Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The...Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.展开更多
Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung ...Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung cancer potential.We aimed to explore the anti–lung cancer effect of BBR and related mechanisms by targeting the glycogen synthase kinase 3β(GSK3β)/β-catenin pathway.Methods:Lung adenocarcinoma(LUAD)cells A549 and NCI-H1975 were treated with BBR.Results:Our results showed that BBR inhibited cell proliferation by decreasing c-Myc levels and induced cel cycle arrest in the G0/G1 phase by lowering cyclin D1 levels.BBR induced apoptosis by upregulating cleaved caspase 3 levels.BBR inhibited cell migration and invasion by decreasing N-cadherin levels.Furthermore,BBR upregulated the expression of GSK3βprotein and phospho-β-catenin proteins in the cytoplasm,while decreasing the expression ofβ-catenin protein.Next,LUAD cel s were exposed to CHIR-99021(a GSK3βinhibitor).This treatment led to an increase in c-Myc,cyclin D1,andβ-catenin levels at specific concentrations.BBR partially reversed the effects of CHIR-99021.Finally,LUAD cells were treated with CHIR-99021(4μmoL/L)combined with BBR(30 and 60μmoL/L)for 24 h.The expression of programmed death ligand 1(PD-L1)was assessed by Western blot analysis.Jurkat T cells and A549 cel s were cocultured for 24 h to examine the lactate dehydrogenase release rate.Results suggested that BBR suppressed the expression of PD-L1 and heightened the immune lethality of T cells.Conclusions:BBR suppressed the proliferative activity of LUAD cell lines A549 and NCI-H1975 in vitro,induced cell cycle arrest and cancer cel apoptosis in the G0/G1 stage,and repressed the migration and invasion of cancer cells.BBR reduced the PD-L1 protein expression and enhanced T-cell–mediated cytotoxicity.These effects appear to be related to BBR's regulation of the GSK3β/β-catenin pathway.展开更多
Glycogen storage diseases(GSDs)are a group of inherited disorders caused by genetic defects in various enzymes involved in glycogen production or breakdown.Hepatic GSDs often have overlapping clinical features,making ...Glycogen storage diseases(GSDs)are a group of inherited disorders caused by genetic defects in various enzymes involved in glycogen production or breakdown.Hepatic GSDs often have overlapping clinical features,making subtyping or prognostication difficult.With the availability and advancement of next-generation sequencing,definitive molecular diagnosis is now available for most patients,with newer variants being increasingly identified.Molecular diagnosis could help in systematic follow-up,anticipating complications and prognostications.However,the mutations reported in the published literature display wide variations across racial and geographical groups.Hence,natural history,long-term outcome,and genotype-phenotypic correlation studies in patients with various hepatic GSDs are needed for a deeper understanding.Considering the emerging evidence of genetic profiling of patients with hepatic GSDs,including the recent study by Vanduangden et al,this editorial aims to review the various clinical subtypes,the spectrum of genetic mutations,and genotype-phenotype correlations for various hepatic GSDs.展开更多
Peach are a fruit with high nutritional and economic value,but their safety and suitability for diabetic patients have been questioned.This study investigated the effects and potential mechanisms of peach pulp(PP)on t...Peach are a fruit with high nutritional and economic value,but their safety and suitability for diabetic patients have been questioned.This study investigated the effects and potential mechanisms of peach pulp(PP)on type 2 diabetes mellitus(T2DM)in mice induced by a high-fat diet(HFD)combined with streptozotocin(STZ).The results showed that PP alleviated hyperglycemia,hyperlipidemia,hyperuricemia,and tissue dysfunction in T2DM mice through the synergistic effect of nutrients and non-nutrient compounds.Analysis of mRNA expression levels revealed that PP improved glucose metabolism in T2DM mice by promoting glycogen synthesis and inhibiting gluconeogenesis.Furthermore,elevated levels of PP resulted in an increase in acetic acid content following a 4 weeks intervention period.Additionally,it led to the restoration of gut microbiota balance by decreasing the Firmicutes/Bacteroidota(F/B)ratio and enhancing the presence of Romboutsia,Allobaculum,Alloprevotella,and Bacteroides after an 8 weeks intervention.Ultimately,our results suggest that PP may offer advantages for individuals with diabetes.展开更多
Oysters are of the most economically important bivalves worldwide.It has high nutritional value and is regarded as a good source of proteins,lipids,glycogen,and amino acids.C.gigas and C.angulata are allopatric congen...Oysters are of the most economically important bivalves worldwide.It has high nutritional value and is regarded as a good source of proteins,lipids,glycogen,and amino acids.C.gigas and C.angulata are allopatric congeneric dominant oysters that are widely cultivated in the northern and southern coast of China,and have shown remarkable differentiation in the nutritional content.Interspecific hybridization and backcross of the two species are effective ways to improve the nutritional quality of the oyster.Sixteen progenies were constructed based on a 4×4 diallel crosses among broodstock of C.gigas(G),C.angulata(A)and their hybrids GA(H)and AG(R).The glycogen,fatty acids,and amino acids performance of these progenies were evaluated in 22 months after fertilization.The glycogen content of AA was significantly lower than that of the other 15 progenies(P<0.05),while only the GH progeny was significantly higher than the GG(P<0.05),with a heterosis value of 21.06%.The backcross progenies GR exhibited significantly higher saturated fatty acids,eicosapentaenoic acid(EPA),and polyunsaturated fatty acids(PUFAs)content than those of GG(P<0.05),and did not show significant differences from AA.The AA showed significantly higher content of total amino acids(TAAs)than GG(P<0.05).The AH progeny displayed significantly higher taurine(Tau)content than GG(P<0.05),and the heterosis value was 27.88%.Therefore,the backcross breeding was shown an effective way to improve the glycogen,fatty acids,and TAAs of GG,and the glycogen of AA.This study provided useful information to characterize the benefits of backcrossing in nutritional quality,which will facilitate the production of differentiated products and increase the efficiency of the oyster industry.展开更多
Mitochondria are central organelles in cellular metabolism,orchestrating energy production,biosynthetic pathways,and signaling networks.Nicotinamide adenine dinucleotide(NAD+)and its reduced form(NADH)are essential fo...Mitochondria are central organelles in cellular metabolism,orchestrating energy production,biosynthetic pathways,and signaling networks.Nicotinamide adenine dinucleotide(NAD+)and its reduced form(NADH)are essential for mitochondrial metabolism,functioning both as redox coenzymes and as signaling agents that help regulate cellular balance.Thus,while its major role is in energy production,NAD+is widely recognized as a metabolic cofactor and also serves as a substrate for various enzymes involved in cellular signaling,like sirtuins(SIRTs),poly(ADP-ribosyl)polymerases(PARPs),mono(ADP-ribosyl)transferases,and CD38.Sirtuins,a family of NAD+-dependent deacetylases,are critical in this regulatory network.SIRT3 removes acetyl groups from and enhances the activity of key enzymes that participate in fatty acid breakdown,the tricarboxylic acid(TCA)cycle,and the electron transport chain(etc),thereby enhancing mitochondrial efficiency and energy production.Mitochondrial NAD+biosynthesis involves multiple pathways,including the de novo synthesis from tryptophan via the kynurenine and the salvage pathway,which recycles nicotinamide back to NAD+.Moreover,NAD+concentrations influence mitochondrial dynamics such as fusion,fission,and mitophagy,which are essential for preserving mitochondrial integrity and function.NAD+alsomodulates the balance between glycolysis and oxidative phosphorylation,influencing the metabolic flexibility of cells.During NAD+depletion,mainly in metabolic disorders,cells often shift towards anaerobic glycolysis,reducing ATP production efficiency and increasing lactate production.This metabolic shift is associated with various pathophysiological conditions,including insulin resistance,neurodegeneration,and muscle wasting.This reviewexplores themultifaceted functions of NAD+in regulating mitochondrialmetabolism.It highlights the underlying causes and pathological outcomes of disrupted NAD+metabolism while exploring potential therapeutic targets and treatment strategies.展开更多
We read with great interest the recent article by Valenzuela et al.1titled“Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability:Insights from McArdle disease”published in the Journ...We read with great interest the recent article by Valenzuela et al.1titled“Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability:Insights from McArdle disease”published in the Journal of Sport and Health Science The study's exploration of the effects of varying carbohydrate(CHO)doses on exercise capacity in Mc Ardle disease,a condition characterized by complete muscle glycogen unavailability,is a significant contribution to the field of sports science and metabolic disorders.展开更多
The agp gene encoding the ADP-glucose pyrophosphorylase involved in cyanobacterial glycogen synthesis was amplified by PCR. The resulting agp fragment was cloned in plasmid pUC118 to generate plasmid pUCA. Part of the...The agp gene encoding the ADP-glucose pyrophosphorylase involved in cyanobacterial glycogen synthesis was amplified by PCR. The resulting agp fragment was cloned in plasmid pUC118 to generate plasmid pUCA. Part of the fragment within the agp DNA was deleted and replaced by an erythromycin resistance cassette to generate plasmid pUCAE, which was used to transform the Synechocystis sp. PCC 6803 wild-type strain and a mutant with resistance to erythromycin was obtained. PCR analysis of the genomic DNA from the resulting mutant indicated that the appropriate deletion and insertion indeed had occurred. The cell growth and Chl a, glycogen content in the mutant showed difference from those in the wild-type strain. The obtained biomass as well as the Chl a content in the mutant strain was higher than that of the wild-type strain, which suggested that the photosynthesis efficiency in the agp(-) strain was higher than that in the wild-type strain. No glycogen was found in the mutant, providing evidence for the correction of the mutant in physiological level.展开更多
The changes and correlations of muscle pH, glycogen, lactic acid and in- tramuscular fat oxidation in Duroc pigs 10 d after their slaughter, and the effects of different storage temperature and time on Duroc muscle pH...The changes and correlations of muscle pH, glycogen, lactic acid and in- tramuscular fat oxidation in Duroc pigs 10 d after their slaughter, and the effects of different storage temperature and time on Duroc muscle pH value, water loss rate, glycogen, lactic acid and 2-thiobarbituric acid （TBA） were studied. The results showed that during the 10 h after the slaughter, the pH value was decreased rapid- ly, the lactic acid content was increased significantly, while the glycogen and TBA contents were remained stable. At the storage temperature of 4 ℃, storage time showed no significant effects on Duroc muscle pH value and glycogen, lactic acid and TBA contents. At the storage temperature of -20 ℃, storage temperature had significant effects on pH value, while no significant effects on other indicators. The correlation analysis demonstrated that during the 10 h after the slaughter, the TBA content was negatively related to glycogen content （P〈0.05）, but positively related to lactic content （P〈0.05）; the pH value was negatively related to lactic acid content （P〈0.05）. At the storage temperature of 4 ℃, the TBA content was negatively relat- ed to water loss rate （P〈0.01） and lactic acid content （P〈0.05）; the water loss rate was positively related to pH value （P〈0.01） and lactic acid content （P〈0.05）. At the storage temperature of -20 ℃, the TBA content was negatively related to pH value （P〈0.01） and positively related to water loss rate （P〈0.05）; the water loss rate was negatively related to pH value （P〈0.01） and lactic acid content （P〈0.05）.展开更多
In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferatoractivated r...In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferatoractivated receptor gamma, were assessed. It was revealed that quercetin possesses good binding affinity to both targets. Quercetin is a major constituent of methanolic extracts of Phyllanthus emblica fruit. The antihyperglycemic effect of quercetin in streptozotocin(STZ)-induced diabetic rats was examined. The isolated quercetin administered at a dose of 75 mg/kg body weight produced a maximum decrease of14.78% in blood glucose levels in the diabetic rats after 7 days of treatment. Furthermore, quercetin doses of 50 and 75 mg/kg were shown to significantly improve the profiles of triglycerides, high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and total cholesterol at the end of the study in STZ-induced diabetic rats. The administration of quercetin(25, 50, and 75 mg/kg body weight)daily for 28 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and urine sugar levels, with a considerable rise in plasma insulin and hemoglobin levels. Therefore, quercetin is a potential drug with antidiabetic and antihyperglycemic action mediated by changes in the levels of glucose, cholesterol, and triglycerides as indicated by in silico and in vivo studies.展开更多
Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis ...Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.展开更多
Glycogen storage diseases （GSD） are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and gl...Glycogen storage diseases （GSD） are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and glycogen synthesis. The overall GSD incidence is estimated 1 case per 20000-43000 live births. There are over 12 types and they are classified based on the enzyme deficiency and the affected tissue. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. Type I a involves the liver, kidney and intestine （and I b also leukocytes）, and the clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia. Type Ilia involves both the liver and muscle, and lib solely the liver. The liver symptoms generally improve with age. Type IV usually presents in the first year of life, with hepatomegaly and growth retardation. The disease in general is progressive to cirrhosis. Type Ⅵ and Ⅳ are a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia. Type Ⅺ is characterized by hepatic glycogenosis and renal Fanconi syndrome. Type Ⅱ is a prototype of inborn lysosomal storage diseases and involves many organs but primarily the muscle. Types V and Ⅶ involve only the muscle.展开更多
AIM: To investigate the molecular signaling mechanism by which the plant-derived, pentacyclic triterpene maslinic acid(MA) exerts anti-diabetic effects. METHOD: HepG2 cells were stimulated with various concentrations ...AIM: To investigate the molecular signaling mechanism by which the plant-derived, pentacyclic triterpene maslinic acid(MA) exerts anti-diabetic effects. METHOD: HepG2 cells were stimulated with various concentrations of MA. The effects of MA on glycogen phosphorylase a(GPa) activity and the cellular glycogen content were measured. Western blot analyses were performed with anti-insulin receptor β(IRβ), protein kinase B(also known as Akt), and glycogen synthase kinase-3β(GSK3β) antibodies. Activation status of the insulin pathway was investigated using phospho-IRβ, as well as phospho-Akt, and phospho-GSK3β antibodies. The specific PI3-kinase inhibitor wortmannin was added to the cells to analyze the Akt expression. Enzyme-linked immunosorbent assay(ELISA) was used to measure the effect of MA on IRβ auto-phosphorylation. Furthermore, the effect of MA on glycogen metabolism was investigated in C57BL/6J mice fed with a high-fat diet(HFD). RESULTS: The results showed that MA exerts anti-diabetic effects by increasing glycogen content and inhibiting glycogen phosphorylase activity in HepG2 cells. Furthermore, MA was shown to induce the phosphorylation level of IRβ-subunit, Akt, and GSK3β. The MA-induced activation of Akt appeared to be specific, since it could be blocked by wortmannin. Finally, MA treatment of mice fed with a high-fat diet reduced the model-associated adiposity and insulin resistance, and increased the accumulated hepatic glycogen content. CONCLUSION: The results suggested that maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase.展开更多
Insulin resistance is the pathophysiological basis of many diseases.Overcoming early insulin resistance highly significant in prevention diabetes,non-alcoholic fatty liver,and atherosclerosis.The present study aimed a...Insulin resistance is the pathophysiological basis of many diseases.Overcoming early insulin resistance highly significant in prevention diabetes,non-alcoholic fatty liver,and atherosclerosis.The present study aimed at evaluating the therapeutic effects of baicalin on insulin resistance and skeletal muscle ectopic fat storage in high fat diet-induced mice,and exploring the potential molecular mechanisms.Insulin resistance in mice was induced with a high fat diet for 16 weeks.Animals were then treated with three different doses of baicalin(100,200,and 400 mg·kg^(-1)·d^(-1)for 14 weeks.Fasting blood glucose,fasting serum insulin,glucose tolerance test(GTT),insulin tolerance test(ITT),and skeletal muscle lipid deposition were measured.Additionally,the AMP-activated protein kinase/acetyl-CoA carboxylase and protein kinase B/Glycogen synthase kinase 3 beta pathways in skeletal muscle were further evaluated.Baicalin significantly reduced the levels of fasting blood glucose and fasting serum insulin and attenuated high fat diet induced glucose tolerance and insulin tolerance.Moreover,insulin resistance was significantly reversed.Pathological analysis revealed baicalin dose-dependently decreased the degree of the ectopic fat storage in skeletal muscle.The properties of baicalin were mediated,at least in part,by inhibition of the AMPK/ACC pathway,a key regulator of de novo lipogenesis and activation of the Akt/GSK-3β pathway,a key regulator of Glycogen synthesis.These data suggest that baicalin,at dose up to 400 mg·kg^(-1)·d^(-1),is safe and able to attenuate insulin resistance and skeletal muscle ectopic fat storage,through modulating the skeletal muscle AMPK/ACC pathway and Akt/GSK-3β pathway.展开更多
基金supported by the National Natural Science Foundation of China,Nos. 82173806 and U1803281Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science,Nos. 2021-I2M-1-030 and 2022-I2M-2-002Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-JKCS-08 (all to RL)。
文摘Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
基金Supported by a grant from the National Natural Science Foundation of China(no.82174457)。
文摘Background:Lung cancer is one of the deadliest cancers worldwide,creating a pressing need to develop novel drugs that inhibit oncogenic signaling pathways.Numerous studies have shown that berberine(BBR)has anti–lung cancer potential.We aimed to explore the anti–lung cancer effect of BBR and related mechanisms by targeting the glycogen synthase kinase 3β(GSK3β)/β-catenin pathway.Methods:Lung adenocarcinoma(LUAD)cells A549 and NCI-H1975 were treated with BBR.Results:Our results showed that BBR inhibited cell proliferation by decreasing c-Myc levels and induced cel cycle arrest in the G0/G1 phase by lowering cyclin D1 levels.BBR induced apoptosis by upregulating cleaved caspase 3 levels.BBR inhibited cell migration and invasion by decreasing N-cadherin levels.Furthermore,BBR upregulated the expression of GSK3βprotein and phospho-β-catenin proteins in the cytoplasm,while decreasing the expression ofβ-catenin protein.Next,LUAD cel s were exposed to CHIR-99021(a GSK3βinhibitor).This treatment led to an increase in c-Myc,cyclin D1,andβ-catenin levels at specific concentrations.BBR partially reversed the effects of CHIR-99021.Finally,LUAD cells were treated with CHIR-99021(4μmoL/L)combined with BBR(30 and 60μmoL/L)for 24 h.The expression of programmed death ligand 1(PD-L1)was assessed by Western blot analysis.Jurkat T cells and A549 cel s were cocultured for 24 h to examine the lactate dehydrogenase release rate.Results suggested that BBR suppressed the expression of PD-L1 and heightened the immune lethality of T cells.Conclusions:BBR suppressed the proliferative activity of LUAD cell lines A549 and NCI-H1975 in vitro,induced cell cycle arrest and cancer cel apoptosis in the G0/G1 stage,and repressed the migration and invasion of cancer cells.BBR reduced the PD-L1 protein expression and enhanced T-cell–mediated cytotoxicity.These effects appear to be related to BBR's regulation of the GSK3β/β-catenin pathway.
文摘Glycogen storage diseases(GSDs)are a group of inherited disorders caused by genetic defects in various enzymes involved in glycogen production or breakdown.Hepatic GSDs often have overlapping clinical features,making subtyping or prognostication difficult.With the availability and advancement of next-generation sequencing,definitive molecular diagnosis is now available for most patients,with newer variants being increasingly identified.Molecular diagnosis could help in systematic follow-up,anticipating complications and prognostications.However,the mutations reported in the published literature display wide variations across racial and geographical groups.Hence,natural history,long-term outcome,and genotype-phenotypic correlation studies in patients with various hepatic GSDs are needed for a deeper understanding.Considering the emerging evidence of genetic profiling of patients with hepatic GSDs,including the recent study by Vanduangden et al,this editorial aims to review the various clinical subtypes,the spectrum of genetic mutations,and genotype-phenotype correlations for various hepatic GSDs.
基金supported by the Zhejiang Key R&D Program of China(2020C02037)the Ningbo Agricultural Research Program of China(2022S1542022S138).
文摘Peach are a fruit with high nutritional and economic value,but their safety and suitability for diabetic patients have been questioned.This study investigated the effects and potential mechanisms of peach pulp(PP)on type 2 diabetes mellitus(T2DM)in mice induced by a high-fat diet(HFD)combined with streptozotocin(STZ).The results showed that PP alleviated hyperglycemia,hyperlipidemia,hyperuricemia,and tissue dysfunction in T2DM mice through the synergistic effect of nutrients and non-nutrient compounds.Analysis of mRNA expression levels revealed that PP improved glucose metabolism in T2DM mice by promoting glycogen synthesis and inhibiting gluconeogenesis.Furthermore,elevated levels of PP resulted in an increase in acetic acid content following a 4 weeks intervention period.Additionally,it led to the restoration of gut microbiota balance by decreasing the Firmicutes/Bacteroidota(F/B)ratio and enhancing the presence of Romboutsia,Allobaculum,Alloprevotella,and Bacteroides after an 8 weeks intervention.Ultimately,our results suggest that PP may offer advantages for individuals with diabetes.
基金Supported by the Key Research and Development Program of Shandong(No.2022LZGC015)the National Key R&D Program of China(No.2022YFD2400304)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA24030105)the Key Technology Research and Industrialization Demonstration Projects of Qingdao(No.22-3-3-hygg-2-hy)the China Agriculture Research System of MOF and MARA(No.CARS-49)。
文摘Oysters are of the most economically important bivalves worldwide.It has high nutritional value and is regarded as a good source of proteins,lipids,glycogen,and amino acids.C.gigas and C.angulata are allopatric congeneric dominant oysters that are widely cultivated in the northern and southern coast of China,and have shown remarkable differentiation in the nutritional content.Interspecific hybridization and backcross of the two species are effective ways to improve the nutritional quality of the oyster.Sixteen progenies were constructed based on a 4×4 diallel crosses among broodstock of C.gigas(G),C.angulata(A)and their hybrids GA(H)and AG(R).The glycogen,fatty acids,and amino acids performance of these progenies were evaluated in 22 months after fertilization.The glycogen content of AA was significantly lower than that of the other 15 progenies(P<0.05),while only the GH progeny was significantly higher than the GG(P<0.05),with a heterosis value of 21.06%.The backcross progenies GR exhibited significantly higher saturated fatty acids,eicosapentaenoic acid(EPA),and polyunsaturated fatty acids(PUFAs)content than those of GG(P<0.05),and did not show significant differences from AA.The AA showed significantly higher content of total amino acids(TAAs)than GG(P<0.05).The AH progeny displayed significantly higher taurine(Tau)content than GG(P<0.05),and the heterosis value was 27.88%.Therefore,the backcross breeding was shown an effective way to improve the glycogen,fatty acids,and TAAs of GG,and the glycogen of AA.This study provided useful information to characterize the benefits of backcrossing in nutritional quality,which will facilitate the production of differentiated products and increase the efficiency of the oyster industry.
基金A fellowship support from the Golda Meir Fellowship Fund,The Hebrew University of Jerusalem,Israel。
文摘Mitochondria are central organelles in cellular metabolism,orchestrating energy production,biosynthetic pathways,and signaling networks.Nicotinamide adenine dinucleotide(NAD+)and its reduced form(NADH)are essential for mitochondrial metabolism,functioning both as redox coenzymes and as signaling agents that help regulate cellular balance.Thus,while its major role is in energy production,NAD+is widely recognized as a metabolic cofactor and also serves as a substrate for various enzymes involved in cellular signaling,like sirtuins(SIRTs),poly(ADP-ribosyl)polymerases(PARPs),mono(ADP-ribosyl)transferases,and CD38.Sirtuins,a family of NAD+-dependent deacetylases,are critical in this regulatory network.SIRT3 removes acetyl groups from and enhances the activity of key enzymes that participate in fatty acid breakdown,the tricarboxylic acid(TCA)cycle,and the electron transport chain(etc),thereby enhancing mitochondrial efficiency and energy production.Mitochondrial NAD+biosynthesis involves multiple pathways,including the de novo synthesis from tryptophan via the kynurenine and the salvage pathway,which recycles nicotinamide back to NAD+.Moreover,NAD+concentrations influence mitochondrial dynamics such as fusion,fission,and mitophagy,which are essential for preserving mitochondrial integrity and function.NAD+alsomodulates the balance between glycolysis and oxidative phosphorylation,influencing the metabolic flexibility of cells.During NAD+depletion,mainly in metabolic disorders,cells often shift towards anaerobic glycolysis,reducing ATP production efficiency and increasing lactate production.This metabolic shift is associated with various pathophysiological conditions,including insulin resistance,neurodegeneration,and muscle wasting.This reviewexplores themultifaceted functions of NAD+in regulating mitochondrialmetabolism.It highlights the underlying causes and pathological outcomes of disrupted NAD+metabolism while exploring potential therapeutic targets and treatment strategies.
文摘We read with great interest the recent article by Valenzuela et al.1titled“Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability:Insights from McArdle disease”published in the Journal of Sport and Health Science The study's exploration of the effects of varying carbohydrate(CHO)doses on exercise capacity in Mc Ardle disease,a condition characterized by complete muscle glycogen unavailability,is a significant contribution to the field of sports science and metabolic disorders.
文摘The agp gene encoding the ADP-glucose pyrophosphorylase involved in cyanobacterial glycogen synthesis was amplified by PCR. The resulting agp fragment was cloned in plasmid pUC118 to generate plasmid pUCA. Part of the fragment within the agp DNA was deleted and replaced by an erythromycin resistance cassette to generate plasmid pUCAE, which was used to transform the Synechocystis sp. PCC 6803 wild-type strain and a mutant with resistance to erythromycin was obtained. PCR analysis of the genomic DNA from the resulting mutant indicated that the appropriate deletion and insertion indeed had occurred. The cell growth and Chl a, glycogen content in the mutant showed difference from those in the wild-type strain. The obtained biomass as well as the Chl a content in the mutant strain was higher than that of the wild-type strain, which suggested that the photosynthesis efficiency in the agp(-) strain was higher than that in the wild-type strain. No glycogen was found in the mutant, providing evidence for the correction of the mutant in physiological level.
基金Supported by Funds for Swine Innovation Team Construction of Shandong Provincial Modern Agriculture Industry Technology System(SDAIT-06-011-03)Fine Breeds Engineering Project of Shandong Province(2011LZ013-01)China Swine Industry Technology System(CARS-36)~~
文摘The changes and correlations of muscle pH, glycogen, lactic acid and in- tramuscular fat oxidation in Duroc pigs 10 d after their slaughter, and the effects of different storage temperature and time on Duroc muscle pH value, water loss rate, glycogen, lactic acid and 2-thiobarbituric acid （TBA） were studied. The results showed that during the 10 h after the slaughter, the pH value was decreased rapid- ly, the lactic acid content was increased significantly, while the glycogen and TBA contents were remained stable. At the storage temperature of 4 ℃, storage time showed no significant effects on Duroc muscle pH value and glycogen, lactic acid and TBA contents. At the storage temperature of -20 ℃, storage temperature had significant effects on pH value, while no significant effects on other indicators. The correlation analysis demonstrated that during the 10 h after the slaughter, the TBA content was negatively related to glycogen content （P〈0.05）, but positively related to lactic content （P〈0.05）; the pH value was negatively related to lactic acid content （P〈0.05）. At the storage temperature of 4 ℃, the TBA content was negatively relat- ed to water loss rate （P〈0.01） and lactic acid content （P〈0.05）; the water loss rate was positively related to pH value （P〈0.01） and lactic acid content （P〈0.05）. At the storage temperature of -20 ℃, the TBA content was negatively related to pH value （P〈0.01） and positively related to water loss rate （P〈0.05）; the water loss rate was negatively related to pH value （P〈0.01） and lactic acid content （P〈0.05）.
基金the DST-SERB Major Research Project,New Delhi,India[Project File No.SB/YS/LS-109/2014]for funding this projectthe Management of A.V.V.M.Sri Pushpam College(Autonomous)+1 种基金Poondi,and Sharmila Institute of Medicinal Products Research Academy(SIMPRA)Thanjavur,India,for providing necessary facilities and support in carrying out this work
文摘In this study, molecular interactions of the ligands, quercetin, gallic acid, and metformin with various diabetes mellitus-related protein targets, such as glycogen phosphorylase and peroxisome proliferatoractivated receptor gamma, were assessed. It was revealed that quercetin possesses good binding affinity to both targets. Quercetin is a major constituent of methanolic extracts of Phyllanthus emblica fruit. The antihyperglycemic effect of quercetin in streptozotocin(STZ)-induced diabetic rats was examined. The isolated quercetin administered at a dose of 75 mg/kg body weight produced a maximum decrease of14.78% in blood glucose levels in the diabetic rats after 7 days of treatment. Furthermore, quercetin doses of 50 and 75 mg/kg were shown to significantly improve the profiles of triglycerides, high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and total cholesterol at the end of the study in STZ-induced diabetic rats. The administration of quercetin(25, 50, and 75 mg/kg body weight)daily for 28 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and urine sugar levels, with a considerable rise in plasma insulin and hemoglobin levels. Therefore, quercetin is a potential drug with antidiabetic and antihyperglycemic action mediated by changes in the levels of glucose, cholesterol, and triglycerides as indicated by in silico and in vivo studies.
文摘Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.
文摘Glycogen storage diseases （GSD） are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and glycogen synthesis. The overall GSD incidence is estimated 1 case per 20000-43000 live births. There are over 12 types and they are classified based on the enzyme deficiency and the affected tissue. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. Type I a involves the liver, kidney and intestine （and I b also leukocytes）, and the clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia. Type Ilia involves both the liver and muscle, and lib solely the liver. The liver symptoms generally improve with age. Type IV usually presents in the first year of life, with hepatomegaly and growth retardation. The disease in general is progressive to cirrhosis. Type Ⅵ and Ⅳ are a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia. Type Ⅺ is characterized by hepatic glycogenosis and renal Fanconi syndrome. Type Ⅱ is a prototype of inborn lysosomal storage diseases and involves many organs but primarily the muscle. Types V and Ⅶ involve only the muscle.
基金supported by the FundamentalResearch Funds for the Central Universities(No.JKP2011004)
文摘AIM: To investigate the molecular signaling mechanism by which the plant-derived, pentacyclic triterpene maslinic acid(MA) exerts anti-diabetic effects. METHOD: HepG2 cells were stimulated with various concentrations of MA. The effects of MA on glycogen phosphorylase a(GPa) activity and the cellular glycogen content were measured. Western blot analyses were performed with anti-insulin receptor β(IRβ), protein kinase B(also known as Akt), and glycogen synthase kinase-3β(GSK3β) antibodies. Activation status of the insulin pathway was investigated using phospho-IRβ, as well as phospho-Akt, and phospho-GSK3β antibodies. The specific PI3-kinase inhibitor wortmannin was added to the cells to analyze the Akt expression. Enzyme-linked immunosorbent assay(ELISA) was used to measure the effect of MA on IRβ auto-phosphorylation. Furthermore, the effect of MA on glycogen metabolism was investigated in C57BL/6J mice fed with a high-fat diet(HFD). RESULTS: The results showed that MA exerts anti-diabetic effects by increasing glycogen content and inhibiting glycogen phosphorylase activity in HepG2 cells. Furthermore, MA was shown to induce the phosphorylation level of IRβ-subunit, Akt, and GSK3β. The MA-induced activation of Akt appeared to be specific, since it could be blocked by wortmannin. Finally, MA treatment of mice fed with a high-fat diet reduced the model-associated adiposity and insulin resistance, and increased the accumulated hepatic glycogen content. CONCLUSION: The results suggested that maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase.
基金supported by a grant provided by Southeast University(No.9224007044)
文摘Insulin resistance is the pathophysiological basis of many diseases.Overcoming early insulin resistance highly significant in prevention diabetes,non-alcoholic fatty liver,and atherosclerosis.The present study aimed at evaluating the therapeutic effects of baicalin on insulin resistance and skeletal muscle ectopic fat storage in high fat diet-induced mice,and exploring the potential molecular mechanisms.Insulin resistance in mice was induced with a high fat diet for 16 weeks.Animals were then treated with three different doses of baicalin(100,200,and 400 mg·kg^(-1)·d^(-1)for 14 weeks.Fasting blood glucose,fasting serum insulin,glucose tolerance test(GTT),insulin tolerance test(ITT),and skeletal muscle lipid deposition were measured.Additionally,the AMP-activated protein kinase/acetyl-CoA carboxylase and protein kinase B/Glycogen synthase kinase 3 beta pathways in skeletal muscle were further evaluated.Baicalin significantly reduced the levels of fasting blood glucose and fasting serum insulin and attenuated high fat diet induced glucose tolerance and insulin tolerance.Moreover,insulin resistance was significantly reversed.Pathological analysis revealed baicalin dose-dependently decreased the degree of the ectopic fat storage in skeletal muscle.The properties of baicalin were mediated,at least in part,by inhibition of the AMPK/ACC pathway,a key regulator of de novo lipogenesis and activation of the Akt/GSK-3β pathway,a key regulator of Glycogen synthesis.These data suggest that baicalin,at dose up to 400 mg·kg^(-1)·d^(-1),is safe and able to attenuate insulin resistance and skeletal muscle ectopic fat storage,through modulating the skeletal muscle AMPK/ACC pathway and Akt/GSK-3β pathway.
