CoNiZn and CoNiFe Nanoparticles: Synthesis, Physical Characterization, and In Vitro Cytotoxicity Evaluations

The polyol method has been used to synthesize CoNiFe and CoNiZn alloy nanoparticles (NPs). The magnetic characteristics of the products have been measured by vibration sample magnetometry (VSM) analysis. At the same time, the microstructure and morphology were inspected by X-ray diffraction (XRD) and scanning electron microscopy (SEM), respectively. Magnetic measurement of samples by the VSM indicated that samples have soft ferromagnetic behavior. Spherical-shaped grains for samples were confirmed by the SEM. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH) assays were used to determine the cytotoxic effects of the synthesized NPs. Cytotoxic evaluations showed that treatment with 25 to 400 µg/mL of CoNiZn and CoNiFe NPs exerted a significant time- and concentration-dependent toxicity in MCF7 and HUVEC cells and markedly enhanced the LDH leakage after 48 h of exposure (p < 0.05 compared with untreated cells). Furthermore, NPs with concentrations higher than 12.5 µg/mL induced evident morphological changes in the studied cell lines. Treatment with 12.5 µg/mL of CoNiZn and CoNiFe NPs was safe and did not affect normal human cell survival. The results of in vitro cytotoxicity assessments show promise in supporting the suitability of the synthesized NPs to build high-performance theranostic nanoplatforms for simultaneous cancer imaging and therapy without affecting normal human cells.

Life without mismatch repair

Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss of MSH2 or MSH6 (MutSα), but not MLH1 or PMS2 (MutLα), caused 5-methylcytosine-dependent hypermutation, indicating that MutSα is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation.

Field size effects on DNA damage and proliferation in normal human cell populations irradiated with X-ray microbeams

To clarify the health risks of internal radiation exposure, it is important to investigate the radiological effects of local exposure at cell levels from radioactive materials taken up by organs. Focusing on the response of cell populations post-irradiation, X-ray microbeams are very effective at reproducing the effects of local exposure within an internal exposure in vitro. The present study aims to clarify the effects of local exposure by investigating the response of normal human cell (MRC-5) populations irradiated with X-ray microbeams of different beam sizes to DNA damage. The populations of MRC-5 were locally irradiated with X-ray microbeams of 1 Gy at 0.02–1.89 mm2 field sizes, and analyzed whether the number of 53BP1 foci as DSB (DNA double strand break) per cell changed with the field size. We found that even at the same dose, the number of DSB per cell increased depending on the X-irradiated field size on the cell population. This result indicated that DNA damage repair of X-irradiated cells might be enhanced in small size fields surrounded by non-irradiated cells. This study suggests that X-irradiated cells received some signal (a rescue signal) from surrounding non-irradiated cells may be involved in the response of cell populations post-irradiation.

The different modes of chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines: crystal packing, conformation investigation and cellular activity

The crystal structures of four new chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines are described, namely, ethyl 5′-benzoyl-5′H,7′H-spiro[cyclohexane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C19H22N4O3S, ethyl 5′-(4-methoxybenzoyl)-5′H,7′H-spiro[cyclohexane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C20H24N4O4S, ethyl 6,6-dimethyl-5-(4-methylbenzoyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C17H20N4O3S, and ethyl 5-benzoyl-6-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C21H20N4O4S. The crystallographic data and cell activities of these four compounds and of the structures of three previously reported similar compounds, namely, ethyl 5′-(4-methylbenzoyl)-5′H,7′H-spiro[cyclopentane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C19H22N4O3S, ethyl 5′-(4-methoxybenzoyl)-5′H,7′H-spiro[cyclopentane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate, C19H22N4O4S, and ethyl 6-methyl-5-(4-methylbenzoyl)-6-phenyl-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C22H22N4O3S, are contrasted and compared. For both crystallization and an MTT assay, racemic mixtures of the corresponding [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines were used. The main manner of molecular packing in these compounds is the organization of either enantiomeric pairs or dimers. In both cases, the formation of two three-centre hydrogen bonds can be detected resulting from intramolecular N—H...O and intermolecular N—H...O or N—H...N interactions. Molecules of different enantiomeric forms can also form chains through N—H...O hydrogen bonds or form layers between which only weak hydrophobic contacts exist. Unlike other [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines, ethyl 5′-benzoyl-5′H,7′H-spiro[cyclohexane-1,6′-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3′-carboxylate contains molecules of only the (R)-enantiomer; moreover, the N—H group does not participate in any significant intermolecular interactions. Molecular mechanics methods (force field OPLS3e) and the DFT B3LYP/6-31G+(d,p) method show that the compound forming enantiomeric pairs via weak N—H...N hydrogen bonds is subject to greater distortion of the geometry under the influence of the intermolecular interactions in the crystal. For intramolecular N—H...O and S...O interactions, an analysis of the noncovalent interactions (NCIs) was carried out. The cellular activities of the compounds were tested by evaluating their antiproliferative effect against two normal human cell lines and two cancer cell lines in terms of half-maximum inhibitory concentration (IC50). Some derivatives have been found to be very effective in inhibiting the growth of Hela cells at nanomolar and submicromolar concentrations with minimal cytotoxicity in relation to normal cells.

Antimicrobial, Antioxidant, and Anticancer Activities of Some Novel Isoxazole Ring Containing Chalcone and Dihydropyrazole Derivatives

Our previous work identified isoxazole-based chalcones and their dihydropyrazole derivatives as two important five-membered heterocycles having antitubercular activity. Hence, in the present study, we biologically evaluated 30 compounds, including 15 isoxazole ring-containing chalcones (17–31) and 15 dihydropyrazoles (32–46) derived from these chalcones for their antimicrobial, antioxidant, and anticancer activities. Chalcones exhibited superior antibacterial and antioxidant activities compared to dihydropyrazoles. Among the chalcones, compound 28 showed potent antibacterial (MIC = 1 µg/mL) and antioxidant activities (IC50 = 5 ± 1 µg/mL). Dihydropyrazoles, on the contrary, demonstrated remarkable antifungal and anticancer activities. Compound 46 (IC50 = 2 ± 1 µg/mL) showed excellent antifungal activity whereas two other dihydropyrazoles 45 (IC50 = 2 ± 1 µg/mL) and 39 (IC50 = 4 ± 1 µg/mL) exhibited potential anticancer activity. The compounds were also tested for their toxicity on normal human cell lines (LO2) and were found to be nontoxic. The active compounds that have emerged out of this study are potential lead molecules for the development of novel drugs against infectious diseases, oxidative stress, and cancer.

Comparative profiling of chromatin open state of various cells and tissues for dissecting the epigenetic causes of various biological processes

Background The comparative study of chromatin open state of various cells and tissues is helpful for dissecting the epigenetic causes of various biological and pathological processes such as development and tumorigenesis. This study comparatively characterized the chromatin open regions (CORs) of two normal human cell lines (HL7702 and MRC-5), nine human cancer cell lines (GM12878, HepG2, PANC-1, A549, HT29, SKOV3, SiHa, C-33A, and HeLa), one mouse cancer cell line (Hepa1-6), and healthy mouse liver tissue with SALP-seq.Results This study therefore made a set of systematic and useful COR profiles of human and mouse cells and tissues. These COR profiles were used to explore the possible epigenetic bases of several interesting scientific problems, including how chromatin state changes contribute to tumorigenesis, how the cancer-related mutation hotspots are formed, why fibroblast was most widely used to prepare iPSCs, and how HPV subtypes differently affect the chromatin structure of cervical cells. The results revealed that the comparative COR profiling can shed new insights into the potential molecular mechanisms underlying these important biological and pathological processes. The comparative COR profiling also demonstrated transcription factors differentially dominate various biological and pathological processes. At last, the comparative COR profiling uncovers new potential markers or targets for cancer diagnosis and therapy.Conclusions The comparative COR profiling with our developed SALP-seq technique can be used to uncover epigenetic bases and molecular mechanisms underlying various biological processes.

Synthesis of Novel and Potential Antimicrobial, Antioxidant and Anticancer Chalcones and Dihydropyrazoles Bearing Isoxazole Scaffold

A series of isoxazole based (E)-1-(isoxazole-5-yl)-3-(substituted phenyl)-prop-2-en-1-ones (chalcones, 3a-3o) and 3-(isoxazol-5-yl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (dihydropyrazoles, 4a-4o) were synthesized, characterized and evaluated for their antimicrobial, antioxidant and anticancer properties. Chalcones exhibited excellent antibacterial and antioxidant activities whereas the dihydropyrazoles shown superior antifungal and anticancer activities. The compound 3l containing 3,4,5-trimethoxy phenyl ring showed the potent antibacterial activity (MIC = 1 µg/mL) as well as the antioxidant activity (IC50 = 5 µg/mL) whereas the dihydropyrazole, 4o (MIC = 0.5 µg/mL) bearing the 2-chloro-3,4-dimethoxyphenyl was the potent antifungal compound identified. The dihydropyrazoles 4n and 4h possessing 2-fluoro-3,4-dimethoxyphenyl and 3,4-dimethoxyphenyl substituents exhibited potent anticancer activity against prostate cancer cell line (DU-145) with MIC 2 and 4 µg/mL respectively. The structure activity relationships had shown that there is a marked influence of both electron withdrawing halogens and electron releasing methoxyl groups on the above biological activities. All the compounds were evaluated for toxicity on normal human cell lines (LO2) and found to be non-toxic. These studies could help to synthesize, explore and identify new isoxazole containing leads for antimicrobial, antioxidant and anticancer properties.

A Novel Dermaseptin Isolated from the Skin Secretion of Phyllomedusa tarsius and Its Cationicity-Enhanced Analogue Exhibiting Effective Antimicrobial and Anti-Proliferative Activities

A novel dermaseptin peptide, dermaseptin-PT9 (DPT9), was isolated and identified from Phyllomedusa tarsius by the combination of molecular cloning and LC-MS analysis. Chemically synthesised DPT9 was broadly effective against the tested microorganisms through the disruption of cell membranes and showed weak haemolytic activity towards horse erythrocytes. It also exhibited anti-proliferative effect against various human cancer cells. Moreover, an analogue with enhanced cationicity, K8, 23-DPT9, in which Asp8 and Glu23 were substituted by lysine residues, had a markedly increased antimicrobial effect against all tested microorganisms and disrupted microbial cell membranes. This analogue also showed no haemolysis at its effective antimicrobial concentrations. In addition, K8, 23-DPT9 displayed an enhanced anti-proliferative effect against cancer cells, while displayed weak activity against the normal human cell line, HMEC-1.

Structure–Antioxidant–Antiproliferative Activity Relationships of Natural C7 and C7–C8 Hydroxylated Flavones and Flavanones

Common food flavonoids: chrysin, apigenin, luteolin, diosmetin, pinocembrin, naringenin, eriodictyol, hesperetin, and their analogues with an additional hydroxyl group at the C-8 position obtained via biotransformation were tested for antioxidant activity using the ABTS, DPPH, and ferric ion reducing antioxidant power (FRAP) methods. They were also tested for antiproliferative activity against selected human cancer cell lines—MV-4-11 (biphenotypic B myelomonocytic leukemia), MCF7 (breast carcinoma), LoVo (colon cancer), LoVo/DX (colon cancer doxorubicin resistant), and DU 145 (prostate cancer)—and two normal human cell lines—MCF 10A (breast cells) and HLMEC (lung microvascular endothelial cells). Flavonoids with a C7–C8 catechol moiety indicated much higher antioxidant activity compared with the C7 hydroxy analogues. However, because they were unstable under the assay conditions, they did not show antiproliferative activity or it was very low.

Synthesis and screening of novel lipophilic diarylpropeones as prospective antitubercular, antibacterial and antifungal agents

Infectious diseases including bacterial, fungal and tuberculosis are responsible for the suffering of humans worldwide. Based on this observation we predetermined to prepare and five novel lipophilic diarylpropenones (Chalcones) (3a-3e) against tubercular, bacterial and fungal strains. The compounds were prepared by base the catalyzed condensation of 2,4,6-trimethyl acetophenone with substituted aromatic aldehydes, purified by recrystallization and characterized by elemental analysis and IR, 1H NMR, and Mass spectroscopic techniques. Further, the compounds were biologically screened for their antitubercular, antibacterial, and antifungal actions. Results of these activities revealed that the compounds possess potential antifungal and antitubercular activities and poor antibacterial activity. The greater activities against tubercular and fungal strains may be due to the lipophilicity rendered by the three magic methyl groups and halogen atoms. The compounds showed no cytotoxicity against the normal human cell line L02. These compounds may act as new scaffolds for the design and development of new molecules against tubercular and fungal infections. Advanced studies need to be carried out in order to determine their potency in vivo.