Efforts made in our pathophysiology teaching to reinforce the capacities of innovation and practice

Pathophysiology is an important course to link basic and clinical medicine. To retain the indispensable role of the course in medical education and to further promote the development of the discipline of pathophysiology,we have made great efforts in the reform of pathophysiology teaching.

Effect of Qi-protecting powder (Huqi San) on expression of c-jun, c-fos and c-myc in diethylnitrosamine-mediated hepatocarcinogenesis

AIM: To study the inhibitory effect of Huqi San (Qi-protecting powder) on rat prehepatocarcinoma induced by diethylinitrosamine (DEN) by analyzing the mutational activation of c-fos proto-oncogene and over-expression of c-jun and c-myc oncogenes. METHODS: A Solt-Farber two-step test model of prehepatocarcinoma was induced in rats by DEN and 2-acetylamino? uorene (AAF) to investigate the modifying effects of Huqi San on the expression of c-jun, c-fos and c-myc in DEN-mediated hepatocarcinogenesis. Huqi San was made of eight medicinal herbs containing glycoprival granules, in which each milliliter contains 0.38 g crude drugs. γ-glutamy-transpeptidase-isoenzyme (γ-GTase) was determined with histochemical methods. Level of 8-hydroxydeoxyguanosine (OHdG) formed in liver and c-jun, c-fos and c-myc proto-oncogenes were detected by immunohistochemical methods. RESULTS: The level of 8-OHdG, a mark of oxidative DNA damage, was signifi cantly decreased in the liver of rats with prehepatocarcinoma induced by DEN who received 8 g/kg body weight or 4 g/kg body weight Huqi San before (1 wk) and after DEN exposure (4 wk). Huqi San-treated rats showed a signifi cant decrease in number of γ-GT positive foci (P < 0.001, prevention group: 4.96 ± 0.72 vs 29.46 ± 2.17; large dose therapeutic group: 7.53 ± 0.88 vs 29.46 ± 2.17). On the other hand, signifi cant changes in expression of c-jun, c-fos and c-myc were found in Huqi San-treated rats. CONCLUSION: Activation of c-jun, c-fos and c-myc plays a crucial role in the pathogenesis of liver cancer.Huqi San can inhibit the over-expression of c-jun, c-fos and c-myc oncogenes and liver preneolastic lesions induced by DEN.

Mistletoe alkali inhibits peroxidation in rat liver and kidney

瞄准：探索槲寄生碱(麻省) 的抗氧化剂和自由基 scavenger 性质。方法：四氯化碳(CCl4 ) 在老鼠导致的氧化压力上的槲寄生碱的抗氧化剂效果被调查。老鼠被划分成四个组(n = 8 ) ：对待 CCl4 的组(1 mL/kg 体重) ，对待的组(90 mg/kg ) ，对待 CCl4+MA 的组和正常控制的麻省组织。在治疗的 4 wk 以后， malondialdehyde (MDA ) 的水平，类脂化合物在肝和肾的浆液和 homogenates 每氧化产品(LPO ) 被测量。另外，谷胱甘肽(GSH ) 的水平，和谷胱甘肽还原酶(GR ) 的活动，谷胱甘肽过氧化物酶(GSPx ) ，超级氧化物歧化酶(草皮) ，和在肝和肾的 glutathione-S-transferase (GST ) 是坚定的。氢氧根自由基上的清除效果由 Fenton 反应生产了在试管内被 ESR 方法作为 OH 作为旋转陷井试剂和 H2O2/UV 用 5,5-dimethyl-1-pyrroline-N-oxide (DMPO ) 学习。采购原料。尿 8-hydroxydeoxyguanosine (8-OHdG ) 被竞争 ELISA 决定。结果：在对待 CCl4 的组，在肝和肾的浆液的 LPO 的水平显著地与控制相比被增加。GSH 的层次和在肝和肾的草皮， GSPx 和 GR 的酶活动显著地与控制比较被减少。在对待 CCl4+MA 的组，在在肝和肾的浆液的 LPO 的层次的变化不与控制相比是统计上重要的。在肝和肾的草皮， GSPx 和 GR 的层次显著地与控制比较被增加。在在对待 CCl4 、对待麻省的组之间的 8-OHdG 的尿排泄有有效差量。结论：氧化应力可以是为 CCl4 的毒性的主要机制。麻省由禁止氧化损坏并且刺激 GST 活动对 CCl4 毒性有保护的效果。因此，麻省的临床的申请应该与碳在情况中被考虑导致四氯化物的损害。

Protective effects of oral glutathione on fasting-induced intestinal atrophy through oxidative stress

AIM To determine whether oral glutathione(GSH)administration can alleviate the effects of fasting-induced intestinal atrophy in the small intestinal mucosa. METHODS Rats were divided into eight groups.One group was fed ad libitum,another was fed ad libitum and received oral GSH,and six groups were administrated saline(SA)or GSH orally during fasting.Mucosal height,apoptosis,and cell proliferation in the jejunum were histologically evaluated.i NOS protein expression(by immunohistochemistry),nitrite levels(by high performance liquid chromatography,as a measure of NO production),8-hydroxydeoxyguanosine formation(by ELISA,indicating ROS levels),glutathione/oxidized glutathione(GSH/GSSG)ratio(by enzymatic colorimetric detection),andγ-glutamyl transpeptidase(Ggt1)mR NA levels in the jejunum(by semi-quantitative RT-PCR)were also estimated. RESULTS O r a l G S H a d m i n i s t r a t i o n w a s d e m o n s t r a t e d t o drastically reduce fasting-induced intestinal atrophy in the jejunum.In particular,jejunal mucosal height was enhanced in GSH-treated animals compared to SA-treated animals[527.2±6.9 for 50 mg/kg GSH,567.6±5.4 for 500 mg/kg GSH vs 483.1±4.9(μm),P<0.01at 72 h].This effect was consistent with decreasing changes in GSH-treated animals compared to SA-treated animals for iN OS protein staining[0.337±0.016for 50 mg/kg GSH,0.317±0.017 for 500 mg/kg GSH vs 0.430±0.023(area of staining part/area of tissue),P<0.01 at 72 h]and NO[2.99±0.29 for 50 mg/kg GSH,2.88±0.19 for 500 mg/kg GSH vs 5.34±0.35(nmol/g tissue),P<0.01 at 72 h]and ROS[3.92±0.46for 50 mg/kg GSH,4.58±0.29 for 500 mg/kg GSH vs6.42±0.52(8-OHdG pg/μg DNA),P<0.01,P<0.05at 72 h,respectively]levels as apoptosis mediators in the jejunum.Furthermore,oral GSH administration attenuated cell proliferation decreases in the fasting jejunum[182.5±1.9 for 500 mg/kg GSH vs 155.8±3.4(5-Brd U positive cells/10 crypts),P<0.01 at 72h].Notably,both GSH concentration and Ggt1 m RNA expression in the jejunum were also attenuated in rats following oral administration of GSH during fasting as compared with fasting alone[0.45±0.12 vs 0.97±0.06(nmol/mg tissue),P<0.01;1.01±0.11 vs 2.79±0.39(Ggt1 m RNA/Gapdh m RNA),P<0.01 for 500 mg/kg GSH at 48 h,respectively]. CONCLUSION Oral GSH administration during fasting enhances jejunal regenerative potential to minimize intestinal mucosal atrophy by diminishing fasting-mediated ROS generation and enterocyte apoptosis and enhancing cell proliferation.

Midkine secretion protects Hep3B cells from cadmium induced cellular damage

AIM: To evaluate role of midkine secretion during Cadmium (Cd) exposure in the human hepatocyte cell line Hep3B cells. METHODS: Different dosages of Cd (0.5-1-5-10 μg/mL) were applied to Hep3B cells and their effects to apoptosis, lactate dehydrogenase (LDH) leakage and midkine secretion were evaluated as time dependent manner. Same experiments were repeated with exogenously applied midkine (250-5000 pg/mL) and/or 5 μg/mL Cd.RESULTS: Cd exposure induced prominent apoptosis and LDH leakage beginning from lower dosages at the 48th h. Cd induced midkine secretion with higher dosages (P < 0.001), (control, Cd 0.5-1-5-10 μg/mL respectively: 1123 ± 73, 1157 ± 63, 1242 ± 90, 1886 ± 175, 1712 ± 166 pg/mL). Exogenous 500-5000 pg/mL midkine application during 5 μg/mL Cd toxicity prevented caspase-3 activation (control, Cd toxicity, 250, 500, 1000, 2500, 5000 pg/mL midkine+ Cd toxicity, respectively: 374 ± 64, 1786 ± 156, 1545 ± 179, 1203 ± 113, 974 ± 116, 646 ± 56, 556 ± 63 cfu) LDH leakage and cell death in Hep3B cells (P < 0.001). CONCLUSION: Our results showed that midkine secretion from Hep3B cells during Cd exposure protects liver cells from Cd induced cellular damage. Midkine has anti-apoptotic and cytoprotective role during Cd toxicity. Further studies are needed to explain the mechanism of midkine secretion and cytoprotective role of midkine during Cd exposure. Midkine may be a promising theurapatic agent in different toxic hepatic diseases.

Spatial Memory Deficit and Tau Hyperphosphorylation Induced by Inhibiting PP2A in Rat Brain

Hyperphosphorylation of Tau in Alzheimer＇s disease （AD） brain appears to be caused by a down-regulation of protein phospbatase 2A （PP2A）. In this study, we selectively inhibited PP2A by injection of okadaic acid （OA） into the Meynert nucleus basalis of rats and found that 0.4 pmol of OA injeetion induced approximately 60% inhibition of PP2A 24 h after injection, 13% inhibition 48 h after injection and no obvious inhibition 72 h after injection. Hyperphosphorylation of Tau at Ser-198/ Ser-199/Ser-202 and Ser-396/Ser-404 and spatial memory deficit of rats were induced 24 h after 0. d prnol of OA injection. This study suggests that a dowreregulation of PP2A may underlie almormal hyperphosphorylation of cytoskeletal proteins leading to neurofibrillary degeneration in AD.

O6-methylguanine DNA methyltransferase is upregulated in malignant transformation of gastric epithelial cells via its gene promoter DNA hypomethylation

BACKGROUND O_(6)-methylguanine-DNA methyltransferase(MGMT)is a suicide enzyme that repairs the mispairing base O_(6)-methyl-guanine induced by environmental and experimental carcinogens.It can transfer the alkyl group to a cysteine residue in its active site and became inactive.The chemical carcinogen N-nitroso compounds(NOCs)can directly bind to the DNA and induce the O_(6)-methylguanine adducts,which is an important cause of gene mutation and tumorigenesis.However,the underlying regulatory mechanism of MGMT involved in NOCs-induced tumorigenesis,especially in the initiation phase,remains largely unclear.AIM To investigate the molecular regulatory mechanism of MGMT in NOCs-induced gastric cell malignant transformation and tumorigenesis.METHODS We established a gastric epithelial cell malignant transformation model induced by N-methyl-N’-nitro-N-nitrosoguanidine(MNNG)or N-methyl-N-nitroso-urea(MNU)treatment.Cell proliferation,colony formation,soft agar,cell migration,and xenograft assays were used to verify the malignant phenotype.By using quantitative real-time polymerase chain reaction(qPCR)and Western blot analysis,we detected the MGMT expression in malignant transformed cells.We also confirmed the MGMT expression in early stage gastric tumor tissues by qPCR and immunohistochemistry.MGMT gene promoter DNA methylation level was analyzed by methylation-specific PCR and bisulfite sequencing PCR.The role of MGMT in cell malignant transformation was analyzed by colony formation and soft agar assays.RESULTS We observed a constant increase in MGMT mRNA and protein expression in gastric epithelial cell malignant transformation induced by MNNG or MNU treatment.Moreover,we found a reduction of MGMT gene promoter methylation level by methylation-specific PCR and bisulfite sequencing PCR in MNNG/MNU-treated cells.Inhibition of the MGMT expression by O_(6)-benzylguanine promoted the MNNG/MNU-induced malignant phenotypes.Overexpression of MGMT partially reversed the cell malignant transformation process induced by MNNG/MNU.Clinical gastric tissue analysis showed that MGMT was upregulated in the precancerous lesions and metaplasia tissues,but downregulated in the gastric cancer tissues.CONCLUSION Our finding indicated that MGMT upregulation is induced via its DNA promoter hypomethylation.The highly expressed MGMT prevents the NOCs-induced cell malignant transformation and tumorigenesis,which suggests a potential novel approach for chemical carcinogenesis intervention by regulating aberrant epigenetic mechanisms.

Arava Treatment,between Beneficial Action on Joint Inflammation and Side Effects on Liver,Myocardium and Kidney in Experimental Murine Arthritis

The purpose of the experiment was the follow-up in time of the course of joint inflammation phenomena in laboratory animals (white female adult Wistar rats) by determining particular biological, hematological, radiological, osteodensitometric, immunological and anatomic-pathological parameters and by assessing the effects of Leflunomide (Arava) on the course of the disease. ARAVA&reg;(Leflunomide) is a pyrimidine synthesis inhibitor. The experimental study was conducted for 8 weeks. We have also assessed the side effects of the therapy on their liver, myocardium and kidney. Leflunomide therapy improved the course of the clinical and paraclinical parameters, but it did not cure the condition. The positive results in the joints were accompanied by many histological alterations. The experiment revealed the toxic visceral effects of Leflunomide on the liver, heart and kidney.

Neural innervation in adipose tissue, gut, pancreas, and liver

Efficient communication between the brain and peripheral organs is indispensable for regulating physiological function and maintaining energy homeostasis. The peripheral nervous system (PNS) in vertebrates, consisting of the autonomic and somatic nervous systems, bridges the peripheral organs and the central nervous system (CNS). Metabolic signals are processed by both vagal sensory nerves and somatosensory nerves. The CNS receives sensory inputs via ascending nerves, serves as the coordination and integration center, and subsequently controls internal organs and glands via descending nerves. The autonomic nervous system consists of sympathetic and parasympathetic branches that project peripheral nerves into various anatomical locations to regulate the energy balance. Sympathetic and parasympathetic nerves typically control the reflexive and involuntary functions in organs. In this review article, we outline the innervation of adipose tissue, gut, pancreas, and liver, to illustrate the neurobiological basis of central-peripheral interactions. We emphasize the importance of understanding the functional atlas of neural control of energy metabolism, and more importantly, provide potential avenues for further research in this area.

Biological nano agent produced by hypoxic preconditioning stem cell for stroke treatment

Exosomes make a significant contribution during stem cell-based therapy due to the abundant contents.Accumulating evidence implies exosomes can act as potential biological nano agents.We herein propose hypoxic preconditioning for neural stem cells(NSCs)that could produce hypoxic exosomes for efficient treatment of ischemic stroke.Hypoxic preconditioning on NSCs significantly altered the miRNAs encapsulated in exosomes.Notably,hypoxic exosomes could target the injured brain to regulate the microenvironment to inhibit neuroinflammation and promote blood–brain barrier permeability recovery.Additionally,the autologous NSCs in Nestin-CreER mice could be activated by hypoxic exosomes to facilitate nerve regeneration.After hypoxic preconditioning,exosomes further exerted therapeutic effects on both survival(25%)and behavioral outcomes in ischemic stroke mice.Overall,hypoxic preconditioning NSCs can produce effective nano agent and may represent a promising strategy for clinical neurorestorative therapy.

Repurposed benzydamine targeting CDK2 suppresses the growth of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.

An integrative profiling of metabolome and transcriptome in the plasma and skeletal muscle following an exercise intervention in diet-induced obese mice

Exercise intervention at the early stage of type 2 diabetes mellitus(T2DM)can aid in the maintenance of blood glucose homeostasis and prevent the development of macrovascular and microvascular complications.However,the exercise-regulated pathways that prevent the development of T2DM remain largely unclear.In this study,two forms of exercise intervention,treadmill training and voluntary wheel running,were conducted for high-fat diet(HFD)-induced obese mice.We observed that both forms of exercise intervention alleviated HFD-induced insulin resistance and glucose intolerance.Skeletal muscle is recognized as the primary site for postprandial glucose uptake and for responsive alteration beyond exercise training.Metabolomic profiling of the plasma and skeletal muscle in Chow,HFD,and HFD-exercise groups revealed robust alterations in metabolic pathways by exercise intervention in both cases.Overlapping analysis identified nine metabolites,including beta-alanine,leucine,valine,and tryptophan,which were reversed by exercise treatment in both the plasma and skeletal muscle.Transcriptomic analysis of gene expression profiles in the skeletal muscle revealed several key pathways involved in the beneficial effects of exercise on metabolic homeostasis.In addition,integrative transcriptomic and metabolomic analyses uncovered strong correlations between the concentrations of bioactive metabolites and the expression levels of genes involved in energy metabolism,insulin sensitivity,and immune response in the skeletal muscle.This work established two models of exercise intervention in obese mice and provided mechanistic insights into the beneficial effects of exercise intervention on systemic energy homeostasis.

Tau-Induced Ca^(2+)/Calmodulin-Dependent Protein Kinase-IV Activation Aggravates Nuclear Tau Hyperphosphorylation

Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer’s disease(AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells.Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca2+concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca2+concentration with a simultaneous increase in the phosphorylation of Ca2+/calmodulin-dependent protein kinase IV(Ca MKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca2+/Ca MKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation ofthe Ca2+/calmodulin complex abolished the okadaic acidinduced tau hyperphosphorylation in the nuclear fraction.We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca2+/Ca MKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca2+concentration may induce a self-perpetuating harmful loop to promote neurodegeneration.

Dopaminergic modulation of synaptic plasticity in rat prefrontal neurons

The prefrontal cortex （PFC） is thought to store the traces for a type of long-term memory - the memory that determines the temporal structure of behavior often termed a ＂rule＂ or ＂strategy＂. Long-term synaptic plasticity might serve as an underlying cellular mechanism for this type of memory. We therefore studied the induction of synaptic plasticity in rat PFC neurons, maintained in vitro, with special emphasis on the functionally important neuromodulator dopamine. First, the induction of long-term potentiation （LTP） was facilitated in the presence of tonic/background dopamine in the bath, and the dose-dependency of this background dopamine followed an ＂inverted-U＂ function, where too high or too low dopamine levels could not facilitate LTP. Second, the induction of long-term depression （LTD） by low-frequency stimuli appeared to be independent of background dopamine, but required endogenous, phasically-released dopamine during the stimuli. Blockade of dopamine receptors during the stimuli and exaggeration of the effect of this endogenouslyreleased dopamine by inhibition of dopamine transporter activity both blocked LTD. Thus, LTD induction also followed an inverted-U function in its dopamine-dependency. We conclude that PFC synaptic plasticity is powerfully modulated by dopamine through inverted-U-shaped dose-dependency.

Effect of Fanbaicao(Herba Potentillae Discoloris) oil on the expression of p21 and CDK4 in HepG2 cells

OBJECTIVE:To research the anti-cancer mechanism of the Traditional Chinese Medicine Fanbaicao(Herba Potentillae Discoloris) oil in the human hepatoma cell line Hep G2.METHODS:Gas chromatography was used to analyze the components of Fanbaicao(Herba Potentillae Discoloris).We tested the inhibitory effect of Fanbaicao(Herba Potentillae Discoloris) oil on the human hepatoma cell line Hep G2 in vitro using 3-(4,5-Dimet hylt hiazol-2-yl)-2,5-dip henyltetrazoliumbromide assays.Fluorescence activating cell sorter analysis was used to examine the levels of apoptosis,and western blot and immunofluorescence were used to detect the expression of p21,p-p21 and CDK4 proteins.RESULTS:Fanbaicao(Herba Potentillae Discoloris)oil contains 45 ingredients,and L-ascorbic acid 2,6-bispalmitate was the main component and accounted for 44.96% of total drive-off peak area.Other components included(Z)-14-met hyl-8-exadecenal-acetal(8.56%),phytol(7.74%) and lauric acid(6.31%).Fanbaicao(Herba Potentillae Discoloris)oil treatment reduced the proliferation of Hep G2 cells and the half growth inhibition concentration(IC50) was 2.03 mg/m L.Furthermore,we also observed significantly increased Hep G2 cell apoptosis in a dose-dependent manner(P < 0.05).Fanbaicao(Herba Potentillae Discoloris) oil significantly increased the expression of p21 and p-p21 and significantly decreased the expression of CDK4 in Hep G2 cells compared with controls(P < 0.01).CONCLUSION:Our results showed that Fanbaicao(Herba Potentillae Discoloris) oil has anti-cancer activities in Hep G2 cells,which is probably related to the upregulation of p21 and p-p21 and downregulation of CDK4 expression.

Transcriptional control of pancreaticβ-cell identity and plasticity during the pathogenesis of type 2 diabetes

Type 2 diabetes(T2D)is caused by insulin resistance and insufficient insulin secretion.Evidence has increasingly indicated that pancreaticβ-cell dysfunction is the primary determinant of T2D disease progression and remission.High plasticity is an important feature of pancreaticβ-cells.During T2D development,pancreaticβ-cells undergo dynamic adaptation.Althoughβ-cell death/apoptosis in later-stage T2D is the major cause ofβ-cell dysfunction,recent studies have revealed thatβ-cell dedifferentiation and reprogramming,which play critical roles inβ-cell functional regulation in the early and middle T2D progression stages,are characterized by(i)a loss of matureβ-cell-enriched genes;(ii)dedifferentiation to a progenitor-like state;and(iii)transdifferentiation into other cell types.The roles of transcription factors(TFs)in the establishment and maintenance ofβ-cell identity during pancreatic development have been extensively studied.Here,we summarize the roles and underlying mechanisms of TFs in the maintenance ofβ-cell identity under physiological and type 2 diabetic conditions.Several feasible approaches for restoring islet functions are also discussed.A better understanding of the transcriptional control ofβ-cell identity and plasticity will pave the way for developing more effective strategies,such asβ-cell regeneration therapy,to treat T2D and associated metabolic disorders.

STING palmitoylation as a therapeutic target

Gain-of-function mutations in the STING-encoding gene TMEM173 are central to the pathology of the autoinflammatory disorder STING-associated vasculopathy with onset in infancy(SAVI).Furthermore,excessive activity of the STING signaling pathway is associated with autoinflammatory diseases,including systemic lupus erythematosus and Aicardi–Goutières syndrome(AGS).Two independent studies recently identified pharmacological inhibitors of STING.Strikingly,both types of compounds are reactive nitrocontaining electrophiles that target STING palmitoylation,a posttranslational modification necessary for STING signaling.As a consequence,the activation of downstream signaling molecules and the induction of type I interferons were inhibited.The compounds were effective at ameliorating inflammation in a mouse model of AGS and in blocking the production of type I interferons in primary fibroblasts from SAVI patients.This mini-review focuses on the roles of palmitoylation in STING activation and signaling and as a pharmaceutical target for drug development.

Metabolic reprogram associated with epithelial-mesenchymal transition in tumor progression and metastasis

Epithelial-mesenchymal Transition(EMT)is a de-differentiation program that imparts tumor cells with the phenotypic and cellular plasticity required for drug resistance,metastasis,and recurrence.This dynamic and reversible events is governed by a network of EMT-transcription factors(EMT-TFs)through epigenetic regulation.Many chromatin modifying-enzymes utilize metabolic intermediates as cofactors or substrates;this suggests that EMT is subjected to the metabolic regulation.Conversely,EMT rewires metabolic program to accommodate cellular changes during EMT.Here we summarize the latest findings regarding the epigenetic regulation of EMT,and discuss the mutual interactions among metabolism,epigenetic regulation,and EMT.Finally,we provide perspectives of how this interplay contributes to cellular plasticity,which may result in the clinical manifestation of tumor heterogeneity.