This study aimed to investigate the effects of infant feces-derived Bifidobacterium breve CCFM1078 on rheumatoid cachexia(RC).Twenty-four female Wistar rats were assigned to 3 groups:CON group(normal saline by gavage)...This study aimed to investigate the effects of infant feces-derived Bifidobacterium breve CCFM1078 on rheumatoid cachexia(RC).Twenty-four female Wistar rats were assigned to 3 groups:CON group(normal saline by gavage),CIA group(collagen-induced arthritis(CIA),normal saline by gavage),and CCFM1078 group(CIA,3×10^(9)CFU/(rat·day)B.breve CCFM1078 gavage).The results demonstrated that B.breve CCFM1078 not only improved skeletal muscle function in CIA rats,but also modulated the gut microbiota,skeletal muscle metabolism and hormone levels,reduced inflammation in the knee joint and skeletal muscles,decreased activity of the nuclear factor κB(NF-κB)inflammatory signaling pathway,enhanced the insulin receptor substrate 1(IRS1)/phosphatidylinositol 3-kinase/protein kinase(PI3K/Akt)signaling pathway,promoted skeletal muscle differentiation,and maintained skeletal muscle fiber diameter,consequently slowing down the progression of RC.These findings suggested that B.breve CCFM1078 may have a beneficial role as part of a dietary intervention for RC,enhancing overall therapeutic effects.展开更多
Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)indu...Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.展开更多
Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,...Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.展开更多
Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive as...Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.展开更多
Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus...Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus,the primary objective of this study is to elucidate the mechanisms by which long non-coding RNA FOXD2-AS1(lncRNA FOXD2-AS1)regulates early osteogenic differentiation in H-BMSCs,thereby identifying potential therapeutic targets.Methods Lentivirus-mediated vectors were constructed to either overexpress or silence FOXD2-AS1 in H-BMSCs.The effects of FOXD2-AS1 on osteogenesis were subsequently assessed by analyzing osteogenic marker expression and alkaline phosphatase(ALP)staining.To clarify the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in this process,AG490 inhibitor(a JAK2/STAT3 pathway inhibitor)and knockdown of STAT3 were used to investigate the mechanisms of FOXD2-AS1.Results FOXD2-AS1 overexpression increased ALP activity and osteogenic marker expression,while its knockdown had the opposite effects.From a mechanistic perspective,FOXD2-AS1 overexpression promoted JAK2 and STAT3 phosphorylation,whereas its suppression attenuated their activation.Also,the osteogenic increase induced by FOXD2-AS1 overexpression was reversed by AG490 treatment or STAT3 silencing,indicating that the pathway plays a role in this process.Conclusion FOXD2-AS1 was identified as a novel genetic switch driving osteogenic commitment via JAK2/STAT3 activation,revealing a new regulatory mechanism and a potential therapeutic target for osteoporosis.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
T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue ...T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.展开更多
Objective:The occurrence and development of atrial fibrillation(AF)are influenced by the autonomic nervous system and inflammation.Acupuncture is an effective treatment for AF.This study explored the protective effect...Objective:The occurrence and development of atrial fibrillation(AF)are influenced by the autonomic nervous system and inflammation.Acupuncture is an effective treatment for AF.This study explored the protective effects of acupuncture in a rat model of paroxysmal AF and investigated its mechanisms.Methods:Male Sprague-Dawley rats(n=130)were randomly divided into blank control(Con),sham operation(Sham),AF,and acupuncture treatment(Acu)groups.A paroxysmal AF model was established by rapid atrial pacing through the jugular vein.Rats in the Acu group were immobilized to receive acupuncture treatment at Neiguan acupoint(PC6)for 20 min daily for seven days.The other groups were immobilized for the same duration over the treatment period but did not receive acupuncture.The AF induction rate,AF duration,cardiac electrophysiological parameters,and heart rate variability were evaluated by monitoring surface electrocardiogram and vagus nerve discharge signals.After the intervention,the rats were euthanized,and atrial morphology was assessed using haematoxylin and eosin staining.The expression of macrophage F4/80 antigen(F4/80)and cluster of differentiation(CD)86 in atrial myocardial tissue was detected using immunohistochemistry,immunofluorescence and flow cytometry.The expression levels or contents of interleukin(IL)-1β,IL-6,tumor necrosis factor-a(TNF-a),a7 nicotinic acetylcholine receptor(a7nAChR),phosphorylated Janus kinase 2(p-JAK2),and phosphorylated signal transducer and activator of transcription 3(p-STAT3)in atrial myocardial tissue were detected using Western blotting,reverse transcription-quantitative polymerase chain reaction,or enzyme-linked immunosorbent assay.The role of a7nAChR in acupuncture treatment was verified by intraperitoneal injection of the a7nAChR antagonist methyllycaconitine(MLA).Results:Compared with the AF group,acupuncture significantly reduced AF duration and induction rate,improved cardiac electrophysiology by enhancing vagus nerve activity and regulating autonomic balance.It also decreased the pro-inflammatory M1 macrophage proportion,alleviating myocardial injury and infiltration.MLA weakened acupuncture's electrophysiological improvement and anti-inflammatory effect.Results suggest that acupuncture triggers the a7nAChR-JAK2/STAT3 pathway and exerts cardioprotection via neuroimmune regulation.Conclusion:Acupuncture significantly reduced the AF induction rate,shortened AF duration,improved cardiac electrophysiological parameters,enhanced vagus nerve activity,and decreased the expression of pro-inflammatory M1 macrophages and inflammatory factors in rats with paroxysmal AF.展开更多
Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell...Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell carcinoma(ESCC)cells to cisplatin(DDP)is not well understood.Methods:Cell counting kit-8 assay examined how GA affected KYSE30 and TE-1 cell viability.5-Ethynyl-2′-deoxyuridine and TdT-mediated dUTP Nick-End labeling staining detected cell proliferation and apoptosis.Clone formation assay,flow cytometry,Carboxyfluorescein diacetate succinimidyl ester fluorescent probes,and Transwell assay determined cell biological properties,and 2′,7′-Dichlorofluorescin diacetate(DCFH-DA)fluorescent probes detected oxidative stress levels.Signal transducer and activator of transcription 3(STAT3)/Notch pathway protein levels after GA and/or Interleukin-6(IL-6)intervention were examined through Western blot.Furthermore,a model for subcutaneous graft tumors was established in nude mice.Results:GA exerted suppressive effects on cell proliferation,and caused apoptosis of KYSE30 and TE-1 cells.IL-6 intervention activated the STAT3/Notch pathway and promoted the malignant biological properties of ESCC cells.In contrast,GA attenuated the effects of IL-6,while STAT3 or Notch inhibitor further enhanced the effects of GA,suggesting that GA inhibited the IL-6/STAT3/Notch pathway.Not only that,GA promoted oxidative stress and enhanced cell sensitivity to DDP both in vitro and in vivo.Conclusion:GA suppresses the malignant progression of ESCC and enhances cell sensitivity to DDP by hindering the IL-6/STAT3/Notch pathway.展开更多
BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear f...BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.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
AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by beh...AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.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
The intestinal mucosa is the intestinal lumen tissue that protects the intestine from invasion,maintains intestinal barrier function,and participates in the immune response.Diseases such as inflammatory enteritis and ...The intestinal mucosa is the intestinal lumen tissue that protects the intestine from invasion,maintains intestinal barrier function,and participates in the immune response.Diseases such as inflammatory enteritis and intestinal infections can cause damage to the intestinal mucosal barrier and dysfunction.The aim of this study was to investigate the improvement mechanism of malvidin-3-O-galactoside(M3G)on small intestinal mucosal barrier function.C57BL/6J male mice were given dextran sodium sulfate(DSS)for 7 days to induce enteritis,and then were fed normally with or without M3G supplementation for another 7 days.The results showed that M3G supplementation significantly improved the disease activity index(DAI)score and small intestinal tissue injury in mice with DSS induced enteritis.M3G ameliorated the small intestinal mucosal mechanical barrier function by modulating the expression of mucin 2(MUC2),zona occludens 1(ZO-1),Occludin,Claudin-1,intestinal fatty acid binding protein(iFABP),and trefoil factor 3(TFF3)in the small intestine mucosa,and the serum levels of D-lactic acid(D-LA),lipopolysaccharide(LPS),and diamine oxidase(DAO)were significantly decreased.Additionally,M3G also relieved the small intestinal immunologic barrier of mice by decreasing the immune protein levels of immunoglobulin A(IgA),immunoglobulin M(IgM),and immunoglobulin G(IgG)in serum,and secretory immunoglobulin A(SIgA)level in small intestine tissue.Furthermore,M3G inhibited the expression of Notch pathway-related proteins such as Notch1,Notch intracellular domain(NICD),delta-like ligand 4(DLL4),delta-like ligand 1(DLL1),and hairy/enhancer of split 1(Hes1).In conclusion,the results demonstrated that M3G can improve intestinal mucosal barrier function by inhibiting Notch pathway.展开更多
Objective:Peritoneal fibrosis(PF)is an adverse event that occurs during long-term peritoneal dialysis,significantly impairing treatment efficiency and adversely affecting patient outcomes.Astragaloside IV(AS-Ⅳ),a pri...Objective:Peritoneal fibrosis(PF)is an adverse event that occurs during long-term peritoneal dialysis,significantly impairing treatment efficiency and adversely affecting patient outcomes.Astragaloside IV(AS-Ⅳ),a principal active component derived from Astragalus membranaceus(Fisch.)Bunge,has exhibited anti-inflammatory and antifibrotic effects in various settings.This study aims to investigate the potential therapeutic efficacy and mechanism of AS-Ⅳin the treatment of PF.Methods:The PF mouse model was established by intraperitoneal injection of 4.25%peritoneal dialysis fluid(100 mL/kg).The epithelial-mesenchymal transition(EMT)of HMrSV5 cells was induced by the addition of 10 ng/mL transforming growth factorβ(TGF-β).The differentially expressed genes in HMrSV5 cells treated with AS-Ⅳwere screened using transcriptome sequencing analysis.The potential targets of AS-Ⅳwere screened using network pharmacology and analyzed using molecular docking and molecular dynamics simulations.Results:Administration of AS-Ⅳat doses of 20,40,or 80 mg/kg effectively mitigated the increase in peritoneal thickness and the development of fibrosis in mice with PF.The expression of the fibrosis markerα-smooth muscle actin in the peritoneum was significantly decreased in AS-Ⅳ-treated mice.The treatment of AS-Ⅳ(10,20,and 40μmol/L)significantly delayed the EMT of HMrSV5 cells induced by TGF-β,as demonstrated by the decreased number of 5-ethynyl-2'-deox yuridine-positive cells,reduced migrated area,and decreased expression of fibrosis markers.A total of 460 differentially expressed genes were detected in AS-Ⅳ-treated HMrSV5 cells through transcriptome sequencing,with notable enrichment in the phosphatidylinositol-4,5-bisphosphate3-kinase(PI3K)-AKT serine/threonine kinase 1(AKT)signaling pathway.The reduced levels of phosphorylated PI3K(p-PI3K)and p-AKT were detected in HMrSV5 cells with AS-Ⅳtreatment.Epidermal growth factor receptor(EGFR)was predicted as a direct target of AS-Ⅳ,exhibiting strong hydrogen bond interactions.The activation of the PI3K-AKT pathway by the compound740Y-P,and the activation of the EGFR pathway by NSC 228155 each partially counteracted the inhibitory effect of AS-Ⅳon the EMT of HMrSV5 cells.Conclusion:AS-Ⅳdelayed the EMT process in peritoneal mesothelial cells and slowed the progression of PF,potentially serving as a therapeutic agent for the early prevention and treatment of PF.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
BACKGROUND MEX3A is a member of the human homologous gene MEX-3 family.It has been shown to promote cell proliferation and migration in various cancers,indicating its potential clinical significance.However,the role o...BACKGROUND MEX3A is a member of the human homologous gene MEX-3 family.It has been shown to promote cell proliferation and migration in various cancers,indicating its potential clinical significance.However,the role of MEX3A in hepatocellular carcinoma(HCC)remains largely unexplored,with limited reports available in the literature.AIM To investigate expression and clinical significance of MEX3A in HCC and explore its potential role in tumor progression.METHODS We analyzed MEX3A mRNA expression in HCC and adjacent tissues using data from The Cancer Genome Atlas(TCGA).The correlation between MEX3A expression and overall survival(OS)was evaluated.Immunohistochemistry was performed on HCC surgical specimens to validate MEX3A expression and its association with clinical parameters,including hepatitis B virus(HBV)positivity,tumor differentiation and tumor size.Additionally,MEX3A knockdown HCC cell lines were constructed to explore the biological functions of MEX3A.Cell prolif-eration was assessed using cell counting kit-8 and clone formation assays,while cell cycle progression was analyzed by flow cytometry.The effects of MEX3A on the Wnt/β-catenin signaling pathway were examined by western blotting and immunofluorescence.Cell migration was evaluated using scratch and Transwell assays.Finally,the role of the transcription factor RORA in mediating MEX3A effects was explored by silencing RORA and analyzing its impact on cell proliferation and protein expression.RESULTS TCGA data analysis revealed that MEX3A mRNA expression was significantly higher in HCC tissues compared to adjacent tissues.Higher MEX3A expression was associated with poorer OS.These findings were validated in HCC surgical specimens.Immunohistochemistry confirmed elevated MEX3A expression in HCC tissues and showed positive correlations with Ki-67 and vimentin levels.MEX3A expression was closely related to HBV positivity,tumor differentiation and tumor size.Mechanistic studies demonstrated that MEX3A knockdown inhibited cell proliferation and cell cycle progression,as shown by reduced expression ofβ-catenin,c-Myc and cyclin D1.Additionally,MEX3A knockdown inhibited the nuclear entry ofβ-catenin,thereby suppressing the activation of downstream oncogenic pathways.MEX3A depletion significantly reduced the migratory ability of HCC cells,likely through downregulation of the epithelial-mesenchymal transition pathway.Transcription factor analysis identified RORA as a potential mediator of MEX3A effects.Silencing RORA antagonized the effects of MEX3A on cell proliferation and the expression ofβ-catenin,c-Myc and cyclin D1.CONCLUSION MEX3A promotes cell proliferation in HCC by regulating the RORA/β-catenin pathway.Our findings suggest that MEX3A could serve as a prognostic marker and therapeutic target for HCC.展开更多
BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a f...BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a focus on the of phosphoinositide 3-kinases(PI3K)/AKT signaling pathway.AIM To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.METHODS Using Metascape,we analyzed the potential targets of tetrahydrocurcumin in HCC.Molecular docking validation was performed using SYBYL2.0.Cell Counting Kit-8,wound healing,and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration,invasion,and apoptosis.The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.RESULTS Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells,promoted their apoptosis,and downregulated the expression of p-PI3K,p-AKT,and B cell leukemia/lymphoma 2,while upregulating caspase-3,p53,and B cell leukemia/lymphoma 2 associated X.CONCLUSION In summary,tetrahydrocurcumin suppresses PI3K/AKT signaling,promotes apoptosis,and prevents the migration and invasion of liver cancer cells.展开更多
基金supported by the National Natural Science Foundation of China(32021005)111 project(BP0719028)the Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province.
文摘This study aimed to investigate the effects of infant feces-derived Bifidobacterium breve CCFM1078 on rheumatoid cachexia(RC).Twenty-four female Wistar rats were assigned to 3 groups:CON group(normal saline by gavage),CIA group(collagen-induced arthritis(CIA),normal saline by gavage),and CCFM1078 group(CIA,3×10^(9)CFU/(rat·day)B.breve CCFM1078 gavage).The results demonstrated that B.breve CCFM1078 not only improved skeletal muscle function in CIA rats,but also modulated the gut microbiota,skeletal muscle metabolism and hormone levels,reduced inflammation in the knee joint and skeletal muscles,decreased activity of the nuclear factor κB(NF-κB)inflammatory signaling pathway,enhanced the insulin receptor substrate 1(IRS1)/phosphatidylinositol 3-kinase/protein kinase(PI3K/Akt)signaling pathway,promoted skeletal muscle differentiation,and maintained skeletal muscle fiber diameter,consequently slowing down the progression of RC.These findings suggested that B.breve CCFM1078 may have a beneficial role as part of a dietary intervention for RC,enhancing overall therapeutic effects.
基金funded by Yunnan Youth Top-notch Talent Support Program(YNWR-QNBJ2018-173)Agricultural Joint project of Yunnan Provincial S&T Programs(202301BD070001-195)+2 种基金S&T project of Yunnan provincial finance(K212020001-01)supported by Yunnan Province Education Department’s Engineering Research Center of Eco-friendly Products from Yunnan Characteristic Edible FungiYunnan Province Yongsheng County Farmer Academician Technology service station.
文摘Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.
基金funded by the Yancheng Municipal Health Commission 2024 Medical Research Project(YK2024166).
文摘Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.
基金supported by the National Natural Science Foundation of China(82071362 and 82270669)Key Project of the Regional Joint Fund of Guangdong Province(2023B1515120077)+3 种基金Basic Research Program of Shenzhen Science and Technology Innovation Commission(JCYJ20210324123001003 and JCYJ20220530144801003)Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research(ZDSYS20230626091402006)the Innovation and Entrepreneurship Training Program for College Students,Sun Yat-sen University(20242150)the Leading Innovation and Entrepreneurship Team Program of Zhejiang Province,China(2023R01005).
文摘Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.
基金supported by the Natural Science Foundation of Hubei Province of China(Grant No.2023AFB671)the National Natural Science Foundation of China(Grant Nos.82360177 and 82560182)+1 种基金the Key Project of Jiangxi Provincial Natural Science Foundation(Grant No.20224ACB206011)“Xuncheng Talents”Project in Jiujiang City,Jiangxi Province(Grant No.JJXC2023071).
文摘Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus,the primary objective of this study is to elucidate the mechanisms by which long non-coding RNA FOXD2-AS1(lncRNA FOXD2-AS1)regulates early osteogenic differentiation in H-BMSCs,thereby identifying potential therapeutic targets.Methods Lentivirus-mediated vectors were constructed to either overexpress or silence FOXD2-AS1 in H-BMSCs.The effects of FOXD2-AS1 on osteogenesis were subsequently assessed by analyzing osteogenic marker expression and alkaline phosphatase(ALP)staining.To clarify the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in this process,AG490 inhibitor(a JAK2/STAT3 pathway inhibitor)and knockdown of STAT3 were used to investigate the mechanisms of FOXD2-AS1.Results FOXD2-AS1 overexpression increased ALP activity and osteogenic marker expression,while its knockdown had the opposite effects.From a mechanistic perspective,FOXD2-AS1 overexpression promoted JAK2 and STAT3 phosphorylation,whereas its suppression attenuated their activation.Also,the osteogenic increase induced by FOXD2-AS1 overexpression was reversed by AG490 treatment or STAT3 silencing,indicating that the pathway plays a role in this process.Conclusion FOXD2-AS1 was identified as a novel genetic switch driving osteogenic commitment via JAK2/STAT3 activation,revealing a new regulatory mechanism and a potential therapeutic target for osteoporosis.
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supported by the National Natural Science Foundation of China(No.81872567).
文摘T-2 toxin,an omnipresent environmental contaminant,poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity.This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin.Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0,10,and 100 nanograms per gram body weight per day(ng/(g·day)),respectively.Morphological,pathological,and ultrastructural alterations in cardiac tissue were meticulously examined.Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites.The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected.The results showed that exposure to T-2 toxin elicited myocardial tissue disorders,interstitial hemorrhage,capillary dilation,and fibrotic damage.Mitochondria were markedly impaired,including swelling,fusion,matrix degradation,and membrane damage.Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiacmetabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway.T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress.In conclusion,the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway.This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.
基金supported by the National Key Research and Development Program of China(No.2019YFC1712100)the National Natural Science Foundation of China(No.82105017)。
文摘Objective:The occurrence and development of atrial fibrillation(AF)are influenced by the autonomic nervous system and inflammation.Acupuncture is an effective treatment for AF.This study explored the protective effects of acupuncture in a rat model of paroxysmal AF and investigated its mechanisms.Methods:Male Sprague-Dawley rats(n=130)were randomly divided into blank control(Con),sham operation(Sham),AF,and acupuncture treatment(Acu)groups.A paroxysmal AF model was established by rapid atrial pacing through the jugular vein.Rats in the Acu group were immobilized to receive acupuncture treatment at Neiguan acupoint(PC6)for 20 min daily for seven days.The other groups were immobilized for the same duration over the treatment period but did not receive acupuncture.The AF induction rate,AF duration,cardiac electrophysiological parameters,and heart rate variability were evaluated by monitoring surface electrocardiogram and vagus nerve discharge signals.After the intervention,the rats were euthanized,and atrial morphology was assessed using haematoxylin and eosin staining.The expression of macrophage F4/80 antigen(F4/80)and cluster of differentiation(CD)86 in atrial myocardial tissue was detected using immunohistochemistry,immunofluorescence and flow cytometry.The expression levels or contents of interleukin(IL)-1β,IL-6,tumor necrosis factor-a(TNF-a),a7 nicotinic acetylcholine receptor(a7nAChR),phosphorylated Janus kinase 2(p-JAK2),and phosphorylated signal transducer and activator of transcription 3(p-STAT3)in atrial myocardial tissue were detected using Western blotting,reverse transcription-quantitative polymerase chain reaction,or enzyme-linked immunosorbent assay.The role of a7nAChR in acupuncture treatment was verified by intraperitoneal injection of the a7nAChR antagonist methyllycaconitine(MLA).Results:Compared with the AF group,acupuncture significantly reduced AF duration and induction rate,improved cardiac electrophysiology by enhancing vagus nerve activity and regulating autonomic balance.It also decreased the pro-inflammatory M1 macrophage proportion,alleviating myocardial injury and infiltration.MLA weakened acupuncture's electrophysiological improvement and anti-inflammatory effect.Results suggest that acupuncture triggers the a7nAChR-JAK2/STAT3 pathway and exerts cardioprotection via neuroimmune regulation.Conclusion:Acupuncture significantly reduced the AF induction rate,shortened AF duration,improved cardiac electrophysiological parameters,enhanced vagus nerve activity,and decreased the expression of pro-inflammatory M1 macrophages and inflammatory factors in rats with paroxysmal AF.
基金Mechanistic Investigation into the Extraction,Purification,and Anti-Esophageal Cancer Effects of Gallic Acid Derived from Rhodiola crenulata(YLUKLM2023001).
文摘Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell carcinoma(ESCC)cells to cisplatin(DDP)is not well understood.Methods:Cell counting kit-8 assay examined how GA affected KYSE30 and TE-1 cell viability.5-Ethynyl-2′-deoxyuridine and TdT-mediated dUTP Nick-End labeling staining detected cell proliferation and apoptosis.Clone formation assay,flow cytometry,Carboxyfluorescein diacetate succinimidyl ester fluorescent probes,and Transwell assay determined cell biological properties,and 2′,7′-Dichlorofluorescin diacetate(DCFH-DA)fluorescent probes detected oxidative stress levels.Signal transducer and activator of transcription 3(STAT3)/Notch pathway protein levels after GA and/or Interleukin-6(IL-6)intervention were examined through Western blot.Furthermore,a model for subcutaneous graft tumors was established in nude mice.Results:GA exerted suppressive effects on cell proliferation,and caused apoptosis of KYSE30 and TE-1 cells.IL-6 intervention activated the STAT3/Notch pathway and promoted the malignant biological properties of ESCC cells.In contrast,GA attenuated the effects of IL-6,while STAT3 or Notch inhibitor further enhanced the effects of GA,suggesting that GA inhibited the IL-6/STAT3/Notch pathway.Not only that,GA promoted oxidative stress and enhanced cell sensitivity to DDP both in vitro and in vivo.Conclusion:GA suppresses the malignant progression of ESCC and enhances cell sensitivity to DDP by hindering the IL-6/STAT3/Notch pathway.
基金Supported by Xi’an Science and Technology Plan Project,No.23YXYJ0162Shaanxi Province Traditional Chinese Medicine Research and Innovation Talent Plan Project,No.TZKN-CXRC-16+2 种基金Project of Shaanxi Administration of Traditional Chinese Medicine,No.SZYKJCYC-2025-JC-010Shaanxi Province Key Research and Development Plan Project-Social Development Field,No.S2025-YF-YBSF-0391the Science and Technology Innovation Cultivation Program of Longhua Hospital affiliated to Shanghai University of Chinese Medicine,No.YD202220。
文摘BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.
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.
基金Supported by the Natural Science Foundation of Chongqing Municipality,China(No.CSTB2022NSCQ-BHX0725)the National Natural Science Foundation of China(No.82401728).
文摘AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.
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Liaoning Provincial Department of Education Project-General Project(LJKMZ20221060)National Key R&D Program of China(2022YFD1600505).
文摘The intestinal mucosa is the intestinal lumen tissue that protects the intestine from invasion,maintains intestinal barrier function,and participates in the immune response.Diseases such as inflammatory enteritis and intestinal infections can cause damage to the intestinal mucosal barrier and dysfunction.The aim of this study was to investigate the improvement mechanism of malvidin-3-O-galactoside(M3G)on small intestinal mucosal barrier function.C57BL/6J male mice were given dextran sodium sulfate(DSS)for 7 days to induce enteritis,and then were fed normally with or without M3G supplementation for another 7 days.The results showed that M3G supplementation significantly improved the disease activity index(DAI)score and small intestinal tissue injury in mice with DSS induced enteritis.M3G ameliorated the small intestinal mucosal mechanical barrier function by modulating the expression of mucin 2(MUC2),zona occludens 1(ZO-1),Occludin,Claudin-1,intestinal fatty acid binding protein(iFABP),and trefoil factor 3(TFF3)in the small intestine mucosa,and the serum levels of D-lactic acid(D-LA),lipopolysaccharide(LPS),and diamine oxidase(DAO)were significantly decreased.Additionally,M3G also relieved the small intestinal immunologic barrier of mice by decreasing the immune protein levels of immunoglobulin A(IgA),immunoglobulin M(IgM),and immunoglobulin G(IgG)in serum,and secretory immunoglobulin A(SIgA)level in small intestine tissue.Furthermore,M3G inhibited the expression of Notch pathway-related proteins such as Notch1,Notch intracellular domain(NICD),delta-like ligand 4(DLL4),delta-like ligand 1(DLL1),and hairy/enhancer of split 1(Hes1).In conclusion,the results demonstrated that M3G can improve intestinal mucosal barrier function by inhibiting Notch pathway.
基金Zhejiang Medical Technology Project(No.2022RC009)Zhejiang Provincial Natural Science Foundation(No.LY23H050005)National Natural Science Foundation of China(No.81900692)。
文摘Objective:Peritoneal fibrosis(PF)is an adverse event that occurs during long-term peritoneal dialysis,significantly impairing treatment efficiency and adversely affecting patient outcomes.Astragaloside IV(AS-Ⅳ),a principal active component derived from Astragalus membranaceus(Fisch.)Bunge,has exhibited anti-inflammatory and antifibrotic effects in various settings.This study aims to investigate the potential therapeutic efficacy and mechanism of AS-Ⅳin the treatment of PF.Methods:The PF mouse model was established by intraperitoneal injection of 4.25%peritoneal dialysis fluid(100 mL/kg).The epithelial-mesenchymal transition(EMT)of HMrSV5 cells was induced by the addition of 10 ng/mL transforming growth factorβ(TGF-β).The differentially expressed genes in HMrSV5 cells treated with AS-Ⅳwere screened using transcriptome sequencing analysis.The potential targets of AS-Ⅳwere screened using network pharmacology and analyzed using molecular docking and molecular dynamics simulations.Results:Administration of AS-Ⅳat doses of 20,40,or 80 mg/kg effectively mitigated the increase in peritoneal thickness and the development of fibrosis in mice with PF.The expression of the fibrosis markerα-smooth muscle actin in the peritoneum was significantly decreased in AS-Ⅳ-treated mice.The treatment of AS-Ⅳ(10,20,and 40μmol/L)significantly delayed the EMT of HMrSV5 cells induced by TGF-β,as demonstrated by the decreased number of 5-ethynyl-2'-deox yuridine-positive cells,reduced migrated area,and decreased expression of fibrosis markers.A total of 460 differentially expressed genes were detected in AS-Ⅳ-treated HMrSV5 cells through transcriptome sequencing,with notable enrichment in the phosphatidylinositol-4,5-bisphosphate3-kinase(PI3K)-AKT serine/threonine kinase 1(AKT)signaling pathway.The reduced levels of phosphorylated PI3K(p-PI3K)and p-AKT were detected in HMrSV5 cells with AS-Ⅳtreatment.Epidermal growth factor receptor(EGFR)was predicted as a direct target of AS-Ⅳ,exhibiting strong hydrogen bond interactions.The activation of the PI3K-AKT pathway by the compound740Y-P,and the activation of the EGFR pathway by NSC 228155 each partially counteracted the inhibitory effect of AS-Ⅳon the EMT of HMrSV5 cells.Conclusion:AS-Ⅳdelayed the EMT process in peritoneal mesothelial cells and slowed the progression of PF,potentially serving as a therapeutic agent for the early prevention and treatment of PF.
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.
基金Supported by Suzhou Municipal Science and Technology Bureau,No.SYS2020081.
文摘BACKGROUND MEX3A is a member of the human homologous gene MEX-3 family.It has been shown to promote cell proliferation and migration in various cancers,indicating its potential clinical significance.However,the role of MEX3A in hepatocellular carcinoma(HCC)remains largely unexplored,with limited reports available in the literature.AIM To investigate expression and clinical significance of MEX3A in HCC and explore its potential role in tumor progression.METHODS We analyzed MEX3A mRNA expression in HCC and adjacent tissues using data from The Cancer Genome Atlas(TCGA).The correlation between MEX3A expression and overall survival(OS)was evaluated.Immunohistochemistry was performed on HCC surgical specimens to validate MEX3A expression and its association with clinical parameters,including hepatitis B virus(HBV)positivity,tumor differentiation and tumor size.Additionally,MEX3A knockdown HCC cell lines were constructed to explore the biological functions of MEX3A.Cell prolif-eration was assessed using cell counting kit-8 and clone formation assays,while cell cycle progression was analyzed by flow cytometry.The effects of MEX3A on the Wnt/β-catenin signaling pathway were examined by western blotting and immunofluorescence.Cell migration was evaluated using scratch and Transwell assays.Finally,the role of the transcription factor RORA in mediating MEX3A effects was explored by silencing RORA and analyzing its impact on cell proliferation and protein expression.RESULTS TCGA data analysis revealed that MEX3A mRNA expression was significantly higher in HCC tissues compared to adjacent tissues.Higher MEX3A expression was associated with poorer OS.These findings were validated in HCC surgical specimens.Immunohistochemistry confirmed elevated MEX3A expression in HCC tissues and showed positive correlations with Ki-67 and vimentin levels.MEX3A expression was closely related to HBV positivity,tumor differentiation and tumor size.Mechanistic studies demonstrated that MEX3A knockdown inhibited cell proliferation and cell cycle progression,as shown by reduced expression ofβ-catenin,c-Myc and cyclin D1.Additionally,MEX3A knockdown inhibited the nuclear entry ofβ-catenin,thereby suppressing the activation of downstream oncogenic pathways.MEX3A depletion significantly reduced the migratory ability of HCC cells,likely through downregulation of the epithelial-mesenchymal transition pathway.Transcription factor analysis identified RORA as a potential mediator of MEX3A effects.Silencing RORA antagonized the effects of MEX3A on cell proliferation and the expression ofβ-catenin,c-Myc and cyclin D1.CONCLUSION MEX3A promotes cell proliferation in HCC by regulating the RORA/β-catenin pathway.Our findings suggest that MEX3A could serve as a prognostic marker and therapeutic target for HCC.
基金the Central Government Guidance Local Science and Technology Development Fund,No.2023JH6/100100021Liaoning Province Education Department Foundation of China,No.JYTMS20231393+2 种基金Scientific Research Project of Liaoning Province Education Department,No.SYYX2019015Science and Technology Fund of Shenyang Medical College,No.20171004,Shenyang Medical College Master’s Science and Technology Innovation Fund,No.Y20220509Liaoning Provincial Department of Education Scientific Research Project,No.LJ212410164032.
文摘BACKGROUND Liver cancer has a high incidence and mortality worldwide,especially in China.Herein,we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma(HCC),with a focus on the of phosphoinositide 3-kinases(PI3K)/AKT signaling pathway.AIM To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.METHODS Using Metascape,we analyzed the potential targets of tetrahydrocurcumin in HCC.Molecular docking validation was performed using SYBYL2.0.Cell Counting Kit-8,wound healing,and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration,invasion,and apoptosis.The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.RESULTS Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells,promoted their apoptosis,and downregulated the expression of p-PI3K,p-AKT,and B cell leukemia/lymphoma 2,while upregulating caspase-3,p53,and B cell leukemia/lymphoma 2 associated X.CONCLUSION In summary,tetrahydrocurcumin suppresses PI3K/AKT signaling,promotes apoptosis,and prevents the migration and invasion of liver cancer cells.
