Acid Moiety Research Articles

Spatiotemporal Control Over Protein Release from Artificial Cells via a Light-Activatable Protease.

The regulation of protein uptake and secretion by cells is paramount for intercellular signaling and complex multicellular behavior. Mimicking protein-mediated communication in artificial cells holds great promise to elucidate the underlying working principles, but remains challenging without the stimulus-responsive regulatory machinery of living cells. Therefore, systems to precisely control when and where protein release occurs should be incorporated in artificial cells. Here, a light-activatable TEV protease (LaTEV) is presented that enables spatiotemporal control over protein release from a coacervate-based artificial cell platform. Due to the presence of Ni2+-nitrilotriacetic acid moieties within the coacervates, His-tagged proteins are effectively sequestered into the coacervates. LaTEV is first photocaged, effectively blocking its activity. Upon activation by irradiation with 365nm light, LaTEV cleaves the His-tags from sequestered cargo proteins, resulting in their release. The successful blocking and activation of LaTEV provides control over protein release rate and triggerable protein release from specific coacervates via selective irradiation. Furthermore, light-activated directional transfer of proteins between two artificial cell populations is demonstrated. Overall, this system opens up avenues to engineer light-responsive protein-mediated communication in artificial cell context, which can advance the probing of intercellular signaling and the development of protein delivery platforms.

Pemuchiamides A and B, Proline-Rich Linear Lipopeptides, Isolated from a Marine Hormoscilla sp. Cyanobacterium.

Pemuchiamides A and B (1 and 2) were isolated from a marine Hormoscilla sp. cyanobacterium collected from Pemuchi Beach on Hateruma Island, Japan. Although 1 and 2 existed as a complex mixture of rotamers in chloroform-d, detailed analyses of their 2D NMR and tandem mass spectra revealed their planar structures, respectively. The absolute configurations of 1 and 2 were established via the degradation and derivatization reactions. Pemuchiamide A (1) exhibited potent growth-inhibitory activity against Trypanosoma brucei rhodesiense, the causative organism of African sleeping sickness, while 2 showed 10-fold weaker activity than 1. This result indicates that the presence of a hydroxy group at the C-3 position of the 4-aminobutanoic acid moiety negatively affects antitrypanosomal activity.

Enhanced Recognition Memory through Dual Modulation of Brain Carbonic Anhydrases and Cholinesterases.

This study introduces a novel multitargeting strategy that combines carbonic anhydrase (CA) activators and cholinesterase (ChE) inhibitors to enhance cognitive functions. A series of tacrine-based derivatives with amine/amino acid moieties were synthesized and evaluated for their dual activity on brain CA isoforms and ChEs (AChE and BChE). Several derivatives, notably compounds 26, 30, 34, and 40, demonstrated potent CA activation, particularly of hCA II and VII, and strong ChE inhibition with subnanomolar to low nanomolar IC50 values. In vivo studies using a mouse model of social recognition memory showed that these derivatives significantly improved memory consolidation at doses 10-100 times lower than the reference compounds (either alone or in combination). Molecular modeling and ADMET predictions elucidated the compound binding modes and confirmed favorable pharmacokinetic and safety profiles. The findings suggest that dual modulation of CA and ChE activities is a promising strategy for treating cognitive deficits associated with neurodegenerative and psychiatric disorders.

Discovery of Cinnamic Acid Derivatives as Potent Anti-H. pylori Agents

Antibiotics are currently used for the treatment of Helicobacter pylori (H. pylori), which is confirmed to be the major cause of gastric disorders. However, the long-term consumption of antibiotics has already caused antibiotic resistance and side effects in vivo. Therefore, there is an emerging need for searching for safe and effective anti-H. pylori agents. Inspired by the excellent bioactivities of cinnamic acid, a series of cinnamic acid derivatives (compounds 1–30) were synthesized and determined for H. pylori inhibition. The initial screening revealed that compound 23, a 2,4-dinitro cinnamic acid derivative containing 4-methoxyphenol, showed excellent H. pylori inhibition with an MIC value of 4 μM. Further studies indicated that compound 23 showed anti-bacterial activity and had a bactericidal effect on H. pylori due to the destruction of the bacterial structure. Molecular docking analysis revealed that the 2,4-dinitro groups in cinnamic acid moiety formed hydrogen bonding with amino acid residues in an active pocket of H. pylori protein. Interestingly, the ester moiety fitted into the hydrophobic pocket, attaining additional stability to compound 23. Above all, the present study reveals that compound 23 could be considered a promising anti-H. pylori agent to treat H. pylori causing gastritis.

Self‐Assembly of UiO‐66 on Conjugated Polyelectrolytes: Toward Enhanced Photophysical Properties

AbstractIn this study, the synthesis and characterization of the fluorescent metal–organic framework (MOF)‐polymer composites is reported based on zirconium‐based MOFs (UiO‐66 and UiO‐66(OH)₂) and a conjugated polyelectrolyte, poly(phenylene ethynylene) carboxylate (PPE‐CO₂‐108). The defect‐rich nature of these Zr‐MOFs facilitates strong interactions between the polyelectrolyte's carboxylic acid moieties and the open metal sites on the Zr clusters within the MOF nanoparticles. The composites are prepared by a simple impregnation approach, where MOF nanocrystals suspended in HEPES buffer are added to the polymeric solution under sonication for 10 min. The obtained MOF composites (i.e., UiO‐66‐CPE and UiO‐66 (OH)2‐CPE) are characterized using powder X‐ray diffraction (PXRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), Brunauer‐Emmett‐Teller (BET) surface area, zeta potential measurements, and UV–vis spectroscopy. The characterization confirmed the homogeneous distribution of the MOF nanocrystals on the polymer as seen in the SEM images, and the interaction with PPE‐CO₂‐108 is confirmed by the decrease in the surface areas from 1050 to 590 m2 g−1 for UiO‐66‐CPE and from 500 to 137 m2 g−1, for UiO‐66(OH)2‐CPE. Fluorescence microscopy revealed strong fluorescence in the microparticles, confirming robust polymer‐MOF interaction. The composites also exhibit improved photostability of the conjugated polyelectrolyte, suggesting their potential for applications in biomedical imaging and other areas requiring stable and bright fluorescent systems.

Novel therapeutic deep eutectic system for the enhancement of ketoconazole antifungal activity and transdermal permeability

In this study, we reported the investigation of a novel therapeutic deep eutectic system (THEDES) formed between capric acid (CA) and ketoconazole (KCZ) to enhance the permeability and efficacy of the antifungal drug KCZ. A THEDES was formulated by combining KCZ and CA at different molar ratios, with a 1:5 ratio (K5) representing the most stable and lowest melting point. Characterization of the interactions between CA and KCZ using NMR and FT-IR spectroscopy revealed a hydrogen bonding interaction between the amine group of KCZ’s imidazole ring and the carboxylic acid moiety of CA. This interaction resulted in converting the solid materials into liquid at room temperature, leading to a significant decrease in the melting points of the components, as confirmed by DSC. Next, the effectiveness of K5 as an antifungal agent against Candida albicans was evaluated. The results indicated a 2-fold reduction in the minimum inhibitory concentration (MIC). In addition, permeability studies conducted using a Franz diffusion cell revealed a significant enhancement in permeability with a 6.19-fold increase in flux compared to commercially available KCZ cream. The findings suggest that fatty acid-based deep eutectic systems, such as the KCZ THEDES, can serve as effective and green drug delivery systems, offering significant enhancements in drug permeability and therapeutic performance. This approach improves the efficacy of drugs and promotes the development of eco-friendly pharmaceutical formulations.

Mussel-Inspired Multifunctional Polyethylene Glycol Nanoparticle Interfaces.

Nanoparticles (NPs) are receiving increasing interest in biomedical applications. However, due to their large surface area, in physiological environments, they tend to interact with plasma proteins, inducing their agglomeration and ultimately resulting in a substantial efficiency decrease in diagnostic and therapeutic applications. To overcome such problems, NPs are typically coated with a layer of hydrophilic and biocompatible polymers, such as PEG chains. However, few examples exist in which this property could be systematically fine-tuned and combined with added properties, such as emission. Herein, we report a novel mussel-inspired catechol-based strategy to obtain biocompatible and multifunctional coatings, using a previously developed polymerization methodology based on the formation of disulfide bridges under mild oxidative conditions. Two families of NPs were selected as the proof of concept: mesoporous silica NPs (MSNPs), due to their stability and known applications, and magnetite NPs (Fe3O4 NPs), due to their small size (<10 nm) and magnetic properties. The PEG coating confers biocompatibility on the NPs and can be further functionalized with bioactive molecules, such as glucose units, through the end carboxylic acid moieties. Once we demonstrated the feasibility of our approach to obtaining PEG-based coatings on different families of NPs, we also obtained multifunctional coatings by incorporating fluorescein functionalities. The resulting coatings not only confer biocompatibility and excellent cell internalization, but also allow for the imaging and tracking of NPs within cells.

Magnetic Silver Nanoparticles Stabilized by Superhydrophilic Polymer Brushes with Exceptional Kinetics and Catalysis.

Stimuli-responsive catalysts with exceptional kinetics and complete recoverability for efficient recyclability are essential in, for example, converting pollutants and hazardous organic compounds into less harmful chemicals. Here, we used a novel approach to stabilize silver nanoparticles (NPs) through magneto/hydro-responsive anionic polymer brushes that consist of poly (acrylic acid) (PAA) moieties at the amine functional groups of chitosan. Two types of responsive catalyst systems with variable silver loading (wt.%) of high and low (PAAgCHI/Fe3O4/Ag (H, L)) were prepared. The catalytic activity was evaluated by monitoring the reduction of organic dye compounds, 4-nitrophenol and methyl orange in the presence of NaBH4. The high dispersity and hydrophilic nature of the catalyst provided exceptional kinetics for dye reduction that surpassed previously reported nanocatalysts for organic dye reduction. Dynamic light scattering (DLS) measurements were carried out to study the colloidal stability of the nanocatalysts. The hybrid materials not only showed enhanced colloidal stability due to electrostatic repulsion among adjacent polymer brushes but also offered more rapid kinetics when compared with as-prepared Ag nanoparticles (AgNPs), which results from super-hydrophilicity and easy accumulation/diffusion of dye species within polymer brushes. Such remarkable kinetics, biodegradability, biocompatibility, low cost and facile magnetic recoverability of the Ag nanocatalysts reported here contribute to their ranking among the top catalyst systems reported in the literature. It was observed that the apparent catalytic rate constant for the reduction of methyl orange dye was enhanced, PAAgCHI/Fe3O4/Ag (H) ca. 35-fold and PAAgCHI/Fe3O4/Ag (L) ca. 23-fold, when compared against the as prepared AgNPs. Finally, the regeneration and recyclability of the nanocatalyst systems were studied over 15 consecutive cycles. It was demonstrated that the nanomaterials display excellent recyclability without a notable loss in catalytic activity.

Extraction, Characterization and Evaluation of Health Applications of Moringa oleifera Seed Oil

In this study, the seeds of Moringa oleifera (MO) plant grown in the Adamawa Region of Cameroon were valorized by extracting their oil using mechanical expression. The oil was allowed to clarify through by gravity and an oil yield of 26.07% was obtained. The extracted MO oil was subjected to physicochemical characterization giving the following results; the density of the oil was 0.896 g/mL, a refractive index of 1.468, a viscosity of 49.80± 0.30 mPa.s, an acid value of 2.69%, a peroxide value of 3.7 meq of O2/kg of oil, a saponification value of 189.34 mg of KOH/g of oil and an iodine index of 67.79g/100g of oil. The determination of relevant secondary metabolites by titration revealed a flavonoid content of 0.66 mg GAE/g, total phenol content of 9.7 mg QE/g, carotenoid content of 0.25 mg beta-caro/g and antioxidant activity gave an IC50 concentration of 17.5 mg/mL. Determination of the fatty acid profile revealed that oleic acid (78.45%) makes up the predominant component in the MO seed oil. The chemical composition of the MO seed oil was further verified by IR spectroscopy whose spectral interpretation revealed a predominance of fatty acid moieties in the oil. From these results, it appears that Moringa oleifera seed oil has moisturizing, antioxidant, anti-inflammatory and nourishing properties and therefore the oil is a potent raw material or bioactive substance in the formulation of cosmetic products like creams for body lotion to combat skin infections and the MO seed can find pharmaceutical applications amongst others.

Abstract P221: Yoda2, a Novel Piezo1 Agonist, Induces Relaxation in Mouse Vascular and Corpus Cavernosum Tissues

Introduction: Piezo1, a mechanosensitive nonselective cation channel, is expressed in endothelial and vascular smooth muscle cells. It plays a critical role in sensing endothelial shear stress, generating nitric oxide (NO), regulating vascular tone, promoting angiogenesis, and controlling blood pressure. Yoda1, a tool compound for Piezo1, has limitations due to its low potency and poor water solubility. To overcome these limitations, a Yoda1 analogue, Yoda2, was developed. Yoda2 features a 4-benzoic acid moiety replacing the pyrazine of Yoda1, thereby enhancing its agonist properties and solubility. We hypothesize that Yoda2 induces relaxation in mouse mesenteric resistance artery (MRA), pudendal artery (PA), and corpus cavernosum (CC), through a NO-dependent mechanism. Methods: Male C57BL/6 mice were euthanized, and their MRA, PA, and CC were isolated and mounted in DMT wire myographs for isometric force measurements. Concentration-response curves to Yoda2 were obtained. Additionally, the contraction of CC induced by electrical field stimulation (EFS) was evaluated in the absence or presence of Yoda2. Data are presented as mean ± S.E.M of 3-4 mice. Non-linear regression curve was performed, and the maximum response (E max ) and pharmacological potency (pEC 50 ) were analyzed using Student's t-test (p&lt;0.05). Results: Yoda2 induced concentration-dependent relaxation in the MRA, PA, and CC, with E max values of 98.31 ± 0.89% for MRA, 95.01 ± 3.75% for PA, and 75.03 ± 15.17% for CC. The role of NO in this pathway was confirmed by the attenuation of Yoda2 effects upon inhibition of NO synthase (NOS) with L-NAME in MRA and PA. Furthermore, Yoda2 (1 µM) decreased the concentration response curves for phenylephrine-induced contraction in PA and MRA. On the other hand, Yoda2 (30 µM) did not change the EFS-induced contraction in CC. Conclusion: This study is the first to demonstrate that Yoda2, a potent and water-soluble Piezo1 channel agonist, induces significant relaxation in the MRA, PA, and CC of mice. Consistent with the effects of Yoda1, the effects of Yoda2 are mediated through NO production.

Unveiling the Mechanisms of Apoptosis Induction by Deep‐Sea‐Derived Polyketide‐Terpenoid Hybrids from Penicillium allii‐sativi: A Focus on Mitochondrial and mTOR Pathways

Comprehensive SummaryA chemical investigation of the deep‐sea‐derived fungus Penicillium allii‐sativi MCCC 3A00580 resulted in the discovery of four new meroterpenoids (1—4) and one related known co‐metabolite (5). These meroterpenoids showcase unique carbon skeletons featuring a common drimane sesquiterpene part with highly diverse polyketide units. Particularly, compound 1 incorporates a salicylic acid moiety while 2 possesses a rare peroxide bridge in the polyketide part. The structures of new compounds were assigned by extensive spectroscopic analysis, quantum calculations, and biogenetic considerations. Notably, 3 significantly blocked the mTOR signaling pathway, resulting in the arrest of cell cycle at G0‐G1 phase and triggering mitochondrial apoptosis in Hela cells. While the previously reported co‐metabolite macrophorin A (MPA) effectively triggered cell death in MDA‐MB‐231 cancer cells by activating apoptosis pathways involving death receptors, mitochondria, mTOR, and TNF.

Aminophenylboronic acid-modified nitrogen-doped graphene quantum dots and their applications in lysine sensing based on interplaying fluorescent mechanisms.

Using nitrogen-doped graphene quantum dots (N-GQDs) and 3-aminophenylboronic acid (APBA), a novel fluorescence nanosensorwas developed. This nanosensor exhibits high selectivity and sensitivity for lysine detection. Its sensing mechanism involves the suppression of electron transfer from APBA to the N-GQDs unit, thereby inhibiting photoinduced electron transfer and initiating internal charge transfer. At an optimal pH of 7, the protonated α-amine and ε-amine groups of lysine interact with the amide and boronic acid moieties, respectively. This interaction results in a redshift of fluorescence, substantially enhancing the response signal. A linear response was observed within a concentration range 0.40-3.01μM, with the detection limit being 0.005μM. A similar linear range was also achieved for the determination of lysine in human serum. Density functional theory calculations correlating molecular orbits and geometries support UV-vis and fluorescence findings. Additionally, the nanosensor wassuccessfully applied to detect lysine in living cells and real samples, including milk and honey. For practical application, we construct a lysine-specific sensing platform using a commercial chip (TCS34725) that collects red, blue, and green signals, thereby facilitating the convenient use of the nanosensor. Overall, this study offers new perspectives on the development and application of fluorescent nanosensors for detecting individual amino acids.

In-situ halloysite functionalization of anionic hybrid gels possessing easily implemented site-specific (alkyl)amide and carboxyl groups

Design of functional materials with tunable properties based on anionically-modified copolymer network of poly (N-isopropyl acrylamide-co-methacrylic acid) P(NIPA-co-MA) containing linear polyacrylamide and various amounts of Halloysite nanotubes (Hal) was presented using a facile route of solution casting. The organic/inorganic nanostructures based on thermo-responsive PNIPA were constructed to create hybrid materials via in situ polymerization with different Hal-loading and then used for the removal of cationic methylene blue (MB) dye from aqueous solutions. To achieve the desired mechanical property, the optimum composition of hybrids was determined following a simple and cost-effective synthesis procedure. In situ one-pot polymerization was promoted by semi-IPN formation, following a much simpler route than traditional preparation approaches for stable cross-linked hybrid formation. The swelling of hybrids decreased by 2.9-fold with loading of 5.40 % Hal, confirming the hydrogen bonding interactions between Hal and PAAm/P(NIPA-co-MA) network. The mechanical properties of Hal-doped hybrid gels showed an increase–decrease tendency with increase of Hal-content from 0.80 to 5.40 % (w/v) due to the high aspect ratio of Hal and strong secondary interactions between Hal and PAAm/P(NIPA-co-MA) chains. The effective cross-link density for Hal-doped hybrids was expressed by a cubic polynomial as a function of Hal concentration. Temperature-sensitive swelling results showed that the advantage of sustained release property of Hal can be combined with excellent controllability of PNIPA-based network. Adsorption results of MB onto Hal-doped hybrids bearing methacrylic acid moieties demonstrated their potential as efficient adsorbents for the removal of cationic dyes. A new route offered by the proposed procedure for design of hybrids containing “green” one-dimensional nanofillers creates an innovative perspective on robust hybrid structures for practical applications.

Design, synthesis, and characterization of a novel pH-responsive azo dye incorporating a 1,3,4-thiadiazole ring for advanced textile applications

This study presents the synthesis and comprehensive characterization of a novel azo dye derived from 2-(5-amino-1,3,4-thiadiazol-2-yl) phenol (1a). The synthesis was initiated by reacting salicylic acid with thiosemicarbazide in the presence of phosphorus oxychloride (POCl3), yielding an 89 % conversion to compound 1a. The subsequent diazotization and coupling of 1a under alkaline conditions led to the formation of the azo dye (1b). Structural elucidation was confirmed through Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR) spectroscopy. The incorporation of the 1,3,4-thiadiazole ring is significant due to its known influence on enhancing dye stability, reactivity, and potential biological activities, while the salicylic acid moiety contributes to the dye's pH responsiveness. A notable pH-dependent color transition from yellow (pH < 6.0) to red (pH > 8.0) was observed, driven by protonation-induced resonance changes. Computational studies, including Frontier Molecular Orbital (FMO) analysis, revealed a Highest Occupied Molecular Orbital (HOMO)-Lowest Unoccupied Molecular Orbital (LUMO) gap of 1.94 eV, indicating efficient electronic transitions critical for its color properties. Molecular Electrostatic Potential (MEP) and Fukui function analyses provided further insights into the dye's reactivity and potential applications. The dyeing properties were rigorously assessed through K/S values, CIELAB color space, and fastness properties on cotton fabric, demonstrating varied color depths and hues influenced by different mordants, with copper and manganese significantly enhancing color intensity. Colorfastness tests revealed good to fair durability, with untreated fabrics showing optimal performance. This thorough characterization underscores the promising potential of this newly synthesized azo dye for applications in pH-responsive textiles and functional materials, highlighting its relevance for advanced textile and material science applications.

Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein–ligand interactions at COX-2 active sites indicative of therapeutic potential.

Preparation of Photocurable Organic-Inorganic Hybrid Composites for Continuous Manufacturing of 3D-Patterned Abrasive.

Photocurable hybrid organic-inorganic composites were prepared via surface modification and 3D-patterned structures were fabricated by utilizing a continuous roll-to-roll manufacturing strategy. The surfaces of nanocrystals were engineered with a bifunctional ligand that is a 2-carboxyethyl acrylate, which possesses a carboxylic acid moiety at one end and an acrylate functionality moiety at the other end, yielding acrylate-functionalized nanocrystals. Micro-scale 3D patterns (protruding pyramidal shapes with each side measuring 147 μm) were continuously manufactured at a speed of 2.5 m/min via UV curing with a soft engraved mold. The surface properties of the functionalized nanocrystals and their UV curing condition were explored with Fourier transform infrared spectroscopy. The morphology of the 3D film was measured using scanning electron microscopy. A pin-on-disk tribometer measurement revealed an improved interaction between the functionalized particles and resins.

(Invited) Tuning Chirality of Graphene Quantum Dots to Empower Medical Imaging and Theranostic Applications

Chiral nanostructures from metals and semiconductor, including graphene-based materials, are increasingly recognized for their potential in polarization-sensitive optoelectronics. Particularly, graphene quantum dots (GQDs) modified with L/D amino acids exhibit unique chiral properties due to edge-specific interactions, offering new possibilities in biomedicine. Our study delves into the interaction of these chiral nanomaterials with biological systems, revealing significant implications for their application in biology and medicine. We discovered that attaching L/D amino acid moieties to GQDs induces nanoscale chirality by helical buckling, influenced by the chiral interactions at the graphene edges. The chirality of GQDs affects their interaction at the nanoscale with cells and tissues. Molecular dynamics simulations show that D-GQDs are more likely to accumulate within cellular membranes compared to L-GQDs. Additionally, experiments on chiral GQD permeation through lipid membranes of extracellular vesicles demonstrated that optimizing chirality via ligand tuning and GQD size can significantly enhance their permeation efficiency into lipid bilayers, exceeding 80%. Leveraging this enhanced transmembrane transport, chiral GQDs have been applied in imaging and efficient drug loading for therapeutic extracellular vesicles. Furthermore, we explored how GQD chirality affects transport in tumor-like cellular spheroids. The results indicate that L-GQDs exhibit a 1.7 times higher apparent diffusion coefficient than D-GQDs, enhancing their transport into these spheroids. In summary, our research underscores the importance of controlling and engineering GQD chirality. This approach not only enhances the transport of drug carriers through biological barriers but also opens new avenues for advanced imaging and theranostic applications.

Trolox, Ferulic, Sinapic, and Cinnamic Acid Derivatives of Proline and GABA with Antioxidant and/or Anti-Inflammatory Properties.

Degenerative conditions, such as neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD)) and cardiovascular diseases, are complex, multifactorial disorders whose pathophysiology has not been fully elucidated yet. As a result, the available treatment options cannot eliminate these diseases radically, but only alleviate the symptoms. Both inflammatory processes and oxidation are key factors in the development and evolution of neurodegeneration, while acetylcholinesterase inhibitors are the most used therapeutic options against AD. In this work, following the multi-targeting compound approach, we designed and synthesized a series of proline and gamma-aminobutyric acid (GABA) amides with various acidic moieties that possess an antioxidant and/or anti-inflammatory potency. Proline is the pharmacophore of nootropic drugs (e.g., piracetam) used for memory improvement, while GABA is the main inhibitory neurotransmitter in the central nervous system. The designed molecules were subjected to a preliminary screening of their bioactivity in antioxidant and anti-inflammatory assays, as well as against acetylcholinesterase. Most of the synthesized compounds could inhibit lipid peroxidation (IC50 as low as 8 μΜ) and oxidative protein glycation (inhibition of up to 48%) and reduce the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH). In addition, all of the compounds were moderate inhibitors of lipoxygenase (LOX) (up to 46% at 100 μΜ) and could decrease carrageenan-induced paw edema in rats by up to 55%. Finally, some of the compounds were moderate acetylcholinesterase inhibitors (IC50 as low as 219 μΜ). The results confirmed the design rationale, indicating that the compounds could be further optimized as multi-targeting molecules directed against degenerative conditions.

Spectral-Sensing System for Distinguishing CH3OH and CD3OD.

Spectrally discriminating CH3OH and CD3OD, and even detecting CH3OH contents in the CD3OD solvent, are important yet have not been achieved so far, likely owing to their very similar chemical/physical properties. Herein, dynamic transesterification reactions, which can be achieved via two-step proton transfers, can be signaled via ultraviolet UV-visible (UV/vis) absorption and fluorescence spectroscopies under mild experimental conditions. Introduction of strong electron-withdrawing groups, such as -NO2, to the aromatic ring (benzoic acid moiety or phenol moiety) of carboxylate esters to activate the esters is important for transesterification reactions and is an intriguing method for modulating the selectivity of the spectral response. The rate constant of the transesterification reaction enhanced with increasing the total number of strong electron-withdrawing groups. Furthermore, the rate constants of esters in which substituent(s) are connected to the phenol moiety are higher than those of corresponding esters in which substituent(s) are connected to the benzoic acid moiety. In transesterification systems, added aliphatic amines mainly play two roles: (i) lowering the energy barrier of the first transesterification step via the formation of intermolecular hydrogen bonding in ternary systems and (ii) deprotonating the released 4-nitrophenol in UV/vis absorption spectral systems to generate an UV/vis absorption spectral signal reporter, i.e., nitrophenolate anions. As a result of the methanol-mediated transesterification reaction, spectral-sensing systems can be established for discriminating CH3OH and CD3OD and even detecting low CH3OH contents in the CD3OD solvent, owing to the kinetic isotope effect. This is the first example of spectral recognition between CD3OD and CH3OH.

Human apolipoprotein E glycosylation and sialylation: from structure to function.

Human apolipoprotein E (ApoE) was first identified as a polymorphic gene in the 1970s; however, the genetic association of ApoE genotypes with late-onset sporadic Alzheimer's disease (sAD) was only discovered 20 years later. Since then, intensive research has been undertaken to understand the molecular effects of ApoE in the development of sAD. Despite three decades' worth of effort and over 10,000 papers published, the greatest mystery in the ApoE field remains: human ApoE isoforms differ by only one or two amino acid residues; what is responsible for their significantly distinct roles in the etiology of sAD, with ApoE4 conferring the greatest genetic risk for sAD whereas ApoE2 providing exceptional neuroprotection against sAD. Emerging research starts to point to a novel and compelling hypothesis that the sialoglycans posttranslationally appended to human ApoE may serve as a critical structural modifier that alters the biology of ApoE, leading to the opposing impacts of ApoE isoforms on sAD and likely in the peripheral systems as well. ApoE has been shown to be posttranslationally glycosylated in a species-, tissue-, and cell-specific manner. Human ApoE, particularly in brain tissue and cerebrospinal fluid (CSF), is highly glycosylated, and the glycan chains are exclusively attached via an O-linkage to serine or threonine residues. Moreover, studies have indicated that human ApoE glycans undergo sialic acid modification or sialylation, a structural alteration found to be more prominent in ApoE derived from the brain and CSF than plasma. However, whether the sialylation modification of human ApoE has a biological role is largely unexplored. Our group recently first reported that the three major isoforms of human ApoE in the brain undergo varying degrees of sialylation, with ApoE2 exhibiting the most abundant sialic acid modification, whereas ApoE4 is the least sialylated. Our findings further indicate that the sialic acid moiety on human ApoE glycans may serve as a critical modulator of the interaction of ApoE with amyloid β (Aβ) and downstream Aβ pathogenesis, a prominent pathologic feature in AD. In this review, we seek to provide a comprehensive summary of this exciting and rapidly evolving area of ApoE research, including the current state of knowledge and opportunities for future exploration.