BackgroundUlcerative colitis (UC) is one of the two major types of inflammatory bowel disease (IBD), characterized by inflammation of the colon and rectum. The colorectal epithelium, which covers the mucosal surface, maintains homeostasis by supporting commensal microorganisms in the outer mucus layer. Most colorectal epithelial cells (CECs) are absorptive colonocytes distributed primarily in the upper portion of the crypts. These CECs constitute the front-line barrier that modulates mucosal immunity and facilitates the transfer of immune molecules into the lumen. In patients with UC, CECs undergo both apoptosis and pyroptosis. Apoptosis is a physiological, programmed, caspase-dependent, and tightly regulated form of cell death that eliminates aged and damaged cells. In contrast, pyroptosis is an inflammatory, caspase-dependent form of lytic cell death that occurs in response to harmful stressors and toxins. Pyroptosis in CECs involves a broad array of signaling and effector molecules, many of which serve as measurable biomarkers with diagnostic, prognostic, and therapeutic potential.ConclusionsDysregulated colorectal microflora significantly contributes to activating the pyroptotic pathway, initiating an inflammasome- and gasdermin-dependent inflammatory cell death process in UC patients. This review discusses the triggers and pathways of pyroptosis in CECs, evaluates recently identified biomarkers, highlights their potential roles in pyroptosis and as therapeutic targets in managing UC, and candidate compounds that have been shown effective UC therapeutics.

The human liver and pancreas are central to metabolic regulation, with the autonomic nervous system orchestrating processes that maintain glucose homeostasis and respond to dynamic physiological demands-ranging from acute energy mobilization during stress to postprandial glucose uptake and storage. However, visualizing and examining the intricate three-dimensional (3D) neural networks within clinical liver and pancreas specimens remains challenging, as conventional two-dimensional (2D) histological methods cannot fully resolve the spatial complexity of autonomic innervation in the liver and pancreas. This review identifies and discusses key biological and technical factors-including tissue autofluorescence, autolysis, photobleaching, and steatosis-that compromise the reliability of 3D neurohistological analysis of the human liver and pancreas. We also highlight emerging optical and chemical methodologies that enable high- and super-resolution 3D tissue imaging, improving signal fidelity, preserving structural detail, and supporting consistent, reproducible analysis. Ultimately, these advances aim to facilitate precise mapping of human liver and pancreas innervation, offering deeper insight into the neural regulation of nutrient assimilation, glucose utilization, and metabolic homeostasis in both physiological and pathological contexts.

BackgroundPPM1D (protein phosphatase Mg2⁺/Mn2⁺ dependent 1D) is a Ser/Thr phosphatase that negatively regulates p53 and functions as an oncogenic driver. Its gene amplification and overexpression are frequently observed in various malignancies and disruption of PPM1D degradation has also been reported as a cause of cancer progression. However, the precise mechanisms regulating PPM1D stability remain to be elucidated.MethodsPPM1D stability and degradation pathways were examined using cycloheximide chase assays in multiple cell lines. Proteasome and lysosome inhibitors were used to determine the degradation mechanism, while ubiquitination dependency was assessed using TAK-243, an E1 ubiquitin-activating enzyme inhibitor. In vitro degradation assays with purified 20S proteasome were performed to evaluate direct proteasomal degradation. Immunoprecipitation followed by mass spectrometry was performed to identify proteasomal regulators of PPM1D, with their functional roles validated through knockdown experiments. Finally, cell viability assays were conducted to assess the therapeutic potential of combined proteasome and PPM1D inhibition.ResultsCycloheximide chase assays demonstrated that wild-type PPM1D is a short-lived protein, whereas a C-terminal truncation mutant exhibits increased stability. PPM1D undergoes rapid, ubiquitin-independent proteasomal degradation via its C-terminal 35 amino acid residues. Additionally, the region spanning residues 450–501 is necessary for ubiquitination-mediated suppression of the ubiquitin-independent degradation pathway. We also found that PPM1D is directly degraded by the 20S proteasome, with the regulatory proteasome subunits PSMD14 and PSME3 acting as activators in this process. Proteasome inhibition resulted in PPM1D accumulation, potentially reducing therapeutic efficacy. Combined proteasome and PPM1D inhibition synergistically enhanced the antitumor effect.ConclusionsThe rapid degradation of the cancer driver PPM1D is achieved through direct recognition by the proteasome, and proteasome inhibitors may reduce therapeutic efficacy due to the accumulation of PPM1D. PPM1D may serve as a suitable model substrate for elucidating the mechanism of ubiquitin-independent proteasomal degradation and represents a potential novel therapeutic target for cancer treatment based on proteasome inhibition.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12929-025-01185-z.

BackgroundTherapeutic options against metallo-β-lactamase producing P. aeruginosa (MBL-PA) are limited due to multi-drug resistance. A jumbo phage isolated from wastewater in Greece was characterized microbiologically and genetically and evaluated for its potential as a therapeutic agent alone or in combination with antibiotics in an experimental thigh infection mouse model.MethodsThe host range of the jumbo phage vB_PaerM_AttikonH10 (AttikonH10) against 20 MBL-PA clinical isolates and 10 susceptible strains, one-step phage growth and growth curves of mid-exponential phase bacteria upon addition of the phage were analyzed. Whole-genome sequencing was performed and the de novo assembled complete phage genome was compared with other jumbo phages. In vivo pharmacokinetics in different tissues as well as the efficacy of two dosing regimens 109 and 106 PFU/mouse administered intraperitoneally alone and in combination with amikacin (384 mg/kg/day) was tested against an MBL-PA clinical isolate in murine thigh infection model.ResultsThe phage formed small plaques in double-layer agar and demonstrated clear or semi-clear lysis in 83.3% (25/30) of P. aeruginosa clinical isolates. Growth curves showed a > 94% growth inhibition in the presence of phage even at the lowest multiplicity of infection ratio tested (10–5). Whole genome analysis indicated a jumbo dsDNA phage with 278,406 bp (36.92% GC) belonging to Phikzvirus that is predicted to host up to 413 putative ORFs and 6 tRNA genes. No known lysogeny-associated genes, virulence factors, or antimicrobial resistance genes were identified within the genome. Phage titres 104–106 PFU/tissue were detected in all mouse tissues with elimination half-life of 3.4 h except in bronchoalveolar lavage where no phages were found. Only the high phage dose (109 PFU/mouse) reduced bacterial load in thigh by 1.09 log10 cfu/thigh compared to placebo, similar to amikacin monotherapy (1.19 log10 cfu/thigh), while their combination achieved a greater reduction of 2.07 log10 cfu/thigh compared to each monotherapy (p = 0.0044–0.0048).ConclusionsThe newly reported Phikzvirus jumbo phage AttikonH10 demonstrated a broad host range, strong lytic activity and synergistic effects with amikacin against MBL-PA isolates making it a candidate for phage therapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12929-025-01169-z.

The application of smart hydrogels has become a booming research frontier in biomedical engineering. With the development of intelligent drug delivery systems, various biomimetic and biodegradable hydrogels are employed for localized drug delivery to tissues in the preclinical applications. These advanced materials are designed to match the diverse environmental and functional requirements of various tissue types and organs. This article discusses the attractive characteristics of smart hydrogels as delivery systems and reviews the design of a range of smart hydrogels, as well as the challenges of tissue-specific drug delivery, focusing on the last 5years of frontward research.

BackgroundThe organic cation transporter 3 (OCT3) is a ubiquitous transporter that carries both endogenous and exogenous substrates, such as histamine and cisplatin. Our investigations have shown that OCT3 directly interacts with the tetraspanin CD63. CD63 is a marker for activated basophils and mast cells, which are granulocytes capable of rapidly releasing large amounts of histamine. This makes them key players in the development of allergic reactions.Methods and resultsIn this work, we demonstrated that OCT3 is present in murine and human basophils and is strongly colocalized with CD63 in a specific region of the plasma membrane, particularly after cell activation leading to histamine release. Furthermore, we confirmed that part of the histamine release from basophils is mediated by OCT3. In a mouse model of contact dermatitis, the presence of OCT3 is crucial for determining the severity of the allergic reaction. The presence of CD63 also seems to be important for regulating the allergic response, although it does not directly affect histamine secretion. RNA-Seq and metabolome analyses revealed that wild-type mice and mice with genetic deletion of OCT3 (OCT3−/−) are phenotypically very similar, and that the observed effects in OCT3−/− organisms can be attributed mainly to the genetic deletion of the OCT3 transporter.ConclusionsIn conclusion, OCT3 is a transporter for histamine in granulocytes, which plays a crucial role in determining the intensity of allergic reactions and may be a target for interventions aimed at reducing their severity.

IntroductionAutism spectrum disorder (ASD) is characterized by disruption of the gut–brain axis, which leads to behavioral, psychiatric, metabolic and gastrointestinal symptoms. Effective ASD treatments are limited. Research highlights the roles of the endocannabinoidome (eCBome) and gut microbiome (GM), both crucial for brain and gut function. This review summarizes research on therapeutic targets within the eCBome–GM–brain axis for ASD and related comorbidities.DiscussionEvidence suggests that reduced levels of eCBome mediators, like oleoylethanolamide and anandamide, and altered cannabinoid type 1 and type 2 (CB1 and CB2) receptors activity may contribute to ASD symptoms, making them promising targets. Modulating the eCBome–GM–brain axis with inhibitors of fatty acid amide hydrolase (FAAH), transient receptor potential vanilloid 1, and monoacylglycerol lipase (MAGL) may improve repetitive, stereotypical, and sensory behaviors, and alleviate sociability impairments, depression and anxiety. However, inhibition of FAAH and MAGL may also induce ADHD-like behaviors, which can be reversed by CB1 inverse agonists. Targeting metabotropic glutamate receptor 5 to increase levels of the eCBome mediator 2-arachidonoylglycerol (2-AG) may benefit ASD-related behaviors. eCBome mediators such as 2-AG, 1/2-palmitoylglycerol and palmitoylethanolamide may also help manage ASD- and GI-related symptoms, and systemic inflammation. Other potential therapeutic targets that deserve further investigation are eCBome-related receptors G-protein-coupled receptor 55 and peroxisome proliferator-activated receptors-alpha and -gamma, and the cyclooxygenase-2/prostaglandin E2 pathway, which may address hyperactivity and repetitive behaviors. Additionally, mucin-degrading genera like Akkermansia and Ruminococcus may improve ASD-related GI symptoms such as hypersensitivity and inflammation. Selective antibiotics against specific Clostridium strains may improve irritability and aggression. In ASD with ADHD and OCD, treatments may involve modulating the CB1 and CB2 receptor, and bacterial families like Ruminococcaceae and Lachnospiraceae. Lastly, modulating the abundance of anti-inflammatory genera like Prevotella and Anaeroplasma, and taxa associated with gut health such as Roseburia may also offer therapeutic value.ConclusionThe eCBome–GM–brain axis is a promising target for ASD treatment, meriting further clinical and preclinical research.

The innate immune system is the host’s initial response to eliminate pathogens and repair tissue damage. Innate immune cells, such as macrophages and dendritic cells, use pattern recognition receptors (PRRs) to recognize microbial structures and stress-induced molecules released from dead or damaged cells, thereby initiating immune responses. Among PRRs, Toll-like receptors (TLRs) are well-studied and are located either on the cell surface or in endosomal compartments. Most endosomal TLRs specifically recognize nucleic acids and are thus referred to as nucleic acid (NA)-sensing TLRs. Upon activation, these receptors induce the production of inflammatory cytokines and type I interferons and initiate subsequent adaptive immunity. These immune responses work to suppress pathogens and inhibit tumor growth. However, excessive cytokine and interferon production can lead to various inflammatory diseases. This review focuses on mammalian nucleic acid-sensing TLRs, summarizing the molecular regulation of their activations, the impact of their dysregulation on human diseases, and therapeutic strategies that target these TLRs.

BackgroundType 2 diabetes is an increasingly prevalent metabolic disorder with moderate to high heritability. Glycemic indices are crucial for diagnosing and monitoring the disease. Previous genome-wide association study (GWAS) have identified several risk loci associated with type 2 diabetes, but data from the Taiwanese population remain relatively sparse and primarily focus on type 2 diabetes status rather than glycemic trait levels.MethodsWe conducted a comprehensive genome-wide meta-analysis to explore the genetics of glycemic traits. The study incorporated a community-based cohort of 145,468 individuals and a hospital-based cohort of 35,395 individuals. The study integrated genetics, transcriptomics, biological pathway analyses, polygenic risk score calculation, and drug repurposing for type 2 diabetes.ResultsThis study assessed hemoglobin A1c and fasting glucose levels, validating known loci (FN3K, SPC25, MTNR1B, and FOXA2) and discovering new genes, including MAEA and PRC1. Additionally, we found that diabetes, blood lipids, and liver- and kidney-related traits share genetic foundations with glycemic traits. A higher PRS was associated with an increased risk of type 2 diabetes. Finally, eight repurposed drugs were identified with evidence to regulate blood glucose levels, offering new avenues for the management and treatment of type 2 diabetes.ConclusionsThis research illuminates the unique genetic landscape of glucose regulation in Taiwanese Han population, providing valuable insights to guide future treatment strategies for type 2 diabetes.

BackgroundAnimal studies established that the locus coeruleus (LC) plays important roles in sleep and wakefulness regulation. Whether it contributes to sleep variability in humans is not yet established. Here, we investigated if the in vivo activity of the LC is related to the variability in the quality of Rapid Eye Movement (REM) sleep.MethodsWe assessed the LC activity of 34 healthy younger (~ 22y) and 18 older (~ 61y) individuals engaged in bottom-up and top-down cognitive tasks using 7-Tesla functional Magnetic Resonance Imaging (fMRI). We further recorded their sleep electroencephalogram (EEG) to evaluate associations between LC fMRI measures and REM sleep EEG metrics.ResultsTheta oscillation energy during REM sleep was positively associated with LC response in the top-down task. In contrast, REM sleep theta energy was negatively associated with LC activity in older individuals during the bottom-up task. Importantly, sigma oscillations power immediately preceding a REM sleep episode was positively associated with LC activity in the top-down task.ConclusionsLC activity during wakefulness was related to REM sleep intensity and to a transient EEG change preceding REM sleep, a feature causally related to LC activity in animal studies. The associations depend on the cognitive task, suggesting that a balanced level of LC tonic activity during wakefulness is required for optimal expression of REM sleep. The findings may have implications for the high prevalence of sleep complaints reported in aging and for disorders such as insomnia, Alzheimer’s, and Parkinson’s disease, for which the LC may play pivotal roles through sleep.