In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS...In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.展开更多
Phytic acid is the principal storage form of phosphorus in plant seeds and an essential signalling molecule in several regulatory processes of plant development.However,it is known as an anti-nutrient compound owing t...Phytic acid is the principal storage form of phosphorus in plant seeds and an essential signalling molecule in several regulatory processes of plant development.However,it is known as an anti-nutrient compound owing to its potent chelating property.Thus,reducing the phytic acid content in crops is desirable.Studies involving regulation of MIPS and IPK1 genes to generate low phytate rice have been reported earlier.However,the functional significance of OsITPK and the effect of its down-regulation on phytic acid content and the associated pleiotropic effects on rice have not yet been investigated.In this study,tissue specific RNA interference(RNAi)-mediated down-regulation of a major ITPK homolog(OsITP5/6K-1)resulted in 46.2%decrease in phytic acid content of T2 transgenic seeds with a subsequent 3-fold enhancement in the inorganic phosphorus content.Silencing of OsITP5/6K-1 altered the transcript levels of essential phytic acid pathway genes,without significantly affecting the transcript levels of other OsITPK homologs.Furthermore,the mapping of elements through X-ray microfluorescence analysis revealed significant changes in the spatial distribution pattern and translocation of elements in low phytate seeds.Additionally,low phytate polished seeds exhibited 1.3-fold and 1.6-fold enhancement in iron and zinc content in the grain endosperm,respectively.Silencing of OsITP5/6K-1 also altered the amino acid and myo-inositol content of the transgenic seeds.Our results successfully established that RNAi-mediated silencing of OsITP5/6K-1 gene significantly reduced the phytate levels in seeds without hampering the germination potential of seeds and plant growth.The present study provided an insight into the mechanism of phytic acid biosynthesis pathway.展开更多
Previous studies have indicated that ERp44 inhibits inositol 1,4,5-trisphosphate(IP3)-induced Ca2+release(IICR)via IP3R1,but the mechanism remains largely unexplored.Using extracellular ATP to induce intracellular cal...Previous studies have indicated that ERp44 inhibits inositol 1,4,5-trisphosphate(IP3)-induced Ca2+release(IICR)via IP3R1,but the mechanism remains largely unexplored.Using extracellular ATP to induce intracellular calcium transient as an IICR model,Ca2+image,pull down assay,and Western blotting experiments were carried out in the present study.We found that extracellular ATP induced calcium transient via IP3Rs(IICR)and the IICR were markedly decreased in ERp44 overexpressed Hela cells.The inhibitory effect of C160S/C212S but not C29S/T396A/ΔT(331–377)mutants of ERp44 on IICR were significantly decreased compared with ERp44.However,the binding capacity of ERp44 to L3V domain of IP3R1(1L3V)was enhanced by ERp44 C160S/C212S mutation.Taken together,these results suggest that the mutants of ERp44,C160/C212,can more tightly bind to IP3R1 but exhibit a weak inhibition of IP3R1 channel activity in Hela cells.展开更多
Objective: To observe the effect of theo polyphenols(TP)on function of trans membranous signal of acute ischemic myocardium in rats. Methods: Model of myocardial ischemia was established. Thirty five male rats wer...Objective: To observe the effect of theo polyphenols(TP)on function of trans membranous signal of acute ischemic myocardium in rats. Methods: Model of myocardial ischemia was established. Thirty five male rats were randomly divided into 5 groups, 7 rats in each group. Non ischemic group:the anterior descending branch of left coronary artery was not ligated;Ischemic group:the time of ischemia continued for 10 min;TP groups:the groups were divided into 3 subgroups, TP dose was respectively 1 mg/kg, 4 mg/kg, 16 mg/kg, TP was administered through celiac injection 20 min before the anterior descending branch of left coronary artery was ligated. Results: The levels of phosphatidylinositol 4, 5 biphosphate(PIP 2), inositol 1, 4, 5 triphosphate(IP 3)in the ischemic group were markedly higher than those in the non ischemic group. The raise of the levels of PIP 2, IP 3caused by acute myocardial ischemia were markedly inhibited by the TP. The relationship of dose effect was observed. Conclusion: TP has inhibitory effect of trans membranous signal system of acute ischemic myocardium. It has protective effect on myocardium.展开更多
In plants, phosphate (Pi) homeostasis is regulated by the interaction of PHR transcription factors with stand-alone SPX proteins, which act as sensors for inositol pyrophosphates. Here, we combined different methods t...In plants, phosphate (Pi) homeostasis is regulated by the interaction of PHR transcription factors with stand-alone SPX proteins, which act as sensors for inositol pyrophosphates. Here, we combined different methods to obtain a comprehensive picture of how inositol (pyro)phosphate metabolism is regulated by Pi and dependent on the inositol phosphate kinase ITPK1. We found that inositol pyrophosphates are more responsive to Pi than lower inositol phosphates, a response conserved across kingdoms. With CE-ESI-MS we could separate different InsP7 isomers in Arabidopsis and rice, and identify 4/6-InsP7 and a PP-InsP4 isomer hitherto not reported in plants. We found that the inositol pyrophosphates 1/3-InsP7, 5-InsP7 and InsP8 increase severalfold in shoots after Pi resupply and that tissue-specific accumulation of inositol pyrophosphates relies on ITPK1 activities and MRP5-dependent InsP6 compartmentalization. Notably, ITPK1 is critical for Pi-dependent 5-InsP7 and InsP8 synthesis in planta and its activity regulates Pi starvation responses in a PHR-dependent manner. Furthermore, we demonstrate that ITPK1-mediated conversion of InsP6 to 5-InsP7 requires high ATP concentrations and that Arabidopsis ITPK1 has an ADP phosphotransferase activity to dephosphorylate specifically 5-InsP7 under low ATP. Collectively, our study provides deeper insights into Pi-dependent changes in nutritional and energetic states with the synthesis of regulatory inositol pyrophosphates.展开更多
文摘In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.
文摘Phytic acid is the principal storage form of phosphorus in plant seeds and an essential signalling molecule in several regulatory processes of plant development.However,it is known as an anti-nutrient compound owing to its potent chelating property.Thus,reducing the phytic acid content in crops is desirable.Studies involving regulation of MIPS and IPK1 genes to generate low phytate rice have been reported earlier.However,the functional significance of OsITPK and the effect of its down-regulation on phytic acid content and the associated pleiotropic effects on rice have not yet been investigated.In this study,tissue specific RNA interference(RNAi)-mediated down-regulation of a major ITPK homolog(OsITP5/6K-1)resulted in 46.2%decrease in phytic acid content of T2 transgenic seeds with a subsequent 3-fold enhancement in the inorganic phosphorus content.Silencing of OsITP5/6K-1 altered the transcript levels of essential phytic acid pathway genes,without significantly affecting the transcript levels of other OsITPK homologs.Furthermore,the mapping of elements through X-ray microfluorescence analysis revealed significant changes in the spatial distribution pattern and translocation of elements in low phytate seeds.Additionally,low phytate polished seeds exhibited 1.3-fold and 1.6-fold enhancement in iron and zinc content in the grain endosperm,respectively.Silencing of OsITP5/6K-1 also altered the amino acid and myo-inositol content of the transgenic seeds.Our results successfully established that RNAi-mediated silencing of OsITP5/6K-1 gene significantly reduced the phytate levels in seeds without hampering the germination potential of seeds and plant growth.The present study provided an insight into the mechanism of phytic acid biosynthesis pathway.
基金by grants from the National Basic Research Program of China(Grant Nos.2011CB8091004 and 2009CB918701)the National Natural Science Foundation of China(Grant No.81100539).
文摘Previous studies have indicated that ERp44 inhibits inositol 1,4,5-trisphosphate(IP3)-induced Ca2+release(IICR)via IP3R1,but the mechanism remains largely unexplored.Using extracellular ATP to induce intracellular calcium transient as an IICR model,Ca2+image,pull down assay,and Western blotting experiments were carried out in the present study.We found that extracellular ATP induced calcium transient via IP3Rs(IICR)and the IICR were markedly decreased in ERp44 overexpressed Hela cells.The inhibitory effect of C160S/C212S but not C29S/T396A/ΔT(331–377)mutants of ERp44 on IICR were significantly decreased compared with ERp44.However,the binding capacity of ERp44 to L3V domain of IP3R1(1L3V)was enhanced by ERp44 C160S/C212S mutation.Taken together,these results suggest that the mutants of ERp44,C160/C212,can more tightly bind to IP3R1 but exhibit a weak inhibition of IP3R1 channel activity in Hela cells.
文摘Objective: To observe the effect of theo polyphenols(TP)on function of trans membranous signal of acute ischemic myocardium in rats. Methods: Model of myocardial ischemia was established. Thirty five male rats were randomly divided into 5 groups, 7 rats in each group. Non ischemic group:the anterior descending branch of left coronary artery was not ligated;Ischemic group:the time of ischemia continued for 10 min;TP groups:the groups were divided into 3 subgroups, TP dose was respectively 1 mg/kg, 4 mg/kg, 16 mg/kg, TP was administered through celiac injection 20 min before the anterior descending branch of left coronary artery was ligated. Results: The levels of phosphatidylinositol 4, 5 biphosphate(PIP 2), inositol 1, 4, 5 triphosphate(IP 3)in the ischemic group were markedly higher than those in the non ischemic group. The raise of the levels of PIP 2, IP 3caused by acute myocardial ischemia were markedly inhibited by the TP. The relationship of dose effect was observed. Conclusion: TP has inhibitory effect of trans membranous signal system of acute ischemic myocardium. It has protective effect on myocardium.
基金This work was funded by grants from the Deutsche Forschungsgemein-schaft(HE 8362/1-1,DFG Eigene Stelle,to R.F.H.G.SCHA 1274/4-1,SCHA 1274/5-1,Research Training Group GRK 2064 and Germany's Excellence Strategy,EXC-2070-390732324,PhenoRob to G.S.+1 种基金JE 572/4-1 and Germany's Excellence Strategy,ClBSS-EXC-2189-Project ID 390939984 to H.J.JLA 4541/1-1 postdoctoral research fellowship to D.L.),grants from the Medical Research Council(MRC award MR/T028904/1 to A.S.),and a DBT-IISc Program to D.L.
文摘In plants, phosphate (Pi) homeostasis is regulated by the interaction of PHR transcription factors with stand-alone SPX proteins, which act as sensors for inositol pyrophosphates. Here, we combined different methods to obtain a comprehensive picture of how inositol (pyro)phosphate metabolism is regulated by Pi and dependent on the inositol phosphate kinase ITPK1. We found that inositol pyrophosphates are more responsive to Pi than lower inositol phosphates, a response conserved across kingdoms. With CE-ESI-MS we could separate different InsP7 isomers in Arabidopsis and rice, and identify 4/6-InsP7 and a PP-InsP4 isomer hitherto not reported in plants. We found that the inositol pyrophosphates 1/3-InsP7, 5-InsP7 and InsP8 increase severalfold in shoots after Pi resupply and that tissue-specific accumulation of inositol pyrophosphates relies on ITPK1 activities and MRP5-dependent InsP6 compartmentalization. Notably, ITPK1 is critical for Pi-dependent 5-InsP7 and InsP8 synthesis in planta and its activity regulates Pi starvation responses in a PHR-dependent manner. Furthermore, we demonstrate that ITPK1-mediated conversion of InsP6 to 5-InsP7 requires high ATP concentrations and that Arabidopsis ITPK1 has an ADP phosphotransferase activity to dephosphorylate specifically 5-InsP7 under low ATP. Collectively, our study provides deeper insights into Pi-dependent changes in nutritional and energetic states with the synthesis of regulatory inositol pyrophosphates.