Phenylpropionic Acid Research Articles

Changes in Rumen Microbiology and Metabolism of Tibetan Sheep with Different Lys/Met Ratios in Low-Protein Diets.

In ruminants, supplementing appropriate amounts of amino acids improves growth, feed utilization efficiency, and productivity. This study aimed to assess the effects of different Lys/Met ratios on the ruminal microbial community and the metabolic profiling in Tibetan sheep using 16S rDNA sequencing and non-target metabolomics. Ninety-two-month-old Tibetan rams (initial weight = 15.37 ± 0.92 kg) were divided into three groups and fed lysine/methionine (Lys/Met) of 1:1 (LP-L), 2:1 (LP-M), and 3:1 (LP-H) in low-protein diet, respectively. Results: The T-AOC, GSH-Px, and SOD were significantly higher in the LP-L group than in LP-H and LP-M groups (p < 0.05). Cellulase activity was significantly higher in the LP-L group than in the LP-H group (p < 0.05). In the fermentation parameters, acetic acid concentration was significantly higher in the LP-L group than in the LP-H group (p < 0.05). Microbial sequencing analysis showed that Ace and Chao1 indicators were significantly higher in LP-L than in LP-H and LP-M (p < 0.05). At the genus level, the abundance of Rikenellaceae RC9 gut group flora and Succiniclasticum were significantly higher in LP-L than in LP-M group (p < 0.05). Non-target metabolomics analyses revealed that the levels of phosphoric acid, pyrocatechol, hydrocinnamic acid, banzamide, l-gulono-1,4-lactone, cis-jasmone, Val-Asp-Arg, and tropinone content were higher in LP-L. However, l-citrulline and purine levels were lower in the LP-L group than in the LP-M and LP-H groups. Banzamide, cis-jasmone, and Val-Asp-Arg contents were positively correlated with the phenotypic contents, including T-AOC, SOD, and cellulase. Phosphoric acid content was positively correlated with cellulase and lipase activities. In conclusion, the Met/Lys ratio of 1:1 in low-protein diets showed superior antioxidant status and cellulase activity in the rumen by modulating the microbiota and metabolism of Tibetan sheep.

Microbiota-derived 3-phenylpropionic acid promotes myotube hypertrophy by Foxo3/NAD+ signaling pathway

BackgroundGut microbiota and their metabolites play a regulatory role in skeletal muscle growth and development, which be known as gut-muscle axis. 3-phenylpropionic acid (3-PPA), a metabolite produced by colonic microorganisms from phenylalanine in the gut, presents in large quantities in the blood circulation. But few study revealed its function in skeletal muscle development.ResultsHere, we demonstrated the beneficial effects of 3-PPA on muscle mass increase and myotubes hypertrophy both in vivo and vitro. Further, we discovered the 3-PPA effectively inhibited protein degradation and promoted protein acetylation in C2C12 and chick embryo primary skeletal muscle myotubes. Mechanistically, we supported that 3-PPA reduced NAD+ synthesis and subsequently suppressed tricarboxylic acid cycle and the mRNA expression of SIRT1/3, thus promoting the acetylation of total protein and Foxo3. Moreover, 3-PPA may inhibit Foxo3 activity by directly binding.ConclusionsThis study firstly revealed the effect of 3-PPA on skeletal muscle growth and development, and newly discovered the interaction between 3-PPA and Foxo3/NAD+ which mechanically promote myotubes hypertrophy. These results expand new understanding for the regulation of gut microbiota metabolites on skeletal muscle growth and development.

Systematic investigation of the material basis, effectiveness and safety of Thesium chinense Turcz. and its preparation Bairui Granules against lung inflammation

BackgroundThesium chinense Turcz. (Named as Bai Rui Cao in Chinese) and its preparations (e.g., Bairui Granules) have been used to treat inflammatory diseases, such as acute mastitis, lobar pneumonia, tonsillitis, coronavirus disease 2019 (COVID-19), and upper respiratory tract infection. However, the material basis, pharmacological efficiency, and safety have not been illustrated.MethodsAnti-inflammatory activity-guided isolation of constituents has been performed using multiple column chromatography, and their structures were elucidated by NMR spectroscopy and ECD calculations. The inhibitory effects on lung inflammation and safety of the crude ethanol extract (CE), Bairui Granules (BG), and the purified active constituents were evaluated using lipopolysaccharide (LPS)-stimulated acute lung inflammation (ALI) mice model or normal mice.ResultsSeven new compounds (1–7) and fifty-six known compounds (8–63) were isolated from T. chinense, and fifty-four were reported from this plant for the first time. The new flavonoid glycosides 1–2, new fatty acids 4–5, new alkaloid 7 as well as the known constituents including flavonoid aglycones 8–11, lignans 46–54, alkaloids 34 and 45, coumarins 57, phenylpropionic acids 27, and simple aromatic compounds 39, 44 and 58 exhibited anti-inflammatory activity. Network pharmacology analysis indicated that anti-inflammation of T. chinense was attributed to flavonoids and alkaloids by regulating inflammation-related proteins (e.g., TNF, NF-κB, TGF-β). Furthermore, constituents of T. chinense including kaempferol-3-O-glucorhamnoside (KN, also named as Bairuisu I, 19), astragalin (AG, Bairuisu II, 12), and kaempferol (KF, Bairuisu III, 8), as well as CE and BG could alleviate lung inflammation caused by LPS in mice by preventing neutrophils infiltration and the expression of the genes for pro-inflammatory cytokines NLRP3, caspase-1, IL-1β, and COX-2. After a 28-day subacute toxicity test, BG at doses of 4.875 g/kg and 9.750 g/kg (equivalent to onefold and twofold the clinically recommended dose) and CE at a dose of 11.138 g/kg (equivalent to fourfold the clinical dose of BG) were found to be safe and non-toxic.ConclusionsThe discovery of sixty-three constituents comprehensively illustrated the material basis of T. chinense. T. chinense and Bairui Granules could alleviate lung inflammation by regulating inflammation-related proteins and no toxicity was observed under the twofold of clinically used doses.

Effect of Fatty Acid Unsaturation on the Intermolecular Weak Interaction at the Low-Rank Coal-Water Interface: Density Functional Theory Calculations and Experimental Study.

The study on the effect of fatty acid saturation on low-rank coal (LRC) flotation is still limited. In this investigation, density functional theory (DFT) combined with Zeta potential and Fourier transform infrared spectroscopy (FTIR) was used to study the mechanism of intermolecular weak interaction at the LRC-water interface of fatty acids (decanoic acid (DA), undecylenic acid (UA), and phenyl propionic acid (PA)) with different saturations and different dodecane (D) composition hydrocarbon oil-fatty acid mixed collectors (D-DA, D-UA, D-PA). The findings demonstrated that the hydrogen bond interaction and electrostatic interaction between the UA/PA with unsaturated bonded carbon chains and the LRC molecular fragments/water molecules were stronger than DA without a saturated bond carbon chain, and UA/PA strengthened its interaction with water molecules on the whole, even PA molecules would preferentially interact with water molecules. The unsaturated bond had a minimal impact on the adsorption of the LRC hydrophobic site, and the strength of the hydrogen bond between the mixed collector and LRC is D-DA > D-UA > D-PA. In the actual flotation process, the strong hydrogen bonding and electrostatic interaction between UA/PA and water molecules weaken the collection performance of the mixed collector D-UA/D-PA for LRC, which also confirmed the research results of DFT, FTIR, and Zeta.

Synthesis, crystal structure and Hirshfeld surface analysis of 4-{(1E)-1-[(car-bamo-thioyl-amino)-imino]-eth-yl}phenyl propano-ate.

The title compound, C12H15N3O2S, adopts an E configuration with respect to the C=N bond. The propionate group adopts an anti-periplanar (ap) conformation. There are short intra-molecular N-H⋯N and C-H⋯O contacts, forming S(5) and S(6) ring motifs, respectively. In the crystal, mol-ecules are connected into ribbons extending parallel to [010] by pairs of N-H⋯S inter-actions, forming rings with R 2 2(8) graph-set motifs, and by pairs of C-H⋯S inter-actions, where rings with the graph-set motif R 2 1(7) are observed. The O atom of the carbonyl group is disordered over two positions, with a refined occupancy ratio of 0.27 (2):0.73 (2). The studied crystal consisted of two domains.

Structural Analysis of 3,5-Bistrifluoromethylhydrocinnamic Acid

The crystal structure of 3,5-bistrifluoromethylhydrocinnamic acid [systematic name: 3-[3,5-bis(trifluoromethyl)phenyl]propanoic acid], C11H8F6O2, has been determined and described. The structure was subject to the Hirshfeld surface-analysis and CE-B3LYP interaction-energies calculations. The title compound crystallises in the monoclinic P21/c space group with one molecule in the asymmetric unit. The propanoic acid side chain of the studied molecule has a bent conformation. The key supramolecular motif in the crystal structure is a centrosymmetric O–H∙∙∙O hydrogen-bonded dimer (R22(8) in the graph set notation). According to CE-B3LYP, the molecules involved in this motif exhibit the strongest pairwise interaction total energy (Etot = −67.9 kJ/mol). On the other hand, there are seven other interacting molecular pairs with significant Etot values in the range of −17 to −28 kJ/mol. In these, the energy is dominated by the dispersive contribution. A survey of the Cambridge Structural Database revealed that in other 3-phenylpropanoic acid structures, the middle dihedral angle of the propanoic acid side chain is always in the trans conformation. This contrasts the current structure where this dihedral angle is in the gauche conformation. According to the Density Functional Theory calculations in the gas phase (at the B3LYP/aug-cc-pvDZ level), the presence of the two CF3 groups (strong electron-withdrawing character) increases the population of the gauche conformers by a substituent electronic effect, and this may be a minor factor contributing to the appearance of this conformation observed in the solid state.

New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses

The spread of COVID-19 continues due to genetic variation in SARS-CoV-2. Highly mutated variants of SARS-CoV-2 have an increased transmissibility and immune evasion. Due to the emergence of various new variants of the virus, there is an urgent need to develop broadly effective specific drugs for therapeutic strategies for the prevention and treatment of COVID-19. Molnupiravir (EIDD-2801, MK-4482), is an orally bioavailable ribonucleoside analogue of β-D-N4-hydroxycytidine (NHC), has demonstrated efficacy against SARS-CoV-2 and was recently approved for COVID-19 treatment. To improve antiviral potency of NHC, we developed a panel of NHC conjugates with lipophilic vectors and ester derivatives with amino- and carboxylic-acids. Most of the synthesized compounds had comparable or higher (2–20 times) antiviral activity than EIDD-2801, against different lineages of SARS-CoV-2, MERS-CoV, seasonal coronaviruses OC43 and 229E, as well as bovine coronavirus. For further studies, we assessed the most promising compound in terms of activity, simplicity and cost of synthesis - NHC conjugate with phenylpropionic acid (SN_9). SN_9 has shown high efficacy in prophylactic, therapeutic and transmission models of COVID-19 infection in hamsters. Importantly, SN_9 profoundly inhibited virus replication in the lower respiratory tract of hamsters and transgenic mice infected with the Omicron sublineages XBB.1.9.1, XBB.1.16 and EG.5.1.1. These data indicate that SN_9 represents a promising antiviral drug candidate for COVID-19 treatment, and NHC modification strategies deserve further investigation as an approach to develop prodrugs against various coronaviruses.

Season-long comparison of trap lures for integrated management of the navel orangeworm (Lepidoptera: Pyralidae) in almond and pistachio

Monitoring navel orangeworm, Amyelois transitella (Lepidoptera: Pyralidae) using pheromone lures is now complicated by the use of mating disruption. Two commercially available lures that are minimally affected by mating disruption use either natural ovipositional substrates (Bait lures) or a combination of phenyl propionate (PPO), a volatile chemical that attracts both sexes and pheromone lures (Combo lures). We compared the season-long trap capture for these two lures in a sterile insect technique (SIT) demonstration project in Fresno County, California, 2020–2023. A total of 194,233 males (96.52%) were caught using Combo lures and 7006 (3.48%) caught using Bait lures, while 95,947 females (48.83%) were caught using Combo lures and 100,532 (51.17%) caught using Bait lures. Capture of A. transitella was 2.3-fold higher in pistachio (278,492) than in almond (119, 316), and within a commodity, there was a moderate correlation in female capture between the two lures; correlation was stronger during the period leading up to July 21 (Julian date 202). For Bait lures, 48.7% of the trap catch in almond occurred by July 21 and 87.1% of the trap catch occurred in pistachio by July 21. For Combo lures, 38.9% of the trap catch in almond occurred by July 21 while 54.6% of the catch occurred in pistachio. Bait lures became less effective after July 21, likely due to diminished attractiveness as new crop nuts split in August through October. Our data indicate that Combo lures are preferable when the goal is consistent season-long capture of A. transitella in almond and pistachio.

Efficient fractionation of corn stover using deep eutectic solvent from lignin-derived 3-phenylpropionic acid: Towards a closed-loop biorefinery

The search for renewable deep eutectic solvents (DESs) for efficient biomass pretreatment based on a closed-loop biorefinery is of great interest and importance. Herein, we reported three novel lignin-based DESs prepared by choline chloride (ChCl) and 3-(4-hydroxyphenyl)propionic acid (HPA), 3-(4-hydroxy-3-methoxyphenyl)propanoic acid (HMPA) and their combination for corn stover pretreatment. The effects of three lignin-based DESs pretreatments on the chemical compositions of raw material, structural features of lignin, and enzymatic digestibility of cellulose were comprehensively analyzed, among which ChCl/HPA DES exhibited superior pretreatment efficiency, affording 58% of delignification, 62% of hemicellulose removal, and 85% of glucose yield. A high abundance of p-coumaric acid in the regenerated and remaining lignin samples makes them a sustainable feedstock to produce hydrogen bond donors of ChCl/HPA DES, as demonstrated by the results from 2D HSQC NMR analysis and catalytic depolymerization of lignins. These results could be conducive to creating an integrated biorefinery strategy for biomass valorization. Mass balance analysis indicated 81% of cellulose, 90% of hemicellulose, and 91% of lignin components in corn stover could be collected after DES pretreatment. This contribution offers a novel and efficient pretreatment method for corn stover fractionation based on a closed-loop biorefinery.

Cross-Validation of Metabolic Phenotypes in SARS-CoV-2 Infected Subpopulations Using Targeted Liquid Chromatography-Mass Spectrometry (LC-MS).

To ensure biological validity in metabolic phenotyping, findings must be replicated in independent sample sets. Targeted workflows have long been heralded as ideal platforms for such validation due to their robust quantitative capability. We evaluated the capability of liquid chromatography-mass spectrometry (LC-MS) assays targeting organic acids and bile acids to validate metabolic phenotypes of SARS-CoV-2 infection. Two independent sample sets were collected: (1) Australia: plasma, SARS-CoV-2 positive (n = 20), noninfected healthy controls (n = 22) and COVID-19 disease-like symptoms but negative for SARS-CoV-2 infection (n = 22). (2) Spain: serum, SARS-CoV-2 positive (n = 33) and noninfected healthy controls (n = 39). Multivariate modeling using orthogonal projections to latent structures discriminant analyses (OPLS-DA) classified healthy controls from SARS-CoV-2 positive (Australia; R2 = 0.17, ROC-AUC = 1; Spain R2 = 0.20, ROC-AUC = 1). Univariate analyses revealed 23 significantly different (p < 0.05) metabolites between healthy controls and SARS-CoV-2 positive individuals across both cohorts. Significant metabolites revealed consistent perturbations in cellular energy metabolism (pyruvic acid, and 2-oxoglutaric acid), oxidative stress (lactic acid, 2-hydroxybutyric acid), hypoxia (2-hydroxyglutaric acid, 5-aminolevulinic acid), liver activity (primary bile acids), and host-gut microbial cometabolism (hippuric acid, phenylpropionic acid, indole-3-propionic acid). These data support targeted LC-MS metabolic phenotyping workflows for biological validation in independent sample sets.

Uremic Toxins and Inflammation: Metabolic Pathways Affected in Non-Dialysis-Dependent Stage 5 Chronic Kidney Disease.

Chronic kidney disease (CKD) affects approximately 12% of the global population, posing a significant health threat. Inflammation plays a crucial role in the uremic phenotype of non-dialysis-dependent (NDD) stage 5 CKD, contributing to elevated cardiovascular and overall mortality in affected individuals. This study aimed to explore novel metabolic pathways in this population using semi-targeted metabolomics, which allowed us to quantify numerous metabolites with known identities before data acquisition through an in-house polar compound library. In a prospective observational design with 50 patients, blood samples collected before the initial hemodialysis session underwent liquid chromatography and high-resolution mass spectrometer analysis. Univariate (Mann-Whitney test) and multivariate (logistic regression with LASSO regularization) methods identified metabolomic variables associated with inflammation. Notably, adenosine-5'-phosphosulfate (APS), dimethylglycine, pyruvate, lactate, and 2-ketobutyric acid exhibited significant differences in the presence of inflammation. Cholic acid, homogentisic acid, and 2-phenylpropionic acid displayed opposing patterns. Multivariate analysis indicated increased inflammation risk with certain metabolites (N-Butyrylglycine, dimethylglycine, 2-Oxoisopentanoic acid, and pyruvate), while others (homogentisic acid, 2-Phenylpropionic acid, and 2-Methylglutaric acid) suggested decreased probability. These findings unveil potential inflammation-associated biomarkers related to defective mitochondrial fatty acid beta oxidation and branched-chain amino acid breakdown in NDD stage 5 CKD, shedding light on cellular energy production and offering insights for further clinical validation.

Chemical profiling and mechanisms of Agarikon pill in a rat model of cigarette smoke-induced chronic obstructive pulmonary disease

Background and aimAgarikon pill (AGKP), a traditional Chinese herbal formula, and has been used for chronic obstructive pulmonary disease (COPD) treatment clinically. However, the active components and exact pharmacological mechanisms are still unclear. We aimed to investigate the therapeutic effects and mechanisms of AGKP on COPD and identify the chemical constituents and active compounds. Experimental procedureThe chemical components of AGKP were identified by ultrahigh-performance liquid chromatography coupled with quadrupole/orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS). Network pharmacology analysis was performed to uncover the potential mechanism of AGKP. The efficiencies and mechanisms of AGKP were further confirmed in COPD animal models. Results and conclusionNinety compounds from AGKP, such as flavonoids, triterpenoids, saponins, anthracenes, derivatives, phenyl propionic acid, and other organic acids, were identified in our study. AGKP improved lung function and pathological changes in COPD model rats. Additionally, inflammatory cell infiltration and proinflammatory cytokine levels were markedly reduced in COPD rats administered AGKP. Network pharmacology analysis showed that the inflammatory response is the crucial mechanism by which AGKP exerts therapeutic effects on COPD rats. WB and PCR data indicated that AGKP attenuated the inflammatory response in COPD model rats. AGKP reduces the pulmonary inflammatory response through the PI3K/AKT and MAPK TLR/NF-κB signaling pathways and exerts therapeutic effects via inhibition of inflammation and mucus hypersecretion on COPD model rats.

Behavior, antioxidant, and metabolomics effects of Allium tuncelianum.

Allium species are consumed extensively as folkloric medicine and dietary elements, but limited studies have been conducted on them. In this study, the effects of an ethanol-water extract obtained from the underground bulb of Allium tuncelianum (Kollmann) Özhatay, B. Mathew & Şiraneci (AT) on the behavioral, antioxidant, and metabolite parameters in rats were evaluated. AT was administered orally once a day at doses of 100 and 400 mg/kg to male Wistar albino rats for 10 consecutive days. The elevated plus maze, rotarod, and hotplate tests were used to examine anxiety-like behaviors, locomotor activities, and pain perception in the rats, respectively. Additionally, untargeted metabolomic analyses were performed on plasma samples and AT extracts using two orthogonal analytical platforms. The phenolic components, mainly fumaric acid, malic acid, vanillic acid, quercetin-3-arabinoside, hydrocinnamic acid, and gallocatechin, were determined in the extract. In addition, arbutin, salicylic acid, trehalose, and nicotinic acid were analyzed in the extract for the first time. The AT extract did not decrease the catalase, glutathione peroxidase, or superoxide dismutase levels; however, diazepam decreased some of those parameters significantly in the brain, liver, and kidney. Although both the AT and diazepam treatments resulted in an increase in anxiolytic-like effects compared to the control group, no significant differences were observed (p > .05). In the metabolomic analysis, significant changes were observed in the rats treated with AT and diazepam, and they caused significant changes in some metabolic pathways, including amino acid and fatty acid metabolism, compared to the control.

Phytochemical analysis, antioxidant and ALR2 inhibitory activity of Sorbus torminalis (L.) fruits at different maturity stages

Thirty four compounds were identified in Sorbus torminalis (L.) fruit extracts of different maturity types by means of LC-DAD-MS (ESI+) fragmentation analysis. Both immature and mature fruits were rich in flavonoid glycosides esterified with hydroxycinnamic, phenolic and dicarboxylic acids along with benzoic, phenylpropanoic and cinnamoyl quinic acid derivatives with many of them being detected for the first time in Sorbus species and in literature. Extracts and fractions were tested for their antioxidant activity (DPPH, chemiluminescence, Rancimat assays) and the estimation of the phenolic content was carried out through Folin-Ciocalteu reagent. Ethyl acetate fraction exhibited the highest scavenging activity determined as EC50 = 1.58 ± 0.22 μg/mL and EC50 = 1.64 ± 0.24 μg/mL for immature and mature fruits respectively with the DPPH test. Chemiluminescence test indicated the same fraction having the strongest antioxidant activity with an IC50 0.41 ± 0.06 μg/mL and IC50 0.50 ± 0.02 μg/mL in both maturity types. The ethyl acetate fraction of the mature fruits is considered the most potent Aldose Reductase 2 (ALR2) inhibitor with 79% demonstrating the high nutritional value of Sorbus torminalis (L.) mature fruits as a defense mechanism against the onset of diabetes mellitus secondary complications leading to the utilization of the plant for nutritional and pharmaceutical purposes.

Mercapto-β-cyclodextrin covalent organic frameworks for enantioselective liquid-liquid extraction

β-Cyclodextrin (β-CD) exhibits exceptional chiral recognition ability, and covalent organic frameworks (COFs) have been reported as highly promising chiral carriers. Therefore, incorporating cyclodextrin into COFs may result in chiral covalent organic frameworks (CCOFs) suitable for chiral applications. In this work, a solvothermal method was employed to synthesize a classical porous covalent organic framework (COF-V), while β-CD underwent a two-step modification process, resulting in the synthesis of mercapto-β-cyclodextrin (β-CD-SH). Subsequently, a β-CD-based covalent organic framework (COF-S-CD) was synthesized through a Thiol-Ene “click” reaction. The synthesized COF-S-CD was successfully applied in enantioselective liquid-liquid extraction for five racemic arylcarboxylic acids, including 2-phenylpropionic acid, 2-(4-methylphenyl) propionic acid, 2-(3-chlorophenyl) propionic acid, 2-(4-nitrophenyl) propionic acid and α-cyclohexylmandelic acid. Under optimized conditions, enantioseparation factors for the five racemates reached 1.78, 2.20, 1.84, 1.76 and 1.96, respectively, which indicated a significant enhancement in chiral recognition ability upon the incorporation of cyclodextrin into the COF material. This new application suggested that the synthesis of covalent organic framework materials incorporating β-CD, with the ability to uniformly disperse in the aqueous phase, holds promising potential for highly effective enantioselective liquid-liquid extraction.

Gamma-delta T cells suppress microbial metabolites that activate striatal neurons and induce repetitive/compulsive behavior in mice

Intestinal γδ T cells play an important role in shaping the gut microbiota, which is critical not only for maintaining intestinal homeostasis but also for controlling brain function and behavior. Here, we found that mice deficient for γδ T cells (γδ-/-) developed an abnormal pattern of repetitive/compulsive (R/C) behavior, which was dependent on the gut microbiota. Colonization of WT mice with γδ-/- microbiota induced R/C behavior whereas colonization of γδ-/- mice with WT microbiota abolished the R/C behavior. Moreover, γδ-/- mice had elevated levels of the microbial metabolite 3-phenylpropanoic acid in their cecum, which is a precursor to hippurate (HIP), a metabolite we found to be elevated in the CSF. HIP reaches the striatum and activates dopamine type 1 (D1R)-expressing neurons, leading to R/C behavior. Altogether, these data suggest that intestinal γδ T cells shape the gut microbiota and their metabolites and prevent dysfunctions of the striatum associated with behavior modulation.

Design, synthesis and anticholinergic properties of novel α-benzyl dopamine, tyramine, and phenethylamine derivatives

Due to the important biological properties of dopamine, phenethylamine, and tyramine derivatives in the central nervous system, herein the synthesis of novel α-benzyl dopamine, phenethylamine, and tyramine derivatives is described. The title compounds were synthesized starting from 3-phenylpropanoic acids and methoxybenzenes in six or seven steps. Firstly, 3-(2,3-dimethoxyphenyl)propanoic acid (11) and 3-(3,4-dimethoxyphenyl)propanoic acid (12) were selectively brominated with N-bromosuccinimide (NBS). The Friedel–Crafts acylation of methoxylated benzenes with these brominated acids or commercially available 3-phenylpropanoic acid in polyphosphoric acid gave the desired dihydrochalcones. α-Carboxylation of dihydrochalcones, reduction of benzylic carbonyl groups, hydrolysis of esters to acid derivatives, and the Curtius rearrangement reaction of acids followed by in situ synthesis of carbamates from alkyl isocyanates and hydrogenolysis of the carbamates afforded the title compounds in good total yields. Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative diseases that become serious over time. However, the exact pathophysiology of both diseases has not been revealed yet. There have been many different approaches to the treatment of patients for many years, especially studies on the cholinergic system cover a wide area. Within the scope of this study, the inhibition effects of dopamine-derived carbamates and amine salts on the cholinergic enzymes AChE and BChE were examined. Dopamine-derived carbamate 24a-i showed inhibition in the micro-nanomolar range; compound 24d showed a Ki value of 26.79 nM against AChE and 3.33 nM against BChE, while another molecule, 24i, showed a Ki range of 27.24 nM and 0.92 nM against AChE and BChE, respectively. AChE and BChE were effectively inhibited by dopamine-derived amine salts 25j-s, with Ki values in the range of 17.70 to 468.57 µM and 0.76–211.23 µM, respectively. Additionally, 24c, 24e and 25m were determined to be 60, 276 and 90 times more selective against BChE than AChE, respectively.

Free and glycosidically bound volatile compounds in quince (Cydonia oblonga Mill) from Kashmir, India

The study reports the presence of 87 free and glycosidically bound volatile compounds in two quince fruit cultivars (Round and Oblong). The major free volatile compounds were ethyl acetate,ethyl (E)-2-butenoate, hexyl butanoate, hexyl 2-methylbutanoate, ethyl 3- phenyl propanoate, α-farnesene, hexanal, 1-hexanol, dihydo-beta-ionol and linalool oxide. The major bound volatiles were ethyl acetate, hexyl pentafluoro propanoate, ethyl hexanoate, γ-elemene, cyclocitral, megastigmatrienone-II and dihydo-beta-ionol. Among all the volatiles, γ-elemene (in glycosidically bound form), cyclocitral, (E)-β-damascenone (in both free and bound form), were found for the first time in quince fruit. Odour activity values (OAVs) of most potent volatiles were calculated for both free and bound volatiles, with 11 compounds having an OAV above 1. Volatiles with higher OAVs in two varieties were β-ionone, (E)-β-damascenone, (Z, E)-α-farnesene, ethyl 2-methyl butanoate and hexanal, with the highest being 425 for (E)-β-damascenone as free form in ‘Round’ variety. In addition, the off-flavours released from quince juice after enzyme treatment or cooking were identified. In particular, megastigmatrienone-II was identified to contribute tobacco flavour. Thus, it can be concluded that variation in free and bound volatiles between the two quince cultivars resulted in the different organoleptic properties, which would assist consumers in selection of the desired quince cultivar.

Shatianyu dietary fiber (Citrus grandis L. Osbeck) promotes the production of active metabolites from its flavonoids during in vitro colonic fermentation.

Recent studies reveal that dietary fiber (DF) might play a critical role in the metabolism and bioactivity of flavonoids by regulating gut microbiota. We previously found that Shatianyu (Citrus grandis L. Osbeck) pulp was rich in flavonoids and DF, and Shatianyu pulp flavonoid extracts (SPFEs) were dominated by melitidin, obviously different from other citrus flavonoids dominated by naringin. The effects of Shatianyu pulp DF (SPDF) on the microbial metabolism and bioactivity of SPFEs is unknown. An in vitro colonic fermentation model was used to explore the effects of SPDF on the microbial metabolism and antioxidant activity of SPFEs in the present study. At the beginning of fermentation, SPDF promoted the microbial degradation of SPFEs. After 24 h-fermentation, the supplemented SPFEs were almost all degraded in SPFEs group, and the main metabolites detected were the dehydrogenation, hydroxylation and acetylation products of naringenin, the aglycone of the major SPFEs components. However, when SPFEs fermented with SPDF for 24 h, 60.7% of flavonoid compounds were retained, and SPFEs were mainly transformed to the ring fission metabolites, such as 3-(4-hydroxyphenyl) propionic acid, 3-phenylpropionic acid and 3-(3-hydroxy-phenyl) propionic acid. The fermentation metabolites of SPFEs showed stronger antioxidant activity than the original ones, with a further increase in SPDF supplemented group. Furthermore, SPFEs enriched microbiota participating in the deglycosylation and dehydrogenation of flavonoids, while co-supplementation of SPDF and SPFEs witnessed the bloom of Lactobacillaceae and Lactobacillus, contributing to the deglycosylation and ring fission of flavonoids. SDPF promote SPFEs to transform to active metabolites probably by regulating gut microbiota. © 2023 Society of Chemical Industry.

Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the destruction of synovial tissue and articular cartilage. Huangqi-Guizhi-Wuwu-Decoction (HGWD), a formula of Traditional Chinese Medicine (TCM), has shown promising clinical efficacy in the treatment of RA. However, the synergistic effects of key response components group (KRCG) in the treatment of RA have not been well studied.MethodsThe components and potential targets of HGWD were extracted from published databases. A novel node influence calculation model that considers both the node control force and node bridging force was designed to construct the core response space (CRS) and obtain key effector proteins. An increasing coverage coefficient (ICC) model was employed to select the KRCG. The effectiveness and potential mechanism of action of KRCG were confirmed using CCK-8, qPCR, and western blotting.ResultsA total of 796 key effector proteins were identified in CRS. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses confirmed their effectiveness and reliability. In addition, 59 components were defined as KRCG, which contributed to 85.05% of the target coverage of effective proteins. Of these, 677 targets were considered key reaction proteins, and their enriched KEGG pathways accounted for 84.89% of the pathogenic genes and 87.94% of the target genes. Finally, four components (moupinamide, 6-Paradol, hydrocinnamic acid, and protocatechuic acid) were shown to inhibit the inflammatory response in RA by synergistically targeting the cAMP, PI3K-Akt, and HIF-1α pathways.ConclusionsWe have introduced a novel model that aims to optimize and analyze the mechanisms behind herbal formulas. The model revealed the KRCG of HGWD for the treatment of RA and proposed that KRCG inhibits the inflammatory response by synergistically targeting cAMP, PI3K-Akt, and HIF-1α pathways. Overall, the novel model is plausible and reliable, offering a valuable reference for the secondary development of herbal formulas.