Cancer represents a significant disease that profoundly impacts human health and longevity.Projections indicate a 47%increase in the global cancer burden by 2040 compared to 2020,accompanied by a further rise in the a...Cancer represents a significant disease that profoundly impacts human health and longevity.Projections indicate a 47%increase in the global cancer burden by 2040 compared to 2020,accompanied by a further rise in the associated economic burden.Consequently,there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer.Natural products(NPs)play a crucial role in the identification and development of anticancer therapeutics.This study identified ustusolate E(UE)and its analog 11α-hydroxy-ustusolate E(HUE)from strain Aspergillus calidoustus TJ403-EL05,and examined their antitumor activities and mechanisms of action.The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS(human gastric cancer cells)and 786-O(human renal clear cell carcinoma cells),induced irreversible DNA damage,blocked the cell cycle at the G_(2)/M phase,and further induced apoptosis in tumor cells.To the best of the authors’knowledge,this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms.The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.展开更多
Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound...Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.展开更多
OBJECTIVE: To examine whether electroacupuncture(EA) treatment inhibited cell apoptosis of intervertebral annulus fibrosis(AF) via tumor necrosis factor-α(TNF-α)-tumor necrosis factor receptor 1(TNFR1)-caspase-8 and...OBJECTIVE: To examine whether electroacupuncture(EA) treatment inhibited cell apoptosis of intervertebral annulus fibrosis(AF) via tumor necrosis factor-α(TNF-α)-tumor necrosis factor receptor 1(TNFR1)-caspase-8 and integrin β1/Akt signaling pathways in a rat model of cervical intervertebral disc degeneration caused by unbalanced dynamic and static forces.METHODS: Thirty-two Sprague-Dawley rats were included in this study, of which 24 rats underwent surgery to induce cervical intervertebral disc degeneration, while eight rats received EA treatment at Dazhui(GV 14). Immunohistochemical staining was used to detect TNF-α, TNFR1, and caspase-8Apoptosis of AF cells was examined with terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling(TUNEL) staining. The m RNA and protein expression levels of integrin β1 andAkt were evaluated with real-time polymerase chain reaction and western blot analysis, respectively.RESULTS: Treatment with EA decreased TUNEL-positive AF cells and lowered TNF-α, TNFR1 and caspase-8 positive cells compared with control groups. EA treatment also increased integrin β1and Akt m RNA and protein levels compared with controls.CONCLUSION: Treatment with EA inhibits AF cell apoptosis through suppression of the TNF-α-TNFR1-caspase-8 signal pathway and increases the expression of integrin β1 and Akt. EA may be a good alternative therapy for treating cervical spondylosis.展开更多
Objective To examine the role of Cd-induced reactive oxygen species（ROS） generation in the apoptosis of neuronal cells. Methods Neuronal cells（primary rat cerebral cortical neurons and PC12 cells） were incubated w...Objective To examine the role of Cd-induced reactive oxygen species（ROS） generation in the apoptosis of neuronal cells. Methods Neuronal cells（primary rat cerebral cortical neurons and PC12 cells） were incubated with or without Cd post-pretreatment with rapamycin（Rap） or N-acetyl-L-cysteine（NAC）. Cell viability was determined by MTT assay, apoptosis was examined using flow cytometry and fluorescence microscopy, and the activation of phosphoinositide 3’-kinase/protein kinase B（Akt）/mammalian target of rapamycin（m TOR） and mitochondrial apoptotic pathways were measured by western blotting or immunofluorescence assays. Results Cd-induced activation of Akt/m TOR signaling, including Akt, m TOR, p70 S6 kinase（p70 S6K）, and eukaryotic initiation factor 4E binding protein 1（4E-BP1）. Rap, an m TOR inhibitor and NAC, a ROS scavenger, blocked Cd-induced activation of Akt/m TOR signaling and apoptosis of neuronal cells. Furthermore, NAC blocked the decrease of B-cell lymphoma 2/Bcl-2 associated X protein（Bcl-2/Bax） ratio, release of cytochrome c, cleavage of caspase-3 and poly（ADP-ribose） polymerase（PARP）, and nuclear translocation of apoptosis-inducing factor（AIF） and endonuclease G（Endo G）. Conclusion Cd-induced ROS generation activates Akt/m TOR and mitochondrial pathways, leading to apoptosis of neuronal cells. Our findings suggest that m TOR inhibitors or antioxidants have potential for preventing Cd-induced neurodegenerative diseases.展开更多
Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a nov...Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a novel miRNA implicated in porcine IMF adipogenesis was found, and its effect and regulatory mechanism were further explored with respect to intramuscular preadipocyte proliferation and differentiation.Results: By porcine adipose tissue miRNA sequencing analysis, we found that miR-146a-5p is a potential regulator of porcine IMF adipogenesis. Further studies showed that miR-146a-5p mimics inhibited porcine intramuscular preadipocyte proliferation and differentiation, while the miR-146a-5p inhibitor promoted cell proliferation and adipogenic differentiation. Mechanistically, miR-146a-5p suppressed cell proliferation by directly targeting SMAD family member 4(SMAD4) to attenuate TGF-β signaling. Moreover, miR-146a-5p inhibited the differentiation of intramuscular preadipocytes by targeting TNF receptor-associated factor 6(TRAF6) to weaken the AKT/mTORC1 signaling downstream of the TRAF6 pathway.Conclusions: MiR-146a-5p targets SMAD4 and TRAF6 to inhibit porcine intramuscular adipogenesis by attenuating TGF-β and AKT/mTORC1 signaling, respectively. These findings provide a novel miRNA biomarker for regulating intramuscular adipogenesis to promote pork quality.展开更多
The architecture and surface modifications have been regarded as effective methods to enhance the bi-ological response of biomaterials in bone tissue engineering.The porous architecture of the implanta-tion was essent...The architecture and surface modifications have been regarded as effective methods to enhance the bi-ological response of biomaterials in bone tissue engineering.The porous architecture of the implanta-tion was essential conditions for bone regeneration.Meanwhile,the design of biomimetic hydroxyap-atite(HAp)coating on porous scaffolds was demonstrated to strengthen the bioactivity and stimulate osteogenesis.However,bioactive bio-ceramics such asβ-tricalcium phosphate(β-TCP)and calcium sili-cate(CS)with superior apatite-forming ability were reported to present better osteogenic activity than that of HAp.Hence in this study,3D-printed interconnected porous bioactive ceramicsβ-TCP/CS scaf-fold was fabricated and the biomimetic HAp apatite coating were constructed in situ via hydrothermal reaction,and the effects of HAp apatite layer on the fate of mouse bone mesenchymal stem cells(mBM-SCs)and the potential mechanisms were explored.The results indicated that HAp apatite coating en-hanced cell proliferation,alkaline phosphatase(ALP)activity,and osteogenic gene expression.Further-more,PI3K/AKT/mTOR signaling pathway is proved to have an important impact on cellular functions.The present results demonstrated that the key molecules of phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT)and mammalian target of rapamycin(mTOR)were activated after the biomimetic hydrox-yapatite coating were constructed on the 3D-printed ceramic scaffolds.Besides,the activated influence on the protein expression of Runx2 and BMP2 could be suppressed after the treatment of inhibitor HY-10358.In vivo studies showed that the constructed HAp coating promoted bone formation and strengthen the bone quality.These results suggest that biomimetic HAp coating constructed on the 3D-printed bioac-tive composite scaffolds could strengthen the bioactivity and the obtained biomimetic multi-structured scaffolds might be a potential alternative bone graft for bone regeneration.展开更多
AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)...AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.展开更多
Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and publ...Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.展开更多
OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,bl...OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,blood glucose levels,serum biochemical indexes,as well as HE/PAS histopathological section were all analyzed to assess the hypoglycemic effect of NRK-C in T2DM mice induced by a high-fat diet(HFD)combined with six intraperitoneal injections of 35 mg·kg^(-1)of streptozotocin(STZ).The Western blotting and immunofluorescence were further applied to determine the regulatory effect of NRK-C on key signaling proteins.RESULTS The fasting blood glucose levels were significantly reduced after 7 weeks of administration of NRK-C.In addition,NRK-C could also significantly improve glucose tolerance,hepatic glycogen levels,and lipid levels(total cholesterol,triglyceride,low density lipoprotein and high density lipoprotein),and significantly reduced insulin resistance of diabetic mice,which played an important role in the antidiabetic effects.Further mechanism research demonstrated that phosphorylated PI3K expression was up-regulated and p-GSK3βexpression was up-regulated after NRK-C intervention,indicating that NRK-C might exert a potential antidiabetic effect by modulating the PI3K/AKT signaling pathway.CONCLUSION All these results suggested that NRK-C might improve T2DM and had the potential to be used as an adjunctive therapy.展开更多
Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate ...Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis.Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling,improved body weights,and attenuated pathological changes in joints of rats with adjuvant-induced arthritis.Additionally,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),and IL-1β in the serum and ankle joints were reduced.Bioinformatics analysis,along with the spleen index and measurements of IL-17 and IL-10 levels,suggested a potential relationship between AS and Th17 cells under arthritic conditions.In vitro,AS was shown to block Th17 cell differentiation,as evidenced by the reduced percentages of CD4^(+)IL-17A^(+)T cells and decreased expression levels of RORγt,IL-17A,IL-17F,IL-21,and IL-22,without affecting the cell viability and apoptosis.This effect was attributed to the limited glycolysis,as indicated by metabolomics analysis,reduced glucose uptake,and p H measurements.Further investigation revealed that AS might bind to hexokinase2(HK2)to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase(GAPDH)or pyruvate kinase M2(PKM2),and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation.Furthermore,AS impaired the activation of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signals in vivo and in vitro,which was abolished by the addition of lactate.In conclusion,AS significantly improved adjuvant-induced arthritis(AIA)in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.展开更多
BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M...BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M2(RRM2)in T2DM and its potential involvement in renal injury through oxidative stress,apoptosis,and ferroptosis.METHODS A cross-sectional study was conducted,comprising 194 patients with T2DM and 120 healthy controls at our hospital between January 2022 and December 2023.The data were analyzed to ascertain the correlation between RRM2 levels and DN onset in patients with T2DM.The apoptosis rate,reactive oxygen species(ROS)levels,oxidative stress,cystine uptake,and ferrous ion(Fe2+)levels were quantified using the HK-2 cell lysates.Reverse transcription quantitative PCR and western blotting were used to assess mRNA and protein expression,respectively.RESULTS Serum RRM2 levels were significantly higher in T2DM patients than in controls(P<0.05)but declined in the macroalbuminuria subgroup.Receiver operating characteristic analysis identified 30 pg/mL as the optimal cut-off(area under the curve=0.958;sensitivity=86%;specificity=95%).RRM2 was negatively correlated with age,diabetes duration,systolic blood pressure,fasting blood glucose,glycosylated hemoglobin,serum creatinine,neutrophil gelatinase-associated lipocalin,kidney injury molecule-1,and malondialdehyde,and positively correlated with estimated glomerular filtration rate,glutathione(GSH),solute carrier family 7 member 11(SLC7A11),and GSH peroxidase 4(GPX4).Logistic regression confirmed RRM2 as an independent protective factor against DN[odds ratio(OR)=0.820,95%confidence interval(95%CI)=0.712-0.945,P=0.006].In vitro,RRM2 overexpression enhanced HK-2 cell proliferation,activated PI3K/Akt signaling,and reduced apoptosis,ROS,oxidative stress,and ferroptosis,accompanied by the restoration of GSH,Nrf2,SLC7A11,and GPX4.These protective effects were abolished by PI3K/Akt inhibition,highlighting RRM2’s renoprotective,pathway-dependent role.CONCLUSION These findings suggest that RRM2 plays a crucial protective role against diabetic renal injury by mitigating oxidative stress,apoptosis,and ferroptosis via PI3K/Akt activation.Serum RRM2 may serve as a novel biomarker for early DN detection,and therapeutic strategies targeting RRM2 may offer potential benefits in preventing diabetic kidney disease progression.展开更多
SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling ...SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases,including the RAS/ERK,JAK/STAT,and PI3K/AKT pathways,which are clinically associated with poor prognosis.Furthermore,SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment(TME).Targeting SHP2 represents a dual therapeutic strategy in CRC:It concurrently regulates RTK signaling and reprograms the immunosuppressive TME.SHP2 inhibitors,administered both as monotherapy and in combination regimens,have advanced into clinical trial phases.Consequently,SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node,positioning it as a high-priority candidate for CRC treatment.展开更多
The published article titled“Knockdown of Rap1b Enhances Apoptosis and Autophagy in Gastric Cancer Cells via the PI3K/Akt/mTOR Pathway”has been retracted from Oncology Research,Vol.24,No.5,2016,pp.287–293.DOI:10.37...The published article titled“Knockdown of Rap1b Enhances Apoptosis and Autophagy in Gastric Cancer Cells via the PI3K/Akt/mTOR Pathway”has been retracted from Oncology Research,Vol.24,No.5,2016,pp.287–293.DOI:10.3727/096504016X14648701447779 URL:https://www.techscience.com/or/v24n5/56977 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a f...BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a focus on the of phosphoinositide 3-kinases(PI3K)/AKT signaling pathway.AIM To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.METHODS Using Metascape,we analyzed the potential targets of tetrahydrocurcumin in HCC.Molecular docking validation was performed using SYBYL2.0.Cell Counting Kit-8,wound healing,and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration,invasion,and apoptosis.The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.RESULTS Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells,promoted their apoptosis,and downregulated the expression of p-PI3K,p-AKT,and B cell leukemia/lymphoma 2,while upregulating caspase-3,p53,and B cell leukemia/lymphoma 2 associated X.CONCLUSION In summary,tetrahydrocurcumin suppresses PI3K/AKT signaling,promotes apoptosis,and prevents the migration and invasion of liver cancer cells.展开更多
BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SN...BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SNHG5)and its regulation of miR-92a-3p and B-cell translocation gene 2(BTG2)in GC progression.METHODS Quantitative reverse transcription PCR and western blot analysis determined the expression of SNHG5,miR-92a-3p,and BTG2 in GC and adjacent non-neoplastic mucosa.Dual-luciferase assays demonstrated interactions of SNHG5 with miR-92a-3p and BTG2.AGS cells were transfected with SNHG5 overexpression and miR-92a-3p knockdown models.Various assays,including CCK-8,colony formation,scratch wound healing,and Transwell assays,were used to determine cell proliferation and migration.An experimental model of a xenograft mouse was used to determine in vivo tumor growth.At the same time histological changes were evaluated by hematoxylin and eosin staining,with western blot analysis used to evaluate signaling pathway protein expression.RESULTS BTG2 and SNHG5 were downregulated in GC tissues,and miR-92a-3p was upregulated.Overexpression of SNHG5 or knockdown of miR-92a-3p reduced GC cell proliferation and migration,and increased BTG2 expression while decreasing PI3K/AKT signaling activity.The dual-luciferase assays demonstrated direct binding of miR-92a-3p to SNHG5 and BTG2.Tumor volume and weight were significantly reduced in mice transplanted with AGS cells treated with miR-92a-3p inhibitor or SNHG5 overexpression compared with control AGS cells.Hematoxylin and eosin staining revealed that treated tumors exhibited degenerative characteristics,including irregular morphology and nucleolysis.CONCLUSION LncRNA SNHG5 inhibited GC cell growth and migration by modulating the PI3K/AKT pathway via the miR-92a-3p/BTG2 axis.展开更多
BACKGROUND Pancreatic cancer(PC)remains one of the most lethal malignancies.While flap endonuclease-1(FEN1)has been implicated in various cancers,its role in PC remains unclear.AIM To investigate the biological functi...BACKGROUND Pancreatic cancer(PC)remains one of the most lethal malignancies.While flap endonuclease-1(FEN1)has been implicated in various cancers,its role in PC remains unclear.AIM To investigate the biological functions and mechanisms of FEN1 in PC progression.METHODS FEN1 expression and its prognostic significance were analyzed using Gene Expression Omnibus,The Cancer Genome Atlas,and Genotype-Tissue Expression databases.FEN1 was knocked down or overexpressed in PC cell lines using lentiviral vectors.Cell proliferation,migration,and invasion were assessed in vitro,while tumorigenicity was evaluated in nude mouse xenografts.Molecular mechanisms were explored through RNA-sequencing and validated by western blot analysis.RESULTS FEN1 was significantly upregulated in PC tissues and correlated with poor prognosis.FEN1 promoted PC cell proliferation,migration,and invasion in vitro,as well as xenograft tumor growth in vivo.Mechanistically,FEN1 regulated epithelial-mesenchymal transition through the AKT/mTOR signaling pathway.CONCLUSION FEN1 functions as an oncogenic driver in PC progression via the AKT/mTOR signaling pathway,suggesting its potential as a therapeutic target.展开更多
Objective To investigate the effect of electroacupuncture(EA)on microRNA(miRNA)expression spectrum and PI3K/Akt/mTOR signaling pathway in uterine tissue of rats with primary dysmenorrhea(PDM),and to explore the potent...Objective To investigate the effect of electroacupuncture(EA)on microRNA(miRNA)expression spectrum and PI3K/Akt/mTOR signaling pathway in uterine tissue of rats with primary dysmenorrhea(PDM),and to explore the potential mechanism of EA in the treatment of PDM.Methods Thirty female SD rats,weighted(200±20)g were randomly divided into control group,model group and EA group,10 rats in each group.By using subcutaneous injection of estradiol diphenhydrate combined with intraperitoneal injection of oxytocin,PDM models were established.Rats in the EA group received EA at“Sanyinjiao”(SP6)and“Guanyuan”(CV4)at dense waves and a frequency of 50 Hz,once a day,20 min each time,for 10 consecutive days.After the 10-day intervention,samples were collected and transmission electron microscopy was used to observe the ultrastructural changes of the cells in uterine tissue in each group.With RNA-seq method,the changes of miRNA expression spectrum in rat uterine tissue were detected.Bioinformatics analysis such as GO functional annotation and KEGG pathway was performed according to differentially expressed miRNAs.Differentially expressed miRNAs were verified by qRT-PCR.Endometrial stromal cells were selected as the target cells and transfected;and they were divided into control group,NC mimics group,mimic miR-144–3p group,NC inhibitor group and inhibitor miR-144–3p group.The apoptosis was determined by using flow cytometrydetect apoptosis,the miRNA and protein expression of PI3K/Akt/mTOR signaling pathway were detected by qRT-PCR and Western blot in each group separately.Results 1.Transmission electron microscope.(1)Control group:no obvious morphological changes in the uterine tissue.(2)Model group:fibroblasts in uterine tissue were irregular,the edema was presented in cellular cytoplasm,the nuclei were irregular and mitochondria swollen seriously;the rough endoplasmic reticulum was expanded moderately.(3)EA group:fibroblasts were spindle-shaped and pyknotic,the cytoplasm increased in electron density,the nuclei were slightly irregular and pyknotic,mitochondria were oval in shape,with little swelling and vacuolation;the rough endoplasmic reticulum was expanded slightly and retained,with a small amount of degranulation.2.Compared with the control group,there were 26 differentially expressed miRNAs in the uterine tissue of rats with PDM.After EA intervention,the expression of miR-144–3p was significantly up-regulated.GO functional analysis of differentially expressed miRNAs in PDM rats after EA showed that the biological functions involved calcium transmembrane transporter activity,mitogen-activated protein kinase binding,epithelial cell migration,tissue migration,etc.3.KEGG pathway analysis showed that PI3K/Akt signaling pathway,MAPK signaling pathway and calcium signaling pathway were enriched.Mimic miR-144-3p increased the apotosis of endometrial stromal cells,and decreased the mRNA and protein expression of PI3K,Akt,and mTOR(P<0.01).Conclusion EA can optimize the cell morphology in the uterine tissue of rats with PDM and affect the miRNA expression spectrum,which may be associated with the effect of EA for up-regulating miR-144–3p expression in endometrial stromal cells,suppressing PI3K/Akt/mTOR signaling pathway and causing apoptosis.展开更多
PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apop...PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apoptosis.MIRI belongs to the category of chest obstruction in traditional Chinese medicine,and its etiology and pathogenesis are mainly“Yang Wei Yin Xian.”Traditional Chinese medicine has the effect of multi-target and multi-component effect,and has played a significant role in the treatment of MIRI in recent years.At present,the monomers of traditional Chinese medicine mainly include saponins,flavonoids,alkaloids,terpenoids,and phenols,and the compounds mainly include Zhigancao Decoction,Zhenyuan Capsule,Jiawei Shenqibai Powder,Qili Qiangxin Capsule,Tongmai Yangxin Pill,Zhilong Huoxue Tongyu Capsule,Guizhi Tongluo Tablets,etc.This paper reviews the research on the improvement of MIRI by regulating PI3K/AKT/mTOR signaling pathway in recent years,and expounds the mechanism and advantages of traditional Chinese medicine in the treatment of MIRI.展开更多
Epidemiological studies have indicated that branched-chain amino acids(BCAAs)increased and gut microbiota disordered in type 2 diabetes mellitus(T2DM).This study aimed to investigate the mechanism of Lactiplantibacill...Epidemiological studies have indicated that branched-chain amino acids(BCAAs)increased and gut microbiota disordered in type 2 diabetes mellitus(T2DM).This study aimed to investigate the mechanism of Lactiplantibacillus plantarum strain 84-3(Lp84-3)combined with Staphylococcus aureus bacteriophage on ameliorating T2DM.Here we perform a case-control study and identify that Staphylococcus_phage was inversely correlated with fasting blood glucose(FBG).It revealed that Lp84-3 could inhibit the growth of S.aureus,and Lp84-3 contains BCAAs degradation enzymes in its genome.Furthermore,Lp84-3 alone or combined with S.aureus bacteriophage interventions can improve blood glucose,insulin resistance,triglycerides,interleukin-1β,tumor necrosis factor-α(TNF-α),BCAAs,and acetyllactate synthase(ALS)in db/db mice.Lp84-3 and S.aureus bacteriophage decreased S.aureus,Malacoplasma iowae,and Oscillibacter sp.,and increased some beneficial such as L.plantarum and Muribaculaceae bacterium.Transcriptomic analyses revealed that Lp84-3 and S.aureus bacteriophage activated the PI3K/AKT/GLUT4 signaling pathway and upregulated key genes of Il22,Hgf,Col6a1,Gh,Itga10,Fgf23,and Prl involved in glucose metabolism in hypothalamus.Collectively,Lp84-3 and S.aureus bacteriophage alleviate T2DM by modulating gut microbiota and enhancing glucose metabolism in hypothalamus,supporting its potential use as a promising functional compound microecological agent for alleviating T2DM.展开更多
OBJECTIVE GubenyiliuⅡ(GYⅡ),a traditional Chinese medicine(TCM)formula used in our hospital,has shown beneficial effects in cancer patients.In this study,we investigated the molecular mechanisms underlying the benefi...OBJECTIVE GubenyiliuⅡ(GYⅡ),a traditional Chinese medicine(TCM)formula used in our hospital,has shown beneficial effects in cancer patients.In this study,we investigated the molecular mechanisms underlying the beneficial effects of GYⅡon murine breast cancer models.METHODS Inhibition of tumor growth and metastasis was evaluated by assessment of tumor weight and analysis of bioluminescent signal after a homograft inoculation.Viability of cultured breast cancer cells was determined using MTT assay andreal-time cell analysis(RTCA).Cell migratory ability was evaluated by Transwell?assay and wound healing assay.Subsequently,the potential anti-tumor and anti-metastatic mechanism was investigated by Western blotting and Immunohistochemistry.RESULTS GYⅡshowed significant inhibitory effects on tumor growth and metastasis in the murine breast cancer model.And GYⅡsuppressed theproliferation of 4T1 and MCF-7 cells in a dose-dependent manner.A better inhibitory effect on 4T1 cells proliferation and migration was found in sub-fractions(SF)of GYⅡ.Moreover,heparanase expression and degree of angiogenesis were reduced in tumor tissues.Western blotting analysis showed decreased expression of heparanase and growth factors in the cells treated with GYⅡand its sub-fractions(SF2 and SF3),there by a reduction in phosphorylation of ERK and AKT.CONCLUSION GYⅡexerts anti-tumor growth and anti-metastatic effects on murine breast cancer model.Sub-fractions 2 and 3 exhibits higher potency of the anti-tumor activity that is,at least partly,associated with decreased heparanase and growth factor sexpression,which subsequently sup-pressed activation of ERK and AKT pathways.展开更多
基金supported by the Program for Changjiang Scholars of the Ministry of Education of the People’s Republic of China (No. T2016088)the National Natural Science Foundation for Distinguished Young Scholars (No. 81725021)+4 种基金the National Key R&D Program of China (No. 2021YFA0910500)the Science and Technology Major Project of Hubei Province (No.2021ACA012)the Innovative Research Groups of the National Natural Science Foundation of China (No. 81721005)the Academic Frontier Youth Team of HUST (No. 2017QYTD19)the Fundamental Research Funds for the Central Universities (No.2172019kfy XJJS166)
文摘Cancer represents a significant disease that profoundly impacts human health and longevity.Projections indicate a 47%increase in the global cancer burden by 2040 compared to 2020,accompanied by a further rise in the associated economic burden.Consequently,there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer.Natural products(NPs)play a crucial role in the identification and development of anticancer therapeutics.This study identified ustusolate E(UE)and its analog 11α-hydroxy-ustusolate E(HUE)from strain Aspergillus calidoustus TJ403-EL05,and examined their antitumor activities and mechanisms of action.The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS(human gastric cancer cells)and 786-O(human renal clear cell carcinoma cells),induced irreversible DNA damage,blocked the cell cycle at the G_(2)/M phase,and further induced apoptosis in tumor cells.To the best of the authors’knowledge,this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms.The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82473601 to Y.L.,82404234 to W.S.,and 82073518 to C.N.)the Foundation of Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning(Grant No.2022-2023ZYBKF04 to C.N.)。
文摘Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.
基金the National Natural Science Foundation of China(No.81273836,Based on Ineegrin/FAK signaling pathways research the effects of electroacupuncture on the contents of apoptosisNo.81001554,Based on Wnt/β-catenin signaling pathways research the effects of electroacupuncture on the annulus fibrosis cells)
文摘OBJECTIVE: To examine whether electroacupuncture(EA) treatment inhibited cell apoptosis of intervertebral annulus fibrosis(AF) via tumor necrosis factor-α(TNF-α)-tumor necrosis factor receptor 1(TNFR1)-caspase-8 and integrin β1/Akt signaling pathways in a rat model of cervical intervertebral disc degeneration caused by unbalanced dynamic and static forces.METHODS: Thirty-two Sprague-Dawley rats were included in this study, of which 24 rats underwent surgery to induce cervical intervertebral disc degeneration, while eight rats received EA treatment at Dazhui(GV 14). Immunohistochemical staining was used to detect TNF-α, TNFR1, and caspase-8Apoptosis of AF cells was examined with terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling(TUNEL) staining. The m RNA and protein expression levels of integrin β1 andAkt were evaluated with real-time polymerase chain reaction and western blot analysis, respectively.RESULTS: Treatment with EA decreased TUNEL-positive AF cells and lowered TNF-α, TNFR1 and caspase-8 positive cells compared with control groups. EA treatment also increased integrin β1and Akt m RNA and protein levels compared with controls.CONCLUSION: Treatment with EA inhibits AF cell apoptosis through suppression of the TNF-α-TNFR1-caspase-8 signal pathway and increases the expression of integrin β1 and Akt. EA may be a good alternative therapy for treating cervical spondylosis.
基金supported by the National Natural Science Foundation of China(No.31101866 and 31302058)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),China Postdoctoral Science Foundation funded project(2015M581874)Jiangsu Planned Projects for Postdoctoral Research Funds(1501072A)
文摘Objective To examine the role of Cd-induced reactive oxygen species（ROS） generation in the apoptosis of neuronal cells. Methods Neuronal cells（primary rat cerebral cortical neurons and PC12 cells） were incubated with or without Cd post-pretreatment with rapamycin（Rap） or N-acetyl-L-cysteine（NAC）. Cell viability was determined by MTT assay, apoptosis was examined using flow cytometry and fluorescence microscopy, and the activation of phosphoinositide 3’-kinase/protein kinase B（Akt）/mammalian target of rapamycin（m TOR） and mitochondrial apoptotic pathways were measured by western blotting or immunofluorescence assays. Results Cd-induced activation of Akt/m TOR signaling, including Akt, m TOR, p70 S6 kinase（p70 S6K）, and eukaryotic initiation factor 4E binding protein 1（4E-BP1）. Rap, an m TOR inhibitor and NAC, a ROS scavenger, blocked Cd-induced activation of Akt/m TOR signaling and apoptosis of neuronal cells. Furthermore, NAC blocked the decrease of B-cell lymphoma 2/Bcl-2 associated X protein（Bcl-2/Bax） ratio, release of cytochrome c, cleavage of caspase-3 and poly（ADP-ribose） polymerase（PARP）, and nuclear translocation of apoptosis-inducing factor（AIF） and endonuclease G（Endo G）. Conclusion Cd-induced ROS generation activates Akt/m TOR and mitochondrial pathways, leading to apoptosis of neuronal cells. Our findings suggest that m TOR inhibitors or antioxidants have potential for preventing Cd-induced neurodegenerative diseases.
基金supported by grants from the National Natural Science Foundation (31872979, 31572366)the National Key Research and Development Program of China (2017YFD0502002)the National Basic Research Programs of China (2015CB943102)。
文摘Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a novel miRNA implicated in porcine IMF adipogenesis was found, and its effect and regulatory mechanism were further explored with respect to intramuscular preadipocyte proliferation and differentiation.Results: By porcine adipose tissue miRNA sequencing analysis, we found that miR-146a-5p is a potential regulator of porcine IMF adipogenesis. Further studies showed that miR-146a-5p mimics inhibited porcine intramuscular preadipocyte proliferation and differentiation, while the miR-146a-5p inhibitor promoted cell proliferation and adipogenic differentiation. Mechanistically, miR-146a-5p suppressed cell proliferation by directly targeting SMAD family member 4(SMAD4) to attenuate TGF-β signaling. Moreover, miR-146a-5p inhibited the differentiation of intramuscular preadipocytes by targeting TNF receptor-associated factor 6(TRAF6) to weaken the AKT/mTORC1 signaling downstream of the TRAF6 pathway.Conclusions: MiR-146a-5p targets SMAD4 and TRAF6 to inhibit porcine intramuscular adipogenesis by attenuating TGF-β and AKT/mTORC1 signaling, respectively. These findings provide a novel miRNA biomarker for regulating intramuscular adipogenesis to promote pork quality.
基金sponsored by the National Science Foundation of China(Nos.32071341,52202358,52003302)The Natural Science Foundation of Guangdong Province(No.2017A030308004)+1 种基金the Guangdong Basic and Applied Basic Research Foundation(No.2021A1515110824)the Science and Technology Project of Guangdong province(No.2018A050506021).
文摘The architecture and surface modifications have been regarded as effective methods to enhance the bi-ological response of biomaterials in bone tissue engineering.The porous architecture of the implanta-tion was essential conditions for bone regeneration.Meanwhile,the design of biomimetic hydroxyap-atite(HAp)coating on porous scaffolds was demonstrated to strengthen the bioactivity and stimulate osteogenesis.However,bioactive bio-ceramics such asβ-tricalcium phosphate(β-TCP)and calcium sili-cate(CS)with superior apatite-forming ability were reported to present better osteogenic activity than that of HAp.Hence in this study,3D-printed interconnected porous bioactive ceramicsβ-TCP/CS scaf-fold was fabricated and the biomimetic HAp apatite coating were constructed in situ via hydrothermal reaction,and the effects of HAp apatite layer on the fate of mouse bone mesenchymal stem cells(mBM-SCs)and the potential mechanisms were explored.The results indicated that HAp apatite coating en-hanced cell proliferation,alkaline phosphatase(ALP)activity,and osteogenic gene expression.Further-more,PI3K/AKT/mTOR signaling pathway is proved to have an important impact on cellular functions.The present results demonstrated that the key molecules of phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT)and mammalian target of rapamycin(mTOR)were activated after the biomimetic hydrox-yapatite coating were constructed on the 3D-printed ceramic scaffolds.Besides,the activated influence on the protein expression of Runx2 and BMP2 could be suppressed after the treatment of inhibitor HY-10358.In vivo studies showed that the constructed HAp coating promoted bone formation and strengthen the bone quality.These results suggest that biomimetic HAp coating constructed on the 3D-printed bioac-tive composite scaffolds could strengthen the bioactivity and the obtained biomimetic multi-structured scaffolds might be a potential alternative bone graft for bone regeneration.
文摘AIM:To highlight the importance of microRNA(miRNA)-21-5p in directing the phosphatase and tensin homolog(PTEN)gene to control the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway in retinal pigment epithelial(RPE)cells in humans subjected to photodamage.METHODS:Human adult RPE cell line-19(ARPE-19)was cultured in vitro and randomly divided into control,damage,overexpression,negative,and PI3K/Akt blocker groups to establish a photodamage model of ARPE-19 cells.The models were subjected to 24h of light exposure,after which the corresponding indices were detected.The cell counting kit-8 assay quantified cell viability,while flow cytometry determined apoptosis rates.The miRNA-21 mimics and miRNA mimic NC were transfected into ARPE-19 cells using a transient transfection technique.Quantitative reverse transcription polymerase chain reaction(SYBR Green)and Western blotting analyzed expression levels of miRNA-21-5p,PTEN,p-PI3K/PI3K,p-mTOR/mTOR,and p-Akt/Akt.Statistical analyses comprised one-way analysis of variance and the Student-Newman-Keuls test for multiple group comparisons.RESULTS:The photodamage group demonstrated reduced cell survival rates than the control group(P<0.01).The overexpression group exhibited higher cell survival rates than the injury group(P<0.01).The negative group showed no difference in viability(P>0.05).The PI3K/Akt blocker group demonstrated lower cell viability,compared with the overexpression group(P<0.01).CONCLUSION:miRNA-21-5p significantly increases ARPE-19 cell survival after photodamage and inhibits lightinduced ARPE-19 cell apoptosis,suggesting that it may play a protective role in RPE by activating the PI3K/Akt/mTOR pathway while downregulating PTEN expression.
基金江苏省卫生健康委员会医学科研重点项目(K2023024)789 Outstanding Talent Program of SAHNMU(789ZYRC202090147)。
文摘Objective:To investigate the biological functions and molecular regulatory mechanisms of kinesin family member 11(KIF11)in colorectal cancer(CRC).Methods:The expression of KIF11 in CRC was examined by qRT⁃PCR and public databases.Functional assays(CCK⁃8,colony formation,EdU,and Transwell)were employed to evaluate KIF11’s roles in CRC progression.Western blot,RIP⁃qPCR,MeRIP⁃qPCR,and RNA stability assays were performed to elucidate the molecular mechanism of N6⁃methyladenosine(m6A)modification for KIF11.RNA sequencing(RNA⁃seq)and correlation analysis were used to examine the downstream mechanism of KIF11 regulation.Results:KIF11 was highly expressed in CRC and promoted CRC proliferation and migration.Mechanistically,methyltransferase⁃like 3(METTL3)/insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)enhanced KIF11 mRNA stability and expression in an m6A⁃dependent way.Furthermore,by means of the PROM1/PI3K/AKT pathway,KIF11 facilitated the progression of CRC.Conclusion:The m6A modification of KIF11 by METTL3/IGF2BP2 contributes to CRC progression via the PI3K/AKT signaling pathway,highlighting its potential as a prognostic biomarker and therapeutic target.
文摘OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,blood glucose levels,serum biochemical indexes,as well as HE/PAS histopathological section were all analyzed to assess the hypoglycemic effect of NRK-C in T2DM mice induced by a high-fat diet(HFD)combined with six intraperitoneal injections of 35 mg·kg^(-1)of streptozotocin(STZ).The Western blotting and immunofluorescence were further applied to determine the regulatory effect of NRK-C on key signaling proteins.RESULTS The fasting blood glucose levels were significantly reduced after 7 weeks of administration of NRK-C.In addition,NRK-C could also significantly improve glucose tolerance,hepatic glycogen levels,and lipid levels(total cholesterol,triglyceride,low density lipoprotein and high density lipoprotein),and significantly reduced insulin resistance of diabetic mice,which played an important role in the antidiabetic effects.Further mechanism research demonstrated that phosphorylated PI3K expression was up-regulated and p-GSK3βexpression was up-regulated after NRK-C intervention,indicating that NRK-C might exert a potential antidiabetic effect by modulating the PI3K/AKT signaling pathway.CONCLUSION All these results suggested that NRK-C might improve T2DM and had the potential to be used as an adjunctive therapy.
基金supported by the project of Central Funds Guiding the Local Science and Technology Development(No.20212ZDD02010)。
文摘Andrographolide sulfonate(AS)is a sulfonated derivative of andrographolide extracted from Andrographis paniculata(Burm.f.)Nees,and has been approved for several decades in China.The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis.Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling,improved body weights,and attenuated pathological changes in joints of rats with adjuvant-induced arthritis.Additionally,the levels of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),and IL-1β in the serum and ankle joints were reduced.Bioinformatics analysis,along with the spleen index and measurements of IL-17 and IL-10 levels,suggested a potential relationship between AS and Th17 cells under arthritic conditions.In vitro,AS was shown to block Th17 cell differentiation,as evidenced by the reduced percentages of CD4^(+)IL-17A^(+)T cells and decreased expression levels of RORγt,IL-17A,IL-17F,IL-21,and IL-22,without affecting the cell viability and apoptosis.This effect was attributed to the limited glycolysis,as indicated by metabolomics analysis,reduced glucose uptake,and p H measurements.Further investigation revealed that AS might bind to hexokinase2(HK2)to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase(GAPDH)or pyruvate kinase M2(PKM2),and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation.Furthermore,AS impaired the activation of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)signals in vivo and in vitro,which was abolished by the addition of lactate.In conclusion,AS significantly improved adjuvant-induced arthritis(AIA)in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
文摘BACKGROUND Type 2 diabetes mellitus(T2DM)is associated with significant metabolic and renal complications,including diabetic nephropathy(DN).AIM To investigate the role of ribonucleotide reductase regulatory subunit M2(RRM2)in T2DM and its potential involvement in renal injury through oxidative stress,apoptosis,and ferroptosis.METHODS A cross-sectional study was conducted,comprising 194 patients with T2DM and 120 healthy controls at our hospital between January 2022 and December 2023.The data were analyzed to ascertain the correlation between RRM2 levels and DN onset in patients with T2DM.The apoptosis rate,reactive oxygen species(ROS)levels,oxidative stress,cystine uptake,and ferrous ion(Fe2+)levels were quantified using the HK-2 cell lysates.Reverse transcription quantitative PCR and western blotting were used to assess mRNA and protein expression,respectively.RESULTS Serum RRM2 levels were significantly higher in T2DM patients than in controls(P<0.05)but declined in the macroalbuminuria subgroup.Receiver operating characteristic analysis identified 30 pg/mL as the optimal cut-off(area under the curve=0.958;sensitivity=86%;specificity=95%).RRM2 was negatively correlated with age,diabetes duration,systolic blood pressure,fasting blood glucose,glycosylated hemoglobin,serum creatinine,neutrophil gelatinase-associated lipocalin,kidney injury molecule-1,and malondialdehyde,and positively correlated with estimated glomerular filtration rate,glutathione(GSH),solute carrier family 7 member 11(SLC7A11),and GSH peroxidase 4(GPX4).Logistic regression confirmed RRM2 as an independent protective factor against DN[odds ratio(OR)=0.820,95%confidence interval(95%CI)=0.712-0.945,P=0.006].In vitro,RRM2 overexpression enhanced HK-2 cell proliferation,activated PI3K/Akt signaling,and reduced apoptosis,ROS,oxidative stress,and ferroptosis,accompanied by the restoration of GSH,Nrf2,SLC7A11,and GPX4.These protective effects were abolished by PI3K/Akt inhibition,highlighting RRM2’s renoprotective,pathway-dependent role.CONCLUSION These findings suggest that RRM2 plays a crucial protective role against diabetic renal injury by mitigating oxidative stress,apoptosis,and ferroptosis via PI3K/Akt activation.Serum RRM2 may serve as a novel biomarker for early DN detection,and therapeutic strategies targeting RRM2 may offer potential benefits in preventing diabetic kidney disease progression.
基金Supported by Zhejiang Provincial Natural Science Foundation for Youths,No.QN25H160012Zhejiang Medical and Health Science and Technology Plan,No.2023RC006.
文摘SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer(CRC)progression,and it is consistently overexpressed in CRC.It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases,including the RAS/ERK,JAK/STAT,and PI3K/AKT pathways,which are clinically associated with poor prognosis.Furthermore,SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment(TME).Targeting SHP2 represents a dual therapeutic strategy in CRC:It concurrently regulates RTK signaling and reprograms the immunosuppressive TME.SHP2 inhibitors,administered both as monotherapy and in combination regimens,have advanced into clinical trial phases.Consequently,SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node,positioning it as a high-priority candidate for CRC treatment.
文摘The published article titled“Knockdown of Rap1b Enhances Apoptosis and Autophagy in Gastric Cancer Cells via the PI3K/Akt/mTOR Pathway”has been retracted from Oncology Research,Vol.24,No.5,2016,pp.287–293.DOI:10.3727/096504016X14648701447779 URL:https://www.techscience.com/or/v24n5/56977 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
基金the Central Government Guidance Local Science and Technology Development Fund,No.2023JH6/100100021Liaoning Province Education Department Foundation of China,No.JYTMS20231393+2 种基金Scientific Research Project of Liaoning Province Education Department,No.SYYX2019015Science and Technology Fund of Shenyang Medical College,No.20171004,Shenyang Medical College Master’s Science and Technology Innovation Fund,No.Y20220509Liaoning Provincial Department of Education Scientific Research Project,No.LJ212410164032.
文摘BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a focus on the of phosphoinositide 3-kinases(PI3K)/AKT signaling pathway.AIM To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.METHODS Using Metascape,we analyzed the potential targets of tetrahydrocurcumin in HCC.Molecular docking validation was performed using SYBYL2.0.Cell Counting Kit-8,wound healing,and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration,invasion,and apoptosis.The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.RESULTS Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells,promoted their apoptosis,and downregulated the expression of p-PI3K,p-AKT,and B cell leukemia/lymphoma 2,while upregulating caspase-3,p53,and B cell leukemia/lymphoma 2 associated X.CONCLUSION In summary,tetrahydrocurcumin suppresses PI3K/AKT signaling,promotes apoptosis,and prevents the migration and invasion of liver cancer cells.
文摘BACKGROUND Gastric cancer(GC)is a widespread malignancy and associated with high rates of morbidity and mortality worldwide.AIM To examine the functional role of long non-coding RNAs small nucleolar RNA host gene 5(SNHG5)and its regulation of miR-92a-3p and B-cell translocation gene 2(BTG2)in GC progression.METHODS Quantitative reverse transcription PCR and western blot analysis determined the expression of SNHG5,miR-92a-3p,and BTG2 in GC and adjacent non-neoplastic mucosa.Dual-luciferase assays demonstrated interactions of SNHG5 with miR-92a-3p and BTG2.AGS cells were transfected with SNHG5 overexpression and miR-92a-3p knockdown models.Various assays,including CCK-8,colony formation,scratch wound healing,and Transwell assays,were used to determine cell proliferation and migration.An experimental model of a xenograft mouse was used to determine in vivo tumor growth.At the same time histological changes were evaluated by hematoxylin and eosin staining,with western blot analysis used to evaluate signaling pathway protein expression.RESULTS BTG2 and SNHG5 were downregulated in GC tissues,and miR-92a-3p was upregulated.Overexpression of SNHG5 or knockdown of miR-92a-3p reduced GC cell proliferation and migration,and increased BTG2 expression while decreasing PI3K/AKT signaling activity.The dual-luciferase assays demonstrated direct binding of miR-92a-3p to SNHG5 and BTG2.Tumor volume and weight were significantly reduced in mice transplanted with AGS cells treated with miR-92a-3p inhibitor or SNHG5 overexpression compared with control AGS cells.Hematoxylin and eosin staining revealed that treated tumors exhibited degenerative characteristics,including irregular morphology and nucleolysis.CONCLUSION LncRNA SNHG5 inhibited GC cell growth and migration by modulating the PI3K/AKT pathway via the miR-92a-3p/BTG2 axis.
基金Supported by Youth Science and Technology Fund Program of the Natural Science Foundation of Gansu Province,No.21JR7RA645 and No.23JRRA1317.
文摘BACKGROUND Pancreatic cancer(PC)remains one of the most lethal malignancies.While flap endonuclease-1(FEN1)has been implicated in various cancers,its role in PC remains unclear.AIM To investigate the biological functions and mechanisms of FEN1 in PC progression.METHODS FEN1 expression and its prognostic significance were analyzed using Gene Expression Omnibus,The Cancer Genome Atlas,and Genotype-Tissue Expression databases.FEN1 was knocked down or overexpressed in PC cell lines using lentiviral vectors.Cell proliferation,migration,and invasion were assessed in vitro,while tumorigenicity was evaluated in nude mouse xenografts.Molecular mechanisms were explored through RNA-sequencing and validated by western blot analysis.RESULTS FEN1 was significantly upregulated in PC tissues and correlated with poor prognosis.FEN1 promoted PC cell proliferation,migration,and invasion in vitro,as well as xenograft tumor growth in vivo.Mechanistically,FEN1 regulated epithelial-mesenchymal transition through the AKT/mTOR signaling pathway.CONCLUSION FEN1 functions as an oncogenic driver in PC progression via the AKT/mTOR signaling pathway,suggesting its potential as a therapeutic target.
基金supported by the National Natural Science Foundation of China(no.82004490)Hunan Natural Science Foundation Youth Project:2021JJ40402the Innovation Platform Open Fund project of the Hunan Education Department(no.20K091).
文摘Objective To investigate the effect of electroacupuncture(EA)on microRNA(miRNA)expression spectrum and PI3K/Akt/mTOR signaling pathway in uterine tissue of rats with primary dysmenorrhea(PDM),and to explore the potential mechanism of EA in the treatment of PDM.Methods Thirty female SD rats,weighted(200±20)g were randomly divided into control group,model group and EA group,10 rats in each group.By using subcutaneous injection of estradiol diphenhydrate combined with intraperitoneal injection of oxytocin,PDM models were established.Rats in the EA group received EA at“Sanyinjiao”(SP6)and“Guanyuan”(CV4)at dense waves and a frequency of 50 Hz,once a day,20 min each time,for 10 consecutive days.After the 10-day intervention,samples were collected and transmission electron microscopy was used to observe the ultrastructural changes of the cells in uterine tissue in each group.With RNA-seq method,the changes of miRNA expression spectrum in rat uterine tissue were detected.Bioinformatics analysis such as GO functional annotation and KEGG pathway was performed according to differentially expressed miRNAs.Differentially expressed miRNAs were verified by qRT-PCR.Endometrial stromal cells were selected as the target cells and transfected;and they were divided into control group,NC mimics group,mimic miR-144–3p group,NC inhibitor group and inhibitor miR-144–3p group.The apoptosis was determined by using flow cytometrydetect apoptosis,the miRNA and protein expression of PI3K/Akt/mTOR signaling pathway were detected by qRT-PCR and Western blot in each group separately.Results 1.Transmission electron microscope.(1)Control group:no obvious morphological changes in the uterine tissue.(2)Model group:fibroblasts in uterine tissue were irregular,the edema was presented in cellular cytoplasm,the nuclei were irregular and mitochondria swollen seriously;the rough endoplasmic reticulum was expanded moderately.(3)EA group:fibroblasts were spindle-shaped and pyknotic,the cytoplasm increased in electron density,the nuclei were slightly irregular and pyknotic,mitochondria were oval in shape,with little swelling and vacuolation;the rough endoplasmic reticulum was expanded slightly and retained,with a small amount of degranulation.2.Compared with the control group,there were 26 differentially expressed miRNAs in the uterine tissue of rats with PDM.After EA intervention,the expression of miR-144–3p was significantly up-regulated.GO functional analysis of differentially expressed miRNAs in PDM rats after EA showed that the biological functions involved calcium transmembrane transporter activity,mitogen-activated protein kinase binding,epithelial cell migration,tissue migration,etc.3.KEGG pathway analysis showed that PI3K/Akt signaling pathway,MAPK signaling pathway and calcium signaling pathway were enriched.Mimic miR-144-3p increased the apotosis of endometrial stromal cells,and decreased the mRNA and protein expression of PI3K,Akt,and mTOR(P<0.01).Conclusion EA can optimize the cell morphology in the uterine tissue of rats with PDM and affect the miRNA expression spectrum,which may be associated with the effect of EA for up-regulating miR-144–3p expression in endometrial stromal cells,suppressing PI3K/Akt/mTOR signaling pathway and causing apoptosis.
基金Natural Science Foundation of Guangxi(Grant No.2021JJD140147)。
文摘PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apoptosis.MIRI belongs to the category of chest obstruction in traditional Chinese medicine,and its etiology and pathogenesis are mainly“Yang Wei Yin Xian.”Traditional Chinese medicine has the effect of multi-target and multi-component effect,and has played a significant role in the treatment of MIRI in recent years.At present,the monomers of traditional Chinese medicine mainly include saponins,flavonoids,alkaloids,terpenoids,and phenols,and the compounds mainly include Zhigancao Decoction,Zhenyuan Capsule,Jiawei Shenqibai Powder,Qili Qiangxin Capsule,Tongmai Yangxin Pill,Zhilong Huoxue Tongyu Capsule,Guizhi Tongluo Tablets,etc.This paper reviews the research on the improvement of MIRI by regulating PI3K/AKT/mTOR signaling pathway in recent years,and expounds the mechanism and advantages of traditional Chinese medicine in the treatment of MIRI.
基金supported by research grants from the Guangdong Province Basic and Applied Basic Research Fund Project(2022A1515110447)Open Fund Project of the State Key Laboratory of Applied Microbiology in South China(SKLAM006-2022)+1 种基金74th batch of general funding from the China Postdoctoral Science Foundation(2023M740774)Guangdong Provincial People’s Hospital,Postdoctoral Research Launch Fund(BY012022017)。
文摘Epidemiological studies have indicated that branched-chain amino acids(BCAAs)increased and gut microbiota disordered in type 2 diabetes mellitus(T2DM).This study aimed to investigate the mechanism of Lactiplantibacillus plantarum strain 84-3(Lp84-3)combined with Staphylococcus aureus bacteriophage on ameliorating T2DM.Here we perform a case-control study and identify that Staphylococcus_phage was inversely correlated with fasting blood glucose(FBG).It revealed that Lp84-3 could inhibit the growth of S.aureus,and Lp84-3 contains BCAAs degradation enzymes in its genome.Furthermore,Lp84-3 alone or combined with S.aureus bacteriophage interventions can improve blood glucose,insulin resistance,triglycerides,interleukin-1β,tumor necrosis factor-α(TNF-α),BCAAs,and acetyllactate synthase(ALS)in db/db mice.Lp84-3 and S.aureus bacteriophage decreased S.aureus,Malacoplasma iowae,and Oscillibacter sp.,and increased some beneficial such as L.plantarum and Muribaculaceae bacterium.Transcriptomic analyses revealed that Lp84-3 and S.aureus bacteriophage activated the PI3K/AKT/GLUT4 signaling pathway and upregulated key genes of Il22,Hgf,Col6a1,Gh,Itga10,Fgf23,and Prl involved in glucose metabolism in hypothalamus.Collectively,Lp84-3 and S.aureus bacteriophage alleviate T2DM by modulating gut microbiota and enhancing glucose metabolism in hypothalamus,supporting its potential use as a promising functional compound microecological agent for alleviating T2DM.
基金The project supported by National Natural Science Foundation of China(81202840,81373815)Specialized Research Fund for the Doctoral Program of Higher Education of China(20131107110014)+1 种基金Beijing Natural Science Foundation(7162084)Swedish Cancer Foundation(150815)
文摘OBJECTIVE GubenyiliuⅡ(GYⅡ),a traditional Chinese medicine(TCM)formula used in our hospital,has shown beneficial effects in cancer patients.In this study,we investigated the molecular mechanisms underlying the beneficial effects of GYⅡon murine breast cancer models.METHODS Inhibition of tumor growth and metastasis was evaluated by assessment of tumor weight and analysis of bioluminescent signal after a homograft inoculation.Viability of cultured breast cancer cells was determined using MTT assay andreal-time cell analysis(RTCA).Cell migratory ability was evaluated by Transwell?assay and wound healing assay.Subsequently,the potential anti-tumor and anti-metastatic mechanism was investigated by Western blotting and Immunohistochemistry.RESULTS GYⅡshowed significant inhibitory effects on tumor growth and metastasis in the murine breast cancer model.And GYⅡsuppressed theproliferation of 4T1 and MCF-7 cells in a dose-dependent manner.A better inhibitory effect on 4T1 cells proliferation and migration was found in sub-fractions(SF)of GYⅡ.Moreover,heparanase expression and degree of angiogenesis were reduced in tumor tissues.Western blotting analysis showed decreased expression of heparanase and growth factors in the cells treated with GYⅡand its sub-fractions(SF2 and SF3),there by a reduction in phosphorylation of ERK and AKT.CONCLUSION GYⅡexerts anti-tumor growth and anti-metastatic effects on murine breast cancer model.Sub-fractions 2 and 3 exhibits higher potency of the anti-tumor activity that is,at least partly,associated with decreased heparanase and growth factor sexpression,which subsequently sup-pressed activation of ERK and AKT pathways.
