Mesenteric adipose-derived exosomal TINAGL1 enhances intestinal fibrosis in Crohn's Disease via SMAD4.

INTRODUCTION: Crohn's Disease (CD) is a chronic inflammatory condition characterized by intestinal fibrosis, severely impacting patient quality of life. The molecular mechanisms driving this fibrosis remain inadequately understood. Recent evidence implicates mesenteric adipose tissue (MAT) in CD pathogenesis, particularly through its exosome secretion, which may influence fibrogenic pathways. Understanding the role of MAT-derived exosomes is crucial for unraveling these molecular processes. OBJECTIVES: This study aims to elucidate the role of MAT-derived exosomes in CD-related intestinal fibrosis. We focus on investigating their molecular composition and the potential impact on fibrosis progression, with an emphasis on identifying novel therapeutic targets. METHODS: We induced chronic intestinal inflammation in mice using dinitrobenzene sulfonic acid (DNBS), simulating CD-like fibrosis. Exosomes were isolated from DNBS-treated mice (MG) and normal controls (NG) for characterization using electron microscopy and proteomic analysis. Additionally, human colonic fibroblasts were exposed to exosomes from CD patients and healthy individuals, with subsequent assessment of fibrogenesis through proteomic and RNA sequencing analyses. RESULTS: Proteomic analyses revealed a significant activation of the TGF-ß signaling pathway in MG-treated mice compared to controls, correlating with enhanced intestinal fibrosis. In vitro experiments demonstrated that colonic fibroblasts exposed to CD patient-derived exosomes exhibited increased fibrogenic activity. Protein docking and co-immunoprecipitation studies suggested a critical interaction between TINAGL1 and SMAD4, enhancing fibrosis. Importantly, in vivo experiments corroborated that recombinant TINAGL1 protein exacerbated DNBS-induced intestinal fibrosis. CONCLUSION: Our findings highlight the pivotal role of MAT-derived exosomes, particularly those carrying TINAGL1, in the progression of intestinal fibrosis in CD. The involvement of the TGF-ß signaling pathway, especially the SMAD4 protein, offers new insights into the molecular mechanisms of CD-related fibrosis and presents potential targets for therapeutic intervention.

Molecular Stratification and Treatment Monitoring of Lung Cancer Using a Small Extracellular Vesicle-Activated Nanocavity Architecture.

Development of molecular diagnostics for lung cancer stratification and monitoring is crucial for the rational planning and timely adjustment of treatments to improve clinical outcomes. In this regard, we propose a nanocavity architecture to sensitively profile the protein signature on small extracellular vesicles (sEVs) to enable accurate, noninvasive staging and treatment monitoring of lung cancer. The nanocavity architecture is formed by molecular recognition through the binding of sEVs with the nanobox-based core-shell surface-enhanced Raman scattering (SERS) barcodes and mirrorlike, asymmetric gold microelectrodes. By imposing an alternating current on the gold microelectrodes, a nanofluidic shear force was stimulated that supported the binding of sEVs and the efficient assembly of the nanoboxes. The binding of sEVs further induced a nanocavity between the nanobox and the gold microelectrode that significantly amplified the electromagnetic field to enable the simultaneous enhancement of Raman signals from four SERS barcodes and generate patient-specific molecular sEV signatures. Importantly, evaluated on a cohort of clinical samples (n = 76) on the nanocavity architecture, the acquired patient-specific sEV molecular signatures achieved accurate identification, stratification, and treatment monitoring of lung cancer patients, highlighting its potential for transition to clinical utility.

Hydrodynamic cultivation of aeration-free oxygenic photogranules is favored by sufficient amounts of organic carbon.

Oxygenic photogranules (OPGs) have great potential for the aeration-free treatment of various wastewater, however, the effects of wastewater carbon composition on OPGs remain unknown. This study investigated the hydrodynamic photogranulation in three types of wastewater with the same total carbon concentration but different inorganic/organic carbon compositions, each operated at two replicated reactors. Results showed that photogranulation failed in reactors fed with only inorganic carbon. In reactors with equal inorganic and organic carbon, loose-structured OPGs formed but then disintegrated. Comparatively, reactors treating organic carbon-based wastewater obtained regular and dense OPGs with better settleability, lower effluent turbidity, excellent structural stability, and higher carbon assimilation rate. Sufficient amounts of organic carbon were crucial for the formation and stability of OPGs as they promoted the secretion of extracellular polymeric substances (EPS) and the growth of filamentous cyanobacteria. This study provides a basis for the startup of OPGs process and facilitates its large-scale application.

High Accuracy of Clinical Verification of Electrohydrodynamic-Driven Nanobox-on-Mirror Platform for Molecular Identification of Respiratory Viruses.

The molecular detection of multiple respiratory viruses provides evidence for the rational use of drugs and effective health management. Herein, we developed and tested the clinical performance of an electrohydrodynamic-driven nanobox-on-mirror platform (E-NoM) for the parallel, accurate, and sensitive detection of four respiratory viral antigens. The E-NoM platform uses gold-silver alloy nanoboxes as the core material with the deposition of a silver layer as a shell on the core surfaces to amplify and enable a reproducible Raman signal readout that facilitates accurate detection. Additionally, the E-NoM platform employs gold microelectrode arrays as the mirror with electrohydrodynamics to manipulate the fluid flow and enhance molecular interactions for an improved biosensing response. The presence of viral antigens binds the nanobox-based core-shell nanostructure on the gold microelectrode and creates the nanocavity with extremely strong "hot spots" to benefit sensitive analysis. Significantly, in a large clinical cohort with 227 patients, the designed E-NoM platform demonstrates the capability of screening respiratory infection with achieved clinical specificity, sensitivity, and accuracy of 100.0, 96.48, and 96.91%, respectively. It is anticipated that the E-NoM platform can find a position in clinical usage for respiratory disease diagnosis.

Chinese parents' intention to vaccinate their 0-5-year-old children with the EV-71 vaccine against hand, foot, and mouth disease and willingness-to-pay.

Background: This study aimed to determine the intention and willingness-to-pay (WTP) of Chinese parents/guardians to vaccinate their children with the EV-71 vaccine. Knowledge levels about hand, foot, and mouth disease (HFMD) and the EV-71 vaccine were also investigated. Methods: A cross-sectional, self-administered online survey was conducted between November 2022 and March 2023. A stratified multi-stage random sampling method was used to recruit parents/guardians of children aged 0-5 years in southeastern China. Results: A total of 3,626 complete responses were received. The mean knowledge score of HFMD was 9.99 (±4.23) out of a total of 14 points. The majority of the participants reported a somewhat willing intent (58.8%), followed by an extremely willing intent (28.9%). Participants who did not consider the EV-71 vaccine expensive (OR = 2.94, 95%CI 2.45-3.53) perceived that the EV-71 vaccine is effective (OR = 2.73, 95%CI 1.52-4.90), and a high knowledge level of HFMD (OR = 1.90, 95%CI 1.57-2.29) had the highest significant odds of having an extremely willing intent to vaccinate their children with the EV-71 vaccine. The median (interquartile range [IQR]) of WTP for the EV-71 vaccine was CNY¥200/USD$28 (IQR CNY¥100-400/USD$14-56). The highest marginal WTP for the vaccine was mainly influenced by the perceived high cost of the vaccine. Those participants who did not consider the EV-71 vaccine expensive had more than 10 times higher odds of vaccinating their children (OR = 10.86, 95%CI 8.49-13.88). Perceived susceptibility, perceived benefits, and perceived barriers were also significant influencing factors in the highest marginal WTP. Conclusion: The findings demonstrate the importance of improving health promotion and reducing the barriers to EV-71 vaccination. Therefore, it is important to improve health promotion and reduce the barriers to EV-71 vaccination.

Augmenting Cancer Therapy with a Supramolecular Immunogenic Cell Death Inducer: A Lysosome-Targeted NIR-Light-Activated Ruthenium(II) Metallacycle.

Though immunogenic cell death (ICD) has garnered significant attention in the realm of anticancer therapies, effectively stimulating strong immune responses with minimal side effects in deep-seated tumors remains challenging. Herein, we introduce a novel self-assembled near-infrared-light-activated ruthenium(II) metallacycle, Ru1105 (λem = 1105 nm), as a first example of a Ru(II) supramolecular ICD inducer. Ru1105 synergistically potentiates immunomodulatory responses and reduces adverse effects in deep-seated tumors through multiple regulated approaches, including NIR-light excitation, increased reactive oxygen species (ROS) generation, selective targeting of tumor cells, precision organelle localization, and improved tumor penetration/retention capabilities. Specifically, Ru1105 demonstrates excellent depth-activated ROS production (∼1 cm), strong resistance to diffusion, and anti-ROS quenching. Moreover, Ru1105 exhibits promising results in cellular uptake and ROS generation in cancer cells and multicellular tumor spheroids. Importantly, Ru1105 induces more efficient ICD in an ultralow dose (10 µM) compared to the conventional anticancer agent, oxaliplatin (300 µM). In vivo experiments further confirm Ru1105's potency as an ICD inducer, eliciting CD8+ T cell responses and depleting Foxp3+ T cells with minimal adverse effects. Our research lays the foundation for the design of secure and exceptionally potent metal-based ICD agents in immunotherapy.

Rationally Designed Benzobisthiadiazole-Based Covalent Organic Framework for High-Performance NIR-II Fluorescence Imaging-Guided Photodynamic Therapy.

Although being applied as photosensitizers for photodynamic therapy, covalent organic frameworks (COFs) fail the precise fluorescence imaging in vivo and phototherapy in deep-tissue, due to short excitation/emission wavelengths. Herein, this work proposes the first example of NIR-II emissive and benzobisthiadiazole-based COF-980. Comparing to its ligands, the structure of COF-980 can more efficiently reducing the energy gap (ΔES1-T1) between the excited state and the triplet state to enhance photodynamic therapy efficiency. Importantly, COF-980 demonstrates high photostability, good anti-diffusion property, superior reactive oxygen species (ROS) generation efficiency, promising imaging ability, and ROS production in deep tissue (≈8 mm). Surprisingly, COF-980 combined with laser irradiation could trigger larger amount of intracellular ROS to high efficiently induce cancer cell death. Notably, COF-980 NPs precisely enable PDT guided by NIR-II fluorescence imaging that effectively inhibit the 4T1 tumor growth with negligible adverse effects. This study provides a universal approach to developing long-wavelength emissive COFs and exploits its applications for biomedicine.

Dysfunction of the triple-network model is associated with cognitive impairment in patients with cerebral small vessel disease.

Purpose: This study aimed to demonstrate the correlations between the altered functional connectivity patterns in the triple-network model and cognitive impairment in patients with cerebral small vascular disease (CSVD). Methods: Resting-state functional magnetic resonance imaging data were obtained from 22 patients with CSVD and 20 healthy controls. The resting-state data were analyzed using independent component analysis and functional network connectivity (FNC) analysis to explore the functional alterations in the intrinsic triple-network model including the salience network (SN), default mode network (DMN), and central executive network (CEN), and their correlations with the cognitive deficits and clinical observations in the patients with CSVD. Results: Compared to the healthy controls, the patients with CSVD exhibited increased connectivity patterns in the CEN-DMN and decreased connectivity patterns in the DMN-SN, CEN-SN, intra-SN, and intra-DMN. Significant negative correlations were detected between the intra-DMN connectivity pattern and the Montreal Cognitive Assessment (MoCA) total scores (r = -0.460, p = 0.048) and MoCA abstraction scores (r = -0.565, p = 0.012), and a positive correlation was determined between the intra-SN connectivity pattern and the MoCA abstraction scores (r = 0.491, p = 0.033). Conclusions: Our study findings suggest that the functional alterations in the triple-network model are associated with the cognitive deficits in patients with CSVD and shed light on the importance of the triple-network model in the pathogenesis of CSVD.

Effects of non-nutritive sweeteners on growth and intestinal health by regulating hypothalamic RNA profile and ileum microbiota in guinea pigs.

BACKGROUND: Non-nutritive sweeteners (NNS) are commonly used in sweetened foods and beverages; however their role in metabolic regulation is still not clear. In this experiment, we used guinea pigs as an animal model to study the effect of NNS on body growth and intestinal health by modifying gut microbiota and hypothalamus-related proteins. RESULTS: For a 28-day feeding experiment a total of 40 guinea pigs were randomly divided into four groups, one control (CN) group and three treatments, in which three NNS were added to the diet: rebaudioside A (RA, 330 mg kg-1), sodium saccharin (SS, 800 mg kg-1), and sucralose (TGS, 167 mg kg-1), respectively. The TGS group exhibited significantly reduced food consumption in comparison with the CN group (P < 0.05) whereas the RA group showed increased food consumption in comparison with the CN group (P < 0.05). Notably, Taste receptor type 1 subunit 2 (T1R2) expression in the hypothalamus was significantly higher in the RA group than in the CN group (P < 0.05). The mRNA expressions of appetite-stimulated genes arouti-related neuropeptide (AGRP), neuropeptide Y (NPY), and thyroid stimulating hormone (TSHB) were significantly higher than those in the CN group (P < 0.05) but mRNA expressions of appetite-suppressed genes tryptophan hydroxylase 2(THP2) were significantly lower in the TGS group (P < 0.05). Furthermore, NNS in the guinea pig diets (RA, SS, TGS) significantly increased the relative abundance of Muribaculaceae but decreased the relative abundance of Clostridia_vadin BB60 in comparison with the CN group (P < 0.05). We also found that dietary supplementation with RA also significantly altered the relative abundance of Lactobacillus. CONCLUSION: Our finding confirmed that dietary supplementation with RA and TGS affected body growth and intestinal health by modulating hypothalamic RNA profiles and ileum microbiota, suggesting that NNS should be included in guinea-pig feeding. © 2024 Society of Chemical Industry.

Agriculture land use transformation: A threat to sustainable food production systems, rural food security, and farmer well-being?

The acquisition of agricultural land is a crucial aspect of survival for numerous rural communities, serving as a fundamental tool for combating poverty and food insecurity and promoting equitable sustainable economic progress. The expropriation of land offers a promising prospect for remedying past inequities and promoting both economic progress and food sufficiency. Limited research has examined the association between land expropriation and food security, livelihood shocks, and the well-being of rural households worldwide. Therefore, this research explores the implications of land expropriation on food security, livelihood shocks, and well-being of land lost rural communities. The data were collected from 384 farmers selected through stratified sampling techniques using face-to-face surveys in rural China. The data were analyzed using descriptive and logit regression models. The descriptive findings showed that land expropriation has detrimental effects on the livelihood, food security, and well-being of the farmers. Furthermore, these impacts are more harmful among land-expropriated households with a lower educational level, a large family size, and women farmers in less developed rural communities. The econometric results evinced that gender, age, education level, marital status, family size, and negative changes in income all significantly affect the impact of land expropriation on the food security of farmers. Similarly, the findings revealed that farmers with lower education levels were more likely to be affected by land loss as compared to farmers with medium and high education levels. Farmers with complete land loss were 1.70 times more likely to suffer livelihood shocks than those with partial land loss. The results also evinced that the well-being of all farmers was not affected equally, and some farmers' well-being was affected more than others due to various socioeconomic backgrounds. Therefore, this study suggests the implementation of public policies that provide support to farmers who have been marginalized due to land acquisition.

Bioengineered Neutrophils for Smart Response in Brain Infection Management.

Brain infections, frequently accompanied by significant inflammation, necessitate comprehensive therapeutic approaches targeting both infections and associated inflammation. A major impediment to such combined treatment is the blood-brain barrier (BBB), which significantly restricts therapeutic agents from achieving effective concentrations within the central nervous system. Here, a neutrophil-centric dual-responsive delivery system, coined "CellUs," is pioneered. This system is characterized by live neutrophils enveloping liposomes of dexamethasone, ceftriaxone, and oxygen-saturated perfluorocarbon (Lipo@D/C/P). CellUs is meticulously engineered to co-deliver antibiotics, anti-inflammatory agents, and oxygen, embodying a comprehensive strategy against brain infections. CellUs leverages the intrinsic abilities of neutrophils to navigate through BBB, accurately target infection sites, and synchronize the release of Lipo@D/C/P with local inflammatory signals. Notably, the incorporation of ultrasound-responsive perfluorocarbon within Lipo@D/C/P ensures the on-demand release of therapeutic agents at the afflicted regions. CellUs shows considerable promise in treating Staphylococcus aureus infections in mice with meningitis, particularly when combined with ultrasound treatments. It effectively penetrates BBB, significantly eliminates bacteria, reduces inflammation, and delivers oxygen to the affected brain tissue, resulting in a substantial improvement in survival rates. Consequently, CellUs harnesses the natural chemotactic properties of neutrophils and offers an innovative pathway to improve treatment effectiveness while minimizing adverse effects.

A selenium-based NIR-II photosensitizer for a highly effective and safe phototherapy plan.

High efficiency, stability, long emission wavelength (NIR-II), and good biocompatibility are crucial for photosensitizers in phototherapy. However, current Food and Drug Administration (FDA)-approved organic fluorophores exhibit poor chemical stability and photostability as well as short emission wavelength, limiting their clinical usage. To address this, we developed Se-IR1100, a novel organic photosensitizer with a photostable and thermostable benzobisthiadiazole (BBTD) backbone. By incorporating selenium as a heavy atom and constructing a D-A-D structure, Se-IR1100 exhibits a maximum fluorescence emission wavelength of 1100 nm. Compared with FDA-approved indocyanine green (ICG), DSPE-PEGylated Se-IR1100 nanoparticles exhibit prominent photostability and long-lasting photothermal effects. Upon 808 nm laser irradiation, Se-IR1100 NPs efficiently convert light energy into heat and reactive oxygen species (ROS), inducing cancer cell death in cellular studies and living organisms while maintaining biocompatibility. With salient photostability and a photothermal conversion rate of 55.37%, Se-IR1100 NPs hold promise as a superior photosensitizer for diagnostic and therapeutic agents in oncology. Overall, we have designed and optimized a multifunctional photosensitizer Se-IR1100 with good biocompatibility that performs NIR-II fluorescence imaging and phototherapy. This dual-strategy method may offer novel approaches for the development of multifunctional probes using dual-strategy or even multi-strategy methods in bioimaging, disease diagnosis, and therapy.

Abnormal causal connectivity of anterior cingulate cortex-visual cortex circuit related to nonsteroidal anti-inflammatory drug efficacy in migraine.

The anterior cingulate cortex (ACC) and visual cortex are integral components of the neurophysiological mechanisms underlying migraine, yet the impact of altered connectivity patterns between these regions on migraine treatment remains unknown. To elucidate this issue, we investigated the abnormal causal connectivity between the ACC and visual cortex in patients with migraine without aura (MwoA), based on the resting-state functional magnetic resonance imaging data, and its predictive ability for the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs). The results revealed increased causal connectivity from the bilateral ACC to the lingual gyrus (LG) and decreased connectivity in the opposite direction in nonresponders compared with the responders. Moreover, compared with the healthy controls, nonresponders exhibited heightened causal connectivity from the ACC to the LG, right inferior occipital gyrus (IOG) and left superior occipital gyrus, while connectivity patterns from the LG and right IOG to the ACC were diminished. Based on the observed abnormal connectivity patterns, the support vector machine (SVM) models showed that the area under the receiver operator characteristic curves for the ACC to LG, LG to ACC and bidirectional models were 0.857, 0.898, and 0.939, respectively. These findings indicate that neuroimaging markers of abnormal causal connectivity in the ACC-visual cortex circuit may facilitate clinical decision-making regarding NSAIDs administration for migraine management.

Chronic gastritis may predict risk of cerebral small vessel disease.

BACKGROUND AND PURPOSE: Chronic gastritis, especially that caused by helicobacter pylori (HP) infection, has been associated with increased risk of ischemic stroke. But the relationship between chronic gastritis and cerebral small vessel disease (CSVD) remains largely undetermined. This study aimed to determine the potential predictors for CSVD, with chronic gastritis and its proxies as alternatives. METHOD: Patients aged 18 years or older with indications for electronic gastroscopy were enrolled. Presence of CSVD was evaluated with brain magnetic resonance imaging (MRI) results. Degree of CSVD was scored according to established criteria. Logistic regression analysis was used for identifying possible risk factors for CSVD. RESULTS: Of the 1191 enrolled patients, 757 (63.6%) were identified as with, and 434 (36.4%) as without CSVD. Multivariate analysis indicated that patients with chronic atrophic gastritis had an increased risk for CSVD than those without (adjusted odds ratio = 1.58; 95% CI, 1.08-2.32; P < 0.05). CONCLUSIONS: Chronic atrophic gastritis is associated with the presence of CSVD. We should routinely screen the presence of CSVD for patients with chronic atrophic gastritis.

HDL-C/LDL-C and Risk of Cerebral White Matter Hyperintensities: A Cross-Sectional Study.

Background and Purpose: At present, there is still a lack of metabolic indices to predict white matter hyperintensities. This study aimed to explore the correlations of the high-density lipoprotein cholesterol (HDL-C)/low-density lipoprotein cholesterol (LDL-C) ratio with the risk of white matter hyperintensities. Methods: Hospitalized patients who underwent inpatient treatment or physical examination due to various chronic diseases between January 18, 2018, and March 20, 2023, were enrolled. Fazekas scores were used to assess the severity of white matter hyperintensities. Logistic regression analysis was used to adjust for possible confounders. Results: Of the 1162 enrolled patients, 770 (66.27%) patients were classified as having no or mild WMHs, and 392 (33.73%) were classified as having moderate or severe WMHs. After adjusting for covariates, the logistic regression analysis indicated that the ratio of HDL-C to LDL-C was related to the severity of WMHs (Model 1, OR = 0.23, 95% CI: 0.07-0.73, P=0.012; Model 2, OR = 2.03, 95% CI: 1.12-3.67, P=0.019). Conclusion: Our findings suggest that the ratio of HDL-C to LDL-C is related to the severity of WMHs and that a high ratio of HDL-C to LDL-C is a protective factor against WMHs. This suggests that the ratio of HDL-C to LDL-C could be used as a metabolic prediction index of WMH severity.

Can Patients with Asymptomatic/Mild Illness and Moderate Illness COVID-19 Have White Matter Damage?

Background and Purpose: Studies have shown that severe coronavirus pandemic 2019 infection could lead to white matter hyperintensities, but the relationship between asymptomatic/mild illness and moderate illness coronavirus pandemic 2019 and white matter hyperintensities remains largely unknown. This study aimed to investigate the relationship between asymptomatic/mild illness and moderate illness coronavirus pandemic 2019 and the risk of white matter hyperintensities. Methods: Hospitalized patients who were confirmed to have coronavirus pandemic 2019 for the first time were enrolled. Fazekas scores were used for assessment of the severity of white matter hyperintensities. We also rated the 90-day functional outcome after discharge. Results: Of the 157 enrolled patients, 124 (78.98%) coronavirus pandemic 2019 patients were classified as having asymptomatic or mild illness, and 33 (21.02%) were classified as having moderate illness. The results showed that the Fazekas scale scores at baseline (periventricular white matter hyperintensities, 1.31±1.16 vs 2.06±1.20; Deep white matter hyperintensities, 1.04±0.97 vs 1.73±1.13 P <0.01) and at follow-up (periventricular white matter hyperintensities, 1.38±1.21 vs 2.09±1.21; Deep white matter hyperintensities, 1.13±1.04 vs 1.79±1.14 P <0.01) were lower in patients with symptomatic or mild illness than in those with moderate illness. Moreover, no significant difference (7.26% vs 3.03%; P =0.377) was observed between the two divided groups in terms of white matter hyperintensities progression. Conclusion: Our findings suggest that moderate COVID-19 is related to severe white matter hyperintensities compared with asymptomatic/mild illness but not to the progression of white matter hyperintensities.

Predicting the efficacy of non-steroidal anti-inflammatory drugs in migraine using deep learning and three-dimensional T1-weighted images.

Deep learning (DL) models based on individual images could contribute to tailored therapies and personalized treatment strategies. We aimed to construct a DL model using individual 3D structural images for predicting the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in migraine. A 3D convolutional neural network model was constructed, with ResNet18 as the classification backbone, to link structural images to predict the efficacy of NSAIDs. In total, 111 patients were included and allocated to the training and testing sets in a 4:1 ratio. The prediction accuracies of the ResNet34, ResNet50, ResNeXt50, DenseNet121, and 3D ResNet18 models were 0.65, 0.74, 0.65, 0.70, and 0.78, respectively. This model, based on individual 3D structural images, demonstrated better predictive performance in comparison to conventional models. Our study highlights the feasibility of the DL algorithm based on brain structural images and suggests that it can be applied to predict the efficacy of NSAIDs in migraine treatment.

Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. METHODS: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1's role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1's regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. RESULTS: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. CONCLUSIONS: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation.

An updated review of gastrointestinal toxicity induced by PD-1 inhibitors: from mechanisms to management.

PD-1 inhibitors, as one of commonly used immune checkpoint inhibitors, enable T-cell activation and prevent immune escape by blocking the PD-1/PD-L1 signaling pathway. They have transformed the treatment landscape for cancer in recent years, due to the advantages of significantly prolonging patients' survival and improving their life quality. However, the ensuing unpredictable immune-related adverse effects (irAEs) plague clinicians, such as colitis and even potentially fatal events like intestinal perforation and obstruction. Therefore, understanding the clinical manifestations and grading criteria, underlying mechanisms, available diverse therapies, accessible biomarkers, and basis for risk stratification is of great importance for the management. Current evidence suggests that irAEs may be a marker of clinical benefit to immunotherapy in patients, so whether to discontinue PD-1 inhibitors after the onset of irAEs and rechallenge after remission of irAEs requires further evaluation of potential risk-reward ratios as well as more data from large-scale prospective studies to fully validate. At the end, the rare gastrointestinal toxicity events caused by PD-1 inhibitors are also sorted out. This review provides a summary of available data on the gastrointestinal toxicity profile caused by PD-1 inhibitors, with the aim of raising clinicians' awareness in daily practice, so that patients can safely benefit from therapy.

Durable cellulose paper by grafting thiol groups and controlling silver deposition for ultrahigh electromagnetic interference shielding.

Electromagnetic interference (EMI) shielding paper with durability and high effectiveness is of significant importance to long-term service for preventing EMI pollution. Herein, we report a practical method for preparing cellulose paper/Ag composite with outstanding durable and ultrahigh EMI shielding performance by electroless silver plating. The silver deposition process, the surface morphology, the silver content and conductivity of the composite can be controlled by varying the amount of N-acetyl-L-cysteine (NAC) grafted onto the cellulose fibers and ammonia amount for silver-ammonia complex formation. Moreover, the grafted NAC with thiol groups on cellulose can enhance the adhesion between silver and cellulose paper, meanwhile, NAC as the reducing agent can result in a more complete flower-shaped silver structure and reducing the reflection of electromagnetic waves in silver layer. The composite exhibited excellent conductivity, EMI shielding effectiveness (SE) up to 106 dB and outstanding durability. After 10,000 bending times and 60 abrasion cycles respectively, the electrical resistance of the composite only increased from 0.030 Ω/sq. to 0.041 Ω/sq. and 0.050 Ω/sq., and the EMI SE decreased to 102 dB and 105 dB.