We present an efficient method for the creation of atomistic model structures of cross-linked polymer matrices. The method consists of preparation of a physical mixture of the monomer and the ...cross-linker molecules in the box followed by a single-step polymerization of the entire mixture. For this purpose, the simulated annealing algorithm is used to identify pairs of reacting atoms that are spatially close. The technique is used to create five structures of cross-linked epoxy as well as cross-linked epoxy−POSS (i.e., polyhedral oligomeric silsesquioxane) nanocomposite. The models so generated are characterized with respect to the density, volume−temperature behavior, and the detailed molecular structure. Our results show that incorporation of POSS particles (at 5 wt %) in the cross-linked epoxy resin leads to a weak tendency for lowering the coefficient of volume thermal expansion but does not cause a measurable change in the glass transition temperature.
Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen ...receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models. In addition, recent studies reported that anti-androgen therapy shows preclinical efficacy in androgen-receptor (AR)-positive TNBC cells. Here we examined the effect of palbociclib in combination with an anti-androgen enzalutamide in TNBC cells.
MDA-MB-453, BT-549, MDA-MB-231 and MDA-MB-468 TNBC cell lines were used for in vitro studies. Protein expressions were assessed by Western blot analysis. Cytostatic effect was examined by MTT assay. Cell cycle and apoptosis were examined by flow cytometry.
Palbociclib showed inhibitory effect in RB-proficient TNBC cells, and enzalutamide inhibited cell viability in AR-positive TNBC cells. Enzalutamide treatment could enhance the palbociclib-induced cytostatic effect in AR-positive/RB-proficient TNBC cells. In addition, palbociclib-mediated G1 arrest in AR-positive/RB-proficient TNBC cells was attenuated by RB knockdown.
Our study provided a preclinical rationale in selecting patients who might have therapeutic benefit from combining CDK4/6 inhibitors with AR antagonists.
Synthetic organic chemists endeavor to develop new reaction conditions, improve product yields, and enhance atom economy (synthetic methodologies), whereas the material scientists strive to create ...novel functional molecules/structures, increase device stabilities, and promote power conversion efficiencies via device engineering (organic optoelectronics). However, these two prominent research fields seem to have no intersections. Since joining national central university in 2012, our research philosophy aims to narrow, or rather to bridge the gap between synthetic methodologies and π‐functional organic materials. In contrast to using multistep synthetic approaches based on Suzuki‐ or Stille coupling reactions, this personal account describes various step‐saving and viable synthesis‐shortcuts developed by our group, to access thiophene‐based small molecules for optoelectronic applications. We expect these succinct and user‐friendly alternative pathways designed by synthetic chemists would help material scientists to reach their target molecules in a more step‐economical manner.
C−H bond activations and organic solar cells seem to be two parallel research fields. We have been endeavouring to bridge the gap from synthetic methodologies to organic optoelectronic materials. This article briefly reviews our recent achievements on the development of step‐saving synthetic routes to various π‐conjugated small molecules for use as the “active ingredients” in dye‐sensitized solar cells (DSSCs) or perovskite solar cells (PSCs), mainly through pre‐optimized direct C−H/C−X or C−H/C−H coupling reactions.
Background
Cisplatin (CP) is a widely used chemotherapeutic drug with subsequent adverse effects on different organs and tissues including skeletal muscle loss and atrophy as the most common clinical ...symptoms. The molecular mechanism of cisplatin‐induced muscle atrophy is not clearly understood. However, recent significant advances indicate that it is related to an imbalance in both the protein status and apoptosis. Capsaicin (CAP) is one of the major ingredients in chilli peppers. It is a valuable pharmacological agent with several therapeutic applications in controlling pain and inflammation with particular therapeutic potential in muscle atrophy. However, the mechanisms underlying its protective effects against cisplatin‐induced muscle loss and atrophy remain largely unknown. This study aims to investigate capsaicin's beneficial effects on cisplatin‐induced muscle loss and atrophy in vitro and in vivo.
Methods
The anti‐muscle‐atrophic effect of capsaicin on cisplatin‐induced muscle loss was investigated using in vivo and in vitro studies. By using the pretreatment model, pretreated capsaicin for 24 h and treated with cisplatin for 48 h, we utilized a C2C12 myotube formation model where cell viability analysis, immunofluorescence, and protein expression were measured to investigate the effect of capsaicin in hampering cisplatin‐induced muscle atrophy. C57BL/6 mice were administered capsaicin (10, 40 mg/kg BW) as a pretreatment for 5 weeks and cisplatin (3 mg/kg BW) for seven consecutively days to assess muscle atrophy in an animal model for protein and oxidative stress examination, and the grip strength was tested to evaluate the muscle strength.
Results
Our study results indicated that cisplatin caused lower cell viability and showed a subset of hallmark signs typically recognized during atrophy, including severe reduction in the myotube diameter, repression of Akt, and mTOR protein expression. However, pretreatment with capsaicin could ameliorate cisplatin‐induced muscle atrophy by up‐regulating the protein synthesis in skeletal muscle as well as down‐regulating the markers of protein degradation. Additionally, capsaicin was able to downregulate the protein expression of apoptosis‐related markers, activated TRPV1 and autophagy progress modulation and the recovery of lysosome function. In vivo, capsaicin could relieve oxidative stress and cytokine secretion while modulating autophagy‐related lysosome fusion, improving grip strength, and alleviating cisplatin‐induced body weight loss and gastrocnemius atrophy.
Conclusions
These findings suggest that capsaicin can restore cisplatin‐induced imbalance between protein synthesis and protein degradation pathways and it may have protective effects against cisplatin‐induced muscle atrophy.
More than 3 years into the global pandemic, the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains a significant threat to public health. Immunities acquired from infection or ...current vaccines fail to provide long term protection against subsequent infections, mainly due to their fast‐waning nature and the emergence of variants of concerns (VOCs) such as Omicron. To overcome these limitations, SARS‐CoV‐2 Spike protein receptor binding domain (RBD)‐based epitopes are investigated as conjugates with a powerful carrier, the mutant bacteriophage Qβ (mQβ). The epitope design is critical to eliciting potent antibody responses with the full length RBD being superior to peptide and glycopeptide antigens. The full length RBD conjugated with mQβ activates both humoral and cellular immune systems in vivo, inducing broad spectrum, persistent, and comprehensive immune responses effective against multiple VOCs including Delta and Omicron variants, rendering it a promising vaccine candidate.
To overcome the limitations of current anti‐SARS‐CoV‐2 vaccines, SARS‐CoV‐2 Spike protein receptor binding domain (RBD)‐based epitopes are investigated as conjugates with a powerful carrier, the mutant bacteriophage Qβ (mQβ). Immunization with the new mQβ‐RBD conjugate activates both humoral and cellular immune systems and induces broad spectrum, persistent, and comprehensive immune responses effective against multiple variants of concerns.
Epithelial ovarian cancer (EOC) patients are generally diagnosed at an advanced stage, usually relapse after initial treatments, which include debulking surgery and adjuvant platinum-based ...chemotherapy, and eventually have poor 5-year survival of less than 50%. In recent years, promising survival benefits from maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of EOC in newly diagnosed and recurrent disease. Identification of
BRCA
mutations and/or homologous recombination deficiency (HRD) is critical for selecting patients for PARPi treatment. However, the currently available HRD assays are not perfect predictors of the clinical response to PARPis in EOC patients. In this review, we introduce the concept of synthetic lethality, the rationale of using PARPi when HRD is present in tumor cells, the clinical trials of PARPi incorporating the HRD assays for EOC, the current HRD assays, and other HRD assays in development.
The purpose of this study was to investigate the preventive effects of fucoidan (Fc) and fucoxanthin (Fx) on hyperuricemic rats. Sprague Dawley (SD) rats were randomly assigned to seven groups: a ...control group, a hyperuricemia (HUA) group, low- and high-dose Fx groups, a Fc group, a combination Fc and Fx group, and a positive control group. Three weeks after the interventions, each group was given potassium oxonate (PO) and hypoxanthine (HX) to induce HUA in all groups except for the control group, and the rats were then sacrificed. Blood and urine were analyzed for biochemical properties, and differences in urine volume were determined. Livers and kidneys were collected to analyze xanthine oxidase (XO) activity and the expression of uric acid (UA) transporter-related proteins (GLUT9, ABCG2, OAT1, URAT1). The results show that HUA was successfully induced by PO/HX after 4 h of administration. The activity of XO was significantly reduced by a combination of Fc and Fx. In the combination group, both ABCG2 and OAT1 increased significantly, whereas GLUT9 and URAT1 decreased significantly. In summary, the combination of Fc and Fx can inhibit the activity of XO in the liver and regulate the expression of proteins related to UA transporter in the kidney to reduce the UA level in serum.
Volumetric and thermal properties of cross-linked epoxy systems consisting of diglycidyl ether of bisphenol A (DGEBA) and poly(oxypropylene) (POP) diamines of four different lengths ranging from 3 to ...68 units were investigated by molecular dynamics (MD) simulations. The cross-linked structures were built by using the simulated annealing polymerization approach. The density, coefficients of volume thermal expansion and glass transition temperature (Tg) of each of the four cross-linked epoxy systems were obtained from their volume–temperature behavior. The density obtained in the simulations agreed well with the experimental value, whereas the coefficients of volume thermal expansion were at least 30% lower than their corresponding experimental results. The predicted Tg values were higher than the experimental values due to the considerably faster cooling rates that are used in the simulations. It was observed that an increase in the chain length of the cross-linker POP-diamines led to a larger difference between the predicted and experimental values of Tg. Three different approaches were used to estimate the expected shift in the experimental Tg to higher values had these measurements been made at cooling rates comparable to those used in MD simulations. It is shown that, in general, the Tg values obtained in MD simulations are consistent with such shifted Tg values that account for the difference in the cooling rates, although no one particular shift approach worked well for all four epoxy systems studied.
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Proteoglycans (PGs) play important roles in many biological processes including tumor progression, cell adhesion, and regulation of growth factor activities. With glycosaminoglycan chains attached to ...the core proteins in nature, PGs are highly challenging synthetic targets due to the difficulties in integrating the sulfated glycans with the peptide backbone. To expedite the synthesis, herein, the utility of human xylosyltransferase I (XT-I), the enzyme responsible for initiating PG synthesis, has been explored. XT-I was found to be capable of efficiently installing the xylose unit onto a variety of peptide structures on mg scales. Furthermore, an unnatural sugar, i.e., 6-azidoglucose can be transferred by XT-I introducing a reactive handle onto the glycopeptide for selective functionalization. XT-I can be coupled with β-4-galactosyl transferase-7 for one pot synthesis of glycopeptides bearing galactose-xylose disaccharide, paving the way toward efficient chemoenzymatic synthesis of PG glycopeptides and glycoproteins.
Breast cancer (BC) incidence is increasing around the globe, including in Taiwan, though the cause of the increasing incidence is less clear. We followed up 11,296 Taiwanese females who did not have ...BC at baseline, and ascertained new invasive BC (N = 351) through data linkage to the National Cancer Registry from 1991 to 2018 to examine whether reproductive, lifestyle and environmental risk factors including polycyclic aromatic hydrocarbons (PAH) were associated with BC risk. We conducted a nested case-control study using baseline blood available from a total of 305 women with BC and 598 women without BC matched on time in cohort. We examined the association of PAH-albumin adducts and BC risk using conditional logistic regression models. Age at menarche (HR 0.6 (95% CI 0.5-0.9) for ≥ 15 vs. < 13 years) and multiparity were associated with BC risk (HR 2.0 (95% CI 1.4-2.8), 2.8 (1.9-4.2), and 2.4 (1.0-5.0) for 3-4, 1-2 and 0 live birth, compared with women ≥ 5 births). PAH-albumin adducts were not associated with BC risk. Given the increasing BC incidence in Taiwan, there is a need to identify environmental factors that are important to this population.
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