Biosynthesis of Multifunctional Transformable Peptides for Inducing Tumor Cell Apoptosis.

Engineered nanomaterials hold great promise to improve the specificity of disease treatment. Herein, a fully protein-based material is obtained from nonpathogenic Escherichia coli (E. coli), which is capable of morphological transformation from globular to fibrous in situ for inducing tumor cell apoptosis. The protein-based material P1 is comprised of a ß-sheet-forming peptide KLVFF, pro-apoptotic protein BAK, and GFP along with targeting moieties. The self-assembled nanoparticles of P1 transform into nanofibers in situ in the presence of cathepsin B, and the generated nanofibrils favor the dimerization of functional BH3 domain of BAK on the mitochondrial outer membrane, leading to efficient anticancer activity both in vitro and in vivo via mitochondria-dependent apoptosis through Bcl-2 pathway. To precisely manipulate the morphological transformation of biosynthetic molecules in living cells, a spatiotemporally controllable anticancer system is constructed by coating P1-expressing E. coli with cationic conjugated polyelectrolytes to release the peptides in situ under light irradiation. The biosynthetic peptide-based enzyme-catalytic transformation strategy in vivo would offer a novel perspective for targeted delivery and shows great potential in precision disease therapeutics.

One-pot cascade synthesis of dibenzothiophene-based heterobiaryls from dibenzothiophene-5-oxide.

A sulfoxide directed C-H metalation/boration/B2Pin2 mediated reduction/Suzuki coupling process to synthesize 4-substituted dibenzothiophene (DBT) in one-pot from dibenzothiophene-5-oxide (DBTO) was developed. A variety of DBT-based heterobiaryls were prepared in satisfactory to good yields. A mechanism was proposed. The application of this methodology was demonstrated by synthesizing a luminescent material.

Investigation on the emulsification mechanism in aqueous enzymatic extraction of edible oil from Schizochytrium sp.

BACKGROUND: The interaction between emulsified substances and lipids generates an emulsification system during the extraction of microalgae edible oil by aqueous enzymatic method. This study aimed to resolve the dynamics of interfacial protein adsorption during the extraction of microalgae oil at different enzymatic times and the effect on the stability of the interfacial membrane formed by the proteins based on interfacial effects. RESULTS: At 1.5 h of enzymatic hydrolysis, the molecular weights of the proteins/peptides were all below 35 kD. In addition, the protein-peptide structure was loose, with the lowest number of disulfide bonds, peak surface hydrophobicity, the highest number of residues, and disordered lipid acyl arrangement. At the same time, the physical stability of the emulsion was the lowest, and the interfacial membrane rupture was distinct. On excessive enzymatic hydrolysis (at 3.0 h), a more uniform interfacial membrane was re-formed on the lipid surface. CONCLUSION: Protein is the main emulsifying substance in the emulsification system. The addition of protease affects the stability of the interfacial membrane formed by proteins. In addition, sufficient enzymatic hydrolysis (1.5 h) inhibited emulsification, while excessive enzymatic hydrolysis (3.0 h) promoted emulsification. © 2023 Society of Chemical Industry.

Safety and pharmacokinetic profile of pretomanid in healthy Chinese adults: Results of a phase I single dose escalation study.

We investigated the safety, tolerability and pharmacokinetic (PK) profile of pretomanid (formerly PA-824) in healthy Chinese volunteers. This was a single-center, double-blind, placebo-controlled, phase I dose escalation study, in which healthy volunteers were consecutively allocated to increasing pretomanid dose groups (50, 100, 200, 400, 600, 800, or 1000 mg) and randomized to receive pretomanid or matching placebo. The primary objective was to evaluate the safety, tolerability and PK profile of pretomanid. In total, 306 volunteers were screened, and 60 were assigned to treatment (pretomanid: n = 46, placebo: n = 14) of whom 83.3% were male, age ranged from 19 to 39 years and BMI ranged from 19.2 to 25.9 kg/m2. At least one adverse event (AE) was reported by 67.4% of subjects assigned to pretomanid and 50.0% of those who received placebo, there were no serious AEs or AEs leading to withdrawal. Drug-related events that occurred in ≥5% of participants assigned to pretomanid were proteinuria (26.1%), insignificant microscopic hematuria (15.2%), conjugated hyperbilirubinemia (6.5%), hyperbilirubinemia (6.5%) and elevated uric acid (6.5%). No relationship between pretomanid dose and AEs was observed. In the PK analysis (n = 46), maximum pretomanid plasma concentration was reached in a median of 4 h in all dose groups except 800 mg (12 h) and the plasma half-life ranged from 20.2 to 25.2 h. No dose proportionality was observed for maximum plasma concentration, or area under the plasma concentration curve. In conclusion, single pretomanid doses from 50 to 1000 mg were well tolerated in healthy Chinese participants and the PK profile was generally consistent with findings in non-Chinese populations.

Transcatheter Mitral Valve Replacement: A Novel Anchor Technology.

BACKGROUND: Mitral valved stents tend to migrate or to develop paravalvular leakage due to high-left ventricular pressure in this cavity. Thus, this study describes a newly developed mitral valved stent anchoring technology. METHODS: Based on an existing mitral valved stent, four anchoring units with curved surgical needles were designed and fabricated using three-dimensional (3D) software and print technology. Mitral nitinol stents assembled with four anchoring units were successively fixed on 10 porcine annuli. Mechanical tests were performed with a tensile force test system and recorded the tension forces of the 10 nitinol stents on the annulus. RESULTS: The average maximum force was 28.3 ± 5.21 N, the lowest was 21.7 N, and the highest was 38.6 N until the stent lost contact with the annulus; for the break force (zero movement of stent from annulus), the average value was 18.5 ± 6.7 N with a maximum value of 26.9 N and a minimum value of 6.07 N. It was additionally observed that the puncture needles of the anchoring units passed into the mitral annulus in all 10 hearts and further penetrated the myocardium in only one additional heart. The anchoring units enhanced the tightness of the mitral valved stent and did not destroy the circumflex coronary artery, coronary sinus, right atrium, aortic root, or the left ventricular outflow tract. CONCLUSION: The new anchoring units for mitral nitinol stents were produced with 3D software and printing technology; with this new type of anchoring technology, the mitral valved stent can be tightly fixed toward the mitral annulus.

Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds.

Axially chiral heterobiaryl frameworks are privileged structures in many natural products, pharmaceutically active molecules, and chiral ligands. Therefore, a variety of approaches for constructing these skeletons have been developed. Among them, de novo synthesis, due to its highly convergent and superior atom economy, serves as a promising strategy to access these challenging scaffolds including C-N, C-C, and N-N chiral axes. So far, several elegant reviews on the synthesis of axially chiral heterobiaryl skeletons have been disclosed, however, atroposelective construction of the heterobiaryl subunits by de novo synthesis was rarely covered. Herein, we summarized the recent advances in the catalytic asymmetric synthesis of the axially chiral heterobiaryl scaffold via de novo synthetic strategies. The related mechanism, scope, and applications were also included.

Water binding stabilizes stacked conformations of ferrocene containing sheet-like aromatic oligoamides.

While water clusters play an essential role in the stability of biological structures, their ability to stabilize synthetic oligomers is less understood. We have synthesized a heptameric sheet-like aromatic oligoamide foldamer with ferrocene as turn unit. It shows strong interactions with water in the solid state and in solution. The water binding limits the fluxional processes resulting from the flexible ferrocene unit, highlighting the importance of such interactions for conformational studies on this class of molecule.

Correction: Water binding stabilizes stacked conformations of ferrocene containing sheet-like aromatic oligoamides.

Correction for 'Water binding stabilizes stacked conformations of ferrocene containing sheet-like aromatic oligoamides' by Ya-Zhou Liu et al., Org. Biomol. Chem., 2021, DOI: 10.1039/d1ob00580d.

Polydopamine nanodots-based cost-effective nanoprobe for glucose detection and intracellular imaging.

The cellular glucose detection remains a vital topic, which could provide some essential information about the glucose-based pathological and physiological processes. In this study, a smart polydopamine nanodots-based cost-effective fluorescence turn-on nanoprobe (denoted as PDA-Ag-GOx) for intracellular glucose detection is established. Silver nanoparticles (AgNPs) are directly formed in one step by the reduction of fluorescent polydopamine nanodots (PDADs) which have much phenolic hydroxyls on the surface. The fluorescence of PDADs could be quenched by AgNPs through surface plasmon-enhanced energy transfer (SPEET) from donor PDADs to acceptor AgNPs. Glucose oxidase (GOx) is modified on the PDA-Ag NPs by covalent bond. In the presence of glucose, GOx could catalyze glucose to produce H2O2 and gluconic acid. The generated acid and H2O2 would degrade AgNPs into Ag+, the PDADs release and restore its fluorescence. The proposed nanoprobe has some advantages, such as cost-effective, easy preparation, and excellent selectivity toward glucose, which could be successfully utilized to intracellular glucose imaging.

Structure-Dependent Guest Recognition with Flexible Ferrocene-Based Aromatic Oligoamide ß-Sheet Mimics.

A series of aromatic oligoamides incorporating an inherently flexible ferrocene dicarboxylic acid unit was synthesized. Solid state, solution, and computational studies on these systems indicated that the aromatic strands can adopt a syn parallel stacked conformation. This results in modular ß-sheet-like molecular clefts that display structure-dependent recognition of small polar molecules. NMR and theoretical studies of the host-guest interaction support an in cleft binding mode and allowed the selectivity of the oligomers to be rationalized on the basis of minor changes in functional-group presentation on the edge of the aromatic strands.

A Multi-crosslinking Nanocapsule-Based Serial-Stimuli-Responsive Leakage-Free Drug-Delivery System In Vitro.

As some stimuli utilized in conventional drug delivery systems can also be found in normal cells, it is inevitable that encapsulated drugs escape from carriers into normal cells. Based on mutual interactions among proteins, polyphenol compounds, and metal ions, we developed a serial-stimuli-responsive drug delivery system. With multi-crosslinking structure, nanocapsules can maintain the integrity of the framework, even with a certain amount of stimuli present, and eventually reach tumor cells to initiate apoptosis, and protect normal cells from being damaged. Meanwhile, the fluorescence of DOX will be quenched when encapsulated in nanocapsules. This property means that the DOX that is released from nanocapsules can be monitored in real-time based on the recovery of fluorescence. These versatile nanocapsules exhibit great potentials to treat cancer.

Design, Synthesis and Anticancer Evaluation of Fangchinoline Derivatives.

Twenty fangchinoline derivatives were synthesized from the natural product fangchinoline, and their anticancer activities on human breast cancer MDA-MB-231 cell line, human prostate cancer PC3 cell line, human melanoma WM9 cell line and human leukaemia HEL and K562 cell lines were evaluated. The biological result showed that those derivatives exhibited potent activities on inhibiting cancer cell growth, and the structure-activity relationships were investigated. Among them, compound 4g, which was protected by benzoyl group in 7-phenolic position and nitrified in 14-position, showed impressive inhibition on all 5 cancer cell lines, especially WM9 cell line, with an IC50 value of 1.07 µM. Further mechanistic studies demonstrated that compound 4g may induce cancer cell death by apoptotic means. These research results suggested that compound 4g could be a lead for the further development toward an anticancer agent against human melanoma WM9 in the future.

The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot †.

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, "Drug Synthesis and Analysis," meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.

Low Overlapping Point Cloud Registration Using Mutual Prior Based Completion Network.

This work presents a new completion method that specifically designed for low-overlapping partial point cloud registration. Based on the assumption that the candidate partial point clouds to be registered belong to the same target, the proposed mutual prior based completion (MPC) method uses these candidate partial point clouds as completion reference for each other to extend their overlapping regions. Without relying on shape prior knowledge, MPC can work for different types of point clouds, such as object, room scene, and street view. The main challenge of this mutual reference approach is that partial clouds without spatial alignment cannot provide a reliable completion reference. Based on the mutual information maximization, a progressive completion structure is developed to achieve pose, feature representation and completion alignment between input point clouds. Experiments on public datasets show encouraging results. Especially for the low-overlapping cases, compared with the state-of-the-art (SOTA) models, the size of overlapping regions can be increased by about 15.0%, and the rotation and translation error can be reduced by 30.8% and 57.7% respectively.

Stereoselective and controllable C3-Amination or C1,C3-di-amination of 2-nitroglycals.

Precise and selective modification of carbohydrates is a critical strategy in producing diverse carbohydrate derivatives for exploiting their functions. We disclosed a simple, efficient, and highly regioselective and stereoselective protocol to controllable amination of 2-nitroglycals under mild conditions in 5 min. A range of 3-amino-carbohydrates including 3-arylamino-2-nitro-glycals and 1,3-di-amino-carbohydrate derivatives were obtained in good to excellent yield with excellent stereoselectivity. The produced 3-amino-2-nitro-glycals can be used as a precursor for further transformation.

The impact of different grazing intensity and management measures on soil organic carbon density in Zhangye grassland.

Studying the spatial and temporal changes of grassland soil organic carbon (SOC) is helpful in promote the management of regional ecosystem carbon sinks. Grazing is one of the main ways of rational utilization of grassland. Different grazing intensities will affect the change of SOC density. Under different grazing intensity and management measures in Zhangye grassland, this study uses the parameter localized CENTURY model to simulate the temporal and spatial variations of SOC density from 1970 to 2022. The results showed that long-term light grazing reduced the average SOC by 195.114 g·m-2 and 1.91%. Moderate and severe grazing, respectively, for a long time made the total SOC density loss of 5.21% and 17.69%. In a short period, mild and moderate grazing reduced total SOC first and then increased it. Under light grazing, total SOC density appeared higher relative changes in the southeast, and lower in the northwest and central. There was no significant difference in the relative changes of total SOC between steppe and desert grasslands under light grazing. The decrease range of steppe was gradually greater than that in desert grassland. Since different management measures were implemented in some sampling sites in 2017, we divided the study period into two periods, 1970-2016 and 2017-2022. The implementation of degraded grassland improvement, fallow grazing, and rotational grazing would increase the total SOC density and mild SOC density, rotational grazing > degraded grassland improvement > rest grazing. Rotational grazing and the improvement of degraded grassland increased the density of active and inert SOC, while resting grazing decreased the density of SOC.

Progress on the mechanism of natural products alleviating androgenetic alopecia.

Androgenetic alopecia (AGA) has become a widespread problem that leads to considerable impairment of the psyche and daily life. The currently approved medications for the treatment of AGA are associated with significant adverse effects, high costs, and prolonged treatment duration. Therefore, natural products are being considered as possible complementary or alternative treatments. This review aims to enhance comprehension of the mechanisms by which natural products treat AGA. To achieve this, pertinent studies were gathered and subjected to analysis. In addition, the therapeutic mechanisms associated with these natural products were organized and summarized. These include the direct modulation of signaling pathways such as the Wnt/ß-catenin pathway, the PI3K/AKT pathway, and the BMP pathway. Additionally, they exert effects on cytokine secretion, anti-inflammatory, and antioxidant capabilities, as well as apoptosis and autophagy. Furthermore, the review briefly discusses the relationship between signaling pathways and autophagy and apoptosis in the context of AGA, systematically presents the mechanisms of action of existing natural products, and analyzes the potential therapeutic targets based on the active components of these products. The aim is to provide a theoretical basis for the development of pharmaceuticals, nutraceuticals, or dietary supplements.

Regulating molecular brush structure on cotton textiles for efficient antibacterial properties.

The molecular brush structures have been developed on cotton textiles for long-term and efficient broad-spectrum antimicrobial performances through the cooperation of alkyl-chain and quaternary ammonium sites. Results show that efficient antibacterial performances can be achieved by the regulation of the alkyl chain length and quaternary ammonium sites. The antibacterial efficiency of the optimized molecular brush structure of [3-(N,N-Dimethylamino)propyl]trimethoxysilane with cetyl modification on cotton textiles (CT-DM-16) can reach more than 99 % against both E. coli and S. aureus. Alkyl-chain grafting displayed significantly improvement in the antibacterial activity against S. aureus with (N,N-Diethyl-3-aminopropyl)trimethoxysilane modification on cotton textiles (CT-DE) based materials. The positive N sites and alkyl chains played important roles in the antibacterial process. Proteomic analysis reveals that the contributions of cytoskeleton and membrane-enclosed lumen in differentially expressed proteins have been increased for the S. aureus antibacterial process, confirming the promoted puncture capacity with alkyl-chain grafting. Theoretical calculations indicate that the positive charge of N sites can be enhanced through alkyl-chain grafting, and the possible distortion of the brush structure in application can further increase the positive charge of N sites. Uncovering the regulation mechanism is considered to be important guidance to develop novel and practical antibacterial materials.

U-shaped association between triglyceride glucose-body mass index with all-cause and cardiovascular mortality in US adults with osteoarthritis: evidence from NHANES 1999-2020.

The association between insulin resistance (IR) and the risk of all-cause mortality and cardiovascular mortality among osteoarthritis (OA) patients remains uncertain. This study aims to clarify the correlation between a novel marker of IR, the triglyceride glucose-body mass index (TyG-BMI), and the risk of all-cause mortality and cardiovascular mortality in OA patients. Data from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2020 were analyzed. Multivariable Cox proportional hazards regression analysis and restricted cubic spline plots were employed to elucidate the association between the TyG-BMI index and the risk of all-cause mortality or cardiovascular mortality in OA patients. Additionally, subgroup analysis was conducted to explore potential interactions and identify populations at elevated risk of mortality. The study cohort comprised 4097 OA patients who were followed up for a period of 20 years, during which 1197 cases of all-cause mortality and 329 cases of mortality attributed to cardiovascular disease were recorded. Our findings revealed a U-shaped nonlinear relationship between the TyG-BMI index and the risk of all-cause mortality or cardiovascular mortality in OA patients, with the lowest mortality risk thresholds identified at 282 and 270, respectively. Moreover, surpassing these thresholds was associated with a 3% increase in the risk of all-cause mortality and a 5% increase in the risk of cardiovascular mortality for every 10-unit increment in TyG-BMI level. Among American OA patients, a U-shaped nonlinear relationship exists between the TyG-BMI index and the risk of all-cause mortality or cardiovascular mortality. These findings underscore the significant role of IR in the progression of OA.

Controllable 1,3-Bis-Functionalization of 2-Nitroglycals with High Regioselectivity and Stereoselectivity Enabled by a H-Bond Catalyst.

The selective modification of carbohydrates is significant for producing their unnatural analogues for drug discovery. C1-functionalization (glycosylation) and C1,C2-difunctionalization of carbohydrates have been well developed. In contrast, C3-functionalization or C1,C3-difunctionalization of carbohydrates remains rare. Herein, we report such processes that efficiently and stereoselectively modify carbohydrates. Specifically, we found that trifluoroethanol (TFE) could promote 1,3-bis-indolylation/pyrrolylation of 2-nitroglycals generated carbohydrate derivatives in up to 93% yield at room temperature; slightly reducing the temperature could install two different indoles at the C1- and C3-positions. Switching TFE to a bifunctional amino thiourea catalyst leads to the generation of C3 monosubstituted carbohydrates, which could also be used to construct 1,3-di-C-functionalized carbohydrates. This approach produced a range of challenging sugar derivatives (over 80 examples) with controllable and high stereoselectivity (single isomer for over 90% of the examples). The potential applications of the reaction were demonstrated by a set of transformations including the synthesis of bridged large-ring molecules and gram scale reactions. Biological activities evaluation demonstrated that three compounds exhibit a potent inhibitory effect on human cancer cells T24, HCT116, AGS, and MKN-45 with IC50 ranged from 0.695 to 3.548 µM.