5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

Background:Colorectal cancer(CRC)is one of the most frequently diagnosed cancers.In many cases,the poor prognosis of advanced CRC is associated with resistance to treatment with chemotherapeutic drugs such as 5-Fluorouracil(5-FU).The epithelial-to-mesenchymal transition(EMT)and dysregulation in protein methylation are two mechanisms associated with chemoresistance in many cancers.This study looked into the effect of 5-FU dose escalation on EMT and protein methylation in CRC.Materials and Methods:HCT-116,Caco-2,and DLD-1 CRC cell lines were exposed to dose escalation treatment of 5-FU.The motility and invasive potentials of the cells before and after treatment with 5-FU were investigated through wound healing and invasion assays.This was followed by aWestern blot which analyzed the protein expressions of the epithelial marker E-cadherin,mesenchymal marker vimentin,and the EMT transcription factor(EMTTF),the snail family transcriptional repressor 1(Snail)in the parental and desensitized cells.Western blotting was also conducted to study the protein expressions of the protein methyltransferases(PMTs),Euchromatic histone lysine methyltransferase 2(EHMT2/G9A),protein arginine methyltransferase(PRMT5),and SET domain containing 7/9(SETD7/9)along with the global lysine and arginine methylation profiles.Results:The dose escalation method generated 5-FU desensitized CRC cells with distinct morphological features and increased tolerance to high doses of 5-FU.The 5-FU desensitized cells experienced a decrease in migration and invasion when compared to the parental cells.This was reflected in the observed reduction in E-cadherin,vimentin,and Snail in the desensitized cell lines.Additionally,the protein expressions of EHMT2/G9A,PRMT5,and SETD7/9 also decreased in the desensitized cells and global protein lysine and arginine methylation became dysregulated with 5-FU treatment.Conclusion:This study showed that continuous,dose-escalation treatment of 5-FU in CRC cells generated 5-FU desensitized cancer cells that seemed to be less aggressive than parental cells.

Unleashing the pathological role of epithelial-to-mesenchymal transition in diabetic nephropathy: The intricate connection with multifaceted mechanism

Renal epithelial-to-mesenchymal transition(EMT)is a process in which epithelial cells undergo biochemical changes and transform into mesenchymal-like cells,resulting in renal abnormalities,including fibrosis.EMT can cause diabetic neph-ropathy through triggering kidney fibrosis,inflammation,and functional impair-ment.The diverse molecular pathways that drive EMT-mediated renal fibrosis are not utterly known.Targeting key signaling pathways involved in EMT may help ameliorate diabetic nephropathy and improve renal function.In such settings,un-derstanding precisely the complicated signaling networks is critical for develo-ping customized therapies to intervene in EMT-mediated diabetic nephropathy.

Retraction: Liquiritigenin Inhibits Colorectal Cancer Proliferation, Invasion, and Epithelial-to-Mesenchymal Transition by Decreasing Expression of Runt-Related Transcription Factor 2

Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.The authors were contacted and invited to comment on the concerns raised and to provide the original,unmodified figures,but did not respond.

Role of epithelial-to-mesenchymal transition in the pulmonary fi brosis induced by paraquat in rats

BACKGROUND:This study aims to explore the characteristics of the epithelial-to-mesenchymal transition(EMT)process and its underlying molecular mechanisms in the period of paraquat(PQ)-induced pulmonary fi brosis(PF).METHODS:Picrosirius red staining and collagen volume fraction were utilized to evaluate the pathological changes of PQ-induced PF in rats.Immunohistochemistry,Western blot,and real-time reverse transcriptase-polymerase chain reaction(RT-PCR)were used to measure the protein and gene expression of EMT markers,EMT-associated transcription factors,and regulators of EMT-related pathways,respectively.RESULTS:The collagen deposition in the alveolar septum and increased PF markers were characteristics of pathological changes in PQ-induced PF,reached a peak on day 14 after PQ poisoning,and then decreased on day 21.The protein and gene expression of the fibrosis marker,EMT markers,transcription factors,and regulators of EMT-related signaling pathways signifi cantly increased at diff erent time points after PQ poisoning compared with corresponding controls(P<0.05),and most of them reached a peak on day 14,followed by a decrease on day 21.The gene expression of EMT markers was significantly correlated with PF markers,transcription factors,and regulators of EMT-related signaling pathways(P<0.05).The mRNA expression of transcription factors was signifi cantly correlated with that of TGF-β1 and Smad2(P<0.05 or P<0.01),instead of Wnt2 andβ-catenin(P>0.05).CONCLUSIONS:EMT process plays a role in the PQ-induced PF,in which most PF and EMT markers have a peak phenomenon,and its underlying molecular mechanisms might be determined by further studies.

Cross-talk between microRNA-let7c and transforming growth factor-β2 during epithelial-to-mesenchymal transition of retinal pigment epithelial cells

AIM: To explore the roles of microRNA-let7 c(miR-let7 c) and transforming growth factor-β2(TGF-β2) and cellular signaling during epithelial-to-mesenchymal transition(EMT) of retinal pigment epithelial cells. METHODS: Retinal pigment epithelial(ARPE-19) cells were cultured with no serum for 12 h, and then with recombinant human TGF-β2 for different lengths of time. ARPE-19 cells were transfected with 1×106 TU/mL miR-let7 c mimcs(miR-let7 cM), miR-let7 c mimcs negative control(miR-let7cMNC) and miR-let7 c inhibitor(miR-let7 cI) using the transfection reagent. The expression of keratin-18, vimentin, N-cadherin, IKB alpha, p65 were detected by Western blot, quantitative polymerase chain reaction and immunofluorescence. RESULTS: The expression of miR-let7c was dramatically reduced and the nuclear factor-kappa B(NF-κB) signaling pathway was activated after induction by TGF-β2(P<0.05). In turn, overexpressed miR-let7 c significantly inhibited TGF-β2-induced EMT(P<0.05). However, miR-let7 c was unable to inhibit TGF-β2-induced EMT when the NF-κB signaling pathway was inhibited by BAY11-7082(P<0.01). CONCLUSION: The miR-let7 c regulates TGF-β2-induced EMT through the NF-κB signaling pathway in ARPE-19 cells.

Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma: Characterization in a 3D-cell culture model

AIM: To analyze the effect of three-dimensional (3D)-arrangement on the expression of epithelial-to-mesenchymal transition markers in pancreatic adenocarcinoma (PDAC) cells.METHODS: HPAF-II, HPAC, and PL45 PDAC cells were cultured in either 2D-monolayers or 3D-spheroids. Ultrastructure was analyzed by transmission electron microscopy. The expression of E-cadherin, &#x003b2;-catenin, N-cadherin, collagen type&#x02005;I&#x02005;(COL-I), vimentin, &#x003b1;-smooth muscle actin (&#x003b1;SMA), and podoplanin was assayed by confocal microscopy in cells cultured on 12-mm diameter round coverslips and in 3D-spheroids. Gene expression for E-cadherin, Snail, Slug, Twist, Zeb1, and Zeb2 was quantified by real-time PCR. E-cadherin protein level and its electrophoretic pattern were studied by Western blot in cell lysates obtained from cells grown in 2D-monolayers and 3D-spheroids.RESULTS: The E-cadherin/&#x003b2;-catenin complex was expressed in a similar way in plasma membrane cell boundaries in both 2D-monolayers and 3D-spheroids. E-cadherin increased in lysates obtained from 3D-spheroids, while cleavage fragments were more evident in 2D-monolayers. N-cadherin expression was observed in very few PDAC cells grown in 2D-monolayers, but was more evident in 3D-spheroids. Some cells expressing COL-I were observed in 3D-spheroids. Podoplanin, expressed in collectively migrating cells, and &#x003b1;SMA were similarly expressed in both experimental conditions. The concomitant maintenance of the E-cadherin/&#x003b2;-catenin complex at cell boundaries supports the hypothesis of a collective migration for these cells, which is consistent with podoplanin expression.CONCLUSION: We show that a 3D-cell culture model could provide deeper insight into understanding the biology of PDAC and allow for the detection of marked differences in the phenotype of PDAC cells grown in 3D-spheroids.

Suspended particulate matter promotes epithelial-to-mesenchymal transition in alveolar epithelial cells via TGF-β1-mediated ROS/IL-8/SMAD3 axis

Epidemiological evidence presents that dust storms are related to respiratory diseases,such as pulmonary fibrosis(PF).However,the precise underlying mechanisms of SPM-elicited adverse effects still need to be investigated.Epithelial-mesenchymal transition(EMT)process is a characteristic of PF.We discussed whether suspended particulate matter(SPM)is involved in EMT induction via transforming growth factor-β1(TGF-β1).In this study,a detailed elemental analysis(55 elements),particle size,and morphology were determined.To investigate the toxicity of SPM,an MTT test was performed to detect cell viability.Next,A549cells were exposed to selected concentrations of SPM(20 and 40μg/mL)for single and repeated exposures.The DCFH-DA assay showed that exposure to SPM could produce reactive oxygen species(ROS).The ELISA assay demonstrated increased levels of interleukin-8(IL-8)and TGF-β1 in the supernatant.Western blot was used to detect the expression of proteins associated with EMT and the SMAD3-dependent pathway.Results of western blot demonstrated that E-cadherin was reduced,whereas p-SMAD3,vimentin,andα-smooth muscle actin were elevated.Our findings indicated that SPM triggered EMT by induction of oxidative stress,inflammation,and the TGF-β1/SMAD3 pathway activation.

Epithelial-to-mesenchymal transition in cancer： complexity and opportunities

The cell-biological program termed the epithelial-to-mesenchymal transition （EMT） plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenehymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.

Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon

Epithelial-to-mesenchymal and mesenchymal-to-epi- thelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-13 and its downstream Smad signaling, the phosphatidylinositol 3＇-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microR- NAs in the development of colorectal cancers via epi- thelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeu- tic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting theATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.

Inhibition of the Tubular Epithelial-to-Mesenchymal Transition in vivo and in vitro by the Uremic Clearance Granule(尿毒清颗粒)

Objective： To investigate the effect of the Uremic Clearance Granule （UCG, 尿毒清颗粒）, a Chinese patent medicine, on tubular epithelial-to-mesenchymal transition （EMT） in a unilateral ureteral obstruction （UUO） model in vivo and transforming growth factor （TGF）- 131 induced EMT of HK-2 cells in vitro. Methods： In vivo study, 50 Sprague Dawley rats were divided into three groups： a sham operation group （n=10）, a UUO group （n=20）, and a UUO with UCG treatment group （n=20）. The UCG was given at a dose of 4.5 g/kg body weight per day by gavage after surgery. In vitro study, HK-2 cells were cultured in 10% fetal bovine serum （FBS）, 10% healthy rat serum, 10% FBS and TGF-13 1 （10 ng/mL）, 10% healthy rat serum and TGF-13 1, or 10% rat serum containing the uremic clearance granule and TGF-13 1. The expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and e^-smooth muscle actin （ot-SMA） in kidney tissues and HK-2 cells were investigated by Western blot analysis and immunofluorescence staining. Results： The rats of the UUO group showed obvious tubulointerstitial fibrosis, compared with the sham operation group rats. Tubulointerstitial fibrosis score was reduced by 17.5%± 1.1% at day 7 and by 20.0%_＋ 1.2% at day 14 in the UCG-treated group, compared with the UUO group. The UCG could maintained expression of E-cadherin and suppressed expression of vimentin and α-SMA in kidney tissues of UUO rats at days 7 and 14, as determined by Western blot analysis and immunofluorescence staining. Rat serum containing the UCG partially inhibited TGF- β 1-induced fibroblast phenotype of HK-2 cells and maintained the epithelial morphology of HK-2 cells in vitro. This occurred partially through a reduction of vimentin expression and an increase of E-cadherin expression. Conclusion： These results suggest that the UCG prevents tubular EMT and may be a promising agent for treating tubulointerstitial fibrosis.

Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer

Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions.Aberrant glycosylation can lead to uncontrolled cell proliferation,cell-matrix interactions,migration and differentiation,and has been shown to be involved in cancer and other diseases.The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream.This cellular transformation process,which is associated by morphological change,loss of epithelial traits and gain of mesenchymal markers,is triggered by the secreted cytokine transforming growth factor-β(TGF-β).TGF-βbioactivity is carefully regulated,and its effects on cells are mediated by its receptors on the cell surface.In this review,we first provide a brief overview of major types of glycans,namely,N-glycans,O-glycans,glycosphingolipids and glycosaminoglycans that are involved in cancer progression.Thereafter,we summarize studies on how the glycosylation of TGF-βsignaling components regulates TGF-βsecretion,bioavailability and TGF-βreceptor function.Then,we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer.Identifying and understanding the mechanisms by which glycosylation affects TGF-βsignaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.

LncRNA GAS5 enhances tumor stem cell-like medicated sensitivity of paclitaxel and inhibits epithelial-to-mesenchymal transition by targeting the miR-18a-5p/STK4 pathway in prostate cancer

The onset of prostate cancer(PCa)is often hidden,and recurrence and metastasis are more likely to occur due to chemotherapy resistance.Herein,we identified downregulated long noncoding RNA(lncRNA)growth arrest-specific 5(GAS5)in PCa that was associated with metastasis and paclitaxel resistance.GAs5 acted as a tumor suppressor in suppressing the proliferation and metastasis of paclitaxel-resistant PCa cells.GAS5 overexpression in vivo inhibited the tumor growth of xenografts and elevated PCa sensitivity to paclitaxel.Combination of GAS5 and paclitaxel treatment showed great potential in PCa treatment.Moreover,mechanistic analysis revealed a novel regulatory network of GAS5/miR-18a-5p/serine/threonine kinase 4(STK4)that inhibits epithelial-to-mesenchymal transition(EMT)and enhances tumor stem cell-like-mediated sensitivity to paclitaxel in PCa.These findings provide a novel direction for the development of a potential adjunct to cancer chemotherapy that aims to improve the sensitivity of chemotherapy drugs in PCa.

Templated synthesis of transition metal phosphide electrocatalysts for oxygen and hydrogen evolution reactions

Transition metal phosphides(TMPs)have been regarded as alternative hydrogen evolution reaction(HER)and oxygen evolution reaction(OER)catalysts owing to their comparable activity to those of noble metal-based catalysts.TMPs have been produced in various morphologies,including hollow and porous nanostructures,which are features deemed desirable for electrocatalytic materials.Templated synthesis routes are often responsible for such morphologies.This paper reviews the latest advances and existing challenges in the synthesis of TMP-based OER and HER catalysts through templated methods.A comprehensive review of the structure-property-performance of TMP-based HER and OER catalysts prepared using different templates is presented.The discussion proceeds according to application,first by HER and further divided among the types of templates used-from hard templates,sacrificial templates,and soft templates to the emerging dynamic hydrogen bubble template.OER catalysts are then reviewed and grouped according to their morphology.Finally,prospective research directions for the synthesis of hollow and porous TMP-based catalysts,such as improvements on both activity and stability of TMPs,design of environmentally benign templates and processes,and analysis of the reaction mechanism through advanced material characterization techniques and theoretical calculations,are suggested.

Correction:Impact of Transition Metal Layer Vacancy on the Structure and Performance of P2 Type Layered Sodium Cathode Material

Following publication of the original article[1],the authors reported that the author Hun-Gi Jung should be affiliated as 3,4 and 5 instead of 4 and 5.The author’s name“A.-Yeon Kim”needed to be updated to“A-Yeon Kim”,removing the period.The correct author’s name and affiliation have been provided in this Correction.The original article[1]has been corrected.

Evolution of Superconducting-Transition Temperature with Superfluid Density and Conductivity in Pressurized Cuprate Superconductors

What factors fundamentally determine the value of superconducting transition temperature Tc in high temperature superconductors has been the subject of intense debate.Following the establishment of an empirical law known as Homes'law,there is a growing consensus in the community that the Tc value of the cuprate superconductors is closely linked to the superfluid density(ρ_(s))of its ground state and the conductivity(σ)of its normal state.However,all the data supporting this empirical law(ρ_(s)=AσT_(c))have been obtained from the ambientpressure superconductors.In this study,we present the first high-pressure results about the connection of the quantities of ρ_(s) and σ with T_(c),through the studies on the Bi_(1.74)Pb_(0.38)Sr_(1.88)CuO_(6+δ)and Bi_(2)Sr_(2)CaCu_(2)O_(8+δ),in which the value of their high-pressure resistivity(ρ=1/σ)is achieved by adopting our newly established method,while the quantity ofρs is extracted using Homes'law.We highlight that the Tc values are strongly linked to the joint response factors of magnetic field and electric field,i.e.,ρ_(s) and σ,respectively,implying that the physics determining T_(c) is governed by the intrinsic electromagnetic fields of the system.

Recent advances in transition metal phosphide materials:Synthesis and applications in supercapacitors

Supercapacitors(SCs)are considered promising energy storge systems because of their outstanding power density,fast charge and discharge rate and long-term cycling stability.The exploitation of cheap and efficient electrode materials is the key to improve the performance of supercapacitors.As the battery-type materials,transition metal phosphides(TMPs)possess high theoretical specific capacity,good electrical conductivity and superior structural stability,which have been extensively studied to be electrode materials for supercapacitors.In this review,we summarize the up-to-date progress on TMPs materials from diversified synthetic methods,diverse nanostructures and several prominent TMPs and their composites in application of supercapacitors.In the end,we also propose the remaining challenges toward the rational discovery and synthesis of high-performance TMP electrodes materials for energy storage.

Synthesis and Modulation of Low-Dimensional Transition Metal Chalcogenide Materials via Atomic Substitution

In recent years,low-dimensional transition metal chalcogenide(TMC)materials have garnered growing research attention due to their superior electronic,optical,and catalytic properties compared to their bulk counterparts.The controllable synthesis and manipulation of these materials are crucial for tailoring their properties and unlocking their full potential in various applications.In this context,the atomic substitution method has emerged as a favorable approach.It involves the replacement of specific atoms within TMC structures with other elements and possesses the capability to regulate the compositions finely,crystal structures,and inherent properties of the resulting materials.In this review,we present a comprehensive overview on various strategies of atomic substitution employed in the synthesis of zero-dimensional,one-dimensional and two-dimensional TMC materials.The effects of substituting elements,substitution ratios,and substitution positions on the structures and morphologies of resulting material are discussed.The enhanced electrocatalytic performance and photovoltaic properties of the obtained materials are also provided,emphasizing the role of atomic substitution in achieving these advancements.Finally,challenges and future prospects in the field of atomic substitution for fabricating low-dimensional TMC materials are summarized.

From VIB‑to VB‑Group Transition Metal Disulfides:Structure Engineering Modulation for Superior Electromagnetic Wave Absorption

The laminated transition metal disulfides(TMDs),which are well known as typical two-dimensional(2D)semiconductive materials,possess a unique layered structure,leading to their wide-spread applications in various fields,such as catalysis,energy storage,sensing,etc.In recent years,a lot of research work on TMDs based functional materials in the fields of electromagnetic wave absorption(EMA)has been carried out.Therefore,it is of great significance to elaborate the influence of TMDs on EMA in time to speed up the application.In this review,recent advances in the development of electromagnetic wave(EMW)absorbers based on TMDs,ranging from the VIB group to the VB group are summarized.Their compositions,microstructures,electronic properties,and synthesis methods are presented in detail.Particularly,the modulation of structure engineering from the aspects of heterostructures,defects,morphologies and phases are systematically summarized,focusing on optimizing impedance matching and increasing dielectric and magnetic losses in the EMA materials with tunable EMW absorption performance.Milestones as well as the challenges are also identified to guide the design of new TMDs based dielectric EMA materials with high performance.

Assessment of challenges and strategies for driving energy transitions in emerging markets:A socio-technological systems perspective

The pursuit of improved quality of life standards has significantly influenced the contemporary mining model in the 21st century.This era is witnessing an unprecedented transformation driven by pressing concerns related to sustainability,climate change,the just energy transition,dynamic operating environments,and complex social challenges.Such transitions present both opportunities and obstacles.The aim of this study is to provide an extensive literature review on energy transition to identify the challenges and strategies associated with navigating transformations in energy systems.Understanding these transformations is particularly critical in the face of the severe consequences of global warming,where an accelerated energy transition is viewed as a universal remedy.Adopting a socio-technological systems perspective,specifically through the application of Actor Network Theory(ANT),this research provides a theoretical foundation while categorising challenges into five distinct domains and outlining strategies across these different dimensions.These insights are specifically tailored for emerging market countries to effectively navigate energy transition while fostering the development of resilient societies.Furthermore,our findings highlight that energy transition encompasses more than a mere technological shift;it entails fundamental changes in various systemic socio-economic imperatives.Through focusing on the role of social structures in transitions,this study makes a significant and innovative contribution to ANT,which has historically been criticised for its limited acknowledgement of social structures.Consequently,we propose an emerging market energy transition framework,which not only addresses technological aspects,but also integrates social considerations.This framework paves the way for future research and exploration of energy transition dynamics.The outcomes of this study offer valuable insights to policymakers,researchers,and practitioners engaged in the mining industry,enabling them to comprehend the multifaceted challenges involved and providing practical strategies for effective resolution.Through incorporating the social dimension into the analysis,we enhance the understanding of the complex nature of energy system transformations,facilitating a more holistic approach towards achieving sustainable and resilient energy transitions in emerging markets and beyond.

Multistate transition and coupled solid-liquid modeling of motion process of long-runout landslide

The recognition,repetition and prediction of the post-failure motion process of long-runout landslides are key scientific problems in the prevention and mitigation of geological disasters.In this study,a new numerical method involving LPF3D based on a multialgorithm and multiconstitutive model was proposed to simulate long-runout landslides with high precision and efficiency.The following results were obtained:(a)The motion process of landslides showed a steric effect with mobility,including gradual disintegration and spreading.The sliding mass can be divided into three states(dense,dilute and ultradilute)in the motion process,which can be solved by three dynamic regimes(friction,collision,and inertial);(b)Coupling simulation between the solid grain and liquid phases was achieved,focusing on drag force influences;(c)Different algorithms and constitutive models were employed in phase-state simulations.The volume fraction is an important indicator to distinguish different state types and solid‒liquid ratios.The flume experimental results were favorably validated against long-runout landslide case data;and(d)In this method,matched dynamic numerical modeling was developed to better capture the realistic motion process of long-runout landslides,and the advantages of continuum media and discrete media were combined to improve the computational accuracy and efficiency.This new method can reflect the realistic physical and mechanical processes in long-runout landslide motion and provide a suitable method for risk assessment and pre-failure prediction.