Objective:To examine the protective effect of saikosaponin D against streptozotocin(STZ)-induced gestational diabetes mellitus in female rats.Methods:Intraperitoneal administration of STZ(40 mg/kg)was used for the ind...Objective:To examine the protective effect of saikosaponin D against streptozotocin(STZ)-induced gestational diabetes mellitus in female rats.Methods:Intraperitoneal administration of STZ(40 mg/kg)was used for the induction of diabetes in pregnant rats,and rats orally received sikosaponin D(10,20,and 40 mg/kg).The body weight,placental weight,fetal weight,fetal index,and various biochemical parameters,including antioxidant,glucose level,cytokines,and apoptosis parameters,were estimated.The expression levels of various mRNAs were also analyzed.Results:Saikosaponin D increased body weight and fetal weight while decreasing placental weight and placental index.Saikosaponin D significantly altered various biochemical parameters such as fasting blood glucose,glycated hemoglobin(HbA1c),hemoglobin,hepatic glycogen,advanced glycation end products,lipid parameters(total cholesterol,triglyceride,low density lipoprotein,high density lipoprotein,very low density lipoprotein),antioxidant parameters(superoxide dismutase,glutathione,glutathione peroxidase,malonaldehyde,catalase),inflammatory cytokines(tumor necrosis factor-α,interleukin-6,interleukin-1β,interleukin-10),apoptosis parameters(Bcl-2,Bax,caspase-3),resistin,adiponectin,leptin,intercellular adhesion molecule 1,vascular cell adhesion molecule-1,and monocyte chemotactic protein-1.Furthermore,saikosaponin D modulated the mRNA expression of TLR4,MyD88,NF-κB,NLRP3,TNF-α,IL-6,CRP,SIRT1,and MAPK.Conclusions:Saikosaponin D exhibits a protective effect against STZinduced gestational diabetes mellitus in rats via regulation of TLR4/MyD88/NF-κB and MAPK signaling pathways.展开更多
Colorectal cancer(CRC)is one of the most common malignancies.In recent years,despite the widespread application of new endoscopic techniques and continuous advancements in treatment methods that have improved the earl...Colorectal cancer(CRC)is one of the most common malignancies.In recent years,despite the widespread application of new endoscopic techniques and continuous advancements in treatment methods that have improved the early diagnosis rate of CRC,the disease often has an insidious onset.Many patients are already in the middle or late stages of the disease when diagnosed,leading to poor treatment outcomes and prognosis.Therefore,further investigation into the pathogenesis of CRC and exploration of new therapeutic targets remain hot topics of research.The mitogen-activated protein kinase(MAPK)signaling pathway belongs to the large family of serine/threonine kinases and is a crucial pathway for signal transduction in eukaryotes.The MAPK signaling pathway can be activated by various extracellular signals such as cytokines,growth factors,and oxidative stress,thereby influencing biological processes like cell cycle,differentiation,malignant transformation,metastatic potential,and apoptosis.It plays a significant regulatory role in the development and progression of malignancies[1].The evolution of CRC involves abnormal regulation of multiple signaling pathways,among which dysregulation of the MAPK signaling pathway is a key molecular event.This article provides a comprehensive overview of the research progress on the MAPK signaling pathway in CRC.展开更多
Objective:To characterize the tumor-suppressive role of LINC00936 in non-small cell lung cancer(NSCLC)through mechanistic exploration of its regulatory pathways.Methods:Bioinformatics interrogation of TCGA/NSCLC cohor...Objective:To characterize the tumor-suppressive role of LINC00936 in non-small cell lung cancer(NSCLC)through mechanistic exploration of its regulatory pathways.Methods:Bioinformatics interrogation of TCGA/NSCLC cohorts assessed LINC00936 expression,clinical correlations,and immune contexture.Functional enrichment analyses predicted pathway associations.In H1299 cells,LINC00936 overexpression(plasmid)and knockdown(siRNA)models were validated by RT-qPCR.Transcriptomic profiling identified differentially expressed genes(DEGs)subjected to KEGG pathway analysis.Results:LINC00936 was significantly downregulated in NSCLC tissues(TCGA,P<0.05)and cell lines(vs.16-HBE,P<0.05),correlating with poor prognosis and altered tumor-infiltrating immune subsets.DEG enrichment implicated Ras/MAPK signaling as the dominant pathway(FDR<0.05).Successful LINC00936 modulation(overexpression/knockdown,P<0.05)confirmed its regulatory capacity.Conclusion:LINC00936 acts as a tumor suppressor in NSCLC via Ras/MAPK pathway modulation,proposing its therapeutic candidacy for precision oncology strategies.展开更多
Two immunomodulatory polysaccharides(Vp2a-Ⅱ and Vp3) were isolated and identified from Apocynum venetum L. flowers, and their innate immune-stimulating functions and working mechanisms were evaluated in RAW264.7 cell...Two immunomodulatory polysaccharides(Vp2a-Ⅱ and Vp3) were isolated and identified from Apocynum venetum L. flowers, and their innate immune-stimulating functions and working mechanisms were evaluated in RAW264.7 cells. Both the level of released nitric oxide(NO) and expression of inducible nitric oxide synthase(iNOS) m RNA were significantly enhanced in the RAW264.7 macrophages cells treated by Vp2a-Ⅱ and Vp3. Vp2a-Ⅱ(100–800 μg/m L) and Vp3(400 μg/mL) could significantly increase the phagocytic activity of RAW264.7 cells and the secretion and m RNA expression of TNF-α and IL-6 in a concentrationdependent manner through affecting mitogen-activated protein kinase(MAPK) activity and nuclear factor κB(NF-κB) nuclear translocation. Vp2a-Ⅱ might activate the MAPK signaling pathways and induce the nuclear translocation of NF-κB p65, whilst Vp3 likely activated the NF-κB and MAPK signaling pathways without influencing the p38 MAPK route.展开更多
Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regul...Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.展开更多
Objective:To investigate the effect of Bushen Antai Granule on the mRNA and protein expression of Ras protein/mitogen activated protein kinase mediated by vascular endothelial growth factor receptor 2 with small inter...Objective:To investigate the effect of Bushen Antai Granule on the mRNA and protein expression of Ras protein/mitogen activated protein kinase mediated by vascular endothelial growth factor receptor 2 with small interference RNA interference.Methods:Method to construct the placenta microvascular endothelial cells,and the preparation of kidney fetus granule drug-containing serum,select the best drug-containing serum concentration,it can be divided into normal group,the serum siRNA-NC normal serum group,drug serum,siRNA normal serum group,siRNA drug serum group,using real-time fluorescent quantitative PCR,Western blotting,immunofluorescence test respectively the RAS/MAPK mRNA and protein expression.Results:Results there was no significant difference in Ras and MAPK mRNA and protein expression between the normal group and the negative control group(P>0.05).The mRNA and protein expressions of Ras and MAPK in the drug serum group were significantly higher than those in the normal serum group(P<0.01).Ras and MAPK mRNA and protein expression were significantly decreased in siRNA1 normal serum group compared with normal serum group(P<0.01).Ras,MAPK mRNA and protein expression in siRNA1 drug serum group were significantly different from that in siRNA1 normal serum group(P<0.01).Conclusion:Conclusion The therapeutic effect of Bushen Antai Granule on recurrent abortion may be realized by upregulation of RAS/MAPK mRNA and protein expression.展开更多
Objective:To investigate the effects of butylphthalide on reducing neuronal apoptosis in rats with cerebral infarction by inhibiting the JNK/P38 MAPK signaling pathway.Methods:Forty-eight SD male rats were divided int...Objective:To investigate the effects of butylphthalide on reducing neuronal apoptosis in rats with cerebral infarction by inhibiting the JNK/P38 MAPK signaling pathway.Methods:Forty-eight SD male rats were divided into DZ group(control group),CI group(model group)and NBP group(butylphthalide group).Rats in CI group and NBP group were used to establish cerebral infarction models.NBP group used NBP.The solution(80 mg/(kg?d))was administered orally,and the remaining two groups were administered with the same volume of peanut oil.After 14 consecutive days of treatment,the Zea Longa score was used to evaluate the neurological function of DZ,CI and NBP rats.Scoring,TTC staining was used to observe the cerebral infarction volume of rats in DZ group,CI group and NBP group,HE staining was used to observe the pathological morphology of brain tissue in DZ group,CI group and NBP group.Neuronal apoptosis,Western blot was used to detect the expression of p-JNK and p-p38MAPK in brain tissues of DZ group,CI group and NBP group.Results:The neurological function of the rats in the CI group was higher than that in the DZ group,and the difference was statistically significant(P<0.05).The neurological function score of the rats in the NBP group was reduced compared with the CI group,and the difference was statistically significant(P<0.05).The cerebral infarction volume in the group was 35.56%higher than that in the DZ group,and the difference was statistically significant(P<0.05).The minor infarct volume in the NBP group was 21.59%,which was less than that in the CI group,and the difference was statistically significant(P<0.05).Nerve cells are neatly sorted,with a large number.The gap between blood vessels and interstitial tissue in the CI group is enlarged,the cells are severely contracted,and the neuron structure is incomplete.Compared with the CI group,the NBP group has reduced neuron contraction and increased number;The dead nerve cells were brown.The apoptosis rate of nerve cells in the CI group was 79.65%higher than that in the DZ group was 5.82%.The difference was statistically significant(P<0.05).The nerve cell apoptosis rate in the NBP group was 30.23%.Compared with CI group,the difference was statistically significant(P<0.05);Western blot results showed that p-JNK and p-p38MAPK protein expression in CI group was higher than that in DZ group,and the difference was statistically significant(P<0.05).The levels of p-JNK and p-p38MAPK proteins in the NBP group were lower than those in the CI group.There was statistically significant(P<0.05).Conclusion:Butylphthalide can improve neurological damage,reduce apoptotic nerve cells,and reduce infarct volume in rats with cerebral infarction,which is related to the inhibition of JNK/P38 MAPK pathway expression.展开更多
Vascular homeostasis is critical for maintaining normal vascular structure and function. Aging is an irreversible trigger of vascular sclerosis, which causes structural and functional damage to blood vessels, leading ...Vascular homeostasis is critical for maintaining normal vascular structure and function. Aging is an irreversible trigger of vascular sclerosis, which causes structural and functional damage to blood vessels, leading to severe atherosclerosis. Endothelial cells (ECs) can respond to mechanical stimuli from the extracellular matrix, causing disruption of endothelial barrier function and activating signaling pathways to regulate cellular behavior under pathological conditions. In this paper, we investigated the effect of substrate stiffness on endothelial cell junctions, and the activation of mitogen-activated protein kinase (MAPK) signaling pathways. An in vitro stiffness model was established using polyacrylamide hydrogels of 1 kPa, 20 kPa and 100 kPa. By transcriptome analysis, we found that the cell-cell junction, cadherin binding, cytoskeleton and classical signaling pathways such as MAPK and Rho GTPase of endothelial cells were regulated by substrate stiffness. The expression of cell junction-related molecules TJP1, TJP2, JAM3 and JCAD was also found to be reduced at higher stiffness. The MAPK signaling pathway-related molecules MAP2K3, MAP2K7, MAP3K3, MAP3K6, MAPK3, MAPK7 were upregulated with increased stiffness. qRT-PCR analysis showed that the gene expression of JCAD was reduced with increased stiffness. Immunofluorescence staining of VE-cadherin indicated that the total fluorescence level of VE-cadherin decreased significantly with increased stiffness, and stiffness impaired the cell-cell junction with increased punctuation and discontinuity. Western blotting analysis confirmed that the protein expression ratio of pp38MAPK/p38MAPK increased with stiffness. Our research suggested that substrate stiffness played an important role in regulating endothelial cell integrity and MAPK signaling pathway.展开更多
Background:Triple-negative breast cancer(TNBC)is a type of highly invasive breast cancer with a poor prognosis.According to new research,long noncoding RNAs(lncRNAs)play a significant role in the progression of cancer...Background:Triple-negative breast cancer(TNBC)is a type of highly invasive breast cancer with a poor prognosis.According to new research,long noncoding RNAs(lncRNAs)play a significant role in the progression of cancer.Although the role of lncRNAs in breast cancer has been well reported,few studies have focused on TNBC.This study aimed to explore the biological function and clinical significance of forkhead box C1 promoter upstream transcript(FOXCUT)in triple-negative breast cancer.Methods:Based on a bioinformatic analysis of the cancer genome atlas(TCGA)database,we detected that the lncRNA FOXCUT was overexpressed in TNBC tissues,which was further validated in an external cohort of tissues from the General Surgery Department of the First Affiliated Hospital of Nanjing Medical University.The functions of FOXCUT in proliferation,migration,and invasion were detected in vitro or in vivo.Luciferase assays and RNA immunoprecipitation(RIP)were performed to reveal that FOXCUT acted as a competitive endogenous RNA(ceRNA)for the microRNA miR-24-3p and consequently inhibited the degradation of p38.Results:lncRNA FOXCUT was markedly highly expressed in breast cancer,which was associated with poor prognosis in some cases.Knockdown of FOXCUT significantly inhibited cancer growth and metastasis in vitro or in vivo.Mechanistically,FOXCUT competitively bounded to miR-24-3p to prevent the degradation of p38,which might act as an oncogene in breast cancer.Conclusion:Collectively,this research revealed a novel FOXCUT/miR-24-3p/p38 axis that affected breast cancer progression and suggested that the lncRNA FOXCUT could be a diagnostic marker and therapeutic target for breast cancer.展开更多
AIM:To investigate the effects of a Chinese medicine formula“Qingxuan Runmu Yin”(QRY)on ocular surface inflammation in a rat model of dry eye,and its mechanism via the toll-like receptor 4(TLR4)/transforming growth ...AIM:To investigate the effects of a Chinese medicine formula“Qingxuan Runmu Yin”(QRY)on ocular surface inflammation in a rat model of dry eye,and its mechanism via the toll-like receptor 4(TLR4)/transforming growth factor kinase 1(TAK1)/p38 mitogen-activated protein kinase(p38MAPK)signaling pathway.METHODS:Seventy-two Sprague-Dawley rats were randomly divided into six groups(n=12 each):the control group,model group,3 groups of QRY(with low-,medium-,and high-doses),and SB203580 group.Dry eye was induced using benzalkonium chloride.Schirmer’s test(SIT)and corneal fluorescein staining(CFS)were performed every 14d throughout the experiment.Histopathological changes in corneal and conjunctival tissues were observed using hematoxylin and eosin(HE)and periodic acid-Schiff(PAS)staining.Protein expression levels of key inflammatory markers and signaling pathway targets were assessed via immunohistochemistry,ELISA,and Western blotting.RESULTS:Compared to the control group,the model group showed significant reductions in SIT and increases in CFS scores,alongside structural disorganization of corneal/conjunctival tissues,decreased conjunctival goblet cell(CGC)numbers,and elevated expression of inflammatory markers[interleukin(IL)-1β,IL-6,tumor necrosis factoralpha(TNF-α),matrix metalloproteinase-9(MMP9)]and pathway proteins(TLR4,p-TAK1,p-p38MAPK;P<0.05).Treatment with QRY(low,medium,and high doses)and SB203580 significantly improved SIT scores,reduced CFS scores,restored corneoconjunctival structure,increased CGC numbers,and decreased expression levels of IL-1β,IL-6,TNF-α,MMP9,TLR4,p-TAK1,and p-p38MAPK proteins compared to the model group(P<0.05).CONCLUSION:QRY may alleviate ocular surface inflammation associated with dry eye by inhibiting the TLR4/TAK1/p38MAPK signaling pathway,highlighting its potential therapeutic efficacy for dry eye.展开更多
Objective:To investigate the effect of serum deprivation response-related protein(SDPR)on hepatocellular carcinoma(HCC)cells through the ASK1-JNK/p38 MAPK signaling pathway.Methods:A total of 30 HCC tissue samples and...Objective:To investigate the effect of serum deprivation response-related protein(SDPR)on hepatocellular carcinoma(HCC)cells through the ASK1-JNK/p38 MAPK signaling pathway.Methods:A total of 30 HCC tissue samples and adjacent non-tumor tissues were collected from HCC patients who underwent hepatectomy in our hospital from June 2023 and June 2024.Quantitative real-time PCR and Western blot were used to measure the expression levels of SDPR,ASK1,JNK,and p38 MAPK in HCC tissues.Cell proliferation,migration,and apoptosis were compared between SDPR-low and SDPR-high HCC tissues.Results:SDPR m RNA levels and SDPR/GAPDH ratios in HCC tissues were significantly lower than those in adjacent tissues(P<0.05).The OD values of SDPR-low HCC tissues on Days 3,4,and 5 were significantly higher than those of SDPR-high HCC tissues(P<0.05).The number of migrated cells at 20 and 40 h in SDPR-low HCC tissues was significantly greater than in SDPR-high tissues,while the apoptosis rate was significantly lower(P<0.05).SDPR-low HCC tissues exhibited significantly reduced m RNA and protein expression levels of ASK1,JNK,and p38 MAPK compared to SDPR-high tissues(P<0.05).Conclusion:SDPR is downregulated in HCC tissues.Low SDPR expression promotes HCC cell proliferation and migration while inhibiting apoptosis,potentially through modulating the expression of proteins in the ASK1-JNK/p38 MAPK signaling pathway.展开更多
Objective The objective of the study was to explore whether Suanzaoren(Semen Ziziphi Spinosae,SZS)extract could improve insomnia by inhibiting the p38 mitogenactivated protein kinase(p38MAPK)/nuclear factor-κB(NF-κB...Objective The objective of the study was to explore whether Suanzaoren(Semen Ziziphi Spinosae,SZS)extract could improve insomnia by inhibiting the p38 mitogenactivated protein kinase(p38MAPK)/nuclear factor-κB(NF-κB)signaling pathway.Methods Forty SPF-grade Sprague-Dawley(SD)rats were included in the study,with 10 randomly selected rats serving as the control group.The remaining rats were injected intraperitoneally with p-chlorophenylalanine(PCPA)for 6 days to establish an insomnia model.After successful modeling,the rats were divided into the model group,SZS extract group(3.0 g/kg),and zopiclone group(1.25 g/kg).The rats in the SZS extract and zopiclone groups were administered with the corresponding drugs via gavage for 7 days,while the rats in the control and model groups received distilled water.Sleep latency and sleep duration were recorded,and behavioral changes were observed through elevated plusmaze and open field tests.The levels of oxidative stress markers and serum inflammatory factors were measured by enzyme-linked immunosorbent assay(ELISA).The expression levels of p38 MAPK,p-p38MAPK,p-NF-κBp65,and NF-κBp65 protein in the cerebral cortex were detected by Western blot.Neuronal structures in the cerebral cortex were observed under a transmission electron microscope.Results Compared with the control group,the model group exhibited abnormal appearances,significant body mass loss(p<0.001),prolonged sleep latency and shortened sleep duration(p<0.001).The SZS extract and zopiclone groups showed significant improvements in these parameters compared with the model group.Compared with the control group,the model group showed significant reduction in total movement distance(p<0.001),fewer entries into the central zone(p<0.01),and significant decrease in rearing frequency(p<0.001);the levels of glutathione peroxidase(GSH-Px)and catalase(CAT)in the hippocampus were significantly reduced(p<0.001);the serum levels of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and the expression levels of p-p38MAPK and p-NF-κBp65 in the cerebral cortex were significantly increased(p<0.05).Compared with the model group,the SZS extract group showed significant increase in movement distance(p<0.01)and rearing frequency(p<0.001),significantly increased the GSH-Px and CAT levels(p<0.001),and decreased the IL-1βand TNF-αlevels(p<0.01);furthermore,the SZS extract group showed a significantly reduced p-p38MAPK and p-NF-κBp65 levels(p<0.05).The SZS extract group showed significant improvement in the neuronal structure compared with the model group.Conclusion SZS extract can inhibit the p38MAPK/NF-κB signaling pathway to improve insomnia.展开更多
BACKGROUND Aplastic anemia(AA)presents a significant clinical challenge as a life-threatening condition due to failure to produce essential blood cells,with the current the-rapeutic options being notably limited.AIM T...BACKGROUND Aplastic anemia(AA)presents a significant clinical challenge as a life-threatening condition due to failure to produce essential blood cells,with the current the-rapeutic options being notably limited.AIM To assess the therapeutic potential of ginsenoside Rg1 on AA,specifically its protective effects,while elucidating the mechanism at play.METHODS We employed a model of myelosuppression induced by cyclophosphamide(CTX)in C57 mice,followed by administration of ginsenoside Rg1 over 13 d.The invest-igation included examining the bone marrow,thymus and spleen for pathological changes via hematoxylin-eosin staining.Moreover,orbital blood of mice was collected for blood routine examinations.Flow cytometry was employed to identify the impact of ginsenoside Rg1 on cell apoptosis and cycle in the bone marrow of AA mice.Additionally,the study further evaluated cytokine levels with enzyme-linked immunosorbent assay and analyzed the expression of key proteins in the MAPK signaling pathway via western blot.RESULTS Administration of CTX led to significant damage to the bone marrow’s structural integrity and a reduction in hematopoietic cells,establishing a model of AA.Ginsenoside Rg1 successfully reversed hematopoietic dysfunction in AA mice.In comparison to the AA group,ginsenoside Rg1 provided relief by reducing the induction of cell apoptosis and inflammation factors caused by CTX.Furthermore,it helped alleviate the blockade in the cell cycle.Treatment with ginsenoside Rg1 significantly alleviated myelosuppression in mice by inhibiting the MAPK signaling pathway.CONCLUSION This study suggested that ginsenoside Rg1 addresses AA by alleviating myelosuppression,primarily through modulating the MAPK signaling pathway,which paves the way for a novel therapeutic strategy in treating AA,highlighting the potential of ginsenoside Rg1 as a beneficial intervention.展开更多
Objective:To investigate whether the antihypertensive mechanism of electroacupuncture(EA)is associated with attenuating phenotype transformation of vascular smooth muscle cells(VSMCs)via phosphoinositide3-kinase(PI3K)...Objective:To investigate whether the antihypertensive mechanism of electroacupuncture(EA)is associated with attenuating phenotype transformation of vascular smooth muscle cells(VSMCs)via phosphoinositide3-kinase(PI3K)/protein kinase B(Akt)and mitogen-activated protein kinase(MAPK)signaling pathways.Methods:Eight Wistar-ktoyo(WKY)rats were set as normal blood pressure group(normal group).A total of 32 spontaneous hypertensive rats(SHRs)were randomly divided into 4 groups using random number tables:a model group,an EA group,an EA+PI3K antagonist group(EA+P group),and an EA+p38 MAPK agonist+extracellular signal-regulated kinase(ERK)agonist group(EA+M group)(n=8/group).SHRs in EA group,EA+P group and EA+M group received EA treatment 5 sessions per week for continuous 4 weeks,while rats in the normal and model groups were bundled in same condition.The systolic blood pressure(SBP),diastolic blood pressure(DBP),and mean arterial pressure(MAP)of each rat was measured at 0 week and the 4th week.After 4-week intervention,thoracic aorta was collected for hematoxylin-eosin(HE)staining,immunohistochemistry[the contractile markersα-smooth muscle actin(α-SMA)and calponin and the synthetic marker osteopontin(OPN)]and Western blot[α-SMA,calponin,OPN,PI3K,phosphorylated-Akt(p-Akt),Akt,p-p42/44 ERK,total p42/44 ERK,p-p38 MAPK and total p38 MAPK].Results:EA significantly reduced SBP,DBP and MAP(P<0.01).HE staining showed that the wall thickness of thoracic aorta in EA group was significantly decreased(P<0.01).From results of immunohistochemistry and Western blot,EA increased the expression ofα-SMA and calponin,and decreased the expression of OPN(P<0.01).In addition,the expression of PI3K and p-Akt increased(P<0.01),while the expression of p-p42/44 ERK and p-p38 MAPK decreased in EA group(P<0.01).However,these effects were reversed by PI3K antagonist,p38 MAPK agonist and ERK agonist.Conclusions:EA was an effective treatment for BP management.The antihypertensive effect of EA may be related with inhibition of phenotypic transformation of VSMCs,in which the activation of PI3K/Akt and the repression of MAPK pathway were involved.展开更多
Nasopharyngeal carcinoma(NPC)is the third most common malignancy with a high recurrence and metastasis rate in South China.Natural compounds extracted from traditional Chinese herbal medicines have been developed and ...Nasopharyngeal carcinoma(NPC)is the third most common malignancy with a high recurrence and metastasis rate in South China.Natural compounds extracted from traditional Chinese herbal medicines have been developed and utilized for the treatment of a variety of cancers with modest properties and slight side effects.Maackiain(MA)is a type of flavonoid that was first isolated from leguminous plants,and it has been reported to relieve various nervous system disorders and exert anti-allergic as well as antiinflammatory effects.In this study,we demonstrated that MA inhibited proliferation,arrested cell cycle and induced apoptosis in nasopharyngeal carcinoma CNE1 and CNE2 cells in vitro and in vivo.The expression of the related proteins associated with these processes were consistent with the above effects.Moreover,transcriptome sequencing and subsequent Western blot experiments revealed that inhibition of the MAPK/Ras pathway may be responsible to the anti-tumor effect of MA on NPC cells.Therefore,the effects of MA and an activator of this pathway,tertiary butylhydroquinone(TBHQ),alone or combination,were investigated.The results showed TBHQ neutralized the inhibitory effects of MA.These data suggest that MA exerts its anti-tumor effect by inhibiting the MAPK/Ras signaling pathway and it has the potential to become a treatment for patients with NPC.展开更多
In this experiment,we investigated the possible mechanism of polysaccharides from Agrocybe cylindracea residue (PACR) on ameliorating the type-2-diabetes-induced liver and colon injuries.Animal experiments have proved...In this experiment,we investigated the possible mechanism of polysaccharides from Agrocybe cylindracea residue (PACR) on ameliorating the type-2-diabetes-induced liver and colon injuries.Animal experiments have proved that PACR could reduce the oxidative damage and inflammatory response.Meanwhile,the PACR could restore lipid levels,decrease the level of liver and colon lesions in injured mice,and finally play a role in protecting liver and colon.The results showed that PACR could be used as a supplement to decrease blood glucose and relieve T2DM and reduce oxidative stress and inflammatory response by inhibiting the activation of p38 MAPK signaling pathway.展开更多
This study aimed to evaluate the therapeutic properties of the traditional Chinese medicine Xuesanqi(XSQ,from the rhizome of Polygonum amplexicaule D.Don)in treating ulcerative colitis.We hypothesized that its many ac...This study aimed to evaluate the therapeutic properties of the traditional Chinese medicine Xuesanqi(XSQ,from the rhizome of Polygonum amplexicaule D.Don)in treating ulcerative colitis.We hypothesized that its many active components can alleviate symptoms of colitis by regulating the gut microbiota,its metabolites,and various signaling pathways.To test our hypotheses,we designed a DSS-induced colitis model in C57BL/6 male mice.Apparent metrics were evaluated in each group of mice and performed histological analysis of relevant tissues.The gut microbial composition was analyzed by 16S rRNA sequencing of bacteria.Simultaneously,the SCFAs content was detected by gas chromatography,inflammatory factor secretion was evaluated by ELISA or western-blot,the expression of tight junction protein and key proteins of the MAPK signaling pathway were analyzed by western-blot.Our result showed that the treatment with XSQ alleviated significant various symptoms such as weight loss,blood in stool,and shortening of colon.In addition,XSQ treatment restored the dysregulated gut microbiota in colitis mice,increased short chain fatty acids(SCFAs)and normalized the MAPK/ERK/JNK signaling pathways,promoted expression of tight junction protein Occludin,Claudin-1,and E-cadherin proteins.Furthermore,we also observed a dose-dependent pattern in these treatment responses.These findings demonstrated the active components of XSQ is a promising new treatment platform for ulcerative colitis.展开更多
BACKGROUND Gastric carcinoma(GC)is the third most frequent cause of cancer-related death,highlighting the pressing need for novel clinical treatment options.In this regard,microRNAs(miRNAs)have emerged as a promising ...BACKGROUND Gastric carcinoma(GC)is the third most frequent cause of cancer-related death,highlighting the pressing need for novel clinical treatment options.In this regard,microRNAs(miRNAs)have emerged as a promising therapeutic strategy.Studies have shown that miRNAs can regulate related signaling pathways,acting as tumor suppressors or tumor promoters.AIM To explore the effect of miR-204-3p on GC cells.METHODS We measured the expression levels of miR-204-3p in GC cells using quantitative real-time polymerase chain reaction,followed by the delivery of miR-204-3p overexpression and miR-204-3p knockdown vectors into GC cells.CCK-8 was used to detect the effect of miR-204-3p on the proliferation of GC cells,and the colony formation ability of GC cells was detected by the clonal formation assay.The effects of miR-204-3p on GC cell cycle and apoptosis were detected by flow cytometry.The BABL/c nude mouse subcutaneous tumor model using MKN-45 cells was constructed to verify the effect of miR-204-3p on the tumorigenicity of GC cells.Furthermore,the study investigated the effects of miR-204-3p on various proteins related to the MAPK signaling pathway,necroptosis signaling pathway and apoptosis signaling pathway on GC cells using Western blot techniques.RESULTS Firstly,we found that the expression of miR-204-3p in GC was low.When treated with the lentivirus overexpression vector,miR-204-3p expression significantly increased,but the lentivirus knockout vector had no significant effect on miR-204-3p.In vitro experiments confirmed that miR-204-3p overexpression inhibited GC cell viability,promoted cell apoptosis,blocked the cell cycle,and inhibited colony formation ability.In vivo animal experiments confirmed that miR-204-3p overexpression inhibited subcutaneous tumorigenesis ability in BABL/c nude mice.Simultaneously,our results verified that miR-204-3p overexpression can inhibit GC cell proliferation by inhibiting protein expression levels of KRAS and p-ERK1/2 in the MAPK pathway,as well as inhibiting protein expression levels of p-RIP1 and p-MLK1 in the necroptosis pathway to promote the BCL-2/BAX/Caspase-3 apoptosis pathway.CONCLUSION MiR-204-3p overexpression inhibited GC cell proliferation by inhibiting the MAPK pathway and necroptosis pathway to promote apoptosis of GC cells.Thus,miR-204-3p may represent a new potential therapeutic target for GC.展开更多
Objective To investigate the neuroprotective effects and the mechanism of this protection of raloxifene （RLX）, a selective estrogen receptor modulator.Methods MTT assay and flow cytometry with annexin V-FITC/PI stai...Objective To investigate the neuroprotective effects and the mechanism of this protection of raloxifene （RLX）, a selective estrogen receptor modulator.Methods MTT assay and flow cytometry with annexin V-FITC/PI staining were performed to evaluate the neuroprotective effects of RLX on Aβ25-35-induced toxicity. The potential mechanisms were studied by Western blotting in cultured rat pheochromocytoma cells （PC12 cells）.Results RLX（1 000 nmol/L）, in combination with Aβ25-35 （30 llmol/L）, increased the cell viability （P 〈0.001）, and reduced the number of apoptotic cells （P 〈0.05）. RLX attenuated Aβ25-35-induced loss of △ψm （P 〈0.01）. The changing of △ψm was similar to the variation of apoptosis. PD98059 （inhibitor of ERK1/2） inhibited the effects of RLX on cell viability and phosphorylation of cleaved caspase-9. No significant difference of cell viability or phosphorylation of cleaved caspase-9 had been found when PC12 cells were incubated with SB203580 （inhibitor of p38MAPK） or SP600125 （inhibitor of JNK）. Afl25.35 induced a time-dependent phosphorylation of p38MAPK and JNK. In PC12 cells treated solely with RLX, ERK1/2 was activated （P〈0.01）. In PC12 cells treated with Aβ25-35 and RLX, Aβ2545-induced phosphorylation of p38MAPK and JNK were inhibited （P〈0.01 and P〈0.001, respectively）.Conclusion RLX inhibited Af125.35-induced cell apoptosis by activating the ERK1/2 pathway in PC12 cells. RLX also attenuated Aβ25-35-induced activation of p38MAPK and JNK. The mitochondria pathway Was involved in this inhibitory effect.展开更多
Three novel sesquiterpenoid heterodimers,designated as auckcostusolides A-C(1-3),were isolated from Aucklandia costus leaves.The structures of compounds 1-3 were elucidated through comprehensive spectroscopic analysis...Three novel sesquiterpenoid heterodimers,designated as auckcostusolides A-C(1-3),were isolated from Aucklandia costus leaves.The structures of compounds 1-3 were elucidated through comprehensive spectroscopic analysis,with their absolute configurations established using a combination of X-ray single-crystal diffraction and electronic circular dichroism(ECD)calculations.Notably,compounds 1 and 2,despite sharing identical planar structures derived from two identical sesquiterpenoids,exhibited oppos-ite configurations at C-11 and C-8'.This configurational difference can be attributed to distinct Diels-Alder cycloaddition processes between the sesquiterpenoid monomers.Additionally,the cytotoxic effects of compounds 1-3 were evaluated against colorectal can-cer HCT116 cells,fibrosarcoma HT1080 cells,and hepatocellular carcinoma HepG2 cells.Compounds 1-3 induced cell death was characterized by endoplasmic reticulum(ER)swelling and cytoplasmic vacuolization,typical morphological changes associated with paraptosis.Mechanistic studies revealed that compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of react-ive oxygen species(ROS),activation of ER stress,and stimulation of the MAPK signaling pathway.展开更多
文摘Objective:To examine the protective effect of saikosaponin D against streptozotocin(STZ)-induced gestational diabetes mellitus in female rats.Methods:Intraperitoneal administration of STZ(40 mg/kg)was used for the induction of diabetes in pregnant rats,and rats orally received sikosaponin D(10,20,and 40 mg/kg).The body weight,placental weight,fetal weight,fetal index,and various biochemical parameters,including antioxidant,glucose level,cytokines,and apoptosis parameters,were estimated.The expression levels of various mRNAs were also analyzed.Results:Saikosaponin D increased body weight and fetal weight while decreasing placental weight and placental index.Saikosaponin D significantly altered various biochemical parameters such as fasting blood glucose,glycated hemoglobin(HbA1c),hemoglobin,hepatic glycogen,advanced glycation end products,lipid parameters(total cholesterol,triglyceride,low density lipoprotein,high density lipoprotein,very low density lipoprotein),antioxidant parameters(superoxide dismutase,glutathione,glutathione peroxidase,malonaldehyde,catalase),inflammatory cytokines(tumor necrosis factor-α,interleukin-6,interleukin-1β,interleukin-10),apoptosis parameters(Bcl-2,Bax,caspase-3),resistin,adiponectin,leptin,intercellular adhesion molecule 1,vascular cell adhesion molecule-1,and monocyte chemotactic protein-1.Furthermore,saikosaponin D modulated the mRNA expression of TLR4,MyD88,NF-κB,NLRP3,TNF-α,IL-6,CRP,SIRT1,and MAPK.Conclusions:Saikosaponin D exhibits a protective effect against STZinduced gestational diabetes mellitus in rats via regulation of TLR4/MyD88/NF-κB and MAPK signaling pathways.
文摘Colorectal cancer(CRC)is one of the most common malignancies.In recent years,despite the widespread application of new endoscopic techniques and continuous advancements in treatment methods that have improved the early diagnosis rate of CRC,the disease often has an insidious onset.Many patients are already in the middle or late stages of the disease when diagnosed,leading to poor treatment outcomes and prognosis.Therefore,further investigation into the pathogenesis of CRC and exploration of new therapeutic targets remain hot topics of research.The mitogen-activated protein kinase(MAPK)signaling pathway belongs to the large family of serine/threonine kinases and is a crucial pathway for signal transduction in eukaryotes.The MAPK signaling pathway can be activated by various extracellular signals such as cytokines,growth factors,and oxidative stress,thereby influencing biological processes like cell cycle,differentiation,malignant transformation,metastatic potential,and apoptosis.It plays a significant regulatory role in the development and progression of malignancies[1].The evolution of CRC involves abnormal regulation of multiple signaling pathways,among which dysregulation of the MAPK signaling pathway is a key molecular event.This article provides a comprehensive overview of the research progress on the MAPK signaling pathway in CRC.
文摘Objective:To characterize the tumor-suppressive role of LINC00936 in non-small cell lung cancer(NSCLC)through mechanistic exploration of its regulatory pathways.Methods:Bioinformatics interrogation of TCGA/NSCLC cohorts assessed LINC00936 expression,clinical correlations,and immune contexture.Functional enrichment analyses predicted pathway associations.In H1299 cells,LINC00936 overexpression(plasmid)and knockdown(siRNA)models were validated by RT-qPCR.Transcriptomic profiling identified differentially expressed genes(DEGs)subjected to KEGG pathway analysis.Results:LINC00936 was significantly downregulated in NSCLC tissues(TCGA,P<0.05)and cell lines(vs.16-HBE,P<0.05),correlating with poor prognosis and altered tumor-infiltrating immune subsets.DEG enrichment implicated Ras/MAPK signaling as the dominant pathway(FDR<0.05).Successful LINC00936 modulation(overexpression/knockdown,P<0.05)confirmed its regulatory capacity.Conclusion:LINC00936 acts as a tumor suppressor in NSCLC via Ras/MAPK pathway modulation,proposing its therapeutic candidacy for precision oncology strategies.
基金supported by Research on Precision Nutrition and Health Food,Department of Science and Technology of Henan Province(CXJD2021006)。
文摘Two immunomodulatory polysaccharides(Vp2a-Ⅱ and Vp3) were isolated and identified from Apocynum venetum L. flowers, and their innate immune-stimulating functions and working mechanisms were evaluated in RAW264.7 cells. Both the level of released nitric oxide(NO) and expression of inducible nitric oxide synthase(iNOS) m RNA were significantly enhanced in the RAW264.7 macrophages cells treated by Vp2a-Ⅱ and Vp3. Vp2a-Ⅱ(100–800 μg/m L) and Vp3(400 μg/mL) could significantly increase the phagocytic activity of RAW264.7 cells and the secretion and m RNA expression of TNF-α and IL-6 in a concentrationdependent manner through affecting mitogen-activated protein kinase(MAPK) activity and nuclear factor κB(NF-κB) nuclear translocation. Vp2a-Ⅱ might activate the MAPK signaling pathways and induce the nuclear translocation of NF-κB p65, whilst Vp3 likely activated the NF-κB and MAPK signaling pathways without influencing the p38 MAPK route.
基金supported by the National Natural Science Foundation of China(31972217 and 32072369)the Central Government Guides Local Science and Technology Development Projects,China(206Z6501G and 216Z6502G)the Research Project of Basic Scientific Research Business Fees in Provincial Universities of Hebei Province,China(KY2021043 and KY2021044)。
文摘Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.
基金National Natural Science Foundation of China(No.81574017)。
文摘Objective:To investigate the effect of Bushen Antai Granule on the mRNA and protein expression of Ras protein/mitogen activated protein kinase mediated by vascular endothelial growth factor receptor 2 with small interference RNA interference.Methods:Method to construct the placenta microvascular endothelial cells,and the preparation of kidney fetus granule drug-containing serum,select the best drug-containing serum concentration,it can be divided into normal group,the serum siRNA-NC normal serum group,drug serum,siRNA normal serum group,siRNA drug serum group,using real-time fluorescent quantitative PCR,Western blotting,immunofluorescence test respectively the RAS/MAPK mRNA and protein expression.Results:Results there was no significant difference in Ras and MAPK mRNA and protein expression between the normal group and the negative control group(P>0.05).The mRNA and protein expressions of Ras and MAPK in the drug serum group were significantly higher than those in the normal serum group(P<0.01).Ras and MAPK mRNA and protein expression were significantly decreased in siRNA1 normal serum group compared with normal serum group(P<0.01).Ras,MAPK mRNA and protein expression in siRNA1 drug serum group were significantly different from that in siRNA1 normal serum group(P<0.01).Conclusion:Conclusion The therapeutic effect of Bushen Antai Granule on recurrent abortion may be realized by upregulation of RAS/MAPK mRNA and protein expression.
基金Key research project of medical science of Hubei province
文摘Objective:To investigate the effects of butylphthalide on reducing neuronal apoptosis in rats with cerebral infarction by inhibiting the JNK/P38 MAPK signaling pathway.Methods:Forty-eight SD male rats were divided into DZ group(control group),CI group(model group)and NBP group(butylphthalide group).Rats in CI group and NBP group were used to establish cerebral infarction models.NBP group used NBP.The solution(80 mg/(kg?d))was administered orally,and the remaining two groups were administered with the same volume of peanut oil.After 14 consecutive days of treatment,the Zea Longa score was used to evaluate the neurological function of DZ,CI and NBP rats.Scoring,TTC staining was used to observe the cerebral infarction volume of rats in DZ group,CI group and NBP group,HE staining was used to observe the pathological morphology of brain tissue in DZ group,CI group and NBP group.Neuronal apoptosis,Western blot was used to detect the expression of p-JNK and p-p38MAPK in brain tissues of DZ group,CI group and NBP group.Results:The neurological function of the rats in the CI group was higher than that in the DZ group,and the difference was statistically significant(P<0.05).The neurological function score of the rats in the NBP group was reduced compared with the CI group,and the difference was statistically significant(P<0.05).The cerebral infarction volume in the group was 35.56%higher than that in the DZ group,and the difference was statistically significant(P<0.05).The minor infarct volume in the NBP group was 21.59%,which was less than that in the CI group,and the difference was statistically significant(P<0.05).Nerve cells are neatly sorted,with a large number.The gap between blood vessels and interstitial tissue in the CI group is enlarged,the cells are severely contracted,and the neuron structure is incomplete.Compared with the CI group,the NBP group has reduced neuron contraction and increased number;The dead nerve cells were brown.The apoptosis rate of nerve cells in the CI group was 79.65%higher than that in the DZ group was 5.82%.The difference was statistically significant(P<0.05).The nerve cell apoptosis rate in the NBP group was 30.23%.Compared with CI group,the difference was statistically significant(P<0.05);Western blot results showed that p-JNK and p-p38MAPK protein expression in CI group was higher than that in DZ group,and the difference was statistically significant(P<0.05).The levels of p-JNK and p-p38MAPK proteins in the NBP group were lower than those in the CI group.There was statistically significant(P<0.05).Conclusion:Butylphthalide can improve neurological damage,reduce apoptotic nerve cells,and reduce infarct volume in rats with cerebral infarction,which is related to the inhibition of JNK/P38 MAPK pathway expression.
文摘Vascular homeostasis is critical for maintaining normal vascular structure and function. Aging is an irreversible trigger of vascular sclerosis, which causes structural and functional damage to blood vessels, leading to severe atherosclerosis. Endothelial cells (ECs) can respond to mechanical stimuli from the extracellular matrix, causing disruption of endothelial barrier function and activating signaling pathways to regulate cellular behavior under pathological conditions. In this paper, we investigated the effect of substrate stiffness on endothelial cell junctions, and the activation of mitogen-activated protein kinase (MAPK) signaling pathways. An in vitro stiffness model was established using polyacrylamide hydrogels of 1 kPa, 20 kPa and 100 kPa. By transcriptome analysis, we found that the cell-cell junction, cadherin binding, cytoskeleton and classical signaling pathways such as MAPK and Rho GTPase of endothelial cells were regulated by substrate stiffness. The expression of cell junction-related molecules TJP1, TJP2, JAM3 and JCAD was also found to be reduced at higher stiffness. The MAPK signaling pathway-related molecules MAP2K3, MAP2K7, MAP3K3, MAP3K6, MAPK3, MAPK7 were upregulated with increased stiffness. qRT-PCR analysis showed that the gene expression of JCAD was reduced with increased stiffness. Immunofluorescence staining of VE-cadherin indicated that the total fluorescence level of VE-cadherin decreased significantly with increased stiffness, and stiffness impaired the cell-cell junction with increased punctuation and discontinuity. Western blotting analysis confirmed that the protein expression ratio of pp38MAPK/p38MAPK increased with stiffness. Our research suggested that substrate stiffness played an important role in regulating endothelial cell integrity and MAPK signaling pathway.
基金funded by the National Natural Science Foundation of China(Nos.82072931 and 82002805)
文摘Background:Triple-negative breast cancer(TNBC)is a type of highly invasive breast cancer with a poor prognosis.According to new research,long noncoding RNAs(lncRNAs)play a significant role in the progression of cancer.Although the role of lncRNAs in breast cancer has been well reported,few studies have focused on TNBC.This study aimed to explore the biological function and clinical significance of forkhead box C1 promoter upstream transcript(FOXCUT)in triple-negative breast cancer.Methods:Based on a bioinformatic analysis of the cancer genome atlas(TCGA)database,we detected that the lncRNA FOXCUT was overexpressed in TNBC tissues,which was further validated in an external cohort of tissues from the General Surgery Department of the First Affiliated Hospital of Nanjing Medical University.The functions of FOXCUT in proliferation,migration,and invasion were detected in vitro or in vivo.Luciferase assays and RNA immunoprecipitation(RIP)were performed to reveal that FOXCUT acted as a competitive endogenous RNA(ceRNA)for the microRNA miR-24-3p and consequently inhibited the degradation of p38.Results:lncRNA FOXCUT was markedly highly expressed in breast cancer,which was associated with poor prognosis in some cases.Knockdown of FOXCUT significantly inhibited cancer growth and metastasis in vitro or in vivo.Mechanistically,FOXCUT competitively bounded to miR-24-3p to prevent the degradation of p38,which might act as an oncogene in breast cancer.Conclusion:Collectively,this research revealed a novel FOXCUT/miR-24-3p/p38 axis that affected breast cancer progression and suggested that the lncRNA FOXCUT could be a diagnostic marker and therapeutic target for breast cancer.
基金Supported by National Natural Science Foundation of China(No.81973908)Natural Science Foundation of Heilongjiang Province(No.PL2024H224)Postgraduate Innovation Fund of Heilongjiang University of Chinese Medicine(No.2023yjscx018).
文摘AIM:To investigate the effects of a Chinese medicine formula“Qingxuan Runmu Yin”(QRY)on ocular surface inflammation in a rat model of dry eye,and its mechanism via the toll-like receptor 4(TLR4)/transforming growth factor kinase 1(TAK1)/p38 mitogen-activated protein kinase(p38MAPK)signaling pathway.METHODS:Seventy-two Sprague-Dawley rats were randomly divided into six groups(n=12 each):the control group,model group,3 groups of QRY(with low-,medium-,and high-doses),and SB203580 group.Dry eye was induced using benzalkonium chloride.Schirmer’s test(SIT)and corneal fluorescein staining(CFS)were performed every 14d throughout the experiment.Histopathological changes in corneal and conjunctival tissues were observed using hematoxylin and eosin(HE)and periodic acid-Schiff(PAS)staining.Protein expression levels of key inflammatory markers and signaling pathway targets were assessed via immunohistochemistry,ELISA,and Western blotting.RESULTS:Compared to the control group,the model group showed significant reductions in SIT and increases in CFS scores,alongside structural disorganization of corneal/conjunctival tissues,decreased conjunctival goblet cell(CGC)numbers,and elevated expression of inflammatory markers[interleukin(IL)-1β,IL-6,tumor necrosis factoralpha(TNF-α),matrix metalloproteinase-9(MMP9)]and pathway proteins(TLR4,p-TAK1,p-p38MAPK;P<0.05).Treatment with QRY(low,medium,and high doses)and SB203580 significantly improved SIT scores,reduced CFS scores,restored corneoconjunctival structure,increased CGC numbers,and decreased expression levels of IL-1β,IL-6,TNF-α,MMP9,TLR4,p-TAK1,and p-p38MAPK proteins compared to the model group(P<0.05).CONCLUSION:QRY may alleviate ocular surface inflammation associated with dry eye by inhibiting the TLR4/TAK1/p38MAPK signaling pathway,highlighting its potential therapeutic efficacy for dry eye.
基金Fujian Provincial Health and Wellness Scientific Research Talent Development Programgrant number:2019-1-5
文摘Objective:To investigate the effect of serum deprivation response-related protein(SDPR)on hepatocellular carcinoma(HCC)cells through the ASK1-JNK/p38 MAPK signaling pathway.Methods:A total of 30 HCC tissue samples and adjacent non-tumor tissues were collected from HCC patients who underwent hepatectomy in our hospital from June 2023 and June 2024.Quantitative real-time PCR and Western blot were used to measure the expression levels of SDPR,ASK1,JNK,and p38 MAPK in HCC tissues.Cell proliferation,migration,and apoptosis were compared between SDPR-low and SDPR-high HCC tissues.Results:SDPR m RNA levels and SDPR/GAPDH ratios in HCC tissues were significantly lower than those in adjacent tissues(P<0.05).The OD values of SDPR-low HCC tissues on Days 3,4,and 5 were significantly higher than those of SDPR-high HCC tissues(P<0.05).The number of migrated cells at 20 and 40 h in SDPR-low HCC tissues was significantly greater than in SDPR-high tissues,while the apoptosis rate was significantly lower(P<0.05).SDPR-low HCC tissues exhibited significantly reduced m RNA and protein expression levels of ASK1,JNK,and p38 MAPK compared to SDPR-high tissues(P<0.05).Conclusion:SDPR is downregulated in HCC tissues.Low SDPR expression promotes HCC cell proliferation and migration while inhibiting apoptosis,potentially through modulating the expression of proteins in the ASK1-JNK/p38 MAPK signaling pathway.
基金funded by the Research on the Mechanism of Suan Zao Ren’s(Semen Ziziphi Spinosae)Hypnotic Effect Based on TXNIP/NLRP3 Signaling Pathway(2023-ZXFZJJ-JW-071).
文摘Objective The objective of the study was to explore whether Suanzaoren(Semen Ziziphi Spinosae,SZS)extract could improve insomnia by inhibiting the p38 mitogenactivated protein kinase(p38MAPK)/nuclear factor-κB(NF-κB)signaling pathway.Methods Forty SPF-grade Sprague-Dawley(SD)rats were included in the study,with 10 randomly selected rats serving as the control group.The remaining rats were injected intraperitoneally with p-chlorophenylalanine(PCPA)for 6 days to establish an insomnia model.After successful modeling,the rats were divided into the model group,SZS extract group(3.0 g/kg),and zopiclone group(1.25 g/kg).The rats in the SZS extract and zopiclone groups were administered with the corresponding drugs via gavage for 7 days,while the rats in the control and model groups received distilled water.Sleep latency and sleep duration were recorded,and behavioral changes were observed through elevated plusmaze and open field tests.The levels of oxidative stress markers and serum inflammatory factors were measured by enzyme-linked immunosorbent assay(ELISA).The expression levels of p38 MAPK,p-p38MAPK,p-NF-κBp65,and NF-κBp65 protein in the cerebral cortex were detected by Western blot.Neuronal structures in the cerebral cortex were observed under a transmission electron microscope.Results Compared with the control group,the model group exhibited abnormal appearances,significant body mass loss(p<0.001),prolonged sleep latency and shortened sleep duration(p<0.001).The SZS extract and zopiclone groups showed significant improvements in these parameters compared with the model group.Compared with the control group,the model group showed significant reduction in total movement distance(p<0.001),fewer entries into the central zone(p<0.01),and significant decrease in rearing frequency(p<0.001);the levels of glutathione peroxidase(GSH-Px)and catalase(CAT)in the hippocampus were significantly reduced(p<0.001);the serum levels of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and the expression levels of p-p38MAPK and p-NF-κBp65 in the cerebral cortex were significantly increased(p<0.05).Compared with the model group,the SZS extract group showed significant increase in movement distance(p<0.01)and rearing frequency(p<0.001),significantly increased the GSH-Px and CAT levels(p<0.001),and decreased the IL-1βand TNF-αlevels(p<0.01);furthermore,the SZS extract group showed a significantly reduced p-p38MAPK and p-NF-κBp65 levels(p<0.05).The SZS extract group showed significant improvement in the neuronal structure compared with the model group.Conclusion SZS extract can inhibit the p38MAPK/NF-κB signaling pathway to improve insomnia.
基金Supported by Hangzhou Municipal Bureau of Science and Technology,No.2021WJCY366.
文摘BACKGROUND Aplastic anemia(AA)presents a significant clinical challenge as a life-threatening condition due to failure to produce essential blood cells,with the current the-rapeutic options being notably limited.AIM To assess the therapeutic potential of ginsenoside Rg1 on AA,specifically its protective effects,while elucidating the mechanism at play.METHODS We employed a model of myelosuppression induced by cyclophosphamide(CTX)in C57 mice,followed by administration of ginsenoside Rg1 over 13 d.The invest-igation included examining the bone marrow,thymus and spleen for pathological changes via hematoxylin-eosin staining.Moreover,orbital blood of mice was collected for blood routine examinations.Flow cytometry was employed to identify the impact of ginsenoside Rg1 on cell apoptosis and cycle in the bone marrow of AA mice.Additionally,the study further evaluated cytokine levels with enzyme-linked immunosorbent assay and analyzed the expression of key proteins in the MAPK signaling pathway via western blot.RESULTS Administration of CTX led to significant damage to the bone marrow’s structural integrity and a reduction in hematopoietic cells,establishing a model of AA.Ginsenoside Rg1 successfully reversed hematopoietic dysfunction in AA mice.In comparison to the AA group,ginsenoside Rg1 provided relief by reducing the induction of cell apoptosis and inflammation factors caused by CTX.Furthermore,it helped alleviate the blockade in the cell cycle.Treatment with ginsenoside Rg1 significantly alleviated myelosuppression in mice by inhibiting the MAPK signaling pathway.CONCLUSION This study suggested that ginsenoside Rg1 addresses AA by alleviating myelosuppression,primarily through modulating the MAPK signaling pathway,which paves the way for a novel therapeutic strategy in treating AA,highlighting the potential of ginsenoside Rg1 as a beneficial intervention.
基金Supported by the National Natural Science Foundation of China(Nos.81704137,82074516)Sichuan Science and Technology Department(No.2019YJ0331)。
文摘Objective:To investigate whether the antihypertensive mechanism of electroacupuncture(EA)is associated with attenuating phenotype transformation of vascular smooth muscle cells(VSMCs)via phosphoinositide3-kinase(PI3K)/protein kinase B(Akt)and mitogen-activated protein kinase(MAPK)signaling pathways.Methods:Eight Wistar-ktoyo(WKY)rats were set as normal blood pressure group(normal group).A total of 32 spontaneous hypertensive rats(SHRs)were randomly divided into 4 groups using random number tables:a model group,an EA group,an EA+PI3K antagonist group(EA+P group),and an EA+p38 MAPK agonist+extracellular signal-regulated kinase(ERK)agonist group(EA+M group)(n=8/group).SHRs in EA group,EA+P group and EA+M group received EA treatment 5 sessions per week for continuous 4 weeks,while rats in the normal and model groups were bundled in same condition.The systolic blood pressure(SBP),diastolic blood pressure(DBP),and mean arterial pressure(MAP)of each rat was measured at 0 week and the 4th week.After 4-week intervention,thoracic aorta was collected for hematoxylin-eosin(HE)staining,immunohistochemistry[the contractile markersα-smooth muscle actin(α-SMA)and calponin and the synthetic marker osteopontin(OPN)]and Western blot[α-SMA,calponin,OPN,PI3K,phosphorylated-Akt(p-Akt),Akt,p-p42/44 ERK,total p42/44 ERK,p-p38 MAPK and total p38 MAPK].Results:EA significantly reduced SBP,DBP and MAP(P<0.01).HE staining showed that the wall thickness of thoracic aorta in EA group was significantly decreased(P<0.01).From results of immunohistochemistry and Western blot,EA increased the expression ofα-SMA and calponin,and decreased the expression of OPN(P<0.01).In addition,the expression of PI3K and p-Akt increased(P<0.01),while the expression of p-p42/44 ERK and p-p38 MAPK decreased in EA group(P<0.01).However,these effects were reversed by PI3K antagonist,p38 MAPK agonist and ERK agonist.Conclusions:EA was an effective treatment for BP management.The antihypertensive effect of EA may be related with inhibition of phenotypic transformation of VSMCs,in which the activation of PI3K/Akt and the repression of MAPK pathway were involved.
基金the Independent Subject of Guangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement(No.KL2022ZZ01)Guangxi Innovation-Driven Development Project(No.GuiKe AA18242040)+3 种基金the National Key R&D Program of China(Nos.2019YFC1711000 and 2019YFC1711008)the Innovation Team Project of Guangxi Botanical Garden of Medicinal Plant(No.GuiYaoChuang2019002)the Innovation and Demonstration of Guangxi Academician Workstation(No.2021AV07007)Government Guided Local Science and Technology Development Project(No.GuiKeZY 20198018).
文摘Nasopharyngeal carcinoma(NPC)is the third most common malignancy with a high recurrence and metastasis rate in South China.Natural compounds extracted from traditional Chinese herbal medicines have been developed and utilized for the treatment of a variety of cancers with modest properties and slight side effects.Maackiain(MA)is a type of flavonoid that was first isolated from leguminous plants,and it has been reported to relieve various nervous system disorders and exert anti-allergic as well as antiinflammatory effects.In this study,we demonstrated that MA inhibited proliferation,arrested cell cycle and induced apoptosis in nasopharyngeal carcinoma CNE1 and CNE2 cells in vitro and in vivo.The expression of the related proteins associated with these processes were consistent with the above effects.Moreover,transcriptome sequencing and subsequent Western blot experiments revealed that inhibition of the MAPK/Ras pathway may be responsible to the anti-tumor effect of MA on NPC cells.Therefore,the effects of MA and an activator of this pathway,tertiary butylhydroquinone(TBHQ),alone or combination,were investigated.The results showed TBHQ neutralized the inhibitory effects of MA.These data suggest that MA exerts its anti-tumor effect by inhibiting the MAPK/Ras signaling pathway and it has the potential to become a treatment for patients with NPC.
基金the financial supports by Mushroom Technology System of Shandong Province(SDAIT-07-05).
文摘In this experiment,we investigated the possible mechanism of polysaccharides from Agrocybe cylindracea residue (PACR) on ameliorating the type-2-diabetes-induced liver and colon injuries.Animal experiments have proved that PACR could reduce the oxidative damage and inflammatory response.Meanwhile,the PACR could restore lipid levels,decrease the level of liver and colon lesions in injured mice,and finally play a role in protecting liver and colon.The results showed that PACR could be used as a supplement to decrease blood glucose and relieve T2DM and reduce oxidative stress and inflammatory response by inhibiting the activation of p38 MAPK signaling pathway.
基金supported by the Natural Science Foundation of Hubei Province(2024AFD252)the Fundamental Research Funds for the Central Universities South-Central Minzu University(Grant Numbers:CZZ24017)the Fundamental Research Funds for Health Commission of Hubei Province(ZY2023M022).
文摘This study aimed to evaluate the therapeutic properties of the traditional Chinese medicine Xuesanqi(XSQ,from the rhizome of Polygonum amplexicaule D.Don)in treating ulcerative colitis.We hypothesized that its many active components can alleviate symptoms of colitis by regulating the gut microbiota,its metabolites,and various signaling pathways.To test our hypotheses,we designed a DSS-induced colitis model in C57BL/6 male mice.Apparent metrics were evaluated in each group of mice and performed histological analysis of relevant tissues.The gut microbial composition was analyzed by 16S rRNA sequencing of bacteria.Simultaneously,the SCFAs content was detected by gas chromatography,inflammatory factor secretion was evaluated by ELISA or western-blot,the expression of tight junction protein and key proteins of the MAPK signaling pathway were analyzed by western-blot.Our result showed that the treatment with XSQ alleviated significant various symptoms such as weight loss,blood in stool,and shortening of colon.In addition,XSQ treatment restored the dysregulated gut microbiota in colitis mice,increased short chain fatty acids(SCFAs)and normalized the MAPK/ERK/JNK signaling pathways,promoted expression of tight junction protein Occludin,Claudin-1,and E-cadherin proteins.Furthermore,we also observed a dose-dependent pattern in these treatment responses.These findings demonstrated the active components of XSQ is a promising new treatment platform for ulcerative colitis.
文摘BACKGROUND Gastric carcinoma(GC)is the third most frequent cause of cancer-related death,highlighting the pressing need for novel clinical treatment options.In this regard,microRNAs(miRNAs)have emerged as a promising therapeutic strategy.Studies have shown that miRNAs can regulate related signaling pathways,acting as tumor suppressors or tumor promoters.AIM To explore the effect of miR-204-3p on GC cells.METHODS We measured the expression levels of miR-204-3p in GC cells using quantitative real-time polymerase chain reaction,followed by the delivery of miR-204-3p overexpression and miR-204-3p knockdown vectors into GC cells.CCK-8 was used to detect the effect of miR-204-3p on the proliferation of GC cells,and the colony formation ability of GC cells was detected by the clonal formation assay.The effects of miR-204-3p on GC cell cycle and apoptosis were detected by flow cytometry.The BABL/c nude mouse subcutaneous tumor model using MKN-45 cells was constructed to verify the effect of miR-204-3p on the tumorigenicity of GC cells.Furthermore,the study investigated the effects of miR-204-3p on various proteins related to the MAPK signaling pathway,necroptosis signaling pathway and apoptosis signaling pathway on GC cells using Western blot techniques.RESULTS Firstly,we found that the expression of miR-204-3p in GC was low.When treated with the lentivirus overexpression vector,miR-204-3p expression significantly increased,but the lentivirus knockout vector had no significant effect on miR-204-3p.In vitro experiments confirmed that miR-204-3p overexpression inhibited GC cell viability,promoted cell apoptosis,blocked the cell cycle,and inhibited colony formation ability.In vivo animal experiments confirmed that miR-204-3p overexpression inhibited subcutaneous tumorigenesis ability in BABL/c nude mice.Simultaneously,our results verified that miR-204-3p overexpression can inhibit GC cell proliferation by inhibiting protein expression levels of KRAS and p-ERK1/2 in the MAPK pathway,as well as inhibiting protein expression levels of p-RIP1 and p-MLK1 in the necroptosis pathway to promote the BCL-2/BAX/Caspase-3 apoptosis pathway.CONCLUSION MiR-204-3p overexpression inhibited GC cell proliferation by inhibiting the MAPK pathway and necroptosis pathway to promote apoptosis of GC cells.Thus,miR-204-3p may represent a new potential therapeutic target for GC.
基金supported by the "Six Talents Peak" of Jiangsu Province,China 973 Program(No.2007CB944005)Science and Technology Development Foundation of Nanjing Medical University(No.2011NJMU152)
文摘Objective To investigate the neuroprotective effects and the mechanism of this protection of raloxifene （RLX）, a selective estrogen receptor modulator.Methods MTT assay and flow cytometry with annexin V-FITC/PI staining were performed to evaluate the neuroprotective effects of RLX on Aβ25-35-induced toxicity. The potential mechanisms were studied by Western blotting in cultured rat pheochromocytoma cells （PC12 cells）.Results RLX（1 000 nmol/L）, in combination with Aβ25-35 （30 llmol/L）, increased the cell viability （P 〈0.001）, and reduced the number of apoptotic cells （P 〈0.05）. RLX attenuated Aβ25-35-induced loss of △ψm （P 〈0.01）. The changing of △ψm was similar to the variation of apoptosis. PD98059 （inhibitor of ERK1/2） inhibited the effects of RLX on cell viability and phosphorylation of cleaved caspase-9. No significant difference of cell viability or phosphorylation of cleaved caspase-9 had been found when PC12 cells were incubated with SB203580 （inhibitor of p38MAPK） or SP600125 （inhibitor of JNK）. Afl25.35 induced a time-dependent phosphorylation of p38MAPK and JNK. In PC12 cells treated solely with RLX, ERK1/2 was activated （P〈0.01）. In PC12 cells treated with Aβ25-35 and RLX, Aβ2545-induced phosphorylation of p38MAPK and JNK were inhibited （P〈0.01 and P〈0.001, respectively）.Conclusion RLX inhibited Af125.35-induced cell apoptosis by activating the ERK1/2 pathway in PC12 cells. RLX also attenuated Aβ25-35-induced activation of p38MAPK and JNK. The mitochondria pathway Was involved in this inhibitory effect.
基金supported by Yunnan RevitalizationTalentSupport Program“Top Team”Project(No.202305AT350001)“Young Talent”Project(No.YNQR-QNRC-2019-091)+5 种基金the National Natural Science Foundation of China(Nos.32170408,32000280,and 32000548)the Ten Thousand Talents Plan of Yunnan Province for Industrial Technology Leading Talents(No.YNWR-CYJS-2019-011)the Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform(No.2022YKZY001)the CAS Pioneer Hundred Talents Program,the Training of Technological Innovation Talents of Yunnan Province(No.202305AD160009)the Special Research Assistant of Chinese Academy of Sciences(No.E3292211Q1)the Young Academic and Technical Leader Raising Foundation of Yunnan Province(No.202005AC160035).
文摘Three novel sesquiterpenoid heterodimers,designated as auckcostusolides A-C(1-3),were isolated from Aucklandia costus leaves.The structures of compounds 1-3 were elucidated through comprehensive spectroscopic analysis,with their absolute configurations established using a combination of X-ray single-crystal diffraction and electronic circular dichroism(ECD)calculations.Notably,compounds 1 and 2,despite sharing identical planar structures derived from two identical sesquiterpenoids,exhibited oppos-ite configurations at C-11 and C-8'.This configurational difference can be attributed to distinct Diels-Alder cycloaddition processes between the sesquiterpenoid monomers.Additionally,the cytotoxic effects of compounds 1-3 were evaluated against colorectal can-cer HCT116 cells,fibrosarcoma HT1080 cells,and hepatocellular carcinoma HepG2 cells.Compounds 1-3 induced cell death was characterized by endoplasmic reticulum(ER)swelling and cytoplasmic vacuolization,typical morphological changes associated with paraptosis.Mechanistic studies revealed that compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of react-ive oxygen species(ROS),activation of ER stress,and stimulation of the MAPK signaling pathway.
