Drought stress orchestrates a phosphorylation-dependent signaling cascade that reprograms transcriptional networks to enhance crop resilience.Through a large-scale transgenic screening,we identified ZmCRK5A,a Ca^(2+)-...Drought stress orchestrates a phosphorylation-dependent signaling cascade that reprograms transcriptional networks to enhance crop resilience.Through a large-scale transgenic screening,we identified ZmCRK5A,a Ca^(2+)-independent calcium-dependent protein kinase(CDPK)-related kinase,as a master regulator of drought tolerance in maize.Mechanistically,ZmCRK5A directly phosphorylates the MYB transcriptional repressor ZmSMH4(Single MYB Histone 4)at three conserved serine residues(Ser42/43/59)within its SANT domain,as demonstrated by in vitro kinase assays and site-directed mutagenesis.This post-translational modification abolishes Zm SMH4's DNA-binding capacity to ACC cis-elements,thereby de-repressing the potassium influx channel gene Zm KCH1(K^(+)Channel 1).Functional validation revealed that Zm KCH1 overexpression confers drought resilience through optimized stomatal dynamics and water retention,whereas clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)-generated zmkch1 mutants display hypersensitivity to water deficit.Crucially,field evaluations demonstrated preserved grain yield alongside enhanced drought tolerance in plants with activated Zm CRK5A-Zm SMH4-Zm KCH1 signaling.Our findings delineate a kinase-transcription factor-ion channel axis that dynamically fine-tunes drought responses while maintaining productivity,providing a strategic framework for engineering stress-adapted crops without yield penalties.展开更多
The spatiotemporal regulation of polar auxin transport by PIN-FORMED(PIN)efflux carriers is essential for coordinating plant development with environmental cues.However,whether and how osmotic stress signaling affects...The spatiotemporal regulation of polar auxin transport by PIN-FORMED(PIN)efflux carriers is essential for coordinating plant development with environmental cues.However,whether and how osmotic stress signaling affects auxin transport to regulate plant stress adaptation remain largely unclear.In this study,we identify SnRK2.5,an abscisic acid–independent member of the SNF1-related protein kinase family,as a key molecular link between osmotic stress signaling and auxin transport regulation in Arabidopsis.Osmotic stress activates SnRK2.5,which directly phosphorylates PIN2 at Ser237 and Ser259.Genetic and cell biological analyses demonstrate that these phosphorylation events govern PIN2 vesicular trafficking,vacuolar targeting,and auxin transport activity.Disruption of these phosphorylation sites impairs PIN2-dependent auxin redistribution,thereby compromising root tropic responses and reducing osmotic stress tolerance.Our findings uncover a regulatory mechanism by which SnRK2.5-mediated phosphorylation of PIN2 dynamically adjusts auxin flux in response to water availability,representing a critical adaptive strategy that optimizes plant growth under osmotic stress.展开更多
Drought stress and abscisic acid(ABA)have been known to play a critical role in modulating sugar accumulation in fruit,and yet,the underlying molecular mechanisms remain elusive.In this study,we have demonstrated that...Drought stress and abscisic acid(ABA)have been known to play a critical role in modulating sugar accumulation in fruit,and yet,the underlying molecular mechanisms remain elusive.In this study,we have demonstrated that drought-mimicking film mulching increased sucrose levels in Satsuma mandarin(Citrus unshiu)fruit,coinciding with upregulation of CuSPS4,which encodes the sucrose phosphate synthase(SPS),in the transcriptome profiling.CuSPS4 was further shown to be drought-and ABA-inducible and functionally essential for sucrose synthesis.Mechanistically,two transcription factors,CuWRKY41 and CuWRKY23,directly bound to and activated the CuSPS4 promoter via the W-box element,with CuWRKY41 additionally regulating CuWRKY23 expression.Consistently,both Cu WRKY41 and Cu WRKY23 positively regulated sucrose synthesis by upregulating Cu SPS4.Meanwhile,the ubstrateinteracting subunit(Cu Sn RK1β1)and catalytic subunit(Cu Sn RK1α)of SUCROSE NON-FERMENTING RELATED KINASE 1(Sn RK1)interacted with Cu WRKY41,triggering Cu Sn RK1α-mediated phosphorylation and subsequent degradation of Cu WRKY41,thereby suppressing its activation.However,ABA promoted cytoplasmic translocation of Cu Sn RK1αand Cu Sn RK1β1 and reduced nuclear interaction with Cu WRKY41,leading to its phosphorylation alleviation and protein stabilization,concurrent with enhanced transcription activation of Cu WRKY23 and Cu SPS4.Taken together,these findings reveal a sophisticated regulatory mechanism whereby drought promotes sucrose accumulation by suppressing Cu Sn RK1α-mediated phosphorylation and degradation of Cu WRKY41,enabling its transcriptional activation of Cu SPS4 directly or via Cu WRKY23.Our study provides significant insights into the molecular basis of drought-induced sucrose accumulation and presents valuable regulatory components that could be targeted for fruit quality improvement.展开更多
Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal ves...Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.展开更多
Objectives:Weaning induces oxidative stress in pigs,increasing the risk of diarrhea and death.Intestinal damage is associated with obstructed intestinal cell cycles.To stop damage caused by reactive oxygen species(ROS...Objectives:Weaning induces oxidative stress in pigs,increasing the risk of diarrhea and death.Intestinal damage is associated with obstructed intestinal cell cycles.To stop damage caused by reactive oxygen species(ROS),N-acetyl cysteine(NAC)has been widely employed.In this study,we examined changes in the intestinal cyclin of weaning piglets and assessed the impact of NAC on intestinal cell cycle arrest and intracellular signaling pathways.Methods:We conducted two animal experiments.In the first,we divided 12 litters of 120 newborn piglets into two groups:a control group and a weaning group.The control piglets were allowed to suckle normally.The weaning group was weaned after 3 weeks and fed a normal diet for piglets.We slaughtered six piglets from the control group and six from the weaning group.We observed cyclin changes and intestinal development at days 0,1,4,and 7 after weaning.In the second experiment,we divided 15 litters of 150 piglets that were 2 weeks old into three groups:the control group,the weaning group,and the NAC group.Control piglets were allowed to suckle normally.Piglets in the weaning and NAC groups were weaned when they were 21 days old.The NAC group was fed a basal diet supplemented with 500 mg/kg NAC,and the weaning group was fed the basal diet alone.The experimental period was 14–25 days of age.Four days after weaning,we slaughtered one piglet from each litter.We then analyzed intestinal cell cycle indexes,intestinal oxidative stress,c-Jun N-terminal kinase(JNK),extracellular signal-regulated kinase(ERK),and p38 phosphorylation.Results:Weaning decreased the piglets’feed intake and daily gain,reduced the serum antioxidant capacity,and increased the intestinal ROS level.Furthermore,the jejunum histology and barrier development of the jejunum exhibited damage after weaning,the microvilli displayed hypoplasia,and the p21 and p27 protein expression levels of the jejunum were significantly elevated.We did not observe any significant differences in cyclin D and E after days 1,4,and 7 post-weaning compared with the control group.We observed,however,significantly increased cyclin D and E expression,lower ERK,JNK,and p38 kinase phosphorylation;villus atrophy alleviation;decreased p21 and p27 expression;and increased average daily intake of feed and weight gain.Conclusion:This research demonstrates that weaning stress inhibits piglet intestinal proliferation by reducing cyclin D and cyclin E expression.NAC downregulates p21 and p27 through modulating mitogen-activated protein kinases(MAPKase)phosphorylation,thereby promoting cell proliferation.The results indicate that NAC promotes intestinal function and the integrity of enterocytes and holds promise as a new feed additive for animal health.展开更多
The immunoregulatory effect of TLSFJM on the expression of T cell IL- 2R and protein tyrosine phosphorylation ( PTP ) was investigated by immunohistochemistry technique. The results showed that TLSFJMcan markedly supp...The immunoregulatory effect of TLSFJM on the expression of T cell IL- 2R and protein tyrosine phosphorylation ( PTP ) was investigated by immunohistochemistry technique. The results showed that TLSFJMcan markedly suppress the expression of IL-2R and PTP on PHA or TPA-stimulated human PBMC and murine IL-2 dependent cell line CTLL-2. However, there was no effect of TLSFJMon the production of IL-1, IL-2 and IL-6 that play an important role in the course of T lymphocyte proliferation and differentiation.展开更多
Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The...Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.展开更多
Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidati...Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.展开更多
基金supported by National Key Research and Development Program of China(2022YFF1001600)BeijingNatural Science Foundation(5244040)+1 种基金STI2030-Major Projects(2030ZD0407101)China Postdoctoral Science Foundation(2022M723435)。
文摘Drought stress orchestrates a phosphorylation-dependent signaling cascade that reprograms transcriptional networks to enhance crop resilience.Through a large-scale transgenic screening,we identified ZmCRK5A,a Ca^(2+)-independent calcium-dependent protein kinase(CDPK)-related kinase,as a master regulator of drought tolerance in maize.Mechanistically,ZmCRK5A directly phosphorylates the MYB transcriptional repressor ZmSMH4(Single MYB Histone 4)at three conserved serine residues(Ser42/43/59)within its SANT domain,as demonstrated by in vitro kinase assays and site-directed mutagenesis.This post-translational modification abolishes Zm SMH4's DNA-binding capacity to ACC cis-elements,thereby de-repressing the potassium influx channel gene Zm KCH1(K^(+)Channel 1).Functional validation revealed that Zm KCH1 overexpression confers drought resilience through optimized stomatal dynamics and water retention,whereas clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)-generated zmkch1 mutants display hypersensitivity to water deficit.Crucially,field evaluations demonstrated preserved grain yield alongside enhanced drought tolerance in plants with activated Zm CRK5A-Zm SMH4-Zm KCH1 signaling.Our findings delineate a kinase-transcription factor-ion channel axis that dynamically fine-tunes drought responses while maintaining productivity,providing a strategic framework for engineering stress-adapted crops without yield penalties.
基金supported by grants from the National Key R&D Program of China(2022YFA1303400)the Fundamental Research Funds for the Central Universities(KJJQ2024007)+2 种基金the National Natural Science Foundation of China(32270301)to Q.Z.the Pinduoduo-China Agricultural University Research Fund(PC2024B01005)the Hainan Provincial Natural Science Foundation of China(323CXTD379)to J.Z.
文摘The spatiotemporal regulation of polar auxin transport by PIN-FORMED(PIN)efflux carriers is essential for coordinating plant development with environmental cues.However,whether and how osmotic stress signaling affects auxin transport to regulate plant stress adaptation remain largely unclear.In this study,we identify SnRK2.5,an abscisic acid–independent member of the SNF1-related protein kinase family,as a key molecular link between osmotic stress signaling and auxin transport regulation in Arabidopsis.Osmotic stress activates SnRK2.5,which directly phosphorylates PIN2 at Ser237 and Ser259.Genetic and cell biological analyses demonstrate that these phosphorylation events govern PIN2 vesicular trafficking,vacuolar targeting,and auxin transport activity.Disruption of these phosphorylation sites impairs PIN2-dependent auxin redistribution,thereby compromising root tropic responses and reducing osmotic stress tolerance.Our findings uncover a regulatory mechanism by which SnRK2.5-mediated phosphorylation of PIN2 dynamically adjusts auxin flux in response to water availability,representing a critical adaptive strategy that optimizes plant growth under osmotic stress.
基金supported by the National Natural Science Foundation of China(32330095)the Hubei Hongshan Laboratory project(2021hszd009)。
文摘Drought stress and abscisic acid(ABA)have been known to play a critical role in modulating sugar accumulation in fruit,and yet,the underlying molecular mechanisms remain elusive.In this study,we have demonstrated that drought-mimicking film mulching increased sucrose levels in Satsuma mandarin(Citrus unshiu)fruit,coinciding with upregulation of CuSPS4,which encodes the sucrose phosphate synthase(SPS),in the transcriptome profiling.CuSPS4 was further shown to be drought-and ABA-inducible and functionally essential for sucrose synthesis.Mechanistically,two transcription factors,CuWRKY41 and CuWRKY23,directly bound to and activated the CuSPS4 promoter via the W-box element,with CuWRKY41 additionally regulating CuWRKY23 expression.Consistently,both Cu WRKY41 and Cu WRKY23 positively regulated sucrose synthesis by upregulating Cu SPS4.Meanwhile,the ubstrateinteracting subunit(Cu Sn RK1β1)and catalytic subunit(Cu Sn RK1α)of SUCROSE NON-FERMENTING RELATED KINASE 1(Sn RK1)interacted with Cu WRKY41,triggering Cu Sn RK1α-mediated phosphorylation and subsequent degradation of Cu WRKY41,thereby suppressing its activation.However,ABA promoted cytoplasmic translocation of Cu Sn RK1αand Cu Sn RK1β1 and reduced nuclear interaction with Cu WRKY41,leading to its phosphorylation alleviation and protein stabilization,concurrent with enhanced transcription activation of Cu WRKY23 and Cu SPS4.Taken together,these findings reveal a sophisticated regulatory mechanism whereby drought promotes sucrose accumulation by suppressing Cu Sn RK1α-mediated phosphorylation and degradation of Cu WRKY41,enabling its transcriptional activation of Cu SPS4 directly or via Cu WRKY23.Our study provides significant insights into the molecular basis of drought-induced sucrose accumulation and presents valuable regulatory components that could be targeted for fruit quality improvement.
基金National Natural Science Foundation of China(Grant Nos.32070838 and 82301874)Open Fund of State Key Laboratory of Reproductive Medicine,Nanjing Medical University(Grant No.SKLRM K202102)。
文摘Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.
基金supported by the Jilin Agricultural Science and Technology University under the Scientific Startup Foundation for Doctors((2022)733)Shanghai Jiao Tong University under the National Natural Science Foundation of China(30972103).
文摘Objectives:Weaning induces oxidative stress in pigs,increasing the risk of diarrhea and death.Intestinal damage is associated with obstructed intestinal cell cycles.To stop damage caused by reactive oxygen species(ROS),N-acetyl cysteine(NAC)has been widely employed.In this study,we examined changes in the intestinal cyclin of weaning piglets and assessed the impact of NAC on intestinal cell cycle arrest and intracellular signaling pathways.Methods:We conducted two animal experiments.In the first,we divided 12 litters of 120 newborn piglets into two groups:a control group and a weaning group.The control piglets were allowed to suckle normally.The weaning group was weaned after 3 weeks and fed a normal diet for piglets.We slaughtered six piglets from the control group and six from the weaning group.We observed cyclin changes and intestinal development at days 0,1,4,and 7 after weaning.In the second experiment,we divided 15 litters of 150 piglets that were 2 weeks old into three groups:the control group,the weaning group,and the NAC group.Control piglets were allowed to suckle normally.Piglets in the weaning and NAC groups were weaned when they were 21 days old.The NAC group was fed a basal diet supplemented with 500 mg/kg NAC,and the weaning group was fed the basal diet alone.The experimental period was 14–25 days of age.Four days after weaning,we slaughtered one piglet from each litter.We then analyzed intestinal cell cycle indexes,intestinal oxidative stress,c-Jun N-terminal kinase(JNK),extracellular signal-regulated kinase(ERK),and p38 phosphorylation.Results:Weaning decreased the piglets’feed intake and daily gain,reduced the serum antioxidant capacity,and increased the intestinal ROS level.Furthermore,the jejunum histology and barrier development of the jejunum exhibited damage after weaning,the microvilli displayed hypoplasia,and the p21 and p27 protein expression levels of the jejunum were significantly elevated.We did not observe any significant differences in cyclin D and E after days 1,4,and 7 post-weaning compared with the control group.We observed,however,significantly increased cyclin D and E expression,lower ERK,JNK,and p38 kinase phosphorylation;villus atrophy alleviation;decreased p21 and p27 expression;and increased average daily intake of feed and weight gain.Conclusion:This research demonstrates that weaning stress inhibits piglet intestinal proliferation by reducing cyclin D and cyclin E expression.NAC downregulates p21 and p27 through modulating mitogen-activated protein kinases(MAPKase)phosphorylation,thereby promoting cell proliferation.The results indicate that NAC promotes intestinal function and the integrity of enterocytes and holds promise as a new feed additive for animal health.
文摘The immunoregulatory effect of TLSFJM on the expression of T cell IL- 2R and protein tyrosine phosphorylation ( PTP ) was investigated by immunohistochemistry technique. The results showed that TLSFJMcan markedly suppress the expression of IL-2R and PTP on PHA or TPA-stimulated human PBMC and murine IL-2 dependent cell line CTLL-2. However, there was no effect of TLSFJMon the production of IL-1, IL-2 and IL-6 that play an important role in the course of T lymphocyte proliferation and differentiation.
基金supported by the National Natural Science Foundation of China,Nos. 82173806 and U1803281Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science,Nos. 2021-I2M-1-030 and 2022-I2M-2-002Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-JKCS-08 (all to RL)。
文摘Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
文摘Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.
