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The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn't inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.

Heparin is a highly sulfated, complex polysaccharide and widely used anticoagulant pharmaceutical. In this work, we chemoenzymatically synthesized perdeuteroheparin from biosynthetically enriched heparosan precursor obtained from microbial culture in deuterated medium. Chemical de-N-acetylation, chemical N-sulfation, enzymatic epimerization, and enzymatic sulfation with recombinant heparin biosynthetic enzymes afforded perdeuteroheparin comparable to pharmaceutical heparin. A series of applications for heavy heparin and its heavy biosynthetic intermediates are demonstrated, including generation of stable isotope labeled disaccharide standards, development of a non-radioactive NMR assay for glucuronosyl-C5-epimerase, and background-free quantification of in vivo half-life following administration to rabbits. We anticipate that this approach can be extended to produce other isotope-enriched glycosaminoglycans.

Background/synopsisLow-dose aspirin is an effective drug for the prevention of cardiovascular disease (CVD) events but individuals with diabetes mellitus can be subject to 'aspirin resistance'. Thus, aspirin's effect in these individuals is controversial. Higher blood levels of seafood-derived omega-3 polyunsaturated fatty acids (ω3) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have beneficial effects in reducing risk of CVD events but few studies have examined the interaction of plasma EPA and DHA with aspirin ingestion.Objective/purposeOur study examined the combinatory effects of EPA, DHA, and aspirin ingestion on HDL-cholesterol (HDL-C) and apoA-I exchange (shown to be associated with CVD event risk).Methods30 adults with Type 2 diabetes mellitus ingested aspirin (81mg/day) for 7 consecutive days, EPA+DHA (2.6g/day) for 28 days, then both for 7 days. Plasma was collected at baseline and at 5 subsequent visits including 4h after each aspirin ingestion. Mixed model methods were used to determine HDL-C-concentrations and apoA-I exchange compared to the baseline visit values. LOWESS curves were used for non-linear analyses of outcomes to help discern change patterns, which was followed by piecewise linear functions for formal testing of curvilinear relationships.ResultsSignificant changes (p < 0.05) compared to baseline in both HDL-C-concentrations and apoA-I exchange were present at different times. After 7 days of aspirin-only ingestion, apoA-I exchange was significantly modified by increasing levels of DHA concentration, with increased apoA-I exchange observed up until log(DHA) of 4.6 and decreased exchange thereafter (p = 0.03). These LOWESS curve effects were not observed for EPA or HDL-C (p > 0.05). Aspirin's effects on apoA-I exchange were the greatest when EPA or DHA concentrations were moderate compared to high or low. Comparison of EPA, DHA, and EPA+DHA LOWESS curves, demonstrated that the majority of the effect is due to DHA.ConclusionOur results strongly suggest that plasma concentrations of EPA and DHA influence aspirin effects on lipid mediators of CVD event risk where their concentrations are most beneficial when moderate, not high or low. These effects on HDL-C cholesterol and apoA-I exchange are novel. Personalized dosing of DHA in those who take aspirin may be a beneficial option for patients with type 2 diabetes mellitus.

Over the last few decades, cancer has been considered a clinical challenge, being among the leading causes of mortality all over the world. Although many treatment approaches have been developed for cancer, chemotherapy is still the most utilized in the clinical setting. However, the available chemotherapeutics-based treatments have several caveats including their lack of specificity, adverse effects as well as cancer relapse and metastasis which mainly explains the low survival rate of patients. Lipid nanoparticles (LNPs) have been utilized as promising nanocarrier systems for chemotherapeutics to overcome the challenges of the currently applied therapeutic strategies for cancer treatment. Loading chemotherapeutic agent(s) into LNPs improves drug delivery at different aspects including specific targeting of tumours, and enhancing the bioavailability of drugs at the tumour site through selective release of their payload, thus reducing their undesired side effects on healthy cells. This review article delineates an overview of the clinical challenges in many cancer treatments as well as depicts the role of LNPs in achieving optimal therapeutic outcomes. Moreover, the review contains a comprehensive description of the many LNPs categories used as nanocarriers in cancer treatment to date, as well as the potential of LNPs for future applications in other areas of medicine and research. [ABSTRACT FROM AUTHOR]

Background: Curcumin has been used in the treatment of several diseases; however, its low pharmacologic profile reduces its therapeutic use. Towards improving its biological activity, nanoformulations have emerged. Thus, we aimed to determine whether curcumin nanoparticles (Cur-NPs) coated with PEG/chitosan improve the treatment of liver cancer (LC) cells and underpin the molecular mechanisms underlying their anti-cancer activity. Methods: Cur-NPs were synthesised in the form of Cur-PLGA-PEG/chitosan NPs. The effect of Cur-NPs was assessed in HepG2 and Huh 7 LC cells and THLE-2 normal liver cells. Results: The size of synthesised Cur-NPS was determined in the standard range of 141.2 ± 47.5 nm. Compared to THLE-2 cells, LC cells treated with Cur-NPs exerted cytotoxicity at 6.25 μg/mL after 48h. Treatment of HepG-2 cells with 2.5 μg/mL of Cur-NPs inhibited cell migration and this inhibition was augmented at 10 μg/mL (p<0.001). Treatment of chicken embryo with 5 μg/mL Cur-NPs reduced angiogenesis (p<0.001) of 4-day-old embryos. The nanoformulation upregulated Bax and p53 and downregulated Bcl-2 in a concentration-dependent manner and subsequently induce apoptosis in HepG-2 cells. Conclusion: Treatment of LC cells with Cur-NPs decreased cell proliferation, migration, and angiogenesis, and induced cell death by promoting the proapoptotic pathway. [ABSTRACT FROM AUTHOR]