Hypoglycemic mechanism of Tegillarca granosa polysaccharides on type 2 diabetic mice by altering gut microbiota and regulating the PI3K-akt signaling pathwaye

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.

Melatonin improves synapse development by PI3K/Akt signaling in a mouse model of autism spectrum disorder

Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.

Zuo Gui Wan Promotes Osteogenesis via PI3K/AKT Signaling Pathway:Network Pharmacology Analysis and Experimental Validation

Objective Osteogenesis is vitally important for bone defect repair,and Zuo Gui Wan(ZGW)is a classic prescription in traditional Chinese medicine(TCM)for strengthening bones.However,the specific mechanism by which ZGW regulates osteogenesis is still unclear.The current study is based on a network pharmacology analysis to explore the potential mechanism of ZGW in promoting osteogenesis.Methods A network pharmacology analysis followed by experimental validation was applied to explore the potential mechanisms of ZGW in promoting the osteogenesis of bone marrow mesenchymal stem cells(BMSCs).Results In total,487 no-repeat targets corresponding to the bioactive components of ZGW were screened,and 175 target genes in the intersection of ZGW and osteogenesis were obtained.And 28 core target genes were then obtained from a PPI network analysis.A GO functional enrichment analysis showed that the relevant biological processes mainly involve the cellular response to chemical stress,metal ions,and lipopolysaccharide.Additionally,KEGG pathway enrichment analysis revealed that multiple signaling pathways,including the phosphatidylinositol-3-kinase/protein kinase B(PI3K/AKT)signaling pathway,were associated with ZGW-promoted osteogensis.Further experimental validation showed that ZGW could increase alkaline phosphatase(ALP)activity as well as the mRNA and protein levels of ALP,osteocalcin(OCN),and runt related transcription factor 2(Runx 2).What’s more,Western blot analysis results showed that ZGW significantly increased the protein levels of p-PI3K and p-AKT,and the increases of these protein levels significantly receded after the addition of the PI3K inhibitor LY294002.Finally,the upregulated osteogenic-related indicators were also suppressed by the addition of LY294002.Conclusion ZGW promotes the osteogenesis of BMSCs via PI3K/AKT signaling pathway.

FGF2 promotes the chemotherapy resistance in colon cancer cells through activating PI3K/Akt signaling pathway

Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected in a sensitive cell group(HCT116)and a resistant cell group(HCT1116-R)using different methods.Fibroblast growth factor 2 levels in the medium were determined by enzyme-linked immunoassay.The protein expressions of FGF2,fibroblast growth factor receptor 1(FGFR1),and phospho-FGFR1 were assessed by Western blotting,and FGF2 mRNA levels were detected by quantitative real-time polymerase chain reaction.Fibroblast growth factor 2 recombinant protein was added to sensitive cells,and FGFR inhibitor AZD4547 was added to resistant cells,and the cell survival rate was determined using the cell counting kit-8 method and the protein expressions of PI3K(phosphatidylinositol 3 kinase),p-PI3K(phospho-PI3K),Akt(protein kinase B),p-Akt(phospho-Akt),mammalian target of rapamycin(mTOR),p-mTOR(phospho-mTOR),Bad(Bcl-xL/Bcl-2-associated death promoter),NF-κB(nuclear factorκB),GSK-3(glycogen synthase kinase-3),FKHR(forkhead box protein O1),and PTEN(phosphatase and tensin homolog deleted on chromosome ten)were detected by Western blotting.Results:Fibroblast growth factor 2 protein and mRNA expression levels in the HCT116-R group were significantly higher than those in the HCT116 group.Fibroblast growth factor 2 increased the survival rate of HCT116 cells;improved tolerance to 5-FU;upregulated p-PI3K,p-Akt,and p-mTOR;and downregulated Bad.The FGFR inhibitor AZD4547 decreased cell survival rate and tolerance to 5-FU;downregulated p-PI3K,p-Akt,and p-mTOR expression;and upregulated Bad.Conclusions:Fibroblast growth factor 2 promotes chemotherapy tolerance in colon cancer cells by activating the Akt/mTOR and Akt/Bad signaling pathways downstream of PI3K.

The effects of hormone-mediated PI3K/AKT signaling on spermatogenesis in Sertoli cells

The phosphoinositide-3-kinase/Akt(PI3K/AKT)signaling pathway is crucial for Sertoli cell development and completing spermatogenesis.Its main role is to promote proliferation and inhibit apoptosis.Many factors activate the PI3K/AKT pathway,like hormones,such as follicle stimulating hormone(FSH),androgen,estrogen,insulin to name a few.Many of these factors have receptors inside or on the surface of Sertoli cells(SCs).This review summarizes how these hormones directly regulate the PI3K/AKT signaling pathway in SCs,which in turn affects SC proliferation and differentiation.Further,hormone-mediated PI3K/AKT signaling also stimulates SC secretion,which is essential for germ cell development,suggesting an indirect role of PI3K/AKT signaling during spermatogenesis.These functions include promoting spermatogonia proliferation and differentiation,meiosis of spermatocytes,sperm maturation,and their release.This review also provides potential hints for clinically treating male infertility issues like cryptorchidism and Sertoli cell-only syndrome.

XB130 inhibits healing of diabetic skin ulcers through the PI3K/Akt signalling pathway

BACKGROUND Diabetic skin ulcers,a significant global healthcare burden,are mainly caused by the inhibition of cell proliferation and impaired angiogenesis.XB130 is an adaptor protein that regulates cell proliferation and migration.However,the role of XB130 in the development of diabetic skin ulcers remains unclear.AIM To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose.Additionally,we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers,along with its molecular mechanisms.METHODS We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers.We investigated the effects of XB130 on wound healing using histological analyses.In addition,we used reverse transcription-quantitative polymerase chain reaction,Western blot,terminal deoxynucleotidyl transferasemediated dUTP nick end labeling staining,immunofluorescence,wound healing,and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells(HUVECs)stimulated with high glucose.Finally,we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers.RESULTS RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers.Knockdown of XB130 promoted the healing of skin wounds in mice,leading to an accelerated wound healing process and shortened wound healing time.At the cellular level,knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs.Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130.CONCLUSION The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs.Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway,which accelerates the healing of diabetic skin ulcers.

Simiao Wan alleviates obesity-associated insulin resistance via PKCε/IRS-1/PI3K/Akt signaling pathway based on network pharmacology analysis and experimental validation

Background:The purpose of the study was to investigatethe active ingredients and potential biochemicalmechanisms of Simiao Wan(SMW)in obesity-associated insulin resistance.Methods:An integrated network pharmacology method to screen the active compoundsand candidate targets,construct the protein-protein-interaction network,and ingredients-targets-pathways network was constructed for topological analysis to identify core targets and main ingredients.To find the possible signaling pathways,enrichment analysis was performed.Further,a model of insulin resistance in HL-7702 cells was established to verify the impact of SMW and the regulatory processes.Results:An overall of 63 active components and 151 candidate targets were obtained,in which flavonoids were the main ingredients.Enrichment analysis indicated that the PI3K-Akt signaling pathway was the potential pathway regulated by SMW in obesity-associated insulin resistance treatment.The result showed that SMW could significantly ameliorate insulin sensitivity,increase glucose synthesis and glucose utilization and reduce intracellular lipids accumulation in hepatocytes.Also,SMW inhibited diacylglycerols accumulation-induced PKCεactivity and decreased its translocation to the membrane.Conclusion:SMW ameliorated obesity-associated insulin resistance through PKCε/IRS-1/PI3K/Akt signaling axis in hepatocytes,providing a new strategy for metabolic disease treatment.

The role and research progress of PI3K/AKT signaling pathway in non-traumatic osteonecrosis of the femoral head

Non-traumatic osteonecrosis of the femoral head(NONFH)is one of the most common orthopedic diseases,influenced by multiple signaling pathways and inflammatory factors.The PI3K/AKT signaling pathway is closely related to various biological processes such as apoptosis,autophagy,and metabolism in cells.Increasing evidence suggests that it plays an important role in the development of femoral head necrosis.This paper aims to explore the mechanism of the PI3K/AKT signaling pathway in the pathogenesis of NONFH by analyzing its regulation of lipid metabolism,cell apoptosis and autophagy,and intravascular coagulation.This study provides new insights for the research of NONFH.

Jiao-tai-wan Up-regulates Hypothalamic and Peripheral Circadian Clock Gene Cryptochrome and Activates PI3K/AKT Signaling in Partially Sleep-deprived Rats

This study aims to explore the effect and mechanism of Jiao-tai-wan （JTW） on systemic and tissue-specific inflammation and insulin resistance in obesity-resistant （OR） rats with chronic partial sleep deprivation （PSD）. OR rats with PSD were orally given JTW and Estazolam for 4 weeks. The amount of food intake and metabolic parameters such as body weight increase rate, fasting plasma glucose （FPG）, fasting insulin （FINS）, homeostasis model assessment-insulin resistance （HOMA-IR） and plasma inflammatory markers were measured. The expression levels of circadian proteins cryptochrome 1 （Cryl） and cryptochrome 2 （Cry2） in hypothalamus, adipose and liver tissues were also determined. Meanwhile, the mRNA expression of inflammatory markers, activity of nuclear factor kappa B （NF-κB） p65 protein, as well as the expression levels of insulin signaling pathway proteins in hypothalamus, adipose and liver tissues were measured. Additionally, cyclic adenosine 3＇, 5＇-monophosphate （cAMP） and activity of vasodilator-stimulated phosphoprotein （VASP） in hypothalamus tissue were measured. JTW significantly decreased the body weight increase rate and food intake, ameliorated systemic inflammation and insulin resistance. JTW effectively ameliorated inflammation and increased PI3K/AKT signaling activation in hypothalamus, adipose and liver. Interestingly, all these changes were associated with the up-regulation of circadian gene Cryl and Cry2 protein expression. We also found that in hypothalamus tissue of PSD rats, down-regulation of Cryl and Cry2 activated cAMP/PKA signaling and then led to inflammation, while JTW inhibited this signaling. These results suggested that JTW has the beneficial effect on ameliorating inflammation and insulin resistance in partially sleep-deprived rats by up-regulating Cry expression.

Baicalin attenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury

Baicalin is a natural active ingredient isolated from Scutellariae Radix that can cross the blood-brain barrier and exhibits neuroprotective effects on multiple central nervous system diseases.However,the mechanism behind the neuroprotective effects remains unclear.In this study,rat models of spinal cord injury were established using a modified Allen's impact method and then treated with intraperitoneal injection of Baicalin.The results revealed that Baicalin greatly increased the Basso,Beattie,Bresnahan Locomotor Rating Scale score,reduced blood-spinal cord barrier permeability,decreased the expression of Bax,Caspase-3,and nuclear factorκB,increased the expression of Bcl-2,and reduced neuronal apoptosis and pathological spinal cord injury.SH-SY5 Y cell models of excitotoxicity were established by application of 10 m M glutamate for 12 hours and then treated with 40μM Baicalin for 48 hours to investigate the mechanism of action of Baicalin.The results showed that Baicalin reversed tight junction protein expression tendencies(occludin and ZO-1)and apoptosis-related protein expression(Bax,Bcl-2,Caspase-3,and nuclear factor-κB),and also led to up-regulation of PI3 K and Akt phosphorylation.These effects on Bax,Bcl-2,and Caspase-3 were blocked by pretreatment with the PI3 K inhibitor LY294002.These findings suggest that Baicalin can inhibit bloodspinal cord barrier permeability after spinal cord injury and reduce neuronal apoptosis,possibly by activating the PI3 K/Akt signaling pathway.This study was approved by Animal Ethics Committee of Xi'an Jiaotong University on March 6,2014.

Sericin can reduce hippocampal neuronal apoptosis by activating the Akt signal transduction pathway in a rat model of diabetes mellitus

In the present study, a rat model of type 2 diabetes mellitus was established by continuous peritoneal injection of streptozotocin. Following intragastric perfusion of sericin for 35 days, blood glucose levels significantly reduced, neuronal apoptosis in the hippocampal CA1 region decreased, hippocampal phosphorylated Akt and nuclear factor kappa B expression were enhanced, but Bcl-xL/Bcl-2 associated death promoter expression decreased. Results demonstrated that sericin can reduce hippocampal neuronal apoptosis in a rat model of diabetes mellitus by regulating abnormal changes in the Akt signal transduction pathway.

Scoparone inhibits pancreatic cancer through PI3K/Akt signaling pathway

BACKGROUND Pancreatic cancer is a highly malignant tumor of the gastrointestinal system whose emerging resistance to chemotherapy has necessitated the development of novel antitumor treatments.Scoparone,a traditional Chinese medicine monomer with a wide range of pharmacological properties,has attracted considerable attention for its antitumor activity.AIM To explore the potential antitumor effect of scoparone on pancreatic cancer and the possible molecular mechanism of action.METHODS The target genes of scoparone were determined using both the bioinformatics and multiplatform analyses.The effect of scoparone on pancreatic cancer cell proliferation,migration,invasion,cell cycle,and apoptosis was detected in vitro.The expression of hub genes was tested using quantitative reverse transcription polymerase chain reaction(qRT-PCR),and the molecular mechanism was analyzed using Western blot.The in vivo effect of scoparone on pancreatic cancer cell proliferation was detected using a xenograft tumor model in nude mice as well as immunohistochemistry.RESULTS The hub genes involved in the suppression of pancreatic cancer by scoparone were obtained by network bioinformatics analyses using publicly available databases and platforms,including SwissTargetPrediction,STITCH,GeneCards,CTD,STRING,WebGestalt,Cytoscape,and Gepia;AKT1 was confirmed using qRT-PCR to be the hub gene.Cell Counting Kit-8 assay revealed that the viability of Capan-2 and SW1990 cells was significantly reduced by scoparone treatment exhibiting IC50 values of 225.2μmol/L and 209.1μmol/L,respectively.Wound healing and transwell assays showed that scoparone inhibited the migration and invasion of pancreatic cancer cells.Additionally,flow cytometry confirmed that scoparone caused cell cycle arrest and induced apoptosis.Scoparone also increased the expression levels of Bax and cleaved caspase-3,decreased the levels of MMP9 and Bcl-2,and suppressed the phosphorylation of Akt without affecting total PI3K and Akt.Moreover,compared with the control group,xenograft tumors,in the 200μmol/L scoparone treatment group,were smaller in volume and lighter in weight,and the percentages of Ki65-and PCNA-positive cells were decreased.CONCLUSION Our findings indicate that scoparone inhibits pancreatic cancer cell proliferation in vitro and in vivo,inhibits migration and invasion,and induces cycle arrest and apoptosis in vitro through the PI3K/Akt signaling pathway.

Panax notogiseng saponin inhibits ischemia-induced apoptosis by activating PI3K/Akt signal pathway in cardiomyocytes

The panax notoginseng saponin(PNS) had been clinically used for the treatment of cardiovascular diseases and stroke in China.It had been demonstrated that PNS could protect cardiomyocytes from injury induced by ischemi- a,but the underlying molecular mechanisms of this protective effect were still unclear.This study was aimed to investigate the protective effect and molecular mechanisms of PNS on apoptosis in H9c2 cells in vitro and rat myocardial ischemia injury model in vivo.Annexin-V/PI assay shew that PNS could protect H9c2 cells from apoptosis induced by serum, glucose and oxygen deprivation(SGOD) in a dose-dependent manner.However,the anti-apoptotic effect of PNS was reversed by LY294002,a specific PI3K inhibitor.This antiapoptotic effect of PNS was confirmed by JC-1,a specific probe of mitochondrial membrane potential staining.PNS could significantly increase phos-Akt in H9c2 cells by Western blot assays and its effect could be inhibited by LY294002.Furthermore,PNS could improve ischemic-induced left ventricular function as reflected by EF,LVDd and LVDs.PNS could also inhibited cellular apoptosis in myocardial tissues in ischemic rats by TUNEL assay.PNS administration also increased the expression of phos-Akt in rat ischemic myocardial tissues.These results suggested that PNS could protect myocardial cells from apoptosis induced by ischemia in vitro model and in vivo model through activating-PI3K/Akt signal pathway which may be meaningful for further understanding the molecular mechanisms of cardiac protection of PNS.And the results might be useful in treatment of myocardial ischemia in future.

Sulforaphane modulates TGFβ2-induced conjunctival fibroblasts activation and fibrosis by inhibiting PI3K/Akt signaling

AIM:To examine the effects of sulforaphane on fibrotic changes of transforming growth factor(TGFβ2)induced human conjunctival fibroblast(HCon Fs).METHODS:HCon Fs were cultured and divided into control,TGFβ2(1 ng/m L),sulforaphane and TGFβ2+sulforaphane groups.Cell viability and apoptosis were detected using the MTT and Apo Tox-Glo Triplex assay.Cell migration was detected using scratch and Transwell assay.Real-time quantitative PCR method was used to evaluate m RNA expression of TGFβ2,matrix metalloproteinase-2(MMP2),myosin light chain kinase(MYLK),integrinαV,integrinα5,fibronectin 1 andα-smooth muscle actin(α-SMA).The protein expression ofα-SMA,p-PI3 K,PI3 K,p-Akt,and Akt were detected by Western blot.RESULTS:The proliferation of HCon Fs was significantly(P<0.05)suppressed by sulforaphane compared to control cells with the increase of the concentration and treatment time.Cell proliferation after 48 h incubation was significantly reduced with 100μmol/L sulforaphane treatment by 17.53%(P<0.05).The Transwell assay showed sulforaphane decreased cell migration by 18.73%compared with TGFβ2-induced HCon F(P<0.05).TGFβ2-induced the increasing expression of fibronectin,type I collagen andα-SMA,and the phosphorylation of PI3 K and Akt were all significantly suppressed by sulforaphane pretreatment.CONCLUSION:Sulforaphane inhibits proliferation,migration,and synthesis of the extracellular matrix in HCon Fs,and inhibiting the PI3 K/Akt signaling pathway.Sulforaphane could be a potential therapeutic drug for prevention of scar formation in filtering bleb after trabeculectomy.

Pretreatment with intestinal trefoil factor alleviates stress-induced gastric mucosal damage via Akt signaling

BACKGROUND Stress-related gastric mucosal damage or ulcer remains an unsolved issue for critically ill patients.Stress ulcer prophylaxis has been part of routine intensive care,but uncertainty and controversy still exist.Co-secreted with mucins,intestinal trefoil factor(ITF)is reported to promote restitution and regeneration of intestinal mucosal epithelium,although the mechanism remains unknown.AIM To elucidate the protective effects of ITF on gastric mucosa and explore the possible mechanisms.METHODS We used a rat model of gastric mucosal damage induced by water immersion restraint stress and lipopolysaccharide-treated human gastric epithelial cell line to investigate the potential effects of ITF on damaged gastric mucosa both in vivo and in vitro.RESULTS ITF promoted the proliferation and migration and inhibited necrosis of gastric mucosal epithelia in vitro.It also preserved the integrity of gastric mucosa by upregulating expressions of occludin and zonula occludens-1.In the rat model,pretreatment with ITF ameliorated the gastric mucosal epithelial damage and facilitated mucosal repair.The protective effects of ITF were confirmed to be exerted via activation of Akt signaling,and the specific inhibitor of Akt signaling LY249002 reversed the protective effects.CONCLUSION ITF might be a promising candidate for prevention and treatment of stressinduced gastric mucosal damage,and further studies should be undertaken to verify its clinical feasibility.

Experimental Study on the Effect of Acupuncture on ERM/PI3/Akt Signal Pathway in Rats with Ischemic Stroke

Objective: To observe the effect of acupuncture on the expression of ERM/PI3K/Akt signaling pathway in the brain tissue around the infarct focus of ischemic stroke model rats. Methods: According to the block randomization method, 80 male SD rats were divided into normal group (n = 10), sham operation group (n = 24), model group (n = 23) and acupuncture group (n = 23). The normal group was bred routinely without any intervention. In the sham operation group, only the skin was cut to find and the nerves and blood vessels were stripped and sutured. The model group and the acupuncture group were sutured to prepare the MCAO model. After the model was successfully established, acupuncture of the acupuncture group rats was given once a day, and the needles were kept for 30 minutes each time. The rats in the sham operation group and the model group only imitated capture and return, and were treated with acupuncture for 2 consecutive courses, each course was 5 days, and the two courses were rested for 2 days. After that, Western blot was used to detect ERM, changes in the concentration of PI3K and Akt proteins. Results: Compared with the normal group, the expression levels of ERM, PI3K, and Akt proteins in the sham operation group were reduced. Compared with the sham operation group, the expression levels of ERM, PI3K, and Akt proteins in the model group were significantly down-regulated. Compared with the model group, the protein expression levels of ERM, PI3K and Akt were significantly up-regulated in the acupuncture group, and the difference was statistically significant (P < 0.05). Conclusion: Acupuncture can significantly up-regulate the expression of ERM, PI3K and Akt proteins, and its effect mechanism may be related to the transduction of ERM/PI3K/Akt signaling pathway in cells.

Pancreas-specific Pten deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling

PTEN， phosphatidylinositol-3-kinase/AKT 小径的一个否定管理者，是胰岛素发信号的一个重要调节的人。决定胰腺的 Pten 的新陈代谢的函数，我们产生了胰特定的 Pten 大美人(PPKO ) 鼠标。PPKO 老鼠扩大了胰并且提高了 acinar 房间的增长。他们也展出了低血糖症， hypoinsulinemia，和改变的氨基的新陈代谢。尤其是， PPKO 老鼠证明 streptozotocin (STZ ) 的推迟的发作导致了糖尿病，到 high-fat-diet (HFD ) 的偏导性的抵抗导致了糖尿病。在 PPKO 老鼠为抵抗调查机制到导致 HFD 的多糖症，我们在主要胰岛素应答的纸巾评估了 AKT phosphorylation：肝，肌肉，和脂肪。我们发现在胰的 Pten 损失引起在肝发信号的 AKT 的举起。AKT 和它的下游的底层 GSK3 尾的 phosphorylation 在 PPKO 老鼠的肝被增加，当没有 Pten 等位基因的可检测的切除， PTEN 水平在 PPKO 老鼠的肝被减少时。戏剧性地揭示的 Proteomics 分析减少了在 PPKO 老鼠的肝 78-kDa 铺平调整葡萄糖的蛋白质(GRP78 ) ，它可以也贡献用 HFD 喂的 PPKO 老鼠的更低的血葡萄糖水平。一起，我们的调查结果在新陈代谢的规定在肝揭示新奇回答到胰腺的缺点，把一种新尺寸加到理解糖尿病抵抗。

Embryonic liver fordin is involved in glucose glycolysis of hepatic stellate cell by regulating PI3K/Akt signaling

AIM To investigate the role of embryonic liver fordin(ELF) in liver fibrosis by regulating hepatic stellate cells(HSCs) glucose glycolysis.METHODS The expression of ELF and the glucose glycolysisrelated proteins were evaluated in activated HSCs. si RNA was used to silence ELF expression in activated HSCs in vitro and the subsequent changes in PI3K/Akt signaling and glucose glycolysis-related proteins were observed.RESULTS The expression of ELF increased remarkably in HSCs of the fibrosis mouse model and HSCs that were cultured for 3 wk in vitro. Glucose glycolysis-related proteins showed an obvious increase in the activated HSCs, such as phosphofructokinase, platelet and glucose transporter 1. ELF-si RNA, which perfectly silenced the expression of ELF in activated HSCs, led to the induction of glucose glycolysis-related proteins and extracellular matrix(ECM) components. Moreover, p Akt, which is an important downstream factor in PI3K/Akt signaling, showed a significant change in response to the ELF silencing. The expression of glucose glycolysisrelated proteins and ECM components decreased remarkably when the PI3K/Akt signaling was blocked by Ly294002 in the activated HSCs. CONCLUSION ELF is involved in HSC glucose glycolysis by regulating PI3K/Akt signaling.

shRNA-interfering LSD1 inhibits proliferation and invasion of gastric cancer cells via VEGF-C/PI3K/AKT signaling pathway

BACKGROUND Histone Lysine Specific Demethylase 1(LSD1)is the first histone demethylase to be discovered,which regulates various biological functions by making lysine of histone H3K4,H3K9 and non-histone substrates demethylated.Abnormal regulation of LSD1 is closely related to the occurrence and development of gastric cancer.The change of LSD1 expression level plays an important role in the proliferation and metastasis of gastric cancer cells.The study of its function and mechanism may provide a theoretical basis for early diagnosis and targeted therapy of gastric cancer.AIM To investigate the effect of downregulation of lysine-specific demethylase 1(LSD1)expression on proliferation and invasion of gastric cancer cells and the possible regulatory mechanisms of the VEGF-C/PI3K/AKT signaling pathway.METHODS The LSD1-specific short hairpin RNA(shRNA)interference plasmid was transiently transfected,and expression of LSD1 was downregulated.The cell proliferation ability of LSD1 was observed by CCK-8 assay after downregulating expression of LSD1.Transwell invasion assay was used to observe the change of cell invasion ability after downregulating expression of LSD1.Expression of phosphorylated phosphoinositide 3-kinase(p-PI3K),PI3K,p-AKT,AKT,vascular endothelial growth factor receptor(VEGFR)-3,matrix metalloproteinase(MMP)-2 and MMP-9 in each group was detected by Western blotting.RESULTS The cell proliferation ability of transiently transfected LSD1-shRNA interference plasmid group was significantly lower than that of the control group(P<0.05).Transwell invasion assay showed that the number of cells across the membrane of the LSD1-shRNA transfection group(238.451±5.216)was significantly lower than that of the control group(49.268±6.984)(P<0.01).Western blotting showed that expression level of VEGF-C,p-PI3K,PI3K,p-AKT,AKT,VEGFR-3,MMP-2 and MMP-9 in the LSD1-shRNA group was significantly lower than that in the control group(P<0.05).CONCLUSION Downregulation of LSD1 expression inhibits metastatic potential of gastric cancer cells,and VEGF-C-mediated activation of PI3K/AKT signaling pathway,which may be an important mechanism for inhibiting lymph node metastasis in gastric cancer cells.

Effect of Buyanghuanwu Decoction on PI3K/AKT Signaling Pathway and Aquaporin AQP4 in Cerebral Hemorrhage Rats

[Objectives] To explore the effect of Buyanghuanwu decoction on PI3K/AKT signaling pathway and aquaporin AQP4 in cerebral hemorrhage rats and clarify the mechanism to provide clear direction and target for cerebral hemorrhage treatment caused by cerebral edema.[Methods]SD rats were randomly divided into six groups: model group,sham operation group,Buyanghuanwu decoction low,medium and high dose groups,and Ginkgo biloba group. Model group,Buyanghuanwu decoction group,G. biloba group were prepared to be intracerebral hemorrhage rat models by referring to Rosenberg law. While the expression of " polarity" of aquaporin AQP4 was detected by immunofluorescence labeling method,the Evans blue( Evans Blue,EB) content of brain tissue was determined by Spectrophotometry. In addition,the water content of brain tissue was detected by wet and dry weight method. [Results] When compared to the model group,the Buyang Huanwu decoction group,G. biloba group of PI3K and AKT proteins expression increased significantly( P < 0. 05) and AQP4 in Astrocyte end feet membrane concentrated expression significantly increased( P < 0. 05),EB content and water content of brain tissue significantly reduced( P <0. 05).[Conclusions]The protective mechanisms of Buyanghuanwu decoction on cerebral hemorrhage can work might because it can activate PI3K/AKT signaling pathway,regulate AQP4 " polar" expression,and reduce the permeability of the blood brain barrier and cerebral edema.