Zanthoxylum bungeanum, commonly known as Chinese pepper, widely used globally as a spice for its unique numbing-tingling sensation and flavor-enhancing properties, owes its key biological activity to sanshool, a major polyunsaturated fatty acid amide component, mainly present in its pericarps. This work comprehensively examines and summarizes sanshool's distribution, biosynthesis, stability, and bioavailability, while reviewing and discussing its potent biological functions and underlying molecular mechanisms, including antioxidation, analgesia, anti-inflammation, antiobesity, and antidiabetic effects. Various delivery systems for improving the stability and bioavailability of sanshool are also summarized and evaluated, including nanoparticles, liposomes, and emulsions. This study aims to provide a comprehensive understanding of sanshool's physiochemical properties and health benefits, facilitating its greater application in the food and nutraceutical industries.

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system and a promising therapeutic target for pain and depression. However, traditional FAAH inhibitors have faced clinical setbacks due to their limited efficacy and off-target effects. Here, we present the rational design and molecular characterization of C13p, a novel PROTAC molecule targeting hFAAH, composed of a 13-carbon linker connecting the FAAH ligand Carb4d and the CRBN ligand pomalidomide. Our results demonstrate that C13p significantly enhances the protein-protein interactions between hFAAH and CRBN, with a binding free energy of -42.2 kcal mol-1 in the ternary complex compared with -30.5 kcal mol-1 in the binary system. Notably, C13p exhibits stronger binding to CRBN (-13.7 kcal mol-1) than to hFAAH (-7.9 kcal mol-1), suggesting a stepwise assembly mechanism where C13p first binds to CRBN and subsequently recruits hFAAH. Dissociation studies reveal that hFAAH dissociates independently from the ternary complex in 81% of trajectories, with an average residence time of 0.58 s, highlighting a cyclic recruitment mechanism. We further identified K508, K505, and K501 as the potential ubiquitination sites on hFAAH, with significantly enhanced solvent exposure upon C13p binding. This work provides the first detailed mechanistic insight into PROTAC-mediated FAAH degradation, offering a novel strategy for developing next-generation therapeutics for depression-pain comorbidity.

An Ultra-High performance liquid chromatography-tandem mass spectrometry method for simultaneous determination of etomidate, analogues, and metabolites in human nail: Unveiling a unique accumulation profile.

Neurovasculoglial cross-talk underlying breakdown of the neurovascular unit is a central, yet poorly understood, component of many neurodegenerative disorders of the CNS, including retinal disease. Primary fatty acid amides have been identified to regulate this cross-talk between vasculature and neuronal tissues, but specific molecules and mechanisms remain unresolved. Here we show, using an unbiased high-resolution metabolomics screen, that erucamide, a 22:1 monounsaturated omega-9 fatty acid amide, is highly dysregulated during photoreceptor degeneration in mice. In vivo delivery of erucamide using organosilane-modified porous silicon nanoparticles activated retinal myeloid cells, leading to the upregulation of angiogenic and neurotrophic cytokines that limited vascular and neuronal degeneration. We identified TMEM19 as a binding protein for erucamide that is crucial for myeloid cell activation and subsequent neuroprotection. These findings reveal a previously unknown primary fatty acid amide pathway that modulates neuroimmune interactions during retinal degenerative diseases. We propose erucamide and analogs as candidate therapeutics.

The agriculturally and pharmaceutically important lysergic acid amides ergonovine and lysergic acid α-hydroxyethylamide (LAH) are synthesized from a lysergyl-alanine precursor. In ergot-alkaloid producing fungi of the family Clavicipitaceae, lysergyl-alanine is assembled and then reduced to ergonovine by a complex of two monomodular nonribosomal peptide synthetases: lysergyl peptide synthetase 2 (Lps2) and Lps3. LAH is the major ergot alkaloid product of these fungi when the Lps2/Lps3 complex interacts with the Bayer-Villiger monooxygenase encoded by easO. An α/β hydrolase fold protein encoded by easP increases LAH accumulation but is not essential for LAH biosynthesis. Lps2 and Lps3 do not occur in the several species of Aspergillus (including A. leporis) that produce LAH and ergonovine. Instead, ergot alkaloid synthesis clusters of these Aspergillus species encode a novel two-module Lps gene, lpsD. We hypothesized the product of lpsD was functionally equivalent to the two separately encoded, monomodular enzymes of the Clavicipitaceae and tested this hypothesis by introducing lpsD of A. leporis into a strain of Aspergillus fumigatus that had been modified previously to accumulate lysergic acid as substrate. Introduction of lpsD resulted in accumulation of ergonovine as evidenced by high-performance liquid chromatography and liquid chromatography-mass spectrometry. The addition of the A. leporis allele of easO into the lpsD-transformed A. fumigatus strain led to accumulation of LAH. Introduction of a construct containing easP as well as easO into the lpsD-transformed A. fumigatus strain resulted in higher concentrations of LAH than in strains containing only lpsD and easO, consistent with previous studies in the Clavicipitaceae. The data support the hypothesis that ergot alkaloid-producing Aspergillus species independently evolved a single enzyme that serves the purpose of the two monomodular peptide synthetases of the Clavicipitaceae.

Amides represent a critical class of chemicals. Direct amide synthesis from fatty acids and ammonia is a highly desirable route for the valorisation of fatty acids. Here, we developed a novel direct amidation electrolysis in liquefied ammonia. This method achieves high selectivity (>80%) without additional reagents.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models, iPS cells derived from ALS patients and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.

Fatty acid amide hydrolase (FAAH) inhibitor reduces persistent inflammatory pain in mice depending on μ- and δ-opioid receptors activity: Involvement of heme oxygenase-1.

Inhibition of endocannabinoid catabolizing enzymes MAGL and FAAH reduces the activity of CaV3 channels in nociceptors and pain hypersensitivity in a rat model of spinal cord injury.

Lantana camara L. is a highly adaptable shrub renowned for its ecological resilience and invasive nature, particularly in semi-arid regions. While its crude extracts are known to possess antimicrobial properties, the specific bioactive molecules responsible remain under-characterised. This study aimed to systematically identify the antibacterial compounds from L. camara leaves collected from the environmental stressor conditions of the Todgarh-Aravalli Forest margin in Rajasthan, India. Extraction efficiency was optimised by comparing hot methanolic Soxhlet extraction with cold poly-solvent maceration. The cold extract demonstrated superior bulk yield and broad-spectrum antibacterial efficacy against four multi-drug resistant (MDR) strains (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus), indicating the presence of thermolabile defensive metabolites. Subsequent liquid-liquid partitioning revealed that the antibacterial activity was overwhelmingly concentrated in the non-polar n-hexane fraction. Direct TLC-bioautography of this fraction against P. aeruginosa successfully isolated a highly active bio-zone spanning an Rf of 0.63-0.78. Chemical profiling of this bioactive eluate via GC-MS/MS putatively identified ten distinct compounds, predominantly branched-chain alkanes (24.6% peak area), alongside the fatty acid amide oleamide, which has documented membrane-interacting potential and the diterpenoid thunbergol. These findings confirm that the robust antibacterial defense mechanism of L. camara relies primarily on lipophilic secondary metabolites, highlighting its potential as a valuable botanical resource for novel therapeutics against antibiotic-resistant pathogens.

Indigenous rhizobacteria drive stepwise detoxification of mancozeb via strain-specific metabolic pathways.

Structure-guided discovery of phenyl-carbamates as novel dual TRPV1 antagonists/FAAH inhibitors.

N-acylmelatonins (NAMs), a class of fatty acid amides featuring melatonin as the polar head group, demonstrate significant biomedical potential. In this study, a homologous series of saturated NAMs (n = 9-18) were synthesized and fully characterized via FTIR, NMR and HRMS. The biophysical self-assembly behaviour was assessed by powder X-ray diffraction and fluorescence spectroscopy. The d-spacing determined from PXRD increases linearly with an increment of ~ 0.90 Å per CH₂ group, suggesting that the NAMs adopt a tilted bilayer structure. Fluorescence spectroscopy was employed to measure the critical micellar concentrations (CMCs) of NAMs by monitoring the spectral changes of 8-anilinonaphthalene-1-sulfonate (ANS). Fluorescence emission and lifetime measurements of NAMs show a red-shift (~ 10nm) in emission maxima and a 2.4-fold emission intensity enhancement due to the hydrophobic acyl chain. Antioxidant properties, determined by DPPH radical scavenging assays, increased with concentration, showcasing potent activity. Notably, NAMs exhibited enhanced antimicrobial efficacy against clinically relevant bacterial and fungal strains, with minimum inhibitory concentrations comparable to standard drugs. In vitro anticancer screening revealed significant cytotoxicity against multiple human cancer cell lines, particularly with medium-chain NAMs. These findings highlight the broad-spectrum therapeutic potential of NAMs, driven by variable acyl chain length, self-assembly characteristics and strong biological applications.

Structure of a stand-alone homodimeric nonribosomal peptide synthetase condensation domain reveals occlusion of the canonical carrier-protein interface.

Plant diseases have consistently threatened global crop safety, impacting both the yield and quality of agricultural products. So, to develop novel and safe disease prevention and control drugs, 20 multisubstituted carbazole analogues bearing hydrazone and peptide scaffolds were designed, synthesized, and evaluated for antifungal and antiviral activities. Carbazole amino acid amides exhibited superior antifungal efficacy, with compound 10b showing potent activity against Sclerotinia sclerotiorum (EC50 = 41.88 μg·mL-1). Conversely, N-acylhydrazone carbazole derivatives demonstrated enhanced antitobacco mosaic virus (TMV) activity, with 6a achieving 80.3% inhibition at 500 μg·mL-1; notably, 10b also displayed significant antiviral effects (66.7% inhibition). Structure-based molecular docking against succinate dehydrogenase (SDH, PDB: 3ABV) and TMV coat protein (TMV-CP, PDB: 1EI7), coupled with electrostatic potential analysis, identified these carbazoles as privileged scaffolds for multitarget green pesticide development to combat resistance and ensure agricultural sustainability.

The global obesity pandemic demands therapeutic innovation beyond incretin-based pharmacotherapy. While glucagon-like peptide-1 (GLP-1) receptor agonists have transformed obesity management, persistent challenges remain: gastrointestinal intolerance, weight-loss plateaus and post-treatment regain underscore the need for complementary and mechanistically orthogonal approaches. Fatty acid amide hydrolase (FAAH) represents a promising, though still exploratory, enzymatic target at the crossroads of appetite, reward and metabolism. This serine hydrolase regulates the degradation of both pro-orexigenic endocannabinoids, notably anandamide (AEA) and anti-orexigenic N-acylethanolamines (NAEs), particularly oleoylethanolamide (OEA). Unlike direct cannabinoid type 1 receptor (CB1 receptor) antagonists, which failed clinically due to severe psychiatric toxicity, FAAH modulation may allow a more spatially and temporally constrained regulation of endogenous lipid signalling. Importantly, FAAH inhibition does not intrinsically discriminate between orexigenic and anorexigenic substrates; thus, its metabolic impact depends on tissue selectivity, substrate bias and nutritional context. By prolonging OEA signalling, FAAH inhibition has the potential to enhance peroxisome proliferator-activated receptor alpha (PPARα) and G protein-coupled receptor 119 (GPR119) pathways, promoting fatty acid β-oxidation, improving hepatic lipid handling, and amplifying nutrient-dependent GLP-1 secretion in preclinical models. However, translational evidence in humans remains limited, and the long-term metabolic efficacy of FAAH inhibition in obesity has yet to be demonstrated. This review examines FAAH biochemistry, its dysregulation in obesity, and the evolving pharmacological landscape of FAAH modulators, with particular attention to peripherally restricted and substrate-biased strategies. Rather than proposing FAAH inhibition as a standalone anti-obesity therapy, we discuss its potential role as a complementary component within multimodal treatment regimens alongside incretin-based drugs.

Radiation-induced intestinal injury (RIII) represents a significant dose-limiting complication of radiotherapy, characterized by substantial loss of intestinal epithelial cells (IECs). While the activation of cannabinoid receptor 2 (CB2R) is protective in immune‑mediated colitis, the intrinsic role of CB2R in IECs and its potential therapeutic relevance in RIII have not been defined. An RIII mouse model was established in wild-type and CB2R-/- mice. Small-molecule CB2R agonists were screened for radioprotective efficacy, followed by pharmacological and siRNA-based interrogation of CB2R signaling in intestinal epithelial cell lines and primary mouse intestinal epithelial cells. RNA sequencing and bioinformatics were combined with permeability assays, immunofluorescence, electron microscopy, and molecular analyses of oxidative stress and ferroptosis to elucidate underlying mechanisms. Irradiation induced CB2R expression in the intestinal epithelium, and genetic ablation of CB2R markedly aggravated RIII. A focused pharmacological screen identified a recently synthesized dual‑target compound, CB2R/FAAH modulator‑2 (CF‑2), which combines CB2R agonistic activity with fatty acid amide hydrolase (FAAH) inhibition and significantly mitigated radiation‑induced colonic injury while exerting protective effects on the small intestine and spleen. Mechanistically, CB2R activation attenuated irradiation‑induced ferroptosis and preserved intestinal epithelial integrity. Integrative transcriptomic analyses identified Homeobox A10 (HoxA10) as a critical epithelial‑enriched transcriptional amplifier that reinforced CB2R/β‑catenin signaling through a positive‑feedback loop, thereby enhancing CB2R‑mediated epithelial protection. This study defines an epithelial‑intrinsic CB2R signaling axis in RIII, linking ferroptosis suppression to preservation of intestinal barrier integrity. CF‑2 is positioned as a promising mechanism‑based candidate for radioprotection.

Identification and characterization of three acyltransferases involved in the hydroxycinnamic acid amide synthesis of goji berry.

The endocannabinoid system (ECS) is a complex signaling network that regulates diverse physiological processes, including pain, mood, metabolism, and immune response, through coordinated interactions among receptors, enzymes, and lipid-derived ligands. Although individual ECS components have been extensively studied, the integrated systems-level organization and structural dependencies of the ECS remain insufficiently characterized in a unified network context. Here, we present a computational, network-based systems analysis of the ECS that integrates protein-protein and protein-chemical interactions into a unified interaction framework, enabling the identification of components that occupy structurally prominent positions in the network, with potential relevance to the role of ECS in diverse physiological processes and therapeutic contexts. We constructed integrated ECS networks by combining experimentally validated protein-protein and protein-chemical interactions from multiple public databases. Network analyses were performed using centrality metrics, community detection algorithms, and targeted perturbations of highly ranked nodes to assess structural organization, modular architecture, and redistribution of topological influence. Centrality analyses systematically identified nodes with high topological prominence across the ECS network. Canonical receptors cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) ranked consistently among the most influential nodes, while non-canonical components such as transient receptor potential vanilloid 1 (TRPV1), G-protein coupled receptor 55 (GPR55), peroxisome proliferator-activated receptor alpha (PPARα), cyclooxygenase-2 (COX-2), fatty acid amide hydrolase (FAAH), and diacylglycerol lipase alpha (DAGLα) also emerged as highly ranked nodes across multiple centrality measures. Closeness and eigenvector centrality further highlighted phytocannabinoids including cannabidiol (CBD), tetrahydrocannabivarin (THCV), and cannabidivarin (CBDV) as structurally well-connected components within the network. Community detection revealed a modular organization separating receptor-mediated signaling components from endocannabinoid metabolic processes, with clusters centered on CB1/CB2 signaling machinery and enzymes such as FAAH and diacylglycerol lipase beta (DAGLβ), which are associated with 2-arachidonoylglycerol (2-AG) turnover. Perturbation analyses demonstrated that removal of dominant hubs, particularly CB1, redistributed centrality and altered shortest-path structure, increasing the relative prominence of nodes such as CB2 and GPR55 while decreasing that of others such as DAGLβ and linoleoyl ethanolamide (LEA). These findings identify structurally influential and configuration-dependent nodes whose prominence becomes apparent through network-level analysis. By mapping the ECS as an integrated interaction network, this study provides a structural framework for understanding how receptors, enzymes, and ligands collectively shape ECS organization. Our results demonstrate that network analysis can identify structurally influential components within the ECS, highlighting nodes whose importance emerges from the overall network organization. The identification of highly ranked and perturbation-sensitive nodes offers a systematic basis for prioritizing underexplored components for hypothesis-driven experimental investigation and pharmacological study. More broadly, this work establishes a network-based foundation for expanding ECS modeling to incorporate additional molecular entities, interaction directionality, signaling dynamics, and tissue- or context-specific interactions, thereby informing future therapeutic strategies targeting the ECS and its interacting molecular pathways across diverse physiological processes and disease pathways.

In the present study, novel amide derivatives of soybean oil fatty acids were synthesized via amidation of hydrolyzed fatty acids with aniline and benzylamine, yielding aromatic amides with structurally distinct amine moieties. These compounds were designed as potentially effective and biodegradable corrosion inhibitors. Comprehensive physicochemical characterization of the amides was performed using FT-IR and ¹H/¹³C NMR spectroscopy, while their thermal stability was assessed through thermogravimetric (TG) derivative thermogravimetric (DTG) and differential thermal analysis (DTA). The corrosion inhibition performance of the synthesized compounds was investigated using electrochemical techniques in CO₂-saturated 1 wt% NaCl solution. Linear polarization resistance (LPR) measurements were employed to study the time dependence of the corrosion rate, whereas potentiodynamic polarization (Tafel) curves were recorded to determine the electrochemical parameters of the corrosion process. The LPR results indicated that the inhibition efficiency of carbon steel increased with increasing inhibitor concentration, reaching 93–96% at 100 ppm. The inhibition mechanism was further elucidated by examining the surface morphology of mild steel using scanning electron microscopy (SEM). SEM images revealed that inhibitor-treated samples exhibited a smoother and less damaged surface compared to the uninhibited system, indicating the formation of a protective film. Adsorption behavior followed the Langmuir adsorption isotherm, and the calculated Gibbs free energy of adsorption (− 39 to − 42 kJ mol⁻¹) suggested strong and spontaneous adsorption with a dominant chemisorption contribution. The antimicrobial activity of the compounds was evaluated against sulfate-reducing bacteria (Desulfovibrio desulfuricans) as well as Gram-negative bacteria (Escherichia coli and coliforms). The benzylamine-derived fatty acid amide demonstrated the highest activity, achieving complete inhibition of D. desulfuricans growth at 50 mg L⁻¹. The results indicate that soybean oil fatty acid amides exhibit dual functionality, combining anticorrosive and antimicrobial properties, and may serve as promising environmentally friendly inhibitors for corrosion protection in oil-field environments affected by microbial activity.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13065-026-01814-0.