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Ethnopharmacological Relevance: Rosa odorata Sweet var. gigantea (Coll. et Hemsl.) Rehd. et Wils is a commonly utilized traditional medicine among the Yi nationality, also known as "Gugongguo", for the treatment of gastrointestinal disorders. Previous studies have indicated that the extract of Rosa odorata sweet var. gigantea (FOE) fruit has demonstrated a protective effect on the stomach; however, its impact on chronic atrophic gastritis (CAG) with severe disease remains unknown., Aim of the Study: This study aimed to investigate the impact of FOE on CAG and its underlying mechanisms both in vitro and in vivo., Materials and Methods: By employing Ultra Performance Liquid Chromatography/Quadrupole-Time of Flight Mass Spectrometry (UPLC-QTOF-MS/MS) and network pharmacology, the primary active compounds and action targets of FOE were identified. In vitro, the impact of FOE on CAG was investigated through scratch, migration, and invasion assays. Subsequently, guided by network pharmacology, EMT and TGF-β signaling pathway-related proteins were assessed using Western blot and immunofluorescence experiments. Additionally, an in vivo CAG rat model was established to validate the effects of FOE and confirm its mechanism of action through hematoxylin-eosin (H&E), immunohistochemistry, Western blot, as well as untargeted metabolomics analysis of rat serum. It was observed that FOE inhibited scratch healing abilities, migration, invasion capabilities, as well as the expression of EMT-related proteins (E-cadherin, N-cadherin, Snail, Vimentin) in CAG model cells (MC cells), providing initial evidence for its efficacy., Results: Through the analysis of UPLC-QTOF-MS/MS, a total of 51 major compounds were identified in the FOE. Subsequent network pharmacological analysis suggested that FOE may regulate Epithelial mesenchymal transition (EMT) through the transforming growth factor β (TGF-β) pathway. Furthermore, experimental verification demonstrated that FOE inhibited the protein expression of TGF-β1 and its downstream protein Smad2/3 in vitro. In vivo findings also indicated similar mechanisms in MC cells, suggesting a reversal of the CAG process and significant inhibition of EMT and TGF-β signaling pathways. Additionally, untargeted metabolomics of rat serum confirmed the therapeutic effect of FOE on CAG and predicted its potential involvement in the arachidonic acid metabolic pathway., Conclusion: This study initially demonstrated that FOE effectively reverses the process of EMT through the TGF-β1/Smad2/3 signaling pathway, thereby providing a therapeutic benefit for CAG., 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 article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Breast cancer (BC) has an extremely high global incidence rate. The Xihuang pill (XHP), a traditional Chinese formula, originates from Hongxu Wang's "Life-Saving Manual of Diagnosis and Treatment of External Diseases" written during the Qing Dynasty. In this book, XHP, was first suggested as an anticancer treatment for BC. However, the regulatory mechanism of XHP on BC requires further investigated., Aim of the Study: To assess the effects of XHP on BC and elucidate the underlying associated signaling network., Materials and Methods: The influence of XHP on cellular viability, proliferation, and apoptosis of MDA-MB-231 and BT-549 cells were examined. The ability to metastasize was evaluated using Transwell invasion and wound healing tests. Western blotting was used to examine the epithelial-mesenchymal transition (EMT) markers expression. RNA sequencing and bioinformatic analysis were utilized to investigate the regulation mechanism of XHP. A subcutaneous tumor model was developed to study the tumor-inhibitory effects of XHP or/and Doxorubicin (Dox) on BALB/c nude mice, and the EMT marker levels in tumor tissues were determined using immunohistochemical labeling., Results: XHP demonstrated anticancer effects on BC cells by suppressing cell proliferation, inducing cellular apoptosis, and inhibiting EMT progression. XHP may regulate the EMT via the TGF-β axis, as shown by RNA sequencing and Western blotting analysis. Furthermore, the combination of XHP and Dox had a stronger therapeutic effect on BC cell proliferation, apoptosis, and metastasis in both cellular and animal models., Conclusions: We were the first to reveal that XHP abrogated EMT progression via modulating the TGF-β axis. Furthermore, the combination therapy of XHP and Dox presents a promising novel therapeutic candidate for BC patients., 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.)

Ethnopharmacological Relevance: Gout is a crystal-related arthropathy caused by monosodium urate (MSU) deposition, resulting from purine metabolism disorders and hyperuricemia (HUA). Gout belongs to the traditional medicine category of Bi syndrome. Biqi capsules (BQ) is a traditional Chinese medicine formula used to treat Bi syndrome. The BQ prescription is derived from the ancient prescription of Hua Tuo, a famous physician in the Han Dynasty., Aim of the Study: To study the effect and mechanism of BQ in treating acute gouty arthritis (AGA) and HUA., Materials and Methods: Analyzing BQ's signaling pathways for gout treatment via network pharmacology. The HUA model was induced orally with adenine and potassium oxonate. The rat AGA model was established by MSU injection. In vitro, MH7A and RAW 246.7 cells were treated with LPS and MSU. Serum uric acid, creatinine, and urea nitrogen levels were evaluated. Kidney and ankle joint pathology was observed via HE staining. Inflammatory signaling pathway proteins, epithelial-mesenchymal transition (EMT) pathway proteins, and uric acid metabolism-related proteins were detected by Western blot., Results: 1780 potential targets for gout treatment were identified, and 1039 target proteins corresponding to BQ's active ingredients were obtained. Pathway enrichment analysis revealed BQ improved gout mainly through inflammatory pathways. Experimental results showed BQ could reduce serum uric acid level and increase uric acid clearance rate by regulating the expression of adenosine deaminase (ADA), and organic anion transporter 1 (OAT1) and glucose transporter 9 (GLUT9) in HUA mice. BQ could improve renal function and injury by inhibiting the NLRP3 pathway in HUA mice' kidneys. Additionally, BQ could alleviate ankle joint swelling and synovial injury, inhibit the TLR4/NLRP3 pathway, and reduce levels of inflammatory factors including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) in AGA rats. The main component of BQ, brucine, could inhibit the activation of NLRP3/NF-κB pathway induced by MSU and reduce the expression level of inflammatory factors (IL-6, IL-1β, and TNF-α) in macrophages. Brucine could inhibit the activation of the EMT pathway and reduce the expression level of inflammatory factors (IL-6, TNF-α) in human fibroblast-like synoviocytes (MH7A cells) induced by MSU., Conclusions: BQ effectively reduced serum uric acid levels, improved kidney and joint damage, and ameliorated the inflammatory response caused by MSU. Its main component, brucine, effectively improved the inflammatory response and reduced the invasive ability of synoviocytes induced by MSU., Competing Interests: Declaration of competing interest The authors have indicated that they have no conflicts of interest with regard to the content of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Renal fibrosis is a crucial factor in the progression of chronic kidney diseases. Previous studies have suggested that apigenin (API) has potential in ameliorating renal fibrosis, but its therapeutic mechanism remains unclear. This study aims to elucidate the mechanisms by which API treats renal fibrosis using network pharmacology and experimental validation. Initially, we used the Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and GeneCards database to identify molecular targets of API and associated genes. Next, we constructed a network of API-renal fibrosis targets, followed by protein-protein interaction (PPI) analysis. Subsequent analyses, such as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We also performed molecular docking studies to explore API's interactions with key proteins. To validate API's mechanism in treating renal fibrosis, we used a Human Kidney-2 (HK-2) cell model of epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1). We identified 77 API target genes, 8434 renal fibrosis target genes, and 64 intersection genes, which were primarily enriched in nuclear factor kappa-B (NF-κB) and Phosphatidylinositide 3-kinases/protein kinase B (PI3K-AKT) pathways. API significantly inhibited EMT in TGF-β1-induced HK-2 cells by regulating the expression of α-Smooth muscle actin (α-SMA) and E-cadherin and suppressing the protein expression of p-PI3K, p-AKT, and p-P65, which are related to the PI3K-AKT and NF-κB pathways. However, co-administration of the PI3K agonist 740Y-P counteracted API's inhibitory effects on these protein expressions. In summary, these findings highlight API's therapeutic potential in treating renal fibrosis by modulating EMT in renal tubular epithelial cells via the PI3K-AKT and NF-κB pathways., 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.)

This investigation explored the hepatoprotective capabilities of Bruceine A (BA) and its underlying mechanisms in mitigating hepatic fibrosis. Hepatic stellate cells (HSCs) and mouse primary hepatocytes were treated with TGF-β and subsequently exposed to BA. To assess the effects of BA on the NR2F2-HMGB1 signaling cascade, these cells underwent transfection with a siRNA vector targeting NR2F2. The interaction between NR2F2 and the HMGB1 promoter was elucidated using a dual luciferase assay. In vivo, C57BL/6 mice were treated with thioacetamide (TAA) to induce liver damage, followed by administration of BA. The study found that BA moderated extracellular matrix (ECM) buildup, epithelial-mesenchymal transition (EMT), and inflammatory mediator levels, while concurrently reducing NR2F2 and HMGB1 expression in activated HSCs. Furthermore, BA lessened pyroptosis in hepatocytes, curtailing the inflammatory response. The absence of NR2F2 in HSCs or hepatocytes hindered BA's inhibitory effect on this pathway. It was demonstrated that NR2F2 binds directly to the HMGB1 promoter. Treatment with BA resulted in diminished serum levels of ALT and AST, mitigated damage in hepatic tissues, and decreased the ECM and neutrophil extracellular traps (NETs), thus protecting hepatocytes from fibrosis. Furthermore, BA suppressed the synthesis of inflammatory mediators such as NLRP3, caspase-1, and IL-1β by blocking the NR2F2-driven HMGB1 pathway, markedly reversing hepatic fibrosis. These observations highlight the efficacy of BA as a viable therapeutic candidate for hepatic fibrosis., 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.)

We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway, we examined whether DIF-1 affect the expression levels of TAZ and YAP. We found that DIF-1-induced proteasomal- and GSK-3-dependent degradation of both TAZ and YAP in human cervical cancer cell line HeLa in a time- and dose-dependent manner. As TAZ/YAP signaling pathway is well known to accelerate the epithelial-mesenchymal transition (EMT) of the cancer cell, we examined the effect of TAZ/YAP signaling pathway on EMT-related proteins. Knockdown of TAZ and YAP proteins by siRNA significantly reduced the expression of fibronectin, vimentin, and Snail. We also found that DIF-1 suppressed the expression levels of TAZ/YAP target gene products and EMT-related protein. Further, overexpression of TAZ and YAP attenuated the inhibitory effects of DIF-1 on these protein expressions. Migration and trans-well invasion assays revealed that DIF-1 significantly inhibited HeLa cell migration and invasion. DIF-1-induced proteasomal- and GSK-3-dependent degradation of TAZ and YAP proteins and inhibition of cell migration and invasion were also observed in human colon cancer cell line HCT-116. These results suggest that DIF-1 inhibits the TAZ/YAP signaling pathway via GSK-3 activation. Further, it has been suggested that the inhibition of EMT induced by DIF-1 is involved with the suppression of TAZ/YAP signaling pathway., Competing Interests: Declaration of competing interest Declarations of interest: none., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Sepsis is a systemic inflammatory response caused by infection. When this inflammatory response spreads to the lungs, it can lead to acute lung injury (ALI) or more severe acute respiratory distress syndrome (ARDS). Pulmonary fibrosis is a potential complication of these conditions, and the early occurrence of pulmonary fibrosis is associated with a higher mortality rate. The underlying mechanism of ARDS-related pulmonary fibrosis remains unclear., Methods: To evaluate the role of mast cell in sepsis-induced pulmonary fibrosis and elucidate its molecular mechanism. We investigated the level of mast cell and epithelial-mesenchymal transition(EMT) in LPS-induced mouse model and cellular model. We also explored the influence of cromolyn sodium and mast cell knockout on pulmonary fibrosis. Additionally, we explored the effect of MC-derived IL-13 on the EMT and illustrated the relationship between mast cell and pulmonary fibrosis., Results: Mast cell was up-regulated in the lung tissues of the pulmonary fibrotic mouse model compared to control groups. Cromolyn sodium and mast cell knockout decreased the expression of EMT-related protein and IL-13, alleviated the symptoms of pulmonary fibrosis in vivo and in vitro. The PI3K/AKT/mTOR signaling was activated in fibrotic lung tissue, whereas Cromolyn sodium and mast cell knockout inhibited this pathway., Conclusion: The expression level of mast cell is increased in fibrotic lungs. Cromolyn sodium intervention and mast cell knockout alleviate the symptoms of pulmonary fibrosis probably via the PI3K/AKT/mTOR signaling pathway. Therefore, mast cell inhibition is a potential therapeutic target for sepsis-induced pulmonary fibrosis., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University (No. 2207016). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Cervical carcinoma has the highest incidence among gynaecological cancers in developing countries where the human papillomavirus (HPV) vaccine is not yet widely used. Cancer stem cells (CSCs) are the key factors affecting treatment efficacy and cancer prognosis. Aldehyde dehydrogenase 1 (ALDH1) is a marker of CSCs, and its expression is closely related to chemotherapy resistance in cervical carcinoma. Bevacizumab is the most widely used molecular targeted drug in the management of cervical carcinoma. We designed and performed a series of in vitro and in vivo experiments to investigate the inhibitory effects of these compounds on ALDH1 and the underlying mechanism involved. The results revealed that bevacizumab significantly inhibited epithelial-mesenchymal transition (EMT) in HeLa cervical cancer cells, as indicated by upregulation of E-cadherin and downregulation of N-cadherin and snail. Anoxic pressure was relieved, and tumour vascularization was inhibited in the tumour microenvironment. NOTCH1 plays a critical role in these processes. Through modulating these tumour biological characteristics via ALDH1, bevacizumab increases the sensitivity of cervical carcinoma to cisplatin, suggesting that bevacizumab in combination with standard chemotherapy may represent a new strategy for overcoming drug resistance. Abbreviation: HPV, human papillomavirus; CSCs, cancer stem cells; ALDH1, aldehyde dehydrogenase 1; EMT, epithelial-mesenchymal transition; OD, optical density; qRT-PCR, RNA analysis by quantitative real-time polymerase chain reaction; RIPA, radioimmunoprecipitation assay; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; PVDF, polyvinylidene difluoride; ECL, electrochemiluminescence; NC, negative control; HE, haematoxylin and eosin; IHC, immunohistochemistry; DAB, 3, 3'-diaminobenzidine; IF, immunofluorescence; DAPI, 4,6-diamidino-2-phenylindole; VEGFA, vascular endothelial growth factor A; ROS, oxygen species; DFS, disease-free survival; OS, overall survival; HIF, hypoxia-inducible factor; PDGFs, platelet-derived growth factors; FGFs, fibroblast growth factors; PlGF, placenta growth factor; RTKs, receptor tyrosine kinases., 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: Breast cancer (BC) is the most prevalent solid cancer affecting women's health globally. Matrine (MAT), a traditional Chinese herb, has exhibited antitumor effects against BC. However, its mechanism of action, particularly whether it involves the control of cell proliferation and epithelial-mesenchymal transition (EMT), remains unknown., Aims: To explore MAT's role in BC and its regulatory mechanisms, as well as to identify targets for the development of novel medicines and improvement of BC treatment modalities., Study Design: Experimental study., Methods: The UALCAN and Lnc2Cancer 3.0 databases were used to predict the expression of LINC01116 in BC. The BC cells (MDA-MB-231 and MCF-7) were treated with various concentrations of MAT, and the optimal dose and timing of MAT action were determined using CCK-8 and quantitative real-time polymerase chain reaction assays. Functional assays such as CCK-8, EdU, Transwell, Western blot, and flow cytometry assays were performed on the BC cells, and the impacts of LINC01116, miR-9-5p, and ITGB1 expression levels on MAT's mechanism of action were assessed. The association between LINC01116, miR-9-5p, and ITGB1 was evaluated using dual luciferase and RNA immunoprecipitation assays. Furthermore, the size and weight of the subcutaneous tumors in mice model were assessed. The effect of LINC01116 overexpression on the in vivo action of MAT and histopathological staining (TUNEL immunofluorescence, hematoxylin & eosin staining, immunohistochemistry staining for Ki67 and Bax) were also assessed., Results: The optimal dose and duration of MAT administration were 8 μm and 24 h, respectively. MAT effectively inhibited BC cell proliferation, EMT progression, and biological functions, while promoting BC cell apoptosis. The animal model experiments also demonstrated that MAT inhibited BC tumor growth in vivo. Furthermore, MAT inhibited LINC01116, which acted as a sponge for miR-9-5p, increasing the ITGB1 level., Conclusion: MAT suppresses BC cell and EMT proliferation via the LINC01116/miR-9-5p/ITGB1 pathway. Thus, MAT may be a promising target for adjuvant anti-BC therapy., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies., Competing Interests: Competing interests: H.M.H. has been working within the past 3 years as a part-time Medical Advisor for Amgen AB. C.A. received research fees from Revolution Medicines, Aelin Therapeutics, Verastem, Roche and Boehringer-Ingelheim. P.A.J has consulting fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Takeda Oncology, ACEA Biosciences, Eli Lilly and Company, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, LOXO Oncology, Daiichi Sankyo, Sanofi Oncology, Voronoi, SFJ Pharmaceuticals, Takeda Oncology, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Biocartis, Allorion Therapeutics, Accutar Biotech and Abbvie, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology and Duality; post-marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp; sponsored research agreements with AstraZeneca, Daichi-Sankyo, PUMA, Boehringer Ingelheim, Eli Lilly and Company, Revolution Medicines and Astellas Pharmaceuticals; stock ownership in Gatekeeper Pharmaceuticals. B.N. is an inventor on patent applications related to the dTAG system (WO/2017/024318, WO/2017/024319, WO/2018/148440, WO/2018/148443, and WO/2020/146250). The Nabet laboratory receives or has received research funding from Mitsubishi Tanabe Pharma America, Inc. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Gram-negative bacteria increase in ovarian cancer (OC) tissues, but its association with OC progression remains largely unknown. The present study aimed to investigate whether and how cancer-associated fibroblasts (CAFs) pretreated by the main components of bacterial outer membrane lipopolysaccharide (LPS) influence the malignancy of OC cells. Specifically, the culture medium of LPS-preconditioned CAFs (LPS-CM) further accelerated cell proliferation, colony formation and tumorigenesis of OC cells SKOV3 and HEY A8, compared with culture medium of CAFs. Next, we found that LPS pretreatment activated the nuclear factor-kappa B (NF-kB) pathway in CAFs to secret cytokines, including interleukin 1β (IL-1β), interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), etc. Neutralization of IL-6 in LPS-CM abolished the promoting effect of LPS-CM on cell proliferation, survival and epithelial-mesenchymal transition (EMT) in SKOV3 and HEY A8 cells. Mechanistically, LPS-CM activated the Janus kinases 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while application with JAK2 inhibitor also reversed the promoting effect of LPS-CM on malignancy of OC cells. In summary, LPS-pretreated CAFs IL-6-dependently accelerate OC progression via activating the JAK2/STAT3 signal pathway, which enriches our understanding of the molecular mechanisms underlying ovaries-colonized gram-negative bacteria in OC progression., Competing Interests: Declarations. Competing Interest: The authors declared no conflict of interest in this study. Ethical Statement: The experiment protocol involving human samples and animals has been approved by the ethics committee of the First People’s Hospital of Yunnan Province, and written informed consents has been obtained from all the patients. All experimental protocols involving animals followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and ARRIVE Guidelines pertaining to animal experimentation. Consent for Publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute respiratory distress syndrome is a disease triggered by severe pulmonary and systemic inflammation that may lead to fibrosis and the decline of lung function. Lung capillary endothelial-to-mesenchymal transition (EndMT) is one of the primary sources of fibroblasts in pulmonary fibrosis. The role of miRNAs as molecular markers of pulmonary fibrosis, and miRNAs as nucleic acid drugs has attracted increasing attention. To mock EndMT process, Human pulmonary microvascular endothelial cells (HPMECs) were induced with lipopolysaccharide (LPS). Similarly, LPS treatment was used to generate a mouse model of LPS-induced EndMT and pulmonary fibrosis. LPS-induced EndMT in HPMECs resulted in a significant reduction of miR-23b-3p. miR-23b-3p inhibited the interstitial transition of HPMECs, and miR-23b-3p could mediate this process via inhibiting dipeptidyl peptidase-4 (DPP4). Dual-luciferase assays confirmed the regulatory mechanism of miR-23b-3p. In our mouse model of LPS-induced pulmonary fibrosis, miR-23b-3p and a DPP4 inhibitor (sitagliptin) individually alleviated LPS-induced EndMT progression and pulmonary fibrosis, and their combined use achieved the strongest remission effect. To sum up, miR-23b-3p alleviates EndMT in pulmonary fibrosis by inhibiting the expression of DPP4., Competing Interests: Declarations. Competing Interests: The authors declare that they have no competing interests., (© 2023. The Author(s).)

The main causes of high mortality in lung cancer patients are the malignant growth and migration of cancer cells. This study aims to investigate the underlying mechanisms of low-temperature plasma-activated medium (PAM) treating human lung cancer (HLC). Changes in the levels of reactive oxygen and nitrogen species both inside and outside the cells were evaluated. Our results showed that prolonged PAM exposure decreased cell viability, raised intracellular reactive oxygen species levels, and hindered cell migration while reducing mitochondrial membrane potential. Protein analysis revealed PAM increased GSK-3β and p-β-catenin expression but decreased PI3K, AKT, p-AKT, p-GSK-3β, Wnt, and β-catenin levels, thereby inhibiting the epithelial-mesenchymal transition. These findings suggest PAM suppresses HLC cells proliferation and migration by blocking the PI3K/AKT-Wnt pathway. The study will provide a valuable theoretical basis for future low-temperature plasma treatment, thereby improving the survival rates and prognosis of lung cancer., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Chronic fibrosis often occurs in transplanted kidneys, leading to progressive functional decline. The underlying mechanisms may involve disruption in the metabolism of renal tubular epithelial cells. The liver kinase B1 (LKB1)-AMPK pathway is a pivotal regulatory hub for glucose and fatty acid metabolism and may play a role in transplanted kidney fibrosis, but it has not been reported. In this study we administered fenofibrate, 2-deoxyglucose, or metformin to modulate metabolism in Brown Norway rat kidney transplants and investigated pathways involved in fibrosis using various assays. We identified an impaired LKB1-AMPK pathway within epithelial cells, resulting in perturbed glucose and fatty acid metabolism, collagen secretion, extracellular matrix remodeling, and epithelial-mesenchymal transition. ACOX1, a pivotal enzyme in the fatty acid peroxisomal β-oxidation pathway, played an important role in transplanted renal fibrosis. Furthermore, several metabolism-targeting drugs, particularly metformin, emerged as potent fibrosis inhibitors. Metformin attenuated fibrosis, improved renal function, and reduced inflammation and macrophage infiltration in the transplanted kidneys. These results provide new perspectives for understanding the complex molecular basis underlying transplanted renal fibrosis and developing novel therapeutic strategies., Competing Interests: Declaration of competing interest We 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.)

Colorectal cancer (CRC) is the second most common cause of cancer-related death and represents a serious worldwide health problem. CRC metastasis decreases the survival rate of cancer patients, underscoring the need to identify novel anticancer agents and therapeutic targets. Here, we introduce Plectalibertellenone A (B) as a promising agent for the inhibition of CRC cell motility and glucose metabolism and explore its mechanism of action in CRC cells. Plectalibertellenone A suppressed TGF-β gene expression and the activation of the TGF-β/Smad signaling pathway, leading to reverse epithelial to mesenchymal transition (EMT) by modulating the expressions of EMT markers and transcriptional factors such as E-cadherin, N-cadherin, vimentin, Slug, Snail, Twist, and ZEB1/2. Furthermore, disruption of Wnt signaling inhibited CRC motility and glucose metabolism including glycolysis and oxidative phosphorylation, primarily affecting glycolytic enzymes, GLUT1, HK2, PKM2, LDHA, and HIF-1α under hypoxic condition. Therefore, Plectalibertellenone A is a potential drug candidate that can be developed into a promising anticancer treatment to prevent CRC metastasis and inhibit glucose metabolism., (© 2024 International Union of Biochemistry and Molecular Biology.)

The lack of targeted therapy for triple-negative breast cancer (TNBC) is among the mainsprings of its poor prognosis. This study aimed to elucidate the role of the androgen receptor (AR) and its splice variant 7 (ARv7) in TNBC patients. Further, the molecular impact of their blockers, Enzalutamide and EPI-001, on the TNBC cell line MDA-MB-231 was investigated. Thereby, immunohistochemical expression of AR/ARv7 was assessed for TNBC Egyptian patients. Moreover, bioinformatics analysis of AR/ARv7 RNA status was carried out on TNBC patients from The Cancer Genome Atlas Breast Carcinoma project (TCGA-BRCA). Data from both groups was correlated with patients' clinicopathological features. Besides, scratch wound healing assay and ELISA were employed to assess the effect of AR/ARv7 blockers on several metastasis markers in MDA-MB-231 cell line. In the Egyptian-TNBC patients, AR expression was associated with worse 7-year DFS (40.6 ± 18.6 %). In addition, ARv7 showed cytoplasmic and nuclear patterns, and both cytoplasmic and nuclear ARv7 + patients demonstrated a worse 7-year DFS (22.7 ± 17.7 % and 20 ± 17.9 %) and overall survival (63.6 ± 14.5 % and 40 ± 21.8 %). Importantly, 80 % of the nuclear ARv7 + patients developed distant metastasis. The data of the TCGA-TNBC patients showed a tendency for poor outcomes in the high ARv7-expressing patients. Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis., Competing Interests: Declaration of interest The authors declare no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In colorectal cancer (CRC), KRAS mutations enhance metachronous metastasis, a condition without prognostic biomarkers or preventive measures. The present study demonstrated that KRAS mutation may be a risk factor for CRC metachronous metastasis through meta‑analysis of public databases. A risk scoring model was constructed using machine learning for predicting metachronous metastasis in KRAS‑mutant CRC. Wound healing and Transwell assay indicated that KRAS inhibitors strongly suppress migration and invasion capabilities of high‑risk CRC cells and these findings were validated through ex vivo organoid and a mouse model of splenic‑liver metastasis. Mechanistically, RNA sequencing, reverse transcription‑quantitative PCR and western blot analyses revealed that KRAS inhibitors suppressed epithelial‑mesenchymal transition (EMT) and transforming growth factor β (TGF‑β) signaling. Notably, addition of TGF‑β1 protein partially reversed the inhibitory effects of KRAS inhibitors on CRC. These results suggested that KRAS inhibitors may prevent CRC metachronous metastasis by downregulating TGF‑β‑mediated EMT, suggesting they can be used prophylactically in high‑risk KRAS‑mutant CRC.

Crizotinib, as the first-generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK-positive non-small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4-ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial-mesenchymal transition (EMT) and metastasis compared to control (A549-vector) or wild type (A549-EML4-ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in mutant cells. Down-regulation of MDM2 inhibited the activation of MEK/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy., (© 2024 International Federation for Cell Biology.)

Developing novel anti‑angiogenic agents with minimal toxicity is notably challenging for cancer therapeutics. The discovery and development of peptides, whether derived from natural sources or synthesized, has potential for developing anti‑angiogenic agents characterized by their ability to penetrate cancer cells, high specificity and low toxicity. The present study identified a Bryopsis plumose ‑derived anticancer and anti‑angiogenesis marine‑derived peptide 06 (MP06). A 22‑amino acid peptide was synthesized and conjugated with fluorescein isothiocyanate (FITC‑MP06) for intracellular localization in H1299 non‑small cell lung cancer cells. Regulatory effects of this peptide on the viability, migration and self‑renewal of lung cancer cells was assessed. Furthermore, anti‑angiogenic effect of MP06 was investigated by monitoring vascular tube formation in human umbilical vein endothelial cells and a zebrafish model. Aquaporin (AQP)3, a membrane channel in various tissues, is involved in regulating stemness, epithelial‑mesenchymal transition (EMT) and angiogenesis. MP06 downregulated AQP3 expression. Consistently, AQP3 knockdown by RNA silencing downregulated its gene expression, leading to a decrease in stemness, EMT and angiogenesis properties in H1299 cells. MP06 could thus serve as a novel therapeutic target with anticancer and angiogenesis properties for non‑small cell lung cancer.

Among the tumors with the highest lethality, gliomas are primary brain tumors associated with common recurrence inclined to metastasize along the neuraxis and occasionally out of the central nervous system. Even though metastasis is the main responsible for death in oncological patients, few dedicated treatments are approved. Therefore, the establishment of effective anti-metastasis agents is the final frontier in cancer research. Interestingly, some copper complexes have demonstrated promising efficacy as antimetastatic agents, but they may cause off-site effects such as the alteration of copper homeostasis in healthy tissues. Thus, the incorporation of copper-based antimetastatic agents in rationally designed nano-architectures can increase the treatment localization reducing the side effects. Here, copper complex loaded hybrid nano-architectures (CuLNAs) are presented and employed to assess the impact of an intracellular copper source on glioma cell invasiveness. The novel CuLNAs are fully characterized and exploited for cell migration modulation in a glioma cell line. The results demonstrate that CuLNAs significantly reduce cell migration without impairing cell proliferation compared to standard gold and copper NAs. A concomitant antimigratory-like regulation of the epithelial-to-mesenchymal transition genes confirmed these results, as the gene encoding for the epithelial protein E-cadherin was upregulated and the other explored mesenchymal genes were downregulated. These findings, together with the intrinsic behaviors of NAs, demonstrate that the inclusion of metal complexes in the nano-architectures is a promising approach for the composition of a family of agents with antimetastatic activity., Competing Interests: Declaration of Competing Interest The Authors declare no competing financial interests that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bisphenol S (BPS), one of the most common alternatives for bisphenol A (BPA), has been implied to increase the risk of breast cancer. Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer with a poor prognosis. However, the association between BPS and TNBC remains unclear. Cancer stem cells (CSCs) have a crucial role in breast cancer initiation, metastasis, and recurrence. Here, we proposed that BPS, equivalent to the human internal exposure and the environmental concentrations, enhanced CSC-like properties by upregulating sphere formation, self-renewal, the percentage of CD44 + /CD24 - cells, and the expression of CSC markers. Moreover, BPS promoted the migration, invasion, and epithelial-mesenchymal transition (EMT) in TNBC cells. Mechanistically, BPS activated the Sonic Hedgehog (SHH) signaling pathway in TNBC cells. Molecular docking analysis further showed that BPS upregulated SHH signaling pathway via directly binding Gli1 protein. Furthermore, inhibitor of SHH pathway or Gli1 siRNA attenuated the promoting effects of BPS on stemness, invasion, and migration of TNBC cells. In summary, our data firstly provide evidence that environmentally relevant BPS concentration treatment significantly enhanced TNBC malignant phenotype by activating the Sonic Hedgehog/Gli1 signaling pathway, raising high concerns about the potential population biology hazards of BPS., 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.)

The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype 1 . Here we identify the oestrous cycle as an important contributor to this heterogeneity. In three mouse models of breast cancer, we show reduced responses to NAC when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage. Similar findings were observed in retrospective premenopausal cohorts of human patients. Mechanistically, the dioestrus stage exhibits systemic and localized changes, including (1) an increased number of cells undergoing epithelial-to-mesenchymal transition linked to chemoresistance 2-4 and (2) decreased tumour vessel diameter, suggesting potential constraints to drug sensitivity and delivery. In addition, an elevated presence of macrophages, previously associated with chemoresistance induction 5 , characterizes the dioestrus phase. Whereas NAC disrupts the oestrous cycle, this elevated macrophage prevalence persists and depletion of macrophages mitigates the reduced therapy response observed when initiating treatment during dioestrus. Our data collectively demonstrate the oestrous cycle as a crucial infradian rhythm determining chemosensitivity, warranting future clinical studies to exploit optimal treatment initiation timing for enhanced chemotherapy outcomes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Substrate topography is vital in determining cell growth and fate of cellular behavior. Although current in vitro studies of the underlying cellular signaling pathways mostly rely on their induction by specific growth factors or chemicals, the influence of substrate topography on specific changes in cells has been explored less often. This study explores the impact of substrate topography, specifically the tricot knit microfibrous structure of alumina textiles, on cell behavior, focusing on fibroblasts and keratinocytes for potential wound healing applications. The textiles, studied for the first time as in vitro substrates, demonstrated support for keratinocyte adhesion, leading to alterations in cell morphology and the expression of E-cadherin and fibronectin. These topography-induced changes resembled the epithelial-to-mesenchymal transition (EMT), crucial for wound healing, and were specific to keratinocytes and absent in identically treated fibroblasts. Biochemically induced EMT in keratinocytes cultured on flat alumina substrates mirrored the changes seen with alumina textiles alone, suggesting the tricot knit microfibrous topography could serve as an in vitro model system to induce EMT-like mechanisms. These results enhance our understanding of how substrate topography influences EMT-related processes in wound healing, paving the way for further evaluation of microfibrous alumina textiles as innovative wound dressings., (© 2024 The Author(s). Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Kidney fibrosis is a commonly observed pathological condition during development of chronic kidney disease. Therapeutic options currently available are effective only in slowing the progression of kidney fibrosis and there is no cure for this disease. Aberrant expression and excessive accumulation of extracellular matrix (ECM) proteins in the peritubular space is a characteristic pathological feature of fibrotic kidney. However, the molecular basis of aberrant regulation of fibrotic genes in kidneys is not clear. In this context, this study aimed to evaluate the role of epigenetic reprogramming in kidney fibrosis. Folic acid (FA)-induced acute kidney injury (AKI) and kidney fibrosis in mice as an in vivo model and long-term arsenic or FA-exposed fibrogenic HK-2 cells as an in vitro model were used to evaluate the role of DNA methylation and histone modifications in fibrosis. DNA demethylating agent 5aza2 deoxycytidine (5-aza-2-dC) and histone deacetylase inhibitor Trichostatin A (TSA) were used to treat FA-injected mice. Results of histopathological and immunofluorescence staining of kidney tissue, serum albumin- creatinine levels, body weight, and gene expression analysis revealed significant protective effects of 5-aza-2-dC and TSA in FA-induced AKI and fibrosis. Insignificant change in the expression of N-cadherin whereas a significant decrease in E-cadherin as well as an increase in the expression of Vimentin and α-SMA suggest partial EMT associated with fibrosis. Aberrant expression of epithelial-mesenchymal-transition (EMT) and ECM-regulators (MMP2, Smad7, and TIMP3) as well as fibrogenic signaling pathways (Notch, TGF-beta, and Wnt signaling), and their restoration by 5-aza-2-dC and TSA treatments suggest epigenetic reprogramming of these genes and signaling pathways during FA-induced fibrosis. In summary, this study provides new information on the role of epigenetic reprogramming of fibrogenic genes and signaling pathways during the development of kidney fibrosis. Attenuation of fibrosis after 5-aza-2-dC and TSA treatments suggest the promise of these epigenetic-based therapeutics in the clinical management of this disease., Competing Interests: Declaration of competing interest There is no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Triple-negative breast cancer (TNBC) is a highly invasive breast cancer subtype that is challenging to treat due to inherent heterogeneity and absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Kinase signaling networks drive cancer growth and development, and kinase inhibitors are promising anti-cancer strategies in diverse cancer subtypes. Kinase inhibitor screens are an efficient, valuable means of identifying compounds that suppress cancer cell growth in vitro , facilitating the identification of kinase vulnerabilities to target therapeutically. The Kinase Chemogenomic Set is a well-annotated library of 187 kinase inhibitor compounds that indexes 215 kinases of the 518 in the known human kinome representing various kinase networks and signaling pathways, several of which are understudied. Our screen revealed 14 kinase inhibitor compounds effectively inhibited TNBC cell growth and proliferation. Upon further testing, three compounds, THZ531, THZ1, and PFE-PKIS 29, had the most significant and consistent effects across a range of TNBC cell lines. These cyclin-dependent kinase (CDK)12/CDK13, CDK7, and phosphoinositide 3-kinase inhibitors, respectively, decreased metabolic activity in TNBC cell lines and promote a gene expression profile consistent with the reversal of the epithelial-to-mesenchymal transition, indicating these kinase networks potentially mediate metastatic behavior. These data identified novel kinase targets and kinase signaling pathways that drive metastasis in TNBC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Osteosarcoma is a highly malignant bone tumor with poor prognosis and limited treatment options due to resistance and side effects., Objectives: This study investigates the effects of N6-(2-hydroxyethyl)-adenosine (HEA) on osteosarcoma cells and its impact on the IGF1 signaling pathway., Methods: Saos2 and MG63 cell lines were treated with HEA. Cell viability, apoptosis, migration, invasion, and EMT markers were assessed. IGF1 expression was analyzed using Western blot, qPCR, and ELISA. IGF1 silencing and recombinant IGF1 treatments were used to explore HEA's mechanisms., Results: HEA significantly decreased osteosarcoma cell viability and induced apoptosis in a dose- and time-dependent manner. It also inhibited cell migration and invasion, and modulated EMT markers by upregulating E-cadherin and downregulating N-cadherin and vimentin. HEA downregulated IGF1 at both the mRNA and protein levels, and reduced IGF1 secretion. Furthermore, HEA inhibited the PI3K-AKT signaling pathway, which is activated by IGF1. IGF1 silencing mimicked HEA's effects, whereas recombinant IGF1 pre-treatment partially reversed HEA's effects on cell viability, apoptosis, and EMT markers., Conclusions: HEA exerts potent anti-cancer effects on osteosarcoma cells both in vitro and in vivo by targeting the IGF1 pathway and inhibiting downstream PI3K-AKT signaling. These results suggest that HEA holds promise as a novel therapeutic agent for osteosarcoma., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Junqiang Ye reports financial support was provided by Longgang Medical Discipline Construction Fund. Yu Dai reports writing assistance was provided by Guangdong Basic and Applied Basic Research Foundation. 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 B.V. All rights reserved.)

Proprotein convertase subtilisin/kexin type 5 (PCSK5) is a member of the proprotein convertase (PC) family, which processes immature proteins into functional proteins and plays an important role in the process of cell migration and transformation. Andrographolide is a non-peptide compound with PC inhibition and antitumor activity. Our research aimed to investigate the functional role of PCSK5 downregulation combined with Andro on GBM progression. Results from the cancer genome atlas (TCGA) and clinical samples revealed a significant upregulation of PCSK5 in GBM tissues than in non-tumor brain tissues. Higher expression of PCSK5 was correlated with advanced GBM stages and worse patient prognosis. PCSK5 knockdown attenuated the epithelial-mesenchymal transition (EMT)-like properties of GBM cells induced by IL-6. PCSK5 knockdown in combination with Andro treatment significantly inhibited the proliferation and invasion of GBM cells in vitro, as well as tumor growth in vivo. Mechanistically, PCSK5 downregulation reduced the expression of p-STAT3 and Matrix metalloproteinases (MMPs), which could be rescued by the p-STAT3 agonist. STAT3 silencing downregulated the expression of MMPs without affecting PCSK5. Furthermore, Andro in combination with PCSK5 silencing significantly inhibited STAT3/MMPs axis. These observations provided evidence that PCSK5 functioned as a potential tumor promoter by regulating p-STAT3/MMPs and the combination of Andro with PCSK5 silencing might be a good strategy to prevent GBM progression., Competing Interests: Declarations. Competing interests: The authors declare no competing interests exist. Ethical approval: This study was approved by the Ethics Committee of GuiZhou Medical University. Animal experiments were carried out according to guidelines approved by the Animal Experimental Research Ethics Committee of GuiZhou Medical University., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Resistance to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) remain a major challenge in ovarian cancer (OC) treatment. However, the underlying mechanism of PARPi resistance is still poorly characterized. Increasing evidence has proven that lymphocyte cytosolic protein 1 (LCP1) promotes tumor progression. The JAK2/STAT3 signaling pathway plays an important role in increasing tumor metastatic ability and chemoresistance in cancer by promoting epithelial - mesenchymal transition (EMT)., Methods: We established an olaparib-resistant OC cell line and studied its toxicologic effects through cell survival, Transwell, colony formation, western blotting and flow cytometry assays. RNA sequencing and screening were then performed to identify genes associated with olaparib resistance. Lymphocyte cytosolic protein 1 (LCP1) was found to be overexpressed in olaparib-resistant OC cells., Results: The inhibition of cell survival and promotion of cell apoptosis induced by olaparib in parental cells were significantly attenuated in olaparib-resistant cells. LCP1 was upregulated in olaparib-resistant cells compared with parental OC cells. Moreover, we found that the protein levels of JAK2/STAT3 signaling pathway components and EMT markers were increased in olaparib-resistant cells. Overexpression of LCP1 increased olaparib resistance in OC cells, and knockdown of LCP1 attenuated olaparib resistance. The changes in the protein levels of JAK2/STAT3 signaling pathway members and EMT markers between the cell types were similar to the changes in the levels of LCP1., Conclusions: These findings indicate that LCP1 expression may play an important role in the resistance of OC to olaparib by activating the JAK2/STAT3 signaling pathway and EMT. LCP1 could be a potential therapeutic target for patients with OC who are resistant to olaparib. Our study provides a new mechanism of olaparib resistance.

Renal fibrosis is an irreversible disease that is common in patients with chronic kidney disease. Elevated levels of the histone acetyltransferase p300 have been reported in various fibrotic diseases, including renal fibrosis, suggesting that p300 may be a promising therapeutic target. To investigate the specific deubiquitinase (DUB) involved in the regulation of p300 protein stability in renal epithelial cells, we tested 13 DUB inhibitors using a kidney tubular epithelial cell line. We found that the p300-specific DUB inhibitor, bAP-15 reduces p300 protein stability by targeting ubiquitin-specific protease 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5). The mRNA levels of USP14 and UCHL5 were increased in patients with chronic kidney disease, and increased protein levels of USP14 and UCHL5 during fibrosis progression were validated using a mouse renal fibrosis model. Both USP14 and UCHL5 interacted with p300 in kidney tubular epithelial cells, with increased binding affinity in response to TGF-β. Moreover, bAP-15-induced p300 degradation inhibited epithelial-to-mesenchymal transition and reduced the expression of pro-fibrotic target genes. Our findings demonstrate an anti-fibrotic effect of bAP-15 through the regulation of p300 stability and suggest that bAP-15 may be a potential therapeutic agent for renal fibrosis., 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.)

Most pancreatic cancer patients are diagnosed at advanced stages, with poor survival rates and drug resistance making pancreatic cancer one of the highest causes of cancer death in the UK. Understanding the underlying mechanism behind its carcinogenesis, metastasis and drug resistance has become an essential task for researchers. We have discovered that a well-established tumour suppressor, EPLIN, has an oncogenic rather than suppressive role in pancreatic cancer. Notably, upregulation of EPLIN was observed in pancreatic cancer samples compared to normal samples at RNA and protein levels. Moreover, the presence of EPLIN resulted in poor clinical outcomes in patients. We also report that inhibition of EPLIN led to reduced cellular growth and migration in pancreatic cancer cells. EPLIN regulates expression and phosphorylation levels of several key players in MAPK and PIK3CA-AKT signalling pathways, as well as key contributors of EMT. Furthermore, EPLIN mediates the inhibitory ability PIK3 kinases, MEK and ERK inhibitors have on cell migration. EPLIN was also found to have an impact on pancreatic cancer cells response to chemotherapeutic and EGFR/HER2 targeted therapeutic agents, namely gemcitabine, fluorouracil (5FU) and neratinib (Nerlynx)., Competing Interests: Declarations. Institutional review board statement: The current study was approved by the Ethics Research Committee of Peking University Cancer Hospital (Ethics approval number: 2006021). Informed consent: Informed consent was obtained from all subjects in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Cancer-associated fibroblasts (CAFs) exert multiple tumor-promoting functions and are key contributors to drug resistance. The mechanisms by which specific subsets of CAFs facilitate oxaliplatin resistance in colorectal cancer (CRC) have not been fully explored. This study found that THBS2 is positively associated with CAF activation, epithelial-mesenchymal transition (EMT), and chemoresistance at the pan-cancer level. Together with single-cell RNA sequencing and spatial transcriptomics analyses, we identified THBS2 specifically derived from subsets of CAFs, termed THBS2 + CAFs, which could promote oxaliplatin resistance by interacting with malignant cells via the collagen pathway in CRC. Mechanistically, COL8A1 specifically secreted from THBS2 + CAFs directly interacts with the ITGB1 receptor on resistant malignant cells, activating the PI3K-AKT signaling pathway and promoting EMT, ultimately leading to oxaliplatin resistance in CRC. Moreover, elevated COL8A1 promotes EMT and contributes to CRC oxaliplatin resistance, which can be mitigated by ITGB1 knockdown or AKT inhibitor. Collectively, these results highlight the crucial role of THBS2 + CAFs in promoting oxaliplatin resistance of CRC by activating EMT and provide a rationale for a novel strategy to overcome oxaliplatin resistance in CRC., Competing Interests: Declarations. Consent for publication: All authors have consented to submit this article for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Recurrence and metastasis stand as the primary contributors to mortality among patients with triple-negative breast cancer post-surgery, presenting a formidable clinical obstacle. Chemodynamic therapy (CDT), leveraging metal-ion-mediated Fenton-like reactions within the tumor microenvironment (TME), emerges as a promising avenue for addressing cancer metastasis. Despite recent progress, challenges such as tumor cell antioxidant defenses and epithelial-mesenchymal transition (EMT) impede the efficacy of CDT. Here, we introduce a novel approach using DNA-templated nanosheets (Dz-MnO 2 ) that combine the functions of Mn 2+ -mediated CDT and DNAzyme-mediated gene therapy to suppress tumor growth and metastasis. The Dz-MnO 2 nanosheets respond effectively to the TME, releasing Mn 2+ and DNAzyme. The DNAzyme exhibits mRNA cleavage activity, specifically targeting oncogenic transcripts to reduce tumor progression. Mn 2+ not only facilitates a Fenton-like reaction, enhancing the chemodynamic treatment effect, but also serves as a cofactor for DNAzyme, improving its catalytic efficiency. Concurrently, the nanosheets robustly silence the Twist1 gene, mitigating the EMT process and reinforcing CDT efficacy by suppressing apoptosis resistance. Results indicate that Dz-MnO 2 nanosheets efficiently polarize M2-tumor-associated macrophages (TAMs) into M1-TAMs by locally mitigating tumor hypoxia via catalyzing the decomposition of H 2 O 2 into O 2 . This collaborative strategy presents a promising approach to enhance CDT, effectively inhibiting tumor recurrence 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. Published by Elsevier B.V.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, and its incidence rate is increasing. PDAC patients are prone to acquired chemotherapy resistance, necessitating the development of novel drugs to provide alternative treatment options. In recent years, traditional folk medicine and its active ingredients have garnered increasing attention for their effectiveness in treating tumors. Here, we discovered that isolinderalactone (ILL), a sesquiterpenoid compound extracted from the traditional Chinese medicine Lindera aggregata (Sims) Kosterm., possesses anti-PDAC pharmacological activity. Our results revealed that ILL decreased the proliferative capacity of PDAC cells in a time- and dose-dependent manner. The migration and invasion abilities of tumor cells were significantly suppressed due to the inhibition of epithelial-to-mesenchymal transition (EMT). Additionally, the cell cycle was arrested in the G2/M phase, leading to apoptosis, and inhibiting inflammatory responses. Mechanistically, bioinformatics analysis of molecular expression changes combined with in vivo and in vitro experiments demonstrated that ILL induces persistent ER stress by activating p38 MAPK signaling pathway, thus promoting the expression of DDIT3, and ultimately suppressing progression-related cell behaviors. Animal experiments confirmed that ILL also inhibited PDAC development in vivo with minimal toxicity. In summary, our study identified ILL as a potential therapeutic compound for PDAC treatment., 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: Gram-negative bacteria are the primary pathogens of endometritis in dairy cows. LPS, the primary pathogenic agent of gram-negative bacteria, triggers an ROS increase, ultimately causing epithelial-mesenchymal transformation (EMT). Its significance in endometritis pathogenesis in dairy cows cannot be overlooked., Purpose: Our previous studies showed that berberine could activate the Nrf2 signalling pathway, but whether it can inhibit the effect of LPS-induced EMT is uncharacterized., Methods: This research examined how berberine protects bovine endometrial epithelial cells (BEECs) by treating them with the compound for 2 h before exposing them to LPS to induce injury. Subsequently, the levels of reactive oxygen species (ROS) and epithelial-mesenchymal transition (EMT) markers in BEECs were quantified using the DCFH-DA probe, RT-qPCR, and Western blotting techniques., Results: Our investigation revealed that the triggering of the Nrf2 signal transduction pathway can effectively prevent LPS-induced EMT by reducing ROS levels in BEECs. Additionally, we found that berberine inhibits LPS-induced EMT by activating Nrf2 to reduce ROS levels., Conclusion: These results suggest that berberine reduces ROS levels by upregulating the Nrf2 pathway in BEECs stimulated with LPS., 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.)

Accumulating evidences have indicated that cancer stem cells (CSCs) can initiate tumor progression and cause recurrence after therapy. However, specific markers of gastric CSCs (GCSCs) from different origins have not been comprehensively revealed. Here, we further detected whether cell populations labelled with CD44 and Lgr5, well-recognized stem markers for gastric cancer (GC), can better emphasize cancer initiation, therapeutic resistance and recurrence. Flow cytometry was utilized to sort the CD44 + Lgr5 + and CD44 + Lgr5- cells from GC cell line HGC-27 and primary GC cells. The influences of CD44 and Lgr5 GCSCs on the malignant behaviors and their potential mechanisms was investigated, respectively. In our study, we reported the identification and validation of CD44 + Lgr5 + cells that presented stronger stemness characteristics, as evidenced by increase of sphere forming ability, elevation of stem cell transcriptional activity. Additionally, CD44 + Lgr5 + double positive cells have lower apoptosis, greater chemotherapy resistance, and higher EMT capacity and LC3 density compared with CD44 + Lgr5- cells. Tumor xenograft experiments also verified the faster carcinogenesis of CD44 + Lgr5 + GCSCs. Furthermore, a series of key proteins in the Wnt, Hedgehog, Notch, and TGF-β pathways were elevated in the CD44 + Lgr5 + double positive subpopulation, except for Notch 1 and Smad 1. In conclusion, the binding of CD44 and Lgr5 can serve as a precise GCSCs marker that initiate malignant progression and chemotherapy resistance in GC by activating Wnt, Hedgehog, Notch, TGF-β pathways. Those evidences raise the needs to target both markers simultaneously as a potential approach for the GC treatment., Competing Interests: Declarations. Ethical approval: All animal experiments were approved by the Animal Ethics Committee of Beijing Viewsolid Biotechnology Co. LTD (VS2126A23528). Conflicts of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Following abdominal surgery, the occurrence of postoperative abdominal adhesion (PAA) is highly prevalent and stands out as one of the most frequently encountered complications. The effect and molecular mechanisms of Ligustrazine nanoparticles (LN) underlying epithelial-mesenchymal transition (EMT) in PAA still remain elusive. Adhesions were induced in Male Sprague-Dawley rats by injuring the cecum (cecal abrasion model), followed by administration of LN and hyaluronate acid (HA). The mechanism was further verified by enzyme-linked immunosorbent assay, wound healing assay, si-RNA and Western blot. Animal experiments revealed that LN effectively ameliorated adhesions, notably decreased tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-8, and fibrosis, and reduced the expression of TGF-β1 and EMT related markers (Fibronectin and E-cadherin). Furthermore, in vitro experiments demonstrated that LN might inhibit the TGF-β1 FOXC2 pathway through suppressing the expression of Fibronectin, P120, and E-cadherin and ameliorating peritoneal adhesion. Collectively, our findings indicate that LN inhibits PAA formation by reducing inflammation, decreasing EMT and promoting peritoneal mesothelial cell repair. Therefore, LN might be considered a potential candidate for the treatment of PPA. However, further clinical studies are required to approve the effectiveness of LN., Competing Interests: Declaration of Competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives : This research aims to investigate the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC), particularly focusing on the role of the epithelial-mesenchymal transition (EMT) within the tumor microenvironment (TME). Materials and Methods : We employed an in vitro three-dimensional organoid model that mirrors the physiology of human lung cancer. These organoids consist of lung cancer cells harboring specific EGFR mutations, human mesenchymal stem cells, and human umbilical vein endothelial cells. We analyzed EMT and drug resistance markers, and evaluated the effects of the anti-angiogenic agent Bevacizumab and micro-RNA miR200c. Results : The study identified a significant link between EMT and EGFR-TKI resistance. Notable findings included a decrease in E-cadherin and an increase in Zinc Finger E-Box Binding Homeobox 1 (ZEB1), both of which influenced EMT and resistance to treatment. Bevacizumab showed promise in improving drug resistance and mitigating EMT, suggesting an involvement of the Vascular Endothelial Growth Factor (VEGF) cascade. Transfection with miR200c was associated with improved EMT and drug resistance, further highlighting the role of EMT in TKI resistance. Conclusions : Our research provides significant insights into the EMT-driven EGFR-TKI resistance in NSCLC and offers potential strategies to overcome resistance, including the use of Bevacizumab and miR200c. However, due to the limitations in organoid models in replicating precise human cancer TME and the potential influence of specific EGFR mutations, further in vivo studies and clinical trials are necessary for validation.

The axis CXCL12-CXCR4 is highly expressed in ovarian cancer where contributes to disease progression. Aim of the work was to evaluate the effect of the newly developed CXCR4 antagonist R54 on human ovarian cancer cells aggressiveness. CXCL12-CXCR4 axis was evaluated in human ovarian cancer cells through proliferation, migration and signaling CXCL12-dependents. Epithelial to mesenchymal transition (EMT) was analyzed through E-CADHERIN, N-CADHERIN, VIMENTIN, SNAIL1 and ΒETA-CATENIN by qRT-PCR, immunofluorescence and immunoblotting. R54 inhibited ovarian cancer cells proliferation and migration CXCL12-induced. Moreover, R54 inhibited CXCL12 dependent pERK1/2 and pAKT and reversed the CXCL12 induced EMT in ovarian cancer cells. Targeting CXCR4 with the new antagonist R54 consistently reverted the mesenchymal transition in human ovarian cancer cells reducing migratory and chemoresistance features., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Russo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Occupational exposure to arsenic (As), cadmium (Cd), and lead (Pb) affects many sectors, necessitating research to understand their transformation mechanisms. In this study, we characterized the process of epithelial-mesenchymal transition (EMT) in a rat hepatic epithelial cell line with decreased expression of catalase and glutamate cysteine ligase catalytic (GCLC) subunit that was exposed to a mixture of As, Cd, and Pb at equimolar occupational exposure concentrations. We evaluated the expression of genes and proteins involved in EMT. Our findings revealed that cells with a decreased antioxidant barrier showed a decreased expression and abundance of epithelial genes when exposed to a mixture of metals. Additionally, we observed alterations in the expression of transcription factors (TFs) associated with EMT and an increase in the expression and abundance of mesenchymal genes. Specifically, we found that E-cadherin expression decreased by ~50% at both the gene and protein levels. In contrast, the expression of vimentin , α-smooth muscle actin , and N-cadherin genes increased by ~70%, whereas their corresponding protein levels increased by nearly 100%. Furthermore, the TFs zinc finger e-box binding homeobox 1 and snail family transcriptional repressor 1 showed a 30% increase in gene expression and an ~80% increase in protein expression. These changes enable the cells to acquire migratory capabilities. Our results confirmed that exposure to this mixture of As, Cd, and Pb can induce EMT in cells with a decreased antioxidant barrier., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 M. Valverde et al.)

Aims: The analgesic effect of ketamine in cancer pain remains controversial. This research investigates the role of ketamine in bone metastasis-induced cancer pain in breast cancer (BC) and its associated molecular network., Methods: BC cell lines MDA-MB-231 and ZR-75-1 were treated with ketamine and malignant behaviors were assessed through CCK-8, colony formation, and Transwell assays. To evaluate the pro-osteoclastic effect in vitro, BC cells were co-cultured with RAW 264.7 cells. Alterations in the expression of SRC proto-oncogene (SRC), early growth response 1 (EGR1), and cystatin E/M (CST6) were induced in BC cells using lentivirus. MDA-MB-231 cells were injected intracardially into nude mice to examine tumor bone metastasis in vivo. Molecular interactions between SRC and EGR1, as well as between EGR1 and CST6 were analyzed via immunoprecipitation and luciferase assays., Results: Ketamine treatment suppressed viability, proliferation, migration and invasiveness, epithelial-mesenchymal transition, and pro-osteoclastic effect in BC cells. Ketamine also reduced osteoclastogenesis and tumor bone metastasis burden and alleviated pain in nude mice. SRC was identified as a target of ketamine. Overexpression of SRC in BC cells blocked the effects of ketamine. SRC bound to the EGR1 promoter, suppressing EGR1 transcription, whereas EGR1 activated CST6 transcription. Either EGR1 or CST6 overexpression counteracted the function of SRC overexpression and decreased the viability of BC cells and their pro-osteoclastic effect in vitro and in vivo., Conclusion: This study demonstrates that ketamine alleviates BC cell-induced osteoclastogenesis and tumor bone metastasis by suppressing SRC and restoring the EGR1/CST6 axis., Competing Interests: Declarations. Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Little is known about how various treatments impact the progression of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. Here, we compared ILD progression in RA patients treated with Janus kinase inhibitors (JAKi) or biological disease-modifying anti-rheumatic drugs (bDMARDs). In vitro experiments were also performed to evaluate the potential effects of the drugs on epithelial-mesenchymal transition (EMT), a key event in pulmonary fibrosis., Methods: This retrospective study included 93 RA-ILD patients who initiated treatment with JAKi, tumour necrosis factor inhibitors (TNFi), or abatacept between 2017 and 2020. Worsening ILD was quantified by changes in chest computed tomography (CT) scans between baseline and follow-up (mean 14 months, range 6-51 months). Response to treatment was evaluated using Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR). Expression of the EMT marker N-cadherin in A549 lung cells was assessed by western blotting., Results and Discussion: Worsening ILD was detected in 19.4% (7/36), 16.7% (5/30), and 22.2% (6/27) of patients treated with JAKi, abatacept, and TNFi, respectively. Multivariate analysis identified female gender (P=0.043) and >10% fibrotic lesions (P=0.015) as significant predictors of worsening ILD. DAS28-ESR-based non-responder status was also significantly associated with worsening ILD (P=0.0085). In vitro, combination treatment with methotrexate and baricitinib significantly impeded EMT progression. Worsening ILD was associated with more extensive fibrotic lesions at baseline and female gender in RA patients treated with JAKi or bDMARDs. JAKi and methotrexate co-treatment may prove beneficial in modifying key events underlying the pathogenesis of RA-ILD., Competing Interests: TK and AK received honoraria for speaking engagements from Eli Lilly, Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Kurushima, Koga, Umeda, Iwamoto, Miyashita, Tokito, Okuno, Yura, Ishimoto, Kido, Sakamoto, Ueki, Mukae and Kawakami.)

Sestrin2 (SESN2) is a stress-inducible protein known for its cytoprotective functions, but its role in diabetic vascular complications remains unclear. This study investigated the impact of SESN2 on methylglyoxal (MGO)-induced endothelial-mesenchymal transition (EndMT). Human endothelial cells were transfected with SESN2 siRNA duplexes to silence SESN2 expression, followed by MGO treatment. SESN2 knockdown significantly exacerbated MGO-induced oxidative stress, as evidenced by the reduced expression of antioxidant markers. Furthermore, SESN2 silencing enhanced the inflammatory response to MGO, demonstrated by the increased levels of pro-inflammatory cytokines. Notably, SESN2 deficiency promoted EndMT, a key process in diabetes-induced cardiovascular complications, as shown by the increased expression of mesenchymal markers and the decreased expression of endothelial markers. These findings suggest that SESN2 plays a critical protective role in endothelial cells against MGO-induced damage. The study provides novel insights into the molecular mechanisms underlying diabetic cardiovascular complications and identifies SESN2 as a potential therapeutic target for preventing endothelial dysfunction in diabetes. Our results indicate that SESN2 downregulation may contribute to the pathogenesis of diabetic vascular complications by promoting EndMT, increased oxidative stress, and inflammation.

The tumor microenvironment (TME) significantly influences cancer progression, and mesenchymal stem cells (MSCs) play a crucial role in interacting with tumor cells via paracrine signaling, affecting behaviors such as proliferation, migration, and epithelial-mesenchymal transition. While conventional 2D culture models have provided valuable insights, they cannot fully replicate the complexity and diversity of the TME. Therefore, developing 3D culture systems that better mimic in vivo conditions is essential. This review delves into the heterogeneous nature of the TME, spotlighting MSC-tumor cellular signaling and advancements in 3D culture technologies. Utilizing MSCs in cancer therapy presents opportunities to enhance treatment effectiveness and overcome resistance mechanisms. Understanding MSC interactions within the TME and leveraging 3D culture models can advance novel cancer therapies and improve clinical outcomes. Additionally, this review underscores the therapeutic potential of engineered MSCs, emphasizing their role in targeted anti-cancer treatments., (© The Author(s) 2024. Published by Oxford University Press.)

Epithelial to mesenchymal transition (EMT) has been shown to play an essential role in the early stages of cancer cell invasion and metastasis. Inducible EMT models can initiate EMT in a controlled manner, thereby providing the opportunity to determine whether a cancer-associated gene influences cancer metastasis by triggering EMT. Moreover, different inducible EMT models enable the investigation of specific mechanisms of EMT modulation by various genes, facilitating a more precise understanding of how these genes influence cancer metastasis through the induction of EMT. Unfortunately, current inducible EMT models still present unmet needs. Therefore, we aimed to establish an inducible EMT model in MCF10A cells, a spontaneously immortalized human fibrocystic mammary cell line, by manipulating the expression of mouse Twist1 (mTwist1). In this study, we first compared the EMT induction capacity between human TWIST1 (hTWIST1) and mTwist1, and selected mTwist1 for further investigation. By monitoring the changes in epithelial and mesenchymal markers at different induction time points, we examined the EMT process in both polyclonal and monoclonal MCF10A cells that express doxycycline (DOX)-inducible mTwist1. Furthermore, our results showed that doxycycline-induced mTwist1 expression triggered EMT at a similar rate to TGFβ1-induced EMT in MCF10A cells. Additionally, this process was reversible upon DOX withdrawal. Thus, we have established a robust inducible EMT model in MCF10A cells, which can be used to further study cancer metastasis-driving genes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Pitavastatin is commonly prescribed to treat hypercholesterolemia through the regulation of cholesterol biosynthesis. Interestingly, it has also demonstrated a great potential for treating brain tumors, although the detailed cytotoxic mechanism, particularly in glioblastoma, remains incompletely understood. This work explores the activity of pitavastatin in 2D and 3D glioblastoma models, in an attempt to provide a more representative and robust overview of its anticancer potential in glioblastoma. The results show that not only is pitavastatin 10-1000 times-fold more effective in reducing tumoral metabolic activity than temozolomide, but also demonstrate a synergistic activity with this alkylating drug. In addition, low micromolar concentrations of this statin strongly impair the growth and the invasion ability of multicellular tumor spheroids. The obtained qRT-PCR and proteomics data highlight the modulation of cell death via apoptosis (BAX/BCL2, CASP9) and autophagy (BECN1, BNIP3, BNIP3L and LC3B), as well as an epithelial to mesenchymal transition blockage (HTRA1, SERPINE1, WNT5A, ALDH3B1 and EPHA2) and remodeling of the extracellular matrix (VCAN, SERPINE1 and TGFBI). Overall, these results lay the foundation for further investigations on the potential combinatory clinical treatment with temozolomide., Competing Interests: Declaration of competing interest The authors declare that there is no financial/personal interest or belief that could affect the manuscript objectivity., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The growth differentiation factor 15 (GDF15) may serve as a biomarker of metformin, which mediates the bodyweight lowering effect of metformin. However, whether GDF15 also serves as a molecular target of metformin to inhibit carcinogenesis remains largely unknown. This study examined the role and molecular mechanisms of GDF15 in the anticancer effects of metformin in non-small cell lung cancer (NSCLC) cells, which has never been reported before. We found that metformin significantly inhibited the migration of NSCLC A549 and NCI-H460 cells and reduced the expression of epithelial-to-mesenchymal transition (EMT)-related molecules, including neuro-cadherin (N-cadherin), matrix metalloproteinase 2 (MMP2), and the zinc finger transcription factor Snail, but increased epithelial cadherin (E-cadherin) expression. Furthermore, metformin increased GDF15 and its upstream transcription factors activated transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) expressions and increased AMP-activated protein kinase (AMPK) phosphorylation in NSCLC cells. GDF15 siRNA partially reverses the inhibitory effect of metformin on NSCLC cell migration. Moreover, metformin-induced increases in GDF15, CHOP, and ATF4 expression and the inhibition of migration were partially reversed by treatment with Compound C, a specific AMPK inhibitor. Meanwhile, metformin significantly inhibited NCI-H460 xenograft tumor growth in nude mice, increased GDF15 expression, and regulated EMT- and migration-related protein expression in xenograft tumors. In conclusion, our results provide novel insights into revealing that GDF15 can serve as a potential molecular target of metformin owing to its anti-cancer effect in NSCLC, which is mediated by AMPK activation., 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.)

Lung cancer is the most common type of malignant tumor worldwide. Plasma-activated medium (PAM) is an innovative cancer treatment method that has received considerable scientific attention. The objective of this study is to evaluate the effects of PAM on the anti-tumor characteristics of non-small cell lung cancer (NSCLC) cells in two-dimensional (2D) and three-dimensional (3D) cultures. The effects of PAM treatment on the proliferative and migratory capabilities of A549 cells in 2D and 3D cultures were assessed using MTT, migration, invasion assays, and cell cycle, respectively. The study also investigated the impact of PAM treatment on the changes in the content of intracellular and extracellular reactive species and analyzed protein expression using the Western Blot method. PAM treatment inhibited the viability, migration, and invasion abilities of A549 cells in both 2D and 3D cultures, suppressed the epithelial-mesenchymal transition (EMT) process, and downregulated the expression of the RAS/ERK signaling pathway, which effectively inhibited tumor spheroid formation. Additionally, the effect of PAM on A549 cells was mediated through ROS-induced oxidative reactions, and PAM treatment exhibited greater cytotoxicity in 2D culture compared to 3D culture. As compared to 2D, the 3D cell culture model provides a viable in vitro cell model for studying the mechanisms of PAM treatment in lung cancer. PAM represents an effective new treatment for NSCLC.

Natural bioactive compounds have become increasingly important antitumor and antimicrobial agents due to their high therapeutic potential and low systemic toxicity. However, they also have significant drawbacks like nontumor targeting and low bioavailability, which limit their wide therapeutic applications. There is an urgent need for a safe and compatible nanoparticle-mediated drug delivery system for the efficient transport of drug candidates into tumor tissues. In this paper, amine-modified zinc oxide nanoparticles are synthesized to load luteolin. The functionalized nanoparticles exhibit good synergistic effects in terms of antitumor and antibacterial activities. They show significant induction of oxidative stress and antitumor effects, while no significant inhibitory effect on normal cells is observed, suggesting that the nanocomposites have good targeting of cancer cells. Autophagy activation and EMT inhibition effects are studied to explain the good antitumor performances. The prepared nanocomposites are demonstrated to be attractive candidates for cancer therapy.

Our previous studies have demonstrated that ubiquitin-specific peptidase 22 (USP22) has the capacity to accelerate renal epithelial-to-mesenchymal transition (EMT) and promote the pathological progression of diabetic tubulointerstitial fibrosis (TIF) by regulating the ubiquitination of Snail1, an EMT transcription factor. Quercetin is a type of flavonol compound widely found in fruits and vegetables that has anti-inflammatory, antioxidant and anti-fibrosis effects. However, whether quercetin promotes the degradation of Snail1 and regulates the pathological progression of TIF by inhibiting USP22 requires further investigation. In this study, we found that quercetin significantly inhibited the expression of USP22 and Snail1 in high glucose (HG)-induced renal tubular epithelial cells (TECs), and reversed the expression of EMT-related proteins and inhibited the overproduction of fibronectin (FN) and Collage Type IV (Collagen IV) induced by high glucose. Additionally, quercetin blocked the deubiquitination of Snail1 mediated by USP22. Further study found that quercetin inhibited the interaction between USP22 and Snail1, thereby reducing the stability of Snail1. Furthermore, quercetin also reduced the protein levels of USP22 and Snail1 in the kidney tissue of diabetic mice and ameliorated renal function, delayed EMT and TIF. In conclusion, quercetin regulates the USP22-Snail1 signal pathway to inhibit the occurrence of EMT both in vitro and in vivo , and ultimately ameliorate the pathological progress of TIF.

Background: Non-small cell lung cancer (NSCLC) is a type of lung cancer, the incidence and mortality rate have been high, and the use of monotherapy is easy to make patients develop tolerance. Atmospheric pressure plasma (APP) is an emerging technology for killing cancer cells in recent years, and combination of berberine (BBR) mechanism has not been fully elucidated for NSCLC. The article's primary goal is to investigate the effect of combination on NSCLC and its associated characterization., Methods and Results: Antiproliferative effects were detected by cell viability assay and colony formation, and flow cytometry analysis of apoptosis and cycling showed that the combination synergistically induced apoptosis. Then, extracellular reactive oxygen species (ROS)levels and DCFH-DA-based kits examined intracellular ROS levels, and their effects on mitochondrial membrane potential were measured. Study reveals that co-induced apoptosis is associated with ROS accumulation. Subsequently, Western blotting (WB) detected the expression of epidermal growth factor receptor (EGFR), and the important signaling pathway proteins Ras/ERK and AKT/mTOR. Results showed that it could downregulation of EGFR protein expression and inhibit of activation of ERK/AKT signaling pathways. Simultaneous wound healing assay and epithelial-to-mesenchymal transition (EMT) marker detection were performed for the assessment of migration and EMT ability of NSCLC cells. Combination therapy inhibited migration and EMT of NSCLC cells., Conclusion: The results of this study show that the combination can synergistically induce apoptosis of NSCLC by regulating ROS production. EGFR downregulation and AKT/ERK signaling pathway inhibition are linked to the synergistic effect., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: No human participants and animal research were included in the article., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)