<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

Ferrocene-based compounds have recently gained widespread importance in cancer treatment becuase of their lower toxicity and cost-effective synthesis. However, ferrocene-based compounds do not exist in nature. Moreover, the synthesis of thianes containing ferrocene is quite rare. In the recent past, our group has reported iodine catalyzed synthesis of ferrocenated benzothiazole and β-ketooxothioacetal by the thermal reaction of ferrocenated β-chlorocinnamaldehyde with 2-aminothiophenol and 2-mercaptoethanol respectively.The molecular structure of both the compounds is quite interesting due to the presence of ferrocene which makes them highly important from an anticancer point of view. In this script, the synergistic effect of ferrocene and thiol has been observed in ferrocene functionalized thiols (Fenton reagents) for tumour growth suppression. The anticancer properties of both the compounds separately as well as in combination show a significant anticancer effect on cancer cell lines HCT116 (Colon), A549 (lung cancer), and MCF7 (Breast cancer). Both compounds and their combinations reflect cell death by generating ROS and depolarization of mitochondrial membrane potential. Gene expression profiling and protein expression studies of apoptosis-related genes (cleaved caspase 9, cleaved caspase 3, cleaved PARP and Bcl-2) were also evaluated. Results indicated that ferrocenated benzothiozole and β-ketooxothioacetal induced apoptosis through oxidative stress-mediated activation of intrinsic apoptosis pathway by generating intracellular ROS, loss of MMP, and alteration of expression of genes related to apoptosis. In addition, the anti-metastatic activity of benzothiozole and β-ketooxothioacetal was seen by wound healing assay showing anti-migratory properties. The properties like anti metastatic activity, cytotoxicity and showing synergistic effect when used in combination make benzothiozole and β-ketooxothioacetal potent platforms for the development of new anticancer agents. Benzothiazole and β-ketooxothioacetal can replace existing organometallic compounds with rare metals like platinum, due to their higher stability, lower cost, and lower toxicity. © 2022

World University root node

Life Sciences

(SoNS) School of Natural Sciences

Journal of Organometallic Chemistry

Evaluation of anticancer activity of ferrocene based benzothiazole and β-ketooxothioacetal

Cancer is the second most common cause of deaths worldwide after noncommunicable diseases. Hepatocellular carcinoma (HCC) is the fourth most deadly type of cancer worldwide. The reasons for this high rate of mortality are linked to the heterogeneity of HCC, late detection, and development of resistance to therapies. This chapter focuses on drug resistance in HCC. This chapter briefly explains the molecular signaling pathways and their role in drug resistance. This chapter further discusses cancer stem cells, stem cell markers, signaling pathways and transcription factors that regulate stem cell-mediated drug resistance in HCC. © 2022 Elsevier Inc. All rights reserved.

Theranostics and Precision Medicine for the Management of Hepatocellular Carcinoma, Volume 2: Diagnosis, Therapeutic Targets, and Molecular Mechanisms

Molecular signaling and its role in drug resistance in hepatocellular carcinomas

Chemotherapy is a general treatment procedure for cancer. The diversity in cancer incidence and the failure of therapy due to chemoresistance lead to increased cancer-related deaths. Therefore, new drugs with fewer secondary complications targeting diverse pathways are the need of the hour. Geranyl isovalerate (GIV), one of the active ingredients of ethyl acetate fraction of Argyreia nervosa is routinely used as a food flavoring agent. In this study, we found that GIV also exhibits anticancer activity when tested against the HCT116 cell line. It influenced the viability of the cells in a dose- and time-dependent manner. We examined whether GIV could induce oxidative stress and affect the mitochondrial membrane potential, thereby leading to apoptosis induction. Moreover, GIV could suppress the expression of antiapoptotic genes, such as BCl2 and PARP, and induce the expression of proapoptotic genes, such as Caspase 3 and 9. This is the first study demonstrating the anticancer activity of GIV and providing evidence for its mechanism of action. In conclusion, this study proposes GIV as a potential lead or supplementary molecule in treating and preventing colorectal cancer (CRC). Based on our findings, we conclude that GIV may be a viable lead or supplementary molecule for treating and preventing CRC. © Copyright © 2021 Rasool, Sharma, Anand, Magani and Tantravahi.

Fulltext

Frontiers in Pharmacology

Evaluation of the Anticancer Properties of Geranyl Isovalerate, an Active Ingredient of Argyreia nervosa Extract in Colorectal Cancer Cells

<p>Two new arene ruthenium(II) complexes with chemical formula [Ru2(η6-p-cymene)2(μ-L1)(μ-Cl)Cl2] [Ru]-1 and [Ru(η6-p-cymene)(L2)Cl2] [Ru]-2 (L1 = 5-phenyl-2H-tetrazole and L2 = 2-(2H-tetrazol-5-yl)pyridine) were synthesized by the reaction of [{(η6-p-cymene)RuCl2}2] with two bidentate ligands L1 and L2. Both the complexes were structurally characterized using single-crystal X-ray diffraction and other analytical techniques. The X-ray crystal structures of both the complexes revealed the coordination of tetrazolate ligands to two Ru(II) centres in bridging mode in [Ru]-1, whereas one Ru(II) centre in [Ru]-2 in chelating fashion, with overall pseudo-octahedral geometry. The resulted complexes were screened for their cytotoxic activity against three different cancer cell lines, HCT116 (colon cancer), HepG2 (liver cancer) and MCF7 (breast cancer) under in vitro conditions. Interestingly, [Ru]-1 showed much higher cytotoxicity with respect to [Ru]-2 against all the screened cancer cell lines and even better than cisplatin. For exploring the mechanism of action of [Ru]-1, reactive oxygen species (ROS) production, alterations in mitochondrial membrane potential and gene expression profiling of apoptosis related genes (Bcl2, caspase-3 and caspase-9) were also evaluated. The cancerous cells treated with [Ru]-1 showed an increase in intracellular ROS levels, disruption of mitochondrial membrane potential, up-regulation of proapoptotic caspase-3 and caspase-9 and down-regulation of antiapoptotic Bcl2. The results concluded that [Ru]-1 induced apoptosis through oxidative stress mediated activation of intrinsic pathway by generating intracellular ROS, loss of MMP and alteration of expression of apoptosis related genes. In addition, antimetastatic activity of [Ru]-1 was observed by wound healing assay showing anti-migratory property. The dual properties, antimetastatic activity and high cytotoxicity make [Ru]-1 potent platform for the development of new anticancer agents. © 2021 John Wiley &amp; Sons, Ltd.</p>

Applied Organometallic Chemistry

In vitro evaluation of cytotoxicity and antimetastatic properties of novel arene ruthenium(II)-tetrazolato compounds on human cancer cell lines

Here, we report the toxic effects of various imidazolium-based ionic liquids (ILs) with varying hydrocarbon chain lengths, on different human cell lines. Multiple biological assays have shown that the ILs with long hydrocarbon chains have stronger adverse effect especially on human liver cancer cells (Huh-7.5 cells). Further, our study has confirmed that the ILs induce necrosis dependent cell death and that it is related to cell membrane damage. To understand the molecular mechanism of such an effect, the cellular membranes were mimicked as lipid monolayers formed at the air-water interface and then as lipid bilayer vesicles. The pressure area-isotherms measured from the monolayer have shown that the interaction of ILs with the lipid layer is energetically favourable. The addition of these ILs reduces the in-plane elasticity of the self-assembled molecular layer. Quasielastic neutron scattering data clearly indicate that ILs in liver lipid vesicles significantly affects the dynamics of the lipid, in particular, the lateral motion of the lipids. It has been concluded that the mammalian cell death induced by these ILs is due to the modulated structure and altered physical properties of the cellular membrane. © 2019 Elsevier B.V.

Physics

Biochimica et Biophysica Acta - Biomembranes

Imidazolium-based ionic liquids cause mammalian cell death due to modulated structures and dynamics of cellular membrane

Background: Salidroside is a glucoside of tyrosol found mostly in the roots of Rhodiola spp. It exhibits diverse biological and pharmacological properties. In the last decade, enormous research is conducted to explore the medicinal properties of salidroside; this research reported many activities like anti-cancer, anti-oxidant, anti-aging, anti-diabetic, anti-depressant, anti-hyperlipidemic, anti-inflammatory, immunomodulatory, etc. Objective: Despite its multiple pharmacological effects, a comprehensive review detailing its metabolism and therapeutic activities is still missing. This review aims to provide an overview of the metabolism of salidroside, its role in alleviating different metabolic disorders, diseases and its molecular interaction with the target molecules in different conditions. This review mostly concentrates on the metabolism, biological activities and molecular pathways related to various pharmacological activities of salidroside. Conclusion: Salidroside is produced by a three-step pathway in the plants with tyrosol as an intermediate molecule. The molecule is biotransformed into many metabolites through phase I and II pathways. These metabolites, together with a certain amount of salidroside may be responsible for various pharmacological functions. The salidroside based inhibition of PI3k/AKT, JAK/ STAT, and MEK/ERK pathways and activation of apoptosis and autophagy are the major reasons for its anti-cancer activity. AMPK pathway modulation plays a significant role in its anti-diabetic activity. The neuroprotective activity was linked with decreased oxidative stress and increased antioxidant enzymes, Nrf2/HO-1 pathways, decreased inflammation through suppression of NF-κB pathway and PI3K/AKT pathways. These scientific findings will pave the way to clinically translate the use of salidroside as a multi-functional drug for various diseases and disorders in the near future. © 2020, Bentham Science Publishers. All rights reserved.

Current Drug Metabolism

Salidroside-can it be a multifunctional drug?

Tropical Calcific Pancreatitis (TCP) is a neglected juvenile form of chronic nonalcoholic pancreatitis. Cathepsin B (CTSB), a lysosomal protease involved in the cellular degradation process, has recently been studied as a potential candidate gene in the pathogenesis of TCP. According to the Cathepsin B hypothesis, mutated CTSB can lead to premature intracellular activation of trypsinogen, a key regulatory mechanism in pancreatitis. So far, CTSB mutations have been studied in pancreatitis and neurode-generative disorders, but little is known about the structural and functional effect of variants in CTSB. In this study, we investigated the effect of single nucleotide variants (SNVs) specifically associated with TCP, using molecular dynamics and simulation algorithms. There were two non-synonymous variants (L26V and S53G) of CTSB, located in the propeptide region. We tried to predict the effect of these variants on structure and function using multiple algorithms: SIFT, Polyphen2, PANTHER, SDM sever, i-Mutant2.0 suite, mCSM algorithm, and Vadar. Further, using databases like miRdbSNP, PolymiRTS, and miRNASNP, two SNPs in the 30UTR region were predicted to affect the miRNA binding sites. Structural mutated models of nsSNP mutants (L26V and S53G) were prepared by MODELLER v9.15 and evaluated using TM-Align, Verify 3D, ProSA and Ramachandran plot. The 3D mutated structures were simulated using GROMACS 5.0 to predict the impact of these SNPs on protein stability. The results from in silico analysis and molecular dynamics simulations suggested that these variants in the propeptide region of Cathepsin B could lead to structural and functional changes in the protein and thus could be pathogenic. Hence, the structural and functional analysis results have given interim conclusions that these variants can have a deleterious effect in TCP pathogenesis, either uniquely or in combination with other mutations. Thus, it could be extrapolated that Cathepsin B gene can be screened in samples from all TCP patients in future, to decipher the distribution of variants in patients. Copyright 2019 Singh et al.

PeerJ

Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics

Tropical calcific pancreatitis (TCP) is a juvenile, non-alcoholic form of chronic pancreatitis with its exclusive presence in tropical regions associated with the low economic status. TCP initiates in the childhood itself and then proliferates silently. mutTCPdb is a manually curated and comprehensive disease specific single nucleotide variant (SNV) database. Extensive search strategies were employed to create a repository while SNV information was collected from published articles. Several existing databases such as the dbSNP, Uniprot, miRTarBase2.0, HGNC, PFAM, KEGG, PROSITE, MINT, BIOGRID 3.4 and Ensemble Genome Browser 87 were queried to collect information specific to the gene. mutTCPdb is running on the XAMPP web server with MYSQL database in the backend for data storage and management. Currently, the mutTCPdb enlists 100 variants of all 11 genes identified in TCP, out of which 45 are non-synonymous (missense, nonsense, deletions and insertions), 46 are present in non-coding regions (UTRs, promoter region and introns) and 9 are synonymous variants. The database is highly curated for disease-specific gene variants and provides complete information on function, transcript information, pathways, interactions, miRNAs and PubMed references along with remarks. It is an informative portal for clinicians and researchers for a better understanding of the disease, as it may help in identifying novel targets and diagnostic markers, hence, can be a source to improve the strategies for TCP management. © The Author(s) 2018. Published by Oxford University Press.

Database

MutTCPdb: A comprehensive database for genomic variants of a tropical country neglected disease - Tropical calcific pancreatitis

Autoimmunity and cancer have a multifarious epidemiology. Often, it is because of an impaired genome, culminating in functional aberrations in the human system. Systemic lupus erythematosus (SLE) is a heterogeneous complex disease which ensues due to the failure of the immune system to distinguish between self and non-self antigens, thus producing autoantibodies against DNA, RNA and proteins. Cancer, the other side of the same coin, results from an excessive proliferation of cells that evade immune regulation as a result of incompetent defense by T-cells, B-cells and macrophages. Recent findings have indicated that lupus autoantibodies could be used as an effective weapon to kill cancerous cells. This is an attempt to take an account of malicious 'lupus autoantibodies' and their role in neutralizing cancerous cells which may help in enhancing the survival rate of cancer patients, hence, killers can be saviors. © 2016 SAGE Publications.

Lupus

Can killers be saviors?

Sorafenib is a small molecule, multi-kinase inhibitor used as an anti-cancer drug for treatment of Liver and Kidney cancers. It is reported to be in phase 2 clinical trials for colorectal cancer (CRC). This drug was reported to inhibit both surface associated and intracellular kinases such as Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), Fibroblast Growth Factor Receptor (FGFR), RAF, BRAF etc. This was shown to be effective against both mutant and wild type BRAF. There are some preliminary clinical reports of patients showing resistance to this drug on long-term usage. Our study aims at developing a resistant cell line model for the above drug and to understand the pathways and mechanisms involved in resistance development. Resistant model of HCT-116 cell line was developed by continuously culturing parental cell line in the presence of the drug. The IC50 values were compared between the parental cells and the cells exposed to drug continuously. BCL2 an anti-apoptotic protein was seen overexpressed in resistant cells in contrast to decreased expression in parental cells supporting the development of resistance.Further the multidrug resistance proteins MDR1 and ABCG-2 are highly up regulated in resistance model reconfirming the resistance development. This study aims at understanding how the JAK-STAT signaling pathway is modulated during drug resistance by expression profiling of molecules from this pathway by real time PCR. In this study, we found that JAK-STAT pathway is suppressed in the parental cells when treated with the sorafenib, but found actively expressed in resistant model. JAK-STAT signaling pathway is known to be activated in cancers and helps in regular proliferation of cancer cells. But as noticed from the above results upon drug treatment in parental cells this pathway get suppressed thereby leading to cell death. The active involvement of JAK-STAT pathway, which supports proliferation, was seen over expressed in drug resistance model.

Biochemical and Cellular Archives

Role of Jak-Stat signaling in sorafenib resistant HCT-116 cells

Cancer of large intestine is commonly referred as colorectal cancer, which is also the third most frequently prevailing neoplasm across the globe. Though, much of work is being carried out to understand the mechanism of carcinogenesis and advancement of this disease but, fewer studies has been performed to collate the scattered information of alterations in tumorigenic cells like genes, mutations, expression changes, epigenetic alteration or post translation modification, genetic heterogeneity. Earlier findings were mostly focused on understanding etiology of colorectal carcinogenesis but less emphasis were given for the comprehensive review of the existing findings of individual studies which can provide better diagnostics based on the suggested markers in discrete studies. Colon Rectal Cancer Gene Database (CoReCG), contains 2056 colon-rectal cancer genes information involved in distinct colorectal cancer stages sourced from published literature with an effective knowledge based information retrieval system. Additionally, interactive web interface enriched with various browsing sections, augmented with advance search facility for querying the database is provided for user friendly browsing, online tools for sequence similarity searches and knowledge based schema ensures a researcher friendly information retrieval mechanism. Colorectal cancer gene database (CoReCG) is expected to be a single point source for identification of colorectal cancer-related genes, thereby helping with the improvement of classification, diagnosis and treatment of human cancers. © The Author(s) 2016.

CoReCG: A comprehensive Database of genes associated with colon-rectal cancer

The currently available anthrax vaccines are limited by being incompletely characterized, potentially reactogenic and have an expanded dosage schedule. Plant based vaccines offer safe alternative for vaccine production. In the present study, we expressed domain IV of Bacillus anthracis protective antigen gene [PA(dIV)] in planta (by nuclear agrobacterium and chloroplast transformation) and E. coli [rPA(dIV)]. The presence of transgene and the expression of PA(dIV) in planta was confirmed by molecular analysis. Expression levels up to 5.3% of total soluble protein (TSP) were obtained with AT rich (71.8% AT content) PA(dIV) gene in transplastomic plants while 0.8% of TSP was obtained in nuclear transformants. Further, we investigated the protective response of plant and E. coli derived PA(dIV) in mice by intraperitoneal (i.p.) and oral immunizations with or without adjuvant. Antibody titers of &gt;104 were induced upon i.p. and oral immunizations with plant derived PA(dIV) and oral immunization with E. coli derived PA(dIV). Intraperitoneal injections with adjuvanted E. coli derived PA(dIV), generated highest antibody titers of &gt;105. All the immunized groups demonstrated predominant IgG1 titers over IgG2a indicating a polarized Th2 type response. We also evaluated the mucosal antibody response in orally immunized groups. When fecal extracts were analyzed, low sIgA titer was demonstrated in adjuvanted plant and E. coli derived PA(dIV) groups. Further, PA(dIV) antisera enhanced B. anthracis spore uptake by macrophages in vitro and also demonstrated an anti-germinating effect suggesting a potent role at mucosal surfaces. The antibodies from various groups were efficient in neutralizing the lethal toxin in vitro. When mice were challenged with B. anthracis, mice immunized with adjuvanted plant PA(dIV) imparted 60% and 40% protection while E. coli derived PA(dIV) conferred 100% and 80% protection upon i.p. and oral immunizations. Thus, our study is the first attempt in highlighting the efficacy of plant expressed PA(dIV) by oral immunization in murine model. © 2011 Elsevier Ltd.