Flexible scaffold-based cheminformatics approach for polypharmacological drug design.

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.

The properties of the rice resistant starch processing and its application in skimmed yogurt.

Extrusion is typically employed to prepare resistant starch (RS). However, the process is complicated. In this study, the effects of twin-screw extrusion on the crystallinity, thermal properties, and functional properties of starch formed in different extrusion zones were investigated. The effects of this process on the rheological properties and microstructure of RS-added skimmed yogurt were also studied. According to the results, the RS content increased from 7.40 % in the raw material to 33.79 % in the extrudate. The A-type crystal structure of the starch was not observed. The dissociation temperature of the extruded starch ranged from 87.76 °C to 100.94 °C. The glycemic index (GI) of skimmed yogurt fortified with 0.4 % RS was 48.7, and the viscosity was also improved. The microstructure exhibited a uniform network of the starch-protein structure. The findings may serve as a theoretical basis for the application of RS in the food industry.

Evaluation of flavor substances of rice bran kvass based on electronic nose and gas chromatography-mass spectrometry.

In this paper, the electronic nose (E-nose) and headspace-solid phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS) were used to analyze the volatiles of rice bran kvass (RBK) with the reference of Qiulin kvass (QLK). Meanwhile, the flavor amino acids of RBK before and after fermentation were determined. The results showed that the kinds of kvass remained consistent in terms of the overall category of volatiles while there were differences in content between them (p < 0.05). A total of 35 volatile compounds, mainly including esters, alcohols, phenols, aldehydes, and acids, were identified by GC-MS in the two kinds of kvass. In addition, the total essential amino acid content and the total sweet amino acid content of RBK increased significantly (p < 0.05) after fermentation. RBK contains both the main flavor of kvass and its own unique characteristics, making it a new member of the Kvass family.

Comparison of lipidome profiles in human milk from Chinese Han and Korean ethnic groups based on UPLC-QTRAP-MS/MS.

The composition of milk lipids varies across different ethnic sources. The lipidome profiles of Chinese Han human milk (HHM) and Chinese Korean human milk (KHM) were investigated in this study. A total of 741 lipids were identified in HHM and KHM. Twenty-eight differentially expressed lipids (DELs) were screened between the 2 milk groups; among these, 6 triacylglycerols (TGs), 13 diacylglycerols (DGs), 7 free fatty acids (FFAs), and 1 monoglyceride (MG) were upregulated in KHM. Carnitine (CAR) was upregulated in HHM. Most DELs showed a single peak distribution in both groups. The correlations, related pathways and diseases of these DELs were further analyzed. The results demonstrated that DG, MG, and FFAs showed highly positive correlations with each other (r >0.8). The most enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) and Human Metabolome Database (HMDB) pathways were inositol phosphate metabolism, and α-linolenic acid and linolenic acid metabolism, respectively. Major depressive disorder-related FFA (20:5) and FFA (22:6) were more abundant in KHM, while HHM showed more obesity-related CAR. These data potentially provide lipidome information regarding human milk from different ethnicities in China.

Effects of Panax notoginseng Saponins Encapsulated by Polymerized Whey Protein on the Rheological, Textural and Bitterness Characteristics of Yogurt.

Panax notoginseng saponins (PNSs) have been used as a nutritional supplement for many years, but their bitter taste limits their application in food formulations. The effects of PNS (groups B, C, and D contained 0.8, 1.0 and 1.2 mg/mL of free PNS, respectively) or Panax notoginseng saponin-polymerized whey protein (PNS-PWP) nanoparticles (groups E, F, and G contained 26.68, 33.35 and 40.03 mg/mL of PNS-PWP nanoparticles, respectively) on the rheological, textural properties and bitterness of yogurt were investigated. Group G yogurt showed a shorter gelation time (23.53 min), the highest elastic modulus (7135 Pa), higher hardness (506 g), higher apparent viscosity, and the lowest syneresis (6.93%) than other groups, which indicated that the yogurt formed a stronger gel structure. The results of the electronic tongue indicated that the bitterness values of group E (-6.12), F (-6.56), and G (-6.27) yogurts were lower than those of group B (-5.12), C (-4.31), and D (-3.79), respectively, which might be attributed to PNS being encapsulated by PWP. The results indicated that PWP-encapsulated PNS could cover the bitterness of PNS and improve the quality of yogurt containing PNS.

2-Phenylcyclopropylmethylamine (PCPMA) as a privileged scaffold for central nervous system drug design.

The use of privileged scaffolds in medicinal chemistry is an effective way to accelerate the drug discovery process, especially at the hit/lead optimization stage. 2-Phenylcyclopropylmethylamine (PCPMA) is a less commonly used chemical scaffold in medicinal chemistry, but many PCPMA-containing compounds exert therapeutic effects for various diseases, in particular central nervous system (CNS) diseases such as depression, schizophrenia, sleep disorder, and Parkinson's disease. The backbone of the PCPMA scaffold enables a unique structure of an amino group linked to a benzene ring through an alkyl linker, making it a useful template for the design of bioactive compounds especially for CNS drug targets including aminergic GPCRs and transporters. This review summarizes the medicinal chemistry studies of PCPMA-containing drugs and drug-like molecules, their mechanisms of action, and biological activities. We conclude that PCPMA is a unique and useful privileged scaffold for CNS drug design.

Mesoporous polydopamine Targeting CDK4/6 Inhibitor toward Brilliant Synergistic Immunotherapy of Breast Cancer.

Immunotherapy utilizing anti-PD-L1 blockade has achieved dramatic success in clinical breast cancer management but is often hampered by the limited immune response. Increasing evidence shows that immunogenic cell death (ICD) recently arises as a promising strategy for enlarging tumor immunogenicity and eliciting systemic anti-tumor immunity effectively. However, developing simple but versatile, highly efficient but low-toxic, biosafe, and clinically available transformed ICD inducers remains a huge demand and is highly desirable. Herein, a multifunctional ICD inducer is purposefully developed A6-MPDA@PAL by integrating photothermal therapy (PTT) nanoplatforms mesoporous polydopamine (MPDA), CDK4/6 inhibitor palbociclib (PAL), and CD44-specific targeting A6 peptide in a simple way for augmenting the immune antitumor efficacy of anti-PD-L1 therapy. Remarkably, the light-inducible nanoplatforms exhibit multiple favorable therapeutic features ensuring a superior and biosafe PTT/chemotherapy efficacy. Together with stronger accumulative ICD induction, single administration of A6-MPDA@PAL can trigger robust systemic antitumor immunity and abscopal effect with the assistance of anti-PD-L1 blockade by fascinating the intratumoral infiltration of T lymphocytes and reversing the immunosuppressive tumor microenvironment simultaneously, therapy achieving brilliant synergistic immunotherapy with effective tumor ablation. This study presents a simple and smart ICD inducer opening up attractive clinical possibilities for reinforcing the anti-PD-L1 therapy against breast cancer.

Strategies for the eradication of intracellular bacterial pathogens.

Intracellular pathogens affect a significant portion of world population and cause millions of deaths each year. They can invade host cells and survive inside them and are extremely resistant to immune systems and antibiotics. Current treatments have limitations, and therefore, new effective therapies are needed to combat this ongoing health challenge. Active research efforts have been made to develop many new strategies to eradicate these intracellular pathogens. In this review, we focus on the intracellular bacterial pathogens and first introduce several representative intracellular bacteria and the diseases they cause. We then discuss the challenges in eradicating these bacteria and summarize the current therapeutics for intracellular bacteria. Finally, recent advances in intracellular bacteria eradication are highlighted.

Tailoring Synthetic Polypeptide Design for Directed Fibril Superstructure Formation and Enhanced Hydrogel Properties.

The biological significance of self-assembled protein filament networks and their unique mechanical properties have sparked interest in the development of synthetic filament networks that mimic these attributes. Building on the recent advancement of autoaccelerated ring-opening polymerization of amino acid N-carboxyanhydrides (NCAs), this study strategically explores a series of random copolymers comprising multiple amino acids, aiming to elucidate the core principles governing gelation pathways of these purpose-designed copolypeptides. Utilizing glutamate (Glu) as the primary component of copolypeptides, two targeted pathways were pursued: first, achieving a fast fibrillation rate with lower interaction potential using serine (Ser) as a comonomer, facilitating the creation of homogeneous fibril networks; and second, creating more rigid networks of fibril clusters by incorporating alanine (Ala) and valine (Val) as comonomers. The selection of amino acids played a pivotal role in steering both the morphology of fibril superstructures and their assembly kinetics, subsequently determining their potential to form sample-spanning networks. Importantly, the viscoelastic properties of the resulting supramolecular hydrogels can be tailored according to the specific copolypeptide composition through modulations in filament densities and lengths. The findings enhance our understanding of directed self-assembly in high molecular weight synthetic copolypeptides, offering valuable insights for the development of synthetic fibrous networks and biomimetic supramolecular materials with custom-designed properties.

Construction and properties of a carbon dots-decorated gelatin-dialdehyde starch hydrogel with pH response release and antibacterial activity.

An antibacterial carbon dot hydrogel (GDSS-PCD) was constructed based on gelatin, dialdehyde starch (DS) and carbon dots (S-PCDs). The formation mechanism of GDSS-PCD hydrogels was attributed to the synergistic cross-linking of hydrogen bonds and dynamic covalent bonds. With increasing S-PCD content, the mechanical and rheological properties of GDSS-PCD hydrogels can be improved, and the micropore size becomes denser. GDSS-PCD hydrogels had pH-dependent swelling and degradation behavior, with a high swelling rate under acidic conditions and relatively low swelling under neutral and alkaline conditions. The cumulative release of S-PCDs from the same hydrogel in an acidic environment was higher than that in an alkaline environment, indicating that the GDSS-PCD hydrogel had a pH-dependent controlled release ability. The release behavior of S-PCDs conformed to the first-order kinetic release model (R2 > 0.95), and the release mechanism was related to Fickian diffusion. The synergistic antibacterial mechanism of GDSS-PCD hydrogels against Staphylococcus aureus suggested that bacterial metabolism leads to an acidic culture environment, which releases S-PCDs and destroys the bacterial cell membrane for antibacterial purposes. In GDSS-PCD hydrogels, S-PCDs play the main antibacterial role, and the hydrogel plays a synergistic role in trapping bacteria. Carbon dot hydrogels are promising materials to fulfil the functions of antibacterial and controlled release in the food and biomedical fields.

Impact of soybean protein isolate concentration on chitosan-cellulose nanofiber edible films: Focus on structure and properties.

Chitosan and cellulose nanofiber films are frequently employed as biodegradable materials for food packaging. However, many exhibit suboptimal hydrophobicity and antioxidant properties. To address these shortcomings, we enhanced the performance by adding different concentrations of soybean protein isolate (SPI) to chitosan-cellulose nanofiber (CS-CNF) films. As SPI concentration varied, the turbidity, particle size, and ζ-potential of the film-forming solutions initially decreased and subsequently increased. This suggests that 1 % SPI augments the electrostatic attraction and compatibility. Rheological analysis confirmed a pronounced apparent viscosity at this concentration. Analyses using Fourier transform infrared spectra, Raman spectra, X-ray diffraction, and Scanning electron microscope revealed the presence of hydrogen bonds and electrostatic interactions between SPI and CS-CNF, indicative of superior compatibility. When SPI concentration was set at 1 %, notable enhancements in film attributes were observed: improvements in tensile strength and elongation at break, a reduction in water vapor permeability by 8.23 %, and an elevation in the contact angle by 18.85 %. Furthermore, at this concentration, the ABTS+ and DPPH scavenging capacities of the film surged by 61.53 % and 46.18 %, respectively. Meanwhile, the films we prepare are not toxic. This research offers valuable insights for the advancement and application of protein-polysaccharide-based films.

Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants.

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure-activity relationships of existing 5-HT2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT2AR agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.

pH-induced physiochemical and structural changes of milk proteins mixtures and its effect on foaming behavior.

Milk proteins are well known to produce aerated food due to the amphiphilicity. However, milk proteins are commonly added in blends for the desirable properties in food industry. In this study, the foaming properties of milk protein mixtures (MPM), a mixtures of whey protein isolated (WPI) and milk protein concentrate (MPC), was studied through foaming capacity (FC), foam stability (FS), and foam morphology at pH 3.0-9.0. Physiochemical, structural, surface properties, and Pearson correlation analysis were measured to gain insight into foaming behavior. Results indicated that MPM showed excellent FC (113.0-114.3 %) and FS (90.7-93.0 %) at pH 6.0-9.0, and foam displayed a smaller size and uniform distribution. MPM solutions showed smaller particles, higher solubility, and lower apparent viscosity at pH 6.0-9.0, which resulted in an increase in surface pressure and adsorption rate (Kdiff), facilitating more protein absorbed to interface. To further investigate structural changes, various spectral methods were used, in which the structure of MPM was changed with pH. Correlation analysis further suggests that Kdiff and solubility positively affect the formation of foam, while free sulfhydryl and ß-sheet contributed to stabilizing foams. These findings provide valuable information on MPM as ingredients for aerated foods under acidic, neutral, and alkaline conditions.

Functional Identification of Olfactory Receptors of Cnaphalocrocis medinalis (Lepidoptera: Crambidae) for Plant Odor.

Cnaphalocrocis medinalis (Lepidoptera: Crambidae) is a migratory insect pest on rice crops. The migratory C. medinalis population in a particular location may be immigrants, local populations, emigrants, or a mix of these. Immigrants are strongly attracted to plant odor. We conducted research to identify the olfactory receptors in a floral scent mixture that is strongly attractive to C. medinalis. Through gene cloning, 12 olfactory receptor (OR) genes were amplified and expressed in Xenopus oocytes in vitro, and three of them were found to be responsive to plant foliar and floral volatiles. These were CmedOR31, a specific receptor for geraniol; CmedOR32, a broad-spectrum OR gene that responded to both foliar and floral odors; and CmedOR1, which strongly responded to 10-4 M phenylacetaldehyde. The electrophysiological response to phenylacetaldehyde was extremely high, with a current of 3200 ± 86 nA and an extremely high sensitivity. We compared the phylogenetic tree and sequence similarity of CmedOR genes and found that CmedOR1 belonged to a uniquely conserved OR pedigree in the evolution of Glossata species, and the ORs of this pedigree strongly responded to phenylacetaldehyde. The expression of OR1 was significantly higher in the females than in the males. Localization of CmedOR1 in the antennae of C. medinalis by fluorescence in situ hybridization showed that CmedOR1 was expressed in both males and females. CmedOR1 may be an odor receptor used by females to locate food sources. The function of these ORs and their role in pest monitoring were discussed.

Effect of different salts on foaming properties of model protein system for infant formula.

This multiscale study aimed to evaluate the effect of different salts (NaCl, KCl, MgCl2, and CaCl2) on foaming capacity (FC) and foam stability (FS) of model protein system (MPS) for infant formula via the changes of surface and structural properties. Results showed that the FC and FS of MPS were increased at NaCl, KCl, and MgCl2 condition, whereas CaCl2 significantly (P < 0.05) decreased FC (79.5 ± 10.6%) and increased FS (93.2 ± 2.2%). The H0 was increased, while the net charge and surface tension was reduced after addition of salts. Structural analysis revealed the reduction of intensity of intrinsic fluorescence spectroscopy and UV (UV) absorption, and the conversion of α-helix into ß-strand, which was attributed to protein agglomeration. Additionally, MgCl2 and CaCl2 exhibited larger size and lower net charge compared with NaCl and KCl, indicating a greater ability to bind to charged amino acids and formed larger aggregates. Correlation analysis indicated that FC was positively related to adsorbed protein and ß-turn, while negatively correlated with particle size. FS showed a positive correlation with ß-strand, apparent viscosity, and zeta potential. However, it exhibited a negative correlation with ß-turn, α-helix, and SH content. These results provide a theoretical reference for further understanding of the effect of salts on the foaming properties of MPS.

Physicochemical and Functional Properties of Thermal-Induced Polymerized Goat Milk Whey Protein.

Goat milk whey protein products are a hard-to-source commodity. Whey protein concentrate was directly prepared from fresh goat milk. The effects of the heating temperature (69-78 °C), time (15-30 min), and pH (7.5-7.9) on the physicochemical and functional properties of the goat milk whey protein were investigated. The results showed that the particle size of the samples significantly increased (p < 0.05) after heat treatment. The zeta potential of polymerized goat milk whey protein (PGWP) was lower than that of native goat milk whey protein. The content of the free sulfhydryl groups of PGWP decreased with increasing heating temperature and time, while an increase in surface hydrophobicity and apparent viscosity of PGWP were observed after heat treatment. Fourier Transform Infrared Spectroscopy analysis indicated that heat treatment and pH had considerable impacts on the secondary structure of goat milk whey protein. Transmission electron microscope images revealed that heat induced the formation of a large and uniform protein network. Additionally, the changes in the physicochemical and structural properties contributed to the improvement of the emulsifying and foaming properties of goat milk whey protein after heat treatment. The results may provide a theoretical basis for the applications of polymerized goat milk whey protein in related products.

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment.

The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds 15a (EC50 = 31.4 nM) and 20a (EC50 = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound 20a also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate.

Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction.

Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are "nonlethal," in that the inhibition of the enzymes' activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm3).

Organic-Solvent-Free "Lego-Like" Modular Preparation of Fab-Nondestructive Antibody-Drug Conjugates with Ultrahigh Drug-to-Antibody Ratio.

Antibody-drug conjugates (ADCs) have exciting possibilities in targeted tumor therapy. However, in the existing ADC preparation processes, the random attachment of the payloads to the antigen-binding fragments (Fab) greatly increases the risk of disrupting its antigen recognition ability, while the drug-antibody ratio (DAR) is low, leading to a cumbersome preparation process and low drug delivery efficiency. Herein, poly(glutamic acid) is used to expand the number of drug binding sites, based on the "click chemistry" of azide and DBCO, and the high affinity of Fc-III-4C peptide to the crystalline fragment (Fc) of the monoclonal antibodies. Various antibody-polymer-drug conjugates are obtained with ultrahigh DAR using this organic-solvent-free "Lego-like" modular construction. Among them, aHER2-P-MMAE with DAR of 41.6 achieves tumor growth inhibition (TGI) of 99.7% for both medium-sized and large SKOV-3 ovarian tumors, and aPDL1-P-MMAE (DAR = 40.7) achieves TGI of 98.5% for MC38 colon tumors. In summary, a universal platform is created to prepare Fab-nondestructive ADCs with ultrahigh DAR, which can be used to develop precision medicine for personalized anticancer therapy.

Deciphering the difference of casein fraction in human milk associated with infant gender using quantitative proteomics.

Human milk is an ideal natural food for infants, and the infant's gender may have impact on protein composition of breast milk. In this study, we used 4D label-free quantitative proteomics techniques to identify and quantitatively analyze casein fraction in breast milk secreted for male and female infants. The results showed that a total of 2064 proteins were identified in human milk, and 95 of them were differentially abundant proteins. Compared to breast milk secreted by mothers of female infants, 21 proteins were up-regulated, and 59 proteins were down-regulated in breast milk secreted by mothers of male infants. The most abundant domain among the differentially abundant proteins was the immunoglobulin V-set domain, which may be involved in immune regulation. Gene Ontology functional analysis revealed that, the main biological processes, molecular functions, and cellular components corresponded to cellular process, binding, and cell part, respectively. The Kyoto Encyclopedia of Genes and Genomes pathways were mainly associated with human diseases and metabolism, with biosynthesis of cofactors being the most involved pathway. The results contribute to our understanding of the composition of casein in breast milk, and may provide information about the nutritional differences in breast milk from mothers of newborns of different genders.