Objective Inflammation and fibrosis are key features of diabetic nephropathy(DN).Triptolide(TP)exhibits anti-inflammatory and anti-fibrotic properties,though its mechanisms of action in DN remain unclear.CREKA(Cys-Arg...Objective Inflammation and fibrosis are key features of diabetic nephropathy(DN).Triptolide(TP)exhibits anti-inflammatory and anti-fibrotic properties,though its mechanisms of action in DN remain unclear.CREKA(Cys-Arg-Glu-Lys-Ala)is a pentapeptide that specifically binds to fibronectin(FN),and the CREKA-modified liposome(CREKA-Lip)represents a novel FN-targeted drug delivery system.This study aimed to investigate the role of TP in diabetic db/db mice and determine whether encapsulation within CREKA-Lip enhances therapeutic efficacy while reducing the multi-organ toxicity of TP.Methods Eight-week-old diabetic db/db mice received tail vein injections twice weekly with vehicle,free TP,or CREKA-Lip/TP for 10 weeks.Urine and serum parameters were measured,and kidney,heart,liver,and testis tissues were collected for pathological evaluation.Protein-protein interaction networks were constructed using Cytoscape and its plug-ins to identify core targets and elucidate the therapeutic mechanism of TP against DN.Inflammatory,fibrotic,apoptotic,and lipid metabolism markers were evaluated in the kidneys of diabetic mice with DN and in high glucose-treated mouse mesangial cells and podocytes using qPCR,Western blot,immunohistochemistry,and immunofluorescence assays.Results TP administration reduced fasting blood glucose levels and glomerular mesangial expansion in diabetic mice.TP significantly suppressed renal inflammation,fibrosis,and apoptosis while enhancing lipid metabolism.Integration of network pharmacology,molecular docking,and transcriptomics revealed that TP ameliorated DN by inhibiting the JAK2-STAT1 signaling pathway.In vitro,TP inhibited high glucose-induced phosphorylation of JAK2 and STAT1,reduced collagen production in mesangial cells,decreased apoptosis,and improved lipid metabolism in podocytes.Moreover,CREKA-Lip/TP exhibited superior efficacy compared with free TP,with a more sustained reduction in urine albumin-to-creatinine ratio and greater inhibition of mesangial expansion.Notably,CREKA-Lip/TP treatment did not induce systemic toxicity.Conclusion TP improves renal inflammation,fibrosis,apoptosis,and lipid homeostasis,thereby ameliorating DN by inhibiting JAK2-STAT1 activation.Targeted delivery of TP via FN-binding CREKA-Lip enhances therapeutic efficacy while minimizing multi-organ toxicity.展开更多
The published article titled“Triptolide inhibits proliferation and migration of human neuroblastoma SH-SY5Y cells by upregulating microRNA-181a”has been retracted from Oncology Research,Vol.26,No.8,2018,PP.1235-1243.
The awn can contribute to photosynthesis and carbohydrates,enhancing grain yield in wheat.We mapped QAwn.sxau-5A,a major QTL for awn development in wheat(Triticum aestivum).This QTL was delimited to a 994-kb interval ...The awn can contribute to photosynthesis and carbohydrates,enhancing grain yield in wheat.We mapped QAwn.sxau-5A,a major QTL for awn development in wheat(Triticum aestivum).This QTL was delimited to a 994-kb interval at the B1 locus on chromosome 5A,which included the candidate gene encoding a zinc finger protein(TraesCS5A01G542800)as an awn length inhibitor(ALI).The Ali-A1 allele for the awnless trait showed abundant sequence differences in the promoter regions compared to the ali-A1 allele for the long-awn trait.The results of the swap experiment on the promoters from the two ALI-A1 alleles showed that the two promoters caused a difference in the protein level,indicating the gene was regulated at the transcript level.However,the ali-A1 allele contained an SNP that caused a premature stop codon in its coding region,resulting in a truncated protein compared to the functional Ali-A1 protein.The Ali-A1 protein contained two ethylene-responsive element binding factor-associated amphiphilic repression(EAR)motifs,one at the N terminus(EAR-N)and the other at the C terminus(EAR-C),and they were involved in interactions with the wheat co-repressor protein TOPLESS(TPL1).The ali-A1 protein retained the EAR-N motif but lost the EAR-C motif,resulting in the attenuated ability to interact with TPL1.The tpl1 mutant produced a longer awn compared to the wild type.Ali-A1 repressed the transcription of two downstream genes,TaLRP-A1 and TaARF-B1,involved in endogenous auxin concentrations and auxin responses in wheat.We concluded that the awn length is regulated not only by the ALI-A1 gene at transcript levels but also by Ali-A1 and TPL1 at the protein level in wheat.展开更多
Rheumatoid arthritis(RA)is a progressive autoimmune disease characterized by bone destruction that is primarily caused by the overactivation of osteoclasts(OCs),which are critical therapeutic targets.Triptolide(TP)has...Rheumatoid arthritis(RA)is a progressive autoimmune disease characterized by bone destruction that is primarily caused by the overactivation of osteoclasts(OCs),which are critical therapeutic targets.Triptolide(TP)has strong anti-RA effects but is limited by its narrow therapeutic window and associated toxicity,necessitating combination therapy to increase its efficacy and reduce side effects.Medicarpin(Med),a flavonoid with anti-inflammatory and anti-bone destruction properties,has shown potential in reducing osteoclastogenesis.However,the mechanisms underlying the synergistic effects of TP and Med on RA treatment remain unclear.We addressed this issue by evaluating the effects of TP,Med,and their combination on a collagen-induced arthritis(CIA)rat model,with a focus on bone erosion as the primary research endpoint.We subsequently performed experimental validation in an in vitro OC dif-ferentiation model to assess the impacts of these treatments on OC formation and function.Based on polymerase chain reaction(PCR)microarray data from RA patients,further investigations focused on N^(6)-methyladenosine(m^(6)A)methylation and its regulatory factors,methyltransferase-like 3(METTL3)and YT521-B homology domain family protein 1(YTHDF1),which have been identified as potential tar-gets of TP and Med.Key findings revealed that the TP and Med combination significantly alleviated bone destruction and inhibited OC differentiation,exerting stronger effects at lower doses than either drug alone.Mechanistically,TP and Med synergistically modulated METTL3 and YTHDF1 to suppress osteo-clastogenesis through distinct m6 A methylation pathways,contributing to the mitigation of RA-associated bone destruction.Overall,our data highlight the potential of the m^(6)A modification as a ther-apeutic mechanism for the combined use of TP and Med for RA treatment,providing a theoretical basis for the clinical application of herbal active ingredient combinations.展开更多
Objective Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson＇s disease （PD）. The present study was undertaken ...Objective Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson＇s disease （PD）. The present study was undertaken to evaluate the activation profile of microglia in 1-methyl-4-phenyl pyridinium （MPP^＋）-induced hemiparkinsonian rats. Triptolide, a potent immunosuppressant and microglia inhibitor, was then examined for its efficacy in protecting dopaminergic neurons from injury and ameliorating behavioral disabilities induced by MPP^＋. Methods The rat model of PD was established by intranigral microinjection of MPP^＋. At baseline and on day 1, 3, 7, 14, 21 following MPP^＋ injection, the degree of microglial activation was examined by detecting the immunodensity of OX-42 （microglia marker） in the substantia nigra （SN）. The number of viable dopaminergic neurons was determined by measuring tyrosine hydroxylase （TH） positive neurons in the SN. Behavioral performances were evaluated by counting the number of rotations induced by apomorphine, calculating scores of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry. Results Intranigral injection of MPP^＋ resulted in robust activa- tion of microglia, progressive depletion of dopaminergic neurons, and ongoing aggravation of behavioral disabilities in rats. Triptolide significantly inhibited microglial activation, partially prevented dopaminergic cells from death and improved behavioral performances. Conclusion These data demonstrated for the first time a neuroprotective effect of triptolide on dopaminergic neurons in MPP^＋ induced hemiparkinsonian rats. The protective effect of triptolide may, at least partially, be related to the inhibition of MPP^＋-induced microglial activation. Our results lend strong support to the use of immunosuppressive agents in the management of PD.展开更多
文摘Objective Inflammation and fibrosis are key features of diabetic nephropathy(DN).Triptolide(TP)exhibits anti-inflammatory and anti-fibrotic properties,though its mechanisms of action in DN remain unclear.CREKA(Cys-Arg-Glu-Lys-Ala)is a pentapeptide that specifically binds to fibronectin(FN),and the CREKA-modified liposome(CREKA-Lip)represents a novel FN-targeted drug delivery system.This study aimed to investigate the role of TP in diabetic db/db mice and determine whether encapsulation within CREKA-Lip enhances therapeutic efficacy while reducing the multi-organ toxicity of TP.Methods Eight-week-old diabetic db/db mice received tail vein injections twice weekly with vehicle,free TP,or CREKA-Lip/TP for 10 weeks.Urine and serum parameters were measured,and kidney,heart,liver,and testis tissues were collected for pathological evaluation.Protein-protein interaction networks were constructed using Cytoscape and its plug-ins to identify core targets and elucidate the therapeutic mechanism of TP against DN.Inflammatory,fibrotic,apoptotic,and lipid metabolism markers were evaluated in the kidneys of diabetic mice with DN and in high glucose-treated mouse mesangial cells and podocytes using qPCR,Western blot,immunohistochemistry,and immunofluorescence assays.Results TP administration reduced fasting blood glucose levels and glomerular mesangial expansion in diabetic mice.TP significantly suppressed renal inflammation,fibrosis,and apoptosis while enhancing lipid metabolism.Integration of network pharmacology,molecular docking,and transcriptomics revealed that TP ameliorated DN by inhibiting the JAK2-STAT1 signaling pathway.In vitro,TP inhibited high glucose-induced phosphorylation of JAK2 and STAT1,reduced collagen production in mesangial cells,decreased apoptosis,and improved lipid metabolism in podocytes.Moreover,CREKA-Lip/TP exhibited superior efficacy compared with free TP,with a more sustained reduction in urine albumin-to-creatinine ratio and greater inhibition of mesangial expansion.Notably,CREKA-Lip/TP treatment did not induce systemic toxicity.Conclusion TP improves renal inflammation,fibrosis,apoptosis,and lipid homeostasis,thereby ameliorating DN by inhibiting JAK2-STAT1 activation.Targeted delivery of TP via FN-binding CREKA-Lip enhances therapeutic efficacy while minimizing multi-organ toxicity.
文摘The published article titled“Triptolide inhibits proliferation and migration of human neuroblastoma SH-SY5Y cells by upregulating microRNA-181a”has been retracted from Oncology Research,Vol.26,No.8,2018,PP.1235-1243.
基金supported by the Grand Science and Technology Special Project in Shanxi Province(202201140601025-2)the National Natural Science Foundation of China(32201749)supported by the Agriculture and Food Research Initiative Competitive Grant 2022-68013-36439(WheatCAP)from the USDA National Institute of Food and Agriculture.
文摘The awn can contribute to photosynthesis and carbohydrates,enhancing grain yield in wheat.We mapped QAwn.sxau-5A,a major QTL for awn development in wheat(Triticum aestivum).This QTL was delimited to a 994-kb interval at the B1 locus on chromosome 5A,which included the candidate gene encoding a zinc finger protein(TraesCS5A01G542800)as an awn length inhibitor(ALI).The Ali-A1 allele for the awnless trait showed abundant sequence differences in the promoter regions compared to the ali-A1 allele for the long-awn trait.The results of the swap experiment on the promoters from the two ALI-A1 alleles showed that the two promoters caused a difference in the protein level,indicating the gene was regulated at the transcript level.However,the ali-A1 allele contained an SNP that caused a premature stop codon in its coding region,resulting in a truncated protein compared to the functional Ali-A1 protein.The Ali-A1 protein contained two ethylene-responsive element binding factor-associated amphiphilic repression(EAR)motifs,one at the N terminus(EAR-N)and the other at the C terminus(EAR-C),and they were involved in interactions with the wheat co-repressor protein TOPLESS(TPL1).The ali-A1 protein retained the EAR-N motif but lost the EAR-C motif,resulting in the attenuated ability to interact with TPL1.The tpl1 mutant produced a longer awn compared to the wild type.Ali-A1 repressed the transcription of two downstream genes,TaLRP-A1 and TaARF-B1,involved in endogenous auxin concentrations and auxin responses in wheat.We concluded that the awn length is regulated not only by the ALI-A1 gene at transcript levels but also by Ali-A1 and TPL1 at the protein level in wheat.
基金supported by the National Natural Science Foundation of China(U22A20374).
文摘Rheumatoid arthritis(RA)is a progressive autoimmune disease characterized by bone destruction that is primarily caused by the overactivation of osteoclasts(OCs),which are critical therapeutic targets.Triptolide(TP)has strong anti-RA effects but is limited by its narrow therapeutic window and associated toxicity,necessitating combination therapy to increase its efficacy and reduce side effects.Medicarpin(Med),a flavonoid with anti-inflammatory and anti-bone destruction properties,has shown potential in reducing osteoclastogenesis.However,the mechanisms underlying the synergistic effects of TP and Med on RA treatment remain unclear.We addressed this issue by evaluating the effects of TP,Med,and their combination on a collagen-induced arthritis(CIA)rat model,with a focus on bone erosion as the primary research endpoint.We subsequently performed experimental validation in an in vitro OC dif-ferentiation model to assess the impacts of these treatments on OC formation and function.Based on polymerase chain reaction(PCR)microarray data from RA patients,further investigations focused on N^(6)-methyladenosine(m^(6)A)methylation and its regulatory factors,methyltransferase-like 3(METTL3)and YT521-B homology domain family protein 1(YTHDF1),which have been identified as potential tar-gets of TP and Med.Key findings revealed that the TP and Med combination significantly alleviated bone destruction and inhibited OC differentiation,exerting stronger effects at lower doses than either drug alone.Mechanistically,TP and Med synergistically modulated METTL3 and YTHDF1 to suppress osteo-clastogenesis through distinct m6 A methylation pathways,contributing to the mitigation of RA-associated bone destruction.Overall,our data highlight the potential of the m^(6)A modification as a ther-apeutic mechanism for the combined use of TP and Med for RA treatment,providing a theoretical basis for the clinical application of herbal active ingredient combinations.
文摘Objective Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson＇s disease （PD）. The present study was undertaken to evaluate the activation profile of microglia in 1-methyl-4-phenyl pyridinium （MPP^＋）-induced hemiparkinsonian rats. Triptolide, a potent immunosuppressant and microglia inhibitor, was then examined for its efficacy in protecting dopaminergic neurons from injury and ameliorating behavioral disabilities induced by MPP^＋. Methods The rat model of PD was established by intranigral microinjection of MPP^＋. At baseline and on day 1, 3, 7, 14, 21 following MPP^＋ injection, the degree of microglial activation was examined by detecting the immunodensity of OX-42 （microglia marker） in the substantia nigra （SN）. The number of viable dopaminergic neurons was determined by measuring tyrosine hydroxylase （TH） positive neurons in the SN. Behavioral performances were evaluated by counting the number of rotations induced by apomorphine, calculating scores of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry. Results Intranigral injection of MPP^＋ resulted in robust activa- tion of microglia, progressive depletion of dopaminergic neurons, and ongoing aggravation of behavioral disabilities in rats. Triptolide significantly inhibited microglial activation, partially prevented dopaminergic cells from death and improved behavioral performances. Conclusion These data demonstrated for the first time a neuroprotective effect of triptolide on dopaminergic neurons in MPP^＋ induced hemiparkinsonian rats. The protective effect of triptolide may, at least partially, be related to the inhibition of MPP^＋-induced microglial activation. Our results lend strong support to the use of immunosuppressive agents in the management of PD.
