Role of aerobic glycolysis in alzheimer's disease and research progress of traditional Chinese medicine

Alzheimer's disease (AD) is an irreversible neurodegenerative disease with a variety of pathogenic factors and complex pathogenesis, so that the disease has a high prevalence and mortality in the world. Although the current diagnosis and treatment equipment and drug research and development keep pace with the times, the current medical technology still can not completely cure the disease, so it is of great significance to explore the pathogenesis and treatment target of AD. The disorder of energy metabolism is one of the characteristic changes in the pathological process of AD. Aerobic glycolysis (AEG) is a special metabolic pathway in the brain, which can rapidly consume glucose to produce energy and substrate for neurons, improve synaptic plasticity, neuroinflammation and oxidative damage, and contribute to the recovery of memory and cognitive function. In recent years, many literatures have reported the mechanism of AEG in AD and the intervention of Tradit Chin Med on this mechanism. The purpose of this paper is to summarize the role of AEG in AD and the related research on the regulation and control of AEG in the treatment of AD by Tradit Chin Med, in order to provide reference and ideas for the prevention and treatment of AD with Tradit Chin Med in the future.

Focal adhesion kinase-related non-kinase ameliorates liver fibrosis by inhibiting aerobic glycolysis via the FAK/Ras/c-myc/ENO1 pathway

BACKGROUND Hepatic stellate cell(HSC)hyperactivation is a central link in liver fibrosis development.HSCs perform aerobic glycolysis to provide energy for their activation.Focal adhesion kinase(FAK)promotes aerobic glycolysis in cancer cells or fibroblasts,while FAK-related non-kinase(FRNK)inhibits FAK phosphorylation and biological functions.AIM To elucidate the effect of FRNK on liver fibrosis at the level of aerobic glycolytic metabolism in HSCs.METHODS Mouse liver fibrosis models were established by administering CCl4,and the effect of FRNK on the degree of liver fibrosis in the model was evaluated.Transforming growth factor-β1 was used to activate LX-2 cells.Tyrosine phosphorylation at position 397(pY397-FAK)was detected to identify activated FAK,and the expression of the glycolysis-related proteins monocarboxylate transporter 1(MCT-1)and enolase1(ENO1)was assessed.Bioinformatics analysis was performed to predict putative binding sites for c-myc in the ENO1 promoter region,which were validated with chromatin immunoprecipitation(ChIP)and dual luciferase reporter assays.RESULTS The pY397-FAK level was increased in human fibrotic liver tissue.FRNK knockout promoted liver fibrosis in mouse models.It also increased the activation,migration,proliferation and aerobic glycolysis of primary hepatic stellate cells(pHSCs)but inhibited pHSC apoptosis.Nevertheless,opposite trends for these phenomena were observed after exogenous FRNK treatment in LX-2 cells.Mechanistically,the FAK/Ras/c-myc/ENO1 pathway promoted aerobic glycolysis,which was inhibited by exogenous FRNK.CONCLUSION FRNK inhibits aerobic glycolysis in HSCs by inhibiting the FAK/Ras/c-myc/ENO1 pathway,thereby improving liver fibrosis.FRNK might be a potential target for liver fibrosis treatment.

ING5 inhibits aerobic glycolysis of lung cancer cells by promoting TIE1-mediated phosphorylation of pyruvate dehydrogenase kinase 1 at Y163

Aerobic glycolysis is critical for tumor growth and metastasis.Previously,we have found that the overexpression of the inhibitor of growth 5(ING5)inhibits lung cancer aggressiveness and epithelial–mesenchymal transition(EMT).However,whether ING5 regulates lung cancer metabolism reprogramming remains unknown.Here,by quantitative proteomics,we showed that ING5 differentially regulates protein phosphorylation and identified a new site(Y163)of the key glycolytic enzyme PDK1 whose phosphorylation was upregulated 13.847-fold.By clinical study,decreased p-PDK1Y163 was observed in lung cancer tissues and correlated with poor survival.p-PDK1Y163 represents the negative regulatory mechanism of PDK1 by causing PDHA1 dephosphorylation and activation,leading to switching from glycolysis to oxidative phosphorylation,with increasing oxygen consumption and decreasing lactate production.These effects could be impaired by PDK1Y163F mutation,which also impaired the inhibitory effects of ING5 on cancer cell EMT and invasiveness.Mouse xenograft models confirmed the indispensable role of p-PDK1Y163 in ING5-inhibited tumor growth and metastasis.By siRNA screening,ING5-upregulated TIE1 was identified as the upstream tyrosine protein kinase targeting PDK1Y163.TIE1 knockdown induced the dephosphorylation of PDK1Y163 and increased the migration and invasion of lung cancer cells.Collectively,ING5 overexpression—upregulated TIE1 phosphorylates PDK1Y163,which is critical for the inhibition of aerobic glycolysis and invasiveness of lung cancer cells.

Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

Metabolic abnormalities is a hallmark of cancer.About 100 years ago,Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells.Recently more and more novel opinions about cancer metabolism supplement to this hypothesis,consist of glucose uptake,lactic acid generation and secretion,acidification of the microenvironment and cancer immune evasion.Here we briefly review metabolic pathways generating lactate,and discuss the function of higher lactic acid in cancer microenvironments.

Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs

Activated phosphoinositide 3-kinaseδsyndrome(APDS)is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function(GOF)mutations in the PIK3CD gene.Patients with APDS display abnormal T cell homeostasis.However,the mechanisms by which PIK3CD GOF contributes to this feature remain unknown.Here,with a cohort of children with PIK3CD GOF mutations from multiple regions of China and a corresponding CRISPR/Cas9 gene-edited mouse model,we reported that hyperactive PI3Kδdisrupted TNaive cell homeostasis in the periphery by intrinsically promoting the growth,proliferation,and activation of TNaive cells.Our results showed that PIK3CD GOF resulted in loss of the quiescence-associated gene expression profile in naive T cells and promoted naive T cells to overgrow,hyperproliferate and acquire an activated functional status.Naive PIK3CD GOF T cells exhibited an enhanced glycolytic capacity and reduced mitochondrial respiration in the resting or activated state.Blocking glycolysis abrogated the abnormal splenic T cell pool and reversed the overactivated phenotype induced by PIK3CD GOF in vivo and in vitro.These results suggest that enhanced aerobic glycolysis is required for PIK3CD GOF-induced overactivation of naive T cells and provide a potential therapeutic approach for targeting glycolysis to treat patients with APDS as well as other immune disorders.

3-Bromopyruvate alleviates the development of monocrotalineinduced rat pulmonary arterial hypertension by decreasing aerobic glycolysis,inducing apoptosis,and suppressing inflammation

Background:Pulmonary arterial hypertension(PH)is a progressive disease with limited therapeutic options,ultimately leading to right heart failure and death.Recent findings indicate the role of the Warburg effect(aerobic glycolysis)in the development of PH.However,the effect of the glycolysis inhibitor 3-bromopyruvate(3-BrPA)on the pathogenesis of PH has not been well investigated.This study aimed to determine whether 3-BrPA inhibits PH and its possible mechanism.Methods:PH was induced in adult Sprague-Dawley rats by a single intraperitoneal injection of monocrotaline(MCT).3-BrPA,or phosphate-buffered saline(PBS)was administered via intraperitoneal injection every other day from the first day of MCT-injection to 4 weeks of follow-up,and indices such as right ventricular systolic pressure(RVSP),right ventricular hypertrophy index(RVHI),pulmonary arteriolar remodeling indicated by percent media thickness(%MT),lactate levels and glucose consumption,were evaluated.Pulmonary arteriolar remodeling and right ventricular hypertrophy were observed in hematoxylin-eosin-stained lung sections.Western blotting,immunohistochemistry,and/or immunofluorescence analyses were used to measure the expression of relevant proteins.A cytochrome C release apoptosis assay and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining were used to measure cell apoptosis.Results:MCT-induced PH showed a significant increase in glucose consumption(0 vs.4 weeks:0.87±0.23 vs.2.94±0.47,P=0.0042)and lactate production(0 vs.4 weeks:4.19±0.34 vs.8.06±0.67,P=0.0004).Treatment with 3-BrPA resulted in a concomitant reduction in glucose consumption(1.10±0.35 vs.3.25±0.47,P=0.0063),lactate production(5.09±0.55 vs.8.06±0.67,P=0.0065),MCT-induced increase in RVSP(39.70±2.94 vs.58.85±2.32,P=0.0004),pulmonary vascular remodeling(%MT,43.45%±1.41%vs.63.66%±1.78%,P<0.0001),and right ventricular hypertrophy(RVHI,38.57%±2.69%vs.62.61%±1.57%,P<0.0001)when compared with those of the PBS-treated group.3-BrPA,a hexokinase 2 inhibitor,exerted its beneficial effect on PH by decreasing aerobic glycolysis and was also associated with inhibiting the expression of glucose transporter protein-1,inducing apoptosis,and suppressing inflammation.Conclusions:3-BrPA might have a potential beneficial effect on the PH treatment.

Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect

Background: Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol(Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis.Methods: We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide(LPS). We screened for potential protein targets of Cel using activity-based protein profiling(ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays(CETSA) and surface plasmon resonance(SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown.Results: Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS(P <0.05). Cel bound to Cys424 of pyruvate kinase M2(PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis(Warburg effect). Cel also bound to Cys106 in high mobility group box 1(HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin(IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A(LDHA).Conclusions: Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.

MiR-194-5p suppresses the warburg effect in ovarian cancer cells through the IGF1R/PI3K/AKT axis

Background:The Warburg effect is considered as a hallmark of various types of cancers,while the regulatory mechanism is poorly understood.Our previous study demonstrated that miR-194-5p directly targets and regulates insulin-like growth factor1 receptor(IGF1R).In this study,we aimed to investigate the role of miR-194-5p in the regulation of the Warburg effect in ovarian cancer cells.Methods:The stable ovarian cell lines with miR-194-5p overexpression or silencing IGF1R expression were established by lentivirus infection.ATP generation,glucose uptake,lactate production and extracellular acidification rate(ECAR)assay were used to analyze the effects of aerobic glycolysis in ovarian cancer cells.Gene expression was analyzed by quantitative polymerase chain reaction(qPCR)and western blot.Immunohistochemistry assays were performed to assess the expression of the IGF1R protein in ovarian cancer tissues.Results:Overexpression of miR-194-5p or silencing IGF1R expression in ovarian cancer cells decreases ATP generation,glucose uptake,lactate production,and ECAR and inhibits both the mRNA and protein expression of PKM2,LDHA,GLUT1,and GLUT3.While the knockdown of miR-194-5p expression led to opposite results.Overexpression of miR-194-5p or silencing IGF1R expression suppressed the phosphatidylinositol-3-kinase/protein kinase B(PI3K/AKT)pathway,whose activation can sustain aerobic glycolysis in cancer cells,and the knockdown of miR-194-5p expression promoted the activation of the PI3K/AKT pathway.Conclusion:Our results suggest that miR-194-5p can inhibit the Warburg effect by negative regulation of IGF1R and further repression of the PI3K/AKT pathway,which provides a theoretical basis for further test of miR-194-5p as a target in the treatment of ovarian cancer.

Metabolic reprogramming in triple-negative breast cancer

Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with other breast cancer subtypes,have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment.Metabolic reprogramming,an emerging hallmark of cancer,is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands;maintain the redox balance;and further promote oncogenic signaling,cell proliferation,and metastasis.Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC.Here,we review the metabolic reprogramming of glycolysis,oxidative phosphorylation,amino acid metabolism,lipid metabolism,and other branched pathways in TNBC and explore opportunities for new biomarkers,imaging modalities,and metabolically targeted therapies.

Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

Hepatocellular carcinoma(HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.

Expression and correlation of pyruvate kinase M2 and miRNA‑122 in sepsis associated AKI

Objective:To investigate the expression and correlation of pyruvate kinase M2 and miRNA-122 in sepsis associated acute kidney injury(S-AKI).Methods:A mouse model of S-AKI was induced by cecal ligation and perforation(CLP),and normal mice were used in the control group.Serum and renal tissue were collected from each group,respectively,and the levels of blood urea nitrogen(BUN)and creatinine(Cr)were detected by biochemical analyzer.The levels of lactate in serum and kidney tissue of mice in each group were detected by colorimetric method.Real-time quantitative PCR(RT-qPCR)was used to detect the expression of miRNA-122 and pkm2 mRNA in kidney tissue in each group.Western blotting was used to detect the expression of PKM2 protein in kidney tissue in each group.Pearson's method was used to analyze the pairwise correlation of miRNA-122,PKM2 and lactate levels.Results:(1)Compared with the control group,the levels of BUN and Cr increased significantly after 12 h and 24 h of CLP treatment(P<0.05).(2)Compared with the control group,after 12 h and 24 h of CLP treatment,the levels of lactate in the serum and kidney tissue of the mice were significantly higher than those in the control group(P<0.05).(3)Compared with the control group,the expression of miRNA-122 in renal tissue began to decrease at 4 h after CLP,and decreased significantly at 12-24 h(P<0.05).Compared with the control group,the expression of pKm2 mRNA and protein in renal tissue began to increase after 4 h of CLP,and increased significantly at 12-24 h(P<0.05).(4)Correlation analysis showed that miRNA-122 was significantly negatively correlated with lactate level(P<0.0001,r=-0.7167).There was a significant positive correlation between pkm2 mRNA and lactate level(P<0.0001,r=0.6817).There was a significant negative correlation between miRNA-122 and pkm2 mRNA expression(P<0.0001,r=-0.8122).Conclusion:In S-AKI,dysregulated expression of miRNA-122 may aggravate the occurrence and development of AKI by regulating the level of PKM2,and promoting aerobic glycolysis and lactate levels.

Self-propelled nanomotor reconstructs tumor microenvironment through synergistic hypoxia alleviation and glycolysis inhibition for promoted anti-metastasis

Solid tumors always exhibit local hypoxia,resulting in the high metastasis and inertness to chemotherapy.Reconstruction of hypoxic tumor microenvironment(TME)is considered a potential therapy compared to directly killing tumor cells.However,the insufficient oxygen delivery to deep tumor and the confronting Warburg effect"compromise the efficacy of hypoxia alleviation.Herein,we construct a cascade enzyme-powered nanomotor(NM-si),which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy.Catalase(Cat)and glucose oxidase(GOx)are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor(NM),with hexokinase-2(HK-2)siRNA further condensed(NM-si).The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along H_(2)O_(2) gradient towards deep tumor,with hypoxia successfully alleviated in the meantime.The autonomous movement also facilitates NM-si with lysosome escaping for efficient HK-2 knockdown to inhibit glycolysis.In vivo results demonstrated a promising anti-metastasis effect of commercially available albumin-bound paclitaxel(PTX@HSA)after pre-treated with NM-si for TME reconstruction.This cascade enzyme-powered nanomotor provides a potential prospect in reversing the hypoxic TME and metabolic pathway for reinforced anti-metastasis of chemotherapy.

Aldolase A promotes proliferation and G1/S transition via the EGFR/MAPK pathway in non-small cell lung cancer

Background:Our previous study demonstrated that aldolase A(ALDOA)is overexpressed in clinical human lung squamous cell carcinoma and that ALDOA promotes epithelial-mesenchymal transition and tumorigenesis.The pre-sent study aimed to explore the function of ALDOA in the modulation of non-small cell lung cancer(NSCLC)prolifera-tion and cell cycle progression and the potential mechanism.Methods:ALDOA was knocked down by short hairpin RNA in H520 and H1299 cells.ALDOA was overexpressed with vectors carrying the full-length ALDOA sequence in H1299 and H157 cells.The proliferation capacities were assessed with immunohistochemical staining,Cell Counting Kit-8 and colony formation assays.The cell cycle distribution was examined by flow cytometry,and molecular alterations were determined by western blotting.Cell synchronization was induced with nocodazole.The stability of cyclin D1 mRNA was tested.The pyruvate kinase M2 and ALDOA protein distributions were examined.Aerobic glycolysis was evaluated with Cell Titer-Glo assay,glucose colorimetric assay and lactate colorimetric assay.Results:ALDOA knockdown inhibited the proliferation and G1/S transition in H520 cells.Conversely,ALDOA over-expression promoted the proliferation and G1/S transition in H157 cells.The cell cycle synchronization assay showed that ALDOA expression increased in the G1 phase and G1/S transition.Furthermore,ALDOA knockdown reduced cyclin D1 expression by regulating epidermal growth factor receptor/mitogen-activated protein kinase(EGFR/MAPK)pathway.Similar results were found in H1299 and H157 cells.The inhibition of mitogen-activated protein kinase kinase 1/2 prompted the nuclear distribution of ALDOA.Additionally,ALDOA knockdown reduced nuclear distribution of PKM2,the extracellular lactate and intracellular adenosine triphosphate concentrations and elevated the extracellular glucose concentration.Conclusions:ALDOA contributed to activation of the EGFR/MAPK pathway,thus promoting cyclin D1 expression and enhancing proliferation and G1/S transition in NSCLC.Additionally,ALDOA facilitated NSCLC aerobic glycolysis.

Potential of electron transfer and its application in dictating routes of biochemical processes associated with metabolic reprogramming

Metabolic reprogramming,such as abnormal utilization of glucose,addiction to glutamine,and increased de-novo lipid synthesis,extensively occurs in proliferating cancer cells,but the underneath rationale has remained to be elucidated.Based on the concept of the degree of reduction of a compound,we have recently proposed a calculation termed as potential of electron transfer(PET),which is used to characterize the degree of electron redistribution coupled with metabolic transformations.When this calculation is combined with the assumed model of electron balance in a cellular context,the enforced selective reprogramming could be predicted by examining the net changes of the PET values associated with the biochemical pathways in anaerobic metabolism.Some interesting properties of PET in cancer cells were also discussed,and the model was extended to uncover the chemical nature underlying aerobic glycolysis that essentially results from energy requirement and electron balance.Enabling electron transfer could drive metabolic reprogramming in cancer metabolism.Therefore,the concept and model established on electron transfer could guide the treatment strategies of tumors and future studies on cellular metabolism.