Exercise training is critical for the early prevention and treatment of obesity and diabetes mellitus.However,the mechanism with gut microbiota and fecal metabolites underlying the effects of voluntary wheel running o...Exercise training is critical for the early prevention and treatment of obesity and diabetes mellitus.However,the mechanism with gut microbiota and fecal metabolites underlying the effects of voluntary wheel running on high-fat diet induced abnormal glucose metabolism has not been fully elaborated.C57BL/6 male mice were randomly assigned to 4 groups according to diets(fed with normal chow diet or high-fat diet)and running paradigm(housed in static cage or with voluntary running wheel).An integrative 16S rDNA sequencing and metabolites profiling was synchronously performed to characterize the effects of voluntary wheel running on gut microbiota and metabolites.It showed that voluntary wheel running prevented the detrimental effects of high-fat feeding on glucose metabolism 16S rDNA sequencing showed remarkable changes in Rikenella and Marvinbryantia genera.Metabolic profiling indicated multiple altered metabolites,which were enriched in secondary bile acid biosynthesis signaling.In conclusion,our study indicated that voluntary wheel running significantly improved glucose metabolism and counteracted the deleterious effects of high-fat feeding on body weight and glucose intolerance.We further found that voluntary wheel running could integratively program gut microbiota composition and fecal metabolites changes,and may regulate muricholic acid metabolism and secondary bile acid biosynthesis in high-fat fed mice.展开更多
BACKGROUND Fibroblast growth factor(FGF)15/19,which is expressed in and secreted from the distal ileum,can regulate hepatic glucose metabolism in an endocrine manner.The levels of both bile acids(BAs)and FGF15/19 are ...BACKGROUND Fibroblast growth factor(FGF)15/19,which is expressed in and secreted from the distal ileum,can regulate hepatic glucose metabolism in an endocrine manner.The levels of both bile acids(BAs)and FGF15/19 are elevated after bariatric surgery.However,it is unclear whether the increase in FGF15/19 is induced by BAs.Moreover,it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.AIM To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy(SG).METHODS By calculating and comparing the changes of body weight after SG with SHAM group,we examined the weight-loss effect of SG.The oral glucose tolerance test(OGTT)test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG.By detecting the glycogen content,expression and activity of glycogen synthase as well as the glucose-6-phosphatase(G6Pase)and phosphoenolpyruvate carboxykinase(Pepck),we evaluated the hepatic glycogen content and gluconeogenesis activity.We examined the levels of total BA(TBA)together with the farnesoid X receptor(FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery.Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4(FGFR4)with its corresponding signal pathways involved in glucose metabolism were detected.RESULTS After surgery,food intake and body weight gain of SG group was decreased compare with the SHAM group.The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG,while the expression of the key enzyme for hepatic gluconeogenesis:G6Pase and Pepck,were depressed.TBA levels in serum and portal vein were both elevated after SG,the FXR-agonistic BA subspecies:Chenodeoxycholic acid(CDCA),lithocholic acid(LCA)in serum and CDCA,DCA,LCA in portal vein were all higher in SG group than that in SHAM group.Consequently,the ileal expression of FXR and FGF15 were also advanced in SG group.Moreover,the hepatic expression of FGFR4 was stimulated in SG-operated rats.As a result,the activity of its corresponding pathway for glycogen synthesis:FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated,while the corresponding pathway for hepatic gluconeogenesis:FGFR4-cAMP regulatory element-binding protein-peroxisome proliferator-activated receptorγcoactivator-1αpathway was suppressed.CONCLUSION Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR.Furthermore,the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.展开更多
Background:Previous studies have shown that exogenous short-chain fatty acids(SCFAs)introduction attenuated the body fat deposition in conventional mice and pigs.However,limited studies have evaluated the effects of e...Background:Previous studies have shown that exogenous short-chain fatty acids(SCFAs)introduction attenuated the body fat deposition in conventional mice and pigs.However,limited studies have evaluated the effects of exogenously introduced SCFAs on the lipid and glucose metabolism independently of the gut microbiota.This study was to investigate the effects of exogenous introduction of SCFAs on the lipid and glucose metabolism in a germ-free(GF)pig model.Methods:Twelve hysterectomy-derived newborn pigs were reared in six sterile isolators.All pigs were hand-fed with sterile milk powder for 21 d,then the sterile feed was introduced to pigs for another 21 d.In the second 21-d period,six pigs were orally administrated with 25 mL/kg sterile saline per day and considered as the GF group,while the other six pigs were orally administrated with 25 mL/kg SCFAs mixture(acetic,propionic,and butyric acids,45,15,and 11 mmol/L,respectively)per day and regarded as FA group.Results:Orally administrated with SCFAs tended to increase the adiponectin concentration in serum,enhance the CPT-1 activity in longissimus dorsi,and upregulate the ANGPTL4 mRNA expression level in colon(P<0.10).Meanwhile,the mRNA abundances of ACC,FAS,and SREBP-1C in liver and CD36 in longissimus dorsi of the FA group were decreased(P<0.05)compared with those in the GF group.Besides,the mRNA expression of PGC-1αin liver and LPL in longissimus dorsi tended to(P<0.10)upregulate and downregulate respectively in the FA group.Moreover,oral administration of SCFAs tended to increase the protein level of GPR43(P<0.10)and decrease the protein level of ACC(P<0.10)in liver.Also,oral administration of SCFAs upregulated the p-AMPK/AMPK ratio and the mRNA expressions of GLUT-2 and GYS2 in liver(P<0.05).In addition,the metabolic pathway associated with the biosynthesis of unsaturated fatty acids was most significantly promoted(P<0.05)by oral administration of SCFAs.Conclusions:Exogenous introduction of SCFAs might attenuate the fat deposition and to some extent improve the glucose control in the pig model,which occurred independently of the gut microbiota.展开更多
Foxtail millet(FM)whole grain has received special attention in recent years.To confirm the hypoglycemic effects of FM,we investigated the effects of FM supplementation on glucose metabolism and gut microbiota in rats...Foxtail millet(FM)whole grain has received special attention in recent years.To confirm the hypoglycemic effects of FM,we investigated the effects of FM supplementation on glucose metabolism and gut microbiota in rats with high-fat diet/streptozotocin(HFD/STZ)-induced diabetes.Specifically,we fully assessed the blood biochemical profiles,pancreatic histopathology,insulin-glucagon immunofluorescence,short-chain fatty acids,and gut microbiota composition of rats with HFD/STZ-induced diabetes before and after FM supplementation.Results showed that both 30% and 48% FM supplementation significantly decreased concentrations of fasting blood glucose,60-min blood glucose,and blood triglycerides(P<0.05);additionally,48% FM supplementation significantly improved blood glucose tolerance and insulin resistance(P<0.05).However,FM supplementation could not effectively repair damage to β-cells over a short period of time.In addition,4 weeks of 48% FM supplementation siginificantly increased the relative abundance of Bifidobacterium and concentration of butyrate,suggesting that the hypoglycemic effects of FM supplementation might be partially mediated by gut microbiota.Collectively,we found a dose-dependent relationship between FM supplementation and improvement of blood glucose metabolism,but did not find a synergistic effect between FM supplementation and metformin(Met)treatment.Our findings provide further support that consuming more whole-grain FM might be beneficial to individuals suffering from type 2 diabetes.展开更多
BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered asso...BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered associated with myocardial remodeling.Nε-(carboxymethyl)lysine(CML)is a representative foodborne toxic product,which can be ingested via daily diet.Therefore,there is a marked need to explore the effects of dietary CML on the myocardium.AIM To explore the effects of dietary CML(dCML)on the heart.METHODS C57 BL/6 mice were divided into a control group and a dCML group.The control group and the dCML group were respectively fed a normal diet or diet supplemented with CML for 20 wk.Body weight and blood glucose were recorded every 4 wk.^(18)F-fluorodeoxyglucose(FDG)was used to trace the glucose uptake in mouse myocardium,followed by visualizing with micro-positron emission tomography(PET).Myocardial remodeling and glucose metabolism were also detected.In vitro,H9C2 cardiomyocytes were added to exogenous CML and cultured for 24 h.The effects of exogenous CML on glucose metabolism,collagen I expression,hypertrophy,and apoptosis of cardiomyocytes were analyzed.RESULTS Our results suggest that the levels of fasting blood glucose,fasting insulin,and serum CML were significantly increased after 20 wk of dCML.Micro-PET showed that ^(18)F-FDG accumulated more in the myocardium of the dCML group than in the control group.Histological staining revealed that dCML could lead to myocardial fibrosis and hypertrophy.The indexes of myocardial fibrosis,apoptosis,and hypertrophy were also increased in the dCML group,whereas the activities of glucose metabolism-related pathways and citrate synthase(CS)were significantly inhibited.In cardiomyocytes,collagen I expression and cellular size were significantly increased after the addition of exogenous CML.CML significantly promoted cellular hypertrophy and apoptosis,while pathways involved in glucose metabolism and level of Cs mRNA were significantly inhibited.CONCLUSION This study reveals that dCML alters myocardial glucose metabolism and promotes myocardial remodeling.展开更多
Compounds with regulating glucose metabolism and improving insulin resistance(IR)activity are abundant in nature and can be obtained from several sources.They have high potential to be used to treat diabetes mellitus....Compounds with regulating glucose metabolism and improving insulin resistance(IR)activity are abundant in nature and can be obtained from several sources.They have high potential to be used to treat diabetes mellitus.These compounds isolated from natural plants can be classified seven categories:terpenoids,alkaloids,quinones,flavonoids,phenols,phenyl propanoids,steroids,and other types of compounds.They exert biological effects by different ways and mechanisms.This review illustrated the potential natural products as a rich resource in regulation of glucose metabolism and IR,as well as their mechanisms.展开更多
To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (sTBI).Methods All 33 patients with sTBI(GCS≤8) were randomly divided into hyp...To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (sTBI).Methods All 33 patients with sTBI(GCS≤8) were randomly divided into hypothermic group and control group.Microdialysis catheters were inserted into the cerebral cortex of perilesion,relative normal brain tissue and subcutaneous tissue of abdomen in order to analyze the concentrations of lactate/pyruvate (L/P),lactate/glucose (L/G) and the glycerol(Gly) in extracellular fluid (ECF).Results In comparison with the control group,the concentration of L/G,L/P and Gly in periphery and that of L/P in ECF of the “normal brain tissue” were significantly decreased in the hypothermic group.In control group,concentration of L/G,L/P and Gly in periphery were higher than those in relative normal brain.In the hypothermic group,L/P concentration in periphery was higher than that in relative normal brain.Conclusion Mild hypothermia protects brain by decreasing concentrations of L/G,L/P and Gly in periphery and L/P concentration in “normal brain tissue”.The energy crisis and membrane phospholipid breakage in periphery are easier to happen after TBI,where mild hypothermia exerts significant protgective role.12 refs,3 tabs.展开更多
Both in nature and in aquaculture,fish may experience periods of food scarcity or hunger.The metabolic regulation of fish when nutritional state changes is a complex process that involves many factors.To study glucose...Both in nature and in aquaculture,fish may experience periods of food scarcity or hunger.The metabolic regulation of fish when nutritional state changes is a complex process that involves many factors.To study glucose metabolism adaptability during fasting and re-feeding in the black carp(Mylopharyngodon piceus),we measured changes in some biochemical indicators related to glucose metabolism.Five fish were sampled on days 0,1,3,5,and 10 of fasting(F,S1,S3,S5,and S10,respectively)and days 1,3,and 5 of re-feeding(RF1,RF3,and RF5,respectively).The serum glucose concentration decreased significantly at S1,reached the lowest point at S10,and increased significantly at RF1(P<0.05).The concentration of liver glycogen decreased significantly at S1 and reached the lowest level at S3,whereas the muscle glycogen level decreased significantly at S5 and reached the lowest value at S10(P<0.05).Both liver and muscle glycogen levels returned to the pre-fasting level at RF5(P<0.05).Regarding glycolysis,the concentrations of pyruvate kinase(PK)and hexokinase(HK)decreased significantly at S5 and increased significantly at RF5 and RF1,respectively(P<0.05).The concentrations of glucokinase(GCK)and insulin decreased significantly at S1 and increased significantly at RF1 and RF3,respectively(P<0.05).The mRNA expression levels of liver GCK and glucose transporter 2(GLUT2)decreased significantly at S1 and increased significantly at RF1 and RF5,respectively(P<0.05).As for gluconeogenesis,the concentration of glucose-6-phosphatase(G6PC)increased significantly at S1 and decreased significantly at RF1(P<0.05).The concentrations of glucagon and glucocorticoid(GC)increased significantly at S3 and significantly decreased at RF1 and RF5,respectively(P<0.05).The mRNA expression levels of liver G6PC and phosphoenolpyruvate carboxykinase(PEPCK)increased significantly at S3 and S1,and both decreased significantly at RF1(P<0.05).These results indicate that coordination between glycolysis and gluconeogenesis might be crucial for glucose homeostasis during fasting and re-feeding in the black carp.展开更多
Highland barley(HB)is a high-altitude cereal with rich nutritional components and potential health benefits.To clarify its hypoglycemic effect and mechanism,we investigated the effect of whole grain HB and fecal micro...Highland barley(HB)is a high-altitude cereal with rich nutritional components and potential health benefits.To clarify its hypoglycemic effect and mechanism,we investigated the effect of whole grain HB and fecal microbiota transplantation(FMT)on glucose metabolism and gut microbiota in high-fat diet and streptozotocin(HFD/STZ)-induced diabetic mice.The results showed that HB(40%)significantly decreased fasting blood glucose and the area under the glucose tolerance curve,significantly increased insulin secretion and improved insulin resistance in HFD/STZ-induced diabetic mice(P<0.05).Inflammatory factors and blood lipid indices were also significantly alleviated after 12 weeks of 40%HB intervention(P<0.05).Additionally,beneficial bacteria,such as Bifidobacterium and Akkermansia,were significantly enriched in the gut of diabetic mice after whole grain HB intervention.Meanwhile,the results of further FMT experiments verified that the fecal microbiota after the 40%HB intervention not only significantly increased the relative abundance of Bifidobacterium and Akkermansia but also effectively improved glucose metabolism and alleviated the inflammatory state in HFD/STZ-induced diabetic mice.Collectively,our study confirmed the bridge role of gut microbiota in improving glucose metabolism of whole grain HB,which could promote the development of precision nutrition.展开更多
Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed ...Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the developme...Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.展开更多
The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules;glucose metabolism decreases dramatically in Alzheimer’s disease(AD)and may b...The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules;glucose metabolism decreases dramatically in Alzheimer’s disease(AD)and may be a fundamental cause for its development.Recent studies reveal that the alternative splicing events of certain genes effectively regulate several processes in glucose metabolism including insulin receptor,insulin-degrading enzyme,pyruvate kinase M,receptor for advanced glycation endproducts,and others,thereby,influencing glucose uptake,glycolysis,and advanced glycation end-products-mediated signaling pathways.Indeed,the discovery of aberrant alternative splicing that changes the proteomic diversity and protein activity in glucose metabolism has been pivotal in our understanding of AD development.In this review,we summarize the alternative splicing events of the glucose metabolism-related genes in AD pathology and highlight the crucial regulatory roles of splicing factors in the alternative splicing process.We also discuss the emerging therapeutic approaches for targeting splicing factors for AD treatment.展开更多
Objective:Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism.It is not clear whether phenolic acids or their metabolites play a major role in vivo.In this s...Objective:Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism.It is not clear whether phenolic acids or their metabolites play a major role in vivo.In this study,caffeic acid(CA)and ferulic acid(FA),the two most ingested phenolic acids,and their glucuronic acid metabolites,caffeic-4’-O-glucuronide(CA4G)and ferulic-4’-O-glucuronide(FA4G),were investigated.Methods:Three insulin resistance models in vitro were established by using TNF-a,insulin and palmitic acid(PA)in HepG2 cells,respectively.We compared the effects of FA,FA4G,CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels.The potential targets and related pathways were predicted by network pharmacology.Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target.To investigate the binding mode,molecular docking was performed.Then,we performed membrane recruitment assays of the AKT pleckstrin homology(PH)domain with the help of the PH-GFP plasmid.AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds.Finally,the downstream signaling pathway of AKT was investigated by Western blot analysis.Results:The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption.AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis.The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds.The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site.CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane,while increasing the activity of AKT.Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3βin the AKT signaling pathway to increase glucose consumption.Conclusion:In conclusion,our results suggested that the metabolites of phenolic acids,which contain glucuronic acid,are the key active substances and that they activate AKT by targeting the PH domain,thus improving glucose metabolism.展开更多
The gut microflora is a combination of all microbes in intestine and their microenvironment,and its change can sensitively reflect the relevant response of the body to external environment and remarkably affect body&#...The gut microflora is a combination of all microbes in intestine and their microenvironment,and its change can sensitively reflect the relevant response of the body to external environment and remarkably affect body's metabolism as well.Recent studies have found that cold exposure affects the body's gut microflora,which can lead to changes in the body's metabolism of glucose and lipid.This review summarizes recent research on the effects of cold exposure on gut microbes and metabolism of glucose and lipid,aiming to provide some new ideas on the approaches and measures for the prevention and treatment of diabetes and obesity.展开更多
Small cell lung cancer(SCLC)is a highly aggressive tumor type for which limited therapeutic progress has been made.Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment,bu...Small cell lung cancer(SCLC)is a highly aggressive tumor type for which limited therapeutic progress has been made.Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment,but most patients with SCLC acquire therapeutic resistance.Given the need for more effective therapies,better elucidation of the molecular pathogenesis of SCLC is imperative.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway is frequently activated in SCLC and strongly associated with resistance to ionizing radiation in many solid tumors.This pathway is an important regulator of cancer cell glucose metabolism,and its activation probably effects radioresistance by influencing bioenergetic processes in SCLC.Glucose metabolism has three main branches-aerobic glycolysis,oxidative phosphorylation,and the pentose phosphate pathway-involved in radioresistance.The interaction between the PI3K/AKT/mTOR pathway and glucose metabolism is largely mediated by hypoxia-inducible factor 1(HIF-1)signaling.The PI3K/AKT/mTOR pathway also influences glucose metabolism through other mechanisms to participate in radioresistance,including inhibiting the ubiquitination of rate-limiting enzymes of the pentose phosphate pathway.This review summarizes our understanding of links among the PI3K/AKT/mTOR pathway,hypoxia,and glucose metabolism in SCLC radioresistance and highlights promising research directions to promote cancer cell death and improve the clinical outcome of patients with this devastating disease.展开更多
Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signalin...Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.展开更多
BACKGROUND An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer(CRC).However,no work is currently available to synthesize the field through bibliometr...BACKGROUND An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer(CRC).However,no work is currently available to synthesize the field through bibliometrics.AIM To analyze the development in the field of“glucose metabolism”(GM),“amino acid metabolism”(AM),“lipid metabolism”(LM),and“nucleotide metabolism”(NM)in CRC by visualization.METHODS Articles within the abovementioned areas of GM,AM,LM and NM in CRC,which were published from January 1,1991,to December 31,2022,are retrieved from the Web of Science Core Collection and analyzed by CiteSpace 6.2.R4 and VOSviewer 1.6.19.RESULTS The field of LM in CRC presented the largest number of annual publications and the fastest increase in the last decade compared with the other three fields.Meanwhile,China and the United States were two of the most prominent contri-butors in these four areas.In addition,Gang Wang,Wei Jia,Maria Notar-nicola,and Cornelia Ulrich ranked first in publication numbers,while Jing-Yuan Fang,Senji Hirasawa,Wei Jia,and Charles Fuchs were the most cited authors on average in these four fields,respectively.“Gut microbiota”and“epithelial-mesenchymal transition”emerged as the newest burst words in GM,“gut microbiota”was the latest outburst word in AM,“metastasis”,“tumor microenvironment”,“fatty acid metabolism”,and“metabolic reprogramming”were the up-to-date outbreaking words in LM,while“epithelial-mesenchymal transition”and“apoptosis”were the most recently occurring words in NM.CONCLUSION Research in“cellular metabolism in CRC”is all the rage at the moment,and researchers are particularly interested in exploring the mechanism to explain the metabolic alterations in CRC.Targeting metabolic vulnerability appears to be a promising direction in CRC therapy.展开更多
BACKGROUND Type 2 diabetes mellitus(T2DM)is a chronic metabolic disease featured by insulin resistance(IR)and decreased insulin secretion.Currently,vitamin D deficiency is found in most patients with T2DM,but the rela...BACKGROUND Type 2 diabetes mellitus(T2DM)is a chronic metabolic disease featured by insulin resistance(IR)and decreased insulin secretion.Currently,vitamin D deficiency is found in most patients with T2DM,but the relationship between vitamin D and IR in T2DM patients requires further investigation.AIM To explore the risk factors of IR and the effects of vitamin D supplementation on glucose and lipid metabolism in patients with T2DM.METHODS Clinical data of 162 T2DM patients treated in First Affiliated Hospital of Harbin Medical University between January 2019 and February 2022 were retrospectively analyzed.Based on the diagnostic criteria of IR,the patients were divided into a resistance group(n=100)and a non-resistance group(n=62).Subsequently,patients in the resistance group were subdivided to a conventional group(n=44)or a joint group(n=56)according to the treatment regimens.Logistic regression was carried out to analyze the risk factors of IR in T2DM patients.The changes in glucose and lipid metabolism indexes in T2DM patients with vitamin D deficiency were evaluated after the treatment.RESULTS Notable differences were observed in age and body mass index(BMI)between the resistance group and the non-resistance group(both P<0.05).The resistance group exhibited a lower 25-hydroxyvitamin D_(3)(25(OH)D_(3))level,as well as notably higher levels of 2-h postprandial blood glucose(2hPG),fasting blood glucose(FBG),and glycosylated hemoglobin(HbA1c)than the non-resistance group(all P<0.0001).Additionally,the resistance group demonstrated a higher triglyceride(TG)level but a lower high-density lipoprotein-cholesterol(HDL-C)level than the non-resistance group(all P<0.0001).The BMI,TG,HDL-C,25(OH)D_(3),2hPG,and HbA1c were found to be risk factors of IR.Moreover,the posttreatment changes in levels of 25(OH)D_(3),2hPG,FBG and HbA1c,as well as TG,total cholesterol,and HDL-C in the joint group were more significant than those in the conventional group(all P<0.05).CONCLUSION Patients with IR exhibit significant abnormalities in glucose and lipid metabolism parameters compared to the noninsulin resistant group.Logistic regression analysis revealed that 25(OH)D_(3)is an independent risk factor influencing IR.Supplementation of vitamin D has been shown to improve glucose and lipid metabolism in patients with IR and T2DM.展开更多
Background Cold regions have long autumn and winter seasons and low ambient temperatures.When pigs are unable to adjust to the cold,oxidative damage and inflammation may develop.However,the differences between cold an...Background Cold regions have long autumn and winter seasons and low ambient temperatures.When pigs are unable to adjust to the cold,oxidative damage and inflammation may develop.However,the differences between cold and non-cold adaptation regarding glucose and lipid metabolism,gut microbiota and colonic mucosal immunological features in pigs are unknown.This study revealed the glucose and lipid metabolic responses and the dual role of gut microbiota in pigs during cold and non-cold adaptation.Moreover,the regulatory effects of dietary glucose supplements on glucose and lipid metabolism and the colonic mucosal barrier were evaluated in cold-exposed pigs.Results Cold and non-cold-adapted models were established by Min and Yorkshire pigs.Our results exhibited that cold exposure induced glucose overconsumption in non-cold-adapted pig models(Yorkshire pigs),decreasing plasma glucose concentrations.In this case,cold exposure enhanced the ATGL and CPT-1αexpression to promote liver lipolysis and fatty acid oxidation.Meanwhile,the two probiotics(Collinsella and Bifidobacterium)depletion and the enrichment of two pathogens(Sutterella and Escherichia-Shigella)in colonic microbiota are not conducive to colonic mucosal immunity.However,glucagon-mediated hepatic glycogenolysis in cold-adapted pig models(Min pigs)maintained the stability of glucose homeostasis during cold exposure.It contributed to the gut microbiota(including the enrichment of the Rikenellaceae RC9 gut group,[Eubacterium]coprostanoligenes group and WCHB1-41)that favored cold-adapted metabolism.Conclusions The results of both models indicate that the gut microbiota during cold adaptation contributes to the protection of the colonic mucosa.During non-cold adaptation,cold-induced glucose overconsumption promotes thermogenesis through lipolysis,but interferes with the gut microbiome and colonic mucosal immunity.Furthermore,glucagon-mediated hepatic glycogenolysis contributes to glucose homeostasis during cold exposure.展开更多
Aims: To investigate the relationship among NLRP3 inflammasome, glucose and lipid metabolism, and insulin resistance (IR) in the serum of patients with diabetes and pre-diabetes. Methods: A total of 100 patients with ...Aims: To investigate the relationship among NLRP3 inflammasome, glucose and lipid metabolism, and insulin resistance (IR) in the serum of patients with diabetes and pre-diabetes. Methods: A total of 100 patients with abnormal blood glucose divided into the pre-diabetes mellitus (PDM) group (N = 46) and the type 2 diabetes mellitus (T2DM) group (N = 54). 20 normoglycemic subjects (NG, N = 20) were selected as a control group. The serum levels of glucose and lipid metabolism, IR, and the expression of NLRP3, ASC and Caspase-1 were measured. Besides, the correlations of NLRP3 inflammasome with glucose and lipid metabolism, and IR were analyzed. Results: Compared with the NG group, the levels of NLRP3, ASC, Caspase-1, FBG, HbA<sub>1</sub>C, TG, LDL-C, FINs, and HOMA-IR were higher (P β were lower (P P β were seen (P P β. Regression analysis further showed that blood glucose related indexes, FINs, and NLRP3 have made a decisive contribution to IR. Conclusions: Collectively, this evidence suggested that NLRP3 is closely related to glucose and lipid metabolism, and IR, and activated in PDM and T2DM.展开更多
基金sponsored by National Natural Science Foundation of China (81800703 and 81970701)Beijing Nova Program (Z201100006820117 and 20220484181)+7 种基金Beijing Municipal Natural Science Foundation (7184252 and 7214258)the Fundamental Research Funds for the Central Universitiesthe Fundamental Research Funds for the Central Universities (BMU2021MX013)Peking University Clinical Scientist Training Program (BMU2023PYJH022)China Endocrine and Metabolism Young Scientific Talent Research Project (2022-N-02-01)Peking University Medicine Seed Fund for Interdisciplinary ResearchChina Diabetes Young Scientific Talent Research ProjectBethune-Merck Diabetes Research Fund of Bethune Charitable Foundation (G2018030)。
文摘Exercise training is critical for the early prevention and treatment of obesity and diabetes mellitus.However,the mechanism with gut microbiota and fecal metabolites underlying the effects of voluntary wheel running on high-fat diet induced abnormal glucose metabolism has not been fully elaborated.C57BL/6 male mice were randomly assigned to 4 groups according to diets(fed with normal chow diet or high-fat diet)and running paradigm(housed in static cage or with voluntary running wheel).An integrative 16S rDNA sequencing and metabolites profiling was synchronously performed to characterize the effects of voluntary wheel running on gut microbiota and metabolites.It showed that voluntary wheel running prevented the detrimental effects of high-fat feeding on glucose metabolism 16S rDNA sequencing showed remarkable changes in Rikenella and Marvinbryantia genera.Metabolic profiling indicated multiple altered metabolites,which were enriched in secondary bile acid biosynthesis signaling.In conclusion,our study indicated that voluntary wheel running significantly improved glucose metabolism and counteracted the deleterious effects of high-fat feeding on body weight and glucose intolerance.We further found that voluntary wheel running could integratively program gut microbiota composition and fecal metabolites changes,and may regulate muricholic acid metabolism and secondary bile acid biosynthesis in high-fat fed mice.
基金the National Natural Science Foundation of China, No. 81600617
文摘BACKGROUND Fibroblast growth factor(FGF)15/19,which is expressed in and secreted from the distal ileum,can regulate hepatic glucose metabolism in an endocrine manner.The levels of both bile acids(BAs)and FGF15/19 are elevated after bariatric surgery.However,it is unclear whether the increase in FGF15/19 is induced by BAs.Moreover,it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.AIM To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy(SG).METHODS By calculating and comparing the changes of body weight after SG with SHAM group,we examined the weight-loss effect of SG.The oral glucose tolerance test(OGTT)test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG.By detecting the glycogen content,expression and activity of glycogen synthase as well as the glucose-6-phosphatase(G6Pase)and phosphoenolpyruvate carboxykinase(Pepck),we evaluated the hepatic glycogen content and gluconeogenesis activity.We examined the levels of total BA(TBA)together with the farnesoid X receptor(FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery.Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4(FGFR4)with its corresponding signal pathways involved in glucose metabolism were detected.RESULTS After surgery,food intake and body weight gain of SG group was decreased compare with the SHAM group.The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG,while the expression of the key enzyme for hepatic gluconeogenesis:G6Pase and Pepck,were depressed.TBA levels in serum and portal vein were both elevated after SG,the FXR-agonistic BA subspecies:Chenodeoxycholic acid(CDCA),lithocholic acid(LCA)in serum and CDCA,DCA,LCA in portal vein were all higher in SG group than that in SHAM group.Consequently,the ileal expression of FXR and FGF15 were also advanced in SG group.Moreover,the hepatic expression of FGFR4 was stimulated in SG-operated rats.As a result,the activity of its corresponding pathway for glycogen synthesis:FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated,while the corresponding pathway for hepatic gluconeogenesis:FGFR4-cAMP regulatory element-binding protein-peroxisome proliferator-activated receptorγcoactivator-1αpathway was suppressed.CONCLUSION Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR.Furthermore,the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.
基金study was supported by National Natural Science Foundation of China(31730091)the National Key Research and Development Program of China(2017YFD0500503).
文摘Background:Previous studies have shown that exogenous short-chain fatty acids(SCFAs)introduction attenuated the body fat deposition in conventional mice and pigs.However,limited studies have evaluated the effects of exogenously introduced SCFAs on the lipid and glucose metabolism independently of the gut microbiota.This study was to investigate the effects of exogenous introduction of SCFAs on the lipid and glucose metabolism in a germ-free(GF)pig model.Methods:Twelve hysterectomy-derived newborn pigs were reared in six sterile isolators.All pigs were hand-fed with sterile milk powder for 21 d,then the sterile feed was introduced to pigs for another 21 d.In the second 21-d period,six pigs were orally administrated with 25 mL/kg sterile saline per day and considered as the GF group,while the other six pigs were orally administrated with 25 mL/kg SCFAs mixture(acetic,propionic,and butyric acids,45,15,and 11 mmol/L,respectively)per day and regarded as FA group.Results:Orally administrated with SCFAs tended to increase the adiponectin concentration in serum,enhance the CPT-1 activity in longissimus dorsi,and upregulate the ANGPTL4 mRNA expression level in colon(P<0.10).Meanwhile,the mRNA abundances of ACC,FAS,and SREBP-1C in liver and CD36 in longissimus dorsi of the FA group were decreased(P<0.05)compared with those in the GF group.Besides,the mRNA expression of PGC-1αin liver and LPL in longissimus dorsi tended to(P<0.10)upregulate and downregulate respectively in the FA group.Moreover,oral administration of SCFAs tended to increase the protein level of GPR43(P<0.10)and decrease the protein level of ACC(P<0.10)in liver.Also,oral administration of SCFAs upregulated the p-AMPK/AMPK ratio and the mRNA expressions of GLUT-2 and GYS2 in liver(P<0.05).In addition,the metabolic pathway associated with the biosynthesis of unsaturated fatty acids was most significantly promoted(P<0.05)by oral administration of SCFAs.Conclusions:Exogenous introduction of SCFAs might attenuate the fat deposition and to some extent improve the glucose control in the pig model,which occurred independently of the gut microbiota.
基金supported by the National Key R&D Program of China(2017YFD0401200)China Agriculture Research System(CARS-07-13.5-A17)+1 种基金General S&T project of Beijing Municipal Commission of Education(KM202010011006)BTBU Youth Fund(PXM2019_014213_000007).
文摘Foxtail millet(FM)whole grain has received special attention in recent years.To confirm the hypoglycemic effects of FM,we investigated the effects of FM supplementation on glucose metabolism and gut microbiota in rats with high-fat diet/streptozotocin(HFD/STZ)-induced diabetes.Specifically,we fully assessed the blood biochemical profiles,pancreatic histopathology,insulin-glucagon immunofluorescence,short-chain fatty acids,and gut microbiota composition of rats with HFD/STZ-induced diabetes before and after FM supplementation.Results showed that both 30% and 48% FM supplementation significantly decreased concentrations of fasting blood glucose,60-min blood glucose,and blood triglycerides(P<0.05);additionally,48% FM supplementation significantly improved blood glucose tolerance and insulin resistance(P<0.05).However,FM supplementation could not effectively repair damage to β-cells over a short period of time.In addition,4 weeks of 48% FM supplementation siginificantly increased the relative abundance of Bifidobacterium and concentration of butyrate,suggesting that the hypoglycemic effects of FM supplementation might be partially mediated by gut microbiota.Collectively,we found a dose-dependent relationship between FM supplementation and improvement of blood glucose metabolism,but did not find a synergistic effect between FM supplementation and metformin(Met)treatment.Our findings provide further support that consuming more whole-grain FM might be beneficial to individuals suffering from type 2 diabetes.
基金Supported by the National Natural Science Foundation of China,No.82070455Natural Science Foundation of Jiangsu Province,No.BK20201225+1 种基金Medical Innovation Team Project of Jiangsu Province,No.CXTDA2017010Research and Innovation Funding Project for College Students in Experimental Animal Center of Jiangsu University。
文摘BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered associated with myocardial remodeling.Nε-(carboxymethyl)lysine(CML)is a representative foodborne toxic product,which can be ingested via daily diet.Therefore,there is a marked need to explore the effects of dietary CML on the myocardium.AIM To explore the effects of dietary CML(dCML)on the heart.METHODS C57 BL/6 mice were divided into a control group and a dCML group.The control group and the dCML group were respectively fed a normal diet or diet supplemented with CML for 20 wk.Body weight and blood glucose were recorded every 4 wk.^(18)F-fluorodeoxyglucose(FDG)was used to trace the glucose uptake in mouse myocardium,followed by visualizing with micro-positron emission tomography(PET).Myocardial remodeling and glucose metabolism were also detected.In vitro,H9C2 cardiomyocytes were added to exogenous CML and cultured for 24 h.The effects of exogenous CML on glucose metabolism,collagen I expression,hypertrophy,and apoptosis of cardiomyocytes were analyzed.RESULTS Our results suggest that the levels of fasting blood glucose,fasting insulin,and serum CML were significantly increased after 20 wk of dCML.Micro-PET showed that ^(18)F-FDG accumulated more in the myocardium of the dCML group than in the control group.Histological staining revealed that dCML could lead to myocardial fibrosis and hypertrophy.The indexes of myocardial fibrosis,apoptosis,and hypertrophy were also increased in the dCML group,whereas the activities of glucose metabolism-related pathways and citrate synthase(CS)were significantly inhibited.In cardiomyocytes,collagen I expression and cellular size were significantly increased after the addition of exogenous CML.CML significantly promoted cellular hypertrophy and apoptosis,while pathways involved in glucose metabolism and level of Cs mRNA were significantly inhibited.CONCLUSION This study reveals that dCML alters myocardial glucose metabolism and promotes myocardial remodeling.
基金supported by National Natural Science Foundation of China(31900292)Science and Technology Development Program of Henan Province(202102110149,192102110112,and 182102410083)Science and Technology Project of Kaifeng(1908005,and 1803010).
文摘Compounds with regulating glucose metabolism and improving insulin resistance(IR)activity are abundant in nature and can be obtained from several sources.They have high potential to be used to treat diabetes mellitus.These compounds isolated from natural plants can be classified seven categories:terpenoids,alkaloids,quinones,flavonoids,phenols,phenyl propanoids,steroids,and other types of compounds.They exert biological effects by different ways and mechanisms.This review illustrated the potential natural products as a rich resource in regulation of glucose metabolism and IR,as well as their mechanisms.
文摘To study the effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury (sTBI).Methods All 33 patients with sTBI(GCS≤8) were randomly divided into hypothermic group and control group.Microdialysis catheters were inserted into the cerebral cortex of perilesion,relative normal brain tissue and subcutaneous tissue of abdomen in order to analyze the concentrations of lactate/pyruvate (L/P),lactate/glucose (L/G) and the glycerol(Gly) in extracellular fluid (ECF).Results In comparison with the control group,the concentration of L/G,L/P and Gly in periphery and that of L/P in ECF of the “normal brain tissue” were significantly decreased in the hypothermic group.In control group,concentration of L/G,L/P and Gly in periphery were higher than those in relative normal brain.In the hypothermic group,L/P concentration in periphery was higher than that in relative normal brain.Conclusion Mild hypothermia protects brain by decreasing concentrations of L/G,L/P and Gly in periphery and L/P concentration in “normal brain tissue”.The energy crisis and membrane phospholipid breakage in periphery are easier to happen after TBI,where mild hypothermia exerts significant protgective role.12 refs,3 tabs.
基金supported by China Agriculture Research System of MOF and MARA(CARS-45-03).
文摘Both in nature and in aquaculture,fish may experience periods of food scarcity or hunger.The metabolic regulation of fish when nutritional state changes is a complex process that involves many factors.To study glucose metabolism adaptability during fasting and re-feeding in the black carp(Mylopharyngodon piceus),we measured changes in some biochemical indicators related to glucose metabolism.Five fish were sampled on days 0,1,3,5,and 10 of fasting(F,S1,S3,S5,and S10,respectively)and days 1,3,and 5 of re-feeding(RF1,RF3,and RF5,respectively).The serum glucose concentration decreased significantly at S1,reached the lowest point at S10,and increased significantly at RF1(P<0.05).The concentration of liver glycogen decreased significantly at S1 and reached the lowest level at S3,whereas the muscle glycogen level decreased significantly at S5 and reached the lowest value at S10(P<0.05).Both liver and muscle glycogen levels returned to the pre-fasting level at RF5(P<0.05).Regarding glycolysis,the concentrations of pyruvate kinase(PK)and hexokinase(HK)decreased significantly at S5 and increased significantly at RF5 and RF1,respectively(P<0.05).The concentrations of glucokinase(GCK)and insulin decreased significantly at S1 and increased significantly at RF1 and RF3,respectively(P<0.05).The mRNA expression levels of liver GCK and glucose transporter 2(GLUT2)decreased significantly at S1 and increased significantly at RF1 and RF5,respectively(P<0.05).As for gluconeogenesis,the concentration of glucose-6-phosphatase(G6PC)increased significantly at S1 and decreased significantly at RF1(P<0.05).The concentrations of glucagon and glucocorticoid(GC)increased significantly at S3 and significantly decreased at RF1 and RF5,respectively(P<0.05).The mRNA expression levels of liver G6PC and phosphoenolpyruvate carboxykinase(PEPCK)increased significantly at S3 and S1,and both decreased significantly at RF1(P<0.05).These results indicate that coordination between glycolysis and gluconeogenesis might be crucial for glucose homeostasis during fasting and re-feeding in the black carp.
基金funded by the National Natural Science Foundation of China(32101876)the Discipline ConstructionFood Science and Engineering(SPKX-202202)grants。
文摘Highland barley(HB)is a high-altitude cereal with rich nutritional components and potential health benefits.To clarify its hypoglycemic effect and mechanism,we investigated the effect of whole grain HB and fecal microbiota transplantation(FMT)on glucose metabolism and gut microbiota in high-fat diet and streptozotocin(HFD/STZ)-induced diabetic mice.The results showed that HB(40%)significantly decreased fasting blood glucose and the area under the glucose tolerance curve,significantly increased insulin secretion and improved insulin resistance in HFD/STZ-induced diabetic mice(P<0.05).Inflammatory factors and blood lipid indices were also significantly alleviated after 12 weeks of 40%HB intervention(P<0.05).Additionally,beneficial bacteria,such as Bifidobacterium and Akkermansia,were significantly enriched in the gut of diabetic mice after whole grain HB intervention.Meanwhile,the results of further FMT experiments verified that the fecal microbiota after the 40%HB intervention not only significantly increased the relative abundance of Bifidobacterium and Akkermansia but also effectively improved glucose metabolism and alleviated the inflammatory state in HFD/STZ-induced diabetic mice.Collectively,our study confirmed the bridge role of gut microbiota in improving glucose metabolism of whole grain HB,which could promote the development of precision nutrition.
基金supported by the Postdoctoral Research Funds of Hebei Medical University(30705010016-3759)Natural Science Foundation of China(32272328)+4 种基金Natural Science Foundation of Hebei Province(B2022321001)National Key Research Project of Hebei Province(20375502D)Postdoctoral Research Project of Hebei Province(B2022003031)Science and Technology Research Program of Hebei Provincial Colleges(QN2023229)Hebei Provincial Key Laboratory of Nutrition and Health(2023YDYY-KF05)。
文摘Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.
基金the Ethics Committee of Zhongnan Hospital ofWuhan University(permit number:KELUN2017082 and KELUN2020100)The tissue samples were obtained with written informed consent from each patient.All animal experiments were approved in accordance with the guidelines of the Animal Ethics and Welfare Committee of Wuhan University of Zhongnan Hospital(permit number:ZN2022005).
文摘Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
基金granted by the joint foundation of Luzhou Government and Southwest Medical University(No.2018LZXNYD-ZK05)the Talent Development Project of the Affiliated Hospital of Southwest Medical University.
文摘The glucose metabolism is crucial for sustained brain activity as it provides energy and is a carbon source for multiple biomacromolecules;glucose metabolism decreases dramatically in Alzheimer’s disease(AD)and may be a fundamental cause for its development.Recent studies reveal that the alternative splicing events of certain genes effectively regulate several processes in glucose metabolism including insulin receptor,insulin-degrading enzyme,pyruvate kinase M,receptor for advanced glycation endproducts,and others,thereby,influencing glucose uptake,glycolysis,and advanced glycation end-products-mediated signaling pathways.Indeed,the discovery of aberrant alternative splicing that changes the proteomic diversity and protein activity in glucose metabolism has been pivotal in our understanding of AD development.In this review,we summarize the alternative splicing events of the glucose metabolism-related genes in AD pathology and highlight the crucial regulatory roles of splicing factors in the alternative splicing process.We also discuss the emerging therapeutic approaches for targeting splicing factors for AD treatment.
基金funded by Guangxi Innovation-driven Development 20 Special Foundation Project(No.AA18118049)Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica(19245-1)“the Fundamental Research Funds for the Central Universities”of Nankai University(No.63191723)。
文摘Objective:Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism.It is not clear whether phenolic acids or their metabolites play a major role in vivo.In this study,caffeic acid(CA)and ferulic acid(FA),the two most ingested phenolic acids,and their glucuronic acid metabolites,caffeic-4’-O-glucuronide(CA4G)and ferulic-4’-O-glucuronide(FA4G),were investigated.Methods:Three insulin resistance models in vitro were established by using TNF-a,insulin and palmitic acid(PA)in HepG2 cells,respectively.We compared the effects of FA,FA4G,CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels.The potential targets and related pathways were predicted by network pharmacology.Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target.To investigate the binding mode,molecular docking was performed.Then,we performed membrane recruitment assays of the AKT pleckstrin homology(PH)domain with the help of the PH-GFP plasmid.AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds.Finally,the downstream signaling pathway of AKT was investigated by Western blot analysis.Results:The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption.AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis.The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds.The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site.CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane,while increasing the activity of AKT.Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3βin the AKT signaling pathway to increase glucose consumption.Conclusion:In conclusion,our results suggested that the metabolites of phenolic acids,which contain glucuronic acid,are the key active substances and that they activate AKT by targeting the PH domain,thus improving glucose metabolism.
文摘The gut microflora is a combination of all microbes in intestine and their microenvironment,and its change can sensitively reflect the relevant response of the body to external environment and remarkably affect body's metabolism as well.Recent studies have found that cold exposure affects the body's gut microflora,which can lead to changes in the body's metabolism of glucose and lipid.This review summarizes recent research on the effects of cold exposure on gut microbes and metabolism of glucose and lipid,aiming to provide some new ideas on the approaches and measures for the prevention and treatment of diabetes and obesity.
基金This study is supported by the National Natural Science Foundation of China(No.81672972).
文摘Small cell lung cancer(SCLC)is a highly aggressive tumor type for which limited therapeutic progress has been made.Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment,but most patients with SCLC acquire therapeutic resistance.Given the need for more effective therapies,better elucidation of the molecular pathogenesis of SCLC is imperative.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway is frequently activated in SCLC and strongly associated with resistance to ionizing radiation in many solid tumors.This pathway is an important regulator of cancer cell glucose metabolism,and its activation probably effects radioresistance by influencing bioenergetic processes in SCLC.Glucose metabolism has three main branches-aerobic glycolysis,oxidative phosphorylation,and the pentose phosphate pathway-involved in radioresistance.The interaction between the PI3K/AKT/mTOR pathway and glucose metabolism is largely mediated by hypoxia-inducible factor 1(HIF-1)signaling.The PI3K/AKT/mTOR pathway also influences glucose metabolism through other mechanisms to participate in radioresistance,including inhibiting the ubiquitination of rate-limiting enzymes of the pentose phosphate pathway.This review summarizes our understanding of links among the PI3K/AKT/mTOR pathway,hypoxia,and glucose metabolism in SCLC radioresistance and highlights promising research directions to promote cancer cell death and improve the clinical outcome of patients with this devastating disease.
基金supported by the National Natural Science Foundation of China,Nos.82230042 and 81930029(to ZY),U2004201(to FG and RYP)the China Postdoctoral Science Foundation,No.2020M683748(to RYP)。
文摘Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.
基金National Natural Science Foundation of China,No.82173063 and No.81972220Wuxi Taihu Lake Talent Plan Supporting for Leading Talents in Medical and Health Profession+2 种基金Wuxi Medical Key Discipline,No.ZDXK2021002China Postdoctoral Science Foundation,No.2022M711370Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.KYCX23_2573.
文摘BACKGROUND An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer(CRC).However,no work is currently available to synthesize the field through bibliometrics.AIM To analyze the development in the field of“glucose metabolism”(GM),“amino acid metabolism”(AM),“lipid metabolism”(LM),and“nucleotide metabolism”(NM)in CRC by visualization.METHODS Articles within the abovementioned areas of GM,AM,LM and NM in CRC,which were published from January 1,1991,to December 31,2022,are retrieved from the Web of Science Core Collection and analyzed by CiteSpace 6.2.R4 and VOSviewer 1.6.19.RESULTS The field of LM in CRC presented the largest number of annual publications and the fastest increase in the last decade compared with the other three fields.Meanwhile,China and the United States were two of the most prominent contri-butors in these four areas.In addition,Gang Wang,Wei Jia,Maria Notar-nicola,and Cornelia Ulrich ranked first in publication numbers,while Jing-Yuan Fang,Senji Hirasawa,Wei Jia,and Charles Fuchs were the most cited authors on average in these four fields,respectively.“Gut microbiota”and“epithelial-mesenchymal transition”emerged as the newest burst words in GM,“gut microbiota”was the latest outburst word in AM,“metastasis”,“tumor microenvironment”,“fatty acid metabolism”,and“metabolic reprogramming”were the up-to-date outbreaking words in LM,while“epithelial-mesenchymal transition”and“apoptosis”were the most recently occurring words in NM.CONCLUSION Research in“cellular metabolism in CRC”is all the rage at the moment,and researchers are particularly interested in exploring the mechanism to explain the metabolic alterations in CRC.Targeting metabolic vulnerability appears to be a promising direction in CRC therapy.
文摘BACKGROUND Type 2 diabetes mellitus(T2DM)is a chronic metabolic disease featured by insulin resistance(IR)and decreased insulin secretion.Currently,vitamin D deficiency is found in most patients with T2DM,but the relationship between vitamin D and IR in T2DM patients requires further investigation.AIM To explore the risk factors of IR and the effects of vitamin D supplementation on glucose and lipid metabolism in patients with T2DM.METHODS Clinical data of 162 T2DM patients treated in First Affiliated Hospital of Harbin Medical University between January 2019 and February 2022 were retrospectively analyzed.Based on the diagnostic criteria of IR,the patients were divided into a resistance group(n=100)and a non-resistance group(n=62).Subsequently,patients in the resistance group were subdivided to a conventional group(n=44)or a joint group(n=56)according to the treatment regimens.Logistic regression was carried out to analyze the risk factors of IR in T2DM patients.The changes in glucose and lipid metabolism indexes in T2DM patients with vitamin D deficiency were evaluated after the treatment.RESULTS Notable differences were observed in age and body mass index(BMI)between the resistance group and the non-resistance group(both P<0.05).The resistance group exhibited a lower 25-hydroxyvitamin D_(3)(25(OH)D_(3))level,as well as notably higher levels of 2-h postprandial blood glucose(2hPG),fasting blood glucose(FBG),and glycosylated hemoglobin(HbA1c)than the non-resistance group(all P<0.0001).Additionally,the resistance group demonstrated a higher triglyceride(TG)level but a lower high-density lipoprotein-cholesterol(HDL-C)level than the non-resistance group(all P<0.0001).The BMI,TG,HDL-C,25(OH)D_(3),2hPG,and HbA1c were found to be risk factors of IR.Moreover,the posttreatment changes in levels of 25(OH)D_(3),2hPG,FBG and HbA1c,as well as TG,total cholesterol,and HDL-C in the joint group were more significant than those in the conventional group(all P<0.05).CONCLUSION Patients with IR exhibit significant abnormalities in glucose and lipid metabolism parameters compared to the noninsulin resistant group.Logistic regression analysis revealed that 25(OH)D_(3)is an independent risk factor influencing IR.Supplementation of vitamin D has been shown to improve glucose and lipid metabolism in patients with IR and T2DM.
基金supported by the National Key R&D Program of China(2021YFD1300403)the Major Program of Heilongjiang Province of China(2021ZX12B08-02).
文摘Background Cold regions have long autumn and winter seasons and low ambient temperatures.When pigs are unable to adjust to the cold,oxidative damage and inflammation may develop.However,the differences between cold and non-cold adaptation regarding glucose and lipid metabolism,gut microbiota and colonic mucosal immunological features in pigs are unknown.This study revealed the glucose and lipid metabolic responses and the dual role of gut microbiota in pigs during cold and non-cold adaptation.Moreover,the regulatory effects of dietary glucose supplements on glucose and lipid metabolism and the colonic mucosal barrier were evaluated in cold-exposed pigs.Results Cold and non-cold-adapted models were established by Min and Yorkshire pigs.Our results exhibited that cold exposure induced glucose overconsumption in non-cold-adapted pig models(Yorkshire pigs),decreasing plasma glucose concentrations.In this case,cold exposure enhanced the ATGL and CPT-1αexpression to promote liver lipolysis and fatty acid oxidation.Meanwhile,the two probiotics(Collinsella and Bifidobacterium)depletion and the enrichment of two pathogens(Sutterella and Escherichia-Shigella)in colonic microbiota are not conducive to colonic mucosal immunity.However,glucagon-mediated hepatic glycogenolysis in cold-adapted pig models(Min pigs)maintained the stability of glucose homeostasis during cold exposure.It contributed to the gut microbiota(including the enrichment of the Rikenellaceae RC9 gut group,[Eubacterium]coprostanoligenes group and WCHB1-41)that favored cold-adapted metabolism.Conclusions The results of both models indicate that the gut microbiota during cold adaptation contributes to the protection of the colonic mucosa.During non-cold adaptation,cold-induced glucose overconsumption promotes thermogenesis through lipolysis,but interferes with the gut microbiome and colonic mucosal immunity.Furthermore,glucagon-mediated hepatic glycogenolysis contributes to glucose homeostasis during cold exposure.
文摘Aims: To investigate the relationship among NLRP3 inflammasome, glucose and lipid metabolism, and insulin resistance (IR) in the serum of patients with diabetes and pre-diabetes. Methods: A total of 100 patients with abnormal blood glucose divided into the pre-diabetes mellitus (PDM) group (N = 46) and the type 2 diabetes mellitus (T2DM) group (N = 54). 20 normoglycemic subjects (NG, N = 20) were selected as a control group. The serum levels of glucose and lipid metabolism, IR, and the expression of NLRP3, ASC and Caspase-1 were measured. Besides, the correlations of NLRP3 inflammasome with glucose and lipid metabolism, and IR were analyzed. Results: Compared with the NG group, the levels of NLRP3, ASC, Caspase-1, FBG, HbA<sub>1</sub>C, TG, LDL-C, FINs, and HOMA-IR were higher (P β were lower (P P β were seen (P P β. Regression analysis further showed that blood glucose related indexes, FINs, and NLRP3 have made a decisive contribution to IR. Conclusions: Collectively, this evidence suggested that NLRP3 is closely related to glucose and lipid metabolism, and IR, and activated in PDM and T2DM.
