Medium-sized rings and macrocycles constitute a privileged class of scaffolds in medicinal chemistry, providing unique access to challenging biological targets through their preorganized, semi-rigid architectures. However, their synthesis remains challenging due to the unfavorable kinetic and thermodynamic constraints during ring closure. Herein, we report the efficient cyclization of ω-isocyano aldehydes via Passerini and Ugi multicomponent reactions (MCRs), alongside related variants. These transformations provide rapid access to structurally diverse medium-sized and macrocyclic α-acyloxy, α-hydroxy, α-acetamido, and α-keto lactams, as well as tetrazole-fused macrocycles, under mild conditions. Notably, this macrocyclization strategy relies on C(sp[3])─C(sp[2]) bond formation while simultaneously generating α-functionalized amide motifs. By avoiding the need to pre-synthesize α-functionalized carboxylic acids, this approach offers a complementary alternative to traditional macrolactamization.

Temporal lobe epilepsy (TLE), the most common form of drug-resistant epilepsy (DRE) in adults, is a frequent chronic neurological disorder. Nevertheless, the precise pathophysiological mechanisms underlying TLE remain largely undefined. Our findings demonstrate that Actin-binding LIM protein 1 (ABLIM1) is broadly expressed in the adult mouse brain, with high expression in the hippocampus. The protein is primarily localized to neurons, enriched in the postsynaptic density (PSD), colocalizes with the scaffold protein PSD95, and directly binds to F-actin. Co-IP experiments confirmed that ABLIM1 interacts with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits GluA1 and GluA2. Following hippocampal stereotaxic injection of adeno-associated virus (AAV) to specifically knock down ABLIM1 expression, we observed reduced F-actin polymerization, decreased dendritic spine density, and thinning of the PSD in the mouse hippocampus. In the chronic epilepsy models induced by kainic acid (KA), ABLIM1 knockdown significantly exacerbated seizure severity and increased seizure susceptibility. Further mechanistic studies revealed that ABLIM1 knockdown specifically reduces membrane expression of GluA2 without altering its total protein levels. Collectively, ABLIM1 may regulate epileptogenesis and disease progression by maintaining postsynaptic structural integrity and GluA2 membrane homeostasis. Thus, the ABLIM1-GluA2 signaling axis represents a potential therapeutic target for DRE.

This case report describes the management of a complex volumetric muscle loss (VML) injury in a 3-year-old mixed-breed dog following severe trauma to the right forelimb, which resulted in extensive multi-muscle defects that were unsuitable for primary closure. After initial stabilization and surgical debridement, reconstruction was achieved using a transpositional flap, while a gold nanoparticles-bioactive glass-alginate-cellulose (BGAuSP-Alg-MCC) composite was implanted to fill the dead space and support tissue regeneration. Postoperative healing was evaluated through clinical follow-up, computed tomography performed immediately and at 1 and 3 months postoperatively, as well as histological and immunohistochemical analyses. Imaging demonstrated progressive integration of the biomaterial, restoration of tissue density comparable to adjacent muscle, and absence of major complications. Histological evaluation demonstrated moderate inflammation and granulation tissue formation, containing numerous blood capillaries (neoangiogenesis), confirmed by CD31 and α-Smooth muscle actin (SMA) immunolabelling. Functional recovery was favorable, with preserved limb mobility and normal gait. These findings provide preliminary evidence of local biocompatibility and support the feasibility of incorporating the BGAuSP-Alg-MCC composite into a multimodal surgical management approach for extensive volumetric muscle loss in canine patients.

We herein disclose a phase-transfer-catalyzed diastereoselective Mannich reaction between β,γ-alkynyl-α-ketimines and in situ generated 1-hydroxy isobenzofulvene anions from 2-alkylidene-1-indanones, enabling the formation of indanone-based α-amino acid derivatives with good results (up to 93% yield with >20 : 1 dr in all cases). The protocol is characterized by mild reaction conditions, broad substrate tolerance, and excellent diastereoselectivity. The practicality of the methodology is underscored by a gram-scale experiment and the coupling of the product with structurally complex pharmaceuticals. Notably, this work represents the first example of a reaction of 1-hydroxyl isobenzofulvene anions with imines.

Efficient production of enantiopure phenylserine (PhSer) is hampered by poor economy and challenging byproduct separation in conventional resolution methods. Phenylserine dehydratase (PSDH) offers an alternative by catalyzing irreversible dehydration, yet its strict stereospecificity toward the l-threo isomer limits its synthetic scope. Herein, structure-guided site-saturation mutagenesis of l-PSDH from Paraburkholderia xenovorans yielded the G93C mutant, which acquired activity against the previously inaccessible d-erythro isomer. Both wild-type and G93C enabled preparative-scale kinetic resolution, affording enantiopure l-threo- and d-erythro-PhSer with improved isolated yields of 43.6% and 43.0%, respectively. To upgrade the byproduct, a multi-enzyme cascade combining PSDHs, d-lactate dehydrogenase, and formate dehydrogenase was constructed, which simultaneously resolved racemic PhSer and converted the phenylpyruvate byproduct in situ into high-value d-phenyllactic acid. This work expands the synthetic utility of PSDHs through stereoselectivity engineering and cascade design, establishing an efficient biocatalytic platform for co-producing enantiopure PhSer and d-phenyllactic acid.

Management of major depressive disorder (MDD) with conventional therapeutics that enhance monoaminergic neurotransmission requires prolonged treatment prior to clinical benefit and a substantial proportion of patients show little or no improvement. Identifying alternative molecular targets is required to develop efficacious, rapid acting antidepressants. In this regard, tianeptine, an established but atypical clinical antidepressant, is of interest. Tianeptine does not directly influence monoamine levels; in rodents it has a relatively rapid onset of antidepressant-like efficacy and, unusually for an antidepressant, exhibits procognitive properties. Here, voltage-clamp recordings from mouse hippocampal CA1 pyramidal neurons demonstrated tianeptine enhanced the amplitude of neurally evoked excitatory postsynaptic currents mediated by glutamate activation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The effect required intracellular polyamines and expression of the GluA1 subunit. These observations suggest that tianeptine relieves the channel block by endogenous polyamines of synaptic GluA1 containing AMPARs (GluA1-AMPARs). The tianeptine effect was abolished by postsynaptic inhibition of G-protein signaling, was reduced in mice lacking either the µ- or the δ-opioid receptor, and inhibited by selective antagonists of these receptors, collectively demonstrating that the facilitation of excitatory transmission was indirectly mediated by activation of opioid receptors. Importantly, enhancement of GluA1-AMPAR function was mimicked by opioid peptide and nonpeptide agonists selective for µ- or δ-receptors. These observations improve understanding of how the antidepressant tianeptine enhances glutamatergic transmission but more generally suggest that endogenous and exogenous opioids act in a similar manner, which may contribute to their behavioral effects.

Docosahexaenoic acid (DHA), the predominant omega-3 (ω-3) fatty acid in the brain, which contributes to synaptic membrane organization and plasticity, is commonly recommended for brain health. However, ω-3 formulations commonly combine DHA with eicosapentaenoic acid (EPA) in varying proportions, and the impact of the DHA ratio on postsynaptic scaffold regulation remains unclear.

Tractional retinal detachment caused by fibroproliferative membrane formation is a vision-threatening complication of proliferative diabetic retinopathy (PDR). Müller cells can acquire myofibroblast-like features during retinal fibroproliferative remodeling, yet the metabolic mechanisms governing these phenotypic changes remain poorly understood. Here, we report that lactate is a metabolic regulator of myofibroblast-like remodeling in Müller cells. Metabolomic profiling revealed elevated vitreous lactate levels in patients with PDR. Consistently, lactate concentrations were increased in the vitreous and retinal tissues of diabetic rats, whereas high-glucose exposure promoted lactate accumulation in primary Müller cells. Increased lactate availability enhanced Müller cell proliferative activity and migration, as well as the expression of myofibroblast-associated proteins, including α-smooth muscle actin, smooth muscle protein 22, and collagen I, whereas oxamate, an inhibitor of lactate dehydrogenase, attenuated these responses. Lactylome profiling and molecular validation revealed K186 of methyl-CpG-binding domain protein 2 (MBD2) as a functionally relevant lactylation site. RNA sequencing of high-glucose-treated Müller cells expressing MBD2-K186R versus MBD2-WT revealed reduced YAP1 expression in the K186R group, suggesting that YAP1 is a downstream effector of MBD2 K186 lactylation. Mechanistically, increased lactate availability enhanced MBD2 K186 lactylation and YAP1 activation, as evidenced by reduced inhibitory phosphorylation of YAP1 and increased nuclear accumulation of YAP1. MBD2 K186R attenuated YAP1 activation and myofibroblast-like changes, whereas YAP1 overexpression partially reversed these effects. Collectively, these findings reveal a lactate-MBD2 K186 lactylation-YAP1 signaling axis that promotes myofibroblast-like remodeling of Müller cells and may contribute to fibroproliferative pathology in PDR.

Lipoxygenase cascade is the source of key plant bioregulators, oxylipins, which are oxidized derivatives of polyunsaturated fatty acids that play a crucial role in growth and development, as well as stress response. The key enzymes of the lipoxygenase cascade are allene oxide synthases (AOS) and hydroperoxide lyases, which are present in all known angiosperms. Although these enzymes play a central role in defining the pattern of the final metabolites of the cascade, significant gaps still exist in understanding their catalytic properties and positional specificity. This paper describes the allene oxide synthase BnAOS from rapeseed (Brassica napus L.), an important agricultural crop and source of valuable rapeseed oil. The BnAOS enzyme belongs to the CYP74A subfamily, which traditionally includes 13-specific allene oxide synthases. However, some members of this group are universal and capable of converting both 13- and 9-hydroperoxides of linoleic and α-linolenic acids. Thus, they direct the biosynthesis of oxylipins towards formation of jasmonates (in the case of conversion of (13S)-hydroperoxide of α-linolenic acid) or other metabolites when using other hydroperoxides as substrates. Our studies have shown that the BnAOS also exhibits dual positional specificity, but, in addition to 13-hydroperoxides, it efficiently converts 16-hydroperoxide of α-linolenic acid ((16S)-HPOT) to form the α-ketol we recently described, 15-oxo-16-hydroxy-9,12-octadecadienoic acid. Thus, BnAOS is a 13/16-specific AOS. Prior to this study, the ability to efficiently convert (16S)-HPOT was described only in the cucumber CsAOS (CYP74A1) and tomato LeAOS3 (CYP74C3).

Prostate cancer progression toward an aggressive, therapy‑resistant disease state remains a major clinical challenge, indicating a need to identify novel molecular drivers of such progression and actionable therapeutic targets. The present study analyzed the role of dynein heavy chain domain 1 (DNHD1), a previously uncharacterized regulator of malignancy, in prostate cancer. Integrative transcriptomic analyses across The Cancer Genome Atlas and independent clinical cohorts revealed that DNHD1 is markedly upregulated in advanced‑stage prostate cancer and positively correlated with increasing Gleason scores. Elevated DNHD1 expression was associated with poor overall survival and disease‑free survival, which supports its clinical relevance as a prognostic biomarker. Functional analyses demonstrated that DNHD1 promoted tumor cell proliferation, colony formation, migration and invasion in vitro. Molecular correlation modeling and pathway analyses revealed histone deacetylase 6 (HDAC6) as a key downstream effector of DNHD1. DNHD1 expression was positively correlated with and regulated HDAC6 expression in clinical datasets. Gain‑of‑function and loss‑of‑function experiments further revealed that HDAC6 is required for DNHD1‑mediated oncogenic phenotypes in prostate cancer, positioning HDAC6 as a functional mediator downstream of DNHD1. The DNHD1‑HDAC6 axis was associated with cilium assembly‑related pathways, suggesting a previously unrecognized association between ciliary regulation and prostate cancer progression. HDAC6 inhibition with tubastatin A effectively suppressed DNHD1‑driven tumor growth and motility, as well as increased acetylated α‑tubulin and decreased androgen receptor signaling. These findings indicated a potential therapeutic vulnerability within the DNHD1‑HDAC6 axis. They implied that in prostate cancer, the DNHD1‑HDAC6 axis, a novel regulatory pathway, promotes aggressiveness and that HDAC6 is a targetable mediator of DNHD1‑driven malignancy. This axis can be considered a prognostic indicator and mechanistic foundation for developing targeted therapeutic strategies for advanced prostate cancer.

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors) are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. By translating chemical signals into rapid electrical depolarization, AMPA receptors, together with NMDA and kainate receptors, coordinate synaptic plasticity at glutamatergic synapses, thereby shaping learning, memory, and higher-order cognitive functions. Neurological disorders characterized by glutamatergic dysfunction represent a major clinical challenge, largely because pharmacological targeting of this system requires a delicate balance between efficacy and adverse effects. Accordingly, the clinical development of direct AMPA receptor agonists and antagonists has been hampered by poor tolerability and the risk of neurotoxicity; to date, only the non-competitive antagonist perampanel has reached clinical use. This therapeutic gap highlights the compelling need to develop safer, more tolerable, and reversible drug candidates capable of modulating synaptic plasticity in disorders characterized by glutamatergic impairment. Within this framework, AMPA receptor allosteric modulators have attracted attention as a promising alternative to direct ligands. Specifically, positive allosteric modulators, or AMPAkines, represent a potentially favourable therapeutic compromise because they facilitate receptor activation while preserving physiological receptor kinetics. Accordingly, this narrative review examines the therapeutic potential of AMPAkines in neurodegenerative and neurodevelopmental disorders and provides a comprehensive overview of their progress in preclinical and clinical studies.

The Mycobacteriales order of bacteria includes important pathogens such as Mycobacterium tuberculosis. These organisms are surrounded by a unique cell envelope architecture that includes a two-layered cell wall composed of peptidoglycan (PG) and arabinogalactan. They also build an outer membrane called the mycomembrane that is made of mycolic acids. Mycolate outer membrane proteins (MOMPs) reside within the mycomembrane and a subset are thought to form pores that allow essential nutrients to permeate the envelope. However, little is known about the structure of these proteins or the mechanism by which they are assembled. Here, we investigate MOMP assembly in Corynebacterium glutamicum (Cglu) using PorH as a model corynebacterial MOMP. PorH is encoded in an operon with the MOMP PorA, and the two small, alpha-helical proteins have been proposed to form hetero-oligomeric pores in the mycomembrane. Consistent with this proposal, AlphaFold2 predicts a high confidence structure of a hetero-oligomeric pore formed by five copies each of PorH and its partner PorA, and we show that PorA is required for the surface assembly of PorH. Using a fluorescence assay for detection of surface-exposed PorH or another MOMP called ProtX, we found that MOMP assembly occurs within zones of active PG synthesis at the cell poles. We also found that PorH and ProtX are linked to the cell wall. Thus, like gram-negative bacteria, Cglu coordinates outer membrane protein assembly with PG biogenesis and uses proteins to connect the mycomembrane and the cell wall.

The chemical profile of the rhizomes of Dioscorea bulbifera L. was systematically investigated. As a result, nineteen known compounds were isolated and structurally characterised, comprising emodin (1), piceid (2), quercetin (3), physcion (4), kaempferol (5), caffeic acid methyl ester (6), resveratrol (7), 3,4,5-trihydroxybenzoic acid (8), resveratrol-2''-O-galloylester (9), bisdemethoxycurcumin (10), resveratrol-O-E-phyllanthine (11), rhein (12), aloe-emodin (13), 5-methoxy-7-hydroxy-1(3H)-benzofuranone (14), questinol (15), vanillic acid (16), β-sitosterol (17), 3,4-dihydroxybenzoic acid (18), and diosgenin (19). All isolated compounds were evaluated for their α-glucosidase inhibitory and antioxidant activity. The results demonstrated that compounds 3, 5, 8, 9, and 18 exhibited antioxidant activity, with radical scavenging rates ranging from 84.19% to 97.73%, while 9, 11, 13, and 15 showed α-glucosidase inhibitory effects, with IC50 values ranging from 0.4556 to 1.3528 mg/mL. These findings indicate that the ethyl acetate fraction of D. bulbifera represents a promising source of multifunctional bioactive constituents and provides a chemical basis.

The therapeutic efficacy of interferon alpha (IFNα) is well-established in various conditions, including Hepatitis B and C, lymphoma and skin cancer, attributed to its potent angiostatic, immunomodulatory, and antiproliferative properties. Clinical applications using this bioactive are, however, hindered by systemic toxicity due to the high doses used, increasing costs and reducing patient adherence. The use of a controlled-release polymeric nanoparticulate system that can potentially decrease the administered dose, and therefore the associated costs, may additionally improve overall patient acceptability without affecting therapeutic efficacy. This study provides for the development, statistical optimization and characterization of poly(lactic-co-glycolic acid) nanoparticles (PLGANPs) for the controlled release of IFNα. A double-emulsion solvent evaporation method was employed for nanoparticle (NP) synthesis, with formulation optimization achieved through a Central Composite Design (CCD) approach to ensure adequate size, stability, and sustained release over five days. Characterization of the optimized IFNα-PLGANPs using dynamic light scattering, zeta potential analysis, scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and drug release studies at pH 7.2 displayed an average particle size of 97.03 nm (PDI = 0.182), zeta potential of - 34.10 mV and a maximum drug release of 5 days, with morphological analysis revealing the formation of spherical NPs with a smooth surface topology, confirming the homogeneity and structural stability of the formulation. These findings underscore the potential of the developed PLGANPs as a suitable platform for the controlled release of IFNα, noting the use of advanced nanotechnology-driven solutions to overcome the limitations of conventional therapies.