The distinction between sporadic and genetic behavioural-variant frontotemporal dementia(bvFTD)regarding some neuropsychological(NP)features remains challenging.Specifically,progranulin(GRN)-associated bvFTD frequentl...The distinction between sporadic and genetic behavioural-variant frontotemporal dementia(bvFTD)regarding some neuropsychological(NP)features remains challenging.Specifically,progranulin(GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer’s disease(AD)diagnosis.In this context,we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia(Mini-Mental State Examination score≥17 and Clinical Dementia Rating Scale score≤1.We identified 21 patients at Centro Hospitalar e Universitário de Coimbra,Portugal with GRN mutations belonging to fifteen different families.As our focus was bvFTD variants,FTD-related aphasic forms(3 patients)were excluded.The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging,age and education.All patients completed the Mini-Mental State Examination,Montreal Cognitive Assessment(MoCA)and a comprehensive NP assessment battery.Results were converted into z-scores.Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests(Kruskal-Wallis test analysis)and eta squared(ŋ2)was calculated as a measure of effect size.Group comparisons show that GRN patients have worse performances on verbal retrieval processes(P=0.039,ŋ2=0.110)and visuoconstructive abilities(P=0.039,ŋ2=0.190)than sporadic bvFTD forms.When compared to AD,GRN patients present a higher impairment in frontal(P=0.001,ŋ2=0.211)and parietal(P=0.041,ŋ2=0.129)measures and a better performance in memory tasks(P=0.020,ŋ2=0.120).Sporadic-bvFTD forms are worse than AD in frontal measures(P=0.032,ŋ2=0.200),being better in both memory(P=0.010,ŋ2=0.131)and visuospatial skills(P=0.023,ŋ2=0.231).Considering these results,we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits.This is particularly expressive in visuoconstructive abilities,which was the more discriminative feature between groups,followed by episodic verbal memory.This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra,Portugal(CE-029/2019)on June 24,2019.展开更多
The 88 kDa glycoprotein known as GP88, Progranulin or PC cell derived growth factor is an autocrine growth factor with a unique cysteine rich motif that is over expressed in breast cancer whereas it is negative in nor...The 88 kDa glycoprotein known as GP88, Progranulin or PC cell derived growth factor is an autocrine growth factor with a unique cysteine rich motif that is over expressed in breast cancer whereas it is negative in normal mammary epithelial cells. It has been shown to play a major role in estrogen independence, tamoxifen resistance and tumorigenesis of breast cancer cells. In the present study, we investigated the effect of GP88 overexpression on the response of the human breast cancer MCF-7 cells to the pure estrogen receptor antagonist fulvestrant (ICI 182,780). While fulvestrant effectively inhibited cell proliferation of empty vector transfected cells, it had no inhibitory effect on the proliferation of GP88 overexpressing breast cancer cells. Mouse xenograft experiments in athymic ovariectomized nude mice showed that GP88 over expressing cells were fulvestrant resistant in vivo in contrast to low GP88 expressing cells. We show that the ability of fulvestrant to induce apoptosis determined by measuring cleavage of poly (ADP-ribose) polymerase was inhibited by GP88. Anti-apoptotic activity of GP88 was associated with sustained expression of bcl-2 and bcl-xL after fulvestrant treatment. In contrast, fulvestrant was still able to inhibit the ability of estrogen to stimulate ERE-luciferase reporter gene activity as well as vEGF expression in GP88 over expressing MCF-7 cells similarly to control MCF-7 cells. Collectively, our data suggest that GP88 prevents apoptosis induced by faslodex and contributes to antiestrogen resistance in human breast cancer.展开更多
Aim: To study serum progranulin (PGRN) level in children with obesity and its relationship to inflamamatory markers and visceral fat. Methods: Fifty obese children and 50 controls aged 10-18 years were recruited. Demo...Aim: To study serum progranulin (PGRN) level in children with obesity and its relationship to inflamamatory markers and visceral fat. Methods: Fifty obese children and 50 controls aged 10-18 years were recruited. Demographic, anthropometric and biochemical features were collected according to a standard protocol. Serum progranulin levels, serum IL-6 and hsCRP were measured using ELISA. Insulin resistance was calculated by the homeostasis model (HOMA-IR) using the following formula: HOMA-IR = fasting insulin (mU/L) × fasting glucose (mmoL/L)/ 22.5. The maximum visceral fat thickness (VFT) and the minimum subcutaneous fat thickness (SFT) were measured by ultrasonography. Results: In the obese group, a significant increase was found in serum PGRN (48.87 ± 42.33 ng/mL) compared to control group (30.18 ± 23.82 ng/mL). Progranulin correlated significantly with VFT (r = 0.475), IL6 (r = 0.368), Insulin(r = 0.440) and HOMA-IR (r = 0.379). The mean serum progranulin in the high tertile VFT group was significantly higher than those in the low tertile and middle tertile groups (P = 0.030 and P = 0.039 respectively). VFT was highly positively correlated to progranulin, SFT, IL6, insulin, HOMA-IR and hsCRP (P = 0.001, 0.000, 0.001, 0.001, 0.003 and 0.003). However, the correlation coefficient between SFT and progranulin was insignificant. Summary: we demonstrated for the first time that serum PGRN concentrations increased in Egyptian obese children. The concentrations of serum PGRN correlated closely with visceral fat and IL6. Conclusion: PGRN may contribute to the pathogenesis of chronic inflammation in obesity. It could be a novel marker of visceral fat in obesity. Thus PGRN could be a potential therapeutic target for management of chronic inflammation in obesity.展开更多
In China,moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome,but its mechanisms are largely unknown.More recently,the focus has been on the wealth of information supporting stres...In China,moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome,but its mechanisms are largely unknown.More recently,the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome,and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis.In the present study,we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms.Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome.The acupoints Guanyuan（CV4） and Zusanli（ST36,bilateral） were simultaneously administered moxibustion.Untreated chronic fatigue syndrome rats and normal rats were used as controls.Results from the forced swimming test,open field test,tail suspension test,real-time PCR,enzyme-linked immunosorbent assay,and western blot assay showed that moxibustion treatment decreased m RNA expression of corticotropin-releasing hormone in the hypothalamus,and adrenocorticotropic hormone and corticosterone levels in plasma,and markedly increased progranulin m RNA and protein expression in the hippocampus.These findings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome,at least in part,by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.展开更多
Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis.However,the underlying mechanism is still not completely understood.In this study,progranulin(PGRN)was isolated as a key regula...Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis.However,the underlying mechanism is still not completely understood.In this study,progranulin(PGRN)was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening.In addition,PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model.Furthermore,estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN.Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling.In addition,loss of PGRN led to the reduction of estrogen receptorα,the important estrogen receptor involved in estrogen regulation of osteoporosis,through enhancing its degradation via K48-linked ubiquitination.These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptorα.展开更多
Progranulin （PGRN） is a growth factor implicated in various pathophysiological processes, including wound healing, inflammation, tumorigenesis, and neurodegeneration. It was previously reported that PGRN binds to tu...Progranulin （PGRN） is a growth factor implicated in various pathophysiological processes, including wound healing, inflammation, tumorigenesis, and neurodegeneration. It was previously reported that PGRN binds to tumor necrosis factor receptors （TNFR） and has thera- peutic effects in inflammatory arthritis （Tang et. al, in Science 332：478-484, 2011）; however, Chen et al. reported their inability to demonstrate the PGRN-TNFR interactions under their own conditions （Chert et. al, in J Neurosci 33：9202-9213, 2013）. A letter-to-editor was then published by the original group in response to the Chen et al. paper that discussed the reasons for the latter＇s inability to recapitulate the interactions. In addition, the group published follow-up studies that further reinforced and dissected the interactions of PGRN- TNFR. Recently, the dispute about the legitimacy of PGRN-TNFR interactions appears to be finally settled with independent confirmations of these interactions in various conditions by numerous laboratories. This review presents a chronological update on the story of PGRN-TNFR interactions, highlighting the independent confirmations of these interactions in various diseases and conditions.展开更多
Background Progranulin is a newly discovered 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC. Its expression is closely correlated with the development and metas...Background Progranulin is a newly discovered 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC. Its expression is closely correlated with the development and metastasis of several cancers. However, no immunohistochemical evidence currently exists to correlate progranulin expression with clinicopathologic features in breast carcinoma biopsies, and the role of progranulin as a new marker of metastatic risk and prognosis in breast cancer has not yet been studied. The aim of this study was to investigate the clinicopathologic and prognostic implications of progranulin expression in breast carcinoma and its correlation with tumor angiogenesis. Methods Progranulin expression was determined immunohistochemically in 183 surgical specimens from patients with breast cancer and 20 tissue samples from breast fibroadenomas. The tumor angiogenesis-related biomarker, vascular endothelial growth factor was assayed and microvessel density was assessed by counting vascular endothelial cells in tumor tissues labeled with endoglin antibody. The relationship between progranulin expression and the clinicopathologic data were analyzed. Results Progranulin proteins were overexpressed in breast cancer. The level of progranulin expression was significantly correlated with tumor size （P=0.004）, lymph node metastasis （P 〈0.001） and TNM staging （P 〈0.001）. High progranulin expression was associated with higher tumor angiogenesis, reflected by increased vascular endothelial growth factor expression （P〈0.001） and higher microvessel density （P=0.002）. Conclusion Progranulin may be a valuable marker for assessing the metastasis and prognosis of breast cancer, and could provide the basis for new combination regimens with antiangiogenic activity.展开更多
Progranulin(PGRN),a multifunctional growth factor-like protein expressed by a variety of cell types,serves an important function in the physiologic and pathologic processes of fibrotic diseases,including wound healing...Progranulin(PGRN),a multifunctional growth factor-like protein expressed by a variety of cell types,serves an important function in the physiologic and pathologic processes of fibrotic diseases,including wound healing and the inflammatory response.PGRN was discovered to inhibit proinflammation effect by competing with tumor necrosis factor-alpha(TNF-a)binding to TNF receptors.Notably,excessive tissue repair in the development of inflammation causes tissue fibrosis.Previous investigations have indicated the significance of PGRN in regulating inflammatory responses.Recently,multiple studies have shown that PGRN was linked to fibrogenesis,and was considered to monitor the formation of fibrosis in multiple organs,including liver,cardiovascular,lung and skin.This paper is a comprehensive review summarizing our current knowledge of PGRN,from its discovery to the role in fibrosis.This is followed by an in-depth look at the characteristics of PGRN,consisting of its structure,basic function and intracellular signaling.Finally,we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.展开更多
Progranulin(PGRN)has recently emerged as a key player in a subset of frontotemporal dementias(FTD).Numerous mutations in the progranulin gene have been identified in patients with familial or sporadic frontotemporal l...Progranulin(PGRN)has recently emerged as a key player in a subset of frontotemporal dementias(FTD).Numerous mutations in the progranulin gene have been identified in patients with familial or sporadic frontotemporal lobar degeneration(FTLD).In order to understand the molecular mechanisms by which PGRN deficiency leads to FTLD,we examined activity of PGRN in mouse cortical and hippocampal neurons and in human neuroblastoma SH-SY5Y cells.Treatment of mouse neurons with PGRN protein resulted in an increase in neurite outgrowth,supporting the role of PGRN as a neurotrophic factor.PGRN treatment stimulated phosphorylation of glycogen synthase kinase-3 beta(GSK-3β)in cultured neurons.Knockdown of PGRN in SH-SY5Y cells impaired retinoic acid induced differentiation and reduced the level of phosphorylated GSK-3β.PGRN knockdown cells were also more sensitized to staurosporineinduced apoptosis.These results reveal an important role of PGRN in neurite outgrowth and involvement of GSK-3βin mediating PGRN activity.Identification of GSK-3βactivation as a downstream event for PGRN signaling provides a mechanistic explanation for PGRN activity in the nervous system.Our work also suggest that loss of axonal growth stimulation during neural injury repair or deficits in axonal repair may contribute to neuronal damage or axonal loss in FTLD associated with PGRN mutations.Finally,our study suggests that modulating GSK-3βor similar signaling events may provide therapeutic benefits for FTLD cases associated with PGRN mutations.展开更多
Multifunctional factor progranulin(PGRN)plays an important role in lysosomes,and its mutations and insufficiency are associated with lysosomal storage diseases,including neuronal ceroid lipofuscinosis and Gaucher dise...Multifunctional factor progranulin(PGRN)plays an important role in lysosomes,and its mutations and insufficiency are associated with lysosomal storage diseases,including neuronal ceroid lipofuscinosis and Gaucher disease(GD).The first breakthrough in understanding the molecular mechanisms of PGRN as regulator of lysosomal storage diseases came unexpectedly while investigating the role of PGRN in inflammation.Challenged PGRN null mice displayed typical features of GD.In addition,GRN gene variants were identified in GD patients and the serum levels of PGRN were significantly lower in GD patients.PGRN directly binds to and functions as a chaperone of the lysosomal enzyme β-glucocerebrosidase(GCaase),whose mutations cause GD.In addition,its C-terminus containing granulin E domain,termed Pcgin(PGRN C-terminus for GCase Interaction),is required for the association between PGRN and GCase.The concept that PGRN acts as a chaperone of lysosomal enzymes was further supported and extended by a recent article showing that PGRN acts as a chaperone molecule of lysosomal enzyme cathepsin D(CSTD),and the association between PGRN and CSTD is also mediated by PGRN’s C-terminal granulin E domain.Collectively,these reports suggest that PGRN may act as a shared chaperone and regulates multiple lysosomal enzymes.展开更多
Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple scleros...Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple sclerosis(MS)have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis(EAE).However,unexpectedly,progranulin-deficient mice(Grn^(−/−))were resistant to EAE,and this resistance was fully restored by wild-type bone marrow transplantation.FACS analyses revealed a loss of MHC-II-positive antigenpresenting cells in Grn^(−/−)mice and a reduction in the number of CD8+and CD4+T-cells along with a strong increase in the number of scavenger receptor class B(CD36+)phagocytes,suggesting defects in antigen presentation along with a compensatory increase in phagocytosis.Indeed,bone marrow-derived dendritic cells from Grn^(−/−)mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation.An increase in the number of CD36+phagocytes was associated with increased local inflammation at the site of immunization,stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes,an increase in the phagocytosis of E.coli particles and latex beads and defects in the clearance of the material.Hence,the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation,and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.展开更多
基金ML was supported by Portuguese Foundation for Science and Technology(FCT),No.SFRH/BD/144001/2019.
文摘The distinction between sporadic and genetic behavioural-variant frontotemporal dementia(bvFTD)regarding some neuropsychological(NP)features remains challenging.Specifically,progranulin(GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer’s disease(AD)diagnosis.In this context,we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia(Mini-Mental State Examination score≥17 and Clinical Dementia Rating Scale score≤1.We identified 21 patients at Centro Hospitalar e Universitário de Coimbra,Portugal with GRN mutations belonging to fifteen different families.As our focus was bvFTD variants,FTD-related aphasic forms(3 patients)were excluded.The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging,age and education.All patients completed the Mini-Mental State Examination,Montreal Cognitive Assessment(MoCA)and a comprehensive NP assessment battery.Results were converted into z-scores.Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests(Kruskal-Wallis test analysis)and eta squared(ŋ2)was calculated as a measure of effect size.Group comparisons show that GRN patients have worse performances on verbal retrieval processes(P=0.039,ŋ2=0.110)and visuoconstructive abilities(P=0.039,ŋ2=0.190)than sporadic bvFTD forms.When compared to AD,GRN patients present a higher impairment in frontal(P=0.001,ŋ2=0.211)and parietal(P=0.041,ŋ2=0.129)measures and a better performance in memory tasks(P=0.020,ŋ2=0.120).Sporadic-bvFTD forms are worse than AD in frontal measures(P=0.032,ŋ2=0.200),being better in both memory(P=0.010,ŋ2=0.131)and visuospatial skills(P=0.023,ŋ2=0.231).Considering these results,we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits.This is particularly expressive in visuoconstructive abilities,which was the more discriminative feature between groups,followed by episodic verbal memory.This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra,Portugal(CE-029/2019)on June 24,2019.
文摘The 88 kDa glycoprotein known as GP88, Progranulin or PC cell derived growth factor is an autocrine growth factor with a unique cysteine rich motif that is over expressed in breast cancer whereas it is negative in normal mammary epithelial cells. It has been shown to play a major role in estrogen independence, tamoxifen resistance and tumorigenesis of breast cancer cells. In the present study, we investigated the effect of GP88 overexpression on the response of the human breast cancer MCF-7 cells to the pure estrogen receptor antagonist fulvestrant (ICI 182,780). While fulvestrant effectively inhibited cell proliferation of empty vector transfected cells, it had no inhibitory effect on the proliferation of GP88 overexpressing breast cancer cells. Mouse xenograft experiments in athymic ovariectomized nude mice showed that GP88 over expressing cells were fulvestrant resistant in vivo in contrast to low GP88 expressing cells. We show that the ability of fulvestrant to induce apoptosis determined by measuring cleavage of poly (ADP-ribose) polymerase was inhibited by GP88. Anti-apoptotic activity of GP88 was associated with sustained expression of bcl-2 and bcl-xL after fulvestrant treatment. In contrast, fulvestrant was still able to inhibit the ability of estrogen to stimulate ERE-luciferase reporter gene activity as well as vEGF expression in GP88 over expressing MCF-7 cells similarly to control MCF-7 cells. Collectively, our data suggest that GP88 prevents apoptosis induced by faslodex and contributes to antiestrogen resistance in human breast cancer.
文摘Aim: To study serum progranulin (PGRN) level in children with obesity and its relationship to inflamamatory markers and visceral fat. Methods: Fifty obese children and 50 controls aged 10-18 years were recruited. Demographic, anthropometric and biochemical features were collected according to a standard protocol. Serum progranulin levels, serum IL-6 and hsCRP were measured using ELISA. Insulin resistance was calculated by the homeostasis model (HOMA-IR) using the following formula: HOMA-IR = fasting insulin (mU/L) × fasting glucose (mmoL/L)/ 22.5. The maximum visceral fat thickness (VFT) and the minimum subcutaneous fat thickness (SFT) were measured by ultrasonography. Results: In the obese group, a significant increase was found in serum PGRN (48.87 ± 42.33 ng/mL) compared to control group (30.18 ± 23.82 ng/mL). Progranulin correlated significantly with VFT (r = 0.475), IL6 (r = 0.368), Insulin(r = 0.440) and HOMA-IR (r = 0.379). The mean serum progranulin in the high tertile VFT group was significantly higher than those in the low tertile and middle tertile groups (P = 0.030 and P = 0.039 respectively). VFT was highly positively correlated to progranulin, SFT, IL6, insulin, HOMA-IR and hsCRP (P = 0.001, 0.000, 0.001, 0.001, 0.003 and 0.003). However, the correlation coefficient between SFT and progranulin was insignificant. Summary: we demonstrated for the first time that serum PGRN concentrations increased in Egyptian obese children. The concentrations of serum PGRN correlated closely with visceral fat and IL6. Conclusion: PGRN may contribute to the pathogenesis of chronic inflammation in obesity. It could be a novel marker of visceral fat in obesity. Thus PGRN could be a potential therapeutic target for management of chronic inflammation in obesity.
基金funded by the National Natural Science Foundation (No.81303034 and 81303031)China Postdoctoral Science Foundation (No.KLF501004)Development Project of Shanghai Peak Disciplines-Integrated Chinese and Western Medicine
文摘In China,moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome,but its mechanisms are largely unknown.More recently,the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome,and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis.In the present study,we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms.Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome.The acupoints Guanyuan（CV4） and Zusanli（ST36,bilateral） were simultaneously administered moxibustion.Untreated chronic fatigue syndrome rats and normal rats were used as controls.Results from the forced swimming test,open field test,tail suspension test,real-time PCR,enzyme-linked immunosorbent assay,and western blot assay showed that moxibustion treatment decreased m RNA expression of corticotropin-releasing hormone in the hypothalamus,and adrenocorticotropic hormone and corticosterone levels in plasma,and markedly increased progranulin m RNA and protein expression in the hippocampus.These findings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome,at least in part,by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.
基金supported by the grants from China Scholarship Council(No.201505320002)the National Institutes of Health(No.R01AR062207,R01AR061484,R01AR076900,R01NS103931)+3 种基金Young Medical Talents Program of Jiangsu Province,China(No.QNRC2016878)National Key R&D Program of China(No.SQ2021YFC2501702)Natural Science Foundation of China(No.82072474)Clinical Medicine Technology Project of Jiangsu Province,China(No.BE2019661).
文摘Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis.However,the underlying mechanism is still not completely understood.In this study,progranulin(PGRN)was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening.In addition,PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model.Furthermore,estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN.Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling.In addition,loss of PGRN led to the reduction of estrogen receptorα,the important estrogen receptor involved in estrogen regulation of osteoporosis,through enhancing its degradation via K48-linked ubiquitination.These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptorα.
文摘Progranulin （PGRN） is a growth factor implicated in various pathophysiological processes, including wound healing, inflammation, tumorigenesis, and neurodegeneration. It was previously reported that PGRN binds to tumor necrosis factor receptors （TNFR） and has thera- peutic effects in inflammatory arthritis （Tang et. al, in Science 332：478-484, 2011）; however, Chen et al. reported their inability to demonstrate the PGRN-TNFR interactions under their own conditions （Chert et. al, in J Neurosci 33：9202-9213, 2013）. A letter-to-editor was then published by the original group in response to the Chen et al. paper that discussed the reasons for the latter＇s inability to recapitulate the interactions. In addition, the group published follow-up studies that further reinforced and dissected the interactions of PGRN- TNFR. Recently, the dispute about the legitimacy of PGRN-TNFR interactions appears to be finally settled with independent confirmations of these interactions in various conditions by numerous laboratories. This review presents a chronological update on the story of PGRN-TNFR interactions, highlighting the independent confirmations of these interactions in various diseases and conditions.
基金This research was supported by a grant from the National Natural Science Foundation of China （No. 30772534）.
文摘Background Progranulin is a newly discovered 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC. Its expression is closely correlated with the development and metastasis of several cancers. However, no immunohistochemical evidence currently exists to correlate progranulin expression with clinicopathologic features in breast carcinoma biopsies, and the role of progranulin as a new marker of metastatic risk and prognosis in breast cancer has not yet been studied. The aim of this study was to investigate the clinicopathologic and prognostic implications of progranulin expression in breast carcinoma and its correlation with tumor angiogenesis. Methods Progranulin expression was determined immunohistochemically in 183 surgical specimens from patients with breast cancer and 20 tissue samples from breast fibroadenomas. The tumor angiogenesis-related biomarker, vascular endothelial growth factor was assayed and microvessel density was assessed by counting vascular endothelial cells in tumor tissues labeled with endoglin antibody. The relationship between progranulin expression and the clinicopathologic data were analyzed. Results Progranulin proteins were overexpressed in breast cancer. The level of progranulin expression was significantly correlated with tumor size （P=0.004）, lymph node metastasis （P 〈0.001） and TNM staging （P 〈0.001）. High progranulin expression was associated with higher tumor angiogenesis, reflected by increased vascular endothelial growth factor expression （P〈0.001） and higher microvessel density （P=0.002）. Conclusion Progranulin may be a valuable marker for assessing the metastasis and prognosis of breast cancer, and could provide the basis for new combination regimens with antiangiogenic activity.
基金supported by the National Natural Science Foundation of China(Nos.81274172,81473267,81973637 and 82373933)The National Traditional Chinese Medicine Inheritance and Innovation“Hundreds and Thousands”Talent Project:Young Qihuang Scholar Support Project of the State Administration of Traditional Chinese Medicine in 2020(China).
文摘Progranulin(PGRN),a multifunctional growth factor-like protein expressed by a variety of cell types,serves an important function in the physiologic and pathologic processes of fibrotic diseases,including wound healing and the inflammatory response.PGRN was discovered to inhibit proinflammation effect by competing with tumor necrosis factor-alpha(TNF-a)binding to TNF receptors.Notably,excessive tissue repair in the development of inflammation causes tissue fibrosis.Previous investigations have indicated the significance of PGRN in regulating inflammatory responses.Recently,multiple studies have shown that PGRN was linked to fibrogenesis,and was considered to monitor the formation of fibrosis in multiple organs,including liver,cardiovascular,lung and skin.This paper is a comprehensive review summarizing our current knowledge of PGRN,from its discovery to the role in fibrosis.This is followed by an in-depth look at the characteristics of PGRN,consisting of its structure,basic function and intracellular signaling.Finally,we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.
文摘Progranulin(PGRN)has recently emerged as a key player in a subset of frontotemporal dementias(FTD).Numerous mutations in the progranulin gene have been identified in patients with familial or sporadic frontotemporal lobar degeneration(FTLD).In order to understand the molecular mechanisms by which PGRN deficiency leads to FTLD,we examined activity of PGRN in mouse cortical and hippocampal neurons and in human neuroblastoma SH-SY5Y cells.Treatment of mouse neurons with PGRN protein resulted in an increase in neurite outgrowth,supporting the role of PGRN as a neurotrophic factor.PGRN treatment stimulated phosphorylation of glycogen synthase kinase-3 beta(GSK-3β)in cultured neurons.Knockdown of PGRN in SH-SY5Y cells impaired retinoic acid induced differentiation and reduced the level of phosphorylated GSK-3β.PGRN knockdown cells were also more sensitized to staurosporineinduced apoptosis.These results reveal an important role of PGRN in neurite outgrowth and involvement of GSK-3βin mediating PGRN activity.Identification of GSK-3βactivation as a downstream event for PGRN signaling provides a mechanistic explanation for PGRN activity in the nervous system.Our work also suggest that loss of axonal growth stimulation during neural injury repair or deficits in axonal repair may contribute to neuronal damage or axonal loss in FTLD associated with PGRN mutations.Finally,our study suggests that modulating GSK-3βor similar signaling events may provide therapeutic benefits for FTLD cases associated with PGRN mutations.
基金This work was supported partly by NIH research grants R01AR062207,R01AR061484a DOD research grant W81XWH-16-1-0482.
文摘Multifunctional factor progranulin(PGRN)plays an important role in lysosomes,and its mutations and insufficiency are associated with lysosomal storage diseases,including neuronal ceroid lipofuscinosis and Gaucher disease(GD).The first breakthrough in understanding the molecular mechanisms of PGRN as regulator of lysosomal storage diseases came unexpectedly while investigating the role of PGRN in inflammation.Challenged PGRN null mice displayed typical features of GD.In addition,GRN gene variants were identified in GD patients and the serum levels of PGRN were significantly lower in GD patients.PGRN directly binds to and functions as a chaperone of the lysosomal enzyme β-glucocerebrosidase(GCaase),whose mutations cause GD.In addition,its C-terminus containing granulin E domain,termed Pcgin(PGRN C-terminus for GCase Interaction),is required for the association between PGRN and GCase.The concept that PGRN acts as a chaperone of lysosomal enzymes was further supported and extended by a recent article showing that PGRN acts as a chaperone molecule of lysosomal enzyme cathepsin D(CSTD),and the association between PGRN and CSTD is also mediated by PGRN’s C-terminal granulin E domain.Collectively,these reports suggest that PGRN may act as a shared chaperone and regulates multiple lysosomal enzymes.
基金supported by the Deutsche Forschungsgemeinschaft(CRC1080,A3 to IT and MSCRC1039 to IT)the research funding program“Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz”(LOEWE)of the State of Hessen,Research Center for Translational Medicine and Pharmacology,TMP.
文摘Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple sclerosis(MS)have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis(EAE).However,unexpectedly,progranulin-deficient mice(Grn^(−/−))were resistant to EAE,and this resistance was fully restored by wild-type bone marrow transplantation.FACS analyses revealed a loss of MHC-II-positive antigenpresenting cells in Grn^(−/−)mice and a reduction in the number of CD8+and CD4+T-cells along with a strong increase in the number of scavenger receptor class B(CD36+)phagocytes,suggesting defects in antigen presentation along with a compensatory increase in phagocytosis.Indeed,bone marrow-derived dendritic cells from Grn^(−/−)mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation.An increase in the number of CD36+phagocytes was associated with increased local inflammation at the site of immunization,stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes,an increase in the phagocytosis of E.coli particles and latex beads and defects in the clearance of the material.Hence,the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation,and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.
