Novel carbamodithioate regulates cellular hypoxia through chemical activation of prolyl hydroxylase-2 for breast cancer chemoprevention.

Inhibition of prolylhydroxylase-2 (PHD-2) in both normoxic and hypoxic cells is a critical component of solid tumours. The present study aimed to identify small molecules with PHD-2 activation potential. Virtually screening 4342 chemical compounds for structural similarity to R59949 and docking with PHD-2. To find the best drug candidate, hits were assessed for drug likeliness, antihypoxic and antineoplastic potential. The selected drug candidate's PHD-2 activation, cytotoxic and apoptotic potentials were assessed using 2-oxoglutarate, MTT, AO/EtBr and JC-1 staining. The drug candidate was also tested for its in-vivo chemopreventive efficacy against DMBA-induced mammary gland cancer alone and in combination with Tirapazamine (TPZ). Virtual screening and 2-oxoglutarate assay showed BBAP-6 as lead compound. BBAP-6 exhibited cytotoxic and apoptotic activity against ER+ MCF-7. In carmine staining and histology, BBAP-6 alone or in combination with TPZ restored normal surface morphology of the mammary gland after DMBA produced malignant alterations. Immunoblotting revealed that BBAP-6 reduced NF-κB expression, activated PHD-2 and induced intrinsic apoptotic pathway. Serum metabolomics conducted with 1H NMR confirmed that BBAP-6 prevented HIF-1α and NF-κB-induced metabolic changes in DMBA mammary gland cancer model. In a nutshell, it can be concluded that BBAP-6 activates PHD-2 and exhibits anticancer potential.

Elucidating the impact of sanitary waste on the formation of fat, oil and grease deposits in sewer systems.

The accumulation of fat, oil and grease (FOG) deposits in sanitary sewer systems is a significant cause of sewer overflows, mainly due to their tendency to adhere to pipe walls. The aim of this study is to (i) develop laboratory-prepared FOG deposits using a mixture of iron (Fe) and aluminium (Al) metal ions, fatty acids, saccharides and cooked oils, in addition to various sanitary waste materials such as paper towels, wipes and pads and (ii) examine the characteristics of these FOG deposits. The goals of this study were to (i) gain a deeper understanding of the impact of sanitary waste on the formation of FOG deposits and (ii) discuss the detailed physiochemical properties of these FOG deposits. The findings revealed that FOG deposits can vary in nature, appearing as either a smooth, paste-like substance or a coarse, semi-solid material, depending on the types of waste present in the sewer. Analysis of the fatty acid profile indicated that the FOG deposits with wipes have the highest viscosity (3.2 × 104 Pa s) and larger composition of smaller chain saturated fatty acids (caprylic acid 0.64%, undecanoic acid 5.61%, lauric acid 4.65%, myristic acid 3.21% and palmitic 8.38%). In contrast, FOG deposits with Fe and Al metal impurities have higher heat resistance and thermal stability (melting point of 125 °C) and have larger composition of long chain fatty acids. Furthermore, FTIR analysis confirmed that these FOG deposits are composed of metallic salts of fatty acids, aligning with samples from sewer lines. Our results suggest that FOG deposit formation involves the aggregation of excess calcium, which compresses free fatty acid micelles, and a saponification reaction between the calcium aggregates and free fatty acids. This research illuminates the complex processes behind FOG deposit formation and their varied characteristics, providing valuable insights into potential strategies for preventing FOG-related sewer blockages.

Clinical metabolomics by NMR revealed serum metabolic signatures for differentiating sarcoidosis from tuberculosis.

BACKGROUND: Pulmonary sarcoidosis (SAR) and tuberculosis (TB) are two granulomatous lung-diseases and often pose a diagnostic challenge to a treating physicians. OBJECTIVE: The present study aims to explore the diagnostic potential of NMR based serum metabolomics approach to differentiate SAR from TB. MATERIALS AND METHOD: The blood samples were obtained from three study groups: SAR (N = 35), TB (N = 28) and healthy normal subjects (NC, N = 56) and their serum metabolic profiles were measured using 1D 1H CPMG (Carr-Purcell-Meiboom-Gill) NMR spectra recorded at 800 MHz NMR spectrometer. The quantitative metabolic profiles were compared employing a combination of univariate and multivariate statistical analysis methods and evaluated for their diagnostic potential using receiver operating characteristic (ROC) curve analysis. RESULTS: Compared to SAR, the sera of TB patients were characterized by (a) elevated levels of lactate, acetate, 3-hydroxybutyrate (3HB), glutamate and succinate (b) decreased levels of glucose, citrate, pyruvate, glutamine, and several lipid and membrane metabolites (such as very-low/low density lipoproteins (VLDL/LDL), polyunsaturated fatty acids, etc.). CONCLUSION: The metabolic disturbances not only found to be well in concordance with various previous reports, these further demonstrated very high sensitivity and specificity to distinguish SAR from TB patients suggesting serum metabolomics analysis can serve as surrogate method in the diagnosis and clinical management of SAR.

Development and in vitro characterization of docetaxel-loaded ligand appended solid fat nanoemulsions for potential use in breast cancer therapy.

CONTEXT: Breast cancer accounts for 23% of all newly occurring cancers in women worldwide and represents 13.7% of all cancer deaths. Available chemotherapeutic agents are limited largely due to the low accumulation of chemotherapeutics at the tumors relative to their accumulation at normal (healthy) organs due to developed multidrug resistance (MDR) which translates into increased toxicities. OBJECTIVES: To enhance the anticancer potency of docetaxel (DTX), by encapsulating it inside the nanosize lipid particles (folate-conjugated PEG-solid fat nanoemulsions) stabilized by soya phosphatidylcholine (PC) for targeting folate receptors in breast cancer. MATERIALS AND METHODS: Tristearin and soya PC-based solid fat nanoemulsions were prepared by cast film technique followed by sonication and modified by coating them with folate receptor-specific ligand (folate-PEG-cholesterol). The surface modified solid fat nanoemulsions and their plain counterparts were characterized for size, shape, lamellarity, zeta potential and entrapment efficiency using scanning electron microscopy, zetasizer and minicolumn centrifugation. The in vitro release profile (dialysis bag technique) and in vitro cytotoxicity (MTT assay) of the developed formulations were evaluated. RESULTS: The TEM photograph showed homogenous and spherical nature of the particles. The IC50 values of docetaxel solution, plain solid fat nanoemulsions, and folate-conjugated PEG-solid fat nanoemulsions were found to be 14.2, 64.9, and 28.8 µM/ml, respectively. Strong fluorescence was observed in the HeLa cells treated with folate-conjugated PEG-solid fat nanoemulsions which showed higher cellular uptake of ligand-appended solid fat nanoemulsions than plain solid fat nanoemulsions. DISCUSSION AND CONCLUSION: The results indicated that folate was effective in promoting the internalization of solid fat nanoemulsions encapsulating DTX to the folate receptor-positive tumor cells. This opens the new possibility for non-immunogenic, site-specific delivery of bioactive(s).

EGFR targeted PLGA nanoparticles using gemcitabine for treatment of pancreatic cancer.

The present study aimed to prepare and characterize anti EGFR monoclonal antibody (mab) conjugated Gemcitabine loaded PLGA nanoparticles for their selective delivery to pancreatic cells and evaluation of the systems in vitro. It was observed that direct covalent coupling of antibodies to glutaraldehyde activated nanoparticles is an appropriate method to achieve cell-type specific drug carrier systems based on polymeric nanoparticles that have potential to be applied for targeted chemotherapy in EGFR positive cancer.