Heat Modulation of Intrinsic MR Contrasts for Tumor Characterization

(1) Background: The longitudinal relaxation time (T1), transverse relaxation time (T2), water proton chemical shift (CS), and apparent diffusion coefficient (ADC) are MR quantities that change with temperature. In this work, we investigate heat-induced intrinsic MR contrast types to add salient information to conventional MR imaging to improve tumor characterization. (2) Methods: Imaging tests were performed in vivo using different rat tumor models. The rats were cooled/heated to steady-state temperatures from 26–36 °C and quantitative measurements of T1, T2, and ADC were obtained. Temperature maps were measured using the proton resonance frequency shift (PRFS) method during the heating and cooling cycles. (3) Results: All tissue samples show repeatable relaxation parameter measurement over a range of 26–36 °C. Most notably, we observed a more than 3.3% change in T1/°C in breast adenocarcinoma tumors compared to a 1% change in benign breast fibroadenoma lesions. In addition, we note distinct values of T2/°C change for rat prostate carcinoma cells compared to benign tissue. (4) Conclusion: These findings suggest the possibility of improving MR imaging visualization and characterization of tissue with heat-induced contrast types. Specifically, these results suggest that the temporal thermal responses of heat-sensitive MR imaging contrast mechanisms in different tissue types contain information for improved (i) characterization of tumor/tissue boundaries for diagnostic and therapy purposes, and (ii) characterization of salient behavior of tissues, e.g., malignant versus benign tumors.

Anticancer Effects of New Ceramides Isolated from the Red Sea Red Algae Hypnea musciformis in a Model of Ehrlich Ascites Carcinoma: LC-HRMS Analysis Profile and Molecular Modeling

Different classes of phytochemicals were previously isolated from the Red Sea algae Hypnea musciformis as sterols, ketosteroids, fatty acids, and terpenoids. Herein, we report the isolation of three fatty acids—docosanoic acid 4, hexadecenoic acid 5, and alpha hydroxy octadecanoic acid 6—as well as three ceramides—A (1), B (2), and C (3)—with 9-methyl-sphinga-4,8-dienes and phytosphingosine bases. Additionally, different phytochemicals were determined using the liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (LC-ESI-HRMS) technique. Ceramides A (1) and B (2) exhibited promising in vitro cytotoxic activity against the human breast adenocarcinoma (MCF-7) cell line when compared with doxorubicin as a positive control. Further in vivo study and biochemical estimation in a mouse model of Ehrlich ascites carcinoma (EAC) revealed that both ceramides A (1) and B (2) at doses of 1 and 2 mg/kg, respectively, significantly decreased the tumor size in mice inoculated with EAC cells. The higher dose (2 mg/kg) of ceramide B (2) particularly expressed the most pronounced decrease in serum levels of vascular endothelial growth factor -B (VEGF-B) and tumor necrosis factor-α (TNF-α) markers, as well as the expression levels of the growth factor midkine in tumor tissue relative to the EAC control group. The highest expression of apoptotic factors, p53, Bax, and caspase 3 was observed in the same group that received 2 mg/kg of ceramide B (2). Molecular docking simulations suggested that ceramides A (1) and B (2) could bind in the deep grove between the H2 helix and the Ser240-P250 loop of p53, preventing its interaction with MDM2 and leading to its accumulation. In conclusion, this study reports the cytotoxic, apoptotic, and antiangiogenic effects of ceramides isolated from the Red Sea algae Hypnea musciformis in an experimental model of EAC.

Anticancer and Antimicrobial Activity of Red Sea Seaweeds Extracts-Mediated Gold Nanoparticles

Biosynthesis of gold nanoparticles (AuNPs) is emerging as a better alternative to traditional chemical-based techniques. During this study, extracts of different marine algae species Ulva rigida (green algae), Cystoseira myrica (brown Algae), and Gracilaria foliifera (red Algae) were utilized as reducing and capping agents to synthesize AuNPs. AuNPs capped by U. rigida, C. myrica, and G. foliifera were confirmed by the appearance of surface plasmonic bands at 528, 540, and 543 nm, respectively. Transmission electron microscopy revealed mostly spherical shapes of AuNPs having a size of about 9 nm, 11 nm, and 13 nm for C. myrica, and G. foliifera extracts, respectively. Fourier transform-infrared spectroscopy (FTIR) illustrated the major chemical constituents of U. rigida, C. myrica, and G. foliifera. LC50 values of the biosynthesized AuNPs against Artemia salina nauplii were calculated at a range of concentrations (5-188 μg ml−1) after 16 to 24h. AuNPs concentration-dependent lethality was noted and U. rigida extracts-mediated AuNPs presented the lowest cytotoxicity. The biosynthesized AuNPs exhibited significant anticancer activity (86.83%) against MCF-7 cell lines (human breast adenocarcinoma cell lines) at 188 µg/ml concentration. G. foliifera demonstrated the highest anticancer value (92.13%) followed by C. myrica (89.82%), and U. rigida (86.83%), respectively. The AuNPs synthesized by different algal extracts showed variable antimicrobial activity against the tested pathogenic microorganisms. AuNPs of U. rigida extracts showed significant antimicrobial activity against dermatophytic fungi Trichosporon cataneum (30 mm) followed by Trichophyton mantigrophytes (25 mm). Furthermore, it also exhibited mild activity against Escherichia coli (17 mm), Cryptococcus neoformans (15 mm), Candida albicans (13 mm), and Staphylococcus aureus (11mm), respectively whereas no effects were observed against Bacillus cereus. To conclude, AuNPs can be effectively synthesized by marine algal species, and particularly U. rigida extracts could be effective reducing agents for the green AuNPs synthesis. These AuNPs could potentially serve as efficient alternative anticancer agents against human breast adenocarcinoma and anti-dermatophytes associated with skin infections.

Exploring the Bioactive Potentials of C60-AgNPs Nano-Composites against Malignancies and Microbial Infections

At present, the potential role of the AgNPs/endo-fullerene molecule metal nano-composite has been evaluated over the biosystems in-vitro. The intra-atomic configuration of the fullerene molecule (C60) has been studied in-vitro for the anti-proliferative activity of human breast adenocarcinoma (MDA-MB-231) cell lines and antimicrobial activity against a few human pathogens that have been augmented with the pristine surface plasmonic electrons and antibiotic activity of AgNPs. Furthermore, FTIR revealed the basic vibrational signatures at ~3300 cm−1, 1023 cm−1, 1400 cm−1 for O-H, C-O, and C-H groups, respectively, for the carbon and oxygen atoms of the C60 molecule. NMR studies exhibited the different footprints and magnetic moments at ~7.285 ppm, explaining the unique underlying electrochemical attributes of the fullerene molecule. Such unique electronic and physico-chemical properties of the caged carbon structure raise hope for applications into the drug delivery domain. The in-vitro dose-dependent application of C60 elicits a toxic response against both the breast adenocarcinoma cell lines and pathogenic microbes. That enables the use of AgNPs decorated C60 endo fullerene molecules to design an effective anti-cancerous drug delivery and antimicrobial agent in the future, bringing a revolutionary change in the perspective of a treatment regime.

Synthesis and crystal structure of cytotoxic copper(II) complex with 1,10-phenanthroline-5,6-dione and isothiazole derivative

Oligopyridine based copper(II) complexes are of interest to scientists as possible anticancer agents due to promising cytotoxic and DNA binding/cleaving properties. In this study, copper(II) complex [Cu(phendione)L2]·C2H5OH with 1,10-phenanthroline-5,6-dione (phendione) and 4,5-dichloro-isothiazole-3-carboxylic acid (HL) was synthesized and characterized by elemental analysis, IR-spectroscopy, X-ray powder diffraction and single-crystal X-ray diffraction. According to X-ray diffraction data, obtained compound is mononuclear complex with square pyramidal coordination environment of the central atom which is surrounded by two isothiazolate molecules and one phendione ligand. The X-ray diffraction data are confirmed by IR-spectroscopy data showing the presence of characteristic stretching vibration bands of the carbonyl and carboxyl groups of oligopyridine ligand and isothiazolate ions, respectively. Density functional theory (DFT) calculations for complex were carried out using the ADF software package to perform geometry optimization and frequency calculations that were in a good agreement with experimental IR spectrum. Cytotoxicity of complex and initial reagents was tested in vitro against HepG2 (human hepatocellular carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines. The complex showed high dose-dependent cytotoxic activity with the IC50 values of 0.60±0.03 µM and 0.96±0.13 µM, respectively, which is higher than the activity of cisplatin against these cell lines. The activity of the complex is due to the presence of phendione ligand, which exhibits a similar cytotoxic activity.

MDM2-Driven Ubiquitination Rapidly Removes p53 from Its Cognate Promoters

MDM2 is the principal antagonist of the tumor suppressor p53. p53 binds to its cognate DNA element within promoters and activates the transcription of adjacent genes. These target genes include MDM2. Upon induction by p53, the MDM2 protein binds and ubiquitinates p53, triggering its proteasomal degradation and providing negative feedback. This raises the question whether MDM2 can also remove p53 from its target promoters, and whether this also involves ubiquitination. In the present paper, we employ the MDM2-targeted small molecule Nutlin-3a (Nutlin) to disrupt the interaction of MDM2 and p53 in three different cancer cell lines: SJSA-1 (osteosarcoma), 93T449 (liposarcoma; both carrying amplified MDM2), and MCF7 (breast adenocarcinoma). Remarkably, removing Nutlin from the culture medium for less than five minutes not only triggered p53 ubiquitination, but also dissociated most p53 from its chromatin binding sites, as revealed by chromatin immunoprecipitation. This also resulted in reduced p53-responsive transcription, and it occurred much earlier than the degradation of p53 by the proteasome, arguing that MDM2 removes p53 from promoters prior to and thus independent of degradation. Accordingly, the short-term pharmacological inhibition of the proteasome did not alter the removal of p53 from promoters by Nutlin washout. However, when the proteasome inhibitor was applied for several hours, depleting non-conjugated ubiquitin prior to eliminating Nutlin, this compromised the removal of DNA-bound p53, as did an E1 ubiquitin ligase inhibitor. This suggests that the ubiquitination of p53 by MDM2 is necessary for its clearance from promoters. Depleting the MDM2 cofactor MDM4 in SJSA cells did not alter the velocity by that p53 was removed from promoters upon Nutlin washout. We conclude that MDM2 antagonizes p53 not only by covering its transactivation domain and by destabilization, but also by the rapid, ubiquitin-dependent termination of p53–chromatin interactions.

Potential benefits of Tricetin in medicine for the treatment of cancers and other health-related disorders: Medicinal importance and therapeutic benefit

Background: Medicinal plants have been used in medicine for the treatment of numerous diseases due to their medicinal properties and pharmacological activities. Popularity of herbal based drugs in the health sector has been increasing due to patient compliance and cost effectiveness. Herbal drugs derived from plant and animal source have been used in the Ayurvedic, Homeopathic, and Naturopathic system of medicine. Medicinal plants have been used as fuel, clothing, shelter and food material in worldwide since very early age. Phytoconstituents are pure plant chemicals found in different parts of the plant material. Flavonoids are important class of phytochemical found in medicinal plants and their derived products. Methods: In order to know the biological importance of tricetin, in the present investigation scientific data of tricetin in respect to their medicinal importance and pharmacological activities were collected and analyzed. Literature database such as Google, PubMed, Science Direct and Scopus has been searched using term tricetin and flavonoid. All the scientific information has been collected from these databases to know the biological importance of tricetin. Analytical data of tricetin have been also collected and analyzed in the present work to know the isolation, separation and identification procedure of trice Results: Scientific data analysis of different research work revealed the presence of tricetin in Triticum dicoccum, Lathyrus pratensis, Eucalyptus globules, Thuja occidentalis and Metasequoia glyptostroboides. Scientific data analysis signified biological importance of tricetin against different form of cancerous disorders, human osteosarcoma, glioblastoma multiforme, human breast adenocarcinoma, human non‑small cell lung cancer and liver cancer. Scientific data analysis also signified biological potential of tricetin against inflammation, neurodegenerative diseases, atherosclerosis, diabetes and respiratory syncytial virus infection. Scientific data analysis revealed the biological importance of tricetin against multidrug resistance and free radicals. Conclusions: Scientific data analysis revealed biological importance and pharmacological activities of tricetin against various form of human disorders including cancer, inflammation, neurodegeneration, atherosclerosis and diabetes.

In vitro/ In vivo Electrochemical Detection of Pt(II) Species

The biodistribution of chemotherapy compounds within tumor tissue is one of the main challenges in the development of antineoplastic drugs, and novel techniques for simple, non-expensive, sensitive, and selective detection of various analytes in tumors are of great importance. In this paper we propose the use of platinized carbon nanoelectrodes (PtNE) for electrochemical detection of platinum-based drugs in various biological models, including single cells and tumor spheroids in vitro, and inside solid tumors in vivo. We have demonstrated quantitative direct detection of Pt(II) in breast adenocarcinoma MCF-7 cells treated with cisplatin and cisplatin-based DNP prodrug. To realize the potential of this technique in advanced tumor models, we measured Pt(II) in 3D tumor spheroids in vitro and tumor-bearing mice in vivo. The concentration gradient of Pt (II) species correlated with the distance from the sample surface in MCF-7 tumor spheroids. We then performed detection of Pt(II) species in tumor-bearing mice treated intravenously with cisplatin and DNP. We found that there was deeper penetration of DNP in comparison to cisplatin. This research demonstrates a novel minimally invasive, real-time electrochemical technique for the study of platinum-based drugs.

Prognostic Analysis of Primary Breast Signet Ring Cell Carcinoma and Mucinous Breast Adenocarcinoma: A SEER Population-Based Study

BackgroundPrimary breast signet ring cell carcinoma (SRCC) is a rare type of breast cancer with typical morphological characteristics, high aggressiveness, and poor prognosis. SRCC is different from mucinous breast adenocarcinoma (MBC). However, only a few studies have explored the clinicopathological features and prognosis of SRCC and MBC.MethodsData retrieved from the Surveillance, Epidemiology, and End-Results (SEER) database (2004–2015) were used to explore the prognostic effect of clinicopathological features and treatment modalities on survival outcomes of SRCC and MBC patients. Kaplan–Meier plot analysis, multivariate Cox proportional risk model, propensity score matching (PSM), and subgroup analysis were performed.ResultsA total of 167 patients with SRCC and 11,648 patients with MBC were included in the study. SRCC patients exhibited higher histological grade (p < 0.001), larger tumor volume (p < 0.001), higher rate of lymph node metastasis (p < 0.001), and higher frequency of distal metastasis (p < 0.001) compared with MBC patients. Cox proportional hazards regression analysis showed that SRCC patients had lower overall survival (OS) and breast cancer-specific survival (BCSS) compared with MBC patients. Subgroup survival analysis showed that the SRCC patients had lower OS and BCSS in subgroups including younger than 60 years old, white race, married, without chemotherapy, and received radiotherapy compared with the MBC patients in these subgroups. In addition, the SRCC patients had lower BCSS in subgroups including other races (including Asian or Pacific Islander and American Indian/Alaska Native), without surgery, and lymph node metastasis.ConclusionThe findings showed that primary breast SRCC patients have unique clinical characteristics and worse prognosis compared with MBC patients. Notably, different treatment methods resulted in different prognosis for SRCC and MBC types; therefore, SRCC patients should be distinguished from MBC patients to improve efficacy of treatment.