Concurrent dysregulation of COX-2 and soluble epoxide hydrolase (sEH) disrupts arachidonic acid homeostasis to drive macrophage activation in inflammatory bowel disease (IBD). Here, we identify tetrandrine (TET), a bisbenzylisoquinoline alkaloid from Stephania tetrandra S. Moore, as a novel dual inhibitor of COX-2 and sEH. In vivo, TET significantly attenuated DSS-induced UC in mice, reversing weight loss, elevated disease activity index, colonic shortening, and histological lesions. TET restored intestinal integrity via downregulating serum pro-inflammatory cytokines (IL-1β, IL-18, and TNF-α), reducing epithelial cell apoptosis and upregulating tight junction proteins. Peptide-centric local stability assay (PELSA) and cellular thermal shift assay (CETSA) identified COX-2 and sEH as direct targets of TET. Mechanistically, TET directly bound to both enzymes with moderate inhibitory activities (IC~50~ = 13.19 and 11.27 μmol/L, respectively). Notably, TET induced ubiquitin-mediated proteasomal degradation of both COX-2 and sEH, while genetic knockout of sEH significantly abrogated the protective effects of TET. Additionally, TET modulated gut microbiota composition, increasing beneficial bacteria including Lachnospiraceae_NK4A136 and Turicibacter. TET demonstrated no detectable toxicity at therapeutic doses and showed superior efficacy compared to sulfasalazine. Collectively, these findings support the therapeutic potential of S. tetrandra-derived alkaloids for IBD treatment through regulation of arachidonic acid metabolism.

Cells die extensively each day under physiological and pathological conditions, yet dying cells and cell corpses are not merely passive endpoints. Increasing evidence shows that they actively shape their microenvironment during death-program execution, signal release or exposure, corpse processing, and responses of neighboring cells and phagocytes. We here summarize six major roles of dying cells and cell corpses: promoting tissue turnover and remodeling, supporting neighboring-cell survival, mediating intercellular communication, providing metabolic substrates and rewiring phagocyte metabolism, facilitating corpse recognition and clearance, and modulating immune responses. Overall, they provide a broader framework for understanding cell death and identifying therapeutic opportunities.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation, epithelial barrier disruption and immune dysfunction. Alleviating and curing these pathological manifestations is the goal of IBD treatment. Despite substantial advances in targeted immunotherapies and anti-inflammatory strategies, achieving sustained intestinal mucosal healing remains a major clinical challenge. Dynamin-related protein 1 (Drp1) is a GTPase that mediates mitochondrial fission and plays a crucial role in maintaining the dynamic balance of mitochondrial morphology and function. In IBD, Drp1 expression is frequently upregulated and continuously activated, resulting in excessive fission and fragmentation of mitochondria. This mitochondrial dysregulation contributes to ATP depletion and excessive reactive oxygen species (ROS) production, thereby exacerbating disease progression and amplifying inflammatory signaling. This review highlights the distinctive role of Drp1 as an integrative node in IBD. Specifically, we connect mitochondrial dynamics with epithelial barrier failure, immune dysregulation, inflammatory cell death, and intestinal microenvironment remodeling. We further emphasize the potential relevance of Drp1 for biomarker-based patient stratification and mechanism-informed therapeutic targeting, thereby distinguishing this review from more descriptive accounts of mitochondrial dysfunction in intestinal inflammation.

The management of inflammatory bowel disease (IBD), which is characterized by immunodeficiency, has attracted increasing attention, highlighting the necessity for more precise and streamlined diagnostic approaches in clinics. Calprotectin, an immune cell-derived protein with inherent anti-inflammatory and antimicrobial properties, plays a pivotal role in immune regulation and intestinal homeostasis. Its expression levels are intricately linked to IBD activity, enabling differentiation between inflammatory and non-inflammatory states while predicting recurrence risks. As a non-invasive biomarker, fecal calprotectin (FC) and serum calprotectin (SC) analysis offers high reproducibility and clinical utility, facilitating both IBD diagnosis and real-time disease monitoring. Beyond its diagnostic specificity in distinguishing IBD from other gastrointestinal disorders, calprotectin also emerges as a promising therapeutic target, due to its dual role in modulating inflammatory pathways and interacting with the gut microbiota. With collaborative advancements in standardized detection protocols and innovative research methodologies, it is anticipated that calprotectin-based strategies will be integrated into mainstream clinical practice for IBD.

BACKGROUND:Cam morphology is associated with acetabular cartilage lesions and early-onset osteoarthritis in patients with femoroacetabular impingement syndrome. Here, we propose a novel iterative rabbit model of cam morphology to characterize the pathophysiology of femoroacetabular impingement-related cartilage lesions. METHODS:We described a repeatable method for establishing a New Zealand white rabbit model of cam morphology by interfering with the epiphyseal tubercle and evaluated the histological outcomes of acetabular cartilage lesions. Cam morphology and subchondral bone were evaluated by micro-CT scanning. The expression of anabolic and catabolic biomarkers of acetabular cartilage was investigated via western blotting and immunohistochemical staining. Chondrocyte apoptosis was detected via TUNEL staining. Kinematics of the hip joint in the sagittal plane were evaluated by a passive optical motion capture system. RESULTS:There were remarkable pathological similarities between this model and human diseases. The cam morphology rabbit model exhibited early cartilage degeneration and subsequent phenotypes of hip osteoarthritis, and this pathological process is not affected by surgical trauma. Hip motion in the cam morphology models resembled that in the healthy controls, and had only a slightly lower joint angle at all phases of the half-bounding gait cycle. This model preserved the natural and predictable movement pattern. CONCLUSIONS:This rabbit model of cam morphology replicates the disease phenotype and allows for scientifically sound evaluation of disease mechanisms. It can be employed to study human cam-type femoroacetabular impingement syndrome.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC50 = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Hispidulin, a dietary flavonoid occurring naturally in brown algae, has attracted considerable interest owing to its functions in modulating inflammatory responses and neutralizing reactive oxygen species. This study examined the consequences of hispidulin in a chemically induced acute colitis model. RNA sequencing (RNA_seq), 16s rRNA_seq, and non-targeted metabolomics were conducted to determine the mechanisms underlying hispidulin-induced effects on colitis. The findings revealed that hispidulin exhibited significant therapeutic benefits against colitis. In addition, treatment with hispidulin led to a decrease in pro-inflammatory cytokine levels as well as serum FITC-dextran concentrations. RNA_seq analysis demonstrated a notable increase in colonic ACAT2 expression in mice with colitis following hispidulin treatment. Furthermore, hispidulin administration resulted in the upregulation of GPX4, a reduction in ROS levels, and inhibition of epithelial ferroptosis in mice with colitis. Both genetic inhibition of ACAT2 in vitro and AAV-mediated knockdown of ACAT2 in vivo substantially negated the effects of hispidulin on GPX4/GSH levels, ROS levels, and lipid hydroperoxide accumulation in both NCM460 cells and epithelial cells derived from DSS exposed murine models. 16s rRNA_seq results showed that hispidulin increased the abundance of Lactobacillus, NK4A136_group, Oscillibacter, Peptococcus, and Adlercreutzia and decreased the abundance of Turicimonas in colitic mice. Non-targeted metabolomics results showed that hispidulin facilitated the metabolism of galactose and promoted unsaturated fatty acid biosynthesis in colitic mice. In summary, hispidulin reduced the advancement of acute colitis in mice by reducing ACAT2-mediated ferroptosis in epithelial cells, as well as altering the composition of the gut microbiota.

As life expectancy rises and the aging population grows, Alzheimer’s disease (AD) has become a significant global health concern. AD is a complex neurodegenerative disorder with an unclear etiology. Current hypotheses primarily focus on β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, and neuroinflammation as key pathological processes. Given the limited efficacy of existing therapeutic strategies, there is an urgent need to explore novel treatment options. Marine natural products have garnered significant attention due to their unique chemical structures and diverse bioactivities, demonstrating potential for multi-target interventions in AD. This review systematically summarizes the roles of marine-derived compounds, including polysaccharides, carotenoids, and polyphenols, in modulating Aβ aggregation, mitigating tau protein pathology, and regulating gut–brain axis dysfunction. Furthermore, the challenges of current research are discussed, with an emphasis on improving blood–brain barrier permeability and optimizing drug delivery systems to facilitate clinical translation.

British Journal of PharmacologyEarly View LETTER TO THE EDITOR Commentary on: Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury Wenfu Cao, Wenfu Cao Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Contribution: Writing - original draft (equal), Writing - review & editing (equal)Search for more papers by this authorXinrui Guo, Xinrui Guo Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Contribution: Writing - original draft (equal)Search for more papers by this authorXinyu Li, Xinyu Li Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Contribution: Writing - original draft (equal)Search for more papers by this authorDapeng Chen, Corresponding Author Dapeng Chen [email protected] orcid.org/0000-0001-9838-1646 Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Correspondence Dapeng Chen, Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian 116044, Liaoning Province, China. Email: [email protected] Contribution: Conceptualization (lead), Supervision (lead), Writing - review & editing (equal)Search for more papers by this author Wenfu Cao, Wenfu Cao Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Contribution: Writing - original draft (equal), Writing - review & editing (equal)Search for more papers by this authorXinrui Guo, Xinrui Guo Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Contribution: Writing - original draft (equal)Search for more papers by this authorXinyu Li, Xinyu Li Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Contribution: Writing - original draft (equal)Search for more papers by this authorDapeng Chen, Corresponding Author Dapeng Chen [email protected] orcid.org/0000-0001-9838-1646 Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning Province, China Correspondence Dapeng Chen, Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian 116044, Liaoning Province, China. Email: [email protected] Contribution: Conceptualization (lead), Supervision (lead), Writing - review & editing (equal)Search for more papers by this author First published: 06 May 2024 https://doi.org/10.1111/bph.16418Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES Degen, M., Santos, J. C., Pluhackova, K., Cebrero, G., Ramos, S., Jankevicius, G., Hartenian, E., Guillerm, U., Mari, S. A., Kohl, B., Müller, D. J., Schanda, P., Maier, T., Perez, C., Sieben, C., Broz, P., & Hiller, S. (2023). Structural basis of NINJ1-mediated plasma membrane rupture in cell death. Nature, 618(7967), 1065–1071. https://doi.org/10.1038/s41586-023-05991-z 10.1038/s41586-023-05991-z CASPubMedWeb of Science®Google Scholar Dong, T., Fan, X., Zheng, N., Yan, K., Hou, T., Peng, L., & Ci, X. (2023). Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury. British Journal of Pharmacology, 180(19), 2532–2549. https://doi.org/10.1111/bph.16085 10.1111/bph.16085 CASPubMedWeb of Science®Google Scholar Kayagaki, N., Stowe, I. B., Alegre, K., Deshpande, I., Wu, S., Lin, Z., Kornfeld, O. S., Lee, B. L., Zhang, J., Liu, J., Suto, E., Lee, W. P., Schneider, K., Lin, W. Y., Seshasayee, D., Bhangale, T., Chalouni, C., Johnson, M. C., Joshi, P., … Dixit, V. M. (2023). Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury. Nature, 618(7967), 1072–1077. https://doi.org/10.1038/s41586-023-06191-5 10.1038/s41586-023-06191-5 CASPubMedGoogle Scholar Whisstock, J. C., & Law, R. H. P. (2023). The role of NINJ1 protein in programmed cellular destruction. Nature, 618(7967), 912–914. https://doi.org/10.1038/d41586-023-01602-z 10.1038/d41586-023-01602-z CASPubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

BackgroundRegulatory T (Treg) cells is required to dampen immune responses against intestinal microbiota, which aid in a healthy body to promise that the resident gut microbiota should not attract the attention of the immune system. Inflammation and inflammatory bowel disease (IBD) can be induced if the immune system fails to ignore the resident gut microbiota and targets them instead. D-mannose, a common monosaccharide in nature, has been shown to ameliorate multiple autoimmune diseases. This study aimed to investigate the therapeutic effect of D-mannose on mice ulcerative colitis (UC) induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS), and elucidate its underlying mechanisms.MethodsTo simulate human IBD, we constructed a mouse model of UC by injecting TNBS into the colon.ResultsOur results demonstrated that D-mannose treatment effectively alleviated TNBS-induced UC in mice, as evidenced by the amelioration of UC symptoms. D-mannose treatment significantly reduced inflammation by decreasing the expression of proinflammatory cytokines and inflammation mediators. D-mannose treatment also significantly inhibited oxidative stress, promoted the expression of GSH and SOD, decreased the expression of MDA. Mechanistically, D-mannose upregulated the proportion of both CD4(+) Tregs and CD8(+) Tregs.ConclusionIn summary, our study provides the first evidence of the therapeutic effect of D-mannose on mice with UC, which is likely mediated by upregulating Treg proportions.

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg−1·d−1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1β. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1β, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

Inhibition of epithelial ferroptosis in colonic tissues relieved clinical symptoms and improved endoscopic presentations in inflammatory bowel disease (IBD). Kumatakenin, the main ingredient of traditional Chinese medicinal cloves and Alpinia purpurata, is reported to possess therapeutic benefits. However, whether kumatakenin could inhibit ferroptosis and further alleviate colitis remains unclear. Here, we measured the effects of kumatakenin on ferroptosis of colonic epithelial cells from colitis mice. The colitis model was induced in mice by oral intake of 2.5% dextran sulfate sodium in drinking water. RNA sequencing was performed to investigate the mechanism underlying kumatakenin-mediated effects on colitis. The results showed that different doses of kumatakenin significantly alleviated symptoms and suppressed intestinal inflammation in the colitis mouse model. Kumatakenin supplementation decreased cellular iron levels and suppressed ferroptosis in epithelial cells from colitis mice. RNA sequencing, qPCR, and pharmacological inhibition assays showed that kumatakenin reduced cellular iron levels and suppressed ferroptosis in epithelial cells from colitis mice at least partially by upregulating expression of enolase (Eno-3). Furthermore, kumatakenin decreased iron levels in epithelial cells by modulating the Eno3-iron regulatory protein (IRP1) axis. Molecular docking results revealed that kumatakenin could bind Eno3 via hydrogen bonding with the amino acid residues Thr208, Val206, and Pro203. This work will provide a scientific basis for the clinical use of kumatakenin in the treatment of colitis.

Carbon dots (CDs) or CDs/polymer composites have been applied in numerous fields. Here, novel CDs were synthesized by carbonization of egg yolk, and characterized by TEM, FTIR, XPS and photoluminescence spectra. The CDs were found to be approximate sphere in shape with an average size of 4.46 ± 1.17 nm, and emitted bright blue photoluminescence under UV irradiation. The photoluminescence of CDs was found selectively quenched by Fe3+ in a linear manner in the range of 0.05–0.45 mM, meaning they could be applied for Fe3+ detection in solution. Moreover, the CDs could be uptaken by HepG2 cells to exhibit bright blue photoluminescence. The intensity could reflect the level of intracellular Fe3+, indicating they could be further used for cell imaging and intracellular Fe3+ monitoring. Next, dopamine was polymerized on the surface of CDs to obtain the polydopamine (PDA)-coated CDs (CDs@PDA). We found PDA coating could quench the photoluminescence of CDs via inner filter effect, and the degree of quenching was linearly related to the logarithm of DA concentration (Log CDA). Also, the selectivity experiment indicated the method had a high selectivity for DA over a number of possible interfering species. This indicated the CDs in combination with Tris buffer could be potentially applied as the assay kit of dopamine. At last, the CDs@PDA exhibited excellent photothermal conversion capability, and they could efficiently kill HepG2 cells under NIR laser irradiation. Overall, the CDs and CDs@PDA in this work exhibited many excellent advantages, and could be potentially used for multi-applications, such as Fe3+ sensor in solution and cellular, cell imaging, dopamine assay kit, as well as photothermal agents for cancer therapy.

To the Editor: Colorectal cancer is one of the most common cancers worldwide, and chronic inflammation caused by colitis, especially ulcerative colitis, increases the risk of colorectal cancer. Compared with sporadic colorectal cancer whose hallmark is constitutive activation of Wingless/β-catenin signaling and the adenoma-carcinoma sequence, p53 and K-ras mutations, which occur earlier, adenomatous polyposis coli occurs later during the progression of colitis-associated colorectal cancer (CAC). Surgery and chemotherapy are the preferred treatments of CAC, but long-term use of first-line chemotherapy agents such as 5-fluorouracil or irinotecan is limited by drug resistance or adverse reactions. Therefore, it is necessary for us to identify "green" drugs. Traditional Chinese medicines (TCMs) are complex and diverse and are found in nature. The anti-inflammatory, antibacterial, antiviral, antioxidant, antitumor, antiradiation, and immunomodulatory activity of TCMs have been extensively studied. TCMs are more able than synthesized drugs to prevent inflammation from progressing to cancer. This review summarizes the advantages of TCMs for treating CAC. With increase of the severity of the inflammation, the risk of cancer development increases. Nuclear factor kappa-B (NF-κB), P53, and the cyclooxygenase-2/prostaglandin E2 signaling pathways are known to be involved in the pathogenesis of CAC. Accumulation of reactive oxygen species causes oxidative stress and destroys DNA, proteins, and lipids, leading to tumors. Most TCMs have anti-inflammatory activity that participates in the prevention or treatment of CAC. Wogonoside administration leads to the return of downstream inflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels close to normal. Wogonoside also reduces neutrophil and macrophage infiltration in CAC.[1] Betaine administration inhibited inflammatory-related cytokines such as TNF-α, IL-6, inducible nitric oxide (NO) synthase, reactive oxygen species, and cyclooxygenase-2. Apple polysaccharide extract is effective as chemoprevention by inhibiting NF-κB-mediated inflammation pathways in colorectal cancer. Inhibition of inflammation in cancer may be key in treating CAC with TCMs. Activation of NF-κB and its signal pathways regulate cell proliferation and apoptosis by up-regulating the expression of cyclins and Bcl-2 family members. Honokiol, a biphenolic compound found in Magnolia grandiflora, induces ferroptosis in colon cancer cells by reducing glutathione peroxidase 4 activity. An ethanol extract of Aster glehni, reduced nuclear factor NF-κB activation by phosphorylation and degradation of inhibitor of kappa Bα, leading to inhibition of NF-κB p65 nuclear translocation. The evidence indicated that A. glehni may have promise as a protective agent against CAC by suppression of the NF-κB signaling pathway. Oral administration of an ethanol extract of Tuber aestivum sprouts significantly decreased the expression of the β-catenin-related cyclin D1 and c-Myc genes in colon tissue from mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC. Low-dose bufalin effectively suppressed tumorigenesis in colorectal cancer models, accompanied by attenuated epithelial cell proliferation (i.e., lower cyclin A, cyclin D1, and cyclin E levels, and higher p21 and p27 levels) and promoted apoptosis (i.e., lower Bcl-2, Bcl-xL, and survivin levels, and higher Bax and Bak levels).[2] TCMs such as wogonoside and Rhizopus nigricans may have superior effectiveness against CAC because they inhibit cell proliferation and promote apoptosis. The host intestinal immune system restrains bacteria, and under normal conditions limits the entry of bacteria into the intestinal epithelium. The gut microbiota interacts with immune cells in the intestinal mucosa to promote the development and maintenance of the immune system. Microbial overstimulation may lead to inappropriate activation of intestinal immune cells and the development of intestinal inflammation. In an AOM/DSS-induced CAC mouse model, the probiotics Alloprevotella, Bacteroides, and Lactobacillus were decreased and the pathogenic bacteria Muribaculaceae, Proteobacteria, Citrobacter, Akkermansia, and Klebsiella were increased. The imbalance led to inflammation and weakening of intestinal barrier function.[3] Enriching probiotics and reducing the abundance of pathogenic bacteria are considered to be useful in the treatment of CAC. For example, isoliquiritigenin reduces the abundance of genera including Escherichia and Enterococcus, which are opportunistic pathogens and increased the levels of probiotics like Butyricicoccus, Clostridium, and Ruminococcus to protect mice from AOM/DSS-induced CAC.[4]Lactobacillus bulgaricus is a widely used probiotic bacterium, was found to inhibit tumor progression and intestinal inflammation in an AOM/DSS-induced CAC mouse model, with reduction of IL-6, TNF-α, IL-17, IL-23, and IL-1β. Recent studies have identified potentially effective CAC treatments that act by improving the intestinal microenvironment, including antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. TNF-α induces a variety of cellular responses by interacting with transmembrane receptors. TNF-α antagonists inhibit CAC growth in AOM/DSS-treated mice. The IL-23/T-helper 17 pathway is involved in the pathophysiology of CAC. Previous studies have shown reduced tumor development in AOM/DSS-treated IL-17A-deficient mice with CAC. The IL-6/IL-6R axis is active in immune cell recruitment and T cell survival and differentiation. Silibinin, dietary cocoa, and Rhizoma Paridis total saponins protected against CAC in mice by inhibiting the IL-6/signal transducer and activator of the transcription 3 protein signaling pathway. Synergistic combinations of TCMs with chemotherapy agents are seen as promising methods to treat CAC by overcoming the weaknesses of single-target drugs.[5] Curcumin combined with resveratrol inhibited the growth of CAC cells more strongly than either agent alone, which was attributed to the enhancement of anti-proliferation and pro-apoptosis activity. Other studies investigated the effects of TCMs as modulators for chemotherapy. Ursolic acid, a pentacyclic triterpenoid found in holy basil, was found to enhance the anticancer effects of capecitabine through inhibition of NF-κB. Curcumin combined with FOLFOX had superior anticancer effectiveness by downregulating epidermal growth factor receptors and insulin-like growth factor-1R signaling. Recent advances in TCMs-induced prevention and therapy of CAC are discussed here and the comprehensive information are shown in Supplementary Table 1, https://links.lww.com/CM9/B515.We aimed to supply new approaches in CAC treatment using TCMs, and TCMs can block the progress from inflammation to cancer, not only inhibits cancer cell growth. This correspondence may uncover the tip of the iceberg of mechanisms underlying TCMs for treating CAC that have not been extensively studied. The huge potential of TCMs may provide new insights into drug design and CAC therapy, especially in preventing the progression from inflammation to cancer. Funding This work was supported by the Basic Scientific research Project of the Liaoning Province Education Department (Grant No. LJKZ0832). Conflicts of interest None.

Background The APLAID syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the PLCG2 gene. We present a 7-year-old APLAID patient who has recurrent blistering skin lesions, skin infections in the perineum, a rectal perineal fistula, and inflammatory bowel disease. Methods To determine the genetic cause of our patient, WES and bioinformatics analysis were performed. Flow cytometry was used for phenotyping immune cell populations in peripheral blood. Cytokines released into plasma were analyzed using protein chip technology. The PBMCs of patient and a healthy child were subjected to single-cell RNA-sequencing analysis. Results The patient carried a novel de novo missense mutation c.2534T>C in exon 24 of the PLCG2 gene that causes a leucine to serine amino acid substitution (p.Leu845Ser). Bioinformatics analysis revealed that this mutation had a negative impact on the structure of the PLCγ2 protein, which is highly conserved in many other species. Immunophenotyping by flow cytometry revealed that in addition to the typical decrease in circulating memory B cells, the levels of myeloid dendritic cells (mDCs) in the children’s peripheral blood were significantly lower, as were the CD4+ effector T cells induced by their activation. Single-cell sequencing revealed that the proportion of different types of cells in the peripheral blood of the APLAID patient changed. Conclusions We present the first case of APLAID with severely reduced myeloid dendritic cells carrying a novel PLCG2 mutation, and conducted a comprehensive analysis of immunological features in the ALPAID patient, which has not been mentioned in previous reports. This study expands the spectrum of APLAID-associated immunophenotype and genotype. The detailed immune analyses in this patient may provide a basis for the development of targeted therapies for this severe autoinflammatory disease.

The sustained activation of the nuclear factor κB (NF-κB) signaling pathway has been observed in human inflammatory bowel disease (IBD). Ophiopogonin D (OP-D) is a small molecular compound isolated from Ophiopogon japonicus, a widely used herbal remedy. In this study, dextran sodium sulfate was used to make a mouse model of experimental colitis and verify the effect of OP-D on the mouse model of experimental colitis. Small molecule-protein molecular docking approaches were also used to discover the mechanisms underlying the OP-D-induced regulation of colitis. In colitis, the OP-D can inhibit the apoptosis of intestinal mucosa cells, restore the intestinal barrier, and alleviate inflammation. The molecular docking simulations showed that OP-D had a high affinity with the REL-homology domain of NF-κB-p65 that affected its translocation to the nucleus. In a cell study, the effects of OP-D on inflammation and barrier dysfunction were significantly decreased by a small interfering RNA targeting NF-κB-p65. Further, the LPS-induced increase in NF-κB-p65 in the nucleus was also significantly inhibited by OP-D. OP-D alleviated experimental colitis by inhibiting NF-κB. New insights into the pathogenesis and treatment options of colitis are provided through this study.

Intestinal ischemia reperfusion (II/R) is a clinical emergency that frequently occurs in a variety of clinical conditions. Severe intestinal injury results in the release of cytotoxic substances and inflammatory mediators which can activate local inflammatory response and bacterial translocation. This triggers multi-organ failure, including lung injury, which is a common complication of II/R injury and contributes to the high mortality rate. Corilagin (Cor) is a natural ellagitannin found in a variety of plants. It has many biological and pharmacological properties, including antioxidant, anti-inflammatory and anti-apoptosis activities. However, no studies have evaluated the effects and molecular mechanisms of Cor in alleviating II/R-induced intestinal and lung damage. In this study, Cor was found to significantly alleviate II/R-induced pathological damage, inflammatory response, oxidative stress, NLRP3 inflammasome activation, and pyroptosis in intestinal and lung tissues both in vivo and in vitro. Further, Cor inhibited the NLRP3 inflammasome activation and pyroptosis in RAW264.7 and MLE-12 cells induced by LPS/nigericin and that in IEC-6 cells induced by nigericin, indicating an amelioration of Cor in II/R-induced intestinal and lung injury via inhibiting NLRP3 inflammasome activation and pyroptosis. Thus, Cor might be a potential therapeutic agent for II/R-induced inflammation and tissue injury.

Inhibition of ferroptosis in intestinal epithelial cells ameliorates clinical symptoms and improves endoscopic presentations in inflammatory bowel disease (IBD). Licorice is used worldwide in food and medicine fields. Liquiritin, a flavonoid component in licorice, is an effective substance used as an anti-inflammatory, antioxidant food that has been shown to improve chemically induced colitis. Herein we evaluated the therapeutic effects of liquiritin on colitis and determined whether liquiritin could affect colitis by modulating ferroptosis in epithelial cells. A colitis model was induced in mice by oral administration with 2.5% DSS dissolved in drinking water. The results showed that liquiritin significantly alleviated symptoms, suppressed intestinal inflammation and restored the epithelial barrier function in the colitis mouse model. Liquiritin supplementation upregulated colonic ferritin expression, increased the storage of cellular iron, reduced the cellular iron level and further inhibited ferroptosis in epithelial cells from the colitis model. Pharmacological stimulation of ferroptosis largely blocked liquiritin-induced alleviation of colitis. Peroxiredoxin-6 (Prdx6) expression was significantly decreased in the DSS group, which was reversed by liquiritin treatment. Genetic or pharmacological silencing of Prdx6 largely reversed liquiritin-induced modulation of the ferritin/iron level and ferroptosis in epithelial cells. Molecular docking results showed that liquiritin could bind to Prdx6 through the hydrogen bond interaction with amino acid residues Thr208, Val206 and Pro203. In conclusion, liquiritin treatment largely alleviated DSS induced colitis by inhibiting ferroptosis in epithelial cells. Liquiritin negatively regulated ferroptosis in epithelial cells in colitis by activating Prdx6, increasing the expression of ferritin and subsequently reducing the cellular iron level.