Objective:Lymphatic endothelial cell(LEC)proliferation is essential for lymphangiogenesis.Hypoxia induces lymphangiogenesis,but it directly inhibits LEC proliferation and the underlying mechanisms have not been fully ...Objective:Lymphatic endothelial cell(LEC)proliferation is essential for lymphangiogenesis.Hypoxia induces lymphangiogenesis,but it directly inhibits LEC proliferation and the underlying mechanisms have not been fully understood.The aim of this study was to investigate the role of carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1)in hypoxia-repressed LEC proliferation.Methods:Human dermal lymphatic endothelial cells(HDLECs)were cultured under normoxic or hypoxic conditions,and cell proliferation was determined using MTT or CCK-8 assays.CEACAM1 expression was silenced by siRNA transfection.Activation of mitogen-activated protein kinases(MAPKs)was examined by Western blotting and blocked by specific inhibitors.Results:Under hypoxia,HDLECs proliferation was suppressed and CEACAM1 expression was downregulated.Silence of CEACAM1 in normoxia inhibited HDLECs proliferation and did not further decrease proliferation in HDLECs in response to hypoxia,suggesting that CEACAM1 may mediate hypoxia-induced inhibition of HDLECs proliferation.In addition,silence of CEACAM1 increased phosphorylation of MAPK molecules:extracellular signal-regulated kinase(ERK),p38 MAPK and Jun N-terminal kinase(JNK)in HDLECs.However,only inhibition of the JNK pathway rescued the reduction of HDLEC proliferation induced by CEACAM1 silence.Conclusion:Our results suggested that hypoxia downregulates CEACAM1 expression by activation of the JNK pathway,leading to inhibition of HDLEC proliferation.These findings may help to understand the mechanisms of LEC-specific response to hypoxia and develop novel therapies for pathological lymphangiogenesis.展开更多
As a transparent avascular tissue located at the front of the eyeball, the cornea is an important barrier to external damage. Both epithelial and endothelial cells of the cornea harbor primary cilia, which sense chang...As a transparent avascular tissue located at the front of the eyeball, the cornea is an important barrier to external damage. Both epithelial and endothelial cells of the cornea harbor primary cilia, which sense changes in the external environment and regulate intracellular signaling pathways. Accumulating evidence suggests that the primary cilium regulates corneal development in several ways, including participation in corneal epithelial stratification and maintenance of corneal endothelial cell morphology.In addition, the primary cilium has been implicated in the pathogenesis of several corneal diseases. In this review, we discuss recent findings that demonstrate the critical role of the primary cilium in corneal development. We also discuss the link between ciliary dysfunction and corneal diseases, which suggests that the primary cilium could be targeted to treat these diseases.展开更多
Primary cilia are hair-like structures that protrude from the cell surface.They are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological activities.M...Primary cilia are hair-like structures that protrude from the cell surface.They are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological activities.Mutations in cilium-associated genes are linked to a group of diseases with overlapping clinical manifestations,collectively known as ciliopathies.A significant proportion of human ciliopathy cases are accompanied by metabolic disorders such as obesity and type 2 diabetes.Nevertheless,the mechanisms through which dysfunction of primary cilia contributes to obesity are complex.In this review,we present an overview of primary cilia and highlight obesity-related ciliopathies.We also discuss the potential role of primary cilia in peripheral organs,with a focus on adipose tissues.In addition,we emphasize the significance of primary cilia in the central regulation of obesity,especially the involvement of ciliary signaling in the hypothalamic control of feeding behavior.This review therefore proposes a framework of both peripheral and central regulation of obesity by primary cilia,which may benefit further exploration of the ciliary role in metabolic regulation.展开更多
Preeclampsia(PE)is a pregnancy-specific hypertensive disorder which poses a severe threat to maternal and fetal health.1 Defective decidualization may contribute to PE.^(2) N6-methyladenosine(m6A)is associated with va...Preeclampsia(PE)is a pregnancy-specific hypertensive disorder which poses a severe threat to maternal and fetal health.1 Defective decidualization may contribute to PE.^(2) N6-methyladenosine(m6A)is associated with various diseases.The regulatory mechanism of m6A in PE is not well established to date.We aimed to identify differentially expressed m6A and explore its regulatory role in the pathogenesis of PE.展开更多
Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan defects.However,the mechanistic link of cilia to CMD complications is still poorly understood.Her...Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan defects.However,the mechanistic link of cilia to CMD complications is still poorly understood.Herein,we describe significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols.Moreover,environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups.Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane,which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly.In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella.These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.展开更多
Crossover recombination is a hallmark of meiosis that holds the paternal and maternal chromosomes(homologs)together for their faithful segregation,while promoting genetic diversity of the progeny.The pattern of crosso...Crossover recombination is a hallmark of meiosis that holds the paternal and maternal chromosomes(homologs)together for their faithful segregation,while promoting genetic diversity of the progeny.The pattern of crossover is mainly controlled by the architecture of the meiotic chromosomes.Environmental factors,especially temperature,also play an important role in modulating crossovers.However,it is unclear how temperature affects crossovers.Here,we examined the distribution of budding yeast axis components(Red1,Hop1,and Rec8)and the crossover-associated Zip3 foci in detail at different temperatures,and found that both increased and decreased temperatures result in shorter meiotic chromosome axes and more crossovers.Further investigations showed that temperature changes coordinately enhanced the hyperabundant accumulation of Hop1 and Red1 on chromosomes and the number of Zip3 foci.Most importantly,temperature-induced changes in the distribution of axis proteins and Zip3 foci depend on changes in DNA negative supercoils.These results suggest that yeast meiosis senses temperature changes by increasing the level of negative supercoils to increase crossovers and modulate chromosome organization.These findings provide a new perspective on understanding the effect and mechanism of temperature on meiotic recombination and chromosome organization,with important implications for evolution and breeding.展开更多
Ciliopathies are multisystem disorders characterized by the dysfunction of motile and/or non-motile cilia,which are microtubule-based structures protruding from the cell surface and function in cell motility and signa...Ciliopathies are multisystem disorders characterized by the dysfunction of motile and/or non-motile cilia,which are microtubule-based structures protruding from the cell surface and function in cell motility and signaling.Common clinical manifestations of ciliopathies include retinal degeneration,mental retardation,renal abnormality,obesity,and skeletal dysplasia[1,2].Fibrosis of vital organs,characterized by the extensive deposition of extracellular matrix components,represents another complication frequently observed in patients and animal models of ciliopathies[3].展开更多
Restraint water-immersion stress(RWIS), a compound stress model, has been widely used to induce acute gastric ulceration in rats. A wealth of evidence suggests that the central nucleus of the amygdala(CEA) is a focal ...Restraint water-immersion stress(RWIS), a compound stress model, has been widely used to induce acute gastric ulceration in rats. A wealth of evidence suggests that the central nucleus of the amygdala(CEA) is a focal region for mediating the biological response to stress. Different stressors induce distinct alterations of neuronal activity in the CEA; however, few studies have reported the characteristics of CEA neuronal activity induced by RWIS. Therefore, we explored this issue using immunohistochemistry and in vivo extracellular single-unit recording. Our results showed that RWIS and restraint stress(RS) differentially changed the c-Fos expression and firing properties of neurons in the medial CEA. In addition,RWIS, but not RS, induced the activation of corticotropinreleasing hormone neurons in the CEA. These findings suggested that specific neuronal activation in the CEA is involved in the formation of RWIS-induced gastric ulcers.This study also provides a possible theoretical explanation for the different gastric dysfunctions induced by different stressors.展开更多
Placentation and tumorigenesis have many common features.Human placentation builds a maternal-fetal connection,circumvents maternal immune rejection of the fetus,and utilizes mechanisms that support tumorigenesis,such...Placentation and tumorigenesis have many common features.Human placentation builds a maternal-fetal connection,circumvents maternal immune rejection of the fetus,and utilizes mechanisms that support tumorigenesis,such as proliferation,invasion,angiogenesis,and immune tolerance.Trophoblasts of the human placenta mimic the behavior of malignant cells,proliferating and invading the uterine decidua until reaching the myometrium and remodeling the spiral arteries that establish a new vascular system and escape the maternal immune response.These processes are under precise temporal and spatial regulation,and their dysregulation is associated with different pregnancy syndromes,including preeclampsia(PE),a pregnancy syndrome that is the leading cause of maternal and perinatal mortality and morbidity.At present,the precise mechanisms underlying the development of PE remain unclear.Here,we summarize and dissect the features between physiological placentation and pathological tumorigenesis to explore the pathogenesis of PE-which we believe to be the result of insufficient placentation,compared to the overaggression of tumorigenesis-to provide novel strategies to prevent and treat PE.展开更多
Dear Editor,Human immunodeficiency virus type 1(HIV-1)infection is mainly initiated on mucosal epithelial surfaces.Exposure to HIV-1 impairs the mucosal epithelial barrier,allowing viral transmission across the mucosa...Dear Editor,Human immunodeficiency virus type 1(HIV-1)infection is mainly initiated on mucosal epithelial surfaces.Exposure to HIV-1 impairs the mucosal epithelial barrier,allowing viral transmission across the mucosal epithelium.1 Interaction of HIV-1 envelope glycoprotein gp120 with its primary receptor,cluster of differentiation 4(CD4),and chemokine coreceptors has been implicated in the disruption of epithelial cell junctions upon HIV-1 exposure.1 However,the molecular details and underlying mechanisms of this disruption remain elusive.展开更多
In vertebrates,most cells can secrete membrane vesicles known as extracellular vesicles(EVs)from the cell surface into the surrounding environment.EVs are known to carry various biological molecules including signalin...In vertebrates,most cells can secrete membrane vesicles known as extracellular vesicles(EVs)from the cell surface into the surrounding environment.EVs are known to carry various biological molecules including signaling proteins,nucleic acids,and lipids.Upon integration with target cells,these bioactive molecules released from EVs can modulate the expression of specific genes,alter the pre-existing cellular functions,and even regulate the release of EV cargoes.Based on current knowledge,EVs are generally categorized into exosomes and microvesicles with distinct specificities and biogenesis.Exosomes are 30-100 nm in diameter and originate from intraluminal vesicles within the endosomal system.In normal and pathological states,the endosomal membrane continuously undergoes inward budding to form multivesicular bodies.Once fused with the plasma membrane,the intraluminal vesicles are released into the extracellular space,giving rise to exosomes(Fig.1a).By contrast,microvesicles,which are 50-1000 nm in diameter,are generated independently of the endosomal system.Microvesicle cargoes initially accumulate at the cytosolic face of discrete plasma membrane microdomains.Then,these membrane microdomains and their cargoes cluster,followed by outward membrane budding and a fission process at the plasma membrane that releases microvesicles into the extracellular environment(Fig.1a).展开更多
A dual-readout sensing platform based on two signal transduction channels can integrate the unique advantages of each sensing pattern,compensate for the deficiency in the adaptive capacity,and enable a more convincing...A dual-readout sensing platform based on two signal transduction channels can integrate the unique advantages of each sensing pattern,compensate for the deficiency in the adaptive capacity,and enable a more convincing performance in analytical applications.Here,we introduce a responsive molecule dye,xylenol orange(XO),to combine with lanthanide terbium ions(Tb^(3+)).The resultant Tb^(3+)-XO complex exhibited tunable optical properties and was used as a novel colorimetric and luminometric dual-readout sensing platform for assaying the anthrax biomarker,dipicolinic acid(DPA).In the presence of Tb^(3+),the XO solution underwent a color change from yellow to magenta;however,upon adding DPA,the color changed back to yellow immediately,accompanied by the characteristic luminescence emission of Tb^(3+).Considering the strong affinity between DPA/XO and metal ions,the proposed sensing platform was further employed for the determination and differentiation of certain metal ions using linear discriminant analysis.This convenient dual-readout sensing platform offers several notable features and significantly promotes the application and development of lanthanide-based materials.展开更多
Endothelial cilia are microtubule-based hair-like protrusions in the lumen of blood vessels that function as fluid mechanosensors to regulate vascular hemodynamics. However, the functions of endothelial cilia in vascu...Endothelial cilia are microtubule-based hair-like protrusions in the lumen of blood vessels that function as fluid mechanosensors to regulate vascular hemodynamics. However, the functions of endothelial cilia in vascular development remain controversial. In this study, depletion of several key proteins responsible for ciliogenesis allows us to identify a cilium-independent role for intraflagellar transport 88(IFT88) in mammalian angiogenesis. Disruption of primary cilia by heat shock does not affect the angiogenic process. However, depletion of IFT88 significantly inhibits angiogenesis both in vitro and in vivo. IFT88 mediates angiogenesis by regulating the migration, polarization, proliferation, and oriented division of vascular endothelial cells. Further mechanistic studies demonstrate that IFT88 interacts with c-tubulin and microtubule plus-end tracking proteins and promotes microtubule stability. Our findings indicate that IFT88 regulates angiogenesis through its actions in microtubule-based cellular processes, independent of its role in ciliogenesis.展开更多
Cilia are hair-like organelles that protrude from the surface of many types of eukaryotic cells.Each cilium possesses a microtubule-based central core,known as the axoneme,surrounded by the ciliary membrane.Ciliogenes...Cilia are hair-like organelles that protrude from the surface of many types of eukaryotic cells.Each cilium possesses a microtubule-based central core,known as the axoneme,surrounded by the ciliary membrane.Ciliogenesis is a multi-step process that typically involves vesicle transport to the centrosome,maturation of the mother centriole into a basal body,docking of the basal body onto the plasma membrane,and extension of the axoneme from the basal body[1].展开更多
Dear Editor,Chromosome movement in mitosis is orchestrated by a microtubule-based protein machinery called the mitotic spindle(Hyman and Karsenti,1996;Compton,2000).The bipolar organization of the mitotic spindle is e...Dear Editor,Chromosome movement in mitosis is orchestrated by a microtubule-based protein machinery called the mitotic spindle(Hyman and Karsenti,1996;Compton,2000).The bipolar organization of the mitotic spindle is essential for the accurate segregation of chromosomes into daughter cells.Defects in bipolar spindle assembly can cause chromosome instability and aneuploidy,which are frequently observed in malignant tumors(Silkworth et al.,2009;McGranahan et al.,2012).The nuclear mitotic apparatus(NuMA)is a protein critical for bipolar spindle organization primarily due to its functions in the formation of spindle poles.Dysregulation of NuMA has been reported in a number of cancer types and is associated with cancer development(Bruning-Richardson et al.,2012).Therefore,it is of great significance to understand the molecular mechanisms by which NuMA contributes to spindle pole assembly.展开更多
Decidualization is the differentiation of endometrial stromal cells into secretory decidual stromal cells.Human decidualization involves some amount of signaling molecules and pathways as well as genetic reprogramming...Decidualization is the differentiation of endometrial stromal cells into secretory decidual stromal cells.Human decidualization involves some amount of signaling molecules and pathways as well as genetic reprogramming,which is driven by the postovulatory rise in progesterone levels and local cyclic adenosine monophosphate production.Decidualization extends from the primary decidual zone to the secondary decidual zone,and then exits through apoptosis.Evidences support that decidual fibroblasts function as the pool of decidual stromal cells during pregnancy.Decidualization undergoes an acute inflammatory phase,an anti-inflammatory secretory phase to the final recession phase.The decidualization of the inner layer of endometrium,termed decidua,is the most critical determinant of pregnancy success,which can promote placenta formation,modulate immune tolerance,foster resistance to oxidative stress,sense embryo quality,and control labor.Failure to adequate decidualization in terms of hormones,biochemistry,and immunology leads to adverse pregnancy outcomes,including diseases such as preeclampsia,miscarriage,premature labor,repeated implantation failures,and some age-related decline in reproductive capacity.The development of animal models and in vitro culture systems combined with emerging technologies provides a powerful system to explore the mechanism of decidualization.However,decidualization is a dynamic,multi-step process,and translating of current research progress into disease predictions and interventions for pregnancy complications remains to be achieved.The study of periodic regeneration and spontaneous decidualization of the endometrium will be beneficial to the diagnosis and treatment of pregnancy diseases.展开更多
Defects in centrosomes are associated with a broad spectrum of hematological malignancies,such as leukemia and lymphoma.Centrosomes in these malignancies display both numerical and structural aberrations,including alt...Defects in centrosomes are associated with a broad spectrum of hematological malignancies,such as leukemia and lymphoma.Centrosomes in these malignancies display both numerical and structural aberrations,including alterations in the number and size of centrioles,inappropriate post-translational modification of centrosomal proteins,and extra centrosome clustering.There is accumulating evidence that centrosome defects observed in hematological malignancies result from multiple factors,including dysregulation of the centrosome cycle and impairment of centriole biogenesis.In this review,we discuss the plausible mechanisms of centrosome defects and highlight their consequences in hematological malignancies.We also illustrate the latest therapeutic strategies against hematological malignancies by targeting centrosome anomalies.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81873473 and No.91939110)Academic Promotion Program of Shandong First Medical University(No.2019QL014)Shandong Taishan Scholarship(Ju Liu).
文摘Objective:Lymphatic endothelial cell(LEC)proliferation is essential for lymphangiogenesis.Hypoxia induces lymphangiogenesis,but it directly inhibits LEC proliferation and the underlying mechanisms have not been fully understood.The aim of this study was to investigate the role of carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1)in hypoxia-repressed LEC proliferation.Methods:Human dermal lymphatic endothelial cells(HDLECs)were cultured under normoxic or hypoxic conditions,and cell proliferation was determined using MTT or CCK-8 assays.CEACAM1 expression was silenced by siRNA transfection.Activation of mitogen-activated protein kinases(MAPKs)was examined by Western blotting and blocked by specific inhibitors.Results:Under hypoxia,HDLECs proliferation was suppressed and CEACAM1 expression was downregulated.Silence of CEACAM1 in normoxia inhibited HDLECs proliferation and did not further decrease proliferation in HDLECs in response to hypoxia,suggesting that CEACAM1 may mediate hypoxia-induced inhibition of HDLECs proliferation.In addition,silence of CEACAM1 increased phosphorylation of MAPK molecules:extracellular signal-regulated kinase(ERK),p38 MAPK and Jun N-terminal kinase(JNK)in HDLECs.However,only inhibition of the JNK pathway rescued the reduction of HDLEC proliferation induced by CEACAM1 silence.Conclusion:Our results suggested that hypoxia downregulates CEACAM1 expression by activation of the JNK pathway,leading to inhibition of HDLEC proliferation.These findings may help to understand the mechanisms of LEC-specific response to hypoxia and develop novel therapies for pathological lymphangiogenesis.
基金This work was supported by the Taishan Scholars Program of Shandong Province(20161201)。
文摘As a transparent avascular tissue located at the front of the eyeball, the cornea is an important barrier to external damage. Both epithelial and endothelial cells of the cornea harbor primary cilia, which sense changes in the external environment and regulate intracellular signaling pathways. Accumulating evidence suggests that the primary cilium regulates corneal development in several ways, including participation in corneal epithelial stratification and maintenance of corneal endothelial cell morphology.In addition, the primary cilium has been implicated in the pathogenesis of several corneal diseases. In this review, we discuss recent findings that demonstrate the critical role of the primary cilium in corneal development. We also discuss the link between ciliary dysfunction and corneal diseases, which suggests that the primary cilium could be targeted to treat these diseases.
基金supported by the National Natural Science Foundation of China(32100948,32100614,31991193)Natural Science Foundation of Shandong Province(ZR2021QC069).
文摘Primary cilia are hair-like structures that protrude from the cell surface.They are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological activities.Mutations in cilium-associated genes are linked to a group of diseases with overlapping clinical manifestations,collectively known as ciliopathies.A significant proportion of human ciliopathy cases are accompanied by metabolic disorders such as obesity and type 2 diabetes.Nevertheless,the mechanisms through which dysfunction of primary cilia contributes to obesity are complex.In this review,we present an overview of primary cilia and highlight obesity-related ciliopathies.We also discuss the potential role of primary cilia in peripheral organs,with a focus on adipose tissues.In addition,we emphasize the significance of primary cilia in the central regulation of obesity,especially the involvement of ciliary signaling in the hypothalamic control of feeding behavior.This review therefore proposes a framework of both peripheral and central regulation of obesity by primary cilia,which may benefit further exploration of the ciliary role in metabolic regulation.
基金supported by grants from the National Key R&D Program of China(No.2019YFA0802600)and NSFC(No.32170863,31871512)to C.ZhangSupport was also obtained from the Shanghai Commission of Science and Technology(No.17DZ2271100)Open Project of Shandong Provincial Key Laboratory of Reproductive Medicine(No.SDKL2017018),China.
文摘Preeclampsia(PE)is a pregnancy-specific hypertensive disorder which poses a severe threat to maternal and fetal health.1 Defective decidualization may contribute to PE.^(2) N6-methyladenosine(m6A)is associated with various diseases.The regulatory mechanism of m6A in PE is not well established to date.We aimed to identify differentially expressed m6A and explore its regulatory role in the pathogenesis of PE.
基金supported by grants from the National Natural Science Foundation of China(31991193 and 32230025)the National Key R&D Program of China(2021YFA1101001).
文摘Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan defects.However,the mechanistic link of cilia to CMD complications is still poorly understood.Herein,we describe significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols.Moreover,environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups.Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane,which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly.In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella.These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.
基金funded by the National Natural Science Foundation of China(32225015,32070837,32370907,32070575,32270895)the National Key Research and Developmental Program of China(2022YFC2702602,2021YFC2700103)the Taishan Scholars Program of Shandong Province(tstp20231256).
文摘Crossover recombination is a hallmark of meiosis that holds the paternal and maternal chromosomes(homologs)together for their faithful segregation,while promoting genetic diversity of the progeny.The pattern of crossover is mainly controlled by the architecture of the meiotic chromosomes.Environmental factors,especially temperature,also play an important role in modulating crossovers.However,it is unclear how temperature affects crossovers.Here,we examined the distribution of budding yeast axis components(Red1,Hop1,and Rec8)and the crossover-associated Zip3 foci in detail at different temperatures,and found that both increased and decreased temperatures result in shorter meiotic chromosome axes and more crossovers.Further investigations showed that temperature changes coordinately enhanced the hyperabundant accumulation of Hop1 and Red1 on chromosomes and the number of Zip3 foci.Most importantly,temperature-induced changes in the distribution of axis proteins and Zip3 foci depend on changes in DNA negative supercoils.These results suggest that yeast meiosis senses temperature changes by increasing the level of negative supercoils to increase crossovers and modulate chromosome organization.These findings provide a new perspective on understanding the effect and mechanism of temperature on meiotic recombination and chromosome organization,with important implications for evolution and breeding.
基金supported by the National Natural Science Foundation of China(31991193,32000524,and 32100656)the National Key R&D Program of China(2021YFA1101001)。
文摘Ciliopathies are multisystem disorders characterized by the dysfunction of motile and/or non-motile cilia,which are microtubule-based structures protruding from the cell surface and function in cell motility and signaling.Common clinical manifestations of ciliopathies include retinal degeneration,mental retardation,renal abnormality,obesity,and skeletal dysplasia[1,2].Fibrosis of vital organs,characterized by the extensive deposition of extracellular matrix components,represents another complication frequently observed in patients and animal models of ciliopathies[3].
基金supported by the National Natural Science Foundation of China (31571104 and 81501149)the Science and Technological Project of Shandong Province of China (2016GSF201058)
文摘Restraint water-immersion stress(RWIS), a compound stress model, has been widely used to induce acute gastric ulceration in rats. A wealth of evidence suggests that the central nucleus of the amygdala(CEA) is a focal region for mediating the biological response to stress. Different stressors induce distinct alterations of neuronal activity in the CEA; however, few studies have reported the characteristics of CEA neuronal activity induced by RWIS. Therefore, we explored this issue using immunohistochemistry and in vivo extracellular single-unit recording. Our results showed that RWIS and restraint stress(RS) differentially changed the c-Fos expression and firing properties of neurons in the medial CEA. In addition,RWIS, but not RS, induced the activation of corticotropinreleasing hormone neurons in the CEA. These findings suggested that specific neuronal activation in the CEA is involved in the formation of RWIS-induced gastric ulcers.This study also provides a possible theoretical explanation for the different gastric dysfunctions induced by different stressors.
基金This study was supported by grants from the National Key R&D Program of China(2019YFA0802600 and 2017YFC1001403)NSFC(31871512 and 31671199)to CZSupport was also obtained by the Shanghai Commission of Science and Technology(17DZ2271100).
文摘Placentation and tumorigenesis have many common features.Human placentation builds a maternal-fetal connection,circumvents maternal immune rejection of the fetus,and utilizes mechanisms that support tumorigenesis,such as proliferation,invasion,angiogenesis,and immune tolerance.Trophoblasts of the human placenta mimic the behavior of malignant cells,proliferating and invading the uterine decidua until reaching the myometrium and remodeling the spiral arteries that establish a new vascular system and escape the maternal immune response.These processes are under precise temporal and spatial regulation,and their dysregulation is associated with different pregnancy syndromes,including preeclampsia(PE),a pregnancy syndrome that is the leading cause of maternal and perinatal mortality and morbidity.At present,the precise mechanisms underlying the development of PE remain unclear.Here,we summarize and dissect the features between physiological placentation and pathological tumorigenesis to explore the pathogenesis of PE-which we believe to be the result of insufficient placentation,compared to the overaggression of tumorigenesis-to provide novel strategies to prevent and treat PE.
基金supported by grants from the National Natural Science Foundation of China(31471262,31701209,and 31771542).
文摘Dear Editor,Human immunodeficiency virus type 1(HIV-1)infection is mainly initiated on mucosal epithelial surfaces.Exposure to HIV-1 impairs the mucosal epithelial barrier,allowing viral transmission across the mucosal epithelium.1 Interaction of HIV-1 envelope glycoprotein gp120 with its primary receptor,cluster of differentiation 4(CD4),and chemokine coreceptors has been implicated in the disruption of epithelial cell junctions upon HIV-1 exposure.1 However,the molecular details and underlying mechanisms of this disruption remain elusive.
基金the National Natural Science Foundation of China(31991193 and 32270807)the Shandong Natural Science Foundation(2022HWYQ-075).
文摘In vertebrates,most cells can secrete membrane vesicles known as extracellular vesicles(EVs)from the cell surface into the surrounding environment.EVs are known to carry various biological molecules including signaling proteins,nucleic acids,and lipids.Upon integration with target cells,these bioactive molecules released from EVs can modulate the expression of specific genes,alter the pre-existing cellular functions,and even regulate the release of EV cargoes.Based on current knowledge,EVs are generally categorized into exosomes and microvesicles with distinct specificities and biogenesis.Exosomes are 30-100 nm in diameter and originate from intraluminal vesicles within the endosomal system.In normal and pathological states,the endosomal membrane continuously undergoes inward budding to form multivesicular bodies.Once fused with the plasma membrane,the intraluminal vesicles are released into the extracellular space,giving rise to exosomes(Fig.1a).By contrast,microvesicles,which are 50-1000 nm in diameter,are generated independently of the endosomal system.Microvesicle cargoes initially accumulate at the cytosolic face of discrete plasma membrane microdomains.Then,these membrane microdomains and their cargoes cluster,followed by outward membrane budding and a fission process at the plasma membrane that releases microvesicles into the extracellular environment(Fig.1a).
基金funded by the National Natural Science Foundation of China(No.21804083)Youth Innovation Promotion Association of the Chinese Academy of Sciences(No.2018258)。
文摘A dual-readout sensing platform based on two signal transduction channels can integrate the unique advantages of each sensing pattern,compensate for the deficiency in the adaptive capacity,and enable a more convincing performance in analytical applications.Here,we introduce a responsive molecule dye,xylenol orange(XO),to combine with lanthanide terbium ions(Tb^(3+)).The resultant Tb^(3+)-XO complex exhibited tunable optical properties and was used as a novel colorimetric and luminometric dual-readout sensing platform for assaying the anthrax biomarker,dipicolinic acid(DPA).In the presence of Tb^(3+),the XO solution underwent a color change from yellow to magenta;however,upon adding DPA,the color changed back to yellow immediately,accompanied by the characteristic luminescence emission of Tb^(3+).Considering the strong affinity between DPA/XO and metal ions,the proposed sensing platform was further employed for the determination and differentiation of certain metal ions using linear discriminant analysis.This convenient dual-readout sensing platform offers several notable features and significantly promotes the application and development of lanthanide-based materials.
基金supported by grants from the National Key R&D Program of China(2017YFA0503502)the National Natural Science Foundation of China(31730050,31871347,and 31900502)。
文摘Endothelial cilia are microtubule-based hair-like protrusions in the lumen of blood vessels that function as fluid mechanosensors to regulate vascular hemodynamics. However, the functions of endothelial cilia in vascular development remain controversial. In this study, depletion of several key proteins responsible for ciliogenesis allows us to identify a cilium-independent role for intraflagellar transport 88(IFT88) in mammalian angiogenesis. Disruption of primary cilia by heat shock does not affect the angiogenic process. However, depletion of IFT88 significantly inhibits angiogenesis both in vitro and in vivo. IFT88 mediates angiogenesis by regulating the migration, polarization, proliferation, and oriented division of vascular endothelial cells. Further mechanistic studies demonstrate that IFT88 interacts with c-tubulin and microtubule plus-end tracking proteins and promotes microtubule stability. Our findings indicate that IFT88 regulates angiogenesis through its actions in microtubule-based cellular processes, independent of its role in ciliogenesis.
基金This work was supported by the National Key R&D Program of China(2018YFA0107001)the National Natural Science Foundation of China(31671403 and 31701169).
文摘Cilia are hair-like organelles that protrude from the surface of many types of eukaryotic cells.Each cilium possesses a microtubule-based central core,known as the axoneme,surrounded by the ciliary membrane.Ciliogenesis is a multi-step process that typically involves vesicle transport to the centrosome,maturation of the mother centriole into a basal body,docking of the basal body onto the plasma membrane,and extension of the axoneme from the basal body[1].
文摘Dear Editor,Chromosome movement in mitosis is orchestrated by a microtubule-based protein machinery called the mitotic spindle(Hyman and Karsenti,1996;Compton,2000).The bipolar organization of the mitotic spindle is essential for the accurate segregation of chromosomes into daughter cells.Defects in bipolar spindle assembly can cause chromosome instability and aneuploidy,which are frequently observed in malignant tumors(Silkworth et al.,2009;McGranahan et al.,2012).The nuclear mitotic apparatus(NuMA)is a protein critical for bipolar spindle organization primarily due to its functions in the formation of spindle poles.Dysregulation of NuMA has been reported in a number of cancer types and is associated with cancer development(Bruning-Richardson et al.,2012).Therefore,it is of great significance to understand the molecular mechanisms by which NuMA contributes to spindle pole assembly.
基金supported by the National Key R&D Program of China(2019YFA0802600)the National Natural Science Foundation of China(32170863,31871512,and 31671199)to C.Z.Support was also received from grants from the Shanghai Commission of Science and Technology(17DZ2271100)Open Project of Shandong Provincial Key Laboratory of Reproductive Medicine(SDKL2017018).
文摘Decidualization is the differentiation of endometrial stromal cells into secretory decidual stromal cells.Human decidualization involves some amount of signaling molecules and pathways as well as genetic reprogramming,which is driven by the postovulatory rise in progesterone levels and local cyclic adenosine monophosphate production.Decidualization extends from the primary decidual zone to the secondary decidual zone,and then exits through apoptosis.Evidences support that decidual fibroblasts function as the pool of decidual stromal cells during pregnancy.Decidualization undergoes an acute inflammatory phase,an anti-inflammatory secretory phase to the final recession phase.The decidualization of the inner layer of endometrium,termed decidua,is the most critical determinant of pregnancy success,which can promote placenta formation,modulate immune tolerance,foster resistance to oxidative stress,sense embryo quality,and control labor.Failure to adequate decidualization in terms of hormones,biochemistry,and immunology leads to adverse pregnancy outcomes,including diseases such as preeclampsia,miscarriage,premature labor,repeated implantation failures,and some age-related decline in reproductive capacity.The development of animal models and in vitro culture systems combined with emerging technologies provides a powerful system to explore the mechanism of decidualization.However,decidualization is a dynamic,multi-step process,and translating of current research progress into disease predictions and interventions for pregnancy complications remains to be achieved.The study of periodic regeneration and spontaneous decidualization of the endometrium will be beneficial to the diagnosis and treatment of pregnancy diseases.
基金This work was supported by a grant from the National Natural Science Foundation of China(31730050).
文摘Defects in centrosomes are associated with a broad spectrum of hematological malignancies,such as leukemia and lymphoma.Centrosomes in these malignancies display both numerical and structural aberrations,including alterations in the number and size of centrioles,inappropriate post-translational modification of centrosomal proteins,and extra centrosome clustering.There is accumulating evidence that centrosome defects observed in hematological malignancies result from multiple factors,including dysregulation of the centrosome cycle and impairment of centriole biogenesis.In this review,we discuss the plausible mechanisms of centrosome defects and highlight their consequences in hematological malignancies.We also illustrate the latest therapeutic strategies against hematological malignancies by targeting centrosome anomalies.
