Discovery of Alkyl Triphenylphosphonium Pinostrobin Derivatives as Potent Anti-Breast Cancer Agents.

Pinostrobin demonstrated anticancer properties, but its hydrophobic feature led to a reduction in bioavailability. The mitochondria-targeted approach successfully synthesized eight new alkyl triphenylphosphonium pinostrobin derivatives (1-8) with good yield in this study. Seven compounds (1-3, 5-8) showed greater cytotoxic potency against the human MCF-7 breast cancer cell line than pinostrobin. Molecular docking studies were performed with two important targets in hormone-dependent anticancer strategies, estrogen receptor α (ERα) ligand binding domains, 3ERT (antagonist recognition and antiproliferative function), and 1GWR (agonist recognition and pro-proliferative function). In addition, the MD simulation study of the two most potent compounds (2 and 3) complexed with both ERα forms suggested that compounds 2 and 3 could serve as favourable antagonists. Furthermore, the in silico ADMET prediction indicated that compounds 2 and 3 could be potential drug candidates.

A new apotirucallane-type protolimonoid from the leaves of Paramignya trimera.

This study presents a phytochemical analysis of the leaves of Paramignya trimera, revealing the isolation of a new apotirucallane-type protolimonoid, identified as 25-O-methyl-1,2-dihydroprotoxylocarpin D (1), along with two known compounds (2 and 3). The known compounds were identified as (20S,21R,23R)-21,23-epoxy-7α,24,25-trihydroxy-21-O-methyl-3-oxoapotirucalla-14-ene (2) and 7α,24,25-trihydroxy-3-oxoapotirucalla-14-en-21,23-olide (3). The three apotirucallane-type protolimonoids (1-3) did not exhibit cytotoxicity against MCF-7 cells at a concentration of 100 µM. Interestingly, when MCF-7 cells were treated with compound 1 at various concentrations, a notable stimulatory response was observed, leading to a significant increase in cell viability, up to 127%.

Preparation of self-assembly silica redox nanoparticles to improve drug encapsulation and suppress the adverse effect of doxorubicin.

Background and Purpose: The utilization of doxorubicin (DOX) in clinal trials is also challenging owing to its adverse effects, including low oral bioavailability, generation of reactive oxygen species (ROS), cardiotoxicity, and epithelial barrier damage. Recently, scavenging of ROS reduced the cytotoxicity of DOX, suggesting a new approach for using DOX as an anticancer treatment. Thus, in this study, non-silica and silica redox nanoparticles (denoted as RNPN and siRNP, respectively) with ROS scavenging features have been designed to encapsulate DOX and reduce its cytotoxicity. Experimental Approach: DOX-loaded RNPN (DOX@RNPN) and DOX-loaded siRNP (DOX@siRNP) were prepared by co-dissolving DOX with RNPN and siRNP, respectively. The size and stability of nanoparticles were characterized by the dynamic light scattering system. Additionally, encapsulation efficiency, loading capacity, and release profile of DOX@RNPN and DOX@siRNP were identified by measuring the absorbance of DOX. Finally, the cytotoxicity of DOX@RNPN and DOX@siRNP against normal murine fibroblast cells (L929), human hepatocellular carcinoma cells (HepG2), and human breast cancer cells (MCF-7) were also investigated. Key results: The obtained result showed that RNPN exhibited a pH-sensitive character while silanol moieties improved the stability of siRNP in physiological conditions. DOX@RNPN and DOX@siRNP were formed at several tens of nanometers in diameter with narrow distribution. Moreover, DOX@siRNP stabilized under different pH buffers, especially gastric pH, and improved encapsulation of DOX owing to the addition of silanol groups. DOX@RNPN and DOX@siRNP maintained anticancer activity of DOX against HepG2, and MCF-7 cells, while their cytotoxicity on L929 cells was significantly reduced compared to free DOX treatment. Conclusion: DOX@RNPN and DOX@siRNP could effectively suppress the adverse effect of DOX, suggesting the potential to become promising nanomedicines for cancer treatments.

Effects of a low-iodine diet in post-thyroidectomy thyroid cancer patients undergoing I131 therapy at the Vietnam National Cancer Hospital.

Background: I131 therapy is regarded as an "internal surgery" (i.e., a non-invasive approach involving no incision or bleeding) that supports "external surgery" (i.e., using a scalpel) in completely eradicating the root cause of thyroid cancer. Limiting iodine intake is of paramount importance in I131 therapy. I131 therapy protocols recommend that patients follow a low-iodine diet, ideally with a maximum iodine intake of 50 µg/day for two weeks before the I131 therapy. Methods: A pre-post compassion uncontrolled clinic intervention study was conducted on a group of over 70 post-thyroidectomy thyroid cancer patients with indications for I131 therapy at the Vietnam National Cancer Hospital from December 2020 to December 2022. Aim: It aimed to assess the effects of a low-iodine diet on post-thyroidectomy thyroid cancer patients with indications for I131 therapy. Results: The study found that following the intervention, the percentage of participants at risk of mild to moderate malnutrition, as assessed by the PG-SGA tool, decreased to 4.3% from 40.0% before the intervention, with a statistically significant difference of p < 0.001. There was a considerable improvement in the low calcemia level among the study participants, with 35.7% of patients experiencing hypocalcemia prior to the intervention, which reduced to 17.1% after the intervention. This difference was statistically significant (p = 0.01). The study also revealed a urinary iodine level improvement among the study participants. Before the intervention, patients' average urinary iodine level was 14.9 ± 11.3 µg/dl. Following the intervention, it reduced to 12.7 ± 3.9 µg/dl, although this difference was not statistically significant (p = 0.29). Patients' quality of life after adhering to the low-iodine diet tended to decline; however, the change in scores before and after the intervention did not show a significant difference. Conclusion: Despite its negative impact on patients' quality of life, active nutrition counseling and intervention during the low-iodine diet contributed to the substantial improvement in the hypocalcemia level and the reduced urinary iodine level among patients, which in turn could enhance the efficacy of the subsequent I131 therapy.

Tailoring chemical compositions of biodegradable mesoporous organosilica nanoparticles for controlled slow release of chemotherapeutic drug.

Biodegradable periodic mesoporous organosilica nanoparticles (B-PMO) are an outstanding nanocarrier due to their biodegradability and high drug load capacities. The present study describes a synthesis of a phenylene-containing tetrasulfide based B-PMO, named P4S. The incorporation of aromatic phenylene groups into the framework creates a strong interaction between nanoparticles (NPs) with aromatic rings in the cordycepin molecules. This results in the low release profile under various conditions. In addition, the replacement of this linker slowed the degradation of nanoparticles. The physicochemical properties of the nanoparticles are evaluated and compared with a biodegradable ethane-containing tetrasulfide based PMO and a non-degradable MCM-41. The biodegradability of P4S is also demonstrated in a reducing environment and the 100 nm spherical nanoparticles completely decomposed within 14 days. The porous structure of P4S has a high loading of hydrophilic cordycepin (approximately 731.52 mg g-1) with a slow releasing speed. The release rates of P4S NPs are significantly lower than other materials, such as liposomes, gelatin nanoparticles, and photo-crosslinked hyaluronic acid methacrylate hydrogels, in the same solution. This specific release behavior could guarantee drug therapeutic effects with minimum side-effects and optimized drug dosages. Most importantly, according to the in vitro cytotoxicity study, cordycepin-loaded P4S NPs could retain the toxicity against liver cancer cell (HepG2) while suppressed the cytotoxicity against normal cells (BAEC).

Secretory expression of ß-mannanase from Bacillus circulans NT 6.7 in Lactobacillus plantarum.

The ß-mannanase gene of Bacillus circulans NT 6.7 was successfully cloned in Lactobacillus plantarum WCFS1 using the pSIP403 expression vector and secreted to the supernatant rather than accumulated in the cells. The highest activity was achieved by controlling the pH at 6 during cultivation. Maximum mannanase activities detected in the supernatant and cell-free extract of 200 ml MRS broth were 8.2 and 0.86 U/ml, respectively. Enzyme activity in the supernatant increased to 27 U/ml by fermentation in a 5-L bioreactor with automatic pH control. The optimum temperature of recombinant ß-mannanase was 50 °C and stable between 30 and 50 °C. The optimum pH was 6 with stability in the range 5-7. Enzyme activity slightly increased with Co2+ but was strongly inhibited by EDTA. The enzyme exhibited high specificity to galactomannan substrates. The main products of copra meal and locust bean gum hydrolysis were manno-oligosaccharides. Therefore, recombinant ß-mannanase produced from a food grade host, L. plantarum WCFS1, showed potential for use in manno-oligosaccharides production and other food-related applications.

Synthesis and cytotoxic evaluation of novel indenoisoquinoline-substituted triazole hybrids.

The synthesis of various substituted triazole-indenoisoquinoline hybrids was performed based on a CuI-catalyzed 1,3-cycloaddition between propargyl-substituted derivatives and the azide-containing indenoisoquinoline. Besides, a variety of N-(alkyl)propargylindenoisoquinolines was used as substrates for the construction of triazole-indenoisoquinoline-AZT conjugated via a click chemistry-mediated coupling with 3'-azido-3'-deoxythymidine (AZT). Thus, twenty three new indenoisoquinoline-substituted triazole hybrids were successfully prepared and evaluated as cytotoxic agents, revealing an interesting anticancer activity of four triazole linker-indenoisoquinoline-AZT hybrids in KB and HepG2 cancer cell lines.

Cloning, secretory expression and characterization of recombinant ß-mannanase from Bacillus circulans NT 6.7.

The mannanase gene of B. circulans NT 6.7 was cloned and expressed in an Escherichia coli expression system. The B. circulans NT 6.7 mannanase gene consists of 1,083 nucleotides encoding a 360-amino acid residue long polypeptide, belonging to glycoside hydrolase family 26. The full-length mannanase gene including its native signal sequence was cloned into the vector pET21d and expressed in E. coli BL21 (DE3). ß-Mannanase activities in the culture supernatant and crude cell extract were 37.10 and 515 U per ml, respectively, with most of the activity in the cell extract attributed to the periplasmic fraction. In contrast, expression of mannanase was much lower when using the B. circulans NT 6.7 mannanase gene without its signal sequence. The optimum temperature of recombinant ß-mannanase activity was 50°C and the optimum pH was 6.0. The enzyme was very specific for ß-mannan substrates with a preference for galactomannan. Hydrolysis products of locust bean gum were various mannooligosaccharides including mannohexaose, mannopentaose, mannotetraose, mannotriose and mannobiose, while mannose could not be detected. In conclusion, this expression system is efficient for the secretory production of recombinant ß-mannanase from B. circulans NT 6.7, which shows good characteristics for various applications.

CD137 expressed on neutrophils plays dual roles in antibacterial responses against Gram-positive and Gram-negative bacterial infections.

Severe sepsis and septic shock caused mainly by bacterial infections are life-threatening conditions that urge the development of novel therapies. However, host responses to and pathophysiology of sepsis have not been clearly understood, which remains a major obstacle for the development of effective therapeutics. Recently, we have shown that stimulation of a costimulatory molecule, CD137, enhanced survival of mice infected with the Gram-positive (G(+)) intracellular bacterium Listeria monocytogenes but decreased survival in a polymicrobial sepsis model. Herein, we report that CD137 deficiency or blocking of CD137 signaling decreased antibacterial responses of mice infected with G(+) bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis) but increased these responses in mice infected with Gram-negative (G(-)) bacteria (Escherichia coli, Pseudomonas aeruginosa, and Salmonella enterica serovar Typhimurium). Consistent with these findings, stimulation of CD137 by administration of agonistic antibody enhanced responses against G(+) bacteria, whereas it decreased these responses against G(-) bacteria. Neutrophils were responsible for CD137-mediated opposite roles in control of G(+) and G(-) bacterial infections. Stimulation of CD137 enhanced activities of neutrophils against S. aureus but decreased these activities against E. coli, while CD137 blocking produced opposite results with the stimulation of CD137 in vivo and in vitro. Furthermore, we found that combined signaling of CD137 and Toll-like receptor 2 (TLR2) induced synergistic production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) by neutrophils, but combined signaling of CD137 and TLR4 did not. Our data strongly suggest that CD137 may play a dual role in sepsis in association with TLRs.

Heterologous expression and characterization of an N-acetyl-ß-D-hexosaminidase from Lactococcus lactis ssp. lactis IL1403.

The lnbA gene of Lactococcus lactis ssp. lactis IL1403 encodes a polypeptide with similarity to lacto-N-biosidases and N-acetyl-ß-D-hexosaminidases. The gene was cloned into the expression vector pET-21d and overexpressed in Escherichia coli BL21* (DE3). The recombinant purified enzyme (LnbA) was a monomer with a molecular weight of approximately 37 kDa. Studies with chromogenic substrates including p-nitrophenyl N-acetyl-ß-D-glucosamine (pNP-GlcNAc) and p-nitrophenyl N-acetyl-ß-D-galactosamine (pNP-GalNAc) showed that the enzyme had both N-acetyl-ß-D-glucosaminidase and N-acetyl-ß-D-galactosaminidase activity, thus indicating that the enzyme is an N-acetyl-ß-D-hexosaminidase. K(m) and k(cat) for pNP-GlcNAc were 2.56 mM and 26.7 s(-1), respectively, whereas kinetic parameters for pNP-GalNAc could not be determined due to the K(m) being very high (>10 mM). The optimal temperature and pH of the enzyme were 37 °C and 5.5, respectively, for both substrates. The half-life of activity at 37 °C and pH 6.0 was 53 h, but activity was completely abolished after 30 min at 50 °C, meaning that the enzyme has relatively low temperature stability. The enzyme was stable in the pH 5.5-8 range and was unstable at pH below 5.5. Studies with natural substrates showed hydrolytic activity on chito-oligosaccharides but not on colloidal chitin or chitosan. Transglycosylation products were not detected. In all, the data suggest that LnbA's role may be to degrade chito-oligosaccharides that are produced by the previously described chitinolytic system of L. lactis.

Cloning and expression of the beta-galactosidase genes from Lactobacillus reuteri in Escherichia coli.

Heterodimeric beta-galactosidase of Lactobacillus reuteri L103 is encoded by two overlapping genes, lacL and lacM. The lacL (1887bp) and lacM (960bp) genes encode polypeptides with calculated molecular masses of 73,620 and 35,682Da, respectively. The deduced amino acid sequences of lacL and lacM show significant identity with the sequences of beta-galactosidases from other lactobacilli and Escherichia coli. The coding regions of the lacLM genes were cloned and successfully overexpressed in E. coli using an expression system based on the T7 RNA polymerase promoter. Expression of lacL alone and coexpression of lacL and lacM as well as activity staining of both native and recombinant beta-galactosidases suggested a translational coupling between lacL and lacM, indicating that the formation of a functional beta-galactosidase requires both genes. Recombinant beta-galactosidase was purified to apparent homogeneity, characterized and compared with the native beta-galactosidase from L. reuteri L103.