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Polycystic ovary syndrome (PCOS) represents a significant cause of infertility among women of reproductive age. Studies have established a close association between granulosa cells (GCs) and the abnormal follicle formation and ovulation processes characteristic of PCOS. The interactions among hsa_circ_0043533, miR-409-3p, and BCL2 were verified through luciferase activity assays. In PCOS patients, granulosa cells exhibit notably reduced apoptosis but enhanced growth, leading to their accumulation and the development of polycystic ovaries. The involvement of non-coding RNAs in PCOS has been documented, with elevated levels of hsa_circ_0043533 observed in this condition. A comprehensive series of experiments were conducted to explore the role of hsa_circ_0043533 in PCOS and elucidate its underlying mechanisms. Silencing hsa_circ_0043533 was found to promote apoptosis and hinder the migration, proliferation, and viability of KGN cells. Furthermore, we uncovered the regulatory effects of hsa_circ_0043533 on the miR-409-3p/BCL2 axis and key markers of Epithelial-Mesenchymal Transition (EMT). Additionally, it was observed that metformin modulates the hsa_circ_0043533/miR-409-3p/BCL2 axis. Overall, this study provides novel insights into the molecular mechanisms regulating granulosa cell proliferation and apoptosis in PCOS, further elucidating the molecular pathogenesis of this condition., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Silicosis is a progressive and chronic occupational lung disease characterized by lung inflammation, silicotic nodule formation, and diffuse pulmonary fibrosis. Emerging evidence indicates that endothelial-mesenchymal transition (EndoMT) plays a crucial role in the development of silicosis. Herein, we conducted a SiO 2 -induced EndoMT model and established a mouse model with pulmonary fibrosis by silica. We identified that SiO 2 effectively increased the expression of mesenchymal markers while decreasing the levels of endothelial markers in endothelial cells. It's further demonstrated that SiO 2 induced the PI3K/Akt signaling pathway activation via LGALS3 synthesis. Next, interfering LGALS3 blocked the process of EndoMT by inhibiting the activity of PI3K/AKT signaling. In vivo, the administration of a specific PI3K inhibitor LY294002 significantly alleviated silica-induced pulmonary fibrosis. Collectively, these results identified that the LGALS3/PI3K/AKT pathway provided a rationale target for the clinical treatment and intervention of silicosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The detoxified pneumolysin derivative ΔA146Ply has been proven to have a direct anti-triple negative breast cancer effect by our group, but its work model remains unclear. In this study, we focused on its ability to inhibit triple-negative breast cancer metastasis. We found that ΔA146Ply suppressed the migration and invasion of triple-negative breast cancer cells by activating mannose receptor and toll-like receptor 4. Their activation triggers the activation of the mammalian target of rapamycin signalling, sequentially leading to autophagy, transforming growth factor-β1, and epithelial-mesenchymal transition inhibition. Furthermore, the combination of doxorubicin and ΔA146Ply significantly inhibited triple-negative breast cancer progression and prolonged survival in tumour-bearing mice. Taken together, our study provides an alternative microbiome-based mannose receptor-targeted therapy for triple-negative breast cancer and a novel theoretical and experimental basis for the downstream signalling pathway of the mannose receptor.

Background: Colorectal cancer (CRC), which is mainly caused by epigenetic and lifestyle factors, is very often associated with functional plasticity during its development. In addition, the malignant plasticity of CRC cells underscores one of their survival abilities to functionally adapt to specific stresses, including inflammation, that occur during carcinogenesis. This leads to the generation of various subsets of cancer cells with phenotypic diversity and promotes epithelial-mesenchymal transition (EMT), formation of cancer cell stem cells (CSCs) and metabolic reprogramming. This can enhance cancer cell differentiation and facilitate tumorigenic potential, drug resistance and metastasis., Aim of Review: The tumor protein p53 acts as one of the central suppressors of carcinogenesis by regulating its target genes, whose proteins are involved in the plasticity of cancer cells, autophagy, cell cycle, apoptosis, DNA repair. The aim of this review is to summarize the latest published research on resveratrol's effect in the prevention of CRC, its regulatory actions, specifically on the p53 pathway, and its treatment options., Key Scientific Concepts of Review: Resveratrol, a naturally occurring polyphenol, is a potent inducer of a variety of tumor-controlling. However, the underlying mechanisms linking the p53 signaling pathway to the functional anti-plasticity effect of resveratrol in CRC are still poorly understood. Therefore, this review discusses novel relationships between anti-cellular plasticity/heterogeneity, pro-apoptosis and modulation of tumor protein p53 signaling in CRC oncogenesis, as one of the crucial mechanisms by which resveratrol prevents malignant phenotypic changes leading to cell migration and drug resistance, thus improving the ongoing treatment of CRC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Non-small-cell lung cancer (NSCLC) is the primary type of lung cancer with the leading cause of fatalities from cancer, and the effective treatment is minimal. Altingia chinensis is a medicinal plant utilized as a traditional folk remedy to alleviate rheumatism, punch injury and paralysis. APE is the petroleum ether extract from A. Chinensis, whose antitumor effects are rarely studied., Purpose: To explore the antitumor effects of APE on NSCLC and its molecular mechanism., Methods: LLC and H1299 cells were used to explore the anticancer effect of APE on NSCLC in vitro. MTT assay and colony formation were employed to evaluate cell viability. Flow cytometry was used to evaluate apoptosis. Wound healing and transwell were employed to evaluate cell migration and invasive capacity. Meanwhile, an LLC tumor-bearing C57BL/6J mice model was established for assessing the anticancer effect of APE on NSCLC in vivo. H&E staining was used to assess histopathology. TUNEL assay was performed to assess apoptosis in tumor tissue. Network pharmacology, CESTA, and kinase assay were employed to analyze potential molecular mechanisms. Western blots were performed to detect proteins involved in apoptosis, EMT, and the PI3K/Akt pathway., Results: This is the first investigation to identify APE's antitumor potential in both NSCLC cells and tumor-bearing mice models. Significantly, APE dose-dependently decreased cell viability and caused morphological changes both in LLC and H1299 cells. Furthermore, APE (31.25, 62.5, and 125 μg/ml) induced apoptosis in NSCLC cells, as demonstrated by increased Annexin V-FITC/PI-stained cells, the cleaved-caspase 3 levels, and the Bax/Bcl-2 ratio. Additionally, APE suppressed cell migration and invasion by the increase of E-cadherin expression and the downregulation of vimentin, implying that APE inhibited cell metastasis via attenuation of EMT. Importantly, intragastric administration of 100 mg/kg APE significantly inhibited tumor growth without apparent side effects. TUNEL assay confirmed the apoptosis in tumor tissue. Western blots validated the alteration of EMT and apoptotic markers in tumor tissue, which matched the in vitro findings. Moreover, APE directly bound to PI3Kα and inhibited its activity, leading to inhibition of the PI3K-Akt pathway., Conclusion: Overall, APE exhibits anti-tumor effects on NSCLC via induction of apoptosis, attenuation of EMT, and its mechanism involves the suppression of the PI3K/Akt pathway. Our study offers new insights for the identification of novel drug development for NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Pulmonary fibrosis is a debilitating lung disease marked by excessive fibrotic tissue accumulation, which significantly impairs respiratory function. Given the limitations of current therapies, there is an increasing interest in exploring traditional herbal formulations like Jie Geng Tang (JGT) for treatment. This study examines the potential of JGT and its bioactive component, quercetin, in reversing bleomycin (BLM)-induced pulmonary fibrosis in mice. We employed a BLM-induced MLE-12 cell damage model for in vitro studies and a bleomycin-induced fibrosis model in C57BL/6 mice for in vivo experiments. In vitro assessments showed that JGT significantly enhanced cell viability and reduced apoptosis in MLE-12 cells treated with BLM. These findings underscore JGT's potential for cytoprotection against fibrotic agents. In vivo, JGT was effective in modulating the expression of E-cadherin and vimentin, key markers of the epithelial-mesenchymal transition (EMT) pathway, indicating its role in mitigating EMT-associated fibrotic changes in lung tissue. Quercetin, identified through network pharmacology analysis as a potential key bioactive component of JGT, was highlighted for its role in the regulatory mechanisms underlying fibrosis progression, particularly through the modulation of the IL-17 pathway and Il6 expression. By targeting inflammatory pathways and key processes like EMT, JGT and quercetin offer a potent alternative to conventional therapies, meriting further clinical exploration to harness their full therapeutic potential in fibrotic diseases., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of The Liaoning Changsheng Biotechnology (CSE20201017). Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Research involving animals: Male C57BL/6 mice, 5–7 weeks old, were sourced from Liaoning Changsheng Biotechnology (Approval No. SCXK(Liao)2020–00001). We divided the mice into five groups with seven animals each: control, BLM (5 mg/kg), two BLM + JGT-E groups treated with 50 mg/kg and 100 mg/kg, and BLM + PFD (100 mg/kg) group. After acclimating for 1 week, the JGT-E treatment was administered orally to the respective groups for 3 days. Mice designated for BLM treatment received a 5 mg/kg dose intratracheally, while controls were given saline. Both JGT-E and PFD treatments were continued daily, based on individual body weights. Three weeks later, the mice were euthanized for analysis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mitochondrial permeability transition pore (mPTP) opening is a key hallmark of injured type II alveolar epithelial cells (AECIIs) in idiopathic pulmonary fibrosis (IPF). Inhibiting mPTP opening in AECIIs is considered a potential IPF treatment. Herein, a "double braking" strategy on mPTP by cyclosporin A (CsA) derived ionizable lipid with 3D structure (3D-lipid) binding cyclophilin D (CypD) and siRNA downregulating mitochondrial calcium uniporter (MCU) expression is proposed for treating IPF. 3D-lipid and MCU targeting siRNA (siMCU) are co-assembled to form stable 3D-LNP/siMCU nanoparticles (NPs), along with helper lipids. In vitro results demonstrated that these NPs effectively inhibit mPTP opening by 3D-lipid binding with CypD and siRNA downregulating MCU expression, thereby decreasing damage-associated molecular patterns (DAMPs) release and suppressing epithelial-to-mesenchymal transition (EMT) process in bleomycin-induced A549 cells. In vivo results revealed that 3D-LNP/siMCU NPs effectively ameliorated collagen deposition, pro-fibrotic factors secretion, and fibroblast activation in bleomycin-induced pulmonary fibrosis (PF) mouse models. Moreover, compared to the commercial MC3-based formulation, optimized Opt-MC3/siRNA NPs with incorporating 3D-lipid as the fifth component, showed superior therapeutic efficacy against PF due to their enhanced stability and higher gene silencing efficiency. Overall, the nanomedicine containing 3D-lipid and siMCU will be a promising and potential approach for IPF treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe -/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury., Competing Interests: Compliance with ethics guidelines. Conflicts of interest Yixiu Zhao, Zhiqi Wang, Jing Ren, Huan Chen, Jia Zhu, Yue Zhang, Jiangfei Zheng, Shifeng Cao, Yanxi Li, Xue Liu, Na An, Tao Ban, Baofeng Yang, and Yan Zhang declare that they have no conflict of interest. Baofeng Yang is a member of the Editorial Board of Frontiers of Medicine, who was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias. All institutional and national guidelines for the care and use of laboratory animals were followed., (© 2024. Higher Education Press.)

Radiation-induced lung injury is a significant complication of thoracic malignant tumor radiotherapy, yet effective treatments remain scarce. Aldehyde dehydrogenase 2 (ALDH2) possesses antioxidant and anti-inflammatory properties, but its specific role in radiation-induced lung injury is not well understood. This study aimed to investigate the impact of ALDH2 on radiation-induced lung injury and elucidate the underlying mechanisms. Through analysis of radiation-induced lung injury datasets, intervention with ALDH2 agonists and inhibitors in an in vivo radiation-induced lung injury model, and establishment of an in vitro radiation-induced lung injury model using A549 stable cells with varying ALDH2 expressions, we discovered that ALDH2 expression is reduced in radiation-induced lung injury. Enrichment analysis suggested that ALDH2 may mitigate radiation-induced lung injury by modulating oxidative stress and inflammation levels. Additionally, single-cell data analysis reveals that ALDH2 is primarily localized in myeloid macrophages within the lungs, with its expression also being reduced in lung cancer patients. Subsequent examination of mouse pathological sections, reactive oxygen species (ROS), and inflammatory factor levels confirmed that ALDH2 can lessen radiation-induced lung injury by suppressing ROS and inflammatory factors. Both in vivo and in vitro Western blot analysis further validated that ALDH2 can attenuate epithelial-mesenchymal transition and inhibit the TGF-β1/Smad pathway. Therefore, ALDH2 shows promise in reducing radiation-induced lung injury by inhibiting ROS and TGF-mediated epithelial-mesenchymal transition, making it a potential target for the treatment of radiation-induced lung injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Efforts have been focused on developing new anti-HCC agents and understanding their pharmacology. However, few agents have been able to effectively combat tumor growth and invasiveness due to the rapid progression of HCC. In this study, we discovered that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moore, effectively inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. FAN treatment also led to the suppression of IL6 and IL1β release, as well as the expression of inflammation-related proteins such as COX-2 and iNOS, and the activation of the NF-κB pathway, thereby reducing inflammation-related EMT. Additionally, FAN directly bound to forkhead box protein M1 (FOXM1), resulting in decreased levels of FOXM1 proteins and disruption of the FOXM1-ADAM17 axis. Our in vivo findings confirmed that FAN effectively hindered the growth and lung metastasis of HCCLM3-xenograft tumors. Importantly, the upregulation of FOXM1 in HCC tissue suggested that targeting FOXM1 inhibition with FAN or its inhibitors could be a promising therapeutic approach for HCC. Overall, this study elucidated the anti-tumor effects and potential pharmacological mechanisms of FAN, and proposed that targeting FOXM1 inhibition may be an effective therapeutic strategy for HCC with potential clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

RAS-selective lethal small molecule 3 (RSL3) is a small-molecule compound that triggers ferroptosis by inactivating glutathione peroxidase 4. However, its effect on the radioresistance of glioma cells and the underlying mechanisms remains unclear. In this study, we found that RSL3 sensitized glioma cells to ionizing radiation (IR) and enhanced IR-induced DNA double-strand breaks (DSBs). Inhibition of ferroptosis pathways partly prevented the clonogenic death caused by the IR/RSL3 combination but did not alleviate the DNA DSBs, indicating that RSL3 promotes IR-induced DNA DSBs via a non-ferroptotic mechanism. We demonstrated that transglutaminase 2 (TGM2) plays a vital role in the radiosensitization effect of RSL3 on glioma cells. Treatment with RSL3 downregulated TGM2 in a dose-dependent manner. Overexpression of TGM2 not only alleviated DNA DSBs but also inhibited clonogenic death caused by the IR/RSL3 combination. Mechanistically, RSL3 triggered oxidative stress in glioma cells, which promoted the S-gluthathionylation of TGM2 via upregulation of glutathione S-transferase P1(GSTP1), culminating in the proteasomal degradation of TGM2. This process resulted in the suppression of DNA repair mechanisms by impeding the nuclear accumulation of TGM2 and disrupting the interaction between TGM2 and topoisomerase IIα after irradiation. We also found that RSL3 inhibited glioma cell epithelial-mesenchymal transition (EMT) in both IR-treated and non-IR-treated cells. Overexpression of TGM2 prevented, while knockdown of TGM2 aggravated the EMT inhibition caused by RSL3, indicating that RSL3 also sensitized glioma cells to IR by inhibiting EMT via a TGM2-dependent mechanism. Furthermore, in mice bearing human U87 tumor xenografts, RSL3 administration synergized with IR to inhibit tumor growth, accompanied by TGM2 inhibition, DNA DSBs, and EMT inhibition in tumor tissues. Taken together, we demonstrated that RSL3 sensitizes glioma cells to IR by suppressing TGM2-mediated DNA repair and EMT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Fibrotic cataracts, the most frequent complications after phacoemulsification, cannot be cured by drugs in clinic. The primary mechanism underlying the disease is the epithelial-mesenchymal transition (EMT). Cimifugin is a natural monomer component of traditional Chinese medicines. Previous researches have demonstrated the effect of cimifugin inhibiting EMT in the lung. The purpose of this work is to evaluate the impact of cimifugin on EMT in the lens and elucidate its precise mechanism. The pathogenesis of fibrotic cataracts was simulated using TGFβ2-induced cell model of EMT and the injury-induced anterior subcapsular cataract animal model. Through H&E staining and immunofluorescence of mice eyeballs, we discovered that cimifugin can inhibit the expansion of fibrotic lesions in vivo. Furthermore, at mRNA and protein levels, we confirmed that cimifugin can allay EMT of lens epithelial cells (LECs) in vitro and in vivo. Additionally, the inhibition of cimifugin on the activation of TGFβ-related signaling pathways was certified by immunoblot. HSP90β, the target of cimifugin, was predicted by network pharmacology and verified by drug affinity responsive target stability, the cellular thermal shift assay, and microscale thermophoresis. Moreover, co-immunoprecipitation revealed the interaction between HSP90β and TGFβ receptor (TGFβR) II. Together, our findings showed that by weakening the binding of HSP90β and TGFβRII, cimifugin suppressed the TGFβ signaling pathways to alleviate fibrotic cataracts. Cimifugin is a promising medication for the treatment of fibrotic cataracts., Competing Interests: Declaration of competing interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a five-year survival rate below 50 %. Standard treatments for HNSCC include surgery, radiotherapy, chemotherapy, and targeted therapies, but they still have significant limitations. Neddylation, a post-translational modification involving the attachment of NEDD8 (neural precursor cells expressed developmentally down-regulated 8) to proteins, is frequently dysregulated in HNSCC, thereby promoting tumor growth. MLN4924, also known as Pevonedistat, is a Neddylation inhibitor that has shown promise in suppressing HNSCC cell proliferation and invasion, establishing it as a potential therapeutic option. However, its precise molecular mechanism remains unclear. This study aims to investigate the mechanism of MLN4924 in HNSCC. This study examined the effects of MLN4924 on HNSCC and its associated molecular pathways. Bioinformatic analysis indicated that NEDD8, a critical component of the Neddylation pathway, is linked to poor prognosis and the mTOR (mammalian target of rapamycin) signaling pathway in HNSCC. MLN4924 significantly suppressed cell migration, invasion, and the epithelial-mesenchymal transition (EMT) pathway, and downregulated NEDD8 expression. Mechanistic studies demonstrated that MLN4924 inhibited the binding of NEDD8 to cullin4 (CUL4) and prevented the Neddylation of tuberous sclerosis complex 2 (TSC2), leading to the inactivation of the mTOR pathway. These findings were confirmed in vivo, where MLN4924 effectively inhibited tumor growth. Overall, MLN4924 disrupted Neddylation pathway and stabilized TSC2, thereby inactivating the mTOR pathway. The study provided a theoretical basis for the clinical potential of MLN4924 in improving treatment outcomes for HNSCC patients, offering a novel strategy for addressing this challenging disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context: Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated., Objective: This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP)., Materials and Methods: After tabersonine (10 μM) and/or CDDP (10 μM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial-mesenchymal transition (EMT) phenotypes., Results: Tabersonine demonstrated inhibitory effects on TNBC cells, with IC 50 values at 48 h being 18.1 μM for BT549 and 27.0 μM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine., Discussion and Conclusions: Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.

Background: Asthma is a prevalent long-term inflammatory condition that causes airway inflammation and remodeling. Increasing evidence indicates that epithelial-mesenchymal transition (EMT) holds a prominent implication in airway reconstruction in patients with asthma. Flavonoids obtained from Chinese Materia Medica (CMM), such as Luteolin (Lut), exhibit various beneficial effects in various asthma models. Lut has been shown to mitigate various asthma symptoms, including airway inflammation, hyperresponsiveness, bronchoconstriction, excessive mucus production, pulmonary autophagy, and neutrophilic asthma. However, whether flavonoids can suppress EMT-associated airway remodeling in asthma and the fundamental mechanisms involved remain unclear, with no studies specifically addressing Lut in this context., Purpose: To evaluate the inhibition of airway remodeling in asthma by Lut and its potential mechanisms, while examining the significance of β-catenin in this process through cellular and animal studies., Methods: A BEAS-2B cell model stimulated by lipopolysaccharide (LPS) was established in vitro. Wound closure and Transwell assays were utilized to assess the cellular migratory ability. EMT- and fibrosis-related markers in LPS-stimulated cells were evaluated using RT-qPCR and western blotting. The status of the β-catenin/E-cadherin and β-catenin destruction complexes was evaluated using western blotting, immunofluorescence (IF) staining, and co-immunoprecipitation (Co-IP) analysis. The regulatory function of Lut in β-catenin-dependent EMT was further validated by β-catenin overexpression with adenovirus transduction and siRNA-mediated knockdown of β-catenin. Moreover, the counts of different types of bronchoalveolar lavage fluid (BALF) inflammatory cells from mice with asthma induced by ovalbumin (OVA) were evaluated in vivo using Congo red staining. Hematoxylin and eosin (H&E), Masson's trichrome, and periodic acid-Schiff (PAS) staining were used to evaluate collagen deposition, mucus production, and inflammation in murine lung tissues. Western blotting and immunohistochemistry (IHC) assays were used to assess EMT- and fibrosis-related markers in the lung tissues in vivo., Result: Six naturally derived flavonoids, including Lut, attenuated cell migration and prevented EMT in LPS-treated BEAS-2B cells. Moreover, Lut suppressed TGF-β1, MMP-9, fibronectin (FN), and α-smooth muscle actin (α-SMA) levels in LPS-stimulated BEAS-2B cells. Additionally, Lut downregulated the levels of β-catenin by modulating the β-catenin/E-cadherin and β-catenin destruction complexes, highlighting the pivotal role of β-catenin in EMT inhibition by Lut in LPS-stimulated BEAS-2B cells. Furthermore, Lut suppressed airway inflammation and attenuated EMT-associated airway remodeling through β-catenin blockade in OVA-induced asthmatic mice. The bronchial wall thickness notably reduced from 37.24 ± 4.00 μm in the asthmatic model group to 30.06 ± 4.40 μm in the Lut low-dose group and 24.69 ± 2.87 μm in the Lut high-dose group., Conclusion: According to our current understanding, this research is the first to reveal that Lut diminishes airway remodeling in asthma by inhibiting EMT via β-catenin regulation, thereby filling a research gap concerning Lut and flavonoids. These results provide a theoretical basis for treating asthma with anti-asthmatic CMM, as well as a candidate and complementary therapeutic approach to treat asthma., Competing Interests: Declaration of competing interest All authors declare no conflict of interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: The gut microbiota is believed to influence atherosclerosis (AS), and Aucubin (Au), a natural compound found in the traditional Chinese medicine Eucommia ulmoides Oliver, is being explored as a potential treatment for cardiovascular disease. Yet, the specific impact of Au on AS through the gut microbiota remains unclear., Purpose: This study aimed to highlight the potential of Au in improving AS by influencing gut microbiota and investigating its potential mechanisms by which it and its metabolites of gut microbiota regulate lipid metabolism, inflammation and endothelial dysfunction., Methods: The impact of Au on AS in ApoE -/- mice was examined, followed by a fecal microbiota transplantation experiment to confirm the influence of Au on AS through gut microbiota. Subsequent analysis of fecal and serum samples using 16S rRNA gene sequencing and metabolomics revealed distinct features of gut microbiota and metabolites. Identified metabolites were then utilized in vivo experiments to investigate underlying mechanisms., Results: Au treatment effectively reduced dietary-induced dyslipidemia and endothelial dysfunction in a dose-dependent manner in atherosclerotic mice. It also improved vascular plaque accumulation and inflammation, increased aortic valve fibrous cap thickness, and decreased necrotic core and collagen fiber area. Subsequently, we observed a substantial increase in indole-3-acrylic acid (IAA), a microbe-derived metabolite, in cecal contents and serum, along with a significant rise in Lactobacillus abundance responsible for IAA production. Our findings demonstrated that IAA played a crucial role in alleviating AS. Furthermore, we discovered that IAA activated the Aryl hydrocarbon receptor (AhR) and suppressed the TGF-β/Smad pathway, potentially ameliorating endothelial-mesenchymal transitions in atherosclerotic mice., Conclusion: These findings suggested that Au's anti-atherosclerotic effects were primarily due to elevated Lactobacillus-derived IAA, thereby potentially contributing to alleviating AS., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Calcium electroporation (CaEP) involves the combination of calcium ions with electroporation, which is induced by pulsed electric fields (PEFs). This study explores the application of high-frequency unipolar nanosecond pulsed electric fields (nsPEFs: 8-14 kV/cm, 200 ns, 10 kHz, 100 kHz, 1 MHz repetition frequency pulse bursts, n = 100) and their potential in inhibiting lung cancer cell growth. As a reference, standard microsecond range parametric protocols were used (100 µs x 8 pulses). Methods included cell permeability quantification through Yo-Pro-1 uptake, cell viability assays, immunofluorescence studies for apoptosis and EMT markers, analysis of cell death types depending on repetition frequency pulse bursts. We determined the susceptibility of human lung cancer to electric pulses, characterized the efficacy of CaEP, and investigated cell death types depending on repetition frequency pulse bursts. We have shown that adding calcium ions to the applied nsPEF protocol increases cytotoxicity. Additionally, the use of these electroporation parameters can modulate key cellular processes, such as the epithelial-mesenchymal transition and apoptosis, as indicated by changes in the expression of markers such as E-cadherin, N-cadherin, BCL-2, and p53. Changes in cell morphology over time were observed using holotomographic microscopy. The study provides insights into the modulation of key cellular processes, indicating that nsPEF technology could improve the outcomes of conventional cancer treatments through enhanced efficacy and potentially mitigating drug resistance mechanisms. The promising results advocate for further research to optimize nsPEF protocols for clinical application, highlighting the potential of electrical fields in advancing cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Nina Rembialkowska reports financial support was provided by National Science Centre, and Wroclaw Medical University provided administrative support and article publishing charges. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The epithelial-mesenchymal transition (EMT), tumor stroma and local metabolic alterations cooperate to establish a unique tumor microenvironment (TME) that fosters tumor progression and metastasis. To tackle this challenge, a precision intelligent nanomissile named HA@AT-Pd has been designed for dual-pronged cancer-associated fibroblast (CAF) transformation and tumor cell elimination. It is observed that HA@AT-Pd inhibits the production of cancer stem cells (CSCs) by blocking the TGF-β/Smad signaling pathway-mediated EMT and reversing activated CAFs to quiescence. Notably, HA@AT-Pd induces energy depletion in breast cancer cells through simultaneously suppressing cellular oxidative phosphorylation and glycolysis. The inhibition of glycolysis results in reduced lactic acid production, thereby converting an immunosuppressive TME into an immune-activating environment. Furthermore, the photothermal effect generated by HA@AT-Pd evokes immunogenic cell death, which can further enhance the anti-tumor immune response. Overall, this multifunctional combination strategy unveils potential therapeutic avenues to inhibit tumor progression and metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tumor cells can survive when detached from the extracellular matrix or lose cell-to-cell connections, leading to a phenomenon known as anoikis resistance (AR). AR is closely associated with the metastasis and proliferation of tumor cells, enabling them to disseminate, migrate, and invade after detachment. Here, we have investigated a novel composite nanoenzyme comprising mesoporous silica/nano-cerium oxide (MSN-Ce@SP/PEG). This nanoenzyme exhibited satisfactory catalase (CAT) activity, efficiently converting high levels of H 2 O 2 within tumor cells into O 2 , effectively alleviating tumor hypoxia. Furthermore, MSN-Ce@SP/PEG nanoenzyme demonstrated high peroxidase (POD) activity, elevating reactive oxygen species (ROS) levels and attenuating AR in hepatocellular carcinoma (HCC) cells. The MSN-Ce@SP/PEG nanoenzyme exhibited satisfactory dual bioactivity in CAT and POD and was significantly enhanced under favorable photothermal conditions. Through the synergistic effects of these capabilities, the nanoenzyme disrupted the epithelial-mesenchymal transition (EMT) process in detached HCC cells, ultimately inhibiting the recurrence and metastasis potential of anoikis-resistant HCC cells. This study represents the first report of a novel nanoenzyme based on mesoporous silica/nano-cerium oxide for treating AR in HCC cells, thereby suppressing HCC recurrence and metastasis. The findings of this work offer a pioneering perspective for the development of innovative strategies to prevent the recurrence and metastasis of HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Gastric cancer (GC) ranks as the fifth most prevalent cancer globally. Owing to the absence of early manifest symptoms, it is difficult to diagnose GC until it has metastasized to other organs. Hence, the prevention and treatment of GC have become major concerns for patients. Echium amoenum , a traditional medicinal plant from the Boraginaceae family, exhibits various biological activities. Although recent studies have reported the anticancer properties of E. amoenum , its effects and mechanisms of action on GC cells are not yet fully understood. This study examined the anticancer effects of the ethyl acetate extract of E. amoenum (EAEC) and its main active ingredient, rosmarinic acid (RA), in GC AGS cells. EAEC and RA suppressed AGS cell growth by inducing apoptosis through caspase mediation and inhibited AGS cell metastasis by influencing the expression of crucial epithelial-mesenchymal transition (EMT) biomarkers. Furthermore, the anti-growth and anti-metastatic effects of EAEC and RA on AGS cells involved inactivation of the STAT3, AKT, and ERK1/2 pathways. Additionally, RA notably inhibited the in vivo tumor growth in AGS cells. Overall, these results indicate that EAEC and RA could serve as potential anticancer and anti-metastasis agents for GC.

Cervical cancer (CC) is a malignant tumor in females characterized by high incidence and mortality rates, often resulting in a poor prognosis for patients. Zoledronic acid (ZA), a third-generation bisphosphonate, exhibits anti-tumor properties across various types of tumors. To further understand the effect of ZA in the treatment of CC, this article included two kinds of human CC cells (CCCs) as the research object, examining the impact of varying levels of ZA on the cells' biological properties. Hela and Siha were cultivated and exposed to ZA at 0, 50, 100, and 200 μM, and the changes of cell proliferation, clone formation, migration, and invasion characteristics were detected. Cell RNA was extracted to detect epithelial-mesenchymal transition (EMT) and the relative expression (RE) of AKT/GSK3β/β-catenin (β-cat) pathway related proteins. The results show that as against 0 μM, the proliferation rate, clone formation cell number, migration distance, and invasive cell number of Hela and Siha were markedly reduced, while E-cadherin (E-cad) was markedly enhanced. N-cadherin (N-cad), vimentin (Vim), p-AKT, p-GSK3β, and β-cat were markedly decreased at 50, 100, and 200 μM ZA; With the increase of ZA concentration, the biological characteristics and protein expression levels of Hela and Siha changed more markedly, showing concentration dependent characteristics (P < 0.05). It was concluded that ZA can influence the malignant biological activities of CCCs., Competing Interests: The Authors declared no conflict of interest, (African Journal of Reproductive Health © 2024.)

The etiology of gallbladder cancer (GBC) is multifactorial, with chronic inflammation resulting from infections, autoimmune diseases, and lifestyle factors playing a pivotal role. Vitamin D deficiency (VDD) has been implicated in the pathogenesis of autoimmune disorders and various malignancies, including GBC. Research on autoimmune diseases highlights the anti-inflammatory properties of vitamin D, suggesting its potential to mitigate disease progression. In oncology, VDD has similarly been linked to increased inflammation, which may contribute to both the initiation and progression of cancer. A critical component in carcinogenesis, as well as in the immunomodulatory effects of vitamin D in autoimmune conditions, is the balance between T-helper 17 (Th17) cells and regulatory T (Treg) cells. We hypothesize that vitamin D may inhibit epithelial-mesenchymal transition (EMT) in GBC by modulating the spatial distribution of tumor-infiltrating T cells, particularly through the regulation of the Th17/Treg balance at the tumor margins. This Th17/Treg imbalance may act as a mechanistic link between VDD and the progression of GBC carcinogenesis. Investigating the role of an Th17/Treg imbalance as a mediator in VDD-induced EMT in GBC not only provides deeper insights into the pathogenesis of GBC but also sheds light on broader mechanisms relevant to the development of other solid organ cancers, given the expanding recognition of the roles of VDD and Th17/Treg cells in cancer biology.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by inflammation and airway remodeling. Lymphoid follicles play a crucial role in acquired immunity and the development of COPD. However, the precise mechanisms of lymphoid follicle formation in COPD and the effects of cigarette smoke (CS) exposure on this process remain unclear. Epithelial-mesenchymal transition (EMT) is implicated in the progression of COPD and may serves as a source of stromal cells that produce chemokines crucial for lymphoid follicle formation. This study aims to clarify the contributions and mechanisms of EMT in lymphoid follicle genesis in COPD, focusing specifically on the role of CXCL13., Methods: Lung tissue samples were obtained from patients with COPD, smokers, and non-smokers. Immunohistochemistry was performed to assess the lymphoid follicles, EMT-related markers, and CXCL13 expression. In vitro experiments were conducted using CS extract (CSE)-stimulated immortalized human bronchial epithelial cells (iHBECs) to induce EMT. The expression of EMT-related markers and CXCL13 in CSE-stimulated iHBECs was analyzed using Western blotting, real-time PCR, and immunofluorescence staining. The effect of an EMT inhibitor on CXCL13 expression was also examined., Results: Patients with COPD and lymphoid follicles exhibited significantly lower forced expiratory volume in 1 s (% predicted) values than those without lymphoid follicles. Enhanced EMT changes were observed in patients with COPD and lymphoid follicles. Increased EMT-related markers and CXCL13 expression were observed in CSE-stimulated iHBECs, and CXCL13 expression gradually increased over time. Inhibiting EMT downregulated CXCL13 expression in iHBECs., Conclusion: Lymphoid follicles are associated with enhanced EMT in COPD. EMT may act as a key driver of the adaptive immune response in COPD by promoting a microenvironment conducive to lymphoid follicles formation through the production of CXCL13. This study provides valuable insights into the mechanisms underlying lymphoid follicle formation in COPD and identifies potential therapeutic targets., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yang et al.)

This study investigates the potential therapeutic effects and molecular mechanisms of hesperidin treatment on cell migration and epithelial-mesenchymal transition, key stages of proliferative vitreoretinopathy (PVR). Human retinal pigment epithelial cells (ARPE-19) were treated with 10 ng/ml transforming growth factor-beta 2 (TGF-β2) alone or in combination with 1.56 μM hesperidin for 48 h. The impact of treatment on cell migration was evaluated using a wound healing assay. Apoptosis was assessed using DNA staining. mRNA and protein expression were evaluated using real-time PCR and Western blot, respectively. Hesperidin inhibits the proliferation and transformation of the cells by inducing apoptosis and reverses the cell morphology modified by TGF-β2. Hesperidin inhibits cell migration induced by TGF-β2. Upon treatment with hesperidin, the levels of mesenchymal markers upregulated by TGF-β2, such as MMP-1, -2, -9, fibronectin, α-SMA and the transcription factors Snail, Slug and ZEB-1, were downregulated. Conversely, the epithelial marker E-cadherin is upregulated with hesperidin treatment. Additionally, TIMP-1 and TIMP-2 expression levels, which are downregulated, increase with the treatment. These results suggest that hesperidin may inhibit the migration and EMT processes of RPE cells involved in the development of PVR, indicating its potential as a therapeutic agent for treating PVR., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no financial, personal or professional conflict of interest. Ethical approval: Not applicable. This article does not contain any studies with human participants or live animals performed by any of the authors. Informed consent: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Lung cancer, the leading cause of death worldwide, is associated with the highest morbidity. Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases. Advances in the domain of cancer treatment have improved the prognosis and quality of life of patients with metastatic NSCLC. Nevertheless, tumor progression or metastasis owing to treatment failure caused by primary or secondary drug resistance remains the cause of death in the majority of cases. Epithelial-mesenchymal transition (EMT), a vital biological process wherein epithelial cancer cells lose their inherent adhesion and transform into more invasive mesenchymal-like cells, acts as a powerful engine driving tumor metastasis. EMT can also induce immunosuppression in the tumor environment, thereby promoting cancer development and poor prognosis among patients with NSCLC. This review aims to elucidate the effect of EMT on metastasis and the tumor immune microenvironment. Furthermore, it explores the possible roles of EMT inhibition in improving the treatment efficacy of NSCLC. Targeting EMT may be an ideal mechanism to inhibit tumor growth and progression at multiple steps.

Idiopathic pulmonary fibrosis (IPF) is a pulmonary disease characterized by excessive extracellular matrix protein deposition in the lung interstitium, subsequently causing respiratory failure. IPF still has a high medical unmet requirement due to the lack of effective treatments to inhibit disease progression. The etiology of IPF remains unclear, but mitochondrial dysfunction is considered to be associated with IPF development. Therefore, targeting mitochondrial abnormalities would be a promising strategy for treating IPF. Recently, exogenous mitochondrial transplantation has been beneficial for treating mitochondrial dysfunction. The current study aimed to examine the therapeutic effect of mitochondrial transplantation on IPF in vitro and in vivo. Mitochondria were isolated from human umbilical cord mesenchymal stem cells, referred to as PN-101. Human lung fibroblasts and human bronchial epithelial cells were exposed to transforming growth factor-β, followed by PN-101 treatment to determine the in vitro efficacy of mitochondrial transplantation. An IPF mouse model established by a single intratracheal instillation of bleomycin was utilized to determine the in vivo efficacy of the intravenously treated mitochondria. PN-101 attenuated mitochondrial damage, inhibited EMC production, and suppressed epithelial-to-mesenchymal transition in vitro. Additionally, intravenous PN-101 administration alleviated bleomycin-induced fibrotic processes in the IPF mouse model with a therapeutic context. Our data indicate that PN-101 is a novel and potential therapeutic agent for IPF.

Distant metastasis is the leading cause of cancer-related mortality, and achieving survival benefits through advancements in systemic therapy remains challenging. Mast cells play a dual role in shaping the tumor microenvironment (TME) and influencing distant metastasis, underscoring the significant research value of targeting mast cells for systemic therapy in advanced cancer. We investigated variations in mast cell infiltration levels in primary and metastatic malignancies using immunocyte infiltration analysis. Mast cell subsets were identified from pan-cancer distant metastasis single-cell sequencing data through dimensionality reduction clustering and cell type annotation, combined with cell trajectory and communication network analyses. A prognostic model was established using WGCNA and 12 machine learning algorithms to identify potential mast cell targets. Drug sensitivity and Mendelian randomization analyses were conducted to select potential drugs targeting mast cells, and their effects on epithelial-mesenchymal transition (EMT) were validated through in vitro experiments, including wound healing, transwell, and western blot assays. Results revealed that activated mast cells show increased infiltration in metastatic tumors, correlating with poor survival duration. XBP1+ mast cells were identified as key components of the inhibitory TME, potentially involved in EMT activation. Simvastatin was identified as a potential drug, reversing EMT induced by XBP1+ mast cells in pan-cancer. Aberrant activation of MEK/ERK signaling in XBP1+ mast cells can stimulate cancer cell EMT by modulating degranulation, while Simvastatin can inhibit EMT by suppressing degranulation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The data utilized in this study is exclusively obtained from publicly available sources and commercial human cell line, eliminating the need for ethical scrutiny. Consent for publication: Not applicable., (© 2024. The Author(s).)

Purpose: Methotrexate (MTX)-induced pulmonary fibrosis is associated with high morbidity and mortality, with limited treatment options available. This study investigates whether disulfiram (DSF) can mitigate MTX-induced pulmonary fibrosis and explores the underlying mechanisms., Methods: Eight-week-old male mice were divided into control, DSF, MTX, and MTX+DSF groups and treated for 8 weeks. Weight, food, and water intake were monitored. Post-treatment, lung tissues were analyzed using HE and Masson staining, and electron microscopy. Real-time qPCR and ELISA were employed to assess inflammatory markers such as IL-1β and TNF-α in lung tissues and serum. PCR, ELISA, and Western blot were used for fibrotic markers including Col1α1, α-SMA, and hydroxyproline. Type 2 alveolar epithelial cell line MLE12 cells were similarly grouped, followed by RNA sequencing and bioinformatics analysis to elucidate the mechanisms by which DSF exerts anti-MTX-induced pulmonary fibrosis effects. ELISA and Western blot were used to measure E-cadherin and α-SMA expression., Results: DSF significantly reduced MTX-induced alveolar septal thickening, pulmonary fibrosis, and inflammatory cell infiltration. It also decreased the expression of inflammatory factors IL-1β and TNF-α, as well as the expression of Col1α1, α-SMA, and others. RNA-seq revealed that DSF induces changes in multiple signaling pathways associated with pulmonary fibrosis, particularly in extracellular matrix-related genes. ELISA and Western blot showed decreased E-cadherin and increased α-SMA in the MTX group, which was partially restored with DSF treatment., Conclusion: DSF alleviates MTX-induced pulmonary fibrosis by reducing epithelial-mesenchymal transition (EMT) in type 2 alveolar epithelial cells. Disulfiram shows potential as a therapeutic agent for MTX-induced pulmonary fibrosis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical Approval: The experiments conducted in this study were approved by the Ethics Committee of Xi’an Medical University (Approval No. XYLS2022246)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acquired resistance to platinum-derived cytostatics poses major challenges in ovarian carcinoma therapy. In this work, we show a shift in the epithelial-mesenchymal transition (EMT) process towards an "ectodermal" conversion of ovarian carcinoma cells in response to cisplatin treatment, a progression we have termed epithelial-mesenchymal-ectodermal transition (EMET). EMET appears to occur via the classical EMT as judged by a) the downregulation of several epithelial markers and b) upregulation of Vimentin, accompanied by various embryonal transcription factors and, importantly, a plethora of neuronal markers, consistent with ectodermal differentiation. Moreover, we isolated cells from ovarian carcinoma cultures exhibiting a dual neural/stemness signature and multidrug resistance (MDR) phenotype. We also found that the epithelial cells differentiate from these neural/stem populations, indicating that the cell of origin in this tumor must in fact be a neural cell type with stemness features. Notably, some transcription factors like PAX6 and PAX9 were not localized in the nucleoplasm of these cells, hinting at altered nuclear permeability. In addition, the neuronal morphology was rapidly established when commercially available and primary ovarian carcinoma cells were cultured in the form of organoids. Importantly, we also identified a cell type in regular ovarian tissues, which possess similar neural/stemness features as observed in 2D or 3D cultures. The signature of this cell type is amplified in ovarian carcinoma tumors, suggesting a neuroepithelial origin of this tumor type. In conclusion, we propose that ovarian carcinomas harbor a small population of cells with an intrinsic neuronal/stemness/MDR phenotype, serving as the cradle from which ovarian carcinoma evolves., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Patients with Triple Negative Breast Cancer (TNBC) currently lack targeted therapies, and consequently face higher mortality rates when compared to patients with other breast cancer subtypes. The tumor microenvironment (TME) cytokine Oncostatin M (OSM) reprograms TNBC cells to a more stem-like/mesenchymal state, conferring aggressive cancer cell properties such as enhanced migration and invasion, increased tumor-initiating capacity, and intrinsic resistance to the current standards of care. In contrast to OSM, Interferon-β (IFN-β) promotes a more differentiated, epithelial cell phenotype in addition to its role as an activator of anti-tumor immunity. Importantly, OSM suppresses the production of IFN-β, although the mechanism of IFN-β suppression has not yet been elucidated., Methods: IFN-β production and downstream autocrine signaling were assessed via quantitative real-time PCR (qRT-PCR) and Western blotting in TNBC cells following exposure to OSM. RNA-sequencing (RNA-seq) was used to assess an IFN-β metagene signature, and to assess the expression of innate immune sensors, which are upstream activators of IFN-β. Cell migration was assessed using an in vitro chemotaxis assay. Additionally, TNBC cells were exposed to TGF-β1, Snail, and Zeb1, and IFN-β production and downstream autocrine signaling were assessed via RNA-seq, qRT-PCR, and Western blotting., Results: Here, we identify the repression of Toll-like Receptor 3 (TLR3), an innate immune sensor, as the key molecular event linking OSM signaling and the repression of IFN-β transcription, production, and autocrine IFN signaling. Moreover, we demonstrate that additional epithelial-mesenchymal transition-inducing factors, such as TGF-β1, Snail, and Zeb1, similarly suppress TLR3-mediated IFN-β production and signaling., Conclusions: Our findings provide a novel insight into the regulation of TLR3 and IFN-β production in TNBC cells, which are known indicators of treatment responses to DNA-damaging therapies. Furthermore, strategies to stimulate TLR3 in order to increase IFN-β within the TME may be ineffective in stem-like/mesenchymal cells, as TLR3 is strongly repressed. Rather, we propose that therapies targeting OSM or OSM receptor would reverse the stem-like/mesenchymal program and restore TLR3-mediated IFN-β production within the TME, facilitating improved responses to current therapies., Competing Interests: Declarations. Ethics approval and consent to participate: Experiments involving animals were performed in compliance with the guidelines approved by the Case Western Reserve University Institutional Animal Care and Use Committee (IACUC). Consent for publication: All authors agree to publish the data presented in this manuscript. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Peritoneal dialysis (PD) serves as a home-based kidney replacement therapy with increasing utilization across the globe. However, long-term use of high-glucose-based PD solution incites repeated peritoneal injury and inevitable peritoneal fibrosis, thus compromising treatment efficacy and resulting in ultrafiltration failure eventually. In the present study, we utilized human mesothelial MeT-5A cells for the in vitro experiments and a PD mouse model for in vivo validation to study the pathophysiological mechanisms underneath PD-associated peritoneal fibrosis. High-glucose PD solution (Dianeal 4.25%, Baxter) increased protein expression of mesothelial-mesenchymal transition (MMT) markers, such as N-cadherin and α-SMA in MeT-5A cells, whereas it decreased catalase expression and stimulated the production of reactive oxygen species (ROS). Furthermore, macrophage influx and increased serum pro-inflammatory cytokines, such as IL-1β, MCP-1, and TNF-α, were observed in the PD mouse model. Interestingly, we discovered that oligo-fucoidan, an oligosaccharide extract from brown seaweed, successfully prevented PD-associated peritoneal thickening and fibrosis through antioxidant effect, downregulation of MMT markers, and attenuation of peritoneal and systemic inflammation. Hence, oligo-fucoidan has the potential to be developed into a novel preventive strategy for PD-associated peritoneal fibrosis.

Renal fibrosis is a common manifestation in the progression of chronic kidney disease (CKD) to kidney failure. Currently, there is no available therapy to prevent the progression of renal fibrosis. Poricoic acid A (PAA) isolated from Poria cocos shows notable antifibrotic effects. However, its potential mechanism is still unclear. This study aimed to evaluate the effects and the potential mechanisms of PAA against renal fibrosis. A mouse model of renal fibrosis was established using unilateral ureteral obstruction (UUO). We showed that PAA administration significantly alleviated renal lesions and collagen deposition in UUO mice. Mice with UUO resulted in epithelial-to-mesenchymal transition (EMT) and the activation of endoplasmic reticulum stress (ERS) in the renal tissues, while PAA treatment significantly inhibited EMT and ERS activation. Additionally, PAA markedly alleviated ERS-mediated apoptosis in UUO mice. Molecular docking results indicated that PAA stably combined to GRP78 and ATF4. In conclusion, these results demonstrated that PAA possesses a significant bioactivity against renal fibrosis and its treatment mechanism might be the inhibition of ERS-mediated apoptosis.

Purpose: 2-Dodecyl-6-methoxy-2,5-diene-1,4-cyclohexanedione (DMDD), isolated from Averrhoa carambola L . root, has demonstrated the potential to reduce blood sugar levels. However, DMDD has poor solubility and bioavailability. This study aimed to formulate DMDD-loaded nanoparticles (DMDD-NPs) using chitosan crosslinked with sodium tripolyphosphate through the ionic crosslinking method and to investigate their effect on diabetic kidney disease (DKD) treatment by inhibiting the development of the epithelial-mesenchymal transition (EMT)., Methods: DMDD-NPs were prepared by ionic crosslinking with sodium tripolyphosphate, optimizing six factors that affect nanoparticle characteristics, including particle size and zeta potential. Encapsulation efficiency (EE) and drug loading rate (DL) were optimized using a Box-Behnken design. The structure and characteristics of DMDD-NPs, including size, EE, DL, and release rates, were analyzed. Cytotoxicity was assessed using the Cell Counting Kit-8 (CCK-8) assay, while the migration capacity of HK-2 cells was evaluated through scratch-wound assays. The expression of EMT-related markers (E-cadherin, Vimentin, and TGF-β1) was assessed by qRT-PCR., Results: The optimized formulation for DMDD-NPs was CS:TPP:DMDD = 10:3:3 (w), at pH 3.5, with 1.0 mg/mL of CS and stirring at 500 rpm for 30 min. In these conditions, the nanoparticles had a particle size of 320.37 ± 2.93 nm, an EE of 85.09 ± 1.43%, and a DL of 15.88 ± 0.51%. The DMDD-NPs exhibited a spherical shape, no leakage and minimal adhesion. The optimal freeze-drying protectant was a combination of 0.025% mannitol and 0.025% lactose. The drug release followed the Higuchi model. DMDD-NPs improved HK-2 cell proliferation at lower concentrations (<24 μg/mL) and showed greater cell migration inhibition than DMDD. DMDD-NPs promoted E-cadherin expression and inhibited vimentin and TGF-β1 expression, suggesting their potential role in preventing EMT for DKD treatment., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Huang et al.)

Hydroxy-polycyclic aromatic hydrocarbons (OH-PAHs) are a growing worldwide concern because of their persistence, ubiquity, and toxicity. Nonetheless, research on the toxicological mechanisms of OH-PAHs remains sparse, particularly concerning the risk of liver cancer. This study evaluated the effects of OH-PAHs on disrupting estrogen receptor α (ERα) and subsequently facilitating hepatocellular invasion and metastasis. Results revealed that all six OH-PAHs exhibited ERα agonistic activities at noncytotoxic levels, which were partially validated using molecular docking (MD) and molecular dynamics simulations (MDS). Furthermore, OH-PAHs with ERα agonistic properties stimulated a concentration-dependent increase in the migration and invasion of HepG2 cells. In addition, they disturbed the expression of target genes associated with epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM), and the invasion effects were significantly reversed by adding an ERα antagonist. Our results suggest an essential role of ERα in the metastasis of liver cancer cells induced by OH-PAHs and emphasize their potential ecological and health hazards., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024. Published by Elsevier B.V.)

Animals are widely exposed to nanosilica as a food additive. However, the negative effects of such nanosilica particles on animals' bladders are unclear. In the present study, we investigated the impact of MPs-SiO 2 on mouse bladder and the underlying mechanisms. Mouse and MBEC cell models exposed to MPs-SiO 2 with different particle sizes were established. At the same time, aminoguanidine hydrochloride (RNS inhibitor) and NF-κB activator were used to further explore its mechanism in vitro. We found that MPs-SiO 2 of three sizes could induce RNS-induced pyroptosis causing EMT both in vitro and in vivo. After inhibiting RNS, the expression of related proteins in downstream pathways was decreased, and fibrosis was alleviated. The above situation was reversed by the addition of NF-κB activator. Furthermore, our data suggest that 300 nm MPs-SiO 2 particles have a greater impact on the bladder than 50 nm particles. This study revealed the potential health risks of MPs-SiO 2 and provided new insights into the toxicology of MPs-SiO 2 .

Background and Aims: The mesothelial-mesenchymal transition (MMT) of mesothelial cells has been recognized as a critical process during progression of peritoneal fibrosis (PF). Despite its crucial role in amino acid transport and metabolism, the involvement of L-type amino acid transporter 1 (LAT1) and the potential therapeutic role of its inhibitor, JPH203, in fibrotic diseases remain unexplored. Considering the paucity of research on amino acid-mediated mTORC1 activation in PF, our study endeavors to elucidate the protective effects of JPH203 against PF and explore the involvement of amino acid-mediated mTORC1 signaling in this context., Methods: We established the transforming growth factor beta 1 (TGF-β1) induced MMT model in primary human mesothelial cells and the peritoneal dialysis fluid (PDF) induced PF model in mice. The therapeutic effects of JPH203 on PF were then examined on these two models by real-time quantitative polymerase chain reaction, western blotting, immunofluorescence staining, Masson's trichrome staining, H&E staining, picro-sirius red staining, and immunohistochemistry. The involvement of amino acid-mediated mTORC1 signaling was screened by RNA sequencing and further verified by western blotting in vitro., Results: LAT1 was significantly upregulated and JPH203 markedly attenuated fibrotic phenotype both in vitro and in vivo. RNA-seq unveiled a significant enrichment of mTOR signaling pathway in response to JPH203 treatment. Western blotting results indicated that JPH203 alleviates PF by inhibiting amino acid-mediated mTORC1 signaling, which differs from the direct inhibition observed with rapamycin., Conclusion: JPH203 alleviates PF by inhibiting amino acid-mediated mTORC1 signaling., Competing Interests: Declaration of competing interest There are no financial or other interests regarding the submitted manuscript that might be construed as a conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: The novel nanomaterials PNA-TN (PN) and PNA-TN-Dox (PND) have been shown to have strong inhibitory effects on breast cancer; however, it is unclear whether PN and PND have anti-head and neck squamous cell carcinoma (HNSCC) activity, and their potential mechanisms of activity are unknown. So, our study aims to explore the therapeutic effects of PN and PND on HNSCC and their possible mechanisms., Methods: We used a series of phenotypic research to evaluate the effects of PN + Laser (L) and PND + L on the biological function of HNSCC cells in vitro and in vivo. We subsequently used mechanism research to examine changes in mRNA and protein expression related to apoptosis, epithelial‒mesenchymal transition (EMT), and the JNK signalling pathway., Results: Our study revealed that PN and PND have strong inhibitory effects on HNSCC cells both in vitro and in vivo. In vitro, PN and PND significantly inhibited the proliferation, migration, invasion and EMT ability of HNSCC cells and promoted apoptosis; the inhibitory effect in the PND + L group was significantly greater than that in the PN + L group. In vivo, both treatments led to significant reductions in tumour volume and weight. Notably, the tumour volume and weight in the PND + L group were significantly lower than those in the PN + L group. Mechanism research confirmed that PN + L activated the expression of apoptosis-related proteins and inhibited the expression of EMT-related proteins via the JNK pathway. Furthermore, the anti-HNSCC effect of PN + L was blocked after the use of a JNK pathway inhibitor., Conclusion: Treatment with PN + L or PND + L significantly inhibited the malignant progress of HNSCC cells, and the therapeutic effect of PND + L was significantly stronger than that of PN + L. The JNK signalling pathway is a key mechanism by which PN exerts its anti-HNSCC activity., Competing Interests: Declarations Ethics approval and consent to participate The Laboratory Animal Welfare and Ethics Committee of Renmin Hospital of Wuhan University reviewed and approved the animal procedures (Approval No: WDRM20240704B). All animal experiments were conducted following the NIH Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80 − 23; revised 1978). Consent for publication All authors have confirmed that all data from this study is publishable and have seen the final version of the article for publication. Written informed consent for publication was obtained from all participants. Competing interests The authors report no conflicts of interest in this work., (© 2024. The Author(s).)

Background: Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model., Aim: The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon-liver metastasis in an animal model, and to elucidate the underlying mechanisms., Methods: Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100 mg/kg) for 21 days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R)., Result: The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling., Conclusion: In conclusion, berberine evidently possess an anti-colon-liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial-mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC., Competing Interests: Declarations Ethics approval and consent to participate The animal study was reviewed and approved by Institutional Animal Care and Use Committee Daejeon University (DJUARB2022-002). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The present study was undertaken to investigate the therapeutic effect and underlying mechanisms of lumbrokinase (LK) on diabetic kidney disease (DKD). Kidney tissue samples from DKD patients and normal controls were collected from hospitals. The type 2 diabetic nephropathy model was induced in db/db mice. The mice were then randomly divided into a model group (DM group) and an LK group. db/m mice were used as the control group (Con group). After 12 weeks of treatment with LK (234 KU/kg/day), biochemical parameters were tested, and pathological changes in the kidney were observed under a light microscope. The epithelial-to-mesenchymal transition (EMT), mRNA m6A methylation proteins, and activated TGF-β1/Smad pathway components were assessed by western blot or immunofluorescence in DKD patients, model mice, and high glucose-stimulated HK-2 cells. We found that the m6A eraser METTL3 was expressed at low levels in DKD patients, model mice, and high glucose-stimulated HK-2 cells. METTL3 overexpression reversed the high glucose-induced activation of the TGF-β1/Smad pathway and EMT through snail in vitro. However, LK can restore the expression of the m6A-modifying enzyme METTL3 in vivo and in vitro, suppressed EMT, and alleviated renal interstitial fibrosis by downregulating snail. Overall, LK ameliorated renal fibrosis through the regulation of Snail via m6A RNA METTL3., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Triple-negative breast cancer is a heterogeneous disease with high recurrence and mortality, linked to cancer stem cells (CSCs). Our study characterized distinct cell subpopulations and signaling pathways to explore chemoresistance. We observed cellular heterogeneity among and within the cells regarding phenotyping and drug response. In untreated BT-549 cells, we noted plasticity properties in both CD44 + /CD24 + /CD146 + hybrid cells and CD44 - /CD24 + /CD146 + epithelial cells, enabling phenotypic conversion into CD44 + /CD24 - /CD146 - epithelial-mesenchymal transition (EMT)-like like breast CSCs (BCSCs). Additionally, non-BCSCs may give rise to ALDH + epithelial-like BCSCs. Enriched BCSCs demonstrated the potential to differentiation into CD44 - /CD24 - /CD146 - cells and exhibited self-renewal capabilities. Similar phenotypic plasticity was not observed in untreated Hs 578T and HMT-3522 S1 cells. BT-549 cells were more resistant to paclitaxel/PTX than to doxorubicin/DOX, a phenomenon potentially linked to the presence of CD24 + cells prior to treatment. Under the CSCs-enriched spheroids model, BT-549 demonstrated extreme resistance to DOX, likely due to the enrichment of BCSCs CD44 + /CD24 - /CD146 - and the tumor cells CD44 - /CD24 - /CD146 - . Additionally, DOX treatment induced the enrichment of plastic and chemoresistant cells, further exacerbating resistance mechanisms. BT-549 exhibited high heterogeneity, leading to significant alterations in cell subpopulations under BCSCs enrichment, demonstrating increased phenotypic plasticity during EMT. This phenomenon appears to play a major role in DOX resistance, as indicated by the presence of the refractory cells CD44 + /CD24 - /CD146 - BCSCs EMT-like, CD44 - /CD24 - /CD146 - tumor cells, and elevated STAT3 expression. Gene expression data from BT-549 CSCs-enriched spheroids suggests that ferroptosis may be occurring via autophagic regulation triggered by RAB7A, highlighting this gene as a potential therapeutic target., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Milene Pereira Moreira has patent #BR 10 2022 011155 3 pending to no. Luciana Maria Silva has patent #BR 10 2022 011155 3 pending to no. Eliza Pereira Franco has patent #BR 10 2022 011155 3 pending to no. Leticia da Conceicao Braga has patent #BR 10 2022 011155 3 pending to no. Geovanni Dantas Cassali has patent #BR 10 2022 011155 3 pending to No. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Metastasis-initiating cells are key players in progression, resistance, and relapse of colorectal cancer (CRC), by leveraging the regulatory relationship between Transforming Growth Factor-beta (TGF-β) signaling and anti-L1 cell adhesion molecule (L1CAM)., Methods: This study introduces a novel strategy for CRC targeted therapy and imaging based on the use of a hybrid nanosystem made of gold nanoparticles-covered porous biosilica further modified with the (L1CAM) antibody., Results: The nanosystem intracellularly delivers galunisertib (LY), a TGF-β inhibitor, aiming to inhibit epithelial-mesenchymal transition (EMT), a process pivotal for metastasis. Anti-L1CAM antibody-functionalized nanoparticles (NPs) target tumor-initiating cells expressing L1CAM, inhibiting cancer growth. The number of antibody molecules conjugated to the single NP is precisely quantified, revealing a high surface coverage that facilitates the tumor targeting. The therapeutic efficacy of the nanosystem is investigated in organoid-like cultures of CRC cells and in vivo mouse models, showing a significant reduction in tumor growth. The spatial distribution of NPs within CRC tumors from mice is investigated using a label-free optical approach based on Raman micro-spectroscopy., Conclusion: This research highlights the multifunctional capabilities of engineered biosilica NPs, which offer new insights in targeted CRC therapy and imaging, improving patient outcomes and paving the way for personalized therapies., Competing Interests: Chiara Tramontano is currently affiliated with Internal Medicine Department, Radboud University Medical Center, Radboud, The Netherlands. The authors report no conflict of interest in this work., (© 2024 Delle Cave et al.)

Cell-based immunotherapies have emerged as promising cancer treatment modalities, demonstrating remarkable clinical efficacy. As interest in applying immune cell-based therapies to solid tumors has gained momentum, experimental models that enable long-term monitoring and mimic clinical administration are increasingly necessary. This study explores the potential of scaffold-based cell culture technologies, specifically three-dimensional (3D) extracellular matrix (ECM)-like frameworks, as promising solutions. These frameworks facilitate unhindered immune cell growth and enable continuous cancer cell culture. The three-dimensional (3D) cell culture model was developed using tailored scaffolds for natural killer (NK) cell culture. Within this framework, A549 lung cancer cells were cocultured with NK cells, allowing real-time monitoring for up to 28 days. The expression of critical markers associated with anticancer drug resistance and epithelial-mesenchymal transition (EMT) was evaluated in cancer cells within this 3D culture context. Compared to conventional 2D monolayer cultures, this 3D scaffold-based culture revealed that solid tumor cells, specifically A549 cells, exhibited heightened resistance to anticancer drugs. Additionally, the 3D culture environment upregulated the expression of EMT markers namely vimentin, N-cadherin, and fibronectin, while NK and zEGFR-CAR-NK cells displayed anticancer effects. In the two-dimensional (2D) coculture, only zEGFR-CAR-NK cells exhibited such effects in the 3D coculture system, highlighting an intriguing inconsistency with the 2D culture model, further confirmed by in vivo experiments. This in vitro 3D cell culture model reliably predicts outcomes in NK immunotherapy experiments. Thus, it represents a valuable tool for investigating drug resistance mechanisms and assessing the efficacy of immune cell-based therapies. By bridging the gap between in vitro and in vivo investigations, this model effectively translates potential treatments into animal models and facilitates rigorous preclinical evaluations.

Ethnopharmacological Relevance: Based on the core pathogenesis of hepatosplenic disorder and qi transformation disorder in ulcerative colitis, Tong-Xie-Yao-Fang (TXYF) is a classical traditional Chinese medicine commonly used to treat ulcerative colitis. Our study revealed that it has the potential to prevent colitis-associated colorectal cancer, which embodies the academic concept in traditional Chinese medicine of treating the disease before it develops., Aim of the Study: This study was aimed at evaluating the therapeutic role of TXYF in treating colitis-associated colorectal cancer and exploring its possible underlying mechanisms., Materials and Methods: A colitis-associated colorectal cancer model was established in mice using azoxymethane and dextran sulfate sodium salt to examine the therapeutic effect of TXYF. The mouse body weights were observed. Hematoxylin-eosin staining was used to evaluate mouse colon histopathology. Colon cancer cells and colon epithelial cells were used to explore the potential molecular mechanisms. The proliferation and apoptosis of cells were detected by CCK8 and cell colony assays, flow cytometry and western blotting. The epithelial-mesenchymal transition (EMT) and mitophagy markers were examined by immunohistochemistry, western blotting, quantitative real-time PCR and immunofluorescence staining., Results: TXYF inhibited the tumorigenesis of mice with colitis-associated colorectal cancer and the growth of inflammatory colon cells. TXYF induced mitophagy in colon cancer cells through the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway to reverse EMT, which was consistent with the results in mice with colitis-associated colorectal cancer., Conclusions: The results of the present study demonstrated that TXYF effectively inhibited the progression of colitis-associated colorectal cancer through the PINK1/Parkin pathway, which provides new evidence for prevention strategies for this disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Herbal products have long been utilized as remedies for various disease conditions, including infections. This study investigates the therapeutic mechanism of a traditional Chinese herbal combination in treating high-risk HPV infections., Methods: The herbal formula was prepared using common herbs: dry Millettia speciosa, Guanzhong (a spermatophyte), Sarsaparilla, White Fruit, and Cockscomb Flower. Eight female patients diagnosed with high-risk HPV were enrolled from January to September 2023 at Shenzhen Hospital of Beijing University of Traditional Chinese Medicine. Cervicovaginal secretions were collected before and after treatment with the herbal remedy and analyzed using non-targeted metabolomics techniques. In vitro studies were conducted using HeLa cells to determine the optimal effective concentration of the remedy, assessed via the CCK8 method. The proliferation and migration of HeLa cells were evaluated using Transwell assays. Quantitative PCR was employed to measure mRNA levels of endothelial-to-mesenchymal transition (EndMT) markers, including VE-Cadherin, eNOS, α-SMA, and Snail., Results: In vivo , significant alterations in cervicovaginal secretion metabolites post-treatment were observed through PCA, OPLS-DA, and volcano plot analyses. KEGG enrichment analysis highlighted crucial signaling pathways such as arginine and proline metabolism, purine metabolism, glycerophospholipid metabolism, and phenylalanine metabolism, indicating the herbal combination's systemic effects on patients. In vitro experiments demonstrated a dose-dependent reduction in HeLa cell proliferation and migration, confirmed by scratch and Transwell assays. Additionally, qPCR analysis revealed down-regulation of α-SMA and Snail, and up-regulation of VE-Cadherin and eNOS, suggesting inhibition of EndMT in HeLa cells., Conclusion: The traditional Chinese herbal combination modulates key metabolic pathways in vivo and inhibits EndMT in vitro , while reducing HeLa cell proliferation and migration. These findings highlight its potential as a therapeutic approach for managing HPV infections, bridging traditional practices with scientific research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 You, Bu, Chen, Sun, Suyang, Feng and Chen.)

Ethnopharmacological Relevance: The Yi-Fei San-Jie pill (YFSJ) is a well-known Chinese medicine that has been used to treat non-small cell lung cancer in China for decades., Aim of the Study: Previous studies have shown that YFSJ combined with gefitinib can effectively inhibit the proliferation of gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines by promoting apoptosis and autophagy, but the molecular biological mechanisms involved and whether YFSJ combined with gefitinib can have synergistic effects still need to be further explored. Thus, the present study aimed to establish an in silico and experimental framework to decipher the underlying mechanism by which YFSJ augments the efficacy of gefitinib in treating NSCLC., Materials and Methods: Integrated approaches, including microarray analysis, network pharmacology, RNA sequencing, bioinformatics algorithm analysis and in vivo and in vitro experiments, were applied to elucidate the underlying mechanism., Results: Analysis of microarray datasets indicated that gefitinib may play a role in the regulation of the epithelial-mesenchymal transition (EMT) of PC9 cells. EMT-related Gene Ontology (GO) terms and the MAPK pathway were found to be enriched in the differentially expressed genes (DEGs), and a decreasing trend was observed in the EMT score. Network pharmacology analysis revealed that the potential NSCLC-related targets of YFSJ also showed enrichment in EMT-related GO terms and the MAPK pathway. Experimental findings demonstrated that combined YFSJ-treated serum and gefitinib treatment significantly inhibited PC9 cell migration and invasion. In addition, the combined treatment dramatically reduced the tumour volume in an animal model. The effectiveness of the combination treatment surpassed that of gefitinib alone in both cell and animal experiments. RNA sequencing analysis revealed significant enrichment of DEGs in EMT-related GO terms for the gefitinib treatment group, YFSJ treatment group, and combination treatment group compared to the control group. Notably, the negative regulation of EMT showed significant enrichment in the DEGs of the combination treatment group. The MAPK pathway was significantly enriched among the different groups. Moreover, combined treatment with YFSJ and gefitinib may exert synergistic anti-NSCLC effects by inhibiting the p-p38 MAPK/GSK3β signalling axis, subsequently suppressing downstream EMT processes., Conclusion: Combined treatment with YFSJ and gefitinib could enhance the sensitivity of NSCLC cells to gefitinib by suppressing EMT through the EGFR/p-p38 MAPK/GSK3β signalling axis. YFSJ may serve as an important adjunctive medication for NSCLC patients receiving gefitinib treatment in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The inhibition of dipeptidyl- peptidase 4 (DPP-4) is an essential therapy for controlling hyperglycemia in patients with type 2 diabetes (T2DM). However, the role of DPP-4 in cancer is not yet clear, with some studies suggesting that it may either promote or suppress tumors. This makes it crucial to have personalized treatment for diabetic women with cancer to effectively manage their diabetes whilst and preventing cancer mortality. To address this issue, we conducted an integrative in-silico analysis and systematic review of the literature to comprehensively examine the relationship between DPP-4 expression and the effects of its inhibitors on prevalent female malignancies. We specifically chose studies that examined the effects of DPP-4 expression and DPP-4 inhibition (DPP-4i) on prevalent cancers in women, such as breast cancer (BC), ovarian cancer (OV), cervical cancer (CC), and endometrial cancer (EC). These studies comprised those conducted both in vivo and in vitro. The review of the literature indicated that DPP-4i may worsen aggressive traits such as metastasis, Epithelial-to-mesenchymal transition (EMT), and chemotherapy resistance in BC cells. However, cohort studies on diabetic and BC patients did not confirm these findings. In vitro studies indicate that on OV, DPP-4 upregulation has been shown to prevent metastasis, while CCappears to be influenced by DPP-4 expression in terms of cell migration. sitagliptin, a pharmaceutical inhibitor of DPP-4, had a significant impact on reducing adhesion in CC cells in vitro. Overexpression of DPP-4 increased cell migration and proliferation in CC and EC cells, and hence the application of sitagliptin is expected to prevent this effect. On the other hand, the result of in-silico data confirmed that a significant correlation exists between DPP-4 expression and immune cell infiltration in breast, ovarian, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) as well as downregulated in these cancers compared to their normal tissue samples. Furthermore, a significant (p < 0.05) effect on OS of BC and CESC patients has been reported due to the elevation of DPP-4 methylation on a specific CPG Island. These findings could aid in creating specialized treatments for diabetic women with specific malignancies, but caution should be exercised when considering the patient's medical history and cancer type., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Lung adenocarcinoma (LUAD) is the most common lung cancer subtype, and the prognosis of affected patients is generally poor. The traditional Chinese medicine Uncaria rhychophaylla has been reported to exhibit anti-lung cancer properties. Accordingly, the main bioactive ingredient in Uncaria rhychophaylla, Corynoxine, may hold great value as a treatment for lung cancer., Methods: The impact of Corynoxine on the viability of LUAD cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in A549 cells was evaluated via flow cytometry. Migration and invasion capabilities were determined through wound healing and Transwell assays, respectively. The key pathways targeted by Corynoxine in LUAD were identified using a network pharmacology approach. Additionally, Western immunoblotting, quantitative real-time PCR (qRT-PCR), and ELISA assays were conducted to validate the underlying mechanisms. The in vivo anti-tumor efficacy of Corynoxine was assessed in xenograft nude mice., Results: In this study, Corynoxine treatment was found to markedly suppress in vitro LUAD cell proliferative, migratory, and invasive activity. It additionally downregulated Vimentin and promoted E-cadherin upregulation consistent with the disruption of epithelial-mesenchymal transition (EMT) induction while also accelerating apoptotic death. Furthermore, network pharmacology analysis revealed that the PI3K/AKT pathway is a potential target of Corynoxine in LUAD. In vitro assays demonstrated that treatment with Corynoxine resulted in the suppression of PI3K/AKT signaling and a consequent drop in cyclooxygenase-2 (COX-2) expression. These findings were further confirmed in vivo in mice harboring A549 tumor xenografts in which Corynoxine was able to interfere with the PI3K/AKT/COX-2 signaling axis., Conclusion: This study elucidated the potential effects of Corynoxine in suppressing proliferation and metastasis in LUAD, along with investigating the underlying mechanisms. These data highlight the promise of Corynoxine as a novel therapeutic tool for the treatment of individuals diagnosed with LUAD., (© 2024. The Author(s).)

Yangzheng mixture has been used as an adjuvant tumor therapy as a traditional Chinese medicine in clinical. However, less is known about the activity of Yangzheng mixture. In our study, we explored the anti-tumor activity of Yangzheng mixture for HCC in vitro and in vivo. The effects of Yangzheng mixture on HCC biological behaviors were assessed using colony formation assay, EdU staining, cell cycle assay, Annexin V/PI staining, and wound healing assay. Migration and invasion of HCC cells were further evaluated via transwell assays, while molecular mechanisms were investigated through western blotting and immunofluorescence staining. Additionally, the anticancer effect of Yangzheng mixture in vivo were examined using H22 xenograft and H22 metastatic hepatocellular carcinoma models. Our results revealed that Yangzheng mixture inhibited colony formation, EdU incorporation, cell migration, and invasion, while arresting cell cycle at the G2-M phase in Bel-7402 and SMMC-7721 cells. Mechanistic studies demonstrated that Yangzheng mixture showed a markedly inhibition on Bel-7402 and SMMC-7721 cells with higher NLRP3 expression. We further confirmed that Yangzheng mixture could activate NLRP3 inflammasome through NF-κB by western blotting and immunofluorescence staining. Additionally, Yangzheng mixture inhibited β-catenin nucleus translocation and reversed EMT process. In vivo, the H22 xenograft model depicted that Yangzheng mixture significantly reduced tumor size and weight compared with control. Moreover, H22 lung metastasis model showed that Yangzheng mixture significantly inhibited liver cancer cell spreading to lungs in mice. Overall, our finding revealed that Yangzheng mixture inhibited HCC proliferation and migration in vitro and in vivo by reversing EMT via NF-κB/NLRP3/β-catenin pathway. These results may serve new therapeutic evidences for Yangzheng mixture application in clinical., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)