Anaplastic thyroid carcinoma (ATC) is an exceptionally aggressive malignancy that, despite accounting for only 1

The role of immunometabolic dysregulation in reflux esophagitis (RE), particularly the metabolic drivers of pathogenic T helper 17 (Th17) cell differentiation, is not fully understood. Although Xuanfu Daizhe Decoction (XDD) is a clinically effective Traditional Chinese Medicine (TCM) formula for RE, its potential to modulate these immunometabolic pathways remains unelucidated. This study aimed to investigate the mechanism by which tryptophan metabolic dysregulation in RE influences Th17 cell differentiation and to evaluate whether XDD exerts therapeutic effects by targeting this pathway. Metabolomic analysis was performed to assess alterations in the tryptophan metabolic pathway in serum from RE patients and RE rat models. Inflamed human esophageal epithelial cells (HEECs) model was established using acidified bile salts to observe kynurenine (KYN) secretion and its effect on Th17 differentiation. siRNA-mediated silencing of the aryl hydrocarbon receptor repressor (AHRR) was employed to clarify the role of AHRR in KYN-AhR-mediated Th17 differentiation. The interventional effects of XDD and its impact on the KYN-AHRR-AhR-Th17 axis were further examined in both cellular and rat models. Metabolomic profiling of clinical samples and RE rat models demonstrated significant dysregulation in the KYN pathway. Furthermore, we identified that inflamed HEECs induced high expression of IDO/TDO to elevate KYN secretion, which promoted Th17 cell differentiation. Mechanistically, KYN disrupted aryl hydrocarbon receptor (AhR) signaling via upregulation of its repressor, AHRR, thereby driving Th17 differentiation. Finally, we demonstrated that XDD treatment alleviated inflammation and tissue injury of RE by modulating the KYN-AHRR-AhR-Th17 axis. This study reveals a novel mechanism in RE whereby esophageal epithelial-derived KYN promotes Th17 differentiation via the AHRR–AhR signaling axis. Furthermore, XDD exerts therapeutic effects by modulating this immunometabolic pathway. These findings provide new insights into RE pathogenesis and experimental evidence supporting the application of XDD in immunometabolic disorders.

Colorectal cancer (CRC) progression is regulated by an immunosuppressive tumor microenvironment, but the epigenetic mechanisms governing this milieu remain unclear. This study identifies the histone demethylase KDM6B as a key regulator of myeloid‐derived suppressor cells (MDSCs) recruitment in CRC. Intestinal epithelial‐specific KDM6B deletion promotes tumor growth by increasing MDSCs‐mediated immunosuppression. Mechanistically, KDM6B directly transcriptionally activates solute carrier family 10 member 2 (SLC10A2), whereas its loss increased H3K27me3 repression at the SLC10A2 promoter, activating the ERK/AP‐1 pathway and subsequent CXCL/CXCR2‐dependent MDSC recruitment. Clinically, KDM6B expression positively correlated with SLC10A2 levels and inversely correlated with MDSC infiltration in human CRC specimens. More importantly, KDM6B knockdown conferred resistance to anti‐PD‐1 therapy in CRC, whereas its overexpression synergized with anti‐PD‐1 therapy. In conclusion, this study establishes the KDM6B–SLC10A2 axis as a novel epigenetic immune checkpoint, highlighting its potential as a therapeutic target for reprogramming the immunosuppressive microenvironment in CRC.

Benzyl isothiocyanate (BITC), a natural compound abundant in cruciferous vegetables, plays an important role in the chemoprevention of various human malignancies. However, the mechanism by which BITC inhibits tumor cell growth is not fully understood. This study combined network pharmacology, molecular docking, cellular experiments, and mouse tumor models to predict and validate the targets and mechanisms of BITC in the treatment of anaplastic thyroid carcinoma (ATC). A total of 10 key targets of BITC and ATC were selected for molecular docking. The key target genes of KEGG were mainly concentrated in the nuclear factor κB signaling pathway and apoptosis signaling pathway. The inhibitory effects of BITC on two ATC cell lines, 8505C and CAL-62, were dose-dependent and time-dependent, with IC50 values of 27.56 and 28.30 μmol/L, respectively. BITC induced apoptosis in ATC cells. Pretreatment with autophagy inhibitor 3MA (2 mmol/L) significantly enhanced growth inhibition caused by BITC in ATC cells. Another autophagy inhibitor, HCQ (20 μmol/L), did not enhance the inhibitory effect of BITC. In CAL-62 xenografted nude mice, BITC (100 mg·kg-1·d-2, ip) significantly inhibited tumor growth. Our results indicate that BITC can inhibit the growth of ATC cells both in vitro and in vivo. Additionally, BITC disrupts autophagic degradation in ATC cells, inhibits the NF-κB pathway, and promotes apoptosis.

BACKGROUND:Cholangiocarcinoma (CCA) is the second most common malignant tumor of the liver and lacks efficient treatments. Our previous study showed that tumor cell-derived microparticles (TMPs) containing MTX (MTX-TMPs) effectively drain the obstruction of the bile duct; however, the underlying mechanism remains unclear. METHODS:Liver function indices and immune cell percentages were analyzed in CCA patients after treatment with MTX-TMPs. An intrahepatic cholangiocarcinoma (ICC) mouse model was established to assess the effect of MTX-TMPs on ICC progression and immunomodulation. The effects of MTX-TMPs on the proinflammatory effects of CCA cells, and on the myeloid-derived suppressor cells (MDSCs) recruitment, migration, apoptosis, differentiation and immunosuppressive functions were investigated using human and mouse MDSCs. RESULTS:MTX-TMPs exhibited significant efficacy in treating patients with CCA, including increasing the proportion of CD45+cells, CD4+T, CD8+T, NK, and NKT cells in patients' bile or peripheral blood, and decreasing the proportion of MDSCs, without inducing abnormalities in liver function parameters. Animal experiments indicated that MTX-TMPs significantly alleviated the progression of ICC and reduced the proportion of MDSCs. The results of cell-based experiments indicated that MTX-TMPs inhibited the expression and secretion of inflammatory and chemotactic factors and the activation of STAT3 and NF-κB in CCA cells. Additionally, MTX-TMPs promoted MDSCs apoptosis, inhibited the recruitment of MDSCs to CCA cells, and suppressed the differentiation and immunosuppressive functions of MDSCs by inhibiting the STAT/CEBPβ signaling pathway. CONCLUSION:Our results indicated that MTX-TMPs alleviated CCA progression by regulating MDSCs, which provide an effective strategy for the treatment of CCA.

Background: Obstructive Jaundice (OJ) is a common clinical condition with potential outcomes, including hepatocyte necrosis, bile duct hyperplasia, significant cholestatic liver fibrosis, and, in severe cases, liver failure. Resveratrol (RES), a polyphenol present in grapes and berries, has demonstrated efficacy in improving OJ. However, the precise mechanism of its action remains unclear. Methods: In this study, we employed network pharmacology to investigate the underlying molecular mechanism of RES in the treatment of OJ. The targets of RES were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), SuperPred, and SwissTargetPrediction database. The targets related to OJ were gathered from the DisGeNET, GeneCards, DrugBank, and Online Mendelian Inheritance in Man (OMIM) databases, and the intersection of these targets was determined using Venny2.1.0. Subsequently, an active component-target network was constructed using Cytoscape software. The Protein-Protein Interaction (PPI) network was generated using the String database and Cytoscape software. Following this, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Bioconductor platform. Finally, quantitative Real-Time PCR (qRT-PCR), Western Blotting (WB), and Enzyme-Linked Immunosorbent Assay (ELISA) were employed to assess RNA and protein expression levels in related pathways. Results: The findings revealed a selection of 56 potential targets for RES, and a search through the online database identified 2,742 OJ-related targets with overlapping in 27 targets. In the PPI network, mTOR, CYP2C9, CYP1A1, CYP3A4, AHR, ESR1, and HSD17B1 emerged as core targets. KEGG analyses demonstrated that the primary pathways of RES in treating OJ, particularly those related to lipid metabolism, include linoleic acid metabolism, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450, lipid and atherosclerosis, tyrosine metabolism, steroid hormone biosynthesis, and pentose and glucuronate interconversions signaling pathways. Furthermore, in vivo experiments indicated that RES significantly ameliorated liver injury induced by Common Bile Duct Ligation (CBDL) in rats with OJ. It lowered serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, reduced liver tissue MDA levels, increased glutathione (GSH) content, and enhanced activity of superoxide dismutase (SOD), alleviating liver damage. Metabolomics analysis revealed that the therapeutic effect of RES in OJ involved alterations in lipid metabolic pathways, hinting at the potential mechanism of RES in treating OJ. ELISA, qRTPCR, and WB analyses confirmed lower expression levels of mTOR, CYP1A1, and CYP2C9 in the RES group compared to the model group, validating their involvement in the lipid metabolism pathway. Conclusion: In conclusion, RES exhibited a protective effect on liver function in rats with OJ. The underlying mechanism appears to be linked to antioxidant activity and modulation of lipid metabolism pathways.

ETHNOPHARMACOLOGICAL RELEVANCE:Chaihu Guizhi Ganjiang Decoction (CGGD), a classical traditional Chinese medicine (TCM), has demonstrated efficacy against pancreatic fibrosis of chronic pancreatitis (CP). However, its regulatory effects on other key pathological aspects of CP remain unclear. AIM OF THE STUDY:This study aimed to investigate the protective effects of CGGD against pancreatic acinar cell ferroptosis of CP and elucidated the underlying mechanisms. MATERIALS AND METHODS:The CP rat model was induced by dibutyltin dichloride (DBTC) for 4 weeks, and the efficacy of CGGD on pancreatic injury and fibrosis was evaluated based on serum analysis and histopathological examination. Network pharmacology combined with proteomics analysis identified potential therapeutic targets of CGGD for CP. Transmission electron microscopy (TEM) confirmed characteristic morphological hallmarks of ferroptosis. Biochemical assays were used to measure tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), as well as iron content. The key mediators of ferroptosis (TFR1, FTH1, SLC7A11, GPX4, p53) were examined by RT-qPCR and Western blot, and GPX4 and p53 localization was further confirmed by immunofluorescence. In vitro, AR42J cells were treated with cerulein, CGGD drug-containing serum (CGGDs), Nutlin-3a (a p53 activator), Erastin (a SLC7A11 inhibitor), or Trp53 siRNA. The key mediators of inflammation and ferroptosis were evaluated using commercial kits, RT-qPCR, Western blot, and immunofluorescence staining. RESULTS:CGGD significantly reduced pancreatic injury, cell death, and fibrosis in DBTC-induced CP rats. Mechanistically, p53 and ferroptosis were identified as critical targets of CGGD in CP. Specifically, CGGD suppressed p53 phosphorylation, inhibited ferroptosis pathway activation, and diminished oxidative stress both in vivo and in vitro. Notably, the reductions of ROS and restoration of GSH induced by CGGD were markedly reversed by cotreatment with Nutlin-3a or Erastin in cerulein-induced AR42J cells. Furthermore, the effectiveness of CGGDs in mitigating ferroptosis and oxidative stress was not further weakened following the knockdown of Trp53. CONCLUSION:Our findings demonstrate that CGGD suppresses ferroptosis in pancreatic acinar cells via the p53/SLC7A11/GPX4 axis, thereby elucidating a novel therapeutic mechanism of CGGD for the treatment of CP.

Liangxue Huoxue decoction(LXHX) is an effective empirical traditional Chinese medicine prescription,which has been clinically used for abdominal infectious disease for many years in Tianjin Nankai Hospital.Acute lung injury (ALI) is a severe inflammatory condition that causes lung inflammation and gut microbiota disruption. The aim of this study was to investigate the effects of LXHX on cecal ligation and puncture (CLP)-induced ALI and the related mechanisms. The principal components of LXHX were identified by high-performance liquid chromatography (HPLC).The effect of LXHX on gut microbiota was determined by 16S rRNA, while its anti-inflammatory, antioxidant, and anti-apoptotic effects were evaluated in lung tissue.16S rRNA sequence analysis showed that LXHX could partially restore the composition and diversity of intestinal flora.LXHX increased the Chao,Shannon,and Simpson index of the fecal microbiota,compared to CLP group. At the class and order level,the abundance of Gammaproteobacteria were increased in CLP group, while the abundance of Bacteroidia decreased. After LXHX treatment the abundance of Gammaproteobacteria decreased,while the abundance of Bacteroides increased.In addition, LXHX can alleviate CLP-induced pulmonary inflammation and edema as evidenced by reduced lung tissue histological damage, the levels of inflammatory cytokines in lung and bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio, as well as total protein levels in BALF. We also observed that LXHX ameliorated pulmonary oxidative damage in CLP-induced mice. In addition,LXHX dramatically prevented the CLP-induced pulmonary cell apoptosis as presented by reduced TUNEL-positive lung cells and expression of Bcl2 and enhanced expressions of Bax.Our results showed that CLP inhibited SIRT1 and Nrf2 expressions while activating NF-κB, however LXHX could increase SIRT1 and Nrf2 expression and inactivate NF-κB.Notably,all these protective effects of LXHX were abrogated by EX527.In conclusion,LXHX protects against CLP-induced ALI by restoring the composition and diversity of intestinal flora,suppressing inflammation,oxidative stress and apoptosis. These beneficial effects might be mediated by through activation of the SIRT1/Nrf2 pathway and inhibition of NF-κB signaling.

Anaplastic thyroid carcinoma is one of the highly fatal cancers and poses a serious threat to human health. Ferroptosis has been widely studied and proved to have an important role in tumor suppression, providing new avenues for cancer therapy; glutathione peroxidase 4(GPX4) and selenoprotein thioredoxin reductase(TXNRD1) are important regulatory targets in ferroptosis.Warburg effect is one of the important energy sources for cancer hypermetabolism, and pyruvate kinase isoenzyme 2 (PKM2) is a key metabolism enzyme that is important in this effect. Shikonin(SKN) is a Chinese herb that has been extensively studied for its anti-tumor ability. The aim of this study was to investigate the mechanism of anti-tumor effect of SKN in ATC cells and to elucidate the role played by ferroptosis and glycolysis in this inhibitory mechanism. The effects of SKN in ATC cell lines CAL-62 and 8505C cells were detected by flow cytometry, Western blotting,real-time quantitative PCR and a fluorescent probe for reactive oxygen species (ROS) to detect changes in intracellular ROS positivity; glucose and lactate assay kits to detect the levels of the raw material of glucose metabolism, glucose (GLU), and the product of glucose metabolism, lactate (LD); and the establishment of the BALB/C nude mice subcutaneous tumor model to analyse the inhibitory effect of SKN on ATC in vivo. The present study demonstrated that SKN inhibits the expression of NF-κB,GPX4,TXNRD1,PKM2,GLUT1.SKN inhibits ATC cell growth by down-regulating the occurrence of intracellular ferroptosis and inhibiting glycolysis in ATC cells.

Background Anaplastic thyroid cancer (ATC) has a dismal prognosis, and the optimal treatment has not yet been confirmed. Euphorbia fischeriana Steud has been proven to exhibit pharmacological properties, including various antitumor effects, that can be used to treat numerous diseases and has been used to treat cancer. 17-Hydroxy-jolkinolide B (17-HJB) is one of the major diterpenoids produced from plants, but little research has investigated how it affects cancer. Methods MTT assays, glucose and lactate concentration detection, Annexin V-FITC detection via cytometry, and Western blotting were performed to research the mechanism of 17-HJB. Results Cell viability was inhibited in a concentration-dependent manner after 17-HJB treatment. 17-HJB inhibited glucose consumption and lactate production, and the expression of the glucose transporter GLUT1 and proteins associated with glycolysis, HK2, PFK1, and PKM2, was significantly downregulated. 17-HJB induced apoptosis, and the expression of signaling proteins related to apoptosis, such as Caspase-3 and cleaved Caspase-3, was upregulated. In vivo, 17-HJB effectively inhibited the growth of ATC tumors. The results of the expression of glycolysis-related enzyme proteins and apoptosis signaling proteins were consistent with those in vitro. Conclusions 17-HJB inhibited the growth of ATCs both in vivo and in vitro. The mechanism may be related to the effects on glucose metabolism and the inhibition of aerobic glycolysis. 17-HJB also induced ATC apoptosis.

Aim: To evaluate the anti-pancreatic cancer effect of novel Tubeimoside I multifunctional liposomes combined with gemcitabine. Methods: Liposomes were prepared through the thin film hydration method, with evaluations conducted on parameters including encapsulation efficiency (EE%), particle size, polydispersity index (PDI), zeta potential (ZP), storage stability, and release over a 7-day period. The cellular uptake rate, therapeutic efficacy in vitro and in vivo and the role of immune microenvironment modulation were evaluated. Results: The novel Tubeimoside I multifunctional liposomal exhibited good stability, significant anti-cancer activity, and immune microenvironment remodeling effects. Furthermore, it showed a safety profile. Conclusion: This study underscores the potential of Novel Tubeimoside I multifunctional liposomal as a promising treatment option for pancreatic cancer.

Background: Liriodendrin (LIR) has been reported to improve cardiac function in rats following myocardial infarction. However, its role and mechanism in reparative myocardial fibrosis remain unclear. Methods: In this study, a rat model of myocardial fibrosis was established via left anterior descending artery ligation and randomly divided into three groups (n = 6 per group): sham-operated, myocardial infarction, and LIR intervention (100 mg/kg/day) groups. The pharmacological effects of LIR were assessed using echocardiography, hematoxylin, and eosin (H&E) staining, and Masson staining. Network pharmacology and bioinformatics were utilized to identify potential mechanisms of LIR, which were further validated via western blot analysis. Results: Our findings demonstrated that LIR improved cardiac function, histology scores, and collagen volume fraction. Moreover, LIR downregulated the expression of Beclin-1, LC3-II, and LC3-I while upregulating the expression of p62, indicating LIR-activated autophagy in the heart after myocardial infarction. Further analysis revealed that the PI3K/Akt signaling pathway was significantly enriched and validated by western blot. This analysis suggested that the ratios of p-PI3K/PI3K, p Akt/Akt, and p-mTOR/mTOR were significantly increased. Conclusion: LIR may attenuate myocardial infarction-induced fibrosis in rats by inhibiting excessive myocardial autophagy, with the potential mechanism involving the activation of the PI3K/Akt/mTOR pathway.

Acute lung injury is significantly associated with the aberrant activation and pyroptosis of alveolar macrophages. Targeting the GPR18 receptor presents a potential therapeutic approach to mitigate inflammation. Verbenalin, a prominent component of Verbena in Xuanfeibaidu (XFBD) granules, is recommended for treating COVID-19. In this study, we demonstrate the therapeutic effect of verbenalin on lung injury through direct binding to the GPR18 receptor. Verbenalin inhibits the activation of inflammatory signaling pathways induced by lipopolysaccharide (LPS) and IgG immune complex (IgG IC) via GPR18 receptor activation. The structural basis for verbenalin's effect on GPR18 activation is elucidated through molecular docking and molecular dynamics simulations. Furthermore, we establish that IgG IC induces macrophage pyroptosis by upregulating the expression of GSDME and GSDMD through CEBP-δ activation, while verbenalin inhibits this process. Additionally, we provide the first evidence that IgG IC promotes the formation of neutrophil extracellular traps (NETs), and verbenalin suppresses NETs formation. Collectively, our findings indicate that verbenalin functions as a “phytoresolvin” to promote inflammation regression and suggests that targeting the C/EBP-δ/GSDMD/GSDME axis to inhibit macrophage pyroptosis may represent a novel strategy for treating acute lung injury and sepsis.

OBJECTIVETo investigate the effect of Liangxue Huoxue decoction on intestinal flora, intestinal barrier and NOD-like receptor protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pyroptosis signaling pathway in mice model of sepsis-induced acute kidney injury (AKI).METHODSThe model of AKI was established by cecal ligation and perforation (CLP). Thirty male C57BL/6 mice were randomly divided into sham operation group (Sham group), sepsis group (CLP group) and sepsis+Liangxue Huoxue decoction (CLP+LXHX group), with 10 mice in each group. Mice in Sham group only underwent laparotomy. Two hours before model establishment, mice in CLP+LXHX group were treated with Liangxue Huoxue decoction (6 g/kg) by gavage; mice in Sham group and CLP group were given equal volume of normal saline by gavages. After 24 hours of modeling, all mice were sacrificed under anesthesia, and the colon and kidney tissues and fresh feces in the colon were taken. The pathological changes of kidney and colon were observed by hematoxylin-eosin (HE) staining under light microscope. Real-time polymerase chain reaction (RT-PCR) was used to detect inflammatory factors (interleukins, IL-1β and IL-18) in renal tissue. The expressions of NLRP3, caspase-1 and GSDMD were detected by Western blotting. The changes of intestinal flora in mice were detected by 16S rDNA high-throughput sequencing.RESULTSCompared with the Sham group, the inflammatory cell infiltration of the kidney tissue was increased and the kidney became vacuolated in CLP group, the mRNA expressions of IL-1β, IL-18, and the protein expressions of NLRP3, caspase-1 and GSDMD were significantly increased in CLP group, the species richness of intestinal microflora decreased significantly, the relative abundance of Enterococcus and Escherichia-Shigella increased significantly, and the relative abundance of Ileibacterium, Alloprevotella, Lachnospiraceae, Klebsiella and Parasutterella increased significantly in CLP group. Compared with CLP group, Liangxue Huoxue decoction can significantly reduce the pathological changes of kidney and colon tissue, reduce the pathological score (1.75±0.43 vs. 3.50±0.50 for kidney tissue, 1.25±0.43 vs. 4.50±0.50 for colon tissue, both P < 0.05), improve the composition of intestinal flora, reduce the relative abundance of Enterococcus and Escherichia-Shigella, and significantly increase the relative abundance of Lactobacillus and Akkermansia. In addition, Liangxue Huoxue decoction can significantly reduce mRNA expressions of IL-1β and IL-18 in kidney tissue [IL-1β mRNA (2-ΔΔCt): 1.59±0.05 vs. 4.61±0.88, IL-18 mRNA (2-ΔΔCt): 1.69±0.17 vs. 2.86±0.63, both P < 0.05] and the protein expressions of NLRP3, caspase-1 and GSDMD (NLRP3/GAPDH: 0.71±0.04 vs. 0.89±0.01, caspase-1/GAPDH: 1.04±0.04 vs. 1.48±0.04, GSDMD/GAPDH: 0.90±0.01 vs. 1.41±0.02, all P < 0.05).CONCLUSIONSLiangxue Huoxue decoction has obvious protective effect on AKI induced by sepsis. It can improve intestinal barrier by regulating intestinal flora, thereby inhibiting the activation of NLRP3/caspase-1/GSDMD signaling pathway in kidney tissue and reducing the expression of proptosis-related inflammatory factors.

Objective:To investigate the synergistic effects and molecular mechanisms of dihydroartemisinin(DHA) and sorafenib(SOR) in inducing ferroptosis in anaplastic thyroid cancer(ATC) cells.Methods:CCK-8 and flow cytometry assays were performed to detect the effects of DHA and SOR on the proliferation and ferroptosis of ATC cells(CAL-62). Real-time fluorescence quantitative PCR and Western blotting assays were performed to detect the expressions of ferroptosis-related genes glutathione peroxidase 4(GPX4), solute carrier family 7 member 11 gene(SCL7A11), lipoxygenase-15(LOX-15), and p53. The levels of iron death intermediate metabolites including lactate dehydrogenase(LDH), glutathione(GSH), malondialdehyde(MDA), ferrous ion(Fe 2+ ), nitric oxide(NO), and reactive oxygen species(ROS)were measured by corresponding assay kits. The corresponding inhibition of DHA and SOR on ATC in vivo was analyzed in a tumor model in nude mice. Results:Compared with the control group, DHA, SOR, and DHA+ SOR treatment significantly inhibited cell proliferation and apoptosis in a dose-dependent manner( P<0.001), with increased LDH, Fe 2+, MDA, and ROS contents and reduced GSH activity( P<0.001), which were promoted by ferrous sulfate(FeSO 4)and reversed by ferroptosis inhibitor-1. Compared with the control group and the drug monotherapy group, 15-LOX-2 and p53 expressions were upregulated in DHA+ SOR group while GPX4 and SCL7A11 expressions were decreased( P<0.001), without significant difference in 15-LOX-1 protein content. In addition, NO level was significantly increased in DHA+ SOR group( P<0.001). DHA and SOR inhibited tumor growth of ATC in vivo. Conclusion:DHA and SOR synergistically induced ferroptosis via upregulating the expression of 15-LOX-2 gene and inhibiting NO synthesis in ATC cells.

The primary objectives of this research were to investigate the protective effects of liriodendrin against IgG immune complex (IgG-IC)-induced acute lung injury (ALI) and to elucidate the underlying mechanisms. This study employed a mouse and cell model of IgG-IC-induced acute lung injury. Lung tissue was stained with hematoxylin–eosin to observe pathological alterations and arterial blood gas analysis was tested. Inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α), were measured using ELISA. The mRNA expression of inflammatory cytokines was assessed via RT-qPCR. Molecular docking and enrichment analysis were combined to identify the most potential signaling pathways modulated by liriodendrin, which were then verified using western blot analysis in IgG-IC-induced ALI models. We identified 253 shared targets between liriodendrin and IgG-IC-induced acute lung injury from the database. Through network pharmacology, enrichment analysis, and molecular docking, SRC was determined to be the most closely associated target of liriodendrin in IgG-IC-induced ALI. Pretreatment with liriodendrin notably reduced the increased cytokine secretion of IL-1β, IL-6, and TNF-α. Histopathological analysis of lung tissue demonstrated a protective effect of liriodendrin on IgG-IC-induced acute lung injury in mice. Arterial blood gas analysis showed liriodendrin ameliorated acidosis and hypoxemia efficiently. Further studies revealed that liriodendrin pretreatment substantially attenuated the elevated phosphorylation levels of SRC’s downstream components (JNK, P38, and STAT3), suggesting that liriodendrin may protect against IgG-IC-induced ALI via the SRC/STAT3/MAPK pathway. Our findings indicate that liriodendrin protects against IgG-IC-induced acute lung injury by inhibiting the SRC/STAT3/MAPK signaling pathway, suggesting that liriodendrin may serve as a potential treatment for acute lung injury caused by IgG-IC.

Induction of cancer cell death is an established treatment strategy, but chemotherapy drug-mediated apoptosis can be evaded by many tumors. Pyroptosis is a type of inflammatory programmed cell death (PCD) that is important for organism immunity. Tubeimoside-I (TBMS1) is a plant-derived component that exhibits antitumor activity. However, it is unclear how TBMS1 induces pyroptosis to inhibit colorectal cancer (CRC). In this study, we demonstrated that TBMS1 is able to induce pyroptosis in murine CRC cells and releases pro-inflammatory cytokines. Mechanistically, we found that TBMS1 inhibits CRC cell proliferation and migration and induces pyroptosis by activating caspase-3 and cleaving gasdermin E (GSDME) through the inhibition of PKM2. In the animal experiments, TBMS1 attenuated the weight of solid tumors, increased the proportion of CD8 + cytotoxic T cells, and reduced the content of M2-type macrophages in the spleen of tumor-bearing mice. Furthermore, TBMS1 inhibited M2-type polarization by blocking STAT6 pathway activation in RAW 264.7 cells. To sum up, our findings suggest that TBMS1 triggers pyroptosis in CRC by acting on the PKM2/caspase-3/GSDME signaling pathway. Additionally, it modulates the antitumor immune response in CRC murine models. This study provides a promising basis for the potential use of TBMS1 in treating CRC.

Background:The incidence of liver cancer is increasing every year. Hepatocellular carcinoma (HCC) accounts for nearly 90% of liver cancer, and the overall 5-year survival rate of become of Hepatocellular carcinoma patients less than 20%. However, the molecular mechanism of HCC progression and prognosis still requires further exploration.Methods:In this study, we downloaded the gene expression data from the Cancer Genome Atlas (TCGA) Genomic Data and the official website of GEO database. Weighted gene co-expression network analysis (WGCNA) and Pearson's correlation coefficient were utilized to detect the gene modules. The shared differentially-expressed genes (DEGs) were screened out by a Venn diagram, and the hub genes were identified through protein-protein interaction (PPI) network analyses. GO and KEGG enrichment analyses were constructed for these hub genes. Overall survival (OS) and correlation analysis were conducted to investigate the relationship between the hub genes and clinical features.Results:We screened out 27 shared DEGs, and the mainly enriched GO terms were mitotic nuclear division, chromosomal region, and tubulin binding. Furthermore, the top three enriched KEGG pathways were "cell cycle", "oocyte meiosis", and "p53 signaling pathway". According to the Maximal Clique Centrality (MCC) algorithm, the top 10 candidate hub genes were MYC, MCM3, CDC20, CCNB1, BIRC5, UBE2C, TOP2A, RRM2, TK1, and PTTG1, among which BIRC5, CDC20, and UBE2C showed a strong correlation with the OS.Conclusions:Three hub genes (BIRC5, CDC20, and UBE2C) were identified and found to be correlated to the progression and prognosis of HCC. These may become potential targets for HCC therapy.

Dihydroartemisinin (DHA) exhibits a direct antitumor effect in various tumor models. However, the mechanism of DHA inducing ferroptosis and activating antitumor immunity remains obscure. Therefore, our study was dedicated to investigate the effect of DHA on ferroptosis and tumor microenvironment and elucidate the underlying molecular mechanism. PDAC orthotopic tumor model was used to investigate tumor proliferation and the population of immune cell in vivo, including M2-type macrophages (M2), myeloid-derived suppressor cells (MDSCs), CD4+T cells, CD8+T cells, NK cells and NKT cells. Levels of GPX4, SLC7A11, P53 and ALOX12 were determined by Real-time PCR and Western blot. CCK8 assay was performed to detect cell viability, and the ferroptosis was distinguished by flow cytometry. Our results showed that DHA inhibited pancreatic cancer cell proliferation. In addition, DHA induced cell ferroptosis by up-regulating the expression of P53 and ALOX12, which was blocked by baicalein (a selective ALOX12 inhibitor). However, DHA also up-regulated the expression of GPX4 and SLC7A11. On the other hand, DHA significantly decreased the suppressive expansion of M2 and MDSCs. Moreover, DHA increased the immune cell population of CD8+T cells, NK cells and NKT cells in the tumor tissues of the tumor-bearing mice. Whereas, the DHA treatment did not affect the frequencies of M2, MDSCs, CD4+T, CD8+T, NK and NKT cells in the spleen. Our research provided experimental evidences on the activity and mechanism of ferroptosis induced by DHA and revealed that DHA regulated tumor local immunosuppressive microenvironment.

Background: Thyroid cancer is one of the most common cancers in the world. Genetic factors are important in the occur-rence and development of thyroid cancer, and genetic diagnosis has become an important basis for the prognosis of benign and malignant nodules. We identify a family of six siblings with inherited thyroid cancer susceptibility. All six members of this generation have been definitely diagnosed with papillary thyroid carcinoma. This work aims at confirming the relevant causa-tive genes for thyroid cancer in this pedigree.Methods: We extract DNA from the peripheral blood of six individuals and perform whole genome sequencing. Sanger sequencing and immunohistochemistry further testify the cathepsin F (CTSF) mutation and expression.Results: We identify 57 single nucleotide variations (SNVs) out of at least 4 affected family members via certain filter criteria. The CTSF gene found in five of the six family members is here considered the most promising candidate gene mutation for familial thyroid cancer. Besides, our research also proves several known genes including CTSB, TEKT4, ESR1, MSH6, DIRC3, GNAS, and BANCR that act as probable oncogenic drivers in this family. The Sanger sequencing identifies the exis-tence and veracity of CTSF somatic mutations. The CTSF immunohistochemistry of thyroid cancer tissue specimens displays that higher CTSF expression in mutated patients than that in wild-type patient as well as pericarcinomatous tissue.Conclusions: We conclude that the evaluation of CTSF gene mutations of patients in thyroid cancer families may be predic-tive and valuable for the familial heredity of thyroid cancer.