Umbrella review of risk factors for inflammatory bowel disease: a study protocol.

INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disorder that arises from complex interactions between genetics, environment and gut microbiota. It encompasses Crohn's disease, ulcerative colitis and IBD-unclassified. The protracted course of IBD imposes a significant burden on patients' quality of life, economic productivity, social functioning, as well as treatment, hospitalisation and surgery. This study aims to conduct an umbrella review of meta-analyses to systematically evaluate the methodology's quality, potential biases and validity of all epidemiological evidence focused on risk factors for IBD while providing an overview of the evidence concerning IBD risk factors. METHODS AND ANALYSIS: We will systematically search, extract and analyse data from reported systematic reviews and meta-analyses that specifically focus on the risk factors of IBD, following the guidelines outlined in Preferred Reporting Items for Overviews of Reviews. Our search will encompass PubMed, Embase, Web of Science and the Cochrane Database of Systematic Reviews from the initial period up until April 2023 (last update), targeting systematic reviews and meta-analyses based on non-interventional studies. Inclusion criteria allow for systematic reviews and meta-analyses evaluating IBD risk factors across all countries and settings, regardless of ethnicity or sex. The identified risk factors will be categorised according to the health ecological model into innate personal traits, behavioural lifestyles, interpersonal networks, socioeconomic status and macroenvironments. To assess methodological quality for each meta-analysis included in our study, two authors will employ a measurement tool to assess the methodological quality of systematic reviews (AMSTAR)-2, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria along with evidence classification criteria. ETHICS AND DISSEMINATION: Ethical approval is not required for this umbrella review. We will seek to submit the results for publication in a peer-reviewed journal or present it at conferences. PROSPERO REGISTRATION NUMBER: CRD42023417175.

The COP9 signalosome stabilized MALT1 promotes Non-Small Cell Lung Cancer progression through activation of NF-κB pathway.

MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.

Tween 80 Micelles Loaded with Fe3O4 Nanoparticles and Artemisinin for Combined Oxygen-Independent Ferroptosis Therapy of Cancer.

Artemisinin has an endoperoxide bridge structure, which can be cleaved by ferrous ions to generate various carbonyl radicals in an oxygen-independent manner, highlighting its potential for treating hypoxic tumors. In our study, we fabricated Tween 80 micelles loaded with Fe3O4 nanoparticles and artemisinin for cancer therapy. The synthesized Fe3O4 nanoparticles and drug-loaded micelles have particle sizes of about 5 nm and 80 nm, respectively, both exhibiting excellent dispersibility and stability. After uptake by MCF-7 cells, drug-loaded micelles release Fe2+ and ART into the cytoplasm, effectively inducing the generation of reactive oxygen species (ROS) in hypoxic conditions, thereby enhancing toxicity against cancer cells. In vitro and in vivo studies have demonstrated that ART and Fe3O4 nanoparticles are encapsulated in Tween 80 to form micelles, which effectively prevent premature release during circulation in the body. Although free ART and Fe3O4 nanoparticles can inhibit tumor growth, TW80-Fe3O4-ART micelles demonstrate a more pronounced inhibitory effect, with a tumor suppression rate of up to 85%. A novel strategy based on artemisinin and ferroptosis is thus offered, holding a favorable prospect for hypoxic cancer therapy.

Value of CT-Based Deep Learning Model in Differentiating Benign and Malignant Solid Pulmonary Nodules ≤ 8 mm.

RATIONALE AND OBJECTIVES: We examined the effectiveness of computed tomography (CT)-based deep learning (DL) models in differentiating benign and malignant solid pulmonary nodules (SPNs) ≤ 8 mm. MATERIALS AND METHODS: The study patients (n = 719) were divided into internal training, internal validation, and external validation cohorts; all had small SPNs and had undergone preoperative chest CTs and surgical resection. We developed five DL models incorporating features of the nodule and five different peri-nodular regions with the Multiscale Dual Attention Network (MDANet) to differentiate benign and malignant SPNs. We selected the best-performing model, which was then compared to four conventional algorithms (VGG19, ResNet50, ResNeXt50, and DenseNet121). Furthermore, another five DL models were constructed using MDANet to distinguish benign tumors from inflammatory nodules and the one performed best was selected out. RESULTS: Model 4, which incorporated the nodule and 15 mm peri-nodular region, best differentiated benign and malignant SPNs. The model had an area under the curve (AUC), accuracy, recall, precision, and F1-score of 0.730, 0.724, 0.711, 0.705, and 0.707 in the external validation cohort. Model 4 also performed better than the other four conventional algorithms. Model 8, which incorporated the nodule and 10 mm peri-nodular region, was the best model for distinguishing benign tumors from inflammatory nodules. The model had an AUC, accuracy, recall, precision, and F1-score of 0.871, 0.938, 0.863, 0.904, and 0.882 in the external validation cohort. CONCLUSION: The study concludes that CT-based DL models built with MDANet can accurately discriminate among small benign and malignant SPNs, benign tumors and inflammatory nodules.

Circular RNA Expression of Peripheral Blood Mononuclear Cells Associated with Risk of Acute Exacerbation in Smoking Chronic Obstructive Pulmonary Disease.

Purpose: Circular RNAs (circRNAs) are newly identified endogenous non-coding RNAs that function as crucial gene modulators in the development of several diseases. By assessing the expression levels of circRNAs in peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD), this study attempted to find new biomarkers for COPD screening. Patients and Methods: We confirmed altered circRNA expression in PBMCs of COPD (n=41) vs controls (n=29). Further analysis focused on the highest and lowest circRNA expression levels. The T-test is used to assess the statistical variances in circRNAs among COPD patients in the smoking and non-smoking cohorts. Additionally, among smokers, the Spearman correlation test assesses the association between circRNAs and clinical indicators. Results: Two circRNAs, hsa_circ_0042590 and hsa_circ_0049875, that were highly upregulated and downregulated in PBMCs from COPD patients were identified and verified. Smokers with COPD had lower hsa_circ_0042590 and higher hsa_circ_0049875, in comparison to non-smokers. There was a significant correlation (r=0.52, P<0.01) between the number of acute exacerbations (AEs) that smokers with COPD experienced in the previous year and the following year (r=0.67, P<0.001). Moreover, hsa_circ_0049875 was connected to the quantity of AEs in the year prior (r=0.68, P<0.0001) as well as the year after (r=0.72, P<0.0001). AUC: 0.79, 95% CI: 0.1210-0.3209, P<0.0001) for hsa_circ_0049875 showed a strong diagnostic value for COPD, according to ROC curve analysis. Hsa_circ_0042590 showed a close second with an AUC of 0.83 and 95% CI: -0.1972--0.0739 (P <0.0001). Conclusion: This research identified a strong correlation between smoking and hsa_circ_0049875 and hsa_circ_0042590 in COPD PBMCs. The number of AEs in the preceding and succeeding years was substantially linked with the existence of hsa_circ_0042590 and hsa_circ_0049875 in COPD patients who smoke. Additionally, according to our research, hsa_circ_0049875 and hsa_circ_0042590 may be valuable biomarkers for COPD diagnosis.

Leech extract alleviates idiopathic pulmonary fibrosis by TGF-ß1/Smad3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Leech, as a traditional Chinese medicine for the treatment of blood circulation and blood stasis, was also widely used to cure pulmonary fibrosis in China. In clinical practice, some traditional Chinese medicine preparation such as Shui Zhi Xuan Bi Hua Xian Tang and Shui Zhi Tong Luo Capsule composed of leech, could improve the clinical symptoms and pulmonary function in patients with idiopathic pulmonary fibrosis (IPF). However, the material basis of the leech in the treatment of IPF were not yet clear. AIM OF THE STUDY: Screen out the components of leech that have the anti-pulmonary fibrosis effects, and further explore the therapeutic mechanism of the active components. MATERIALS AND METHODS: In this study, the different molecular weight components of leech extract samples were prepared using the semi-permeable membranes with different pore sizes. The therapeutic effects of the leech extract groups with molecular weight greater than 10 KDa (>10 KDa group), between 3 KDa and 10 KDa (3-10 KDa group), and less than 3 KDa (<3 KDa group) on pulmonary fibrosis were firstly investigated by cell proliferation and cytotoxicity assay (MTT), cell wound healing assay, immunofluorescence staining (IF) and Western blot (WB) assay through the TGF-ß1-induced fibroblast cell model. Then bleomycin-induced pulmonary fibrosis (BML-induced PF) mouse model was constructed to investigate the pharmacological activities of the active component group of leech extract in vivo. Pathological changes of the mouse lung were observed by hematoxylin-eosin staining (H&E) and Masson's trichrome staining (Masson). The hydroxyproline (HYP) content of lung tissues was quantified by HYP detection kit. The levels of extracellular matrix-related fibronectin (FN) and collagen type Ⅰ (Collagen Ⅰ), pyruvate kinase M2 (PKM2) monomer and Smad7 protein were determined via WB method. PKM2 and Smad7 protein were further characterized by IF assays. RESULTS: Using TGF-ß1-induced HFL1 cell line as a PF cell model, the in vitro results demonstrated that the >10 KDa group could significantly inhibited the cell proliferation and migration, downregulated the expression level of cytoskeletal protein vimentin and α-smooth muscle actin (α-SMA), and reduced the deposition of FN and Collagen Ⅰ. In the BML-induced PF mouse model, the >10 KDa group significantly reduced the content of HYP, downregulated the expression levels of FN and Collagen Ⅰ in lung tissues, and delayed the pathological changes of lung tissue structure. The results of WB and IF assays further indicated that the >10 KDa group could up-regulate the expression level of PKM2 monomer and Smad7 protein in the cellular level, thereby delaying the progression of pulmonary fibrosis. CONCLUSIONS: Our study revealed that the >10 KDa group was the main material basis of the leech extract that inhibited pulmonary fibrosis through TGF-ß1/Smad3 signaling pathway.

Size Switchable Self-Assembled Iron Oxide Aggregations Loaded with Doxorubicin for Deep Penetration and Enhanced Chemotherapy of Cancer.

Iron oxide nanoparticles (Fe3O4 NPs) have been reported to be a promising agent for cancer therapy due to their outstanding ability in catalyzing the Fenton reaction and causing peroxidation. Generally, particles with size of hundreds of nanometers exhibit enhanced accumulation in tumor due to the enhanced permeation and retention effect. However, the large size hinders penetration within the dense collagen matrix. Here, we propose a multistage system to realize pH-responsive size switch for efficient drug delivery. In this system, ultrasmall Fe3O4 (∼4 nm) NPs are simultaneously modified with hydrophilic mPEG and hydrophobic N,N-dibutylethylenediamine (DBE) to form pH-responsive self-assembled iron oxide aggregations (SIOA). In the acidic tumor microenvironment, the protonation of DBE makes it transit from the hydrophobic to hydrophilic state, causing the disassembly of the SIOA and the release of loaded doxorubicin. The multistage Fe3O4 NPs demonstrate enhanced accumulation and efficient diffusion within the tumor, holding a promise for drug delivery and cancer therapy.

Design and synthesis of 1H-benzo[d]imidazole selective HDAC6 inhibitors with potential therapy for multiple myeloma.

Pan-HDAC inhibitors exhibit significant inhibitory activity against multiple myeloma, however, their clinical applications have been hampered by substantial toxic side effects. In contrast, selective HDAC6 inhibitors have demonstrated effectiveness in treating multiple myeloma. Compounds belonging to the class of 1H-benzo[d]imidazole hydroxamic acids have been identified as novel HDAC6 inhibitors, with the benzimidazole group serving as a specific linker for these inhibitors. Notably, compound 30 has exhibited outstanding HDAC6 inhibitory activity (IC50 = 4.63 nM) and superior antiproliferative effects against human multiple myeloma cells, specifically RPMI-8226. Moreover, it has been shown to induce cell cycle arrest in the G2 phase and promote apoptosis through the mitochondrial pathway. In a myeloma RPMI-8226 xenograft model, compound 30 has demonstrated significant in vivo antitumor efficacy (T/C = 34.8%) when administered as a standalone drug, with no observable cytotoxicity. These findings underscore the immense potential of compound 30 as a promising therapeutic agent for the treatment of multiple myeloma.

Regulation of Ion Homeostasis for Enhanced Tumor Radio-Immunotherapy.

Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase inhibitor (CAI) is loaded onto pH-responsive calcium carbonate (CaCO3 ) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO3 /CAI@Lipsome (CCL) for enhance tumor radio-immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca2+ ) and CAI, as well as increasing the pH value of extracellular fluid. CAI restrains the flow of hydrogen ion (H+ ) inside and outside the tumor cells, resulting in the reversal of tumor acidic microenvironment and the increase of intracellular H+ , both of which can improve the sensitivity of tumor to radiotherapy. Afterward, the increased intracellular H+ together with radiotherapy-causes reactive oxygen species promotes calcium influx, leading to cellular calcium overload. Moreover, the CCL-tailored content of H+ and Ca2+ strengthens radiotherapy-induced immunogenic cell death and dendritic cell maturation, amplifying systemic anti-tumor adaptive immunity. Meanwhile, macrophages in the CCL-treated tumors are polarized from pro-tumor M2 to anti-tumor M1 under X-ray exposure, owing to the neutralization of tumor acidic microenvironment and enhances Ca2+ content. Therefore, multi-directional regulation of the intra/extra tumor cell pH/calcium by simple nano-preparation would provide a powerful way to improve the efficacy of radio-immunotherapy.

Online short videos promoting public breast cancer literacy: a pretest-posttest control group trial on efficiency, attitude, and influencing factors.

Background: Short videos on social media are playing an increasingly important role in cancer health education today. It is important to explore how the actual communication effect of health videos and the knowledge absorption of users are influenced by different factors of the video creation process. Objective: The objective of our study is to access the factors influencing breast cancer health education through short videos on efficiency and quality. Methods: Three pairs of videos about breast health were created and participants completed questionnaires before and after watching the videos. A paired t-test was used to analyze within-group change scores. RM-ANOVA was used to assess the relationship between the pretest, posttest, and three variables. Results: Watching short videos can significantly increase viewers' knowledge of related health topics (p < 0.05). The viewers' concentration level while watching was significantly higher for the video with background music (BGM) than for the video without BGM (p = 0.006). The viewers' willingness to share was significantly higher for the video with a progress bar than for the video without a progress bar (p = 0.02). Using an interpreter wearing a doctor's uniform instead of casual wear and setting a progress bar can significantly improve the efficiency of knowledge absorption (p < 0.05). Conclusion: A uniformed interpreter, BGM and a progress bar are factors influencing the efficiency of short health videos. They can be applied in video making to explore better ways of promoting cancer health education in the new mobile Internet environment.

Development of alternative herbals remedy for gastric cancer based on transcriptomic analysis of immune infiltration and ferroptosis.

Objective: Screening out potential herbal medicines and herbal ingredients for the treatment of gastric cancer based on transcriptomic analysis of immune infiltration and ferroptosis. Methods: Gene expression profiles of gastric tumour tissues and normal tissue samples were obtained from the GEO database and the samples were analysed for immune cell infiltration condition and differential expressed genes of ferroptosis. Key genes were screened by protein-protein interaction (PPI) and enrichment analysis, and molecular docking was used to predict and preliminary validate potential herbal and traditional Chinese medicine components for gastric cancer based on the key genes. Finally, RT-QPCR was used to validate the prediction results. Results: Immune cell infiltration analysis revealed high levels of infiltration of activated CD4 memory T cells, monocytes, M0 macrophages in gastric tumor tissues, while plasma cells and resting mast cells had higher levels of infiltration in the paraneoplastic tissues. Differential gene expression analysis identified 1,012 upregulated genes and 880 downregulated genes, of which 84 immune related differentially expressed genes such as CTSB, PGF and PLAU and 10 ferroptosis-related differentially expressed genes such as HSF1, NOX4 and NF2 were highly expressed in gastric cancer tissues. The results of enrichment analysis showed that they mainly involve 343 biological processes such as extracellular matrix organization and extracellular structural organization; 37 cellular components such as complexes of collagen trimer and basement membrane; 35 molecular functions such as signal receptor activator activity and receptor ligand activity; 19 regulatory pathways such as cytokine-cytokine receptor interactions and retinol metabolism. Finally, two key genes, TLR4 and KRAS, were selected and 12 herbal medicines such as Radix Salviae liguliobae, Rhizoma Coptidis, Rhizoma Polygoni cuspidati and 27 herbal ingredients such as resveratrol, salvianolic acid b were predicted on the basis of key genes. Molecular docking results showed that KRAS binds tightly to coumarin and magnolol, while TLR4 can bind tightly to resveratrol, curcumin, salvianolic acid b, shikonin. Subsequently, the effect of resveratrol and magnolol was experimentally verified. Conclusion: Herbal medicines such as S. liguliobae, Rhizoma Coptidis, Rhizoma P. cuspidati and herbal ingredients such as resveratrol, curcumin, salvianolic acid b may provide research directions and alternative therapeutic approaches for immunomodulation of TME and ferroptosis of tumour cells in gastric cancer.

General Anesthesia Versus Regional Anesthesia in the Elderly Patients Undergoing Hip Fracture Surgeries: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Surgery is the preferred treatment option for the elderly patients with hip fractures. However, the choice of general anesthesia (GA) or regional anesthesia (RA) remains controversial. The quality of evidence has further improved with the advent of several high-quality randomized clinical trials (RCTs) in the last two years. The purpose of this study was to compare the clinical outcomes of two anesthetic techniques in elderly patients undergoing hip fracture surgeries. METHODS: Eligible studies were identified from PubMed/MEDLINE, Web of Science, Scopus, EMBASE and reference lists from January 2000 to June 2022 in this current systematic review and meta-analysis. The outcomes included the surgery-related outcomes (duration of surgery, duration of anesthesia, intraoperative blood loss and number of transfusions) and postoperative outcomes (30-day mortality, postoperative delirium,cardiovascular events and other complications). RESULTS: A total of 10 RCTs were included, and a total of 3594 patients were analyzed. RA was associated with shorter duration of surgery, shorter length of hospital stays and less intraoperative blood loss compared to GA. There were no significant differences between the two groups in the number of blood transfusions, duration of anesthesia, 30-day mortality or postoperative delirium. CONCLUSIONS: Our pooled analysis identified no significant differences in terms of the safety between RA and GA, while RA reduces intraoperative blood loss, length of hospital stays and duration of surgery. These results suggest that RA appears to be preferable for the elderly patients with hip fractures.

Role of Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma.

Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.

Cancer-associated mutations in SF3B1 disrupt the interaction between SF3B1 and DDX42.

While cancer-associated SF3B1 mutations causes alternative RNA splicing, the molecular mechanism underlying the alternative RNA splicing is not fully elucidated. Here, we analysed the proteins that interacted with the wild-type and K700E-mutated SF3B1 and found that the interactions of two RNA helicases, DDX42 and DDX46, with the mutated SF3B1 were reduced. Overexpression of DDX42 restored the decreased interaction between DDX42 and the K700E-mutated SF3B1, and suppressed some alternative RNA splicing associated with the SF3B1 mutation. Mutation that decreased the ATP hydrolysis activities of DDX42 abolished the suppressive effects of DDX42 on the alternative RNA splicing, suggesting that the ATP hydrolysis activity of DDX42 is involved in the mechanism of the altered RNA splicing associated with the SF3B1 mutation. Our study demonstrates an important function of the interaction between DDX42 and SF3B1 on regulating RNA splicing and revealed a potential role of DDX42 in the altered RNA splicing associated with the SF3B1 mutation.

Targeting MALT1 Suppresses the Malignant Progression of Colorectal Cancer via miR-375/miR-365a-3p/NF-κB Axis.

Colorectal cancer (CRC) is a malignant tumor with the second highest morbidity and the third highest mortality in the world, while the therapeutic options of targeted agents remain limited. Here, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), known as the upstream of the NF-κB signaling pathway, was identified to be highly upregulated in CRC tumors and cell lines. Furthermore, the downregulation of MALT1 or inhibition of its proteolytic function by MI-2 suppressed the cell proliferation and migration of CRC cells. In vivo, suppressing the MALT1 expression or its proteasome activity effectively reduced the size of the subcutaneous tumor in nude mice. Mechanistically, miR-375 and miR-365a-3p were identified to inhibit NF-κB activation via targeting MALT1. Overall, our results highlight that a novel regulatory axis, miRNA-MALT1-NF-κB, plays a vital role in the progression of CRC and provides novel and hopeful therapeutic targets for clinical treatment.

Alveolar macrophage-derived progranulin mediated pro-inflammatory Il-6 expression via regulating Creb1 in silicosis model.

Progranulin (PGRN) is a secreted factor involved in inflammatory diseases. However, the function of PGRN in silica-induced lung inflammation has not been elucidated. In this study, we demonstrated that PGRN in serum and lung tissues was markedly increased in silicosis mouse model. And immunohistochemistry results showed that PGRN was mainly expressed in alveolar macrophages, which was further confirmed in silica-treated alvelar macrophages cell line (MH-S) in vitro. PGRN promoted pro-inflammatory cytokines transcription such as interleukin (Il)-6, tumor necrosis factor-α (Tnf-α) and Il-1ß in MH-S cells, and the increasing of Il-6 was most obvious. Knockdown of PGRN blocked the silica-induced elevation of intracellular Il-6 in MH-S cells. Furthermore, we also found that PGRN could increase the phosphorylation of Cyclic AMP-responsive element-binding protein 1 (Creb1), a transcriptional regulator of Il-6. Inhibition of p-Creb1 by the phosphorylation inhibitor of Creb1 (666-15) decreased PGRN-induced intracellular Il-6 production in MH-S cells. In conclusion, PGRN was highly increased in silicosis mouse model and upregulated inflammatory cytokines expression. These findings suggested that PGRN might be a key mediator in silica-induced inflammation and provided a new clue for the diagnosis and drug therapy of silicosis.

Nicotinamide Mononucleotide Ameliorates Silica-Induced Lung Injury through the Nrf2-Regulated Glutathione Metabolism Pathway in Mice.

Nicotinamide mononucleotide (NMN) is a natural antioxidant approved as a nutritional supplement and food ingredient, but its protective role in silicosis characterized by oxidative damage remains unknown. In this study, we generated a silicosis model by intratracheal instillation of silica, and then performed histopathological, biochemical, and transcriptomic analysis to evaluate the role of NMN in silicosis. We found that NMN mitigated lung damage at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1, Gstm2, and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Gene interaction analysis showed that Nrf2 interacted with Gstm1 and Mgst1 through Gtsm2. Promisingly, oxidative damage mediated by these genes occurred mainly in fibroblasts. In summary, NMN alleviates silica-induced oxidative stress and lung injury by regulating the endogenous glutathione metabolism pathways. This study reveals that NMN supplementation might be a promising strategy for mitigating oxidative stress and inflammation in silicosis.

E239K mutation abolishes the suppressive effects of lysine-specific demethylase 1 on migration and invasion of MCF7 cells.

Lysine-specific demethylase 1 (LSD1) is an important histone demethylase that mediates epithelial to mesenchymal transition (EMT). The E239K mutation of LSD1 was identified in a luminal breast cancer patient from the COSMIC Breast Cancer dataset. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with WT LSD1, but not E239K mutated LSD1, suppressed the invasion and migration of the LSD1 knockdown cells, indicating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion and migration of MCF7 cells. Further analysis showed that the E239K mutation abolished LSD1-mediated invasion and migration of MCF7 cells through downregulation of estrogen receptor α (ERα). Most importantly, the E239K mutation disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of the ERα gene; the reduced enrichment of LSD1 at the promoter region of the ERα gene caused enhanced histone H3K9 methylation, which subsequently suppressed the transcription of the ERα gene. In summary, the E239K mutation abolishes the suppressive function of LSD1 on migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3.

Exploring the sulfate patterns of chondroitin sulfate/dermatan sulfate and keratan sulfate in human pancreatic cancer.

This study was designed to explore the sulfation patterns of chondroitin sulfate (CS)/dermatan sulfate (DS), and keratan sulfate (KS) and the expression of carbohydrate sulfotransferases (CHSTs) in 26 pancreatic tumor and normal tissues. CS/DS and KS profiles were simultaneously determined. Pancreatic tumor tissues exhibited increased ΔDi-0S, ΔDi-4S, and ΔDi-6S levels, with absolute ΔDi-4S content being highest, followed by ΔDi-6S. However, as for the contents of KS-6S and KS-6S,6'S, there were no significant regular change. The expression levels of CHST1 and CHST4 were 37 and 15 times higher than those in normal tissues. PCA and OPLS-DA revealed that ΔDi-4S and ΔDi-6S levels could be reliably used to differentiate between healthy and cancerous tissues. The up-regulation of CHST3, CHST12, CHST13, and CHST15 was directly correlated with C-4 and C-6 sulfation. These data provide a foundation for future studies of the role of ΔDi-4S and ΔDi-6S in the progression of pancreatic cancer.

MicroRNA-373-3p inhibits the growth of cervical cancer by targeting AKT1 both in vitro and in vivo.

OBJECTIVE: In this study, we aimed to investigate the function of microRNA-373-3p (miR-373-3p) in the pathogenesis of cervical cancer. METHODS: Human and mouse cervical cancer cell lines were transfected with miR-373-3p mimic and inhibitor. Cell proliferation and viability were evaluated with Cell Counting Kit-8 (CCK-8) assay and Lactate Dehydrogenase (LDH) assay, respectively. The AKT1-targeting role of miR-373-3p was analyzed by qPCR and Western blot. Finally, a mouse xenograft cervical tumor model was adopted to study the in vivo effect of miR-373-3p on tumor growth and the expression of AKT1. RESULTS: Over-expression of miR-373-3p significantly reduced the proliferation of cervical carcinoma cell line in vitro. In addition, miR-373-3p overexpression also inhibited cervical cancer growth in tumor-bearing mice. Mechanistically, we found that AKT1 gene can be targeted by miR-373-3p. MiR-373-3p mimic decreased the mRNA and protein expression of AKT1, while the miR-373-3p inhibitor increased the level of AKT1 in cervical cancer cells. AKT1 overexpression rescued the proliferation of cervical cancer cells transfected with miR-373-3p. CONCLUSION: MiR-373-3p can serve as a novel anti-tumor microRNA in cervical cancer by targeting AKT1.