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The Wnt signaling pathway: Aging gracefully as a protectionist?
Abstract
No longer considered to be exclusive to cellular developmental pathways, the Wnt family of secreted cysteine-rich glycosylated proteins has emerged as versatile targets for a variety of conditions that involve cardiovascular disease, aging, cancer, diabetes, neurodegeneration, and inflammation. In particular, modulation of Wnt signaling may fill a critical void for the treatment of disorders that impact upon both cellular survival and cellular longevity. Yet, in some scenarios, Wnt signaling can become the catalyst for disease development or promote cell senescence that can compromise clinical utility. This double edge sword in regards to the role of Wnt and its signaling pathways highlights the critical need to further elucidate the cellular mechanisms governed by Wnt in conjunction with the development of robust pharmacological ligands that may open new avenues for disease treatment. Here we discuss the influence of the Wnt pathway during cell survival, metabolism, and aging in order for one to gain a greater insight for the novel role of Wnt signaling as well as exemplify its unique cellular pathways that influence both normal physiology and disease.
... In regard to obesity, increased body weight leads to impaired glucose tolerance that results in DM progression [14][15][16][17][18][19][20][21][22][23][24]. Obesity can especially increase the risk of developing DM in young individuals and can affect stem cell proliferation, aging, inflammation, oxidative stress injury, and mitochondrial function [25][26][27][28][29][30][31][32][33][34]. ...
... DM can lead to both autonomic neuropathy [112] and peripheral nerve disorders [39,113,114]. In the immune and vascular systems, DM can result in low-grade and acute inflammation [19,34,[115][116][117], endothelial dysfunction [63,118,119], cardiovascular disease [7,24,25,30,31,[120][121][122][123][124][125][126][127], and impairment of the neurovascular unit [3,22,41,94,97,101,119,[128][129][130]. ...
... Individuals with two ε4 alleles of APOE-ε4 have reduced expression of antiviral defense genes and have more severe neuroinflammation and microvascular injury in the brain [151,355,394]. APOE-ε4 during SARS-CoV-2 infection and long COVID may result in cognitive loss and cerebrovascular disease in the nervous system [11,30,61,66,85,167,177,199,395,396]. ...
It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer’s disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.
... The Wnt/β-catenin signaling pathway plays an important regulatory role in cell proliferation, differentiation, development, and metabolism [9,10], and its activation was associated with the repair of fatty liver injury or promotion of liver regeneration in NAFLD [11]. Activation of Wnt/β-catenin signaling was also proved to improve hepatic steatosis, inflammatory response, and apoptosis in rats with alcoholic liver disease [12] and promoted hepatocyte proliferation and alleviated apoptosis in a model of liver ischemiareperfusion injury [13]. ...
... Data are expressed as mean ± SD (n = 4/group); p < 0:05 was defined as statistically significant. DM: saline-treated type 1 diabetes group; DMI: insulin treatment group; DML: liraglutide treatment group; DMIL: insulin+liraglutide treatment group; NC: normal glucose tolerance group; * : compared to NC; #: compared to DM; †: compared to DMI; ‡: compared to DML. 9 Mediators of Inflammation carbamazepine-or lipopolysaccharide-induced liver damage [41,42]. Furthermore, the expression level of β-catenin, the most critical cofactor in the typical Wnt/β-catenin pathway, has been shown to be significantly decreased in animal models of liver injury, and its activation may attenuate oxidative stress and apoptosis in the liver by regulating cellular redox homeostasis [12,13]. ...
Liraglutide has been extensively applied in the treatment of type 2 diabetes mellitus and also has hepatoprotective effects. However, the role of liraglutide treatment on liver injury in a mouse model of type 1 diabetes mellitus (T1DM) induced by streptozotocin (STZ) and its underlying mechanisms remain to be elucidated. In the present study, diabetes was initiated in experimental animals by single-dose intraperitoneal inoculation of STZ. Forty female C57BL/6J mice were equally assigned into five groups: diabetic group, insulin+diabetic group, liraglutide+diabetic group, insulin+liraglutide+diabetic group, and control group for eight weeks. Diabetic mice exhibited a significantly elevated blood glucose level and decreased body weight, and morphological changes of increased steatosis and apoptosis were observed in the liver compared with the control. Furthermore, a significant increase in the levels of malondialdehyde and inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin 1β (IL-1β) and the proapoptotic proteins caspase-3 and Bax were observed in the livers of diabetic mice, together with marked increases in antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as antiapoptotic protein Bcl-2, all of which were significantly mitigated by treatment with liraglutide, insulin, and their combinations. Interestingly, liraglutide monotherapy showed better efficacy in ameliorating liver injury in T1DM mice than insulin monotherapy, similar to the combined drug therapy. Furthermore, the expression of Wnt/β-catenin signaling pathway-associated molecules was upregulated in the liver of mice treated with liraglutide or insulin. The results of the present study suggested that liraglutide improves T1DM-induced liver injury and may have important implications for the treatment of nonalcoholic fatty liver disease (NAFLD) in patients with T1DM.
... The Wnt signalling pathway plays an important role in biological development and is involved in the processes of cell apoptosis, migration, invasion and differentiation [2,3]. Wnt signalling regulation has been extensively studied and described. ...
... The Wnt signalling pathway plays an important role in biological development. It contributes to the processes of cell apoptosis, migration, invasion and differentiation in embryonic and tissue development [2,3]. The Wnt/β-catenin signalling pathway is closely related to the occurrence and development of fibrotic diseases [25][26][27]. ...
Diabetic nephropathy (DN) commonly causes end-stage renal disease (ESRD). Increasing evidence indicates that abnormal miRNA expression is tightly associated with chronic kidney disease (CKD). This work aimed to investigate whether miR-27a can promote the occurrence of renal fibrosis in DN by suppressing the expression of secreted frizzled-related protein 1 (Sfrp1) to activate Wnt/β-catenin signalling. Therefore, we assessed the expression levels of miR-27a, Sfrp1, Wnt signalling components and extracellular matrix (ECM)-related molecules invitro and in vivo. Sfrp1 was significantly downregulated in a high-glucose environment, while miR-27a levels were markedly increased. A luciferase reporter assay confirmed that miR-27a downregulated Sfrp1 by binding to the 3' untranslated region directly. Further, NRK-52E cells under high-glucose conditions underwent transfection with miR-27a mimic or the corresponding negative control, miR-27a inhibitor or the corresponding negative control, si-Sfrp1, or combined miR-27a inhibitor and si-Sfrp1. Immunoblotting and immunofluorescence were performed to assess the relative expression levels of Wnt/β-catenin signalling and ECM components. The mRNA levels of Sfrp1, miR-27a and ECM-related molecules were also detected by quantitative real-time PCR (qPCR). We found that miR-27a inhibitor inactivated Wnt/β-catenin signalling and reduced ECM deposition. Conversely, Wnt/β-catenin signalling was activated, while ECM deposition was increased after transfection with si-Sfrp1. Interestingly, miR-27a inhibitor attenuated the effects of si-Sfrp1. We concluded that miR-27a downregulated Sfrp1 and activated Wnt/β-catenin signalling to promote renal fibrosis.
... In the context of AD, circulating WNT9A was elevated in patients with AD [32], and the WNT9A gene was upregulated in the hippocampi of memory-impaired mice [47]. Indeed, the Wnt signaling pathway, one of the parts of which is WNT9A, has been shown to play a role in AD pathogenesis through the regulation of inflammation, neurogenesis, β-amyloid production, and tau phosphorylation [46,48]. R-spondin 1 (RSPO1) is an activator of the Wnt/β-catenin signaling pathway [49,50]. ...
Dementia is a progressive and debilitating neurological disease that affects millions of people worldwide. Identifying the minimally invasive biomarkers associated with dementia that could provide insights into the disease pathogenesis, improve early diagnosis, and facilitate the development of effective treatments is pressing. Proteomic studies have emerged as a promising approach for identifying the protein biomarkers associated with dementia. This pilot study aimed to investigate the plasma proteome profile and identify a panel of various protein biomarkers for dementia. We used a high-throughput proximity extension immunoassay to quantify 1090 proteins in 122 participants (22 with dementia, 64 with mild cognitive impairment (MCI), and 36 controls with normal cognitive function). Limma-based differential expression analysis reported the dysregulation of 61 proteins in the plasma of those with dementia compared with controls, and machine learning algorithms identified 17 stable diagnostic biomarkers that differentiated individuals with AUC = 0.98 ± 0.02. There was also the dysregulation of 153 plasma proteins in individuals with dementia compared with those with MCI, and machine learning algorithms identified 8 biomarkers that classified dementia from MCI with an AUC of 0.87 ± 0.07. Moreover, multiple proteins selected in both diagnostic panels such as NEFL, IL17D, WNT9A, and PGF were negatively correlated with cognitive performance, with a correlation coefficient (r2) ≤ −0.47. Gene Ontology (GO) and pathway analysis of dementia-associated proteins implicated immune response, vascular injury, and extracellular matrix organization pathways in dementia pathogenesis. In conclusion, the combination of high-throughput proteomics and machine learning enabled us to identify a blood-based protein signature capable of potentially differentiating dementia from MCI and cognitively normal controls. Further research is required to validate these biomarkers and investigate the potential underlying mechanisms for the development of dementia.
... Recently, a new computational approach based on the analysis of networks of co-located loci has identified wg among novel genes associated with longevity in Drosophila [111]. Experimental data suggest both a positive and a negative role of the Wnt in cell senescence, aging-associated diseases, and organism longevity [112,113]. For example, reduced Wnt signaling has been shown to protect against mutant Huntingtin toxicity in Drosophila and prolong the lifespan of flies with Huntington's disease [114]. ...
The transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the main downstream effectors of the evolutionarily conserved Hippo signaling pathway. YAP/TAZ are implicated in the transcriptional regulation of target genes that are involved in a wide range of key biological processes affecting tissue homeostasis and play dual roles in the aging process, depending on the cellular and tissue context. The aim of the present study was to investigate whether pharmacological inhibitors of Yap/Taz increase the lifespan of Drosophila melanogaster. Real-time qRT-PCR was performed to measure the changes in the expression of Yki (Yorkie, the Drosophila homolog of YAP/TAZ) target genes. We have revealed a lifespan-increasing effect of YAP/TAZ inhibitors that was mostly associated with decreased expression levels of the wg and E2f1 genes. However, further analysis is required to understand the link between the YAP/TAZ pathway and aging.
... Endothelial cell growth can be slowed by the sFRP family of proteins, which are soluble inhibitors of Wnt signaling. The two-domain structure of 2 sFRPs consists of a CRD like those found in FZD receptors and a netrin-like domain (NLD) that is structurally similar to TIMP [93,117,118]. The soluble modulators Fzd and sFRP may compete for binding Wnt ligands [119]. ...
Most colorectal cancers (CRC) are associated with activated Wnt signaling, making it the fourth most prevalent type of cancer globally. To function properly, the Wnt signaling pathway requires secreted glycoproteins known as Wnt ligands (Wnts). Humans have 19 Wnts, which suggest a complicated signaling and biological process, and we still know little about their functions in developing CRC. This review aims to describe the canonical Wnt signaling in CRC, particularly the Wnt3a expression pattern, and their association with the angiogenesis and progression of CRC. This review also sheds light on the inhibition of Wnt3a signaling in CRC. Despite some obstacles, a thorough understanding of Wnts is essential for effectively managing CRC.
... DVL is then phosphorylated, resulting in the inhibition of GSK-3β and accumulation of free β-catenin. The free β-catenin then translocates to the nucleus and activates genes that influence cellular processes [53,54]. ...
The elderly proportion of the population is gradually increasing, which poses a great burden to society, the economy, and the medical field. Aging is a physiological process involving multiple organs and numerous reactions, and therefore it is not easily explained or defined. At present, a growing number of studies are focused on the mechanisms of aging and potential strategies to delay aging. Some clinical drugs have been demonstrated to have anti-aging effects; however, many still have deficits with respect to safety and long-term use. Polysaccharides are natural and efficient biological macromolecules that act as antioxidants, anti-inflammatories, and immune regulators. Not surprisingly, these molecules have recently gained attention for their potential use in anti-aging therapies. In fact, multiple polysaccharides have been found to have excellent anti-aging effects in different animal models including Caenorhabditis elegans, Drosophila melanogaster, and mice. The anti-aging qualities of polysaccharides have been linked to several mechanisms, such as improved antioxidant capacity, regulation of age-related gene expression, and improved immune function. Here, we summarize the current findings from research related to anti-aging polysaccharides based on various models, with a focus on the main anti-aging mechanisms of oxidative damage, age-related genes and pathways, immune modulation, and telomere attrition. This review aims to provide a reference for further research on anti-aging polysaccharides.
... The Drosophila wg gene is the structural homolog of vertebrate Wnt genes [44] , encoding secreted glycoproteins that act as signaling molecules essential for growth, development, and tissue homeostasis [45,46]. Experimental data suggest both a positive and a negative role of the Wnt in cell senescence, aging-associated diseases, and organism longevity [47,48]. For example, the opposing roles of Wnt ligands mom-2/Wnt (pro-aging) and lin-44/Wnt (anti-aging) have been revealed in Caenorhabditis elegans [49]. ...
The transcriptional coactivators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are the main downstream effectors of the evolutionary conserved Hippo signaling pathway. YAP/TAZ is implicated in the transcriptional regulation of target genes that are involved in a wide range of key biological processes affecting tissue homeostasis and play dual roles in the aging process depending on cellular and tissue context. The aim of the present study was to investigate whether pharmacological inhibitors of Yap/Taz may increase the lifespan of Drosophila melanogaster. qRT-PCR was performed to measure the changes in the expression level of Yki (Yorkie, the Drosophila homolog of YAP/TAZ) target genes. We have revealed a lifespan increasing effect of YAP/TAZ inhibitors that was mostly associated with decreased expression level of wg and E2f1 genes. However further analysis is required to understand how YAP/TAZ pathway is linked with aging.
... Wnt signaling cascade plays an essential role during embryogenesis and adult tissue homeostasis [5]. It also plays an important role in axis formation [6], midbrain development [7] and regulation of early events in the developing nervous system [8]. Various Wnt ligands (Wnt-3, -3a, -7b and -8b) contribute in the development of the forebrain [9], a region which gives rise to the hippocampus. ...
... During increased TIMELESS expression, cell growth pathways are fostered that involve the wingless pathway of Wnt/βcatenin and resistance against chemotherapy to lead to cell apoptosis, such as with cisplatin, is increased [89]. Wnt proteins are cysteine-rich glycosylated proteins that can affect development of neurons, immune system function, tissue fibrosis, angiogenesis, stem cell development, and cancer [111][112][113][114]. Yet, detrimental effects with Wnt pathways can result to promote increased vascular growth of tumors [111,115,116] and tumorigenesis [40, [117][118][119][120][121]. As a result, these mechanisms may work in conjunction with TIMELESS. ...
Introduction
Dementia and cognitive loss impact a significant proportion of the global population and present almost insurmountable challenges for treatment since they stem from multifactorial etiologies. Innovative avenues for treatment are highly warranted.
Methods and results
Novel work with biological clock genes that oversee circadian rhythm may meet this critical need by focusing upon the pathways of the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless Wnt pathway. These pathways are complex in nature, intimately associated with autophagy that can maintain circadian rhythm, and have an intricate relationship that can lead to beneficial outcomes that may offer neuroprotection, metabolic homeostasis, and prevention of cognitive loss. However, biological clocks and alterations in circadian rhythm also have the potential to lead to devastating effects involving tumorigenesis in conjunction with pathways involving Wnt that oversee angiogenesis and stem cell proliferation.
Conclusions
Current work with biological clocks and circadian rhythm pathways provide exciting possibilities for the treating dementia and cognitive loss, but also provide powerful arguments to further comprehend the intimate and complex relationship among these pathways to fully potentiate desired clinical outcomes.
... Importantly, an age-related hypomethylation was found in igf1, which is in accordance with the age-related hypomethylated DMRs found in the promoters and exons of members of the IGF signaling pathway in humans (Heyn et al., 2012). The wnt1, also found hypomethylated in senescent compared to the immature fish, is part of the Wnt signaling pathway, which has a protective role of the cell in situation of oxidative stress; a cellular condition that has been linked to ageing in the oxidative stress theory of aging and empirically supported by observations in some model organisms C. elegans, Drosophila or mice (Maiese et al., 2008;Muller et al., 2007). The other two genes affected by age were amhr2 and cyp11a, both involved in the adult reproductive cycle (Piferrer and Guiguen, 2008) suggestive of a link between their regulation and the age-dependent reproductive status of the fish. ...
Epigenetic mechanisms, influenced by intrinsic and environmental factors are crucial for the regulation of gene expression and, ultimately, the phenotype. The European sea bass is used as a model to study these influences on DNA methylation and the phenotype during early development and later in life. We identify loci altered with age, suggestive of the existence of a piscine epigenetic clock. We show that moderate early developmental temperature increases are associated with genome-wide changes in DNA methylation and with parent-specific responses of genes involved in sexual development. Furthermore, we highlight a genome-wide inverse relationship of gene expression with the DNA methylation of the first intron. Lastly, we provide one of the first empirical demonstrations in support of the neural crest cell deficit hypothesis to explain Darwin’s domestication syndrome. Together, these results constitute the most integrative analysis of DNA methylation patterns in a fish species under intrinsic and ecologically relevant contexts.
http://hdl.handle.net/10261/143896
... These findings suggest that accelerated musculoskeletal aging is associated with poor health in other organ systems. In particular, we found that the most significant SNP associated with accelerated knee aging lies in the WNT16 gene, which is involved in signaling and is linked to aging in different organ systems [45][46][47][48] , such as the brain 49 , the heart 50 and the intestines 51 . We explore the hypothesis of multidimensional aging more in detail in a different paper 52 . ...
With age, the musculoskeletal system undergoes significant changes, leading to diseases such as arthritis and osteoporosis. Due to the aging of the world population, the prevalence of such diseases is therefore expected to starkly increase in the coming decades. While numerous biological age predictors have been developed to assess musculoskeletal aging, it remains unclear whether these different approaches and data capture a single aging process, or if the diverse joints and bones in the body age at different rates. In the following, we leverage 42,000 full body, spine, hip and knee X-ray images and musculoskeletal biomarkers from the UK Biobank and use artificial intelligence to build the most accurate musculoskeletal aging predictor to date (RMSE=2.65+/-0.01 years; R-Squared=87.6+/-0.1%). Our predictor is composite and can be used to assess spine age, hip age and knee age, in addition to general musculoskeletal aging. We find that accelerated musculoskeletal aging is moderately correlated between these different musculoskeletal dimensions (e.g hip vs. knee: Pearson correlation=.351+/-.004). Musculoskeletal aging is heritable at more than 35%, and the genetic factors are partially shared between joints (e.g hip vs. knee: genetic correlation=.52+/-.04). We identified single nucleotide polymorphisms associated with accelerated musculoskeletal aging in approximately ten genes for each musculoskeletal dimension. General musculoskeletal aging is for example associated with a TBX15 variant linked to Cousin syndrome and acromegaloid facial appearance syndrome. Finally, we identified biomarkers, clinical phenotypes, diseases, environmental and socioeconomic variables associated with accelerated musculoskeletal aging in each dimension. We conclude that, while the aging of the different components of the musculoskeletal system is connected, each bone and joint can age at significantly different rates.
... These two complexes differ in regulatory proteins as the first is regulated by Raptor while the second by Rictor [458]. mTOR and WNT pathways work in concert to guarantee cardiac and endothelial cells life cycle [459][460][461][462]. Overall, mTOR function has been seen to regulate proliferation/differentiation of embryonic stem cells, maintaining pluripotency of embryonic stem cells when needed [463,464]. ...
Aging can be seen as process characterized by accumulation of oxidative stress induced damage. Oxidative stress derives from different endogenous and exogenous processes, all of which ultimately lead to progressive loss in tissue and organ structure and functions. The oxidative stress theory of aging expresses itself in age-related diseases. Aging is in fact a primary risk factor for many diseases and in particular for cardiovascular diseases and its derived morbidity and mortality. Here we highlight the role of oxidative stress in age-related cardiovascular aging and diseases. We take into consideration the molecular mechanisms, the structural and functional alterations, and the diseases accompanied to the cardiovascular aging process.
... Ding et al., 2018;Maiese, 2015g, 2018dPal, Sonowal, Shukla, Srivastava, & Ramana, 2019), cardiovascular disease (Alexandru, Popov, & Georgescu, 2012;Barchetta et al., 2019;Chiu et al., 2017;S. Ding et al., 2018;Esterline et al., 2018;Maiese et al., 2007;Maiese, Li, Chong, & Shang, 2008;Perez-Hernandez et al., 2016;Thackeray et al., 2011), immune function disorders (Kell & Pretorius, 2018;X. Lin & Zhang, 2018;Maiese, 2015c;Woodhams & Al-Salami, 2017;Y. ...
Non-communicable diseases (NCDs) that involve neurodegenerative disorders and metabolic disease impact over 400 million individuals globally. Interestingly, metabolic disorders, such as diabetes mellitus, are significant risk factors for the development of neurodegenerative diseases. Given that current therapies for these NCDs address symptomatic care, new avenues of discovery are required to offer treatments that affect disease progression. Innovative strategies that fill this void involve the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), AMP activated protein kinase (AMPK), trophic factors that include erythropoietin (EPO), and the programmed cell death pathways of autophagy and apoptosis. These pathways are intriguing in their potential to provide effective care for metabolic and neurodegenerative disorders. Yet, future work is necessary to fully comprehend the entire breadth of the mTOR pathways that can effectively and safely translate treatments to clinical medicine without the development of unexpected clinical disabilities.
... Previous studies have shown that WISP1 regulates the posttranslational phosphorylation of AMP-activated protein kinase (AMPK), which is involved in glucose homeostasis, adipocyte differentiation, and lipid accumulation [31][32][33][34]. Moreover, WISP1 also phosphorylates and activates mammalian target of rapamycin (mTOR) [12,35,36] and silent mating type information regulation 2 homolog 1 (SIRT1) [21,37], molecules that play a vital role in stem cell regulation, programmed cell death, and cellular energy homeostasis [38]. As a potential endogenous reparative response to injury, WISP1 may further provide novel therapies for restoring pancreatic function and controlling lipid metabolism [39]. ...
Background:
Obese women with gestational diabetes mellitus (GDM) have a higher risk of adverse outcomes than women with obesity or GDM alone. Our study is aimed at investigating the discriminatory power of circulatory Wnt1-inducible signaling pathway protein-1 (WISP1), a novel adipocytokine, on the copresence of prepregnancy overweight/obesity and GDM and at clarifying the relationship between the WISP1 level and clinical cardiometabolic parameters.
Methods:
A total of 313 participants were screened from a multicenter prospective prebirth cohort: Born in Shenyang Cohort Study (BISCS). Subjects were examined with a 2 × 2 factorial design for body mass index (BMI) ≥ 24 and GDM. Between 24 and 28 weeks of pregnancy, follow-up individuals underwent an OGTT and blood sampling for cardiometabolic characterization.
Results:
We observed that the WISP1 levels were elevated in prepregnancy overweight/obesity patients with GDM, compared with nonoverweight subjects with normal blood glucose (3.45 ± 0.89 vs. 2.91 ± 0.75 ng/mL). Multilogistic regression analyses after adjustments for potential confounding factors revealed that WISP1 was a strong and independent risk factor for prepregnancy overweight/obesity with GDM (all ORs > 1). In addition, the results of the ROC analysis indicated that WISP1 exhibited the capability to identify individuals with prepregnancy overweight/obesity and GDM (all AUC > 0.5). Finally, univariate and multivariate linear regression showed that WISP1 level was positively and independently correlated with fasting blood glucose, systolic blood pressure, and aspartate aminotransferase and was negatively correlated with HDL-C and complement C1q.
Conclusions:
WISP1 may be critical for the prediction, diagnosis, and therapeutic strategies against obesity and GDM in pregnant women.
... Wnt1 inducible signaling pathway protein 1 (WISP1), a matricellular protein and a downstream target of the wingless pathway Wnt1 [5], offers exceptional promise to target DM and metabolic dysfunction that can address underlying disease progression [6,7]. WISP, also known as CCN4, is a member of the CCN family of proteins. ...
The prevalence of diabetes mellitus (DM) continues to increase throughout the world. In the United States (US) alone, approximately ten percent of the population is diagnosed with DM and another thirty-five percent of the population is considered to have prediabetes. Yet, current treatments for DM are limited and can fail to block the progression of multi-organ failure over time. Wnt1 inducible signaling pathway protein 1 (WISP1), also known as CCN4, is a matricellular protein that offers exceptional promise to address underlying disease progression and develop innovative therapies for DM. WISP1 holds an intricate relationship with other primary pathways of metabolism that include protein kinase B (Akt), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and mammalian forkhead transcription factors (FoxOs). WISP1 is an exciting prospect to foster vascular as well as neuronal cellular protection and regeneration, control cellular senescence, block oxidative stress injury, and maintain glucose homeostasis. However, under some scenarios WISP1 can promote tumorigenesis, lead to obesity progression with adipocyte hyperplasia, foster fibrotic hepatic disease, and lead to dysregulated inflammation with the progression of DM. Given these considerations, it is imperative to further elucidate the complex relationship WISP1 holds with other vital metabolic pathways to successfully develop WISP1 as a clinically effective target for DM and metabolic disorders.
... In the last decade, we have explored the functional role of adult neurogenesis in PD by addressing the molecular and cellular NSC regulatory mechanisms underlying the age-dependent decline of neurogenic potential in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP + )-induced rodent model of basal ganglia injury, investigating the potential to stimulate adult neurogenesis as a means to support neuroprotective and neurorestorative therapies (L'Episcopo, Serapide, et al., 2011b;L'Episcopo et al., 2011aL'Episcopo et al., , 2013L'Episcopo et al., , 2012L'Episcopo et al., , 2014aL'Episcopo, Tirolo, Serapide, et al., 2018aMarchetti, 2018;. Particularly, we concentrated on the key pathway regulating DAergic neurogenesis, from neurodevelopment through aging and neurodegeneration: the wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin (WβC) signalling cascade (Brodski, Blaess, Partanen, & Prakash, 2019;Inestrosa & Arenas, 2010;Maiese, 2015;Maiese, Faqi, Chong, & Shang, 2008;Marchetti, 2018;Nusse & Clevers, 2017;Nusse & Varmus, 1982;Palomer et al., 2019;Salinas, 2012;Tapia-Rojas & Inestrosa, 2018;Toledo et al., 2017;Wurst & Prakash, 2014). The ...
A common hallmark of age-dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC-signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct-periventricular region (Aq-PVR) Wnt-sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β-catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial-derived factors regulating WβC-dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in "turning off" the WβC neurogenic switch via down-regulation of the nuclear factor erythroid-2-related factor 2/Wnt-regulated signalosome, a key player in the maintenance of antioxidant self-defense mechanisms and NSC homeostasis. Harnessing WβC-signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.
... By in vivo microdialysis, ASS234 showed an expressive rise in the extracellular levels of 5-HT and NA in hippocampus whereas in the prefrontal cortex, DA and NA also increased significantly. 85 Recent evidence suggests that the wingless-type MMTV integration site family (Wnt) signaling pathway is involved in neuroprotective activities related to AD. 86 Thus, a study with ASS234 was undertaken to determine whether this compound was able to activate Wnt signaling pathway. The results indicated that ASS234 was able to induce canonical and noncanonical Wnt pathways, which represent another possible mechanism through which this compound mediates its protective actions. ...
Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aβ expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.
... Wnt signals are pleiotropic, with effects that include mitogenic stimulation, cell fate specification, and differentiation. As the volume of Wnt literature is increasing rapidly, a few aspects of current interest have been selected here, mainly focused on Wnt signaling through its receptors (Frizzleds) to β-catenin, which is often called the canonical pathway [25][26][27]. Recent studies have demonstrated that the activation of the Wnt/β-catenin signaling pathway is closely related to stem cell aging [28,29]. ...
This is a study on the relationship between the protective effect of ginsenoside Rg1 on senescent neural stem cells and Wnt- β /catenin signaling pathway. Background . Recent studies have shown that overactivation of the Wnt/ β -catenin signaling pathway is closely related to stem cell senescence. Whether Rg1 delays the senescence of NSCs is related to the regulation of this signaling pathway. Methods . The whole brain of Nestin-GFP transgenic newborn rat was extracted, and NSCs were extracted and cultured to P3 generation. The following indicators were detected: (1) NSC culture identification, (2) the effect of LiCl on the proliferation and survival rate of NSCs, (3) the effect of ginsenoside Rg1 on the proliferation and survival of NSCs, (4) the growth of NSCs in each group observed by an optical microscope, (5) the cell cycle of each group detected by flow cytometry, (6) the proliferative ability of each group detected by BrdU, (7) the fluorescence intensity of Nestin and Sox2 of NSCs in each group observed by a fluorescence microscope, (8) the positive rate of senescence staining analyzed by SA- β -Gal staining, (9) the localization of β -catenin in NSCs observed by laser confocal microscopy, and (10) the changes of the Wnt/ β -catenin pathway-related proteins in each group detected by Western blotting. Results . LiCl activates the Wnt/ β -catenin pathway and promotes mouse neural stem cell senescence. Ginsenoside Rg1 promotes proliferation of neural stem cells and inhibits Wnt/ β -catenin pathway activation. Conclusions . LiCl can activate the Wnt/ β -catenin signaling pathway of NSCs, and ginsenoside Rg1 can antagonize the senescence of NSCs caused by activation of the Wnt/ β -catenin signaling pathway and delay brain aging.
... Potential mechanisms by which TCF7L2 variants influence T2DM include defective insulin secretion [1,16,27], deficient insulin processing [33], and decreased sensitivity to GLP-1 [17]. In tissues that are a target for insulin action, GLP-1 is believed to interact with its receptor on the cell membrane and stimulate the synthesis and activation of proteins participating in the intracellular signaling cascade for insulin [2,19]. ...
Abstract Background Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and reduces blood glucose in type 2 diabetes mellitus (T2DM). TCF7L2 rs7903146 polymorphism has been associated with decreased insulin secretion, reduced GLP-1 action, and possible impaired peripheral insulin sensitivity. Objectives To evaluate the postprandial pancreatic hormone response in patients with T2DM carriers of the TCF7L2 variant rs7903146 (CT/TT) compared with noncarriers of this variant (CC) after treatment with the GLP-1 agonist exenatide. Methods Intervention study. Patients with T2DM (n = 162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism (SNP). Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C (HbA1c), HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon before and after treatment with exenatide for 8 weeks. Results Patients with genotypes CC and CT/TT presented similar glucose area under the curve (AUC) 0–180 min before treatment and a similar decrease after treatment (p
... Earlier and more recent findings underscored that Wnt1/β-catenin signaling cascades play a prominent role in mDAergic development [26][27][28][29][30]. Studies focusing on genetic networks recapitulating the early signals for the development of mDA neurons identified Wnt1 as a critical morphogen for mDA neurons, where activation of Wnt1/β-catenin signaling is required for mDA neuron specification [28][29][30][31][32]. In the adult brain, growing evidence highlights that a Wnt/Fzd/β-catenin tone is involved in the maintenance of neuronal health, while its dysregulation is associated with neuronal dysfunction and death [44][45][46][47][48]. ...
Wingless-type mouse mammary tumor virus (MMTV) integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation to axonal extension, synapse formation, neurogenesis, and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional β-catenin protein which is a potent co-activator of transcription factors such as lymphoid enhancer factor (LEF) and T-cell factor (TCF). Accumulating evidence points to dysregulation of Wnt/β-catenin signaling in major neurodegenerative disorders. This review highlights a Wnt/β-catenin/glial connection in Parkinson’s disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. Major findings of the last decade document that Wnt/β-catenin signaling in partnership with glial cells is critically involved in each step and at every level in the regulation of nigrostriatal DAergic neuronal health, protection, and regeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, focusing on Wnt/β-catenin signaling to boost a full neurorestorative program in PD.
... Hence, through glial expression of specific chemokines, such as CCL3, CXCl10, and CXCL11, astrocyte-derived Wnt1 is significantly up-modulated, both a mRNA and protein levels, and a progressive time-dependent neurorepair of nigrostriatal DA neurons and downregulation ofinflammation is observed (L'Episcopo et al., 2011a). Then, via astrocyte-microglia crosstalk and the release of Wnt1-like proteins in astrocytes, the resulting Wnt/β-catenin activation in microglial cells can inhibit GSK-3β activation, resulting in a downregulation of proinflammatory mediators (Chong and Maiese, 2007;Maiese et al., 2008;L'Episcopo et al., 2011aL'Episcopo et al., ,b, 2013L'Episcopo et al., , 2014bSchaale et al., 2011;Wang et al., 2012;Marchetti and Pluchino, 2013; Figure 2). In fact, the pharmacologic antagonism of GSK-3β restrain inflammatory microglial activation via the inhibition of proinflammatory cytokines through interactions at the level of NFκB (Beurel et al., 2010;Beurel, 2011;L'Episcopo et al., 2011a,b;; Figure 2). ...
Meningiomas rank among the most prevalent solid tumors in the human central nervous system, exhibiting a wide spectrum of prognoses, with particularly challenging outcomes in cases of malignant meningiomas. Cellular senescence (CS) is recognized as a significant prognostic and therapeutic indicator in numerous types of tumors. However, the characterization of CS in meningiomas has remained largely unexplored. This study delves into cellular senescence (CS) as a prognostic and therapeutic factor in meningiomas, a relatively unexplored area. Using CellAge database genes, we established a CS score index. Survival analysis, employing R packages like "survival" and "survminer," identified genes with significant Recurrence-Free Survival (RFS) differences. Weighted Gene Co-expression Network Analysis (WGCNA) and Multi-scale Embedded Gene Co-expression Network Analysis (MEGENA) revealed hub genes. The Tumor Immune Dysfunction and Exclusion (TIDE) score assessed immunotherapy potential, while the RNAactDrug database predicted drug sensitivity.
Our analysis unveiled a strong link between CS score, meningioma recurrence, and grade. Notably, we observed differential senescence-associated secretory phenotype (SASP) expression in recurrent versus non-recurrent meningiomas. Single cell sequencing exposed distinct senescence subgroups and heterogeneity within meningioma. We also elucidated mechanisms through which CS negatively affects prognosis. TBL3, an identified hub gene, emerged as a promising prognostic factor and therapeutic target. Our study pinpointed Panobinostat and Palbociclib as potential TBL3 and CS inhibitors, potentially broadening therapeutic options, especially for malignant meningiomas. In summary, this research underscores the potential of CS as both a prognostic indicator and a target for therapeutic interventions in the context of meningiomas.
Metabolic disorders and diabetes (DM) impact more than five hundred million individuals throughout the world and are insidious in onset, chronic in nature, and yield significant disability and death. Current therapies that address nutritional status, weight management, and pharmacological options may delay disability but cannot alter disease course or functional organ loss, such as dementia and degeneration of systemic bodily functions. Underlying these challenges are the onset of aging disorders associated with increased lifespan, telomere dysfunction, and oxidative stress generation that lead to multi-system dysfunction. These significant hurdles point to the urgent need to address underlying disease mechanisms with innovative applications. New treatment strategies involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are dependent upon programmed cell death pathways, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide, and growth factor applications. Non-coding RNAs, Wnt signaling, and AMPK are cornerstone mechanisms for overseeing complex metabolic pathways that offer innovative treatment avenues for metabolic disease and DM but will necessitate continued appreciation of the ability of each of these cellular mechanisms to independently and in unison influence clinical outcome.
Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, b-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to b- nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.
As a significant non-communicable disease, cardiovascular disease is the leading cause of death for both men and women, comprises almost twenty percent of deaths in most racial and ethnic groups, can affect greater than twenty-five million individuals worldwide over the age of twenty, and impacts global economies with far-reaching financial challenges. Multiple factors can affect the onset of cardiovascular disease that include high serum cholesterol levels, elevated blood pressure, tobacco consumption and secondhand smoke exposure, poor nutrition, physical inactivity, obesity, and concurrent diabetes mellitus. Yet, addressing any of these factors cannot completely eliminate the onset or progression of cardiovascular disorders. Novel strategies are necessary to target underlying cardiovascular disease mechanisms. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), a histone deacetylase, can limit cardiovascular injury, assist with stem cell development, oversee metabolic homeostasis through nicotinamide adenine dinucleotide (NAD+) pathways, foster trophic factor protection, and control cell senescence through the modulation of telomere function. Intimately tied to SIRT1 pathways are mammalian forkhead transcription factors (FoxOs) which can modulate cardiac disease to reduce oxidative stress, repair microcirculation disturbances, and reduce atherogenesis through pathways of autophagy, apoptosis, and ferroptosis. AMP activated protein kinase (AMPK) also is critical among these pathways for the oversight of cardiac cellular metabolism, insulin sensitivity, mitochondrial function, inflammation, and the susceptibility to viral infections such as severe acute respiratory syndrome coronavirus that can impact cardiovascular disease. Yet, the relationship among these pathways is both intricate and complex and requires detailed insight to successfully translate these pathways into clinical care for cardiovascular disorders.
Disorders of metabolism affect multiple systems throughout the body but may have the greatest impact on both central and peripheral nervous systems. Currently available treatments and behavior changes for disorders that include diabetes mellitus (DM) and nervous system diseases are limited and cannot reverse the disease burden. Greater access to healthcare and a longer lifespan have led to an increased prevalence of metabolic and neurodegenerative disorders. In light of these challenges, innovative studies into the underlying disease pathways offer new treatment perspectives for Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. Metabolic disorders are intimately tied to neurodegenerative diseases and can lead to debilitating outcomes, such as multi-nervous system disease, susceptibility to viral pathogens, and long-term cognitive disability. Novel strategies that can robustly address metabolic disease and neurodegenerative disorders involve a careful consideration of cellular metabolism, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP-activated protein kinase (AMPK), growth factor signaling, and underlying risk factors such as the apolipoprotein E (APOE-4) gene. Yet, these complex pathways necessitate comprehensive understanding to achieve clinical outcomes that target disease susceptibility, onset, and progression.
Almost three million individuals suffer from multiple sclerosis (MS) throughout the world, a demyelinating disease in the nervous system with increased prevalence over the last five decades, and is now being recognized as one significant etiology of cognitive loss and dementia. Presently, disease modifying therapies can limit the rate of relapse and potentially reduce brain volume loss in patients with MS, but unfortunately cannot prevent disease progression or the onset of cognitive disability. Innovative strategies are therefore required to address areas of inflammation, immune cell activation, and cell survival that involve novel pathways of programmed cell death, mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and associated pathways with the apolipoprotein E (APOE-ε4) gene and severe acute respiratory syndrome coronavirus (SARS-CoV-2). These pathways are intertwined at multiple levels and can involve metabolic oversight with cellular metabolism dependent upon nicotinamide adenine dinucleotide (NAD+). Insight into the mechanisms of these pathways can provide new avenues of discovery for the therapeutic treatment of dementia and loss in cognition that occurs during MS.
Background
Parkinson’s disease (PD) is a progressive late-onset neurodegenerative disease leading to physical and cognitive decline. Mutations of leucine-rich repeat kinase 2 ( LRRK2 ) are the most common genetic cause of PD. LRRK2 is a complex scaffolding protein with known regulatory roles in multiple molecular pathways. Two prominent examples of LRRK2-modulated pathways are Wingless/Int (Wnt) and nuclear factor of activated T-cells (NFAT) signaling. Both are well described key regulators of immune and nervous system development as well as maturation. The aim of this study was to establish the physiological and pathogenic role of LRRK2 in Wnt and NFAT signaling in the brain, as well as the potential contribution of the non-canonical Wnt/Calcium pathway.
Methods
In vivo cerebral Wnt and NFATc1 signaling activity was quantified in LRRK2 G2019S mutant knock-in (KI) and LRRK2 knockout (KO) male and female mice with repeated measures over 28 weeks, employing lentiviral luciferase biosensors, and analyzed using a mixed-effect model. To establish spatial resolution, we investigated tissues, and primary neuronal cell cultures from different brain regions combining luciferase signaling activity, immunohistochemistry, qPCR and western blot assays. Results were analyzed by unpaired t-test with Welch’s correction or 2-way ANOVA with post hoc corrections.
Results
In vivo Wnt signaling activity in LRRK2 KO and LRRK2 G2019S KI mice was increased significantly ∼3-fold, with a more pronounced effect in males (∼4-fold) than females (∼2-fold). NFATc1 signaling was reduced ∼0.5-fold in LRRK2 G2019S KI mice. Brain tissue analysis showed region-specific expression changes in Wnt and NFAT signaling components. These effects were predominantly observed at the protein level in the striatum and cerebral cortex of LRRK2 KI mice. Primary neuronal cell culture analysis showed significant genotype-dependent alterations in Wnt and NFATc1 signaling under basal and stimulated conditions. Wnt and NFATc1 signaling was primarily dysregulated in cortical and hippocampal neurons respectively.
Conclusions
Our study further built on knowledge of LRRK2 as a Wnt and NFAT signaling protein. We identified complex changes in neuronal models of LRRK2 PD, suggesting a role for mutant LRRK2 in the dysregulation of NFAT, and canonical and non-canonical Wnt signaling.
Background:
Motor and cognitive decline as part of the normal aging process is linked to alterations in synaptic plasticity and reduction of adult neurogenesis in the dorsal striatum. Neuroinflammation, particularly in the form of microglial activation, is suggested to contribute to these age-associated changes.
Objective and methods:
To explore the molecular basis of alterations in striatal function during aging we analyzed RNA-Seq data for 117 postmortem human dorsal caudate samples and 97 putamen samples acquired through GTEx.
Results:
Increased expression of neuroinflammatory transcripts including TREM2, MHC II molecules HLA-DMB, HLA-DQA2, HLA-DPA1, HLA-DPB1, HLA-DMA and HLA-DRA, complement genes C1QA, C1QB, CIQC and C3AR1, and MHCI molecules HLA-B and HLA-F was identified. We also identified down-regulation of transcripts involved in neurogenesis, synaptogenesis, and synaptic pruning, including DCX, CX3CL1, and CD200, and the canonical WNTs WNT7A, WNT7B, and WNT8A. The canonical WNT signaling pathway has previously been shown to mediate adult neurogenesis and synapse formation and growth. Recent findings also highlight the link between WNT/β-catenin signaling and inflammation pathways.
Conclusions:
These findings suggest that age-dependent attenuation of canonical WNT signaling plays a pivotal role in regulating striatal plasticity during aging. Dysregulation of WNT/β-catenin signaling via astrocyte-microglial interactions is suggested to be a novel mechanism that drives the decline of striatal neurogenesis and altered synaptic connectivity and plasticity, leading to a subsequent decrease in motor and cognitive performance with age. These findings may aid in the development of therapies targeting WNT/β-catenin signaling to combat cognitive and motor impairments associated with aging.
Epigenetic shifts are a hallmark of aging that impact transcriptional networks at regulatory level. These shifts may modify the effects of genetic regulatory variants during aging and contribute to disease pathomechanism. However, these shifts occur on the backdrop of epigenetic changes experienced throughout an individual's development into adulthood; thus, the phenotypic, and ultimately fitness, effects of regulatory variants subject to developmental- versus aging-related epigenetic shifts may differ considerably. Natural selection therefore may act differently on variants depending on their changing epigenetic context, which we propose as a novel lens through which to consider regulatory sequence evolution and phenotypic effects. Here, we define genomic regions subjected to altered chromatin accessibility as tissues transition from their fetal to adult forms, and subsequently from early to late adulthood. Based on these epigenomic datasets, we examine patterns of evolutionary constraint and potential functional impacts of sequence variation (e.g., genetic disease risk associations). We find that while the signals observed with developmental epigenetic changes are consistent with stronger fitness consequences (i.e., negative selection pressures), they tend to have weaker effects on genetic risk associations for aging-related diseases. Conversely, we see stronger effects of variants with increased local accessibility in adult tissues, strongest in young adult when compared to old. We propose a model for how epigenetic status of a region may influence the effects of evolutionary relevant sequence variation, and suggest that such a perspective on gene regulatory networks may elucidate our understanding of aging biology.
Diabetic nephropathy (DN) remains the major cause of end‐stage renal disease. MicroRNAs (miRNAs) have been reported to perform biological functions in many diseases. This investigation elucidated the biological role of miR‐17‐5p in DN. In this study, high glucose‐cultured human mesangial cells (HMCs) were used as a cell model of DN. The miR‐17‐5p and KIF23 expression was measured by RT‐qPCR. Cell apoptosis was detected by flow cytometry. The protein levels of apoptosis markers, fibrosis markers, and Wnt/β‐catenin signaling‐related genes were assessed using western blotting. The interaction of miR‐17‐5p with KIF23 was tested by a luciferase reporter assay. We found that miR‐17‐5p was upregulated in both DN patients and high glucose‐treated HMCs. Silencing miR‐17‐5p attenuated the apoptosis and fibrosis in high glucose‐treated HMCs. MiR‐17‐5p binds to KIF23 3′UTR and negatively regulates KIF23 expression. KIF23 knockdown could suppress the role of miR‐17‐5p inhibition in high glucose‐treated HMCs. Additionally, inhibition of miR‐17‐5p activated Wnt/β‐catenin signaling in HMCs through upregulating KIF23 expression. Suppression of Wnt/β‐catenin signaling antagonized the effect of miR‐17‐5p in HMCs. In conclusion, miR‐17‐5p inhibition alleviates the apoptosis and fibrosis in high glucose‐treated HMCs by targeting KIF23 activating Wnt/β‐catenin signaling.
Lifespan is increasing throughout the world and is accompanied by a rise in non-communicable diseases (NCDs) that can lead to disability and death for over forty million individuals each year. Neurodegenerative diseases are a significant component of NCDs and by the year 2030, it is estimated that over eighty million individuals will be impacted by neurodegenerative disorders such as dementia. In the United States (US) alone, treatment for dementia will require over two trillion US dollars every year to finance. Given the complexity and limited ability to treat neurodegenerative disorders, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its integrated pathways with mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), circadian clock genes, and non-coding ribonucleic acids (RNAs) offer exciting considerations for the development of new treatment strategies for neurodegenerative disease. SIRT1 relies upon these pathways to oversee apoptosis, autophagy, and oxidative stress as well as cell development and cell proliferation controlled by trophic factors, such as erythropoietin (EPO), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). However, a critical balance of activity is necessary among these pathways with SIRT1 and, if absent, can lead to cellular loss or tumorigenesis. Future investigations to gain essential insight into the extensive relationships held among SIRT1, FoxOs, mTOR, circadian clock genes, and non-coding ribonucleic acids (RNAs) are vital for the innovative and effective translation of these pathways into efficacious treatments for neurodegenerative disease.
Metabolic disorders including diabetes mellitus (DM) are considered a significant component of the increasing prevalence of non-communicable diseases (NCDs) occurring throughout the world. It is predicted that the number of individuals with DM is expected to rise to seven hundred million individuals by the year 2045. Furthermore, the care for disorders such as DM can consume more than seventeen percent of the Gross Domestic Product in nations such as the United States. Given that present therapies for metabolic disorders may offer some clinical benefit and gradually slow disease progression, metabolic diseases can affect multiple organs of the body and ultimately lead to disability and death. Given these challenges, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its associated pathways with AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and the vitamin nicotinamide offer exciting prospects for the development of innovative therapeutic strategies that are highly warranted. SIRT1 is intimately tied to AMPK, mTOR, and nicotinamide during metabolic disease to limit oxidative stress, increase lifespan, improve insulin sensitivity, maintain mitochondrial function, oversee nutritional intake, regulate -cell function, and limit the development of obesity. Yet, these pathways hold a complex relationship that also involves the regulation of autophagy, apoptosis, and growth factors, such as erythropoietin (EPO), that requires a fine balance to maintain glucose homeostasis and limit potential cellular toxicity. Future studies for SIRT1 and its association with AMPK, mTOR, and nicotinamide are critical to gain further insight for novel treatment strategies for metabolic diseases that limit potential unwarranted clinical outcomes.
Neurodegenerative disorders impact more than one billion individuals worldwide and are intimately tied to metabolic disease that can affect another nine hundred individuals throughput the globe. Nicotinamide is a critical agent that may offer fruitful prospects for neurodegenerative diseases and metabolic disorders, such as diabetes mellitus. Nicotinamide protects against multiple toxic environments that include reactive oxygen species exposure, anoxia, excitotoxicity, ethanolinduced neuronal injury, amyloid (Aß) toxicity, age-related vascular disease, mitochondrial dysfunction, insulin resistance, excess lactate production, and loss of glucose homeostasis with pancreatic β-cell dysfunction. However, nicotinamide offers cellular protection in a specific concentration range with dosing outside of this range leading to detrimental effects. The underlying biological pathways of nicotinamide that involve the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and mammalian forkhead transcription factors (FoxOs) may offer insight for the clinical translation of nicotinamide into a safe and efficacious therapy through the modulation of oxidative stress, apoptosis, and autophagy. Nicotinamide is a highly promising target for the development of innovative strategies for neurodegenerative disorders and metabolic disease, but the fruits of this foundation depend greatly on gaining further understanding of nicotinamide’s complex biology.
Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.
Neurogenesis process in the chronic phase of ischemic stroke has become the focus of research on stroke treatment recently, mainly through the activation of related pathways to increase the differentiation of neural stem cells (NSCs) in the brain sub-ventricular zone (SVZ) and subgranular zone (SGZ) of hippocampal dentate gyrus (DG) areas into neurons, promoting neurogenesis. While there is still debate about the longevity of active adult neurogenesis in humans, the SVZ and SGZ have the capacity to upregulate neurogenesis in response to cerebral ischemia, which opens discussion about potential treatment strategies to harness this neuronal regenerative response. Wnt signaling pathway is one of the most important approaches potentially targeting on neurogenesis after cerebral ischemia, appropriate activation of which in NSCs may help to improve the sequelae of cerebral ischemia. Various therapeutic approaches are explored on preclinical stage to target endogenous neurogenesis induced by Wnt signaling after stroke onset. This article describes the composition of Wnt signaling pathway and the process of neurogenesis after cerebral ischemia, and emphatically introduces the recent studies on the mechanisms of this pathway for post-stroke neurogenesis and the therapeutic possibility of activating the pathway to improve neurogenesis after stroke.
Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic beta-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.
Background:
Liver ischemia reperfusion injury (LIRI) is a common problem during surgical procedures of the liver. It causes severe inflammatory responses and cell death, eventually leading to serious liver damage. Agmatine (AGM) is an endogenous polyamine with analgesic, anti-inflammatory, and antiapoptotic effects. However, it is still unknown whether AGM can protect the liver from damage caused by LIRI.
Methods:
For the in vivo experiments, a mouse model of partial warm hepatic ischemia reperfusion was established using C57BL/6 mice and then serum transaminase concentrations were analyzed. Histopathology was used to evaluate the degree of liver injury and quantitative real-time PCR was used to measure the amount of inflammatory cytokines. For in vitro experiments, a cellular model of cobalt chloride (CoCl2)-induced hypoxia was established using AML12 cells. Flow cytometry was performed to measure the apoptosis levels. Western blotting analysis was conducted to measure the levels of proteins involved in apoptosis and Wnt/β-catenin signaling. We also chose 2 inhibitors of the Wnt/β-catenin signaling to elucidate the relationship between AGM and the Wnt/β-catenin signaling.
Results:
AGM showed protective effects against LIRI-induced liver damage, inflammatory responses, and cell apoptosis along with alleviation of CoCl2-induced hepatocyte injury. AGM activated the Wnt/β-catenin signaling pathway during LIRI and CoCl2-induced hepatocyte injury; however, when the Wnt/β-catenin pathway was inhibited, the protective effects of AGM declined.
Conclusions:
AGM showed protective effects against LIRI by activating the Wnt/β-catenin signaling pathway.
Introduction: Dementia is the 7th leading cause of death that imposes a significant financial and service burden on the global population. Presently, only symptomatic care exists for cognitive loss, such as Alzheimer’s disease.
Areas Covered: Given the advancing age of the global population, it becomes imperative to develop innovative therapeutic strategies for cognitive loss. New studies provide insight to the association of cognitive loss with metabolic disorders, such as diabetes mellitus.
Expert Opinion: Diabetes mellitus is increasing in incidence throughout the world and affects 350 million individuals. Treatment strategies identifying novel pathways that oversee metabolic and neurodegenerative disorders offer exciting prospects to treat dementia. The mechanistic target of rapamycin (mTOR) and circadian clock gene pathways that include AMP activated protein kinase (AMPK), Wnt1 inducible signaling pathway protein 1 (WISP1), erythropoietin (EPO), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) provide novel strategies to treat cognitive loss that has its basis in metabolic cellular dysfunction. However, these pathways are complex and require precise regulation to maximize treatment efficacy and minimize any potential clinical disability. Further investigations hold great promise to treat both the onset and progression of cognitive loss that is associated with metabolic disease.
Liver failure is one of the major risk factors for death worldwide, and the only effective liver transplantation is currently very limited. Adult stem cells can be induced into hepatocytes in vitro and implanted into the body to repair damaged liver. However, most of the induction time in vitro is relatively long, which is not suitable for practical application. Therefore, search for new seed cells that can rapidly differentiate into functional hepatocytes is crucial for the clinical application of cell transplantation therapy. In this study, we explored a three-step protocol to rapidly induce human minor salivary gland mesenchymal stem cells (hMSG-MSCs) into hepatocytes in vitro, and finally obtained hepatocyte-like cells within 6 days. After a series of relevant detection from gene, protein and functional levels, we confirmed that the finally induced cells were mature hepatocyte-like cells with certain hepatocyte functions to some extent. Besides, we injected the preliminary induced cells into mice with acute liver injury, showing a good repair effect on the damaged liver. All these results indicate that the hMSG-MSCs have potential to be a kind of seed cells for rapid hepatic differentiation.
The world's population continues to age at a rapid pace. By the year 2050, individuals over the age of 65 will account for sixteen percent of the world's population and life expectancy will increase well over eighty years of age. Accompanied with the aging of the global population is a significant rise in non-communicable diseases (NCDs). Neurodegenerative disorders will form a significant component for NCDs. Currently, dementia is the 7th leading cause of death and can be the result of multiple causes that include diabetes mellitus, vascular disease, and Alzheimer's disease (AD). AD may represent at least sixty percent of these cases. Current treatment for these disorders is extremely limited to provide only some symptomatic relief at present. Sirtuins and in particular, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), represent innovative strategies for the treatment of cognitive loss. New work has revealed that SIRT1 provides protection against memory loss through mechanisms that involve oxidative stress, A toxicity, neurofibrillary degeneration, vascular injury, mitochondrial dysfunction, and neuronal loss. In addition, SIRT1 relies upon other avenues that can include trophic factors, such as erythropoietin, and signaling pathways, such as Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). Yet, SIRT1 can have detrimental effects as well that involve tumorigenesis and blockade of stem cell differentiation and maturation that can limit reparative processes for cognitive loss. Further investigations with sirtuins and SIRT1 should be able to capitalize upon these novel targets for dementia and cognitive loss.
beta-Catenin, a cytoplasmic protein known for its association with cadherin cell adhesion molecules, is also part of a signaling cascade involved in embryonic patterning processes such as the determination of the dorsoventral axis in Xenopus and determination of segment polarity in Drosophila. Previous studies suggest that increased cytoplasmic levels of beta-catenin correlate with signaling, raising questions about the need for in- teraction with cadherins in this process. We have tested the role of the beta-catenin-cadherin interaction in axis formation. Using beta-catenin deletion mutants, we demonstrate that significant binding to cadherins can be eliminated without affecting the signaling activity. Also, depletion of the soluble, cytosolic pool of beta-catenin by binding to overexpressed C-cadherin completely inhibited beta-catenin-inducing activity. We conclude that binding to cadherins is not required for beta-catenin signaling, and therefore the signaling function of beta-catenin is independent of its role in cell adhesion. Moreover, because beta-catenin signaling is antagonized by binding to cadherins, we suggest that cadherins can act as regulators of the intracellular beta-catenin signaling pathway.
The transcription factor NF-kappaB has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-kappaB, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-kappaB family members play important roles. In this review, we provide an overview of established NF-kappaB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-kappaB transcriptional activity.
Apoptosis mediates the precise and programmed natural death of neurons and is a physiologically important process in neurogenesis during maturation of the central nervous system. However, premature apoptosis and/or an aberration in apoptosis regulation is implicated in the pathogenesis of neurodegeneration, a multifaceted process that leads to various chronic disease states, such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and diabetic encephalopathy. The current review focuses on two major areas (a) the fundamentals of apoptosis, which includes elements of the apoptotic machinery, apoptosis inducers, and emerging concepts in apoptosis research, and (b) apoptotic involvement in neurodegenerative disorders, neuroprotective treatment strategies/modalities, and the mechanisms of, and signaling in, neuronal apoptosis. Current and new experimental models for apoptosis research in neurodegenerative diseases are also discussed.
In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome1, juvenile intestinal polyposis2 and Cowden disease3, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways4,5. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced
Wnt signaling plays a critical role in develop- ment and oncogenesis. Although significant progress has been made in understanding the downstream sig- naling cascade of Wnt signaling, little is known regard- ing Wnt signaling modification of the cell death machin- ery. Given that numerous oncogenes transform cells by providing cell survival function, we hypothesized that Wnt signaling may inhibit apoptosis. Here, we report that cells expressing Wnt-1 were resistant to cancer therapy-mediated apoptosis. Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, includ- ing both vincristine and vinblastine. Furthermore, we found that Wnt-1-mediated cell survival was dependent on the activation of b -catenin/T cell factor (Tcf) tran- scription. Inhibition of b -catenin/Tcf transcription by expression of the dominant-negative mutant of Tcf-4 blocked Wnt-1-mediated cell survival and rendered cells sensitive to apoptotic stimuli. These results pro- vide the first demonstration that Wnt-1 inhibits cancer therapy-mediated apoptosis and suggests that Wnt-1 may exhibit its oncogenic potential through a mecha- nism of anti-apoptosis. 1 Abbreviations used in this paper: Apaf-1, apoptotic protease-activating factor-1; APC, adenomatous polyposis coli; b -gal, b -galactosidase; DN, dominant-negative mutant; EGFP, enhanced green fluorescent protein; GFP, green fluorescent protein; GSK-3 b , glycogen synthase kinase-3 b ; IAP, inhibitors of apoptosis; I k B, inhibitor of k B; IKK, I k B kinase; JNK, c-Jun NH 2 -terminal kinase; Lef, lymphocyte enhancer factor; NF- k B, nu- clear factor kappa B; PI, propidium iodide; PI3K, phosphatidyinositol-3 kinase; PS, phosphatidylserine; Tcf, T cell factor; TNF, tumor necrosis fac- tor; VCR, vincristine; VBL, vinblastine.
The transcription factors of the Rel/NF-κB family are key regulators of immune and inflammatory responses and contribute to
lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities
of the Rel/NF-κB oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-κB control.
Our recent finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a direct transcriptional target of NF-κB raised
the issue of whether NF-κB is a specific or global regulator of death antagonists in the Bcl-2 family. Here, we demonstrate
that NF-κB differentially regulates the expression of particular Bcl-2-related death inhibitors and that it directly activates
the expression of Bcl-xL. While Bcl-xL was significantly upregulated by c-Rel and RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-κB factors
also upregulated bcl-x gene expression and this effect was antagonized by an inhibitor of NF-κB activity. The expression of bcl-x suppressed apoptosis in the presence or absence of NF-κB activity. Functional analysis of thebcl-x promoter demonstrated that it is directly controlled by c-Rel. These results establish that NF-κB directly regulates the
expression of distinct prosurvival factors in the Bcl-2 family, such as Bcl-xL and Bfl-1/A1. These findings raise the possibility that some of these factors may contribute to oncogenesis associated with
aberrant Rel/NF-κB activity.
Although Wingless (Wg)/Wnt signaling has been implicated in heart development of multiple organisms, conflicting results have
been reported regarding the role of Wnt/β-catenin pathway in cardiac myogenesis: Wg/armadillo signaling promotes heart development
in Drosophila, whereas activation of Wnt/β-catenin signaling inhibits heart formation in avians and amphibians. Using an in vitro system of mouse ES cell differentiation into cardiomyocytes, we show here that Wnt/β-catenin signaling exhibits developmental
stage-specific, biphasic, and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis. Activation of the
Wnt/β-catenin pathway in the early phase during embryoid body (EB) formation enhances ES cell differentiation into cardiomyocytes
while suppressing the differentiation into hematopoietic and vascular cell lineages. In contrast, activation of Wnt/β-catenin
signaling in the late phase after EB formation inhibits cardiomyocyte differentiation and enhances the expression of hematopoietic/vascular
marker genes through suppression of bone morphogenetic protein signaling. Thus, Wnt/β-catenin signaling exhibits biphasic
and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis, depending on the stage of development.
The Wnt proteins constitute a large family of extracellular signalling molecules that are found throughout the animal kingdom and are important for a wide variety of normal and pathological developmental processes
Although casein kinase Iε (CKIε) has been shown to regulate the Wnt signaling pathway positively, its mode of action is not
clear. In this study we show that CKIε activates the Wnt signaling pathway in co-operation with Dvl. CKIε and Axin associated
with different sites of Dvl, and CKIε and Dvl interacted with distinct regions on Axin. Therefore, these three proteins formed
a ternary complex. Either low expression of Dvl or CKIε alone did not accumulate β-catenin, but their co-expression accumulated
greatly. Dvl and CKIε activated the transcriptional activity of T cell factor (Tcf) synergistically. Although the Dvl mutant
that binds to Axin but not to CKIε activated Tcf, it did not synergize with CKIε. Another Dvl mutant that does not bind to
Axin did not activate Tcf irrespective of the presence of CKIε. Furthermore, Dvl and CKIε co-operatively induced axis duplication
of Xenopus embryos. These results indicate that Dvl and CKIε synergistically activated the Wnt signaling pathway and that the binding
of the complex of Dvl and CKIε to Axin is necessary for their synergistic action.
Transcripts for the α1 chain of mouse type XVIII collagen were found to be heterogeneous at their 5′-ends and to encode three
variant N-terminal sequences of the ensuing 1315-, 1527-, or 1774-residue collagen chains. The variant mRNAs appeared to originate
from the use of two alternate promoters of the α1(XVIII) chain gene, resulting in the synthesis of either short or long Nterminal
non-collagenous NC1 domains, the latter being further subject to modification due to alternative splicing of the transcripts.
As a result, the 1527- and 1774-residue polypeptides share the same signal peptide, and the lengths of their NC1 domains are
517 or 764 amino acid residues, respectively, while the 1315-residue polypeptide has a different signal peptide and a 301-residue
NC1 domain. The longest NC1 domain was strikingly characterized by a 110-residue sequence with 10 cysteines, which was found
to be homologous with the previously identified frizzled proteins belonging to the family of G-protein-coupled membrane receptors.
Thus, it is proposed that the cysteine-rich motif, termed fz, represents a new sequence motif that can be found in otherwise
unrelated proteins. Tissues containing mainly one or two NC1 domain mRNA variants or all three NC1 domains were identified,
indicating that there is tissue-specific utilization of two alternate promoters and alternative splicing of α1(XVIII) transcripts.
NF-κB is one of the most important modulators of stress and inflammatory gene expression in the nervous system. In the adult brain, NF-κB upregulation has been demonstrated in neurons and glial cells in response to experimental injury and neuropathological disorders, where it has been related to both neurodegenerative and neuroprotective activities. Accordingly, the aim of this study was to evaluate the cellular and temporal patterns of NF-κB activation and the expression of its endogenous inhibitor IκBα following traumatic brain injury (TBI) during the early postnatal weeks, when the brain presents elevated levels of plasticity and neuroprotection. Our results showed that cortical trauma to the 9-day-old rat brain induced a very fast upregulation of NF-κB, which was maximal within the first 24 hours after injury. NF-κB was mainly observed in neuronal cells of the degenerating cortex as well as in astrocytes located in the corpus callosum adjacent to the injury, where a pulse-like pattern of microglial NF-κB activation was also found. In addition, astrocytes of the corpus callosum, and microglial cells to a lower extent, also showed de novo expression of IκBα within the time of NF-κB activation. This study suggests an important role of NF-κB activation in the early mechanisms of neuronal death or survival, as well as in the development of the glial and inflammatory responses following traumatic injury to the immature rat brain. © 2002 Wiley-Liss, Inc.
Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.
In addition to its documented role in the proteolytic processing of Notch-1 and the β-amyloid precursor protein, presenilin 1 (PS1) associates with β-catenin. In this study, we show that this interaction plays a critical role in regulating β-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic β-catenin, leading to a β-catenin/LEF-dependent increase in cyclin D1 transcription and accelerated entry into the S phase of the cell cycle. Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner. The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind β-catenin (PS1Δcat) or by two different familial Alzheimer's disease mutants. In contrast, PS1Δcat restores Notch-1 proteolytic cleavage and Aβ generation in PS1-deficient cells, indicating that PS1 function in modulating β-catenin levels can be separated from its roles in facilitating γ-secretase cleavage of β-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of β-catenin in the absence of PS1, a phenotype that may account for the increased stability in PS1-deficient cells. Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of β-catenin.
β-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell–cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated β-catenin levels in colorectal cancer caused by mutations in β-catenin or by the adenomatous polyposis coli molecule, which regulates β-catenin degradation, result in the binding of β-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes. Here, we show that the cyclin D1 gene is a direct target for transactivation by the β-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of β-catenin activation, wild-type adenomatous polyposis coli, axin, and the cytoplasmic tail of cadherin suppressed cyclin D1 promoter activity in colon cancer cells. Cyclin D1 protein levels were induced by β-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased β-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.
The APC tumor-suppressor protein associates with beta-catenin, a cell adhesion protein that is upregulated by the WNT1 oncogene. We examined the effects of exogenous APC expression on the distribution and amount of beta-catenin in a colorectal cancer cell containing only mutant APC. Expression of wild-type APC caused a pronounced reduction in total beta-catenin levels by eliminating an excessive supply of cytoplasmic beta-catenin indigenous to the SW480 colorectal cancer cell line. This reduction was due to an enhanced rate of beta-catenin protein degradation. Truncated mutant APC proteins, characteristic of those associated with cancer, lacked this activity. Mutational analysis revealed that the central region of the APC protein, which is typically deleted or severely truncated in tumors, was responsible for the down-regulation of beta-catenin. These results suggest that the tumor-suppressor activity of mutant APC may be compromised due to a defect in its ability to regulate beta-catenin.
Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are neuroprotective during anoxia and nitric oxide (NO) toxicity. Signal transduction systems that modulate protein kinase C (PKC) also can modulate the toxic effects of anoxia and NO. We therefore examined whether PKC was involved in the protective effects of bFGF and EGF during anoxia and NO toxicity. Down-regulation or inhibition of PKC activity before anoxia or NO exposure prevented hippocampal neuronal degeneration. Yet, this protective effect of inhibition of PKC activity was not present with the coadministration of growth factors. Combined inhibition of PKC activity and application of bFGF or EGF lessened the protective mechanisms of the growth factors. In addition, the protective ability of the growth factors was lost during anoxia and NO exposure with the activation of PKC, suggesting that at least a minimal degree of PKC activation is necessary for growth factor protection. Although modulation of PKC activity may be a necessary prerequisite for protection against anoxia and NO toxicity by bFGF and EGF, only inhibition of PKC activity, rather than application of the growth factors, was protective following exposure to NO. These results suggest that the mechanism of protection by bFGF and EGF during anoxia and NO toxicity appears initially to be dependent on a minimum degree of PKC activation, but that other signal transduction pathways independent of PKC also may mediate protection by peptide growth factors.
Little is known about the signaling pathways by which motoneurons induce synapses on muscle fibers, and no receptors for synapse-inducing signals have yet been identified. Because several other inductive events in development are mediated by receptor tyrosine kinases (RTKs), and because phosphotyrosine staining within muscle fibers is concentrated at synaptic sites, one possibility is that synapse-inducing signals are transduced by a RTK within the muscle fiber. We have used PCR to search for tyrosine kinases within the electric organ of the electric ray Torpedo californica, since this tissue is homologous to muscle but is much more densely innervated and is therefore a rich source of synaptic molecules. We have isolated a RTK that is specifically expressed in electric organ and skeletal muscle. The kinase domain of this receptor is related to the trk family of neurotrophin receptors, but unlike any previously described receptor, the extracellular region of this Torpedo RTK contains a kringle domain close to the transmembrane domain.
We have identified a Drosophila gene, Dror, which encodes a putative receptor tyrosine kinase (RTK) and maps to cytological location 31B/C on the second chromosome. In embryos, this gene is expressed specifically in the developing nervous system. The Dror protein appears to be a homolog of two human RTKs, Ror1 and Ror2. Dror and Ror1 proteins share 36% amino acid identity in their extracellular domains and 61% identity in their catalytic tyrosine kinase (TK) domains. Ror1 and Ror2 were originally identified on the basis of the similarity of their TK domains to the TK domains of members of the Trk family of neurotrophin receptors. The Dror protein shows even greater similarity to the Trk proteins within this region than do the human Ror proteins. In light of its similarity to trk and its neural-specific expression pattern, we suggest that Dror may encode a neurotrophic receptor that functions during early stages of neural development in Drosophila.
Undiagnosed Type 2 diabetes has become a common condition in the US, comprising one-third of all cases of the disease. We believe that screening for and detection of undiagnosed Type 2 diabetes is an important endeavor. In this review we provide evidence that diabetes is a condition that is appropriate for population screening and detection. This includes evidence that: 1. Type 2 diabetes is a significant health problem. It affects more than 16 million adults in the US and places these individuals at high risk for serious complications of the eyes, nerves, kidneys, and cardiovascular system. 2. There is a latent phase before diagnosis of Type 2 diabetes. During this period of undiagnosed disease, risk factors for diabetic micro- and macrovascular complications are markedly elevated and diabetic complications are developing. 3. Diagnostic criteria for diabetes have been established and are based on plasma glucose values. These criteria define a group of individuals with significant hyperglycemia who also have a high frequency of risk factors for micro- and macrovascular disease. 4. The natural history of Type 2 diabetes is understood. In most patients, diabetes proceeds inexorably from genetic predisposition, through the stage of insulin resistance and hyperinsulinemia, to beta cell failure and overt clinical disease. 5. There are effective and acceptable therapies available for Type 2 diabetes and its complications. Treating hyperglycemia to prevent complications is more effective than treating these complications after they have developed. Furthermore, guidelines for treatment to prevent cardiovascular disease in people known to have diabetes are more stringent than in those individuals who are not known to have diabetes. 6. There is a suitable test for screening for undiagnosed Type 2 diabetes that has high sensitivity and specificity - measurement of fasting plasma glucose. Guidelines for identifying persons at high risk for diabetes have been established. Copyright (C) 2000 John Wiley & Sons, Ltd.
Microglia of the central nervous system serve a variety of functions that may ultimately lead to the development or detriment of neighboring neuronal and vascular cells. These scavengers of the nervous system have been associated with a variety of neurodegenerative disorders, but the toxic potential of microglia is equally balanced by the protective nature of these cells to exclude foreign microorganisms and promote new tissue proliferation and reorganization. To this extent, our work outlines a series of endogenous microglial cellular pathways that can constitute protection for microglia against during oxygen-glucose deprivation (OGD). We demonstrate in both primary microglia and the microglial cell line EOC 2 that endogenous microglial protection against OGD relies upon the activation and expression of the phosphatidylinositol 3-kinase pathways of mammalian target of rapamycin (mTOR) and protein kinase B (Akt1), since pharmacological inhibition of mTOR or Akt1 as well as the gene silencing of Aktl protein expression leads to significantly increased microglial apoptotic cell injury, DNA fragmentation, and membrane phosphatidylserine exposure. The mTOR pathway may offer endogenous protection through mechanisms that do not entirely rely upon inhibition of glycogen synthase kinase-3B (GSK-3 beta) activity while Akt1 appears to converge upon the necessary blockade of GSK-3B. Closely aligned to these endogenous protective mechanisms is the subcellular presence and nuclear translocation of nuclear factor-kappa B p65 (NF-kappa B p65), since microglial cell injury is significantly increased during the gene silencing of NF-kappa B p65. Elucidating the underlying pathways that can afford endogenous protection and maintain functional integrity of microglia should offer new prospects for the treatment of a broad range of nervous system disorders.
The nonreceptor tyrosine kinase, encoded by the v-AbI oncogene of Abelson murine leukemia virus induces transformation of progenitor B cells. The v-AbI oncogene promotes cell cycle progression and inhibits pre-B cell differentiation. The temperature-sensitive form of Abelson murine leukemia virus offers a reversible model to study the role of v-AbI in regulating growth and differentiation. Inactivation of v-AbI elevates p27 and Foxo3a levels and activates NF-kappa B/Rel, which leads to G, arrest and induction of Ig L chain gene rearrangement, respectively. In turn, v-AbI reactivation reduces p27 and Foxo3a levels, thus permitting G(1)-arrested cells to reenter the cell cycle. However, the cell lines derived from SCID mice that are defective in the catalytic subunit of DNA-dependent protein kinase retain elevated levels of p27 and Foxo3a proteins despite reactivation of v-AbI. Consequently, these cells are locked in the G, phase for an extended period of time. The few cells that manage to bypass the G, arrest become tumorigenic and fail to undergo pre-B cell differentiation induced by v-AbI inactivation. Deregulation of p27, Foxo3a, c-myc, and NF-kappa B/Rel was found to be associated with the malignant transformation of SCID temperature-sensitive form of Abelson murine leukemia virus pre-B cells.
Cell to cell interaction is one of the key processes effecting angiogenesis and endothelial cell function. There are many factors which can mediate this interaction including Wnt-signaling-related molecules. Wnt signaling is involved in many developmental processes and cellular functions. There is increasing evidence suggesting that Wnt signaling has a role in regulating endothelial cell growth although the precise mechanism is unclear. In this study, we established a coculture system to examine how Wnt-1 signaling regulates human umbilical vein endothelial cell (HUVEC) growth and behavior. We found that Wnt-1 signals inhibited BrdU incorporation in HUVECs and the number of labeled cells also decreased in proportion to the number of Wnt-1-expressing cells present (P < 0.05). Moreover, HUVECs cocultured with Wnt-1-expressing C57MG cells clumped together rather than remaining scattered throughout the culture. These effects were dependent on cell contact. Treatment of HUVEC with LiCl, which inhibits the activity of GSK-3β and mimicked Wnt-1 signaling, also inhibited the BrdU incorporation in endothelial cells. Our results suggest that Wnt signaling has a role in endothelial cell growth control and this is mediated through cell–cell contact. They also suggest that Wnt signaling might participate in angiogenesis by regulating endothelial cell growth and function.
The autosomal recessive mouse mutation retinal degeneration 6 (rd6 ) causes small, white retinal spots and progressive photoreceptor degeneration similar to that observed in human flecked retinal diseases. Using a positional cloning approach, we determined that rd6 mice carry a splice donor mutation in the mouse homolog of the human membrane-type frizzled-related protein (Mfrp) gene that results in the skipping of exon 4. We found that mRNA of Mfrp is predominantly expressed in the eye, and at a lower level in the brain. To determine where in the eye Mfrp is expressed, in situ hybridization was done and showed that Mfrp is expressed specifically in the retinal pigment epithelium (RPE) and ciliary epithelium of the eye. The deduced amino acid sequence of MFRP contains a region with similarities to the cysteine-rich domain (CRD) of frizzled, a gene originally found in Drosophila that controls tissue polarity. The CRD is essential for Wnt binding and signaling. Wnt signaling has been shown to be involved in the control of gene expression, cell adhesion, planar polarity, proliferation and apoptosis. We also observed the localization of Wnt family proteins in the apical membrane of the RPE. Our results provide genetic evidence for an involvement of the Mfrp gene expressed by RPE in the degeneration of photoreceptors.
Research on the relation between diabetes mellitus and dementia has produced conflicting results, and the relation has not been investigated among Blacks and Hispanics. In this study, Cox proportional hazards models were used to analyze longitudinal data from 1,262 elderly subjects without dementia at baseline (1991-1996) who were followed for an average of 4.3 years between 1992 and 1997. Outcomes were incident Alzheimer's disease and dementia associated with stroke. The prevalence of diabetes was 20% at baseline. The adjusted relative risk of Alzheimer's disease among persons with diabetes as compared with those without diabetes was 1.3 (95% confidence interval (CI): 0.8, 1.9). The adjusted relative risk for the composite outcome of Alzheimer's disease and cognitive impairment without dementia (without stroke) in subjects with diabetes was 1.6 (95% Cl: 1.2, 2.1). The adjusted relative risk of stroke-associated dementia in persons with diabetes was 3.4 (95% CI: 1.7, 6.9). Among Blacks and Hispanics, approximately one third of the risk of stroke-associated dementia was attributable to diabetes (33% (95% CI: 31, 36) and 36% (95% CI: 33, 37), respectively), as compared with 17% (95% Cl: 13, 22) among Whites. The finding of an association between diabetes and the composite outcome of Alzheimer's disease and cognitive impairment without dementia (without stroke) is consistent with prior reports of a modest relation between diabetes and Alzheimer's disease.
β-Catenin and T cell factor (Tcf) are distal components of the highly conserved Wnt pathway that govern cell fate and proliferation in lower organisms. Thus, we hypothesized that the regulation of β-catenin and Tcf played a critical role in vascular remodeling. The first objective was to define β-catenin expression in vascular smooth muscle cells (VSMCs) after balloon injury. Indeed, β-catenin mRNA and protein were significantly elevated 7 days after balloon injury in the rat carotid artery. We hypothesized that β-catenin accumulation in response to vascular injury inhibited VSMC apoptosis. In line with our hypothesis, transfection of a degradation-resistant β-catenin transgene into rat VSMCs significantly inhibited apoptosis. Accumulation of β-catenin also resulted in a 10-fold increase in the activation of Tcf. To test if Tcf was necessary to confer β-catenin–induced survival, loss of function studies were carried out with a dominant negative Tcf-4 transgene lacking the β-catenin binding domain, Tcf4(N31). Indeed, loss of Tcf-4 activity abolished β-catenin–induced survival. We further postulated that β-catenin and Tcf promoted cell cycle progression by activating cyclin D1, a target gene of Tcf-4. β-Catenin activated cyclin D1, and this activation was partially blocked with loss of Tcf-4. In parallel, blockade of Tcf-4 resulted in inhibition of [³H]thymidine incorporation and partial blockade of the G1-S phase transition. In conclusion, β-catenin and Tcf-4 play a dual role in vascular remodeling by inhibiting VSMC apoptosis and promoting proliferation.
Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage–induced growth arrest of hematopoietic cells can be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by γ-irradiation (γ-IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override γ-IR–induced cell-cycle arrest. Similarly, the ability of cytokines to override γ-IR–induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage induced checkpoints. Together, these findings suggest a novel role for PI-3K/Akt pathways in the modulation of growth arrest responses to DNA damage in hematopoietic cells.
THE kidney has been widely exploited as a model system for the study of tissue inductions regulating vertebrate organogenesis1,2. Kidney development is initiated by the ingrowth of the Wolfian duct-derived ureteric bud into the presumptive kidney mesenchyme. In response to a signal from the ureter, mesenchymal cells condense, aggregate into pretubular clusters and undergo an epithelial conversion generating a simple tubule. This then undergoes morphogenesis and is transformed into the excretory system of the kidney, the nephron. We report here that the expression of Wnt-4, which encodes a secreted glycoprotein, correlates with, and is required for, kidney tubulogenesis. Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchymal and ureteric development are unaffected. Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development.
Interactions between cells help to elaborate pattern within the vertebrate central nervous system (CNS)1. The genes Wnt-1 and Wnt-3a, which encode members of the Wnt family of cysteine-rich secreted signals, are coexpressed at the dorsal midline of the developing neural tube, coincident with dorsal patterning2, 3. Each signal is essential for embryonic development, Wnt-1 for midbrain patterning4, 5 and Wnt-3a for formation of the paraxial mesoderm6, but the absence of a dorsal neural-tube phenotype in each mutant suggests that Wnt signalling may be redundant. Here we demonstrate that in the absence of both Wnt-1 and Wnt-3a there is a marked deficiency in neural crest derivatives, which originate from the dorsal neural tube7, and a pronounced reduction in dorsolateral neural precursors within the neural tube itself. These phenotypes do not seem to result from a disruption in the mechanisms responsible for establishing normal dorsoventral polarity. Rather, our results are consistent with a model in which local Wnt signalling regulates the expansion of dorsal neural precursors. Given the widespread expression of different Wnt genes in discrete areas of the mammalian neural tube3, this may represent a general model for the action of Wnt signalling in the developing CNS.
After the developing embryo has formed a primary vascular plexus by a process termed vasculogenesis, further blood vessels are generated by both sprouting and non-sprouting angiogenesis, which are progressively pruned and remodelled into a functional adult circulatory system. Recent results, particularly from the study of mice lacking some of the signalling systems involved, have greatly improved our understanding of the molecular basis underlying these events, and may suggest new approaches for treating conditions such as cancer that depend on angiogenesis.
Neuronal survival after ischemic injury is determined through the induction of several biological pathways. We examined whether lubeluzole, an agent efficacious in both clinical and experimental models of cerebral ischemia, modulated the signal transduction mechanisms of nitric oxide (NO), a downstream mediator of anoxic neurodegeneration. Both pretreatment [NO survival = 23 ± 3%, NO/lubeluzole (750 nM) survival = 63 ± 2%, p < 0.001] and coadministration [NO survival = 25 ± 3%, NO/lubeluzole (750 nM) survival = 59 ± 3%, p < 0.001] of lubeluzole with NO generators equally protected cultured hippocampal neurons in a dose-dependent manner against the toxic effects of NO, suggesting that the agent protects by acutely modifying toxic cellular pathways rather than preconditioning the neuron before injury. The protection observed with lubeluzole was stereospecific but was not limited to pre- or coadministration. Lubeluzole also was found to significantly protect against the toxicity of NO for a period of 4–6 h after NO exposure [NO survival = 31 ± 2%, NO/lubeluzole (750 nM) survival at 6 h = 56 ± 3%, p < 0.001]. We conclude that the neuroprotective ability of lubeluzole is unique and involves the direct modulation of the NO pathway. In addition, the mechanisms of NO toxicity are dynamic and reversible processes that, if left unaltered, will lead to neuronal injury. Further investigation of the downstream signal transduction mechanisms below the level of NO generation may elucidate the specific cellular events responsible for neurodegeneration.
OBJECTIVES: To learn whether managed care patients with Alzheimer's disease (AD) are more or less costly to care for than patients with other forms of dementia or patients without dementia during the last few years of life.
DESIGN: Case control study.
SETTING: A health maintenance organization base population.
PARTICIPANTS: Three groups of subjects (mean age 85) who were deceased members of a dementia registry obtained from a health maintenance organization base population: 263 subjects with clinically diagnosed probable AD, 133 subjects with other forms of dementia, and 100 cognitively intact controls.
MEASUREMENTS: Utilization records were examined for the 3 years preceding death.
RESULTS: In all subcategories and in aggregate, utilization and costs of care were either similar or lower for patients with AD than for the other groups, even after controlling for age, gender, and comorbidity.
CONCLUSIONS: Persons with AD do not incur higher costs than persons with other types of dementia or age-matched persons without dementia in a mature health maintenance organization during the last few years of life, when utilization is likely to be highest.
Many constituents of Wnt signaling pathways are expressed in the developing and mature nervous systems. Recent work has shown that Wnt signaling controls initial formation of the neural plate and many subsequent patterning decisions in the embryonic nervous system, including formation of the neural crest. Wnt signaling continues to be important at later stages of development. Wnts have been shown to regulate the anatomy of the neuronal cytoskeleton and the differentiation of synapses in the cerebellum. Wnt signaling has been demonstrated to regulate apoptosis and may participate in degenerative processes leading to cell death in the aging brain.
β-catenin is a protein involved in cell-cell adhesion and proliferation. In neoplastic diseases, defects in the regulation of the cellular β-catenin content and cytoplasmic accumulation of the protein contribute to the uncontrolled cell proliferation and migration. Whether β-catenin plays a role in the controlled proliferative and migratory responses to injury, eg, of vascular endothelial cells during neovascularization after myocardial infarction (MI), is not known. In the present study, we examined the localization of β-catenin in the infarcted rat heart at different time points after MI. Cytoplasmic β-catenin was observed in the endothelial cells of the newly formed and pre-existing blood vessels in the infarct area in the first week after MI, but not in the uninjured parts of the heart and not at later time points. Adenomatous polyposis coli (APC) protein was also detected; interaction of APC with β-catenin has been reported to be critical in epithelial tube formation in vitro. Moreover, the expression of dishevelled-1, an upstream regulatory molecule of the cellular β-catenin content, was observed in vascular endothelial cells in the infarct area. These findings suggest a role for the β-catenin-APC complex in the proliferation and migration of vascular endothelial cells during neovascularization of the infarct area.
The function of the frizzled (fz) locus is required to coordinate the cytoskeletons of pupal epidermal cells so that a parallel array of cuticular hairs and bristles is produced. We report here the molecular cloning and characterization of the fz locus. The locus is very large. Mutations that inactivate the gene are spread over 100 kb of genomic DNA. The major mRNA product of the gene is a 4-kb RNA that is encoded by 5 exons spread over more than 90 kb of genomic DNA. Conceptual translation of this mRNA indicates that it encodes an integral membrane protein that is likely to contain both extracellular and cytoplasmic domains.
The function of the frizzled (fz) locus in Drosophilia melanogaster is required to coordinate the cytoskeletons of epidermal cells to produce a parallel array of cuticular hairs and bristles (for example on the wild-type wing all hairs point towards the distal tip). In fz mutants it is not the structure of individual hairs and bristles that is altered, but their orientation with respect to their neighbours and the organism as a whole. Mitotic clone analysis indicates that fz has two functions in the developing wing. It is required for the proximal-distal transmission of an intercellular polarity signal, a process that is expected to be at least partly extracellular. It is also required for cells to respond to the polarity signal, which is expected to be a cytoplasmic function. The fz locus could encode either one bifunctional or two single-function proteins. We report here that, in pupae, fz produces a messenger RNA that encodes a protein with seven putative transmembrane domains. Thus, the Fz protein should contain both extracellular and cytoplasmic domains, which could function in the transmission and interpretation of polarity information, respectively. This is the first reported sequence for the protein product of a tissue polarity gene.
We have asked whether oncogenesis by the mouse mammary tumor virus (MMTV), a slowly oncogenic retrovirus, involves integration of viral DNA within a certain region of the host genome. We first identified a C3H mouse mammary tumor bearing a single new MMTV provirus and cloned a 19 kilobase (kb) DNA restriction fragment containing a junction of viral and host sequences. Host sequences from this clone were used to retrieve 25 kb of the uninterrupted locus (termed MMTV int1) from a bacteriophage library of normal mouse DNA. Hybridization with subcloned DNA fragments of MMTV int1 detected abnormal restriction fragments in digests of DNA from 18 of 26 C3H mammary tumors. The rearrangements all appeared to be due to the insertion of an MMTV provirus, and the integration sites were located in at least five clusters over a total distance of 19 kb. A polyadenylated 2.6 kb RNA species transcribed from int1 was found in the few tumors tested, but not in lactating mammary glands from C3H mice. Of 12 tested viral oncogenes, none exhibited homology with cloned DNA from this locus. We propose that tumorigenesis by MMTV is strongly favored by proviral insertion within the int1 locus, perhaps as a consequence of enhanced expression of a novel cellular oncogene.
Wnt-1 and Wnt-3a proto-oncogenes have been implicated in the development of midbrain and hindbrain structures. Evidence for such a role has been derived from in situ hybridization studies showing Wnt-1 and -3a expression in developing cranial and spinal cord regions and from studies of mutant mice whose Wnt-1 genes have undergone targeted disruption by homologous recombination. Wnt-1 null mutants exhibit cranial defects but no spinal cord abnormalities, despite expression of the gene in these regions. The absence of spinal cord abnormalities is thought to be due to a functional compensation of the Wnt-1 deficiency by related genes, a problem that has complicated the analysis of null mutants of other developmental genes as well. Herein, we describe the attenuation of Wnt-1 expression using antisense oligonucleotide inhibition in mouse embryos grown in culture. We induce similar mid- and hindbrain abnormalities as those seen in the Wnt-1 null mutant mice. Attenuation of Wnt-1 expression was also associated with cardiomegaly resulting in hemostasis. These findings are consistent with the possibility that a subset of Wnt-1 expressing cells include neural crest cells known to contribute to septation of the truncus arteriosus and to formation of the visceral arches. Antisense knockout of Wnt-3a, a gene structurally related to Wnt-1, targeted the forebrain and midbrain region, which were hypoplastic and failed to expand, and the spinal cord, which exhibited lateral outpocketings at the level of the forelimb buds. Dual antisense knockouts of Wnt-1 and Wnt-3a targeted all brain regions leading to incomplete closure of the cranial neural folds, and an increase in the number and severity of outpocketings along the spinal cord, suggesting that these genes complement one another to produce normal patterning of the spinal cord. The short time required to assess the mutant phenotype (2 days) and the need for limited sequence information of the target gene (20-25 nucleotides) make this antisense oligonucleotide/whole embryo culture system ideal for testing the importance of specific genes and their interactions in murine embryonic development.
The three-dimensional structure of an HNF-3/fork head DNA-recognition motif complexed with DNA has been determined by X-ray crystallography at 2.5 A resolution. This alpha/beta protein binds B-DNA as a monomer, through interactions with the DNA backbone and through both direct and water-mediated major and minor groove base contacts, inducing a 13 degrees bend. The transcription factor fold is very similar to the structure of histone H5. In its amino-terminal half, three alpha-helices adopt a compact structure that presents the third helix to the major groove. The remainder of the protein includes a twisted, antiparallel beta-structure and random coil that interacts with the minor groove.