Low Molecular Weight Research Articles

Development and Validation of LC-MS method for determination of Genotoxic Impurity N, O-Dimethyl Hydroxylamine by Chemical Derivatization in Investigational Drug Substance

Background: Conventional chromatographic techniques and direct analysis pose challenges in detecting certain potential genotoxic impurities, primarily due to factors such as the absence of a chromophore, low molecular weight, and insufficient chromatographic retention caused by high polarity. One such compound, N, O-Dimethyl Hydroxylamine, is of particular concern due to its structural similarity to Hydroxylamine, a recognized genotoxic impurity. Method: In response to this challenge, this article proposes a rapid derivatization approach utilizing Dansyl Chloride, coupled with Liquid Chromatography-Mass Spectrometry (LC-MS) for the detection of the derivatized product in the investigational drug substance. To preserve confidentiality, the specific name and structure of the drug substance have not been disclosed. Results: The developed method exhibits a reliable range of detection spanning from 5 ppm to 60 ppm with respect to a nominal drug substance concentration of 10 mg/mL. Throughout the method validation process, it demonstrated specificity, sensitivity, linearity, accuracy, and repeatability. Conclusion: This methodology presents a versatile solution applicable in scenarios where N, ODimethyl Hydroxylamine serves as a reagent in the synthesis process of drug substances.

Biodegradable composites from poly(butylene adipate‐co‐terephthalate) with soybean protein isolate: Preparation, characterization, and performances

AbstractSoy protein isolate (SPI), a widely available and inexpensive natural polymer, can be used as a filler to reduce the cost of poly(butylene adipate‐co‐terephthalate) (PBAT) materials. To improve the compatibility between SPI and PBAT, a series of polycaprolactone‐based polyurethane prepolymers (PCLPUs) with different soft segment molecular weights were synthesized and used as compatibilizers to prepare SPI/PBAT composites. At the same time, the effect of PCLPU soft segment molecular weight on the properties of SPI/PBAT composites was studied. Structural, morphological, and property analyses were carried out on the composite materials; the results showed that PCLPU was an effective compatibilizer for SPI/PBAT composite materials. The –NCO group at its end forms a urethane bond with the hydroxyl group in SPI and PBAT. At the same time, the soft segment of PCLPU is physically crosslinked with PBAT to produce a dual physical and chemical effect. The lower the soft segment molecular weight of PCLPU added, the better the performance of the SPI/PBAT composite materials. This is observed because PCLPU with a lower soft segment molecular weight contains more –NCO functional groups, which can better achieve compatibilization between SPI and PBAT through chemical crosslinking. The addition of 5% PCLPU‐500 content to the SPI/PBAT composite material increased its tensile elongation, impact strength, and tensile strength by 867%, 264%, and 150%, respectively, compared with those of the SPI/PBAT composite material without a compatibilizer, achieving toughening and strengthening with good processability and biodegradability. This work provides a simple, effective solution for preparing high‐performance, green, and low‐cost biodegradable composite materials.Highlights PBAT composites were prepared using soy protein isolate (SPI) as filler. Different types of PCLPU exist as a reactive compatibilizer for PBAT and SPI. Polycaprolactone‐based polyurethane prepolymer significantly improves the interfacial compatibility of PBAT composites. SPI/PBAT film has good degradability and is a rich source of nitrogen.

Valorization of chitosan for sustainable soap production: Development, performance evaluation, and hygiene applications

This study investigates a new method for making soap by using chitosan (CH) obtained from discarded cephalopod waste. This strategy aims to tackle the environmental issues related to trash disposal. Low molecular weight chitosan (LMWCH) was developed by extracting chitin, converting into chitosan and subjecting it to gamma irradiation for reducing the molecular weight. The chitosan has a molecular weight of 982 Da, making it well-suited for being included in soap compositions and providing strong anti-microbial activity. The soap that was produced demonstrated desirable attributes, such as a moisture content of 17.13%, a pH level of 9, and a stable fatty acid content, indicating its potential for successful commercial use. The soap had significant antibacterial activity against common pathogens such as Methicillin Resistant Staphylococcus aureus (MRSA) and Candida albicans ( C.albicans). After 36 h, it produced zones of inhibition measuring 7.7 ± 1.05 mm and 8.4 ± 0.5 mm respectively. The research’s reliability is based on its meticulous experimental technique, which included comprehensive characterization of both the chitosan derivative and the final soap product. Moreover, conducting antimicrobial testing on widely recognized pathogens enhances the credibility of the soap’s possible practical uses in hygiene goods. Overall, this study underscores the feasibility of utilizing waste materials for sustainable soap production while offering potential antimicrobial benefits, thus contributing to both environmental conservation and public health.

200℃ ТЕМПЕРАТУРАДА АУЫР МҰНАЙДЫ БУМЕН ТЕРМИЯЛЫҚ ӨҢДЕУДІҢ ТИІМДІЛІГІН АРТТЫРУ ҮШІН БЕТТІК БЕЛСЕНДІ ЗАТТАРДЫ ҚОЛДАНУ

In the presented work influence of surfactants on of the oil transformation regularities in hydrothermal conditions was studied. The oil with density 0,9727 g/cm3 was chosen as objects of research. It has been established that the introduction of surfactants reduces the content of resinous asphaltenes as a result of peptizing action on asphaltene aggregates. As a result, more carbon-heteroatom bonds in asphaltenes are involved in the processes of destructive hydrogenation. According to the results of SARA - and chromato-mass-spectral analysis, a change of mass fractions of each fraction is observed. When using the surfactant "SA-3" the content of saturated hydrocarbons is 20% higher than in the original sample, while in the oil sample with the surfactant "SBG" the content is almost unchanged. The content of aromatic hydrocarbons increased significantly with the addition of "SBG" by 19%, and with the addition of "SA-3" by 10%, which is due to the newly formed low molecular weight saturated and aromatic hydrocarbons. Asphaltene content also changed significantly, the sample with the addition of "SA-3" showed a decrease of 12% and with the addition of "Biolub green" a decrease of 9% relative to the original oil. The dynamic viscosity at 20℃ of the original oil is 3000 mPa∙s at a shear rate of 1.3 s-1. When using non-ionic surfactants of GK "Mirrico" of "Biolub green" type after the experiments, the viscosity decreases by 22%, and when adding "SA-3" surfactants by 30%. The use of surfactants in the development of heavy oil fields by steam-heat methods will increase the oil recovery factor.

Oxidation of Polycyclic Aromatic Hydrocarbons (PAHs) Triggered by a Photochemical Synergistic Effect between High- and Low-Molecular-Weight PAHs.

Photooxidation of polycyclic aromatic hydrocarbons (PAHs), which are widely observed in atmospheric particulate matter (PM), largely determines their atmospheric fate. In the environment, PAHs are highly complex in chemical composition, and a great variety of PAHs tend to co-occur. Despite extensive investigation on the photochemical behavior of individual PAH molecules, the photochemical interaction among these coexisting PAHs is still not well understood. Here, we show that during photooxidation, there is a strong photochemical synergistic effect among PAHs extracted from soot particles. We find that neither small PAHs with low molecular weights of 200-350 Da and 4-8 aromatic rings (named PAHsmall) nor large PAHs with high molecular weights of 350-600 Da and 8-14 aromatic rings (named PAHlarge) undergo photooxidation under red-light irradiation (λ = 648 nm), even though PAHlarge can absorb light with this wavelength. Interestingly, when PAHlarge is mixed with PAHsmall, substantial photooxidation is observed for both PAHlarge and PAHsmall. Comparisons of in situ infrared (IR), high-resolution mass spectrometry, and electron paramagnetic resonance analysis indicate that the presence of PAHsmall inhibits the light quenching effect arising from the π-π stacking of PAHlarge. This leads to the formation of singlet oxygen (1O2), which initiates the photooxidation. Our findings reveal a new mechanism for the photooxidation of PAHs and suggest that complex atmospheric PAHs exhibit distinct photoreactivity from simple systems.

Shape-stable composite of synthetic phase change materials from balsa wood by epoxy/PEG through alkaline method

Phase change materials have excellent thermal energy storage capacity, making them an appealing option for energy management applications. Stabilizing the form of phase change materials enhances their practical effectiveness. This research focuses on sustaining the shape of low molecular weight PEG phase change materials in wood structures made from natural balsa wood. The alkalization process is used to modify the wood, after which the PEG/epoxy polymers are infused into the wood structure to form a synthetic phase change material. The process of treating wood with alkali involves partially removing lignin from the wood, creating specific spaces. Results from optical transmittance analysis demonstrate that wood treated with alkali and wood infused with phase change polymer exhibit high optical transmittance. SEM images also illustrate the presence of spaces in delignified wood treated with Epoxy/PEG 400 and Epoxy/PEG 600. The synthetic phase change material remains stable at temperatures below 310°C and possesses a ∆Hc of 170.1J/g to 162.8 J/g. The phase transition temperatures during heating are 56.4°C and 57.2°C, cooling is 25.7°C and 30.1°C.

Biochemical composition of biological substances extracted from red deer antlers

We aim to study biologically active agents in biological substances obtained from different parts of red deer antlers. Frozen red deer antlers were separated into skin and antler base, crushed, and subjected to ultrasonic enzymatic hydrolysis. The press cake from the extraction of antler base was dried in a vacuum unit. The content of protein, fat, ash, and moisture in the obtained biological substances was studied. In addition, the amino acid, fatty acid, and mineral compositions were analyzed, as well as the molecular weight distribution of peptide fractions. The concentrates from the skin and base of red deer antlers were found to contain the maximum of proteins (73.68–74.41%). The mineral biological substances comprise the maximum of macroand microelements (84.17%), in particular, a high level of 136,000 mg /kg of phosphorus, 29,230 mg /kg of sodium, and 5,140 mg /kg of calcium. All biological substances are characterized by a low-fat content in the range from 0.3 to 1.76%. Similar to the protein content, the total amount of amino acids prevails in concentrates from the skin and base of red deer antlers, equaling 40.90 and 43.66 g /100 g, respectively. Moreover, in both samples, the amount of essential amino acids is higher than that of non-essential ones. The amount of vitamins is low, being represented by B1, B2, B6 water-soluble vitamins. The fatty acid composition is most balanced in the concentrate from the red deer antler base, containing omega-3 and omega-6. The ratio of unsaturated to saturated fatty acids is equal to 0.96. In the concentrate from antler skin, the maximum content (54.7%) of peptides with a low molecular weight of less than 2.9 kDa and up to 6.4 kDa was found using the molecular-weight distribution of peptide fractions.

Synthesis of grafted copolymers of cod collagen and acrylamides in the presence of alkylborane – p-quinone system

The graft polymerization of acrylamide and N-isopropylacrylamide onto collagen in the presence of triethylborohexamethylenediamine complex and a number of p-quinones, including benzoquinone, naphthoquinone, 2,5-di-tretbutyl-p-benzoquinone, and duroquinone, was studied. In all cases, p-quinones act as polymerization retarders, reducing monomer conversion. An exception is the graft polymerization of acrylamide onto collagen in the presence of benzoquinone, which acts as a polymerization inhibitor. The proportion of the synthetic fragment in the obtained copolymers is determined by the structure of the monomer and p-quinone. The molecular weight distribution curves contain modes related to unreacted collagen, which differ significantly from those of the initial collagen in terms of intensity. This is related to the formation of a grafted copolymer of cross-linked structure, which cannot be analyzed by gel permeation chromatography. The degradation of copolymers under the action of enzymes was controlled by gel permeation chromatography. Enzymatic hydrolysis of copolymers proceeds slower than that of collagen, which confirms the formation of a copolymer. Following three hours after the onset of hydrolysis, the molecular weight distribution curves contain low-molecular weight modes of collagen and low-intensity modes related to polyacrylamide. The morphology of copolymers differs from that of collagen and polyacrylamides. Cytotoxicity evaluation of copolymers is an important research stage, determining their prospects as the basis of materials for regenerative medicine. An analysis of extracts obtained from the copolymers using culture medium by MTT assay showed a high rank of their toxicity, which can be reduced by dilution of collagen and N-isopropylacrylamide copolymer extracts with aqueous solutions. For the copolymers of collagen and acrylamide, the toxicity is maintained due to the high toxicity of the monomer. Their toxicity can be reduced by extraction of unreacted acrylamide with chloroform.

Assessing Direct Oral Anti-Coagulant And Therapeutic Low Molecular Weight Heparin Prescriptions At A University Teaching Hospital

Abstract Background A 2017-2018 survey identified anti-thrombotics as the most commonly implicated agents in reported medication incidents across Irish acute hospitals [State Claims Agency, 2020, Medication Incidents Report (2017-2018)]. Of the top 10 anti-thrombotics reported, 2 were Low Molecular Weight Heparins (LMWHs) and 3 were Direct Oral Anti-Coagulants (DOACs). 3 years after the survey results were published, we audited our hospital's compliance with the Health Service Executive's guidelines for prescribing DOACs and LMWHs. Methods Over 3 consecutive weeks, data was collected by doctors and clinical pharmacists across 6 wards and the intensive and coronary care units. In-patients on a DOAC or therapeutic LMWH were chosen for kardex and laboratory result review. Results 83 patients were included. The average age was 79 years. 81%(n=67) were on a DOAC. 91% were being treated for non-valvular atrial fibrillation (NVAF), 3% for pulmonary embolism (PE), 3% for deep vein thrombosis and 3% had no indication documented. 33%(n=22) had indications for dose reduction but only 77%(n=17) of them were prescribed the appropriate reduced dose. 3%(n=2) had no dose reduction indications but were inappropriately prescribed a reduced dose. 3%(n=2) were on dialysis, 1%(n=1) had their creatinine clearance persistently below 15ml/min and 1%(n=1) inappropriately received once daily dosing of apixaban for 3 days. 19%(n=16) of all participants were on therapeutic LMWH. Treatment indications included acute coronary syndrome in 63%, suspected PE in 19%, newly diagnosed NVAF in 6% and bridging anti-coagulation while a DOAC is temporarily held in 13%. 6%(n=1) were inappropriately prescribed an under-dose. Conclusion Overall, there was an error rate of 16%(n=11) in DOAC prescriptions and 6%(n=1) in LMWH prescriptions. To address this, we propose an educational intervention for prescribers and the introduction of e-prescriptions with built-in alerts for errors. We plan to re-audit once these recommendations are implemented.

Myricetin-loaded SBA-15 silica nanoparticles for enhanced management of pyrexia, pain, and inflammation through modulation of MAPK/NF-κB and COX-2/PGE-2 pathways: Evidence from the biochemical, histological, and metabolomic analysis

Myricetin (MYR) is a natural flavonoid that has several biological functions. However, some of its beneficial effects are diminished due to low water solubility, stability, and bioavailability. Herein, several kinds of silica nanoparticles (MCM-41 and SBA-15) were loaded with MYR to improve its biological activity as an analgesic, antipyretic, and anti-inflammatory component, thereby overcoming its drawbacks. The nanoparticles (MYR@SBA-15) were formulated optimally, transforming MYR into an amorphous state. This transformation was confirmed via several strategies, including differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder x-ray diffraction. As a result, there was a significant enhancement in the solubility and rate of dissolution in water. The anti-inflammatory benefits as an innovative strategy and the underlying mechanism of action of MYR and its SBA-15 silica nanoparticles (MYR@SBA-15) were investigated based on the biochemical, histological, immunohistochemical, and metabolomic assays alongside their antipyretic and analgesic characteristics. Compared to the usage of raw MYR, the administration of MYR@SBA-15 at doses of 25, 50, and 100 mg/kg significantly decreases pain perception by inhibiting the body’s writhing motions induced by acetic acid. Furthermore, it helps regulate increased body temperature caused by baking yeast and effectively stabilizes it. It reduces the release of NO and PGE-2 in a concentration-dependent manner by down-regulating iNOS and COX-2 expression in the inflammatory model. MYR and MYR@SBA-15 also inhibit the nuclear translocation of NF-κB, downregulate the expression of mitogen-activated protein kinases (MAPKs), such as p38, ERK1/2, and JNK protein, and reduce the generation of proinflammatory cytokines, such as TNF-α. In addition, inflammatory cardinal signs like paw edema caused by carrageenan in rats are greatly suppressed by MYR and MYR@SBA-15 treatment when compared to the untreated group. More noteworthy outcomes are shown in the MYR@SBA-15, particularly at a dose of 100 mg/kg. These results of biochemical and immuno-histochemistry suggest that MYR@SBA-15 may be a useful analgesic antipyretic and may also help reduce inflammation by altering MAPKs/NF-κB and COX-2/PGE-2 signaling cascades. Serum metabolomics study demonstrated modifications in various low molecular weight metabolites with arthritis development. These metabolite levels were restored to normal when MYR@SBA-15 was administered via modulating several metabolic pathways, i.e., pyrimidine, energy metabolism, and proteins. Overall, MYR-loaded SBA-15 silica nanoparticles have demonstrated significant promise in enhancing the disturbed metaboloic pathways and providing a substantial capacity to regulate several oxidative stress and inflammatory mediators.

Zinc Phthalocyanine Core-First Star Polymers Through Nitroxide Mediated Polymerization and Nitroxide Exchange Reaction.

Nitroxide-mediated polymerization (NMP) and nitroxide exchange reaction (NER) are very efficient methodologies that require only suitable alkoxyamine derivatives and create different polymeric architectures in a controlled manner. Herein, the synthesis of star polymers containing TEMPO-substituted symmetric zinc phthalocyanine (ZnPc) is presented via NMP and NER. Moreover, linear polymer formation is conducted in a single arm on TEMPO-substituted asymmetric ZnPc to elucidate the properties of star polymers. All linear and star polymers are characterized by FT-IR, UV-vis, fluorescence, GPC, NMR, and EPR techniques. The results show that the proposed reactions are capable of forming controlled star-shaped polymers. The increasing arm number (from a single to four arms) results in variable dispersity values (Đ) (1.2-3) due to different arm lengths, especially in NMP. However, this difficulty has been overcome via NER, and star polymers have been successfully synthesized with relatively low molecular weight (30 K > 10 K) and low dispersity (1.2-1.9). The results clearly indicate that while styrene and 4-vinyl benzyl chloride monomers are introduced to the structure equally, star polymers with phthalocyanine can be synthesized in a controlled manner, and their quarternized derivatives have the potential to be effective as photoactive agents in photodynamic therapy.

Anticoagulant therapy in pregnant women with mechanical and bioprosthetic heart valves.

The aim of the present study was to review maternal and fetal outcomes in pregnant women with prosthetic heart valves. A retrospective record review of pregnant women with prosthetic heart valves on anticoagulation was performed at the Specialist Cardiac Antenatal Clinic, Johannesburg South Africa from 2015 to 2023. Fifty pregnancies with mechanical heart valves and three with tissue valves, on anticoagulation for comorbid atrial fibrillation were identified. The majority were of African ethnicity at a mean age of 33 ± 6 years. Anti-Xa adjusted enoxaparin was commenced at 10.5 ± 5.6 weeks' gestation until delivery in 48 (90.6%) pregnancies and warfarin was continued in five (9.4%) pregnancies. The live birth rates on enoxaparin and warfarin were 56.3% (95% confidence interval [CI]: 42.3-69.3) and 20.0% (95% CI: 2.0-64.0), respectively. There were 12 (22.6%) miscarriages at a mean of 11.3 ± 3.7 weeks' gestation, four (7.5%) intrauterine fetal deaths on warfarin and two (3.8%) warfarin embryopathy/fetopathy. The rates of antepartum/secondary postpartum bleeding and primary postpartum bleeding were 29.4% (95% CI: 18.6-43.1) and 5.9% (95% CI: 1.4-16.9), respectively. Maternal complications included anemia (n = 11, 20.8%), arrhythmia (n = 2, 3.8%), heart failure (n = 2, 3.8%) and paravalvular leak (n = 2, 3.8%). There was one (1.9%) mitral valve thrombosis and one (1.9%) stuck valve in pregnancies who defaulted warfarin prior to pregnancy. There were no maternal deaths. Multidisciplinary management of pregnant women with prosthetic heart valves with anti-Xa adjusted low molecular weight heparin throughout pregnancy represents an effective anticoagulation option for low-middle-income countries.

Subcellular expression of CYP2E1 in HepG2 cells impacts response to free oleic and palmitic acid

AimsCytochrome P450 2E1 (CYP2E1) is a mammalian monooxygenase expressed at high levels in the liver that metabolizes low molecular weight pollutants and drugs, as well as endogenous fatty acids and ketones. Although CYP2E1 has been mainly studied in the endoplasmic reticulum (ER, microsomal fraction), it also localizes in significant amounts to the mitochondria, where it has been far less studied. We investigated the effects of CYP2E1 expression in mitochondria, endoplasmic reticulum, or both organelles in transgenic HepG2 cells exposed to free oleic and palmitic acid, including effects on cytotoxicity, lipid storage, respiration, and gene expression. ResultsWe found that HepG2 cells expressing CYP2E1 in both the ER and mitochondria have exacerbated levels of palmitic acid cytotoxicity and inhibited respiration. CYP2E1 expression did not impact lipid accumulation from fatty acid exposures, but mitochondrial CYP2E1 expression promoted lipid droplet depletion during serum starvation. In contrast to HepG2 cells, differentiated HepaRG cells express abundant CYP2E1, but they are not sensitive to palmitic acid cytotoxicity. Oleic acid exposure prompted less cytotoxicity, and CYP2E1 expression in the ER prevented an oleic-acid-induced increase in respiration. HepG2 cells exposed to mixtures of palmitic and oleic acid are protected from palmitic acid cytotoxicity. Additionally, we identified that CYP2E1 was decreased at the gene and protein level in hepatocellular carcinoma. Moreover, patients with tumors that had higher CYP2E1 expression had a better prognosis compared to patients with lower CYP2E1 expression. InnovationThis study has demonstrated that transgenic CYP2E1 subcellular localization plays an important role in sensitivity to cytotoxicity, lipid storage, and respiration in the hepatoma cell line HepG2 exposed to palmitic and oleic acid. HepaRG cells, in contrast, were insensitive to palmitic acid. This work demonstrates the clear importance of CYP2E1 in dictating lipotoxicity and differential roles for the mitochondrial and ER forms of the enzyme. Additionally, our data supports a potentially unique role for CYP2E1 in cancer cells. ConclusionThere lies a role for CYP2E1 in altering lipotoxicity, and since CYP2E1 is known to be upregulated in both liver disease and hepatocellular carcinoma, it is important to better define how the role of CYP2E1 changes during disease progression.

Discussion on the evaluation of the therapeutic efficacy of uterine artery blood flow parameters and serum PLGF and sFlt-1 in patients with recurrent spontaneous abortion

ObjectiveTo investigate the effects of different drug treatments on uterine artery blood flow parameters, serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and sFlt-1/PLGF in patients with recurrent spontaneous abortion and to explore the predictive value of uterine artery blood flow parameters, serum PLGF, sFlt-1, and sFlt-1/PLGF for pregnancy outcomes.MethodsThis retrospective cohort study included 173 patients who experienced recurrent spontaneous abortion and 100 control patients. Patients with recurrent spontaneous abortion were divided into an aspirin group (75 patients), aspirin combined with low molecular weight heparin (LMWH) group (68 patients), and non-drug group (30 patients) based on different drug treatments. Uterine artery blood flow parameters at gestational weeks 30-31+6 were monitored for the four groups, and serum samples were collected at gestational weeks 30-31+6 to measure the levels of serum PLGF and sFlt-1 and calculate the sFlt-1/PLGF ratio.Results1. Uterine artery blood flow parameters at gestational weeks 30-31+6 were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group (p<0.05). 2. Serum PLGF levels and the sFlt-1/PLGF ratio at gestational weeks 30-31+6 were significantly lower in the non-drug group than in the aspirin group, combined drug group, and control group, while serum sFlt-1 levels were significantly greater in the non-drug group than in the aspirin group, combined drug group, and control group (p<0.05). 3. Serum PLGF, sFlt-1, and sFlt-1/PLGF had lower diagnostic efficiency for predicting hypertensive disorders during pregnancy than the combined diagnostic efficiency of serum PLGF, sFlt-1, and sFlt-1/PLGF with uterine artery blood flow parameters at gestational weeks 30-31+6.ConclusionAspirin and aspirin combined with LMWH can upregulate serum PLGF and decrease serum sFlt-1 levels in patients with recurrent spontaneous abortion, reduce the miscarriage rate, and significantly improve pregnancy outcomes. The combination of serum PLGF, sFlt-1, sFlt-1/PLGF, and uterine artery blood flow parameters can effectively predict hypertensive disorders during pregnancy.

Optimization of Potent, Efficacious, Selective and Blood-Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Herein, we report the optimization of a series of epidermal growth factor receptor (EGFR) Exon20 insertion (Ex20Ins) inhibitors using structure-based drug design (SBDD), leading to the discovery of compound 28, a potent and wild type selective molecule, which demonstrates efficacy in multiple EGFR Ex20Ins xenograft models and blood-brain barrier penetration in preclinical species. Building on our earlier discovery of an in vivo probe, SBDD was used to design a novel bicyclic core with a lower molecular weight to facilitate blood-brain barrier penetration. Further optimization including strategic linker replacement and diversification of the ring system interacting with the c-helix enabled photolytic and metabolic stability improvements. Together with refinement of molecular properties important for achieving high brain exposure, including molecular weight, H-bonding, and polarity, 28 was identified.

In-depth analysis of natural organic matter fractions in drinking water treatment performance: Fate and role of humic substances in trihalomethanes formation potential

In this study we investigate the compositional changes in dissolved organic matter (DOM) fractions across diverse water sources and treatment processes in three Drinking Water Treatment Plants (DWTPs). High-Performance Size Exclusion Chromatography coupled with Diode Array Detection and Organic Carbon Detection (HPSEC-DAD-OCD) was employed to characterize DOM fractions, offering insights into treatment optimization. We examine bulk water parameters, DOM distributions, and the efficiency of treatment trains in reducing DOM fractions. Results reveal distinct DOM composition profiles in river-sourced versus reservoir-sourced waters, with implications for treatment processes. Coagulation, Granular Activated Carbon (GAC) adsorption, Electrodialysis Reversal (EDR), and Ion Exchange (IEX) were evaluated for their efficacy in removing DOM fractions. The analysis highlights the effectiveness of coagulation in reducing high molecular weight (MW) fractions, while GAC filtration targets lower MW fractions. EDR shows significant removal of anions and aromatics, while IEX demonstrates high removal efficiencies for removing humic substances (HS) fractions. Spectroscopic analysis further elucidates changes HS sub-fractions and their role in disinfection by-products (DBP) formation. To quantitatively assess the relationship between HS sub-fractions and trihalomethane formation potentials (THMFP), Pearson correlation analysis were conducted, unveiling robust associations between HS sub-fractions and THM-FP that can be predicted by surrogate parameters such as A254.

Effect of low molecular weight phenols on the in-mouth sensory perception of high molecular weight phenols by analyzing reconstituted wines

This research aimed to assess the contribution of monomeric phenols to the perception of bitterness and astringency by means of wine reconstitution experiments. Six wines with distinct total polyphenol indexes were selected and fractioned by preparative liquid chromatography into two fractions. Thirty-one reconstituted wines were prepared by combining distinct low molecular weight fractions (L) with different high molecular weight fractions (H). In-mouth attributes of reconstituted and reference wines were described by a trained sensory panel. Fractions were chemically characterized by UPLC-MS. No significant differences among sensory results were found between reference and reconstituted wines. Bitterness and astringency perception were strongly influenced by total proanthocyanidins content. Flavan-3-ol monomers and dimers were only responsible for astringency in wines with a low content of proanthocyanidins, as was the case in rosé wine. Quercetin-3-O-glucuronide and several anthocyanins presented correlations with bitterness in the reconstituted wines; notwithstanding, several interactions with this attribute were observed.

Organic matter excreted by the protozoan Tetrahymena thermophila and its effects on the bioaccumulation of nanoparticles

Although organic matter (exudate) excreted by aquatic organisms is an important component of dissolved organic matter (DOM) in the natural environment, its potential effects on the bioaccumulation of nanoparticles (NPs) remain unclear. In the present study, we examined the effects of the exudates from the protozoan Tetrahymena thermophila on the bioaccumulation (including uptake and cell surface adsorption) of iron oxide (Fe2O3, polyacrylate coated) and silica (SiO2) NPs in T. thermophila. The exudates were mostly (93.6%, in carbon) composed of < 1-kDa molecules (e.g., lipids). When the exudates were mixed with the NPs, significant adsorption occurred on SiO2 NPs but not on Fe2O3 NPs. Independent of their adsorption by the NPs, the exudates significantly inhibited the bioaccumulation of both SiO2 NPs and Fe2O3 NPs by T. thermophila. This inhibitory effect was shown to be mainly due to their inhibition of NP adsorption on the cell surface. By contrast, the exudates had negligible effects on the uptake of either NP type, most likely due to their low molecular weight. Since DOM in the aquatic environment is dominated by molecules < 1kDa, the potential effects of low-molecular-weight DOM, such as exudates from aquatic organisms, on the bioaccumulation of NPs merits greater attention. Environmental ImplicationNanoparticles (NPs) are hazardous materials widespread in the natural environment. Previous studies showed that dissolved organic matter (DOM) in aquatic environments determine the environmental behavior and ecological effects of NPs. Although organic matter (exudate) excreted by aquatic organisms is an important component of DOM, its potential effects on the bioaccumulation of NPs remain unclear. In the present study, we found that the exudates inhibited the cell-surface adsorption of NPs but had no effects on NP uptake, as different from the well-known effects of DOM on NP bioaccumulation. This finding merits attention during evaluations of the environmental risks of NPs.

Bovine serum albumin and lysozyme nanofibers as versatile platforms for preserving loaded bioactive compounds

In this study, the electrospinning procedure was optimized to create polyethylene oxide (PEO) NFs highly enriched in proteins with non-structural functions while preserving their activity. For this purpose, several immune-related proteins of low, medium and high molecular weights were used as molecular models. Initially, the electrospinning parameters were adjusted using 3 % w/w PEO and bovine serum albumin (BSA, 5–20 % w/w). As determined by FESEM, their average diameters ranged from 301 to 752 nm, and those with higher protein content (15–20 %) yielded more uniform NFs in both size and morphology terms. Protein integrity remained stable as determined by SDS-PAGE and FTIR. Similar results were observed for the polypeptide lysozyme (LYZ) when incorporated in NFs under these settings. To further explore the potential of these materials, the antimicrobial peptide piscidin (PIS) and an antibody (Ab, HRP-IgG) were used to produce BSA/PIS, LYZ/PIS and BSA/Ab NFs and evaluate the preservation of their activity. The antibacterial assays showed that, in most bacterial species, the activity of PIS remained consistent after being incorporated into the NFs. Furthermore, the activity of HRP-IgG was maintained within the NFs, with enhanced preservation observed in BSA/Ab NFs. These findings expand the possibilities of protein utilization across various applications through nanomaterials.

Relationships of Leg Ischemia Symptoms and Carotid Artery Atherosclerosis with Hypertensive-Disorders-of-Pregnancy-Associated Peptides in Patients with Lower Extremity Arterial Disease.

Objectives: We have proposed seven peptides with low molecular weights in blood as biomarkers for the diagnosis of hypertensive disorders of pregnancy (HDP). The purpose of this cross-sectional study was to investigate the relationships of the HDP-associated peptides with symptoms of leg ischemia and degree of atherosclerosis in patients with lower extremity arterial disease (LEAD). Methods: The subjects were 165 outpatients with LEAD (145 men and 20 women aged 74.3 ± 8.1 years [47-93 years]). Their symptoms of leg ischemia, leg arterial flow, and degree of atherosclerosis were evaluated using the Rutherford classification of Clinical Ischemia Category, ankle-brachial index (ABI) and the intima-media thickness (IMT) of carotid arteries, respectively. Serum concentrations of the HDP-related peptides were measured by mass spectrometry. Results: The grade of the Rutherford classification was positively associated with levels of the peptides with m/z 2091 and 2378 and was inversely associated with levels of the peptide with m/z 2081. The category of the Rutherford classification was inversely associated with ABI. There were no HDP-associated peptides that showed significant relationships with IMT. Conclusions: The peptides with m/z 2081, 2091, and 2378 are possible biomarkers of leg ischemia but are not associated with carotid atherosclerosis in LEAD patients.