Sanjukta Mukherjee

Background: Imperata cylindrica is a medicinal spice used in traditional medicine to cure several ailments including cancer, wounds, hypertension, and inflammation. The current study aimed to compile phytochemicals and pharmacological data on Imperata cylindrica. Methods: A bibliographic study was carried out by analyzing conventional textbooks, authentic published studies, and consulting wide-reaching accepted scientific databases. In this review, an attempt is being made to establish an up-to-date chemical profile of I. cylindrica and the classification of its compounds in the main classes of plant secondary metabolites. Moreover, our study highlights the traditional usage of I. cylindrica and the reported investigations regarding the pharmacological properties of this plant. Results: The 43 phytochemicals isolated by various investigators mainly from the roots of I. cylindrica could be classified as bioactive phenolic compounds (coumarins, flavonoids, phenols, lignan glycosides, nor-lignans, phenolic acids, and aurone), few of them also belong to the group of terpenoids (sesquiterpenoids and triterpenoids), steroids and phytosterols. Based on the examined published data, the roots, and leaves of I. cylindrica are outstanding cytotoxic agents against several sensitive and resistant primary cancers through apoptosis induce, G1 cell cycle arrest (roots), and G2/M cell cycle arrest (leaves). Moreover, the root extract prevents metastasis invasion through inhibition of the PI3K/AKT/Snail pathway and the epithelial to mesenchymal transition (EMT) process via modulation of certain key genes. I. cylindrica tackles the growth of sensitive and multidrug-resistant (MDR) pathogenic microorganisms from various species and potentiates the antimicrobial activities of certain families of antibiotics towards MDR bacterial strains. The plant also has significant antihypertensive, anti-hyperglycemic, anti-parasitic, antioxidant activity, and several other pharmacological properties. Various studies characterized the Imperata cylindrica root extract as non-toxic to humans by oral route. Conclusion: From the outcome of this review, I. cylindrica is a potent candidate for drug formulation against primary and metastatic cancers, some drug-resistant microbial infections, and hypertension.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, a major subset of which is caused by the clonal integration of Merkel Cell Polyomavirus (MCV). Recent studies by Cheng et al. (2017) reported that virus-derived small T antigen protein-bound EP400 complex drives expression of genes essential for cellular transformation. On close analysis of their ChIP-Seq data, we uncovered that the complex binds to the promoter region of the microRNA-183 cluster. The miRNA183 cluster is a cluster of 3 miRNAs (miR183, 182 & 96) expressed and regulated together. These miRNAs are conserved across species, highly expressed in human embryonic stem cells and necessary for sensory/ mechanosensory organ development. We hypothesized that the MCV oncoproteins regulate host miRNA expression directly; an interaction novel in polyomaviruses. We tested miRNA expression via qPCR in both virus positive and negative MCC cell lines and found the former showed a much higher level. Further, fibroblasts expressing T antigens displayed an increase in miR182 expression in comparison to control. Knock-down of T antigens in MCC cells correspondingly decreased miR182 levels. To investigate its regulation we performed luciferase assays for the miRNA predicted promoter that showed increased activity in the presence of T antigens. Intriguingly, the seed sequence of miR182 completely matches to a piRNA called piR62011. Upon reanalysis of a MCC small RNA library, piR62011 emerged as the highest expressed. We found it expressed in MKL-1, a MCV positive cell line as well. Finally, to translate our findings into therapy for MCC, we screened small molecule (CMBL) library by performing surface plasmon resonance (SPR) assay and identified small molecules that binds to pre-miRNA182 and are testing them for their activity to kill MCC.

MiRNAs (miRs) have been proven to be well-validated therapeutic targets. Emerging evidence has demonstrated that intricate, intrinsic and paradoxical functions of miRs are context-dependent because of their multiple upstream regulators, broad spectrum of downstream molecular targets and distinct expression in various tissues, organs and disease states. Targeted therapy has become an emerging field of research. One key for the development of successful miR-based/targeted therapy is to acquire integrated knowledge of its regulatory network and its association with disease phenotypes to identify critical nodes of the underlying pathogenesis. Herein, we systematically summarized the comprehensive role of miR-24-3p (miR-24), along with its passenger strands miR24-1-5p* (miR-24-1) and miR-24-2-5p* (miR-24-2), emphasizing their microenvironment, intracellular targets, and associated gene networks and regulatory phenotypes in 18 different cancer types and 13 types of other disorders. MiR-24 targets and regulates numerous genes in various cancer types and enhances the expression of several oncogenes (e.g., cMyc, BCL2 and HIF1), which are challenging in terms of druggability. In contrast, several tumor suppressor proteins (p21 and p53) have been reported to be downregulated by miR-24. MiR-24 also regulates the cell cycle and is associated with numerous cancer hallmarks such as apoptosis, proliferation, metastasis, invasion, angiogenesis, autophagy, drug resistance and other diseases pathogenesis. Overall, miR-24 plays an emerging role in the diagnosis, prognosis and pathobiology of various diseases. MiR-24 is a potential target for targeted therapy in the era of precision medicine, which expands the landscape of targetable macromolecules, including undruggable proteins.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a limited expansion of CGG repeats in the FMR1 gene. Degeneration of neurons in FXTAS cell models can be triggered by accumulation of polyglycine protein (FMRpolyG), a by-product of translation initiated upstream to the repeats. Specific aims of our work included testing if naphthyridine-based molecules could (i) block FMRpolyG synthesis by binding to CGG repeats in RNA, (ii) reverse pathological alterations in affected cells and (iii) preserve the content of FMRP, translated from the same FMR1 mRNA. We demonstrate that cyclic mismatch binding ligand CMBL4c binds to RNA structure formed by CGG repeats and attenuates translation of FMRpolyG and formation of nuclear inclusions in cells transfected with vectors expressing RNA with expanded CGG repeats. Moreover, our results indicate that CMBL4c delivery can reduce FMRpolyG-mediated cytotoxicity and apoptosis. Importantly, its therapeutic potential is also observed once the inclusions are already formed. We also show that CMBL4c-driven FMRpolyG loss is accompanied by partial FMRP reduction. As complete loss of FMRP induces FXS in children, future experiments should aim at evaluation of CMBL4c therapeutic intervention in differentiated tissues, in which FMRpolyG translation inhibition might outweigh adverse effects related to FMRP depletion.

Imperata cylindrica is traditionally used to cure several diseases including cancer, wounds, and hypertension. The present study was designed to investigate the anticancer activity of the methanolic root extract of I. cylindrica (IC‐MeOH). The water‐soluble tetrazolium‐1 and colony formation assays were used to check the proliferation ability of the cells. Cell apoptosis and cell cycle were measured by flow cytometry‐based fluorescence‐activated cell sorting. The ultrahigh‐performance liquid chromatography‐high‐resolution mass spectrometry (UHPLC‐HRMS) analysis was used for the metabolites profiling of IC‐MeOH. Based on high‐mass accuracy, spectral data, and previous reports, tentative compound identifications were assigned. Our findings revealed that IC‐MeOH inhibited the proliferation of HeLa and CaSki cells. The plant extract was also found to induce a concentration‐ and time‐dependent apoptosis and cell cycle arrest in the G0/G1 phase (IC₅₀ value) in CaSki cell line. Analysis of IC‐MeOH permitted the identification of 10 compounds already reported for their anticancer activity, epicatechin, curcumin, (‐)‐yatein, caffeic acid, myricetin, jatrorrhizine, harmaline, cinnamaldehyde, dobutamine, and syringin. In conclusion, IC‐MeOH is a rich source of cytotoxic metabolites that inhibits human cervical cancer proliferation via apoptosis and cell cycle arrest.

Cyclophane‐containing bis(2‐amino‐1,8‐naphthyridine) moieties attached to variable linkers at the C2‐position (linker B) were synthesized as cyclic mismatch‐binding ligands (CMBLs). Ring‐closing metathesis (RCM) is used as a key step for the introduction of double bonds at the linker B. Decreasing the size of the linker of the substrate, formation of the RCM products with an increasing trans/cis (E/Z) ratio was observed with moderate to high overall yields. Concentration‐dependent fluorescence spectra were observed for CMBLs with longer linkers (n=3), whereas concentration‐independent spectra were observed for CMBLs with shorter linkers (n=2 and/or 1) with a marked exception of the E‐alkene 6 a. Concomitant changes in the absorption as well as in the fluorescence spectra were also observed for the CMBLs with an increasing hydrophobicity of the solvent. Absorption and fluorescence spectra of the CMBLs in solutions containing 99–100 % methanol resembled to that of the monomer. The binding behavior of these CMBLs with repeat DNA structures was investigated by using a surface plasmon resonance (SPR) assay and circular dichroism (CD) spectra. The cyclic E‐alkenes 1 a (n=3) and 3 a (n=2) show an orthogonal binding relationship with d(CCTG)₉ and d(CAG)₉. However, the selectivity for the cyclic Z‐alkenes increased with decreasing the length of the linker from compound 2 b (n=3) to compound 7 b (n=1). These compounds display a large molecular diversity, which allowed the tuning of the binding affinity and selectivity of the CMBLs by varying the linkers towards various biologically significant repeat DNA structures.