AMPA receptors (AMPARs) are key molecular mediators of fast excitatory neurotransmission and synaptic plasticity in the central nervous system. Increasing evidence indicates that maladaptive regulation of AMPAR trafficking, subunit composition, and phosphorylation contributes to central sensitization underlying chronic pain. Experimental models demonstrate that inflammation or nerve injury induces GluA2 internalization and insertion of calcium-permeable AMPARs in the spinal dorsal horn and supraspinal regions, such as the anterior cingulate cortex, insula, amygdala, and nucleus accumbens. These alterations enhance excitatory transmission and sustain pain perception. Translational advances in molecular neuroimaging have enabled visualization of such mechanisms in vivo. The positron emission tomography (PET) radioligand [11C]K-2 allows quantitative mapping of AMPAR density in the human brain, while FDG-PET captures pain-related metabolic abnormalities within the pain matrix, including the anterior cingulate, insula, and thalamus. Integrating AMPAR-PET with MRI provides a multiscale framework linking molecular receptor dynamics with network-level reorganization. Furthermore, longitudinal PET and MRI studies demonstrate partial reversibility of structural and functional brain alterations following effective treatments, suggesting that pain-related neuroplasticity is modifiable. These insights highlight the potential of AMPAR-targeted imaging biomarkers to objectively characterize chronic pain mechanisms, guide therapeutic stratification, and evaluate treatment response. Establishing standardized multimodal imaging protocols and large collaborative databases will be essential to translate these discoveries into mechanism-based diagnostics and interventions for chronic pain .
p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates ("p62 bodies") that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylation at Ser403 acts as a threshold-dependent modulator of a condensate's physical properties and promotes their rapid autophagic clearance. Phosphorylation within p62 bodies drives a transition from large, fluid droplets to compact, gel-like condensates that efficiently capture LC3-positive isolation membranes and accelerate the autophagic removal of ubiquitinated proteins. PP2A holoenzymes containing PPP2R5A/B/E, recruited via a KEAP1 bridge, counteract TBK1 by dephosphorylating Ser403. Homozygous p62S403E/S403E knock-in embryonic stem cells differentiate into post-mitotic neurons enriched in miniaturized, gel-like p62 bodies. Consistently, phosphorylation-mimetic knock-in mice show similar remodeling of p62 condensates in vivo, demonstrating that this phosphorylation-driven mechanism maintains proteostasis across scales. We propose that Ser403 phosphorylation functions as a molecular switch that couples the material state of p62 condensates to their stability and serves as a central control point for p62-mediated protein degradation.
Amsonia elliptica (Thunb.) Roem. et Schult is important as traditional medicine and as ornamentals. This plant biosynthesizes more than 20 terpenoid indole alkaloids (TIAs), including amsonine (β-yohimbine) and tabersonine. It is known that many TIAs have biological activity, and it is thought that plants biosynthesize these chemicals to adapt to their surrounding environment. However, the regulatory mechanisms and ecological meaning governing seasonal fluctuations in the biosynthesis and accumulation of TIAs in medicinal plants, particularly in representative members of the Apocynaceae family, remain largely unresolved. We used LC–MS/MS to investigate TIAs accumulated in A. elliptica leaf tissue. Based on the information of accumulated TIA products, we proposed the TIA metabolic pathway and intermediates in A. elliptica leaf. In addition, we sampled the leaves of A. elliptica over time from spring to winter and used LC–MS/MS to investigate the amount of TIA metabolites in the A. elliptica leaf tissues. As a result, it was revealed that the accumulation of the main intermediate, i.e. strictosidine, changed depending on the season, and that a dimeric form of TIA accumulated before leaf fall. Here, we report how A. elliptica changes TIAs accumulation in response to season, based on the information on the relative quantification of intermediates and major accumulated TIAs present in leaf of A. elliptica. These findings demonstrate that A. elliptica dynamically regulates TIA biosynthesis in response to seasonal changes, highlighting the species' adaptive metabolic plasticity.
Objective Legumain, also known as asparaginyl endopeptidase or delta-secretase, is a cysteine protease that plays a significant role in various biological and pathological processes. This study investigated the role of the legumain-protease-activated receptor 2 (PAR2) signaling pathway in mechanical hypersensitivity in a rat model of tongue cancer.Methods Squamous cell carcinoma (SCC) cells were injected subcutaneously into the tongue. Mechanical head withdrawal reflex threshold (MHWT) was recorded after SCC inoculation or activated-legumain administration. The expression of legumain in the cancerous tongue and PAR2 in the trigeminal ganglion was measured. The effects of legumain inhibition on the MHWT in SCC-inoculated tongues were assessed.Results The SCC-inoculated tongue resulted in a significant decrease in MHWT. Legumain levels were elevated in the SCC-inoculated tongue, and administration of activated-legumain induced mechanical allodynia. Conversely, legumain inhibitor administration mitigated SCC-induced reduction in MHWT. PAR2 was identified in trigeminal ganglion neurons that innervate the tongue, and its blockade reduced mechanical hypersensitivity in the SCC-inoculated tongue.Conclusions These findings suggest that legumain released from SCC cells activates PAR2 on primary afferent terminals, leading to the mechanical sensitization of cancerous tongues. This study provides novel insights into the peripheral mechanisms of oral SCC pain.
There are concerns regarding postoperative infections following laparoscopic colectomy with intracorporeal anastomosis. Thus, in this study, we aimed to determine the optimal preoperative bowel preparation to reduce postoperative infectious complications in patients undergoing laparoscopic colectomy with intracorporeal anastomosis. This secondary analysis of the ICAN study—a multicenter, retrospective cohort study involving 46 institutions affiliated with the Japan Society of Laparoscopic Colorectal Surgery—included 615 patients with colon adenocarcinoma undergoing laparoscopic colectomy with intracorporeal anastomosis between January 2020 and December 2021. Patients were analyzed after applying eligibility criteria and propensity score matching based on age ≥ 65 years, sex, body mass index ≥ 30, American Society of Anesthesiologists Physical Status, diabetes, and the number of intracorporeal anastomosis cases previously performed at the institution. Among them, 312 received combined oral antibiotics and mechanical bowel preparation, whereas 156 received other preparations (mechanical preparation alone, oral antibiotics alone, and no preparation). The primary outcome was surgical wound infection incidence (Clavien–Dindo grade ≥ II) at initial discharge. Secondary outcomes included intraperitoneal infections, anastomotic leakage, ileus, and postoperative hospital stay. Surgical wound infection (1/312 [0.3
