Inflammation underlies many chronic diseases,and inflammatory bowel disease(IBD)is a condition characterized by long-term inflammation of the gut.Egg whites have been shown to contain many beneficial active substances...Inflammation underlies many chronic diseases,and inflammatory bowel disease(IBD)is a condition characterized by long-term inflammation of the gut.Egg whites have been shown to contain many beneficial active substances.Therefore,we obtained 2 peptides from salted egg white:Val-Val-His-Phe(VF-4)and Asp-Thr-Gln-Ala-Met-Pro-Phe-Arg(DR-8).The sodium dextran sulfate(DSS)-induced mice colitis model was used to evaluate its regulatory effect on colitis in vivo.The results showed that VF-4 and DR-8 improved the clinical symptoms of DSS-induced colitis,attenuated colon tissue damage,inhibited the activation of nuclear factor kappa-B(NF-κB)/mitogen-activated protein kinase(MAPK)/phosphoinositide 3-kinase-Akt(PI3K-AKT)signaling pathways,and inhibited the expression of inflammatory cytokines.16S rRNA gene sequencing showed that VF-4 and DR-8 administration increased the relative abundance of intestinal beneficial bacteria including Lactobacillus,Blautia,and down-regulated the relative abundance of inflammation-related bacteria including Acinetobacter,Lachnospiraceae_NK4A136_group,Klebsiella.Moreover,the degree of correlation between pro-inflammatory cytokines and microbiota was as follows:interleukin-6(IL-6)>tumor necrosis factor-α(TNF-α)>interleukin-1β(IL-1β)>interferon-γ(IFN-γ).In conclusion,this study suggests that salted egg white peptides VF-4 and DR-8 have a significant antiinflammatory effect in vivo.It also provides a strategy for the treatment of IBD and a new way for the highvalue utilization of salted egg white.展开更多
Objective To evaluate the expression pattern of non-SMC condensin II complex subunit D3(NCAPD3)in hepatocellular carcinoma(HCC)tissues,assess its association with clinical characteristics,and explore the effects of NC...Objective To evaluate the expression pattern of non-SMC condensin II complex subunit D3(NCAPD3)in hepatocellular carcinoma(HCC)tissues,assess its association with clinical characteristics,and explore the effects of NCAPD3 on HCC cells and the potential underlying mechanisms.Methods NCAPD3 expression in HCC tumors and adjacent noncancerous tissues was quantified via quantitative PCR.Patients were divided into high-and low-expression groups on the basis of NCAPD3 levels,and associations with clinical parameters were assessed.The effects of NCAPD3 knockdown and the phosphatidylinositol-3-kinase(PI3K)agonist Y-P 740 on cell functions were examined via cell proliferation,Transwell migration,and invasion assays.Differentially expressed genes following NCAPD3 knockdown in SMMC-7721 cells were identified via mRNA sequencing.Western blotting was performed to measure NCAPD3,AKT serine/threonine kinase 1(AKT1),and phosphorylated AKT1 levels.Results NCAPD3 mRNA expression was notably upregulated in HCC tissues as compared with that in adjacent noncancer tissues.A positive correlation was observed between NCAPD3 expression and both lymphatic and distant metastases in patients with HCC.NCAPD3 knockdown reduced the proliferation and metastasis of SMMC-7721 and Huh-7 cells.mRNA sequencing revealed 140 downregulated genes and 125 upregulated genes.Further validation experiments confirmed that NCAPD3 modulated the PI3K-AKT signalling pathway and that the PI3K agonist Y-P 740 counteracted the effects of NCAPD3 knockdown.Conclusions Elevated NCAPD3 expression was strongly correlated with HCC metastasis.NCAPD3 inhibition impedes HCC cell growth and metastatic potential by suppressing the PI3K–AKT signalling pathway.展开更多
目的本研究旨在运用RNA测序和生物信息学等预测姜黄素对三阴性乳腺癌(triple negative breast cancer,TNBC)Hs578T细胞的抗癌机制,并通过体外实验对潜在的分子机制进行验证。方法用姜黄素处理Hs578T细胞后,采用CCK-8法检测姜黄素对细胞...目的本研究旨在运用RNA测序和生物信息学等预测姜黄素对三阴性乳腺癌(triple negative breast cancer,TNBC)Hs578T细胞的抗癌机制,并通过体外实验对潜在的分子机制进行验证。方法用姜黄素处理Hs578T细胞后,采用CCK-8法检测姜黄素对细胞增殖能力的影响,使用流式细胞术检测姜黄素对细胞凋亡和周期的影响,再使用Transwell实验检测姜黄素对细胞运动能力的影响。然后进行转录组测序、构建PPI网络和富集分析对姜黄素的抗癌机制进行预测,最后使用蛋白免疫印迹技术检测姜黄素对Hs578T细胞增殖相关蛋白的影响。结果姜黄素作用于Hs578T细胞24 h后,CCK8检测结果提示姜黄素的IC50约为20μmol/L。使用20μmol/L姜黄素刺激的Hs578T细胞为实验组,未进行姜黄素刺激的细胞为对照组。较对照组,实验组结果显示姜黄素能显著抑制Hs578T细胞的增殖能力,具有时间和浓度依赖性;显著诱导细胞凋亡,阻滞细胞周期于G2/M期;显著抑制细胞的迁移和侵袭能力,相较于对照组差异均具有统计学意义(P<0.05)。PPI网络分析的结果显示差异表达基因表达的蛋白质之间具有相互作用关系。转录组测序和生物信息学分析的结果显示,姜黄素通过参与多条信号通路发挥抗癌作用,如癌症中的信号通路、PI3K-Akt信号通路等。蛋白印迹结果显示姜黄素能在Hs578T细胞中显著抑制m TOR、p-Akt、Akt、p-S6、S6蛋白表达。结论姜黄素可能通过抑制PI3K-Akt信号通路相关蛋白的表达来发挥其抗增殖作用,为临床姜黄素治疗TNBC提供了理论依据和实验基础。展开更多
复发性流产是女性常见的妊娠病之一,对女性的身心健康造成一定的伤害和压力,中医称之为“滑胎”。现有中医理论认为,肾气亏虚,冲任不固,胎失所系,是导致滑胎的主要病机。PI3K-AKT信号通路在细胞增殖、存活和代谢调节中发挥重要作用,最...复发性流产是女性常见的妊娠病之一,对女性的身心健康造成一定的伤害和压力,中医称之为“滑胎”。现有中医理论认为,肾气亏虚,冲任不固,胎失所系,是导致滑胎的主要病机。PI3K-AKT信号通路在细胞增殖、存活和代谢调节中发挥重要作用,最近研究发现,PI3K-AKT信号通路可影响胚胎植入过程各种细胞功能的调节,其异常可最终导致复发性流产。本文通过回顾相关研究文献,就PI3K-AKT信号通路在复发性流产发生的作用机制、补肾中药及中药复方在此通路防治复发性流产的机制展开综述,以期为中医药防治复发性流产的研究提供参考。Recurrent abortion is one of the common pregnancy diseases in women, which causes certain harm and pressure to women’s physical and mental health. It is referred to “habitual abortion” in traditional Chinese medicine. According to the existing theory of traditional Chinese medicine, kidney qi deficiency, Chongren deficiency and fetal displacement are the main causes of fetal slip. The PI3K-AKT signaling pathway plays an important role in the regulation of cell proliferation, survival and metabolism. Recent studies have found that the PI3K-AKT signaling pathway can affect the regulation of various cell functions during embryo implantation, and its abnormality may eventually lead to recurrent abortion. By reviewing relevant research literature, this paper reviewed the mechanism of PI3K-AKT signaling pathway in recurrent abortion, and the mechanism of kidney-tonifying Chinese medicine and Chinese medicine compound in preventing recurrent abortion through this pathway, in order to provide reference for the research on the prevention and treatment of recurrent abortion by traditional Chinese medicine.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
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
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
Background Colitis caused by bacterial infection is a major global health challenge.Unfortunately,current treatment options are limited.We previously disclosed that L.reuteri SXDT-32 was enriched in the feces of an an...Background Colitis caused by bacterial infection is a major global health challenge.Unfortunately,current treatment options are limited.We previously disclosed that L.reuteri SXDT-32 was enriched in the feces of an ancient diarrhearesistant pig breed(Mashen pig)in China over 2500 years old.As diarrhea is often closely associated with intestinal inflammation,L.reuteri SXDT-32 was identified as a potential beneficial bacterium to prevent intestinal inflammation.However,the precise mechanisms involved remained unclear.Results Our tests showed that L.reuteri SXDT-32 alleviated colonic damage induced by pathogenic E.coli SKLAN202302 in weaned pigs by enhancing barrier integrity and inhibiting inflammation.The transcriptomics revealed that L.reuteri SXDT-32 protected against inflammatory injury by inhibiting the PI3K-AKT signaling pathway.Metabolite analysis indicated that the content of shikimic acid(SA)was substantially elevated in the colonic mucosa of L.reuteri SXDT-32-fed piglets(P<0.05).In addition,Liquid Chromatography-Mass Spectrometer(LC-MS)analysis showed significant increases in SA content in both the colonic chyme of L.reuteri SXDT-32-fed piglets and the supernatant of in vitro grown cultures of L.reuteri SXDT-32(P<0.05).Polymerase chain reaction(PCR)analysis identified gene aroE from L.reuteri SXDT-32,which is a key gene directly linked to SA synthesis,and elevated shikimate dehydrogenase(SD,encoded by aroE)was also detected in both L.reuteri SXDT-32 and the colonic mucosa of piglets fed L.reuteri SXDT-32(P<0.01).In vitro Caco-2 cell experiments demonstrated that SA,L.reuteri SXDT-32,and the supernatant from in vitro grown cultures of L.reuteri SXDT-32 exhibited comparable inhibitory effects on the PI3K-Akt pathway to those of the PI3K inhibitor LY294002.Conclusions L.reuteri SXDT-32 alleviated intestinal inflammation in piglets by producing SA that inhibits the PI3K-Akt pathway.This study provides an innovative approach for the treatment and prevention of colitis caused by bacterial infection.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
Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced man...Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.展开更多
基金the financial support provided by the Project of Jiangxi Provincial Department of Education,China(GJJ200433)。
文摘Inflammation underlies many chronic diseases,and inflammatory bowel disease(IBD)is a condition characterized by long-term inflammation of the gut.Egg whites have been shown to contain many beneficial active substances.Therefore,we obtained 2 peptides from salted egg white:Val-Val-His-Phe(VF-4)and Asp-Thr-Gln-Ala-Met-Pro-Phe-Arg(DR-8).The sodium dextran sulfate(DSS)-induced mice colitis model was used to evaluate its regulatory effect on colitis in vivo.The results showed that VF-4 and DR-8 improved the clinical symptoms of DSS-induced colitis,attenuated colon tissue damage,inhibited the activation of nuclear factor kappa-B(NF-κB)/mitogen-activated protein kinase(MAPK)/phosphoinositide 3-kinase-Akt(PI3K-AKT)signaling pathways,and inhibited the expression of inflammatory cytokines.16S rRNA gene sequencing showed that VF-4 and DR-8 administration increased the relative abundance of intestinal beneficial bacteria including Lactobacillus,Blautia,and down-regulated the relative abundance of inflammation-related bacteria including Acinetobacter,Lachnospiraceae_NK4A136_group,Klebsiella.Moreover,the degree of correlation between pro-inflammatory cytokines and microbiota was as follows:interleukin-6(IL-6)>tumor necrosis factor-α(TNF-α)>interleukin-1β(IL-1β)>interferon-γ(IFN-γ).In conclusion,this study suggests that salted egg white peptides VF-4 and DR-8 have a significant antiinflammatory effect in vivo.It also provides a strategy for the treatment of IBD and a new way for the highvalue utilization of salted egg white.
基金supported by grants from Guangxi Nanning Qingxiu District Key Research and Development Program of Science and Technology Plan(no.2020050)Guangxi Medical and Health Appropriate Technology Development,Promotion and Application Project(no.S2021097)+1 种基金Guangxi Key Research and Development Program(no.AB22080064)Guangxi Natural Science Foundation(no.2017GXNSFAA198126).
文摘Objective To evaluate the expression pattern of non-SMC condensin II complex subunit D3(NCAPD3)in hepatocellular carcinoma(HCC)tissues,assess its association with clinical characteristics,and explore the effects of NCAPD3 on HCC cells and the potential underlying mechanisms.Methods NCAPD3 expression in HCC tumors and adjacent noncancerous tissues was quantified via quantitative PCR.Patients were divided into high-and low-expression groups on the basis of NCAPD3 levels,and associations with clinical parameters were assessed.The effects of NCAPD3 knockdown and the phosphatidylinositol-3-kinase(PI3K)agonist Y-P 740 on cell functions were examined via cell proliferation,Transwell migration,and invasion assays.Differentially expressed genes following NCAPD3 knockdown in SMMC-7721 cells were identified via mRNA sequencing.Western blotting was performed to measure NCAPD3,AKT serine/threonine kinase 1(AKT1),and phosphorylated AKT1 levels.Results NCAPD3 mRNA expression was notably upregulated in HCC tissues as compared with that in adjacent noncancer tissues.A positive correlation was observed between NCAPD3 expression and both lymphatic and distant metastases in patients with HCC.NCAPD3 knockdown reduced the proliferation and metastasis of SMMC-7721 and Huh-7 cells.mRNA sequencing revealed 140 downregulated genes and 125 upregulated genes.Further validation experiments confirmed that NCAPD3 modulated the PI3K-AKT signalling pathway and that the PI3K agonist Y-P 740 counteracted the effects of NCAPD3 knockdown.Conclusions Elevated NCAPD3 expression was strongly correlated with HCC metastasis.NCAPD3 inhibition impedes HCC cell growth and metastatic potential by suppressing the PI3K–AKT signalling pathway.
文摘复发性流产是女性常见的妊娠病之一,对女性的身心健康造成一定的伤害和压力,中医称之为“滑胎”。现有中医理论认为,肾气亏虚,冲任不固,胎失所系,是导致滑胎的主要病机。PI3K-AKT信号通路在细胞增殖、存活和代谢调节中发挥重要作用,最近研究发现,PI3K-AKT信号通路可影响胚胎植入过程各种细胞功能的调节,其异常可最终导致复发性流产。本文通过回顾相关研究文献,就PI3K-AKT信号通路在复发性流产发生的作用机制、补肾中药及中药复方在此通路防治复发性流产的机制展开综述,以期为中医药防治复发性流产的研究提供参考。Recurrent abortion is one of the common pregnancy diseases in women, which causes certain harm and pressure to women’s physical and mental health. It is referred to “habitual abortion” in traditional Chinese medicine. According to the existing theory of traditional Chinese medicine, kidney qi deficiency, Chongren deficiency and fetal displacement are the main causes of fetal slip. The PI3K-AKT signaling pathway plays an important role in the regulation of cell proliferation, survival and metabolism. Recent studies have found that the PI3K-AKT signaling pathway can affect the regulation of various cell functions during embryo implantation, and its abnormality may eventually lead to recurrent abortion. By reviewing relevant research literature, this paper reviewed the mechanism of PI3K-AKT signaling pathway in recurrent abortion, and the mechanism of kidney-tonifying Chinese medicine and Chinese medicine compound in preventing recurrent abortion through this pathway, in order to provide reference for the research on the prevention and treatment of recurrent abortion by traditional Chinese medicine.
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 National Natural Science Foundation of China(U22 A20515)National High-Level Talents Special Support Program of China(2021-WR-01)Agricultural Science and Technology Innovation Program(ASTIPIAS07).
文摘Background Colitis caused by bacterial infection is a major global health challenge.Unfortunately,current treatment options are limited.We previously disclosed that L.reuteri SXDT-32 was enriched in the feces of an ancient diarrhearesistant pig breed(Mashen pig)in China over 2500 years old.As diarrhea is often closely associated with intestinal inflammation,L.reuteri SXDT-32 was identified as a potential beneficial bacterium to prevent intestinal inflammation.However,the precise mechanisms involved remained unclear.Results Our tests showed that L.reuteri SXDT-32 alleviated colonic damage induced by pathogenic E.coli SKLAN202302 in weaned pigs by enhancing barrier integrity and inhibiting inflammation.The transcriptomics revealed that L.reuteri SXDT-32 protected against inflammatory injury by inhibiting the PI3K-AKT signaling pathway.Metabolite analysis indicated that the content of shikimic acid(SA)was substantially elevated in the colonic mucosa of L.reuteri SXDT-32-fed piglets(P<0.05).In addition,Liquid Chromatography-Mass Spectrometer(LC-MS)analysis showed significant increases in SA content in both the colonic chyme of L.reuteri SXDT-32-fed piglets and the supernatant of in vitro grown cultures of L.reuteri SXDT-32(P<0.05).Polymerase chain reaction(PCR)analysis identified gene aroE from L.reuteri SXDT-32,which is a key gene directly linked to SA synthesis,and elevated shikimate dehydrogenase(SD,encoded by aroE)was also detected in both L.reuteri SXDT-32 and the colonic mucosa of piglets fed L.reuteri SXDT-32(P<0.01).In vitro Caco-2 cell experiments demonstrated that SA,L.reuteri SXDT-32,and the supernatant from in vitro grown cultures of L.reuteri SXDT-32 exhibited comparable inhibitory effects on the PI3K-Akt pathway to those of the PI3K inhibitor LY294002.Conclusions L.reuteri SXDT-32 alleviated intestinal inflammation in piglets by producing SA that inhibits the PI3K-Akt pathway.This study provides an innovative approach for the treatment and prevention of colitis caused by bacterial infection.
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supported by the Key Project of the National Natural Science Foundation of China(81920108018 to T.L.and P.S.)Ministry of Science and Technology of the People’s Republic of China(2022ZD0205200)+4 种基金Natural Science Foundation of Sichuan Province(2022NSFSC1607)Key R&D Program of Zhejiang(2022C03096 to T.L.)Special Foundation for Brain Research from Science and Technology Program of Guangdong(2018B030334001)Project for Hangzhou Medical Disciplines of Excellence&Key Project for Hangzhou Medical Disciplines。
文摘Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.
