tumor accumulation of mononuclear cells in the tumors treated with TANVΔ66R/mIL-2, compared to wtTANV or TANVΔ66R.

Conclusion: We conclude that TANVΔ66R/mIL-2 is potentially therapeutic for human melanomas


Read more here: http://www.eurekaselect.com/153638/article


EDITOR’S CHOICE – ECPIRM, a Potential Therapeutic Agent for Cutaneous T-Cell Lymphoma, Inhibits Cell Proliferation and Promotes Apoptosis via a JAK/STAT Pathway

Journal: Anti-Cancer Agents in Medicinal Chemistry

Author(s): Hua Yang, Pengcheng Ma*, Yuping Cao, Mengli Zhang, Lingjun Li, Jun Wei, Lei Tao, Kun Qian

Graphical Abstract:



Background: Retinoids are important agents for the treatment of cutaneous T-cell lymphomas (CTCL). But side effects and drug resistance caused by activation of RAR/RXR limited their clinical application. Therefore, it is urgent to develop new agents to fight against CTCL. ECPIRM, a 13-cis retinoic acid derivative, was reported that it inhibited proliferation and induced apoptosis of SCL-1 cells.

Objective: The aim of this study was to evaluate the biological activities and mechanisms of ECPIEM.

Methods: The effect of ECPIRM on cell proliferation was determined by MTT assay and Trypan blue exclusion assay while FACS analysis was used to detect changes in cell cycle and apoptosis in HUT78 cells. The influence of ECPIRM on RAR/RXR and JAK/STAT signaling was evaluated by western blot analysis.

Results: ECPIRM, better than other agents (all-trans retinoic acid,13-cis-retinoic acid or bexarotene), inhibited proliferation and induced apoptosis significantly in HUT78 cells, but with little cytotoxicity on normal lymphocytes. Then ECPIRM induced G0/G1 phase arrest by decreasing the expression of cyclinD1, cyclinE, CDK2 and CDK4 while increasing p21. Furthermore, the unaffected expression of RAR and RXR members suggested that ECPIRM acted independently of RAR/RXR pathway in HUT78 cells. But decreased phosphorylation of JAK1, STAT3, STAT5 and downregulated Bcl-xL, Cyclin D1 and c-Myc indicated that ECPIRM inhibited the activation of JAK/STAT signaling.

Conclusion: ECPIRM inhibited proliferation, induced apoptosis and G0/G1 phase arrest in HUT78 cells through inhibiting JAK/STAT pathway but not RAR/RXR pathway, which presented ECPIRM as a promising candidate for the treatment of CTCL patients.

Read more here: http://www.eurekaselect.com/151116/article



EDITOR’S CHOICE – Stereoselective Reactions Catalyzed by N-Heterocyclic Carbenes

Journal: Mini-Reviews in Organic Chemistry

Author(s):  Xiao-Hua Cai*, Bing Xie

Graphical Abstract:



N-Heterocyclic carbenes (NHCs) as one of the most powerful reagents, ligands and organocatalysts for various reactions have been widely used in modern synthetic applications. Especially, the chiral NHCs have attracted intense attention in stereoselective reactions from synthetic chemists based on their highly efficiency and unique catalytic properties with excellent diastereoselectivity and enantioselectivity. A great deal of exciting achievements in the synthesis and applications of chiral NHC catalysts have been attained over the past decades. This review will mainly summarize recent advances in the chiral NHC-catalysed stereoselective reactions according to the use of NHCs including the generation of equivalents acyl anions, homoenolates, azolium enolates/acyl azoliums and oxidative NHC catalysis.

Read more here: http://www.eurekaselect.com/156466/article


EDITOR’S CHOICE – Manganese Peroxidase from Luffa acutangula Fruit Juice

Journal: Current Biochemical Engineering

Author(s): N. Rai, M. Yadav*, H.S. Yadav

Graphical Abstract:



Background: Only one manganese peroxidase from Musa paradisiaca leaf has been purified and characterized but from other plant sources are still to be reported with efficient manganese peroxidase activity.

Objective: To assay enzyme activity and to study the enzymatic properties like Km, pH optima and temperature optima of the manganese peroxidase present in Luffa acutangula fruit juice. To study the nature of inhibition by different inhibitors on manganese peroxidase.

Method: Fresh L. acutangula fruit was cut, crushed, squeezed and centrifuged to get the clear juice extract. Manganese peroxidase activity was assayed and the steady state enzyme kinetics of the MnP catalysed reaction was studied spectrophotometrically at λ=270nm. The pH optima and the temperature optima of the enzyme was determined by measuring the steady state velocity of enzyme catalysed reaction in reaction solutions of varying pH and at varying temperature. The steady state velocity of enzyme catalyzed reaction was monitored at different concentrations of inhibitors.

Results: The Michaelis Menten constants for the enzyme for Mn(II) and H2O2 were 22µM and 20µM. The pH and temperature optima of the enzyme were 4 and 22 °C. Sodium azide showed uncompetitive type whereas ethylenediamine and ethylenediamine tetra acetic acid showed competitive type of inhibition.

Conclusion: It is the second manganese peroxidase reported from a plant source. The enzymatic properties are similar to manganese peroxidase from Musa paradisiaca stem juice and other reported fungal manganese peroxidases.

Read more here: http://www.eurekaselect.com/149356/article


EDITOR’S CHOICE – Crystalline Ethylene Oxide and Propylene Oxide Triblock Copolymer Solid Dispersion Enhance Solubility, Stability and Promoting Time- Controllable Release of Curcumin

JOURNAL: Recent Patents on Drug Delivery & Formulation

AUTHOR(S): Thais F.R. Alves, Franciely C.C. das Neves Lopes, Marcia A. Rebelo, Juliana F. Souza, Katiusca da Silva Pontes, Carolina Santos, Patricia Severino, Jose M.O. Junior, Daniel Komatsu, Marco V. Chaud

Graphical Abstract:



Aims and Background: The design and development of an effective medicine are, however, often faced with a number of challenges. One of them is the close relationship of drug’s bioavailability with solubility, dissolution rate and permeability. The use of curcumin’s (CUR) therapeutic potential is limited by its poor water solubility and low chemical stability. The purpose was to evaluate the effect of polymer and solid dispersion (SD) preparation techniques to enhance the aqueous solubility, dissolution rate and stability of the CUR. The recent patents on curcumin SD were reported as (i) curcumin with polyvinylpyrrolidone (CN20071 32500 20071214, WO2006022012 and CN20151414227 20150715), (ii) curcumin-zinc/polyvinylpyrrolidone (CN20151414227 20150715), (iii) curcumin-poloxamer 188 (CN2008171177 20080605), (iv) curcumin SD prepared by melting method (CN20161626746-20160801).

Materials and Methods: SD obtained by co-preciptation or microwave fusion and the physical mixture of CUR with Poloxamer-407 (P-407), Hydroxypropylmetylcellulose-K4M (HPMC K4M) and Polyvinylpyrrolidone-K30 (PVP-K30) were prepared at the ratios of 1:2; 1:1 and 2:1. The samples were evaluated by solubility, stability, dissolution rate and characterized by SEM, PXRD, DSC and FTIR.

Results: The solubility, stability (pH 7.0) and dissolution rate were significantly greater for SD (CUR:P-407 1:2). The PXRD,SEM and DSC indicated a change in the crystalline state of CUR. The enhancement of solubility was dependent on a combination of factors including the weight ratio, preparation techniques and carrier properties. The drug release data fitted well with the Weibull equation, indicating that the drug release was controlled by diffusion, polymer relaxation and erosion occurring simultaneously.

Conclusion: Thus, these SDs, specifically CUR:P-407 1:2 w/w, can overcome the barriers of poor bioavailability to reap many beneficial properties.

Read more here: http://www.eurekaselect.com/159171/article



EDITOR’S CHOICE – Deciphering the Role of microRNAs in Regulation of Immune Surveillance, Self-Tolerance and Allograft Transplant Outcome

Journal: Current Stem Cell Research & Therapy

Author(s): Cherry S. Leung, Song Lu, Jiatao Li, William KK Wu, Kathy O. Lui


MicroRNAs are small non-coding RNAs that can modulate gene expression at posttranscriptional level, and they participate in almost all important biological processes. Immune system is elaborately regulated to maintain the equilibrium between immunity and tolerance. Recent studies have revealed significant functions of microRNAs in the maintenance of immune homeostasis using both cell and transgenic mouse models. In collaboration with various transcriptional factors and cytokines, microRNAs constitute an effective and flexible regulatory network governing the development and activation of immune cells; as well as maintenance of immune tolerance. In this review, microRNAs involved in T cell development, proliferation, and lineage differentiation will be summarized. Based on current knowledge, the function of microRNAs in establishing and maintaining immune tolerance will also be discussed in relation to determining the outcome of allograft transplantation.

Read more here: http://www.eurekaselect.com/138941/article