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Langkocyclines: novel angucycline antibiotics from Streptomyces sp. Acta 3034(*)

Kalyon B, Tan GY, Pinto JM, Foo CY, Wiese J, Imhoff JF, et al.

J Antibiot (Tokyo), 2013 Oct;66(10):609-16.
PMID: 23820614 DOI: 10.1038/ja.2013.53

Langkocyclines A1-A3 and B1 and B2, five new angucycline antibiotics produced by Streptomyces sp. Acta 3034, were detected in the course of our HPLC-diode array screening. The producing strain was isolated from the rhizospheric soil of a Clitorea sp. collected from Burau Bay, Langkawi, Malaysia, and was characterized by morphological, physiological and chemotaxonomic features in addition to 16S ribosomal RNA gene sequence information. Strain Acta 3034 is closely related to Streptomyces psammoticus NBRC 13971(T) and Streptomyces lanatus NBRC 12787(T). Langkocyclines consist of an angular tetracyclic benz[a]anthracene skeleton and hydrolyzable O-glycosidic sugar moieties. The yellow-colored A-type langkocyclines differ in their aglycon from the blue-lilac-colored B-type langkocyclines. The A-type langkocycline aglycon is identical to that of aquayamycin and urdamycin A. The chemical structures of the langkocyclines were elucidated by HR-MS, 1D and 2D NMR experiments. They are biologically active against Gram-positive bacteria and exhibit a moderate antiproliferative activity against various human tumor cell lines.

Matched MeSH terms: NIH 3T3 Cells
Fulltext Derivation of an endogenous small RNA from double-stranded Sox4 sense and natural antisense transcripts in the mouse brain

Ling KH, Brautigan PJ, Moore S, Fraser R, Cheah PS, Raison JM, et al.

Genomics, 2016 Mar;107(2-3):88-99.
PMID: 26802803 DOI: 10.1016/j.ygeno.2016.01.006

Natural antisense transcripts (NATs) are involved in cellular development and regulatory processes. Multiple NATs at the Sox4 gene locus are spatiotemporally regulated throughout murine cerebral corticogenesis. In the study, we evaluated the potential functional role of Sox4 NATs at Sox4 gene locus. We demonstrated Sox4 sense and NATs formed dsRNA aggregates in the cytoplasm of brain cells. Over expression of Sox4 NATs in NIH/3T3 cells generally did not alter the level of Sox4 mRNA expression or protein translation. Upregulation of a Sox4 NAT known as Sox4ot1 led to the production of a novel small RNA, Sox4_sir3. Its biogenesis is Dicer1-dependent and has characteristics resemble piRNA. Expression of Sox4_sir3 was observed in the marginal and germinative zones of the developing and postnatal brains suggesting a potential role in regulating neurogenesis. We proposed that Sox4 sense-NATs serve as Dicer1-dependent templates to produce a novel endo-siRNA- or piRNA-like Sox4_sir3.

Matched MeSH terms: NIH 3T3 Cells
The in vivo fate of nanoparticles and nanoparticle-loaded microcapsules after oral administration in mice: Evaluation of their potential for colon-specific delivery

Ma Y, Fuchs AV, Boase NR, Rolfe BE, Coombes AG, Thurecht KJ

Eur J Pharm Biopharm, 2015 Aug;94:393-403.
PMID: 26117186 DOI: 10.1016/j.ejpb.2015.06.014

Anti-cancer drug loaded-nanoparticles (NPs) or encapsulation of NPs in colon-targeted delivery systems shows potential for increasing the local drug concentration in the colon leading to improved treatment of colorectal cancer. To investigate the potential of the NP-based strategies for colon-specific delivery, two formulations, free Eudragit® NPs and enteric-coated NP-loaded chitosan-hypromellose microcapsules (MCs) were fluorescently-labelled and their tissue distribution in mice after oral administration was monitored by multispectral small animal imaging. The free NPs showed a shorter transit time throughout the mouse digestive tract than the MCs, with extensive excretion of NPs in faeces at 5h. Conversely, the MCs showed complete NP release in the lower region of the mouse small intestine at 8h post-administration. Overall, the encapsulation of NPs in MCs resulted in a higher colonic NP intensity from 8h to 24h post-administration compared to the free NPs, due to a NP 'guarding' effect of MCs during their transit along mouse gastrointestinal tract which decreased NP excretion in faeces. These imaging data revealed that this widely-utilised colon-targeting MC formulation lacked site-precision for releasing its NP load in the colon, but the increased residence time of the NPs in the lower gastrointestinal tract suggests that it is still useful for localised release of chemotherapeutics, compared to NP administration alone. In addition, both formulations resided in the stomach of mice at considerable concentrations over 24h. Thus, adhesion of NP- or MC-based oral delivery systems to gastric mucosa may be problematic for colon-specific delivery of the cargo to the colon and should be carefully investigated for a full evaluation of particulate delivery systems.

Matched MeSH terms: NIH 3T3 Cells
Improvement of physicochemical properties of nanocolloidal carrier loaded with low water solubility drug for parenteral cancer treatment by Response Surface Methodology

Izadiyan Z, Basri M, Fard Masoumi HR, Abedi Karjiban R, Salim N, Kalantari K

Mater Sci Eng C Mater Biol Appl, 2019 Jan 01;94:841-849.
PMID: 30423770 DOI: 10.1016/j.msec.2018.10.015

Nanoemulsions have been used as a drug carrier system, particularly for poorly water-soluble drugs. Sorafenib is a poorly soluble drug and also there is no parenteral treatment. The aim of this study is the development of nanoemulsions for intravenous administration of Sorafenib. The formulations were prepared by high energy emulsification method and optimized by using Response Surface Methodology (RSM). Here, the effect of independent composition variables of lecithin (1.16-2.84%, w/w), Medium-Chain Triglycerides (2.32-5.68%, w/w) and polysorbate 80 (0.58-1.42%, w/w) amounts on the properties of Sorafenib-loaded nanoemulsion was investigated. The three responses variables were particle size, zeta potential, and polydispersity index. Optimization of the conditions according to the three dependent variables was performed for the preparation of the Sorafenib-loaded nanoemulsions with the minimum value of particle size, suitable rage of zeta potential, and polydispersity index. A formulation containing 0.05% of Sorafenib kept its properties in a satisfactory range over the evaluated period. The composition with 3% Medium-Chain Triglycerides, 2.5% lecithin and 1.22% polysorbate 80 exhibited the smallest particle size and polydispersity index (43.17 nm and 0.22, respectively) with the zeta potential of -38.8 mV was the optimized composition. The fabricated nanoemulsion was characterized by the transmission electron microscope (TEM), viscosity, and stability assessment study. Also, the cytotoxicity result showed that the optimum formulations had no significant effect on a normal cell in a low concentration of the drug but could eliminate the cancer cells. The dose-dependent toxicity made it a suitable candidate for parenteral applications in the treatment of breast cancer. Furthermore, the optimized formulation indicated good storage stability for 3 months at different temperatures (4 ± 2 °C, 25 ± 2 °C and 45 ± 2 °C).

Matched MeSH terms: NIH 3T3 Cells
Fulltext Radiosensitization Effects by Bismuth Oxide Nanoparticles in Combination with Cisplatin for High Dose Rate Brachytherapy

Sisin NNT, Abdul Razak K, Zainal Abidin S, Che Mat NF, Abdullah R, Ab Rashid R, et al.

Int J Nanomedicine, 2019;14:9941-9954.
PMID: 31908451 DOI: 10.2147/IJN.S228919

Purpose: The aim of this study was to investigate the potential of the synergetic triple therapeutic combination encompassing bismuth oxide nanoparticles (BiONPs), cisplatin (Cis), and high dose rate (HDR) brachytherapy with Ir-192 source in breast cancer and normal fibroblast cell line.
Methods: In vitro models of breast cancer cell lines (MCF-7, MDA-MB-231) and normal fibroblast cell line (NIH/3T3) were employed. Cellular localization and cytotoxicity studies were conducted prior to inspection on the radiosensitization effects and generation of reactive oxygen species (ROS) on three proposed radiosensitizers: BiONPs, Cis, and BiONPs-Cis combination (BC). The optimal, non-cytotoxic concentration of BiONPs (0.5 mM) and the 25% inhibitory concentration of Cis (1.30 µM) were applied. The radiosensitization effects were evaluated by using a 0.38 MeV Iridium-192 HDR brachytherapy source over a prescribed dose range of 0 Gy to 4 Gy.
Results: The cellular localization of BiONPs was visualized by light microscopy and accumulation of the BiONPs within the vicinity of the nuclear membrane was observed. Quantification of the sensitization enhancement ratio extrapolated from the survival curves indicates radiosensitization effects for MCF-7 and MDA-MB-231 when treated with BiONPs, Cis, and BC. However, NIH/3T3 cells exhibited contradictive behavior as it only reacted towards the BC combination. Nonetheless, the MCF-7 cell line loaded with BC shows the highest SER of 4.29. ROS production analysis, on the other hand, shows that Cis and BC radiosensitizers generated the highest free radicals in comparison to BiONPs alone.
Conclusion: A BiONPs-Cis combination was unveiled as a novel approach that offers promising radiosensitization enhancement that will increase the efficiency of tumor control while preserving the normal tissue at a reduced dose. This data is the first precedent to prove the synergetic implication of BiONPs, Cis, and HDR brachytherapy that will be beneficial for future chemoradiotherapy strategies in cancer care.

Matched MeSH terms: NIH 3T3 Cells
Fulltext New Hybrid Hydrazinyl Thiazole Substituted Chromones: As Potential α-Amylase Inhibitors and Radical (DPPH & ABTS) Scavengers

Salar U, Khan KM, Chigurupati S, Taha M, Wadood A, Vijayabalan S, et al.

Sci Rep, 2017 12 05;7(1):16980.
PMID: 29209017 DOI: 10.1038/s41598-017-17261-w

Current research is based on the identification of novel inhibitors of α-amylase enzyme. For that purpose, new hybrid molecules of hydrazinyl thiazole substituted chromones 5-27 were synthesized by multi-step reaction and fully characterized by various spectroscopic techniques such as EI-MS, HREI-MS, 1H-NMR and 13C-NMR. Stereochemistry of the iminic bond was confirmed by NOESY analysis of a representative molecule. All compounds 5-27 along with their intervening intermediates 1-4, were screened for in vitro α-amylase inhibitory, DPPH and ABTS radical scavenging activities. All compounds showed good inhibition potential in the range of IC50 = 2.186-3.405 µM as compared to standard acarbose having IC50 value of 1.9 ± 0.07 µM. It is worth mentioning that compounds were also demonstrated good DPPH (IC50 = 0.09-2.233 µM) and ABTS (IC50 = 0.584-3.738 µM) radical scavenging activities as compared to standard ascorbic acid having IC50 = 0.33 ± 0.18 µM for DPPH and IC50 = 0.53 ± 0.3 µM for ABTS radical scavenging activities. In addition to that cytotoxicity of the compounds were checked on NIH-3T3 mouse fibroblast cell line and found to be non-toxic. In silico studies were performed to rationalize the binding mode of compounds (ligands) with the active site of α-amylase enzyme.

Matched MeSH terms: NIH 3T3 Cells
Fulltext Enhancing the Bioconversion of Azelaic Acid to Its Derivatives by Response Surface Methodology

Khairudin N, Basri M, Fard Masoumi HR, Samson S, Ashari SE

Molecules, 2018 Feb 13;23(2).
PMID: 29438284 DOI: 10.3390/molecules23020397

Azelaic acid (AzA) and its derivatives have been known to be effective in the treatment of acne and various cutaneous hyperpigmentary disorders. The esterification of azelaic acid with lauryl alcohol (LA) to produce dilaurylazelate using immobilized lipase B from Candida antarctica (Novozym 435) is reported. Response surface methodology was selected to optimize the reaction conditions. A well-fitting quadratic polynomial regression model for the acid conversion was established with regards to several parameters, including reaction time and temperature, enzyme amount, and substrate molar ratios. The regression equation obtained by the central composite design of RSM predicted that the optimal reaction conditions included a reaction time of 360 min, 0.14 g of enzyme, a reaction temperature of 46 °C, and a molar ratio of substrates of 1:4.1. The results from the model were in good agreement with the experimental data and were within the experimental range (R² of 0.9732).The inhibition zone can be seen at dilaurylazelate ester with diameter 9.0±0.1 mm activities against Staphylococcus epidermidis S273. The normal fibroblasts cell line (3T3) was used to assess the cytotoxicity activity of AzA and AzA derivative, which is dilaurylazelate ester. The comparison of the IC50 (50% inhibition of cell viability) value for AzA and AzA derivative was demonstrated. The IC50 value for AzA was 85.28 μg/mL, whereas the IC50 value for AzA derivative was more than 100 μg/mL. The 3T3 cell was still able to survive without any sign of toxicity from the AzA derivative; thus, it was proven to be non-toxic in this MTT assay when compared with AzA.

Matched MeSH terms: NIH 3T3 Cells
Fulltext Characterization and safety evaluation of partially purified bacteriocin produced by Escherichia coli E isolated from fermented pineapple Ananas comosus (L.) Merr

Le VT, Leelakriangsak M, Lee SW, Panphon S, Utispan K, Koontongkaew S

Braz J Microbiol, 2019 Jan;50(1):33-42.
PMID: 30637641 DOI: 10.1007/s42770-018-0014-5

Antibacterial activity of cell-free supernatant from Escherichia coli E against selected pathogenic bacteria in food and aquaculture was the highest against Edwardsiella tarda 3, a significant aquaculture pathogen. Biochemical properties of the bacteriocins were studied and bacteriocin was found to be sensitive to proteinase K, demonstrating its proteinaceous nature. In addition, pH and temperature affected bacteriocin activity and stability. The bacteriocins were partially purified by ammonium sulfate precipitation. The antibacterial activity was only detected in 20% ammonium sulfate fraction and direct detection of its activity was performed by overlaying on the indicator strains. The inhibition zone associated with the antibacterial activity was detected in the sample overlaid by E. tarda 3 and Staphylococcus aureus DMST8840 with the relative molecular mass of about 27 kDa and 10 kDa, respectively. Bacteriocin showed no cytotoxic effect on NIH-3T3 cell line; however, two virulence genes, aer and sfa, were detected in the genome of E. coli E by PCR. The characteristics of bacteriocins produced by E. coli E exhibited the antibacterial activity against both Gram-positive and Gram-negative pathogenic bacteria and the safe use determined by cytotoxicity test which may have interesting biotechnological applications.

Matched MeSH terms: NIH 3T3 Cells
Designing and in-vitro characterization of micelle forming amphiphilic PEGylated rapamycin nanocarriers for the treatment of gastric cancer

Kumar PV, Lokesh BV

Curr Drug Deliv, 2014;11(5):613-20.
PMID: 25268676

The present study aims to develop and explore the use of PEGylated rapamycin (RP-MPEG) micelles for the treatment of gastric cancer. RP-MPEG was synthesized and characterized by using IR, H(1) NMR and C(13) NMR. RP-MPEG was prepared in the form of micelles and characterized by using field emission scanning electron microscopy, dynamic light scattering, zeta sizer, chromatographic analyses and photostability studies. The cytotoxicity studies of RP-MPEG micelles were conducted on specific CRL 1739 human gastric adenocarcinoma and CRL 1658 NIH-3T3 mouse embryonic fibroblast cell lines. RP-MPEG micelles showed the particle size distribution of 125±0.26 nm with narrow size distribution (polydispersity index 0.127±0.01). The surface charge of RP-MPEG micelles was found to be -12.3 mV showing enhanced anticancer activity against the CRL 1739 human gastric adenocarcinoma cell lines with an IC50 value of 1 mcg/ml.

Matched MeSH terms: NIH 3T3 Cells
Fulltext Identification of small molecule inhibitors of p27(Kip1) ubiquitination by high-throughput screening

Ooi LC, Watanabe N, Futamura Y, Sulaiman SF, Darah I, Osada H

Cancer Sci, 2013 Nov;104(11):1461-7.
PMID: 23910095 DOI: 10.1111/cas.12246

Dysregulation of p27(Kip1) due to proteolysis that involves the ubiquitin ligase (SCF) complex with S-phase kinase-associated protein 2 (Skp2) as the substrate-recognition component (SCF(Skp2)) frequently results in tumorigenesis. In this report, we developed a high-throughput screening system to identify small-molecule inhibitors of p27(Kip1) degradation. This system was established by tagging Skp2 with fluorescent monomeric Azami Green (mAG) and CDK subunit 1 (Cks1) (mAGSkp2-Cks1) to bind to p27(Kip1) phosphopeptides. We identified two compounds that inhibited the interaction between mAGSkp2-Cks1 and p27(Kip1): linichlorin A and gentian violet. Further studies have shown that the compounds inhibit the ubiquitination of p27(Kip1) in vitro as well as p27(Kip1) degradation in HeLa cells. Notably, both compounds exhibited preferential antiproliferative activity against HeLa and tsFT210 cells compared with NIH3T3 cells and delayed the G1 phase progression in tsFT210 cells. Our approach indicates a potential strategy for restoring p27(Kip1) levels in human cancers.

Matched MeSH terms: NIH 3T3 Cells
Fulltext Sustainable drug release from polycaprolactone coated chitin-lignin gel fibrous scaffolds

Abudula T, Gauthaman K, Mostafavi A, Alshahrie A, Salah N, Morganti P, et al.

Sci Rep, 2020 11 24;10(1):20428.
PMID: 33235239 DOI: 10.1038/s41598-020-76971-w

Non-healing wounds have placed an enormous stress on both patients and healthcare systems worldwide. Severe complications induced by these wounds can lead to limb amputation or even death and urgently require more effective treatments. Electrospun scaffolds have great potential for improving wound healing treatments by providing controlled drug delivery. Previously, we developed fibrous scaffolds from complex carbohydrate polymers [i.e. chitin-lignin (CL) gels]. However, their application was limited by solubility and undesirable burst drug release. Here, a coaxial electrospinning is applied to encapsulate the CL gels with polycaprolactone (PCL). Presence of a PCL shell layer thus provides longer shelf-life for the CL gels in a wet environment and sustainable drug release. Antibiotics loaded into core-shell fibrous platform effectively inhibit both gram-positive and -negative bacteria without inducting observable cytotoxicity. Therefore, PCL coated CL fibrous gel platforms appear to be good candidates for controlled drug release based wound dressing applications.

Matched MeSH terms: NIH 3T3 Cells
Water-Soluble Dioxidovanadium(V) Complexes of Aroylhydrazones: DNA/BSA Interactions, Hydrophobicity, and Cell-Selective Anticancer Potential

Sahu G, Banerjee A, Samanta R, Mohanty M, Lima S, Tiekink ERT, et al.

Inorg Chem, 2021 Oct 18;60(20):15291-15309.
PMID: 34597028 DOI: 10.1021/acs.inorgchem.1c01899

Five new anionic aqueous dioxidovanadium(V) complexes, [{VO2L1,2}A(H2O)n]α (1-5), with the aroylhydrazone ligands pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L1) and furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L2) incorporating different alkali metals (A = Na+, K+, Cs+) as countercation were synthesized and characterized by various physicochemical techniques. The solution-phase stabilities of 1-5 were determined by time-dependent NMR and UV-vis, and also the octanol/water partition coefficients were obtained by spectroscopic techniques. X-ray crystallography of 2-4 confirmed the presence of vanadium(V) centers coordinated by two cis-oxido-O atoms and the O, N, and O atoms of a dianionic tridentate ligand. To evaluate the biological behavior, all complexes were screened for their DNA/protein binding propensity through spectroscopic experiments. Finally, a cytotoxicity study of 1-5 was performed against colon (HT-29), breast (MCF-7), and cervical (HeLa) cancer cell lines and a noncancerous NIH-3T3 cell line. The cytotoxicity was cell-selective, being more active against HT-29 than against other cells. In addition, the role of hydrophobicity in the cytotoxicity was explained in that an optimal hydrophobicity is essential for high cytotoxicity. Moreover, the results of wound-healing assays indicated antimigration in case of HT-29 cells. Remarkably, 1 with an IC50 value of 5.42 ± 0.15 μM showed greater activity in comparison to cisplatin against the HT-29 cell line.

Matched MeSH terms: NIH 3T3 Cells
Fulltext Curculigoside and polyphenol-rich ethyl acetate fraction of Molineria latifolia rhizome improved glucose uptake via potential mTOR/AKT activated GLUT4 translocation

Ooi J, Azmi NH, Imam MU, Alitheen NB, Ismail M

J Food Drug Anal, 2018 10;26(4):1253-1264.
PMID: 30249324 DOI: 10.1016/j.jfda.2018.03.003

Adipose tissue is one of the major organs responsible for rapid restoration of postprandial glucose fluxes. Being the major isoform of glucose transporter in adipose tissue, regulations of insulin-dependent GLUT4 trafficking have always been of research interest. The present study aimed to examine the molecular mechanisms underlying the efficacy of curculigoside and polyphenol-rich ethyl acetate fraction (EAF) of Molineria latifolia rhizome in triggering glucose uptake. We assessed the adipogenic potential and glucose uptake stimulatory activity of curculigoside and EAF by employing a murine 3T3-L1 adipocyte model. The transcriptional and translational expressions of selected intermediates in the insulin signalling pathway were evaluated. While curculigoside neither promoted adipogenesis nor activated peroxisome proliferator activated receptor gamma, treatment with polyphenol-rich EAF resulted otherwise. However, both treatments enhanced insulin-stimulated uptake of glucose. This was coupled with increased availability of GLUT4 at the plasma membrane of the differentiated adipocytes although the total GLUT4 protein level was unaffected. In addition, the treatment increased the phosphorylation of both AKT and mTOR, which have been reported to be associated with GLUT4 translocation. The present findings proposed that curculigoside and EAF increased glucose transport activity of 3T3-L1 adipocytes via GLUT4 translocation as a result of potential mTOR/AKT activation. The more potent efficacy observed with EAF suggested potential synergistic and multi-targeted action.

Matched MeSH terms: NIH 3T3 Cells
Chemical composition and cytotoxic properties of Clinacanthus nutans root extracts

Teoh PL, Cheng AY, Liau M, Lem FF, Kaling GP, Chua FN, et al.

Pharm Biol, 2017 Dec;55(1):394-401.
PMID: 27931178

CONTEXT: Clinacanthus nutans Lindau (Acanthaceae) is a medicinal plant that has been reported to have anti-inflammatory, antiviral, antimicrobial and antivenom activities. In Malaysia, it has been widely claimed to be effective in various cancer treatments but scientific evidence is lacking.
OBJECTIVE: This study investigates the chemical constituents, anti-proliferative, and apoptotic properties of C. nutans root extracts.
MATERIALS AND METHODS: The roots were subjected to solvent extraction using methanol and ethyl acetate. The anti-proliferative effects of root extracts were tested at the concentrations of 10 to 50 μg/mL on MCF-7 and HeLa by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay for 72 h. Morphological changes were observed under light microscope. Pro-apoptotic effects of root extracts were examined using flow cytometric analysis and RT-PCR. The chemical compositions of root extracts were detected using GC-MS.
RESULTS: The proliferation of MCF-7 cells was inhibited with the IC50 values of 35 and 30 μg/mL, respectively, for methanol and ethyl acetate root extracts. The average inhibition of HeLa cells was ∼25%. Induction of apoptosis in MCF-7 was supported by chromatin condensation, down-regulation of BCL2 and unaltered expression of BAX. However, only ethyl acetate extract caused the loss of mitochondrial membrane potential. GC-MS analysis revealed the roots extracts were rich with terpenoids and phytosterols.
DISCUSSION AND CONCLUSIONS: The results demonstrated that root extracts promote apoptosis by suppressing BCL2 via mitochondria-dependent or independent manner. The identified compounds might work solely or cooperatively in regulating apoptosis. However, further studies are required to address this.

Matched MeSH terms: NIH 3T3 Cells

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