Lactobacillus plantarum-Derived Extracellular Vesicles Modulate Macrophage Polarization and Gut Homeostasis for Alleviating Ulcerative Colitis.

Extracellular vesicles released by probiotics have been demonstrated to effectively alleviate intestinal inflammation, yet the precise underlying mechanisms remain unclear. In this research, for the first time, Lactobacillus plantarum UJS001 (LP-UJS) was isolated from fermented sauerkraut in Zhenjiang, China. Thereafter, the therapeutic effect of LP-UJS-derived extracellular vesicles (LP-UJS-EVs) on dextran sulfate sodium-induced ulcerative colitis (UC) in mice was analyzed to elucidate the immune mechanisms. According to our findings, LP-UJS-EVs played a pivotal role in restoring the intestinal barrier and alleviating intestinal inflammation. Notably, LP-UJS-EVs induced M2 polarization of macrophages, promoted the release of IL-10 and TGF-ß, inhibited the release of histamine, IL-6, and TNF-α, and exerted regulatory effects on intestinal microflora, as evidenced by the reduced abundances of Coprococcus, Parabacteroides, Staphylococcus, and Allobaculum, alongside the enhanced abundance of Prevotella. Furthermore, both LP-UJS and LP-UJS-EVs affected the lysine degradation pathway and significantly increased the abundance of related metabolites, especially oxoadipic acid. In summary, our results underscore the substantial therapeutic potential of LP-UJS and its secreted EVs in the treatment of UC.

Polydopamine nanoparticles cross-linked hyaluronic acid photothermal hydrogel with cascading immunoinducible effects for in situ antitumor vaccination.

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.

Integrated gut microbiome and metabolome analysis reveals the inhibition effect of Lactobacillus plantarum CBT against colorectal cancer.

The microecological stability of the gut microbiota plays a pivotal role in both preventing and treating colorectal cancer (CRC). This study investigated whether Lactobacillus plantarum CBT (LP-CBT) prevents CRC by inducing alterations in the gut microbiota composition and associated metabolites. The results showed that LP-CBT inhibited colorectal tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS)-treated mice by repairing the intestinal barrier function. Furthermore, LP-CBT decreased pro-inflammatory cytokines and anti-inflammatory cytokines. Importantly, LP-CBT remodeled intestinal homeostasis by increasing probiotics (Coprococcus, Mucispirillum, and Lactobacillus) and reducing harmful bacteria (Dorea, Shigella, Alistipes, Paraprevotella, Bacteroides, Sutterella, Turicibacter, Bifidobacterium, Clostridium, Allobaculum), significantly influencing arginine biosynthesis. Therefore, LP-CBT treatment regulated invertases and metabolites associated with the arginine pathway (carbamoyl phosphate, carboxymethyl proline, L-lysine, 10,11-epoxy-3-geranylgeranylindole, n-(6)-[(indol-3-yl)acetyl]-L-lysine, citrulline, N2-succinyl-L-ornithine, and (5-L-glutamyl)-L-glutamate). Furthermore, the inhibitory effect of LP-CBT on colorectal cancer was further confirmed using the MC38 subcutaneous tumor model. Collectively, these findings offer compelling evidence supporting the potential of LP-CBT as a viable preventive strategy against CRC.

Interplay of Sphingolipid Metabolism in Predicting Prognosis of GBM Patients: Towards Precision Immunotherapy.

Background: In spite of numerous existing bio-surveillance systems for predicting glioma (GBM) prognosis, enhancing the efficacy of immunotherapy remains an ongoing conundrum. The continual scrutiny of the dynamic interplay between the sphingolipid metabolic pathway and tumor immunophenotypes has unveiled potential implications. However, the intricate orchestration of functional and regulatory mechanisms by long non-coding RNAs (lncRNAs) in GBM, particularly in the context of sphingolipid metabolism, remains cryptic. Methods: We harnessed established R packages to intersect gene expression profiles of GBM patients within the The Cancer Genome Atlas (TCGA) database with the compilation of sphingolipid metabolism genes from GeneCards. This enabled us to discern markedly distinct lncRNAs, which were subsequently deployed to construct a robust prognostic model utilizing Lasso-Cox regression analysis. We then scrutinized the immune microenvironment across various risk strata using the ssGSEA and CIBERSORT algorithms. To evaluate mutation patterns and drug resistance profiles within patient subgroups, we devised the "Prophytic" and "Maftools" packages, respectively. Results: Our investigation scrutinized lncRNAs linked to sphingolipid metabolism, utilizing glioma specimens from TCGA. We meticulously curated 1224 sphingolipid-associated genes gleaned from GeneCards and pinpointed 272 differentially expressed mRNAs via transcriptomic analysis. Enrichment analyses underscored their significance in sphingolipid processes. A prognostic model founded on 17 meticulously selected lncRNAs was systematically constructed and validated. This model adeptly stratified GBM patients into high- and low-risk categories, yielding highly precise prognostic insights. We also discerned correlations between immune cell infiltration and genetic mutation discrepancies, along with distinct therapeutic responses through drug sensitivity analysis. Notably, computational findings were corroborated through experimental validation by RT-PCR. Conclusion: In summation, our exhaustive inquiry underscores the multifaceted utility of the sphingolipid metabolic pathway as an autonomous diagnostic and prognostic indicator for glioma patients. Furthermore, we amalgamate a profusion of substantiated evidence concerning immune infiltration and gene mutations, thereby reinforcing the proposition that sphingolipid metabolism may function as a pivotal determinant in the panorama of immunotherapeutic interventions.

MBD3 promotes epithelial-mesenchymal transition in gastric cancer cells by upregulating ACTG1 via the PI3K/AKT pathway.

BACKGROUND: Gastric cancer (GC) is a common malignancy and a leading cause of cancer-related death with high morbidity and mortality. Methyl-CpG binding domain protein 3 (MBD3), a key epigenetic regulator, is abnormally expressed in several cancers, participating in progression and metastasis. However, the role of MBD3 in GC remains unknown. METHODS: MBD3 expression was assessed via public databases and validated by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The prognosis of MBD3 was analysed via bioinformatics based on the TCGA dataset. The migration, invasion and proliferation of GC cells were examined by transwell, wound healing, cell counting kit (CCK)-8, colony-formation and xenograft mouse models. Epithelial-mesenchymal transition (EMT) and phosphatidylinositide 3-kinases/ protein Kinase B (PI3K/AKT) pathway markers were evaluated by Western blotting. RNA sequencing was used to identify the target of MBD3. RESULTS: MBD3 expression was higher in GC tissues and cells than in normal tissues and cells. Additionally, high MBD3 levels were associated with poor prognosis in GC patients. Subsequently, we proved that MBD3 enhanced the migration, invasion and proliferation abilities of GC cells. Moreover, western blot results showed that MBD3 promoted EMT and activated the PI3K/AKT pathway. RNA sequencing analysis showed that MBD3 may increase actin γ1 (ACTG1) expression to promote migration and proliferation in GC cells. CONCLUSION: MBD3 promoted migration, invasion, proliferation and EMT by upregulating ACTG1 via PI3K/AKT signaling activation in GC cells and may be a potential diagnostic and prognostic target.

Correction: Ding et al. MBD3 as a Potential Biomarker for Colon Cancer: Implications for Epithelial-Mesenchymal Transition (EMT) Pathways. Cancers 2023, 15, 3185.

In the published paper [...].

LncRNA UCA1 promotes pancreatic cancer cell migration by regulating mitochondrial dynamics via the MAPK pathway.

PURPOSE: Long non-coding RNA urothelial cancer associated 1 (UCA1) serves as an oncogene in various cancers. However, the mechanism underlying the role of UCA1 in pancreatic cancer remains unclear. This study aimed to explore the role of UCA1 in pancreatic cancer. METHODS: The expression and prognosis of UCA1 were analyzed using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The results were validated by immunohistochemistry (IHC) and qRT-PCR. The biofunctions of UCA1 were analyzed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The migration abilities and mitochondrial dynamics of PC cells were examined using the Transwell assay, mitochondrial membrane potential (MMP), and fluorescence. The mitochondrial-related protein and MAPK/ERK pathway markers were evaluated using western blotting. RESULTS: UCA1 expression was significantly higher in pancreatic cancer tissues than in normal tissues. High UCA1 expression indicated poor clinical outcomes and was associated with clinical features in patients with pancreatic cancer. Additionally, high UCA1 expression is a potential independent marker for poor prognosis. Subsequently, we demonstrated that UCA1 enhanced the migration capability, increased MMP, enhanced mitochondrial fusion, and inhibited mitochondrial autophagy in pancreatic cancer cells via the MAPK/ERK pathway. CONCLUSION: UCA1 promotes the migration by regulating the mitochondrial dynamics of pancreatic cancer cells via the MAPK/ERK pathway. Our findings suggest that UCA1 may serve as a potential biomarker in pancreatic cancer prognosis.

ALKBH5-PYCR2 Positive Feedback Loop Promotes Proneural-Mesenchymal Transition Via Proline Synthesis In GBM.

AlkB homolog 5, RNA demethylase (ALKBH5) is abnormally highly expressed in glioblastoma multiforme (GBM) and is negatively correlated with overall survival in GBM patients. In this study, we found a new mechanism that ALKBH5 and pyrroline-5-carboxylate reductase 2 (PYCR2) formed a positive feedback loop involved in proline synthesis in GBM. ALKBH5 promoted PYCR2 expression and PYCR2-mediated proline synthesis; while PYCR2 promoted ALKBH5 expression through the AMPK/mTOR pathway in GBM cells. In addition, ALKBH5 and PYCR2 promoted GBM cell proliferation, migration, and invasion, as well as proneural-mesenchymal transition (PMT). Furthermore, proline rescued AMPK/mTOR activation and PMT after silencing PYCR2 expression. Our findings reveal an ALKBH5-PYCR2 axis linked to proline metabolism, which plays an important role in promoting PMT in GBM cells and may be a promising therapeutic pathway for GBM.

PERK/ATF3-Reduced ER Stress on high potassium environment in the suppression of tumor ferroptosis.

Potassium (K+) is a vital intracellular cation. In the human body, it regulates membrane potential, electrical excitation, protein synthesis, and cell death. Recent studies revealed that dying cancer cells release potassium into the tumor microenvironment (TME), thereby influencing cell survival-related events. Several investigations reported that potassium channels and high potassium levels influence apoptosis. Increasing extracellular potassium and inhibiting K+ efflux channels significantly block the apoptotic machinery. However, it is unknown whether a high-potassium environment also affects other types of cell death such as ferroptosis. In the present study, cell counting kit (CCK-8), colony formation ability, and 5-ethynyl-2'-deoxyuridine (EdU) assays demonstrated that a high-potassium environment reverses erastin-induced ferroptosis. RNA sequencing (RNA-Seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analyses indicated that high potassium levels attenuated the unfolded protein response that is characteristic of endoplasmic reticulum (ER) stress. The ER transmembrane proteins PRKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) are recognized as ER stress sensors. Here, the PERK blocker GSK2606414 significantly rescued ferroptosis. The present work also disclosed that the ER-related gene activating transcription factor 3 (ATF3) played a vital role in regulating ferroptosis in a high-potassium environment. The foregoing results revealed the roles of potassium and the TME in cancer cell ferroptosis and provided a potential clinical therapeutic strategy for cancer.

MBD3 as a Potential Biomarker for Colon Cancer: Implications for Epithelial-Mesenchymal Transition (EMT) Pathways.

The tumor EMT is a crucial event in tumor pathogenesis and progression. Previous research has established MBD3's significant role in pancreatic cancer EMT. However, MBD3's precise role in colon cancer remains unclear and warrants further investigation. Pan-cancer analysis revealed MBD3's differential expression in various tumors and its significant association with tumor occurrence, growth, and progression. Moreover, analysis of single-cell sequencing and clinical data for colon cancer revealed MBD3 expression's negative correlation with clinical indicators such as survival prognosis. Functional enrichment analysis confirmed the association between MBD3 and EMT in colon cancer. Pathological examinations, western blotting, and qRT-PCR in vitro and in vivo validated MBD3's differential expression in colon cancer. Transwell, CCK-8, clone formation, and in vivo tumorigenesis experiments confirmed MBD3's impact on migration, invasion, and proliferation. Our findings demonstrate MBD3 as a potential prognostic marker and therapeutic target for colon cancer.

Hypoxia-elicited Exosomes Promote the Chemoresistance of Pancreatic Cancer Cells by Transferring LncROR via Hippo Signaling.

Recent studies have found that hypoxia contributes to tumor progression and drug resistance by inducing the secretion of exosomes. However, the mechanism underlying this resistance in pancreatic cancer remains to be explored. In this study, we investigated the effect of hypoxia-induced tumor-derived exosomes (Hexo) on stemness and resistance to gemcitabine in pancreatic cancer cells, as well as the molecular mechanisms involved in this process. Firstly, we discovered that hypoxia promoted stemness and induced resistance to gemcitabine in pancreatic cancer cells. Secondly, we showed that exosomes secreted by pancreatic cancer cells under normoxic or hypoxic conditions can be transfected into tumor cells. Thirdly, it was demonstrated that Hexo promotes proliferation, stemness, and resistance to gemcitabine in pancreatic cancer cells, as well as inhibits the apoptosis and cell cycle arrest induced by gemcitabine. Finally, it was verified that Hexo inactivated the Hippo/Yes-associated protein (Hippo/YAP) pathway in pancreatic cancer cells by transferring exosomal long non-coding RNA regulator of reprogramming (lncROR). In summary, the hypoxic tumor microenvironment could promote stemness and induce resistance to gemcitabine in pancreatic cancer cells. Mechanistically, Hexo enhanced stemness to promote chemoresistance in pancreatic cancer cells by transferring lncROR via Hippo signaling. Thus, exosomal lncROR may serve as a candidate target of chemotherapy for pancreatic cancer.

LncRNA FAM83A-AS1 promotes epithelial-mesenchymal transition of pancreatic cancer cells via Hippo pathway.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been proved to play a vital role in pancreatic cancer (PC). However, the role of lncRNA FAM83A-AS1 in PC remains unclear. In this study, we explored the biological function and underlying mechanism of FAM83A-AS1 in PC cells. METHODS: The FAM83A-AS1 expression was assessed via public databases and validated by qRT-PCR. The biofunction and immune cell infiltration of FAM83A-AS1 were analyzed through GO, KEGG, GESA and ssGSEA. The migration, invasion and proliferation abilities of PC cells were examined by Transwell, wound healing, CCK8 and colony formation. The EMT and Hippo pathway markers were evaluated by western blot. RESULTS: FAM83A-AS1 expression was higher in PC tissues and cells than normal. Additionally, FAM83A-AS1 was associated with poor prognosis of PC and involved in cadherin binding and immune infiltration. Subsequently, we proved FAM83A-AS1 overexpression enhanced the migration, invasion and proliferation abilities of PC cells, whereas FAM83A-AS1 downregulation inhibited those. Moreover, western blot results showed that FAM83A-AS1 knockdown increased the E-cadherin expression and decreased the expression of N-cadherin, ß-catenin, Vimentin, Snail and Slug. On the contrary, FAM83A-AS1 upregulation results in the opposite effects. Besides, FAM83A-AS1 overexpression inhibited the expression of p-YAP, p-MOB1, p-Lats1, SAV1, MST1 and MST2 as well as the results of FAM83A-AS1 knockdown were opposite. CONCLUSION: FAM83A-AS1 promoted EMT of PC cells via Hippo signaling inactivation and may be a potential diagnosis and prognosis target.

Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.

Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which aerobic glycolysis, often known as the "Warburg effect," is essential to the fast proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant cells often remove lactate along with H+, yet the acidification of TME is inevitable. Not only does the highly concentrated lactate within the TME serve as a substrate to supply energy to the malignant cells, but it also works as a signal to activate multiple pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis, as well as immune escape. In this review, we aim to discuss the latest findings on lactate metabolism in tumor cells, particularly the capacity of extracellular lactate to influence cells in the tumor microenvironment. In addition, we examine current treatment techniques employing existing medications that target and interfere with lactate generation and transport in cancer therapy. New research shows that targeting lactate metabolism, lactate-regulated cells, and lactate action pathways are viable cancer therapy strategies.

Cascade biomimetic intelligent nanotheranostic agents for imaging-guided tumor synergistic therapy.

Aim: Achieving drug-targeting delivery and environment-responsive releasing to realize imaging-guided precise tumor therapy. Materials & methods: Graphene oxide (GO) was used as the drug-delivery system to load indocyanine green (ICG) and doxorubicin (DOX) to form a GO/ICG&DOX nanoplatform, in which GO can quench the fluorescence of ICG and DOX. MnO2 and folate acid-functionalized erythrocyte membrane were further coated into the surface of GO/ICG&DOX to obtain an FA-EM@MnO2-GO/ICG&DOX nanoplatform. Results: The FA-EM@MnO2-GO/ICG&DOX nanoplatform has longer blood circulation time, precise targeting delivery to tumor tissues and catalase-like activity. Both in vitro and in vivo results demonstrated that the FA-EM@MnO2-GO/ICG&DOX nanoplatform has better therapeutic efficacy. Conclusion: The authors successfully fabricated a glutathione-responsive FA-EM@MnO2-GO/ICG&DOX nanoplatform, which can achieve drug-targeting delivery and precise drug release.

Tripartite motif-containing 68-stabilized modulator of apoptosis-1 retards the proliferation and metastasis of lung cancer.

Non-small cell lung cancer (NSCLC) is a major global health threat with high incidence and mortality. Modulator of apoptosis-1 (MOAP1), also named MAP-1, belongs to the PNMA gene family and plays a key role in regulating apoptosis and tumor growth. However, its influences on NSCLC are largely unclear, and thus were explored in our present study, particularly the underlying mechanisms. Here, we initially find that MOAP1 expression is significantly decreased in NSCLC patients compared with the normal ones, and negatively correlated with the TNM and pathologic stages among patients. Additionally, MOAP1 low expression predicts a poorer prognosis than that of the NSCLC patients expressing higher MOAP1. Our in vitro studies confirm much lower MOAP1 expression in NSCLC cell lines. Of note, promoting MOAP1 expression strongly reduces the proliferation and induces apoptosis in NSCLC cells, accompanied with cell cycle arrest distributed in G0/G1 phase. Moreover, we find that MOAP1 has a negative correlation with Th2 cells' infiltration, but a positive correlation with the infiltration levels of eosinophils. Epithelial mesenchymal transition (EMT) process is also greatly restrained in NSCLC cells with MOAP1 over-expression, as proved by the reduced migration and invasion of cells. We further identify a positive correlation between MOAP1 and tripartite motif-containing 68 (TRIM68) in patients with NSCLC. Further analysis shows that TRIM68 directly interacts with MOAP1 and stabilizes MOAP1. Importantly, TRIM68 can activate MOAP1 by inducing the K63-linked polyubiquitination of MOAP1. Finally, animal studies verify that promoting MOAP1 efficiently suppresses tumor growth and lung metastasis in the nude mice. Collectively, our results reveal a novel mechanism through which MOAP1 stabilized by TRIM68 inhibits NSCLC development and targeting MOAP1 for its up-regulation may be a promising therapeutic strategy for NSCLC treatment.

NIR responsive nanoenzymes via photothermal ablation and hypoxia reversal to potentiate the STING-dependent innate antitumor immunity.

Despite advances in combined photothermal/immunotherapy of tumor, the therapeutic effect has been impaired due to hypoxic microenvironment and inadequate immune activation. Manganese ions directly activated the stimulator of interferon genes (STING) pathway and induced innate antitumor immunity. Herein, a near infrared light (NIR)-responsive nanoenzyme (PB-Mn/OVA NE) was constructed by doping manganese into the ovalbumin (OVA)-templated Prussian blue (PB) nanoparticles. The resultant PB-Mn/OVA NEs exhibited favorable catalase activity to produce oxygen, which was conducive to alleviate the tumor hypoxic microenvironment. Under 808 â€‹nm NIR irradiation, the PB-Mn/OVA NEs with outstanding photothermal conversion efficiency of 30% significantly destroyed tumor cells by inducing immunogenic cell death (ICD). Impressively, the PB-Mn/OVA NEs could activate the cGAS-STING pathway to promote the maturation and the antigen cross-presentation ability of dendritic cells (DCs), which further activated cytotoxic T lymphocytes and memory T lymphocytes. Overall, this work presents a powerful nanoenzyme formula to integrate photothermal ablation and hypoxic reversal for triggering robust innate and adaptive antitumor immune response.

Immunoinducible Carbon Dot-Incorporated Hydrogels as a Photothermal-Derived Antigen Depot to Trigger a Robust Antitumor Immune Response.

Immunogenic tumor cell death (ICD) induced by photothermal therapy (PTT) fails to elicit a robust antitumor immune response partially due to its inherent immunosuppressive microenvironment and poor antigen presentation. To address these issues, we developed an immunoinducible carbon dot-incorporated hydrogel (iCD@Gel) through a dynamic covalent Schiff base reaction using mannose-modified aluminum-doped carbon dots (M/A-CDs) as a cross-linking agent. The M/A-CDs possessed superior photothermal conversion efficiency and served as nanocarriers to load cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) for inducing the maturation of dendritic cells (DCs) via mannose receptor-mediated targeting delivery. Upon intratumoral injection, the as-prepared iCD@Gel induced ICD, and damage-associated molecular patterns (DAMPs) were released via photothermal ablation under 808 nm NIR irradiation. Subsequently, the iCD@Gel synergized with the DAMPs to significantly promote the maturation and antigen cross-presentation ability of DCs. This work provides a promising strategy to develop carbon dot-based therapeutic hydrogels for photothermal therapy and immune activation.

Treatment of inflammatory bowel disease: Potential effect of NMN on intestinal barrier and gut microbiota.

Nicotinamide mononucleotide (NMN) exerts physiological effects in mammals through its conversion to nicotinamide adenine dinucleotide (NAD+). In this study, we established experimental models of colitis by mixing drinking water of C57BL/6J mice with dextran sodium sulphate (DSS), and then fed them with the same concentration of NMN or at the same time. After NMN treatment, we observed improved morphology of inflamed intestines, slightly restored length of colon, improved barrier function and reduced proinflammatory factors expression in serum. Also, significant alterations in the composition and abundance of intestinal flora in IBD mice were found. The abundance of Firmicutes, Verrucomicrobia, Akkermansia and Lactobacillus, considered as beneficial bacteria, increased, while Bacteroidetes and Muribaculaceae unclassifiably decreased. Taken together, these results suggest that NMN may improve intestinal inflammation, reduce intestinal mucosal permeability and repair gut flora dysbiosis in IBD.

Vitamin C Sensitizes Pancreatic Cancer Cells to Erastin-Induced Ferroptosis by Activating the AMPK/Nrf2/HMOX1 Pathway.

Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc- inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.