BACKGROUND The ubiquitin-proteasome pathway(UPP)has been proven to play important roles in cancer.AIM To investigate the prognostic significance of genes involved in the UPP and develop a predictive model for liver ca...BACKGROUND The ubiquitin-proteasome pathway(UPP)has been proven to play important roles in cancer.AIM To investigate the prognostic significance of genes involved in the UPP and develop a predictive model for liver cancer based on the expression of these genes.METHODS In this study,UPP-related E1,E2,E3,deubiquitylating enzyme,and proteasome gene sets were obtained from the Kyoto Encyclopedia of Genes and Genomes(KEGG)database,aiming to screen the prognostic genes using univariate and multivariate regression analysis and develop a prognosis predictive model based RESULTS Five genes(including autophagy related 10,proteasome 20S subunit alpha 8,proteasome 20S subunit beta 2,ubiquitin specific peptidase 17 like family member 2,and ubiquitin specific peptidase 8)were proven significantly correlated with prognosis and used to develop a prognosis predictive model for liver cancer.Among training,validation,and Gene Expression Omnibus sets,the overall survival differed significantly between the high-risk and low-risk groups.The expression of the five genes was significantly associated with immunocyte infiltration,tumor stage,and postoperative recurrence.A total of 111 differentially expressed genes(DEGs)were identified between the high-risk and low-risk groups and they were enriched in 20 and 5 gene ontology and KEGG pathways.Cell division cycle 20,Kelch repeat and BTB domain containing 11,and DDB1 and CUL4 associated factor 4 like 2 were the DEGs in the E3 gene set that correlated with survival.CONCLUSION We have constructed a prognosis predictive model in patients with liver cancer,which contains five genes that associate with immunocyte infiltration,tumor stage,and postoperative recurrence.展开更多
Though there were a lot of reports about the totally different responses to the inhibition of ubiquitin-proteasome pathway in different kinds of cell lines, much less has been known about the responses in primary huma...Though there were a lot of reports about the totally different responses to the inhibition of ubiquitin-proteasome pathway in different kinds of cell lines, much less has been known about the responses in primary human leukemic cells. In this study, the effects of inhibition of ubiquitin-proteasome pathway on human bone marrow (BM) mononuclear cells (MNCs) obtained from 10 normal persons and 8 leukemia patients were examined. The results showed that the responses obviously varied individually. Among them, BM MNCs in 3 cases of leukemic patients were extremely sensitive, demonstrated by that >90% cells were induced to undergo apoptosis within 24 h, but MNCs in 10 cases of normal persons showed resistance to the inhibition and no apoptosis was observed. Furthermore, Western blots revealed that the Bcl-2 expression was relatively high in the sensitive primary leukemia cells, and especially the cleavage of 26 ku Bcl-2 into a 22 ku fragment occurred during the induction of apoptosis. In contrast, the Bcl-2 expression was either undetectable or detectable but no cleavage of that above was observed in the cells insensitive to the inhibition of the pathway (including BM MNCs in normal persons). Together with the observations on the leukemic cell lines, these findings suggested the correlation of the specific cleavage of Bcl-2 into a shortened fragment with the sensitivity of cells to the inhibition of ubiquitin-proteasome pathway, which provides clues to the further understanding of the mechanisms of that dramatically different responses existing in different kinds of cells to the inhibition of ubiquitin-proteasome pathway.展开更多
Diabetic peripheral neuropathy is a common complication of diabetes mellitus.Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies.However,existing limited treatments for diab...Diabetic peripheral neuropathy is a common complication of diabetes mellitus.Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies.However,existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research.Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy,it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods.This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods.Various metabolic mechanisms(e.g.,polyol,hexosamine,protein kinase C pathway)are associated with diabetic peripheral neuropathy,and researchers are looking for more effective treatments through these pathways.展开更多
Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2...Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.展开更多
BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations...BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.展开更多
Purpose: This review article provides the readers with an in-depth insight in understanding and interpreting various research literatures on the masseter vestibular evoked myogenic potentials(mVEMP). The article also ...Purpose: This review article provides the readers with an in-depth insight in understanding and interpreting various research literatures on the masseter vestibular evoked myogenic potentials(mVEMP). The article also reviews the contemporary researches involving the clinical applications of the mVEMP. Conclusions: Masseter VEMP is an evolving yet clinically promising neuro-otology test tool that has recently gained more research interest and is considered an additional tool to diagnose various vestibular disorders. Masseter VEMP assesses the functional integrity of the acoustic-masseteric and vestibulo-masseteric reflex pathways. The mVEMP could be used as a complementary test to evaluate the same peripheral generator as the cervical VEMP but a different central pathway i.e., vestibulo-trigeminal pathway. Various research studies that have experimented on parameters such as the effect of different electrode montages(zygomatic vs mandibular configurations), stimulation rates, filter settings and stimuli used to evoke mVEMP have been discussed in this article that could assist in the optimization of a comprehensive clinical protocol. The latency and the amplitude of mVEMP waveforms serve as significant parameters in differentiating normals from those of the clinical populations. Along with the cVEMPs and oVEMPs, mVEMP might help diagnose brainstem lesions in REM Sleep behaviour disorders, Multiple Sclerosis and Parkinson's disease. However, further studies are required to probe in this area of research.展开更多
Valine is an essential amino acid and a type of branched-chain amino acid. Due to the involvement of branchedchain amino acids in various metabolic pathways, there has been a surge of interests in valine nutrition and...Valine is an essential amino acid and a type of branched-chain amino acid. Due to the involvement of branchedchain amino acids in various metabolic pathways, there has been a surge of interests in valine nutrition and its role in animal physiology. In pigs, the interactions between valine and other branched-chain amino acids or aromatic amino acids are complex. In this review, we delve into the interaction mechanism, metabolic pathways, and biological functions of valine. Appropriate valine supplementation not only enhances growth and reproductive performances, but also modulates gut microbiota and immune functions. Based on past observations and interpretations, we provide recommended feed levels of valine for weaned piglets, growing pigs, gilts, lactating sows, barrows and entire males. The summarized valine nutrient requirements for pigs at different stages offer valuable insights for future research and practical applications in animal husbandry.展开更多
Acute pancreatitis(AP)is a leading cause of gastrointestinal-related hospitalizations in the United States,resulting in 300000 admissions per year with an estimated cost of over$2.6 billion annually.The severity of AP...Acute pancreatitis(AP)is a leading cause of gastrointestinal-related hospitalizations in the United States,resulting in 300000 admissions per year with an estimated cost of over$2.6 billion annually.The severity of AP is determined by the presence of pancreatic complications and end-organ damage.While moderate/severe pancreatitis can be associated with significant morbidity and mortality,the majority of patients have a mild presentation with an uncomplicated course and mortality rate of less than 2%.Despite favorable outcomes,the majority of mild AP patients are admitted,contributing to healthcare cost and burden.In this Editorial we review the performance of an emergency department(ED)pathway for patients with mild AP at a tertiary care center with the goal of reducing hospitalizations,resource utilization,and costs after several years of implementation of the pathway.We discuss the clinical course and outcomes of mild AP patients enrolled in the pathway who were successfully discharged from the ED compared to those who were admitted to the hospital,and identify predictors of successful ED discharge to select patients who can potentially be triaged to the pathway.We conclude that by implementing innovative clinical pathways which are established and reproducible,selected AP patients can be safely discharged from the ED,reducing hospitalizations and healthcare costs,without compromising clinical outcomes.We also identify a subset of patients most likely to succeed in this pathway.展开更多
Background Mastitis is an inflammatory disease of the mammary gland that has serious economic impacts on the dairy industry and endangers food safety.Our previous study found that the body has a gut/rumen-mammary glan...Background Mastitis is an inflammatory disease of the mammary gland that has serious economic impacts on the dairy industry and endangers food safety.Our previous study found that the body has a gut/rumen-mammary gland axis and that disturbance of the gut/rumen microbiota could result in‘gastroenterogenic mastitis'.However,the mechanism has not been fully clarified.Recently,we found that long-term feeding of a high-concentrate diet induced mastitis in dairy cows,and the abundance of Stenotrophomonas maltophilia(S.maltophilia)was significantly increased in both the rumen and milk microbiota.Accordingly,we hypothesized that‘gastroenterogenic mastitis'can be induced by the migration of endogenous gut bacteria to the mammary gland.Therefore,this study investigated the mechanism by which enterogenic S.maltophilia induces mastitis.Results First,S.maltophilia was labelled with superfolder GFP and administered to mice via gavage.The results showed that treatment with S.maltophilia promoted the occurrence of mastitis and increased the permeability of the blood-milk barrier,leading to intestinal inflammation and intestinal leakage.Furthermore,tracking of ingested S.maltophilia revealed that S.maltophilia could migrate from the gut to the mammary gland and induce mastitis.Subsequently,mammary gland transcriptome analysis showed that the calcium and AMPK signalling pathways were significantly upregulated in mice treated with S.maltophilia.Then,using mouse mammary epithelial cells(MMECs),we verified that S.maltophilia induces mastitis through activation of the calcium-ROS-AMPK-mTOR-autophagy pathway.Conclusions In conclusion,the results showed that enterogenic S.maltophilia could migrate from the gut to the mammary gland via the gut-mammary axis and activate the calcium-ROS-AMPK-mTOR-autophagy pathway to induce mastitis.Targeting the gut-mammary gland axis may also be an effective method to treat mastitis.展开更多
Background:Glioblastoma,a notably malignant tumor within the central nervous system,is distinguished by its aggressive behavior.Silvestrol,a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A(eIF4A),...Background:Glioblastoma,a notably malignant tumor within the central nervous system,is distinguished by its aggressive behavior.Silvestrol,a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A(eIF4A),has shown significant potential as an anticancer compound.Yet,the impact of silvestrol on glioblastoma,especially its molecular mechanisms,has not been fully elucidated.Methods:This investigation employed a variety of in vitro assays,such as cell counting kit-8(CCK-8),clonogenic,5-ethynyl-2′-deoxyuridine(EDU),wound healing,and flow cytometry,to evaluate cell cycle progression,apoptosis,cell viability,and migration.Western blot analysis was also performed to study the apoptosis and extracellular regulated kinase(ERK)pathways.After the ERK pathway was inhibited,differentially expressed genes(DEGs)in U87 cells were identified,followed by an analysis of target genes using the gene expression profiling interactive analysis(GEPIA)database.Results:Silvestrol significantly suppressed the proliferation,migration,and colony formation of glioma cells.It caused cell cycle arrest and enhanced apoptosis in these cells.Additionally,silvestrol stimulated the ERK pathway,with these effects being reversible by an ERK phosphorylation inhibitor.Transcriptome combined with GEPIA,GSCA,UALCAN,TIMER database screened 4 potential drug targets of silvestrol:chromosome 1 open reading frame 226(C1ORF226),mannosidase beta A(MANBA),IQ motif and Sec7 domain 2(IQSEC2),neuregulin 1(NRG-1).Among them,C1ORF226 was lower risk gene while MANBA,IQSEC2,and NRG-1 were high-risk genes.Furthermore,silvestrol notably reduced MANBA mRNA levels,which could be reversed by inhibiting ERK phosphorylation.Furthermore,silvestrol markedly decreased NRG-1 protein levels,with an additional reduction observed when the ERK pathway was blocked.Conclusion:Silvestrol’s anti-glioma effects are primarily due to the suppression of MANBA expression via the ERK pathway and possibly by hindering the translation of NRG-1 protein,thus reducing its expression.The downregulation of MANBA and NRG-1 proteins may be crucial in hindering glioma development and progression.These results highlight the intricate relationship between the ERK pathway and gene expression regulation in silvestrol’s therapeutic effectiveness against glioma.展开更多
Objective:To investigate the potential mechanism of Wendan decoction in obesity by screening target genes with promoter region methylation changes and constructing a multiple signaling pathways network based on promot...Objective:To investigate the potential mechanism of Wendan decoction in obesity by screening target genes with promoter region methylation changes and constructing a multiple signaling pathways network based on promoter methylation.Methods:The methylation degree of Itgad,Col8a1,Adra2b,Jund,Rab2a,Wnt8b,Fzd9,B4galt7,Pik3cd,Creb1,Stard8,and Mmp1 in the abdominal adipose tissue of obese rats was determined using the Agena MassARRAY system.Western blot was performed to assess protein expression levels.Target genes were identified based on the methylation degree in the promoter region and protein expression.Enrichment analysis of signaling pathways was conducted to identify relevant target genes and obtain a multiple signaling pathway network associated with obesity.Core and terminal effector molecules in the pathway networks were selected as research targets for reverse transcription-polymerase chain reaction(RT-PCR)analysis.Results:Four genes(Adra2b,Creb1,Itgad,and Pik3cd)showed a degree of promoter methylation consistent with their respective protein expression levels.Among them,Adra2b,Creb1,and Pik3cd expression increased,while that of Itgad decreased.Enrichment analysis revealed that Creb1 and Pik3cd were involved in 6 signaling pathways related to obesity:tumor necrosis factor(TNF)signaling pathway,growth hormone synthesis/secretion and action,adenosine 5'-monophosphate-activated protein kinase(AMPK)signaling pathway,relaxin signaling pathway,cyclic nucleotide(cAMP)signaling pathway,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt)signaling pathway.Subsequently,a multiple signaling pathways network was constructed based on promoter methylation.Key molecules including protein kinase B(AKT),mechanistic target of rapamycin complex 1(mTORC1),and unc-51 like autophagy activating kinase 1(ULK1),as well as terminal effector molecules interleukin-1β(IL-1β),interleukin-6(IL-6),and chemokine(C-X-C motif)ligand 2(CXCL2)were selected as research targets.Wendan decoction decreased the expressions of AKT,mTORC1,IL-1β,IL-6,and CXCL2 while up-regulating ULK1 expression.Conclusion:The mechanism of Wendan decoction in preventing obesity involves the regulation of multiple signaling pathways through the control of Creb1 and Pik3cd gene promoter methylation.However,the associated multi-path gene regulation mechanism in preventing obesity is complex.Thus,further exploration is needed to elucidate the role of methylation changes in this mechanism.展开更多
Fructose and glucose are often widely used in food processing and may contribute to many metabolic diseases.To observe the effects of different doses of glucose and fructose on human metabolism and cellular communicat...Fructose and glucose are often widely used in food processing and may contribute to many metabolic diseases.To observe the effects of different doses of glucose and fructose on human metabolism and cellular communication,volunteers were given low,medium,and high doses of glucose and fructose.Serum cytokines,glucose,lactate,nicotinamide adenine dinucleotide(NADH)and metabolic enzymes were assayed,and central carbon metabolic pathway networks and cytokine communication networks were constructed.The results showed that the glucose and fructose groups basically maintained the trend of decreasing catabolism and increasing anabolism with increasing dose.Compared with glucose,low-dose fructose decreased catabolism and increased anabolism,significantly enhanced the expression of the inflammatory cytokine interferon-γ(IFN-γ),macrophage-derived chemokine(MDC),induced protein-10(IP-10),and eotaxin,and significantly reduced the activity of isocitrate dehydrogenase(ICDH)and pyruvate dehydrogenase complexes(PDHC).Both medium and high doses of fructose increase catabolism and anabolism,and there are more cytokines and enzymes with significant changes.Furthermore,multiple cytokines and enzymes show strong relevance to metabolic regulation by altering the transcription and expression of enzymes in central carbon metabolic pathways.Therefore,excessive intake of fructose should be reduced to avoid excessive inflammatory responses,allergic reactions and autoimmune diseases.展开更多
Cyanidin-3-glucoside(C3G)is the most common anthocyanin in dark grains and berries and is a food functional factor to improve visual health.However,the mechanisms of C3G on blue light-induced retinal pigment epithelia...Cyanidin-3-glucoside(C3G)is the most common anthocyanin in dark grains and berries and is a food functional factor to improve visual health.However,the mechanisms of C3G on blue light-induced retinal pigment epithelial(RPE)cell photooxidative damage needs further exploration.We investigated the effects of C3G on blue light-irradiated A2E-containing RPE cells and explored whether sphingolipid,mitogen-activated protein kinase(MAPK),and mitochondria-mediated pathways are involved in this mechanism.Blue light irradiation led to mitochondria and lysosome damage in RPE cells,whereas C3G preserved mitochondrial morphology and function and maintained the lysosomal integrity.C3G suppressed the phosphorylation of JNK and p38 MAPK and mitochondria-mediated pathways to inhibit RPE cell apoptosis.Lipidomics data showed that C3G protected RPE cells against blue light-induced lipid peroxidation and apoptosis by maintaining sphingolipids balance.C3G significantly inhibited ceramide(Cer d18:0/15:0,Cer d18:0/16:0 and Cer d18:0/18:0)accumulation and elevated galactosylceramide(GalCer d18:1/15:0 and GalCer d18:1/16:0)levels in the irradiated A2E-containing RPE cells.Furthermore,C3G attenuated cell membrane damage by increasing phosphatidylcholine and phosphatidylserine levels.C3G inhibited apoptosis and preserved the structure of mitochondria and lysosome by regulating sphingolipid signaling and suppression of MAPK activation in RPE cells.Thus,dietary supplementation of C3G prevents retinal photooxidative damage.展开更多
Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in ...Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.展开更多
Background:Paclitaxel is a compound derived from Pacific yew bark that induces various cancer cell apoptosis.However,whether it also has anticancer activities in KOSC3 cells,an oral cancer cell line,is unclear.Methods:...Background:Paclitaxel is a compound derived from Pacific yew bark that induces various cancer cell apoptosis.However,whether it also has anticancer activities in KOSC3 cells,an oral cancer cell line,is unclear.Methods:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,flow cytometry,and western blotting assays were carried out to assess cell viability,subG1 phase of the cell cycle,and apoptosis-related protein expression,respectively.Results:Ourfindings indicate that paclitaxel could inhibit cell viability and increase the expression of apoptotic markers,including plasma membrane blebbing and the cleavage of poly ADP-ribose polymerase in KOSC3 cells.Also,the treatment with paclitaxel remarkably elevated the percentage of the subG1 phase in KOSC3 cells.In addition,treatment with a pan-caspase inhibitor could recover paclitaxel-inhibited cell viability.Moreover,caspase-8,caspase-9,caspase-7,and BH3 interacting domain death agonist(Bid)were activated in paclitaxel-treated KOSC3 cells.Conclusions:Paclitaxel induced apoptosis through caspase cascade in KOSC3 cells.展开更多
Hepatocellular carcinoma(HCC),a common malignancy worldwide,still lacks effective clinical treatment.The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms.In our...Hepatocellular carcinoma(HCC),a common malignancy worldwide,still lacks effective clinical treatment.The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms.In our study,we initially confirmed a higher level of PRDX2 in the bile of HCC patients compared to those with choledocholithiasis by 2-DE,LC-MS,and ELISA.Subsequently,we demonstrated the high expression of peroxiredoxin 2(PRDX2)in HCC based on the TCGA database and clinical sample analysis.Furthermore,PRDX2 overexpression enhanced the viability of HCC cells.And PRDX2 silencing induced senescence of HCC cells.In vivo,knockdown of PRDX2 significantly reduced the weight of xenograft tumors.PRDX2 also was found to activate the Wnt/β-catenin pathway by inducingβ-catenin nuclear translocation.Consequently,we proved that silencing PRDX2 could inhibit proliferation and Wnt/β-catenin pathway while promoting senescence in HCC cells.展开更多
Hyperoside and quercetin are similar in molecular structures.In this study,the antioxidant regulatory targets of hyperoside and quercetin are mainly in the nuclear factor(erythroid-2-derived)-related factor 2(Nrf2)pat...Hyperoside and quercetin are similar in molecular structures.In this study,the antioxidant regulatory targets of hyperoside and quercetin are mainly in the nuclear factor(erythroid-2-derived)-related factor 2(Nrf2)pathway predicted by network pharmacology.And the antioxidant effect and mechanism of hyperoside and quercetin were measured and compared in H_(2)O_(2)-induced Hep G2 cells and Caenorhabditis elegans.The findings indicated that quercetin was more effective than hyperoside in reducing oxidative damage,which was proved by improved cell viability,decreased reactive oxygen species(ROS)production,decreased cellular apoptosis,and alleviated mitochondrial damage.In addition,quercetin was more efficient than hyperoside in enhancing the expression of Nrf2-associated m RNAs,increasing the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),and catalase(CAT),and reducing the cellular malondialdehyde(MDA)content.Quercetin was superior to hyperoside in prolonging the lifespan of worms,decreasing the accumulation of lipofuscin,inhibiting ROS production,and increasing the proportion of skn-1 in the nucleus.With the Nrf2 inhibitor ML385,we verified that quercetin and hyperoside primarily protected the cells against oxidative damage via the Nrf2 signalling pathway.Furthermore,molecular docking and dynamics simulations demonstrated that the quercetin-Kelch-like ECH-associated protein 1(Keap1)complex was more stable than the hyperoside-Keap1 complex.The stable structure of the complex might hinder the binding of Nrf2 and Keap1 to release Nrf2 and facilitate its entry into the nucleus to play an antioxidant role.Overall,quercetin had a better antioxidant than hyperoside.展开更多
BACKGROUND Prohibitin 1(PHB1)has been identified as an antiproliferative protein that is highly conserved and ubiquitously expressed,and it participates in a variety of essential cellular functions,including apoptosis...BACKGROUND Prohibitin 1(PHB1)has been identified as an antiproliferative protein that is highly conserved and ubiquitously expressed,and it participates in a variety of essential cellular functions,including apoptosis,cell cycle regulation,prolifera-tion,and survival.Emerging evidence indicates that PHB1 may play an important role in the progression of hepatocellular carcinoma(HCC).However,the role of PHB1 in HCC is controversial.AIM To investigate the effects of PHB1 on the proliferation and apoptosis of human HCC cells and the relevant mechanisms in vitro.METHODS HCC patients and healthy individuals were enrolled in this study according to the inclusion and exclusion criteria;then,PHB1 levels in the sera and liver tissues of these participates were determined using ELISA,RT-PCR,and immunohistoche-mistry.Human HepG2 and SMMC-7721 cells were transfected with the pEGFP-PHB1 plasmid and PHB1-specific shRNA(shRNA-PHB1)for 24-72 h.Cell prolif-eration was analysed with an MTT assay.Cell cycle progression and apoptosis were analysed using flow cytometry(FACS).The mRNA and protein expression levels of the cell cycle-related molecules p21,Cyclin A2,Cyclin E1,and CDK2 and the cell apoptosis-related molecules cytochrome C(Cyt C),p53,Bcl-2,Bax,caspase 3,and caspase 9 were measured by real-time PCR and Western blot,respectively.RESULTS Decreased levels of PHB1 were found in the sera and liver tissues of HCC patients compared to those of healthy individuals,and decreased PHB1 was positively correlated with low differentiation,TNM stage III-IV,and alpha-fetoprotein≥400μg/L.Overexpression of PHB1 significantly inhibited human HCC cell proliferation in a time-dependent manner.FACS revealed that the overexpression of PHB1 arrested HCC cells in the G0/G1 phase of the cell cycle and induced apoptosis.The proportion of cells in the G0/G1 phase was significantly increased and the proportion of cells in the S phase was decreased in HepG2 cells that were transfected with pEGFP-PHB1 compared with untreated control and empty vector-transfected cells.The percentage of apoptotic HepG2 cells that were transfected with pEGFP-PHB1 was 15.41%±1.06%,which was significantly greater than that of apoptotic control cells(3.65%±0.85%,P<0.01)and empty vector-transfected cells(4.21%±0.52%,P<0.01).Similar results were obtained with SMMC-7721 cells.Furthermore,the mRNA and protein expression levels of p53,p21,Bax,caspase 3,and caspase 9 were increased while the mRNA and protein expression levels of Cyclin A2,Cy-clin E1,CDK2,and Bcl-2 were decreased when PHB1 was overexpressed in human HCC cells.However,when PHB1 was upregulated in human HCC cells,Cyt C expression levels were increased in the cytosol and decreased in the mitochondria,which indicated that Cyt C had been released into the cytosol.Conversely,these effects were reversed when PHB1 was knocked down.CONCLUSION PHB1 inhibits human HCC cell viability by arresting the cell cycle and inducing cell apoptosis via activation of the p53-mediated mitochondrial pathway.展开更多
Objective:To observe the effect and possible mechanism of action of Bushen Bitong recipe(BSBT)containing serum on IL-1β-induced chondrocyte apoptosis.Methods:Generation 3 rat chondrocytes were randomized into Control...Objective:To observe the effect and possible mechanism of action of Bushen Bitong recipe(BSBT)containing serum on IL-1β-induced chondrocyte apoptosis.Methods:Generation 3 rat chondrocytes were randomized into Control,IL-1β,IL-1β+BSBT(L),IL-1β+BSBT(M),and IL-1β+BSBT(H)groups(5%,10%and 15%BSBT-containing serum),and then 24h after intervention respectively,the cell proliferation and Apoptosis rate;Western blot detected the expression levels of Bcl-2,BAX,Caspase-3,SOX9,NF-κB p65,MMP-13 proteins in chondrocytes.ELISA detected the levels of TNF-α,IL-6,and bFGF in the supernatants of chondrocyte culture.Results:Compared with Control group,cell proliferation activity decreased,apoptosis rate increased,NF-κB p65,MMP-13 protein level and TNF-α,IL-6 level increased,and SOX9 protein level and bFGF level decreased in IL-1βgroup;compared with IL-1βgroup,different concentrations of BSBT-containing serum group,cell proliferation activity increased,and apoptosis rate decreased.NF-κB p65,MMP-13 protein level and TNF-α,IL-6 level decreased,SOX9 protein level and bFGF level increased;compared with IL-1β+BSBT(L)group,cell proliferation activity increased,apoptosis rate decreased in IL-1β+BSBT(M)and IL-1β+BSBT(H)groups,and NF-κB p65,MMP-13 protein level and TNF-αlevel decreased.13 protein levels and TNF-αand IL-6 levels decreased,and SOX9 protein levels and bFGF levels increased.Conclusion:BSBT-containing serum may promote IL-1β-induced proliferation of chondrocytes,reduce apoptosis,improve the microenvironment of chondrocytes,and promote cartilage repair through the SOX9/NF-κB/MMP-13 signaling pathway.展开更多
Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we...Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.展开更多
基金the Tianjin Municipal Natural Science Foundation,No.21JCYBJC01110。
文摘BACKGROUND The ubiquitin-proteasome pathway(UPP)has been proven to play important roles in cancer.AIM To investigate the prognostic significance of genes involved in the UPP and develop a predictive model for liver cancer based on the expression of these genes.METHODS In this study,UPP-related E1,E2,E3,deubiquitylating enzyme,and proteasome gene sets were obtained from the Kyoto Encyclopedia of Genes and Genomes(KEGG)database,aiming to screen the prognostic genes using univariate and multivariate regression analysis and develop a prognosis predictive model based RESULTS Five genes(including autophagy related 10,proteasome 20S subunit alpha 8,proteasome 20S subunit beta 2,ubiquitin specific peptidase 17 like family member 2,and ubiquitin specific peptidase 8)were proven significantly correlated with prognosis and used to develop a prognosis predictive model for liver cancer.Among training,validation,and Gene Expression Omnibus sets,the overall survival differed significantly between the high-risk and low-risk groups.The expression of the five genes was significantly associated with immunocyte infiltration,tumor stage,and postoperative recurrence.A total of 111 differentially expressed genes(DEGs)were identified between the high-risk and low-risk groups and they were enriched in 20 and 5 gene ontology and KEGG pathways.Cell division cycle 20,Kelch repeat and BTB domain containing 11,and DDB1 and CUL4 associated factor 4 like 2 were the DEGs in the E3 gene set that correlated with survival.CONCLUSION We have constructed a prognosis predictive model in patients with liver cancer,which contains five genes that associate with immunocyte infiltration,tumor stage,and postoperative recurrence.
文摘Though there were a lot of reports about the totally different responses to the inhibition of ubiquitin-proteasome pathway in different kinds of cell lines, much less has been known about the responses in primary human leukemic cells. In this study, the effects of inhibition of ubiquitin-proteasome pathway on human bone marrow (BM) mononuclear cells (MNCs) obtained from 10 normal persons and 8 leukemia patients were examined. The results showed that the responses obviously varied individually. Among them, BM MNCs in 3 cases of leukemic patients were extremely sensitive, demonstrated by that >90% cells were induced to undergo apoptosis within 24 h, but MNCs in 10 cases of normal persons showed resistance to the inhibition and no apoptosis was observed. Furthermore, Western blots revealed that the Bcl-2 expression was relatively high in the sensitive primary leukemia cells, and especially the cleavage of 26 ku Bcl-2 into a 22 ku fragment occurred during the induction of apoptosis. In contrast, the Bcl-2 expression was either undetectable or detectable but no cleavage of that above was observed in the cells insensitive to the inhibition of the pathway (including BM MNCs in normal persons). Together with the observations on the leukemic cell lines, these findings suggested the correlation of the specific cleavage of Bcl-2 into a shortened fragment with the sensitivity of cells to the inhibition of ubiquitin-proteasome pathway, which provides clues to the further understanding of the mechanisms of that dramatically different responses existing in different kinds of cells to the inhibition of ubiquitin-proteasome pathway.
基金supported by the Projects of the National Key R&D Program of China,Nos.2021YFC2400803(to YO),2021YFC2400801(to YQ)the National Natural Science Foundation of China,Nos.82002290(to YQ),82072452(to YO),82272475(to YO)+5 种基金the Young Elite Scientist Sponsorship Program by Cast,No.YESS20200153(to YQ)the Sino-German Mobility Programme,No.M-0699(to YQ)the Excellent Youth Cultivation Program of Shanghai Sixth People’s Hospital,No.ynyq202201(to YQ)the Shanghai Sailing Program,No.20YF1436000(to YQ)the Medical Engineering Co-Project of University of Shanghai for Science and Technology,10-22-310-520(to YO)a grant from Shanghai Municipal Health Commission,No.202040399(to YO).
文摘Diabetic peripheral neuropathy is a common complication of diabetes mellitus.Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies.However,existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research.Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy,it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods.This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods.Various metabolic mechanisms(e.g.,polyol,hexosamine,protein kinase C pathway)are associated with diabetic peripheral neuropathy,and researchers are looking for more effective treatments through these pathways.
基金funded by the National Key Research and Development Program of China(2020YFD0900902)Zhejiang Province Public Welfare Technology Application Research Project(LGJ21C20001)Zhejiang Provincial Key Research and Development Project of China(2019C02076 and 2019C02075)。
文摘Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.
基金Supported by National Natural Science Foundation of China,No.82205025,No.82374355 and No.82174293Subject of Jiangsu Province Hospital of Chinese Medicine,No.Y21023Forth Batch of Construction Program for Inheritance Office of Jiangsu Province Famous TCM Experts,No.[2021]7.
文摘BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.
文摘Purpose: This review article provides the readers with an in-depth insight in understanding and interpreting various research literatures on the masseter vestibular evoked myogenic potentials(mVEMP). The article also reviews the contemporary researches involving the clinical applications of the mVEMP. Conclusions: Masseter VEMP is an evolving yet clinically promising neuro-otology test tool that has recently gained more research interest and is considered an additional tool to diagnose various vestibular disorders. Masseter VEMP assesses the functional integrity of the acoustic-masseteric and vestibulo-masseteric reflex pathways. The mVEMP could be used as a complementary test to evaluate the same peripheral generator as the cervical VEMP but a different central pathway i.e., vestibulo-trigeminal pathway. Various research studies that have experimented on parameters such as the effect of different electrode montages(zygomatic vs mandibular configurations), stimulation rates, filter settings and stimuli used to evoke mVEMP have been discussed in this article that could assist in the optimization of a comprehensive clinical protocol. The latency and the amplitude of mVEMP waveforms serve as significant parameters in differentiating normals from those of the clinical populations. Along with the cVEMPs and oVEMPs, mVEMP might help diagnose brainstem lesions in REM Sleep behaviour disorders, Multiple Sclerosis and Parkinson's disease. However, further studies are required to probe in this area of research.
基金supported by Postdoctoral Innovation Talents’ Support Programthe National Natural Science Foundation of China (32130099)+1 种基金the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project (TSBICIP-CXRC-038)Laboratory of Lingnan Modern Agriculture Project (NT2021005)。
文摘Valine is an essential amino acid and a type of branched-chain amino acid. Due to the involvement of branchedchain amino acids in various metabolic pathways, there has been a surge of interests in valine nutrition and its role in animal physiology. In pigs, the interactions between valine and other branched-chain amino acids or aromatic amino acids are complex. In this review, we delve into the interaction mechanism, metabolic pathways, and biological functions of valine. Appropriate valine supplementation not only enhances growth and reproductive performances, but also modulates gut microbiota and immune functions. Based on past observations and interpretations, we provide recommended feed levels of valine for weaned piglets, growing pigs, gilts, lactating sows, barrows and entire males. The summarized valine nutrient requirements for pigs at different stages offer valuable insights for future research and practical applications in animal husbandry.
文摘Acute pancreatitis(AP)is a leading cause of gastrointestinal-related hospitalizations in the United States,resulting in 300000 admissions per year with an estimated cost of over$2.6 billion annually.The severity of AP is determined by the presence of pancreatic complications and end-organ damage.While moderate/severe pancreatitis can be associated with significant morbidity and mortality,the majority of patients have a mild presentation with an uncomplicated course and mortality rate of less than 2%.Despite favorable outcomes,the majority of mild AP patients are admitted,contributing to healthcare cost and burden.In this Editorial we review the performance of an emergency department(ED)pathway for patients with mild AP at a tertiary care center with the goal of reducing hospitalizations,resource utilization,and costs after several years of implementation of the pathway.We discuss the clinical course and outcomes of mild AP patients enrolled in the pathway who were successfully discharged from the ED compared to those who were admitted to the hospital,and identify predictors of successful ED discharge to select patients who can potentially be triaged to the pathway.We conclude that by implementing innovative clinical pathways which are established and reproducible,selected AP patients can be safely discharged from the ED,reducing hospitalizations and healthcare costs,without compromising clinical outcomes.We also identify a subset of patients most likely to succeed in this pathway.
基金supported by the National Natural Science Foundation of China(32102738,32122087,and 31972749)Scientific research project of Education Department of Jilin Province(No.JJKH20251201KJ)。
文摘Background Mastitis is an inflammatory disease of the mammary gland that has serious economic impacts on the dairy industry and endangers food safety.Our previous study found that the body has a gut/rumen-mammary gland axis and that disturbance of the gut/rumen microbiota could result in‘gastroenterogenic mastitis'.However,the mechanism has not been fully clarified.Recently,we found that long-term feeding of a high-concentrate diet induced mastitis in dairy cows,and the abundance of Stenotrophomonas maltophilia(S.maltophilia)was significantly increased in both the rumen and milk microbiota.Accordingly,we hypothesized that‘gastroenterogenic mastitis'can be induced by the migration of endogenous gut bacteria to the mammary gland.Therefore,this study investigated the mechanism by which enterogenic S.maltophilia induces mastitis.Results First,S.maltophilia was labelled with superfolder GFP and administered to mice via gavage.The results showed that treatment with S.maltophilia promoted the occurrence of mastitis and increased the permeability of the blood-milk barrier,leading to intestinal inflammation and intestinal leakage.Furthermore,tracking of ingested S.maltophilia revealed that S.maltophilia could migrate from the gut to the mammary gland and induce mastitis.Subsequently,mammary gland transcriptome analysis showed that the calcium and AMPK signalling pathways were significantly upregulated in mice treated with S.maltophilia.Then,using mouse mammary epithelial cells(MMECs),we verified that S.maltophilia induces mastitis through activation of the calcium-ROS-AMPK-mTOR-autophagy pathway.Conclusions In conclusion,the results showed that enterogenic S.maltophilia could migrate from the gut to the mammary gland via the gut-mammary axis and activate the calcium-ROS-AMPK-mTOR-autophagy pathway to induce mastitis.Targeting the gut-mammary gland axis may also be an effective method to treat mastitis.
基金This research was supported by the Chongqing Science and Health Joint Medical Research Project(2020FYYX150).
文摘Background:Glioblastoma,a notably malignant tumor within the central nervous system,is distinguished by its aggressive behavior.Silvestrol,a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A(eIF4A),has shown significant potential as an anticancer compound.Yet,the impact of silvestrol on glioblastoma,especially its molecular mechanisms,has not been fully elucidated.Methods:This investigation employed a variety of in vitro assays,such as cell counting kit-8(CCK-8),clonogenic,5-ethynyl-2′-deoxyuridine(EDU),wound healing,and flow cytometry,to evaluate cell cycle progression,apoptosis,cell viability,and migration.Western blot analysis was also performed to study the apoptosis and extracellular regulated kinase(ERK)pathways.After the ERK pathway was inhibited,differentially expressed genes(DEGs)in U87 cells were identified,followed by an analysis of target genes using the gene expression profiling interactive analysis(GEPIA)database.Results:Silvestrol significantly suppressed the proliferation,migration,and colony formation of glioma cells.It caused cell cycle arrest and enhanced apoptosis in these cells.Additionally,silvestrol stimulated the ERK pathway,with these effects being reversible by an ERK phosphorylation inhibitor.Transcriptome combined with GEPIA,GSCA,UALCAN,TIMER database screened 4 potential drug targets of silvestrol:chromosome 1 open reading frame 226(C1ORF226),mannosidase beta A(MANBA),IQ motif and Sec7 domain 2(IQSEC2),neuregulin 1(NRG-1).Among them,C1ORF226 was lower risk gene while MANBA,IQSEC2,and NRG-1 were high-risk genes.Furthermore,silvestrol notably reduced MANBA mRNA levels,which could be reversed by inhibiting ERK phosphorylation.Furthermore,silvestrol markedly decreased NRG-1 protein levels,with an additional reduction observed when the ERK pathway was blocked.Conclusion:Silvestrol’s anti-glioma effects are primarily due to the suppression of MANBA expression via the ERK pathway and possibly by hindering the translation of NRG-1 protein,thus reducing its expression.The downregulation of MANBA and NRG-1 proteins may be crucial in hindering glioma development and progression.These results highlight the intricate relationship between the ERK pathway and gene expression regulation in silvestrol’s therapeutic effectiveness against glioma.
基金supported by the National Natural Science Foundation of China(81960851)Jiangxi Natural Science Foundation(20202BABL206132)Key Research Office of Traditional Chinese Medicine Syndrome Foundation of Jiangxi Administration of Traditional Chinese Medicine(8-4),and Science and Technology Innovation Team Development Program of Jiangxi University of Chinese Medicine(CXTD22016).
文摘Objective:To investigate the potential mechanism of Wendan decoction in obesity by screening target genes with promoter region methylation changes and constructing a multiple signaling pathways network based on promoter methylation.Methods:The methylation degree of Itgad,Col8a1,Adra2b,Jund,Rab2a,Wnt8b,Fzd9,B4galt7,Pik3cd,Creb1,Stard8,and Mmp1 in the abdominal adipose tissue of obese rats was determined using the Agena MassARRAY system.Western blot was performed to assess protein expression levels.Target genes were identified based on the methylation degree in the promoter region and protein expression.Enrichment analysis of signaling pathways was conducted to identify relevant target genes and obtain a multiple signaling pathway network associated with obesity.Core and terminal effector molecules in the pathway networks were selected as research targets for reverse transcription-polymerase chain reaction(RT-PCR)analysis.Results:Four genes(Adra2b,Creb1,Itgad,and Pik3cd)showed a degree of promoter methylation consistent with their respective protein expression levels.Among them,Adra2b,Creb1,and Pik3cd expression increased,while that of Itgad decreased.Enrichment analysis revealed that Creb1 and Pik3cd were involved in 6 signaling pathways related to obesity:tumor necrosis factor(TNF)signaling pathway,growth hormone synthesis/secretion and action,adenosine 5'-monophosphate-activated protein kinase(AMPK)signaling pathway,relaxin signaling pathway,cyclic nucleotide(cAMP)signaling pathway,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt)signaling pathway.Subsequently,a multiple signaling pathways network was constructed based on promoter methylation.Key molecules including protein kinase B(AKT),mechanistic target of rapamycin complex 1(mTORC1),and unc-51 like autophagy activating kinase 1(ULK1),as well as terminal effector molecules interleukin-1β(IL-1β),interleukin-6(IL-6),and chemokine(C-X-C motif)ligand 2(CXCL2)were selected as research targets.Wendan decoction decreased the expressions of AKT,mTORC1,IL-1β,IL-6,and CXCL2 while up-regulating ULK1 expression.Conclusion:The mechanism of Wendan decoction in preventing obesity involves the regulation of multiple signaling pathways through the control of Creb1 and Pik3cd gene promoter methylation.However,the associated multi-path gene regulation mechanism in preventing obesity is complex.Thus,further exploration is needed to elucidate the role of methylation changes in this mechanism.
基金financially supported by National Natural Science Foundation of China(31901782)。
文摘Fructose and glucose are often widely used in food processing and may contribute to many metabolic diseases.To observe the effects of different doses of glucose and fructose on human metabolism and cellular communication,volunteers were given low,medium,and high doses of glucose and fructose.Serum cytokines,glucose,lactate,nicotinamide adenine dinucleotide(NADH)and metabolic enzymes were assayed,and central carbon metabolic pathway networks and cytokine communication networks were constructed.The results showed that the glucose and fructose groups basically maintained the trend of decreasing catabolism and increasing anabolism with increasing dose.Compared with glucose,low-dose fructose decreased catabolism and increased anabolism,significantly enhanced the expression of the inflammatory cytokine interferon-γ(IFN-γ),macrophage-derived chemokine(MDC),induced protein-10(IP-10),and eotaxin,and significantly reduced the activity of isocitrate dehydrogenase(ICDH)and pyruvate dehydrogenase complexes(PDHC).Both medium and high doses of fructose increase catabolism and anabolism,and there are more cytokines and enzymes with significant changes.Furthermore,multiple cytokines and enzymes show strong relevance to metabolic regulation by altering the transcription and expression of enzymes in central carbon metabolic pathways.Therefore,excessive intake of fructose should be reduced to avoid excessive inflammatory responses,allergic reactions and autoimmune diseases.
基金funded by the National Natural Science Foundation of China(31901698)Young Elite Scientists Sponsorship Program by the China Association for Science and Technology(2019QNRC001)。
文摘Cyanidin-3-glucoside(C3G)is the most common anthocyanin in dark grains and berries and is a food functional factor to improve visual health.However,the mechanisms of C3G on blue light-induced retinal pigment epithelial(RPE)cell photooxidative damage needs further exploration.We investigated the effects of C3G on blue light-irradiated A2E-containing RPE cells and explored whether sphingolipid,mitogen-activated protein kinase(MAPK),and mitochondria-mediated pathways are involved in this mechanism.Blue light irradiation led to mitochondria and lysosome damage in RPE cells,whereas C3G preserved mitochondrial morphology and function and maintained the lysosomal integrity.C3G suppressed the phosphorylation of JNK and p38 MAPK and mitochondria-mediated pathways to inhibit RPE cell apoptosis.Lipidomics data showed that C3G protected RPE cells against blue light-induced lipid peroxidation and apoptosis by maintaining sphingolipids balance.C3G significantly inhibited ceramide(Cer d18:0/15:0,Cer d18:0/16:0 and Cer d18:0/18:0)accumulation and elevated galactosylceramide(GalCer d18:1/15:0 and GalCer d18:1/16:0)levels in the irradiated A2E-containing RPE cells.Furthermore,C3G attenuated cell membrane damage by increasing phosphatidylcholine and phosphatidylserine levels.C3G inhibited apoptosis and preserved the structure of mitochondria and lysosome by regulating sphingolipid signaling and suppression of MAPK activation in RPE cells.Thus,dietary supplementation of C3G prevents retinal photooxidative damage.
基金supported by the National Natural Science Foundation of China(81503187)。
文摘Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.
基金The present study was supported by the National Science and Technology Council,Taiwan(MOST-107-2320-B-471-001 to YYL and MOST-110-2320-B-006-025-MY3 to BMH)by An Nan Hospital(ANHRF111-55 to TCC and BMH).
文摘Background:Paclitaxel is a compound derived from Pacific yew bark that induces various cancer cell apoptosis.However,whether it also has anticancer activities in KOSC3 cells,an oral cancer cell line,is unclear.Methods:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,flow cytometry,and western blotting assays were carried out to assess cell viability,subG1 phase of the cell cycle,and apoptosis-related protein expression,respectively.Results:Ourfindings indicate that paclitaxel could inhibit cell viability and increase the expression of apoptotic markers,including plasma membrane blebbing and the cleavage of poly ADP-ribose polymerase in KOSC3 cells.Also,the treatment with paclitaxel remarkably elevated the percentage of the subG1 phase in KOSC3 cells.In addition,treatment with a pan-caspase inhibitor could recover paclitaxel-inhibited cell viability.Moreover,caspase-8,caspase-9,caspase-7,and BH3 interacting domain death agonist(Bid)were activated in paclitaxel-treated KOSC3 cells.Conclusions:Paclitaxel induced apoptosis through caspase cascade in KOSC3 cells.
基金National Nature Science Foundation of China(Nos.81960118,81860115,81760116 and 82060116)Guizhou Science and Technology Project:Qiankehe Foundation(No.(2020)1Y300)+8 种基金Natural Science Foundation of Sichuan(No.2022NSFSC0837)Science and Technology Project of Chengdu(No.2022-YF05-01811-SN)Science and Technology Project of Guizhou Province(No.YQK(2023)032)Guizhou Medical University Doctoral Start-Up Fund(No.gyfybsky-2021-27)Guizhou Medical University Doctoral Start-Up Fund(No.gyfybsky-2021-26)Guizhou Science and Technology Department(No.(2019)1259)Guizhou Science and Technology Department Guizhou Science and Technology Platform Talents(No.(2017)5718)Science and Technology Fund of Guizhou Provincial Health Commission(No.gzwki2021-382)The Affiliated Hospital of Guizhou Medical University Excellent Reserve Talent in 2023(No.gyfyxkrc-2023-06).
文摘Hepatocellular carcinoma(HCC),a common malignancy worldwide,still lacks effective clinical treatment.The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms.In our study,we initially confirmed a higher level of PRDX2 in the bile of HCC patients compared to those with choledocholithiasis by 2-DE,LC-MS,and ELISA.Subsequently,we demonstrated the high expression of peroxiredoxin 2(PRDX2)in HCC based on the TCGA database and clinical sample analysis.Furthermore,PRDX2 overexpression enhanced the viability of HCC cells.And PRDX2 silencing induced senescence of HCC cells.In vivo,knockdown of PRDX2 significantly reduced the weight of xenograft tumors.PRDX2 also was found to activate the Wnt/β-catenin pathway by inducingβ-catenin nuclear translocation.Consequently,we proved that silencing PRDX2 could inhibit proliferation and Wnt/β-catenin pathway while promoting senescence in HCC cells.
基金supported by the Open Project Program of the State Key Laboratory of Food Nutrition and Safety,Tianjin University of Science and Technology(No.SKLFNS-KF-202201)the Open Project of the Key Laboratory of Environmental Pollution Monitoring and Disease Control,Ministry of Education,Guizhou Medical University,China(No.GMU-2022-HJZ-06)。
文摘Hyperoside and quercetin are similar in molecular structures.In this study,the antioxidant regulatory targets of hyperoside and quercetin are mainly in the nuclear factor(erythroid-2-derived)-related factor 2(Nrf2)pathway predicted by network pharmacology.And the antioxidant effect and mechanism of hyperoside and quercetin were measured and compared in H_(2)O_(2)-induced Hep G2 cells and Caenorhabditis elegans.The findings indicated that quercetin was more effective than hyperoside in reducing oxidative damage,which was proved by improved cell viability,decreased reactive oxygen species(ROS)production,decreased cellular apoptosis,and alleviated mitochondrial damage.In addition,quercetin was more efficient than hyperoside in enhancing the expression of Nrf2-associated m RNAs,increasing the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),and catalase(CAT),and reducing the cellular malondialdehyde(MDA)content.Quercetin was superior to hyperoside in prolonging the lifespan of worms,decreasing the accumulation of lipofuscin,inhibiting ROS production,and increasing the proportion of skn-1 in the nucleus.With the Nrf2 inhibitor ML385,we verified that quercetin and hyperoside primarily protected the cells against oxidative damage via the Nrf2 signalling pathway.Furthermore,molecular docking and dynamics simulations demonstrated that the quercetin-Kelch-like ECH-associated protein 1(Keap1)complex was more stable than the hyperoside-Keap1 complex.The stable structure of the complex might hinder the binding of Nrf2 and Keap1 to release Nrf2 and facilitate its entry into the nucleus to play an antioxidant role.Overall,quercetin had a better antioxidant than hyperoside.
基金the Key Research and Development Program of Shaanxi,No.2021SF-227 and No.2020SF-297the Natural Science Basic Research Program of Shaanxi,No.2023-JC-YB-770。
文摘BACKGROUND Prohibitin 1(PHB1)has been identified as an antiproliferative protein that is highly conserved and ubiquitously expressed,and it participates in a variety of essential cellular functions,including apoptosis,cell cycle regulation,prolifera-tion,and survival.Emerging evidence indicates that PHB1 may play an important role in the progression of hepatocellular carcinoma(HCC).However,the role of PHB1 in HCC is controversial.AIM To investigate the effects of PHB1 on the proliferation and apoptosis of human HCC cells and the relevant mechanisms in vitro.METHODS HCC patients and healthy individuals were enrolled in this study according to the inclusion and exclusion criteria;then,PHB1 levels in the sera and liver tissues of these participates were determined using ELISA,RT-PCR,and immunohistoche-mistry.Human HepG2 and SMMC-7721 cells were transfected with the pEGFP-PHB1 plasmid and PHB1-specific shRNA(shRNA-PHB1)for 24-72 h.Cell prolif-eration was analysed with an MTT assay.Cell cycle progression and apoptosis were analysed using flow cytometry(FACS).The mRNA and protein expression levels of the cell cycle-related molecules p21,Cyclin A2,Cyclin E1,and CDK2 and the cell apoptosis-related molecules cytochrome C(Cyt C),p53,Bcl-2,Bax,caspase 3,and caspase 9 were measured by real-time PCR and Western blot,respectively.RESULTS Decreased levels of PHB1 were found in the sera and liver tissues of HCC patients compared to those of healthy individuals,and decreased PHB1 was positively correlated with low differentiation,TNM stage III-IV,and alpha-fetoprotein≥400μg/L.Overexpression of PHB1 significantly inhibited human HCC cell proliferation in a time-dependent manner.FACS revealed that the overexpression of PHB1 arrested HCC cells in the G0/G1 phase of the cell cycle and induced apoptosis.The proportion of cells in the G0/G1 phase was significantly increased and the proportion of cells in the S phase was decreased in HepG2 cells that were transfected with pEGFP-PHB1 compared with untreated control and empty vector-transfected cells.The percentage of apoptotic HepG2 cells that were transfected with pEGFP-PHB1 was 15.41%±1.06%,which was significantly greater than that of apoptotic control cells(3.65%±0.85%,P<0.01)and empty vector-transfected cells(4.21%±0.52%,P<0.01).Similar results were obtained with SMMC-7721 cells.Furthermore,the mRNA and protein expression levels of p53,p21,Bax,caspase 3,and caspase 9 were increased while the mRNA and protein expression levels of Cyclin A2,Cy-clin E1,CDK2,and Bcl-2 were decreased when PHB1 was overexpressed in human HCC cells.However,when PHB1 was upregulated in human HCC cells,Cyt C expression levels were increased in the cytosol and decreased in the mitochondria,which indicated that Cyt C had been released into the cytosol.Conversely,these effects were reversed when PHB1 was knocked down.CONCLUSION PHB1 inhibits human HCC cell viability by arresting the cell cycle and inducing cell apoptosis via activation of the p53-mediated mitochondrial pathway.
基金National Natural Science Foundation of China(No.82360934)Science and Technology Innovation Leading Talents Project of Xinjiang Uygur Autonomous Region(No.2022TSYCLJ0007)+1 种基金Xinjiang Uygur Autonomous Region Key Research and Development Task Special Project(No.2021B03006)Natural Science Foundat ion of Xinj iang Uygur Autonomous Region(No.2022D01C170,2022D01C171)。
文摘Objective:To observe the effect and possible mechanism of action of Bushen Bitong recipe(BSBT)containing serum on IL-1β-induced chondrocyte apoptosis.Methods:Generation 3 rat chondrocytes were randomized into Control,IL-1β,IL-1β+BSBT(L),IL-1β+BSBT(M),and IL-1β+BSBT(H)groups(5%,10%and 15%BSBT-containing serum),and then 24h after intervention respectively,the cell proliferation and Apoptosis rate;Western blot detected the expression levels of Bcl-2,BAX,Caspase-3,SOX9,NF-κB p65,MMP-13 proteins in chondrocytes.ELISA detected the levels of TNF-α,IL-6,and bFGF in the supernatants of chondrocyte culture.Results:Compared with Control group,cell proliferation activity decreased,apoptosis rate increased,NF-κB p65,MMP-13 protein level and TNF-α,IL-6 level increased,and SOX9 protein level and bFGF level decreased in IL-1βgroup;compared with IL-1βgroup,different concentrations of BSBT-containing serum group,cell proliferation activity increased,and apoptosis rate decreased.NF-κB p65,MMP-13 protein level and TNF-α,IL-6 level decreased,SOX9 protein level and bFGF level increased;compared with IL-1β+BSBT(L)group,cell proliferation activity increased,apoptosis rate decreased in IL-1β+BSBT(M)and IL-1β+BSBT(H)groups,and NF-κB p65,MMP-13 protein level and TNF-αlevel decreased.13 protein levels and TNF-αand IL-6 levels decreased,and SOX9 protein levels and bFGF levels increased.Conclusion:BSBT-containing serum may promote IL-1β-induced proliferation of chondrocytes,reduce apoptosis,improve the microenvironment of chondrocytes,and promote cartilage repair through the SOX9/NF-κB/MMP-13 signaling pathway.
基金supported by the Key Project of the National Natural Science Foundation of China,No.81930070(to SF)the National Natural Science Foundation of China,No.81972074(to XY)the Key Program of Natural Science Foundation of Tianjin,No.19JCZDJC34900(to XY)。
文摘Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.