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Mycalin A, a polybrominated C15 acetogenin isolated from the encrusting sponge Mycale rotalis, displays an antiproliferative activity on human melanoma (A375) and cervical adenocarcinoma (HeLa) cells and induces cell death by an apoptotic mechanism. Various analogues and degraded derivatives of the natural substance have been prepared. A modification of the left-hand part of the molecule generates the most active substances. A structurally simplified lactone derivative of mycalin A, lacking the C1–C3 side chain, is the most active among the synthesized compounds exhibiting a strong cytotoxicity on both A375 and HeLa cells but not but not on human dermal fibroblast (HDF) used as healthy cells. Further evidence on a recently discovered chlorochromateperiodate-catalyzed process, used to oxidise mycalin A, have been collected.

The dynamics of cellular heat production and propagation remains elusive at a subcellular level. Here we report the first small molecule fluorescent thermometer selectively targeting the endoplasmic reticulum (ER thermo yellow), with the highest sensitivity reported so far (3.9%/°C). Unlike nanoparticle thermometers, ER thermo yellow stains the target organelle evenly without the commonly encountered problem of aggregation and successfully demonstrates the ability to monitor intracellular temperature gradients generated by external heat sources in various cell types. We further confirm the ability of ER thermo yellow to monitor heat production by intracellular Ca 2+ changes in HeLa cells. Our thermometer anchored at nearly-zero distance from the ER, i.e. the heat source, allowed the detection of the heat as it readily dissipated and revealed the dynamics of heat production in real time at a subcellular level.

HeLa is the most widely used model cell line for studying human cellular and molecular biology. To date, no genomic reference for this cell line has been released, and experiments have relied on the human reference genome. Effective design and interpretation of molecular genetic studies performed using HeLa cells require accurate genomic information. Here we present a detailed genomic and transcriptomic characterization of a HeLa cell line. We performed DNA and RNA sequencing of a HeLa Kyoto cell line and analyzed its mutational portfolio and gene expression profile. Segmentation of the genome according to copy number revealed a remarkably high level of aneuploidy and numerous large structural variants at unprecedented resolution. Some of the extensive genomic rearrangements are indicative of catastrophic chromosome shattering, known as chromothripsis. Our analysis of the HeLa gene expression profile revealed that several pathways, including cell cycle and DNA repair, exhibit significantly different expression patterns from those in normal human tissues. Our results provide the first detailed account of genomic variants in the HeLa genome, yielding insight into their impact on gene expression and cellular function as well as their origins. This study underscores the importance of accounting for the strikingly aberrant characteristics of HeLa cells when designing and interpreting experiments, and has implications for the use of HeLa as a model of human biology.

Key message Atropa acuminata aqueous leaf extract biosynthesized silver nanoparticles showed strong antioxidant, anticancerous (HeLa cells) and anti-inflammatory activities. Besides, this bio syn-AgNP also proved effective against mosquito vectors causing malaria, dengue and filariasis. Present study highlights eco-friendly and sustainable approach for the synthesis of silver nanoparticles (AgNP) using aqueous leaf extract of A. acuminata , a critically endangered medicinal herb. The addition of 1 mM silver nitrate to aqueous leaf extract resulted in the synthesis of AgNP when solution was heated at 60 °C for 30 min at pH 7. Absorption band at 428 nm, as shown by UV–Vis spectroscopy confirmed the synthesis of AgNP. XRD patterns revealed the crystalline nature of AgNP and TEM analysis showed that most of the nanoparticles were spherical in shape. Zeta potential of AgNP was found to be − 33.5 mV which confirmed their high stability. FT-IR investigations confirmed the presence of different functional groups involved in the reduction and capping of AgNP. The synthesized AgNP showed effective DPPH (IC 50 —16.08 µg/mL), H 2 O 2 (IC 50 —25.40 µg/mL), and superoxide (IC 50 —21.12 µg/mL) radical scavenging activities. These plant-AgNP showed significant inhibition of albumin denaturation (IC 50 —12.98 µg/mL) and antiproteinase activity (IC 50 —18.401 µg/mL). Besides, biosynthesized AgNP were found to have strong inhibitory effect against a cervical cancer (HeLa) cell line (IC 50 —5.418 µg/mL) as well as larvicidal activity against 3rd instar larvae of Anopheles stephensi (LC 50 —18.9 ppm, LC 90 —40.18 ppm), Aedes aegypti (LC 50 —12.395 ppm, LC 90 —36.34 ppm) and Culex quinquefasciatus (LC 50 —17.76 ppm, LC 90 —30.82 ppm) and were found to be non-toxic against normal cell line (HEK 293), and a non-target organism ( Mesocyclops thermocyclopoides ). This is the first report on the synthesis of AgNP using aqueous leaf extract of A. acuminata , validating their strong therapeutic potential.

The turnover of integrin receptors is critical for cell migration and adhesion dynamics. Here we find that force development at integrins regulates adaptor protein recruitment and endocytosis. Using mobile RGD (Arg-Gly-Asp) ligands on supported lipid membranes (RGD membranes) and rigid RGD ligands on glass (RGD-glass), we find that matrix force-dependent integrin signals block endocytosis. Dab2, an adaptor protein of clathrin-mediated endocytosis, is not recruited to activated integrin-beta3 clusters on RGD-glass; however, it is recruited to integrin-mediated adhesions on RGD membranes. Further, when force generation is inhibited on RGD-glass, Dab2 binds to integrin-beta3 clusters. Dab2 binding to integrin-beta3 excludes other adhesion-related adaptor proteins, such as talin. The clathrin-mediated endocytic machinery combines with Dab2 to facilitate the endocytosis of RGD-integrin-beta3 clusters. From these observations, we propose that loss of traction force on ligand-bound integrin-beta3 causes recruitment of Dab2/clathrin, resulting in endocytosis of integrins. Force is known to recruit adaptor proteins to the intracellular tails of integrin extracellular matrix receptors. Here the authors show that matrix force-dependent β3 integrin signals block endocytosis by preventing the recruitment of the clathrin adaptor Dab2.

Nonsense-mediated mRNA decay (NMD) typifies an mRNA surveillance pathway. Because NMD necessitates a translation event to recognize a premature termination codon on mRNAs, truncated misfolded polypeptides (NMD-polypeptides) could potentially be generated from NMD substrates as byproducts. Here, we show that when the ubiquitin–proteasome system is overwhelmed, various misfolded polypeptides including NMD-polypeptides accumulate in the aggresome: a perinuclear nonmembranous compartment eventually cleared by autophagy. Hyperphosphorylation of the key NMD factor UPF1 is required for selective targeting of the misfolded polypeptide aggregates toward the aggresome via the CTIF–eEF1A1–DCTN1 complex: the aggresome-targeting cellular machinery. Visualization at a single-particle level reveals that UPF1 increases the frequency and fidelity of movement of CTIF aggregates toward the aggresome. Furthermore, the apoptosis induced by proteotoxic stresses is suppressed by UPF1 hyperphosphorylation. Altogether, our data provide evidence that UPF1 functions in the regulation of a protein surveillance as well as an mRNA quality control. Nonsense-mediated mRNA decay (NMD) is a translation-coupled process that eliminates mRNAs containing premature translation-termination codons. Here the authors identify a role for the NMD factor UPF1 in protein quality control, whereby truncated misfolded polypeptides are cleared through autophagy.

Large genomes with elevated mutation rates are prone to accumulating deleterious mutations more rapidly than natural selection can purge (Muller’s ratchet). As a consequence, it may lead to the extinction of small populations. Relative to most unicellular organisms, cancer cells, with large and nonrecombining genome and high mutation rate, could be particularly susceptible to such “mutational meltdown.” However, the most common type of mutation in organismal evolution, namely, deleterious mutation, has received relatively little attention in the cancer biology literature. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard the rate of cell proliferation. The main mutation events are copy number variations (CNVs), which, estimated from fitness data, happen at a rate of 0.29 event per cell division on average. The mean fitness reduction, estimated reaching 18% per mutation, is very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely face mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large enough. Because CNVs are common in most cell lines and tumor tissues, the observations hint at cancer cells’ vulnerability, which could be exploited by therapeutic strategies.

Cervical cancer is the most common cancer among women of childbearing age. Nandhi Mezhugu is a Siddha herbo-mineral drug widely used to treat cancer. Due to a lack of scientific evidence, the present study was intended to evaluate the anti cancer activity of Nandhi Mezhugu in the HeLa cell line. The cells were cultured in Dulbecco’s modified Eagle medium, then treated with different concentrations of the test drug (10 to 200 µg/ml). The anti proliferative activity of the drug was evaluated using an MTT assay. Cell apoptosis and cell cycle were measured by flow cytometry and typical nuclear changes of apoptotic processes were observed under the microscope using the dual acridine orange/ethidium bromide fluorescent staining method. The study result showed that the percentage of cell viability decreased with an increase in the concentration of the test drug. The MTT assay data showed that the test drug Nandhi Mezhugu had the antiproliferative effect on cervical cancer cells with IC 50 of 139.7 ± 13.87 µg/ml. Further studies such as flow cytometry and dual staining method also revealed the apoptotic effect of the test drug. Nandhi Mezhugu can be effectively used as an anti cancer formulation to treat cervical cancer. Thus, the current study brings forth scientific evidence for the efficacy of Nandhi Mezhugu against the HeLa cell line. Further studies will be needed to prove the promising efficacy of Nandhi Mezhugu .

The pyrimidine heterocycle plays an important role in anticancer research. In particular, the pyrimidine derivative families of uracil show promise as structural scaffolds relevant to cervical cancer. This group of chemicals lacks data-driven machine learning quantitative structure-activity relationships (QSARs) that allow for generalization and predictive capabilities in the search for new active compounds. To achieve this, a dataset of pyrimidine and uracil compounds from ChEMBL were collected and curated. A workflow was developed for data-driven machine learning QSAR using an intuitive dataset design and forwards selection of molecular descriptors. The model was thoroughly externally validated against available data. Blind validation was also performed by synthesis and antiproliferative evaluation of new synthesized uracil-based and pyrimidine derivatives. The most active compound among new synthesized derivatives, 2,4,5-trisubstituted pyrimidine was predicted with the QSAR model with differences of 0.02 compared to experimentally tested activity.

Melittin, an amphipathic 26-residue peptide, is the main component of honey bee venom. Studies have been demonstrated that melittin has an inhibitory effect on proliferation of cancer cells. However, the precise mechanism of action is not completely understood. In the present study we have shown that purified melittin from Iranian honey bee venom shows anti-cancer effects on human cervical cancer cell line through induction of apoptosis. The venom was collected from Iranian honey bee (Apis mellifera meda) and melittin isolated using reversed phase HPLC. Biological activity of melittin was analyzed by hemolytic test on human red blood cells. In order to investigate whether melittin inhibits proliferation of cervical cancer cells, the viability of the melittin treated HeLa cell line was measured via MTT assay. Finally, cell death analysis was performed using Propidum iodide and Annexin V-FITC dual staining. The results showed that the half hemolytic concentration (HD50) induced by mellitin was 0.5 µg/ml in free FBS solution. IC50 obtained after 12 h at 1.8 µg/ml by MTT assay. According to flow cytometric analysis, melittin induced apoptosis at concentrations more than 1 µg/ml. These results suggest that melittin induces apoptotic cell death in cervical cancerous cells as observed by flow cytometric assay. It is concluded that melittin could be regarded as a potential candidate in future studies to discovery of new anticancer agents.