Inhibitory roles of protein kinase B and peroxisome proliferator-activated receptor gamma coactivator on hepatic HMG-CoA reductase promoter activity

Since we had previously demonstrated that siRNAs to tristetraprolin (TTP) markedly inhibited insulin stimulation of hepatic HMG-CoA reductase (HMGR) transcription, we investigated the effects of transfecting rat liver with TTP constructs. We found that transfecting diabetic rats with TTP did not increase HMGR transcription but rather led to modest inhibition. We then investigated whether co-transfection with protein kinase B, hepatic form (AKT2), might lead to phosphorylation and result in activation of HMGR transcription. We found that this treatment resulted in near complete inhibition of transcription. Transfection with peroxisome proliferator-activated receptor g coactivator (PGC-1a) also inhibited HMGR transcription. These results show that although TTP is needed for activation of HMGR transcription, it cannot by itself activate this process. AKT2 and PGC-1a, which mediate the activation of gluconeogenic genes by insulin, exert the opposite effect on HMGR.

Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

Mechanism of acupuncture in attenuating cerebral ischaemia-reperfusion injury based on nuclear receptor coactivator 4 mediated ferritinophagy

OBJECTIVE:To explore the effect of acupuncture treatment on cerebral ischaemia-reperfusion injury(CIRI)and reveal the underlying mechanism of the effect based on nuclear receptor coactivator 4(NCOA4)mediated ferritinophagy.METHODS:Sprague-Dawley male rats were divided into four groups:the sham group,model group,acupuncture group,and sham acupuncture group.After 2 h of middle cerebral artery occlusion(MCAO),reperfusion was performed for 24 h to induce CIRI.The rats were treated with acupuncture at the Neiguan(PC6)and Shuigou(GV26)acupoints.Their neurological function was evaluated by taking their Bederson scores at 2 h after ischaemia and 24 h after reperfusion.Triphenyltetrazolium chloride staining was applied to assess the cerebral infarct volume at 24 h after reperfusion.The malondialdehyde(MDA)and ferrous iron(Fe^(2+))levels were observed after 24 h of reperfusion using an assay kit.Western blotting was performed to detect the expression of NCOA4 and ferritin heavy chain 1(FTH1)at 24 h after reperfusion.Moreover,the colocalization of ferritin with neurons,NCOA4 with microtubule-associated protein 1 light chain 3(LC3),and NCOA4 with ferritin was visualized using immunofluorescence staining.RESULTS:Acupuncture significantly improved neurological function and decreased cerebral infarct volume in the acupuncture group.Following CIRI,the expression of NCOA4,LC3 and FTH1 was increased,which enhanced ferritinophagy and induced an inappropriate accumulation of Fe^(2+)and MDA in the ischaemic brain.However,acupuncture dramatically downregulated the expression of NCOA4,LC3 and FTH1,inhibited the overactivation of ferritinophagy,and decreased the levels of MDA and Fe^(2+).CONCLUSIONS:Acupuncture can inhibit NCOA4-mediated ferritinophagy and protect neurons against CIRI in a rat model.

Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis

Transcriptional coactivators regulate the rate of gene expression in the nucleus.Nuclear receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains unclear.Here,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions.Unexpectedly,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic specks.Mechanistically,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active caspase-1.Of note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in macrophages.Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in mice.Consistent with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results.Conclusively,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.

Irisin/BDNF signaling in the muscle-brain axis and circadian system: A review

In mammals,the timing of physiological,biochemical and behavioral processes over a 24-h period is controlled by circadian rhythms.To entrain the master clock located in the suprachiasmatic nucleus of the hypothalamus to a precise 24-h rhythm,environmental zeitgebers are used by the circadian system.This is done primarily by signals from the retina via the retinohypothalamic tract,but other cues like exercise,feeding,temperature,anxiety,and social events have also been shown to act as non-photic zeitgebers.The recently identified myokine irisin is proposed to serve as an entraining non-photic signal of exercise.Irisin is a product of cleavage and modification from its precursor membrane fibronectin typeⅢdomain-containing protein 5(FNDC5)in response to exercise.Apart from well-known peripheral effects,such as inducing the"browning"of white adipocytes,irisin can penetrate the blood-brain barrier and display the effects on the brain.Experimental data suggest that FNDC5/irisin mediates the positive effects of physical activity on brain functions.In several brain areas,irisin induces the production of brain-derived neurotrophic factor(BDNF).In the master clock,a significant role in gating photic stimuli in the retinohypothalamic synapse for BDNF is suggested.However,the brain receptor for irisin remains unknown.In the current review,the interactions of physical activity and the irisin/BDNF axis with the circadian system are reconceptualized.

Activation of G-protein-coupled receptor 39 reduces neuropathic pain in a rat model

Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.

Association between peroxisome proliferator-activated receptor-γ coactivator-1α gene polymorphisms and type 2 diabetes in southern Chinese population:role of altered interaction with myocyte enhancer factor 2C

Background Some single nucleotide polymorphisms （SNPs） in the peroxisome proliferator-activated receptor-y coactivator （PGC）-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1α and type 2 diabetes in the southern Chinese population and to determine whether the common variants： Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor （MEF） 2C. Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism （PCR-SSCP） and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP）. A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C. Results Three frequent SNPs （Thr394Thr, Gly482Ser and Thr528Thr） were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls （40.1% vs 29.3%, P〈0.01）. Even in controls, the 482Ser（A） carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly（G） carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr （A） had a synergic effect on the interaction between 482Ser variant and MEF2C. Conclusions The results suggested that the 482Ser variant of PGC-1α conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants （Gly482Ser, Thr394Thr） in the PGC-1α gene and MEF2C.

CREB-binding proteins (CBP) as a transcriptional coactivator of GATA-2

The GATA family consists of six members, GATA 1-6. In this study, we focused on GATA-2, which is expressed predominantly in hematopoietic progenitor cells and plays the key role in keeping these cells in the undifferentiated status. CREB-binding proteins (CBP) are essential transcriptional coacti- vators for a large number of regulated DNA-binding transcription factors, including GATA-1. But there have been no reports on whether CBP is still a co-activator of GATA-2. Here, we used the immunopre- cipitation and pull-down experiments to show that the GATA-2 and CBP were physically binding to- gether, and clarified the binding sites CH1, CH3 , CH452 and CT1430 in CBP and N-finger, C-finger and N-C-finger in GATA-2. Luciferase assay results in our experiment indicated that CBP could increase GATA-2 transcriptional activity in the dose-dependent manner. GATA-1 is mainly expressed in differen- tiated hematopoietic cells, but still has overlap expression with GATA-2. CBP is a coactivator of GATA-2 and GATA-1. The investigation on the mechanism that could decide whether CBP binds to GATA-2 to keep hematopoietic cells in the progenitor status or to GATA-1 to start differentiation will be a very in- teresting and very meaningful project in the near future.

The CREB Regulated Transcription Coactivator 2 Suppresses HIV-1 Transcription by Preventing RNA PolⅡfrom Binding to HIV-1 LTR

The CREB-regulated transcriptional co-activators(CRTCs),including CRTC1,CRTC2 and CRTC3,enhance transcription of CREB-targeted genes.In addition to regulating host gene expression in response to cAMP,CRTCs also increase the infection of several viruses.While human immunodeficiency virus type 1(HIV-1)long terminal repeat(LTR)promoter harbors a cAMP response element and activation of the cAMP pathway promotes HIV-1 transcription,it remains unknown whether CRTCs have any effect on HIV-1 transcription and HIV-1 infection.Here,we reported that CRTC2 expression was induced by HIV-1 infection,but CRTC2 suppressed HIV-1 infection and diminished viral RNA expression.Mechanistic studies revealed that CRTC2 inhibited transcription from HIV-1 LTR and diminished RNA PolⅡoccupancy at the LTR independent of its association with CREB.Importantly,CRTC2 inhibits the activation of latent HIV-1.Together,these data suggest that in response to HIV-1 infection,cells increase the expression of CRTC2 which inhibits HIV-1 gene expression and may play a role in driving HIV-1 into latency.

Effect of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Alpha Variants on Spontaneous Clearance and Fibrosis Progression during Hepatitis C Virus Infection in Moroccan Patients

Hepatitis C virus(HCV)is still one of the main causes of liver disease worldwide.Metabolic disorders,including nonalcoholic fatty liver disease(NAFLD),induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma.An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)activity is crucial to prevent NAFLD installation.The present study aims to investigate the associations between two common PPARGC1A polymorphisms(rs8192678 and rs12640088)and the outcomes of HCV infection in a North African context.A series of 592 consecutive Moroccan subjects,including 292 patients with chronic hepatitis C(CHC),100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay.PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection(adjusted ORs=0.76 and 0.79 respectively,P[0.05,for both).Furthermore,multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression(OR=0.71;95%CI 0.20–2.49;P=0.739;OR=1.28;95%CI 0.25–6.54;P=0.512,respectively).We conclude that,in the genetic context of South Mediterranean patients,rs8192678 and rs12640088 polymorphisms of PPARGC1 A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.

Inhibition of autophagy rescues HT22 hippocampal neurons from erastin-induced ferroptosis

Ferroptosis is a regulated form of cell death which is considered an oxidative iron-dependent process.The lipid hydroperoxidase glutathione peroxidase 4 prevents the iron(Fe2+)-dependent formation of toxic lipid reactive oxygen species.While emerging evidence indicates that inhibition of glutathione peroxidase 4 as a hallmark of ferroptosis in many cancer cell lines,the involvement of this biochemical pathway in neuronal death remains largely unclear.Here,we investigate,first whether the ferroptosis key players are involved in the neuronal cell death induced by erastin.The second objective was to examine whether there is a cross talk between ferroptosis and autophagy.The third main was to address neuron response to erastin,with a special focus on ferritin and nuclear receptor coactivator 4-mediated ferritinophagy.To test this in neurons,erastin(0.5-8μM)was applied to hippocampal HT22 neurons for 16 hours.In addition,cells were cultured with the autophagy inhibitor,3-methyladenin(10 mM)and/or ferroptosis inhibitors,ferrostatin 1(10-20μM)or deferoxamine(10-200μM)before exposure to erastin.In this study,we demonstrated by immunofluorescence and western blot analysis,that erastin downregulates dramatically the expression of glutathione peroxidase 4,the sodium-independent cystine-glutamate antiporter and nuclear receptor coactivator 4.The protein levels of ferritin and mitochondrial ferritin in HT22 hippocampal neurons did not remarkably change following erastin treatment.In addition,we demonstrated that not only the ferroptosis inhibitor,ferrostatin1/deferoxamine abrogated the ferroptotic cell death induced by erastin in hippocampal HT22 neurons,but also the potent autophagy inhibitor,3-methyladenin.We conclude that(1)erastin-induced ferroptosis in hippocampal HT22 neurons,despite reduced nuclear receptor coactivator 4 levels,(2)that either nuclear receptor coactivator 4-mediated ferritinophagy does not occur or is of secondary importance in this model,(3)that ferroptosis seems to share some features of the autophagic cell death process.

Micro RNA-124 slows down the progression of Huntington's disease by promoting neurogenesis in the striatum

MicroRNA-124 contributes to neurogenesis through regulating its targets, but its expression both in the brain of Huntington＇s disease mouse models and patients is decreased. However, the effects of microRNA-124 on the progression of Huntington＇s disease have not been reported. Results from this study showed that microRNA-124 increased the latency to fall for each R6/2 Hunting- ton＇s disease transgenic mouse in the rotarod test. 5-Bromo-2＇-deoxyuridine （BrdU） staining of the striatum shows an increase in neurogenesis. In addition, brain-derived neurotrophic factor and peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein levels in the striatum were increased and SRY-related HMG box transcription factor 9 protein level was de- creased. These findings suggest that microRNA-124 slows down the progression of Huntington＇s disease possibly through its important role in neuronal differentiation and survival.

Estrogen Receptor α(ERα) Target Gene LRP16 Interacts with ERα and Enhances Receptor's Transcriptional Activity

Objective：It has been shown that LRP16 is an estrogen-induced gene through its receptor α（ERα）. Although there is evidence demonstrating that inhibition of LRP16 gene expression in MCF-7 human breast cancer cells partially attenuates its estrogen-responsiveness, the underlying molecular mechanism is still unclear. Here, the effect of LRP16 expression on the ERα signaling transduction was investigated. Methods： Cotransfection assays were used to measure the effect of LRP16 on ERα-mediated transcriptional activity. GST-pulldown and immunoprecipitation （ColP） assays were employed to investigate the physical interaction of LRP16 and ERα. The mammalian two-hybrid method was used to map the functional interaction region. Results： the results of cotransfection assays demonstrated that the transcriptional activities of ERα were enhanced in α LRP16 dose-dependent manner in MCF-7 in the presence of estrogen, however, it was abolished in the absence of E2 in MCF-7 cells. The physical interaction of LRP16 and ERα proteins was confirmed by GST-pulldown in vitro and ColP in vivo assays, which was enhanced by E2 but not dependent on its presence. Furthermore, the results of the mammalian two-hybrid assays indicated that the binding region of ERα to LRP16 located at the A/B AF-1 functional domain and E2 stimulated the binding of LRP16 to the full-length ERα molecule but not to the A/B region alone. Conclusion： These results support a role for estrogenically regulated LRP16 as an ERα coactivator, providing a positive feedback regulatory loop for ERα signal transduction. Based on this function of LRP16, we propose that ERα-positive breast cancer patients with high expression of LRP16 might benefit from targeting LRP16 therapy.

The role of mitochondria in redox signaling of muscle homeostasis

In the past,contraction-induced production of reactive oxygen species(ROS)has been implicated in oxidative stress to skeletal muscle.As research advances,clear evidence has revealed a more complete role of ROS under both physiologic and pathologic conditions.Central to the role of ROS is the redox signaling pathways that control exercise-induced major physiologic and cellular responses and adaptations,such as mitochondrial biogenesis,mitophagy,mitochondrial morphologic dynamics,antioxidant defense,and inflammation.The current review focuses on how muscle contraction and immobilization may activate or inhibit redox signalings and their impact on muscle mitochondrial homeostasis and physiologic implications.

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

BACKGROUND Sodium glucose cotransporter 2(SGLT2)inhibitors are newly developed oral antidiabetic drugs.SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90%of the glucose filtered by the renal glomeruli.SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion.The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies.However,the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood.AIM To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice.METHODS We analyzed 8-wk-old male obese(ob/ob)mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin(3 mg/kg or 10 mg/kg)for 4 wk.We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liverhistology, immunoblotting, and reverse transcription-polymerase chain reactionanalyses were performed.RESULTSHepatic lipid accumulation was significantly ameliorated in ob/ob mice treatedwith 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective ofbody weight changes. Ipragliflozin had no appreciable effects on hepatic oxidativestress-related gene expression levels or macrophage infiltration, but significantlyreduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozinincreased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in theliver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γcoactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα),and fibroblast growth factor-21 (FGF21) were also significantly higher inipragliflozin-treated ob/ob mice than in untreated ob/ob mice.CONCLUSIONOur study suggests that the liver steatosis-ameliorating effects of ipragliflozin inob/ob mice may be mediated partly by hepatic SIRT1 signaling, possibly throughthe PGC-1α/PPARα-FGF21 pathway.

CANFIS—a computer aided diagnostic tool for cancer detection

In this investigation, an approach using Coac-tive Neuro-Fuzzy Inference System (CANFIS) as diagnosis system for breast cancer has been proposed on Wisconsin Breast Cancer Data (WBCD). It is occasionally difficult to attain the ultimate diagnosis even for medical experts due to the complexity and non-linearity of the rela-tionships between the large measured factors, which can be possibly resolved with a human like decision-making process using Artificial Intelligence (AI) algorithms. CANFIS is an AI algorithm which has the advantages of both fuzzy inference system and neural networks and can deal with ambiguous data and learn from the past data by itself. The Multi Layer Percep-tron Neural Network (MLPNN), Probabilistic Neural Network (PNN) Principal Component Analysis (PCA), Support Vector Machine (SVM) and Self Organizing Map (SOM) were also tested and benchmarked for their

可改善人体触觉功能的新技术

一份新的研究报告称,德国科学家最近发明了一种新技术,利用这一技术可改善人体的触觉功能,而且用两种不同的药物能加强或者减弱这种作用.研究人员认为,这一发现将会引导我们发明一种治疗老年人、中风患者和其他情况下出现的感觉障碍性疾病的新方法.

Mitochondrial dysfunction in a rat model and the related risk of metabolic disorders

OBJECTIVE:To explore whether kidney Yang deficiency(KYD)is prone to metabolic disorders may be linked to impaired mitochondrial function in thermogenesis and metabolic tissues.METHODS:A rat model of KYD was used,which was established using Sprague Dawley rat dams with warm preference subjected to herbal treatment that can improve kidney Yang.The human relevance was confirmed by reduced serum corticosterone levels,and increased preference for warm location.RESULTS:KYD Rats were underdeveloped.Adenosinetriphosphate(ATP)production was reduced in the brown fat,but increased in the muscle.However,oxidative phosphorylated complexes to generate ATP and mitochondrial biogenesis marker were reduced in both tissues.When the second insult of high-fat diet(HFD)was introduced,KYD rats gained less weight yet developed more severe lipid and glucose metabolic disorders.This may be driven by disregulated liver gluconeogenesis marker forkhead box protein O1 and lipid metabolic regulator cholesterol 7 alpha-hydroxylase.CONCLUSION:KYD rats exhibited reduced mitochondrial function in the brown fat,but were partially compensated by skeletal muscle,associated with the phenotype of warm preference and metabolic disorder,which was further exacerbated by additional HFD consumption.Future studies can focus on treatment targetting mitochondria function to reverse this phenotype.

Computational design of BC_(3)N_(2) based single atom catalyst for dramatic activation of inert CO_(2) and CH4 gasses into CH_(3)COOH with ultralow CH_(4) dissociation barrier

The production of CH_(3)COOH from CO_(2)and CH_(4) has stimulated much interest due to the high energy density of C2 species.Various kinds of catalysts have been developed while the high dissociation barrier of CH_(4) and low selectivity still hinders the efficiency of the reaction.We have herein proposed a novel catalyst with single metals loaded on 2D BC_(3)N_(2) substrate(M@2D-BC_(3)N_(2))based on density functional theory.Among numerous candidates,Pt@2D-BC_(3)N_(2) possesses the most favorable reactivity with an ultralow barrier of CH_(4) splitting(0.26 e V),which is due to the efficient capture ability of CH_(4) on Pt site.Besides,the selectivity for CH_(3)COOH is also very high,which mainly stems from the unique electronic properties of molecules and substrate:The degenerated states,including s,px,pyand pz,in CO_(2)reflects the existence of delocalizedπbonds between C and O.This can interact with states of Pt(s),Pt(pz),Pt(dxz),Pt(dyz),and Pt(z2)in Pt@2D-BC_(3)N_(2).The kinetics model also proves that our system can promote CH_(3)COOH production via simply increasing the temperature or the coverage of CH_(4) and CO_(2).Our results provide a reasonable illustration in clarifying mechanism and propose promising candidates with high reactivity for further study.