Role of major adipokines in hypertension:A literature review

The incidence and prevalence of hypertension are increasing as a consequence of the obesity epidemic.Adipocytes and their variety of factors make contributions to the long-term regulation of blood pressure.The pathophysiologic states of hypertension,including obesity,are regulated by the production of adipocytederived factors.Increased body mass index was closely linked to elevated blood pressure.Mostly the hypertensive subjects were obese as well as overweight.There are numerous adipokines,however,this review article only focuses on the major adipokines including chemerin,visfatin,retinol-binding protein 4,plasminogen activator inhibitor-1,monocyte chemotactic protein-1,omentin-1,lipocalin-2,vaspin,progranulin,complement c1q tumor necrosis factor-related protein,and nesfatin-1 role in the pathogenesis of hypertension.This review article concludes the significant association of major adipokines in the pathogenesis of hypertensives.New research should be focused on other newly reported adipokine roles in hypertensive subjects and the management of these adipokines in hypertensive subjects.The discovery of this information could result in the creation of antihypertensive medications,particularly those that focus on obesity-related hypertension.

Ad36感染对维吾尔族肥胖患者progranulin表达的调节作用

目的探讨腺病毒36型(Ad36)感染对维吾尔族肥胖患者颗粒蛋白前体(progranulin)表达的调节作用。方法根据肥胖诊断标准将维吾尔族人群样本分为肥胖组(115)与非肥胖组(117),收集血清标本232份,脂肪标本102份。血清中和反应法检测样本血清中的Ad36抗体。采用实时荧光定量PCR(real time quantitative-PCR)方法检测研究对象大网膜和皮下的脂肪组织progranulin的mRNA表达水平,利用酶联免疫吸附实验(ELISA)测定血清progranulin的蛋白表达水平。免疫组化方法检测脂肪组织巨噬细胞CD68蛋白表达,了解巨噬细胞浸润情况。结果 1肥胖患者Ad36感染率(54/115,47.0%)明显高于非肥胖者(38/117,32.5%),差异有统计学意义(P<0.05)。2Ad36感染的肥胖组血清progranulin的蛋白表达水平(408.45±156.92)显著高于非肥胖组(326.11±158.60),差异有统计学意义(P<0.05);两组的腹部大网膜、皮下脂肪组织progranulin mRNA表达水平差异无统计学意义(P均>0.05)。3Ad36感染的肥胖组巨噬细胞浸润(14 730.16±2 227.39)明显高于非肥胖组(10 786.50±2 772.80),差异有统计学意义(P<0.05)。结论 Ad36感染可能与维吾尔族肥胖发生有关,其机制可能为通过调节血清progranulin的蛋白表达水平而实现。

Atsttrin reduces lipopolysaccharide-induced neuroinflammation by inhibiting the nuclear factor kappa B signaling pathway

Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide(10 μg/μL). Atsttrin(2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide(10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor α and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor α in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy.

Umbilical cord blood mesenchymal stem cells protect amyloid-β42 neurotoxicity via paracrine

AIM:To understand the neuroprotective mechanism of human umbilical cord blood-derived mesenchymal stem cells(hUCB-MSCs) against amyloid-β42(Aβ42) exposed rat primary neurons.METHODS:To evaluate the neuroprotective effect of hUCB-MSCs,the cells were co-cultured with Aβ42-exposed rat primary neuronal cells in a Transwell apparatus.To assess the involvement of soluble fac-tors released from hUCB-MSCs in neuroprotection,an antibody-based array using co-cultured media was conducted.The neuroprotective roles of the identified hUCB-MSC proteins was assessed by treating recombi-nant proteins or specific small interfering RNAs(siRNAs) for each candidate protein in a co-culture system.RESULTS:The hUCB-MSCs secreted elevated levels ofdecorin and progranulin when co-cultured with rat pri-mary neuronal cells exposed to Aβ42.Treatment with recombinant decorin and progranulin protected from Aβ42-neurotoxicity in vitro.In addition,siRNA-mediat-ed knock-down of decorin and progranulin production in hUCB-MSCs reduced the anti-apoptotic effects of hUCB-MSC in the co-culture system.CONCLUSION:Decorin and progranulin may be involved in anti-apoptotic activity of hUCB-MSCs exposed to Aβ42.

Moxibustion upregulates hippocampal progranulin expression

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.

Neuropsychological features of progranulin-associated frontotemporal dementia: a nested case-control study

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.

Progranulin基因突变会造成额颞叶型痴呆症

据美国BIOCOMPARE科技新闻网（2006／7／19）报道，英属哥伦比亚大学及曼彻斯特大学的研究人员发现，前颗粒蛋白（Progranulin）基因突变会造成额颞叶型痴呆症（Frontotemporal Dementia，FTD）。

GP88 (Progranulin) Confers Fulvestrant (Faslodex, ICI 182,780) Resistance to Human Breast Cancer Cells

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.

Relation between serum progranulin, inflammatory markers and visceral fat in childhood obesity

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.

Progranulin:A promising biomarker and therapeutic target for fibrotic diseases

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.

New discovery rarely runs smooth： an update on progranulin/TNFR interactions

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.

Clinicopathologic and prognostic implications of progranulin in breast carcinoma

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.

Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3β

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.

Progranulin acts as a shared chaperone and regulates multiple lysosomal enzymes

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.