Role Of Gelsolin Research Articles

Gelsolin regulates intestinal stem cell regeneration and Th17 cellular function

Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis.Graphical abstract

Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD.

Transcriptomic analyses have advanced the understanding of complex disease pathophysiology including chronic obstructive pulmonary disease (COPD). However, identifying relevant biologic causative factors has been limited by the integration of high dimensionality data. COPD is characterized by lung destruction and inflammation with smoke exposure being a major risk factor. To define novel biological mechanisms in COPD, we utilized unsupervised and supervised interpretable machine learning analyses of single cell-RNA sequencing data from the gold standard mouse smoke exposure model to identify significant latent factors (context-specific co-expression modules) impacting pathophysiology. The machine learning transcriptomic signatures coupled to protein networks uncovered a reduction in network complexity and novel biological alterations in actin-associated gelsolin (GSN), which was transcriptionally linked to disease state. GSN was altered in airway epithelial cells in the mouse model and in human COPD. GSN was increased in plasma from COPD patients, and smoke exposure resulted in enhanced GSN release from airway cells from COPD patients. This method provides insights into rewiring of transcriptional networks that are associated with COPD pathogenesis and provide a novel analytical platform for other diseases.

Gelsolin alleviates rheumatoid arthritis by negatively regulating NLRP3 inflammasome activation.

Despite numerous biomarkers being proposed for rheumatoid arthritis (RA), a gap remains in our understanding of their mechanisms of action. In this study, we discovered a novel role for gelsolin (GSN), an actin-binding protein whose levels are notably reduced in the plasma of RA patients. We elucidated that GSN is a key regulator of NLRP3 inflammasome activation in macrophages, providing a plausible explanation for the decreased secretion of GSN in RA patients. We found that GSN interacts with NLRP3 in LPS-primed macrophages, hence modulating the formation of the NLRP3 inflammasome complex. Reducing GSN expression significantly enhanced NLRP3 inflammasome activation. GSN impeded NLRP3 translocation to the mitochondria; it contributed to the maintenance of intracellular calcium equilibrium and mitochondrial stability. This maintenance is crucial for controlling the inflammatory response associated with RA. Furthermore, the exacerbation of arthritic symptoms in GSN-deficient mice indicates the potential of GSN as both a diagnostic biomarker and a therapeutic target. Moreover, not limited to RA models, GSN has demonstrated a protective function in diverse disease models associated with the NLRP3 inflammasome. Myeloid cell-specific GSN-knockout mice exhibited aggravated inflammatory responses in models of MSU-induced peritonitis, folic acid-induced acute tubular necrosis, and LPS-induced sepsis. These findings suggest novel therapeutic approaches that modulate GSN activity, offering promise for more effective management of RA and a broader spectrum of inflammatory conditions.

Emerging roles of plasma gelsolin in tumorigenesis and modulating the tumor microenvironment.

The protein expression of gelsolin, an actin scavenger controlling cytoskeletal remodeling, cell morphology, differentiation, movement, and apoptosis, has been found to be significantly decreased in several pathological conditions including neurodegenerative diseases, inflammatory disorders, and cancers. Its extracellular isoform, called plasma gelsolin (pGSN), is one of the most abundant plasma proteins in the circulation, and has emerged as a novel diagnostic biomarker for early disease detection. Current evidence reveals that gelsolin can function as either an oncoprotein or a tumor suppressor depending on the carcinoma type. Interestingly, recent studies have shown that pGSN is also involved in immunomodulation, revealing the multifunctional roles of pGSN in tumor progression. In this review, we discuss the current knowledge focusing on the roles of gelsolin in inflammation and wound healing, cancers, and tumor microenvironment. Future prospects of pGSN related studies and clinical application are also addressed.

Gelsolin is an important mediator of Angiotensin II-induced activation of cardiac fibroblasts and fibrosis.

Myocardial fibrosis is a characteristic of various cardiomyopathies, and myocardial fibroblasts play a central role in this process. Gelsolin (GSN) is an actin severing and capping protein that regulates actin assembly and may be involved in fibroblast activation. While the role of GSN in mechanical stress-mediated cardiac fibrosis has been explored, its role in myocardial fibrosis in the absence of mechanical stress is not defined. In this study, we investigated the role of GSN in myocardial fibrosis induced by Angiotensin II (Ang II), a profibrotic hormone that is elevated in cardiovascular disease. We utilized mice lacking GSN (Gsn-/- ) and cultured primary adult cardiac fibroblasts (cFB). In vivo, Ang II infusion in mice resulted in significantly less severe myocardial fibrosis in Gsn-/- compared with Gsn+/+ mice, along with diminished activation of the TGFβ1-Smad2/3 pathway, and reduced expression of cardiac extracellular matrix proteins (collagen, fibronectin, periostin). Moreover, Gsn-deficient hearts exhibited suppressed activity of the AMPK pathway and its downstream effectors, mTOR and P70S6Kinase, which could contribute to the suppressed TGFβ1 activity. In vitro, the Ang II-induced activation of cFBs was reduced in Gsn-deficient fibroblasts evident from decreased expression of αSMA and periostin, diminished actin filament turnover; which also exhibited reduced activity of the AMPK-mTOR pathway, and P70S6K phosphorylation. AMPK inhibition compensated for the loss of GSN, restored the levels of G-actin in Gsn-/- cFBs and promoted activation to myofibroblasts by increasing αSMA and periostin levels. This study reveals a novel role for GSN in mediating myocardial fibrosis by regulating the AMPK-mTOR-P70S6K pathway in cFB activation independent from mechanical stress-induced factors.

Gelsolin Governs the Neuroendocrine Transdifferentiation of Prostate Cancer Cells and Suppresses the Apoptotic Machinery.

Interleukin 6 (IL6) is increased in patients with progressive prostate cancer and induces its transdifferentiation to neuroendocrine prostate cancer. Neuroendocrine prostate cancer has become one of the greatest challenges in treating castration-resistant disease and is linked to poor prognosis. It is necessary to understand better the cellular events associated with IL6-mediated neuroendocrine differentiation to prevent it and identify potential new therapeutic targets. In the present study, an IL6-inducible neuroendocrine differentiation model established specifically for this purpose was applied using LNCaP cells. Proteomics and western blot analyses were used to identify proteins involved in neuroendocrine differentiation. Subsequently, the role of gelsolin (GSN) in the neuroendocrine differentiation model was characterized (knock-down analyses, microscopic co-localization analyses, apoptosis assay) and GSN expression levels in patient material were investigated. This study revealed that GSN is a crucial factor in the neuroendocrine differentiation process. It was shown that siRNA-mediated knock-down of GSN can inhibit neuroendocrine differentiation, making it a valid target for preventing IL6-mediated neuroendocrine differentiation.

The gelsolin level in patients with primary Sjogren's syndrome.

Gelsolin (GSN) is a multifunctional protein that can regulate cell proliferation, apoptosis, inflammation and infection. GSN has been reported to be involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and many other diseases. The role of GSN in primary Sjogren's syndrome (pSS) remains still unclear. The aim of this study is to investigate the changes of GSN level in serum and whole blood cells of pSS patients and evaluate the relationship between GSN and fatigue or other clinical indicators. The cross-sectional study included 47 pSS patients (1 male and 46 females, average age: 52.83±12.63 years) and 51 healthy controls (all females, average age: 50.61±9.86 years). The patients were collected from the Second Affiliated Hospital of Harbin Medical University, China, without the age and sex differences. The levels of GSN in serum of pSS patients and the healthy controls were measured by Western blotting. The sequencing gene expression omnibus (GEO) data from National Center for Biotechnology Information (NCBI) about GSN levels in the whole blood cells of pSS patients and the healthy controls were analyzed by R language. Compared with healthy controls, the level of GSN was significantly decreased in the serum of pSS patients (98.89 ± 28.94 vs. 131.6 ± 37.1 µg/ml, p<0.001). The expression of GSN in the whole blood cells of pSS patients was significantly lower than that in the healthy controls (6.4 ± 0.19 vs. 6.6 ± 0.17, p<0.01). Compared to non-fatigued pSS patients, the level of GSN was down-regulated in serum (85.69 ± 27.08 vs. 111.52 ± 24.71 µg/ml, p<0.01) and whole blood cells (6.43 ± 0.18 vs. 6.58 ± 0.21, p<0.001) in fatigue pSS patients. However, there was no significant correlation between the level of GSN and EULAR Sjogrens syndrome disease activity index (ESSDAI) in pSS patients (p=0.73). GSN is decreased in serum and whole blood cells of pSS patients, and it is much lower in fatigue patients than that in non-fatigue patients. The correlation between the level of GSN and ESSDAI was not significant in pSS patients.

Gelsolin Promotes Cancer Progression by Regulating Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma and Correlates with a Poor Prognosis.

Gelsolin (GSN), a cytoskeletal protein, is frequently overexpressed in different cancers and promotes cell motility. The biological function of GSN in hepatocellular carcinoma (HCC) and its mechanism remain unclear. The expression of GSN was assessed in a cohort of 188 HCC patients. The effects of GSN on the migration and invasion of tumour cells were examined. Then, the role of GSN in tumour growth in vivo was determined by using a cancer metastasis assay. The possible mechanism by which GSN promotes HCC progression was explored. As a result, GSN was overexpressed in HCC tissues. High GSN expression was significantly correlated with late Edmondson grade, encapsulation, and multiple tumours. Patients with high GSN expression had worse overall survival (OS) and disease-free survival (DFS) than those with low GSN expression. GSN expression was identified as an independent risk factor in both OS (hazard risk (HR) = 1.620, 95% confidence interval (CI) = 1.105–2.373, P < 0.001) and DFS (HR = 1.744, 95% CI = 1.205–2.523, P=0.003). Moreover, GSN knockdown significantly inhibited the migration and invasion of HCC tumour cells, while GSN overexpression attenuated these effects by regulating epithelial-mesenchymal transition (EMT) In conclusion, GSN promotes cancer progression and is associated with a poor prognosis in HCC patients. GSN promotes HCC progression by regulating EMT.

The effects of plasma gelsolin on human erythroblast maturation for erythrocyte production

Gelsolin is an actin binding protein present in blood plasma and in cytoplasm of cells including macrophages. Gelsolin has important functions in cell cycle regulation, apoptotic regulation, and morphogenesis. Even though bone marrow macrophages and serum factors are critical for regulating erythropoiesis, the role of gelsolin on human erythroblasts has not been studied. Here, we investigated the effects of human recombinant plasma gelsolin (pGSN) on human immature erythroblasts. CD34+ cells isolated from cord blood were differentiated into erythroid cells in serum-free medium. When pGSN was applied to the culture medium, it accelerated basophilic and polychromatic erythroblast maturation and increased the enucleation rate with highly expressed erythropoiesis-related mRNAs. Also, pGSN was effective in reducing dysplastic changes caused by vincristine, suggesting its role in cell cycle progression at G2/M checkpoints. Also, pGSN activated caspase-3 during maturation stages in which caspase-3 functions as a non-apoptotic maturational signal or a pro-apoptotic signal depending on maturation stages. Our results suggest that pGSN has a pivotal role in maturation of erythroblasts and this factor might be one of the way how bone marrow macrophages and previously unknown serum factors work to control erythropoiesis. pGSN might be used as additive for in vitro production of erythrocytes.

Respiratory chain enzyme deficiency induces mitochondrial location of actin-binding gelsolin to modulate the oligomerization of VDAC complexes and cell survival.

Despite considerable knowledge on the genetic basis of mitochondrial disorders, their pathophysiological consequences remain poorly understood. We previously used two-dimensional difference gel electrophoresis analyses to define a protein profile characteristic for respiratory chain complex III-deficiency that included a significant overexpression of cytosolic gelsolin (GSN), a cytoskeletal protein that regulates the severing and capping of the actin filaments. Biochemical and immunofluorescence assays confirmed a specific increase of GSN levels in the mitochondria from patients' fibroblasts and from transmitochondrial cybrids with complex III assembly defects. A similar effect was obtained in control cells upon treatment with antimycin A in a dose-dependent manner, showing that the enzymatic inhibition of complex III is sufficient to promote the mitochondrial localization of GSN. Mitochondrial subfractionation showed the localization of GSN to the mitochondrial outer membrane, where it interacts with the voltage-dependent anion channel protein 1 (VDAC1). In control cells, VDAC1 was present in five stable oligomeric complexes, which showed increased levels and a modified distribution pattern in the complex III-deficient cybrids. Downregulation of GSN expression induced cell death in both cell types, in parallel with the specific accumulation of VDAC1 dimers and the release of mitochondrial cytochrome c into the cytosol, indicating a role for GSN in the oligomerization of VDAC complexes and in the prevention of apoptosis. Our results demonstrate that respiratory chain complex III dysfunction induces the physiological upregulation and mitochondrial location of GSN, probably to promote cell survival responses through the modulation of the oligomeric state of the VDAC complexes.

Gelsolin: A new insight of its role on gastric cancer dissemination

Gastric cancer (GC) is one of the most prevalent cancers worldwide, with more than 700,000 cases of death. Histopathologically, GC can be classified into two main subtypes, the intestinal- and diffuse-type GC. These two subtypes differ not only in histological parameters, but also show distinct profiles of gene alternations. In this research highlight, we provide a summary of gene mutations in both the intestinal- and diffuse-type GC, and also highlight our recent findings on the role gelsolin, an actin-regulating protein, in GC dissemination. We recently found that gelsolin is differentially expressed in intestinal and diffuse type GC, and uncovered its involvement in the HGF/c-Met oncogenic pathway, which is a frequent activated signaling pathway in GC dissemination. Other roles of gelsolin in cancer development have also been discussed, with a focus on its potential link to oncogenic pathways and gene alternations in cancer metastasis. Our work provides a potential link between gelsolin and pro-invasive pathways in GC, and hence suggest a potential avenue for combating GC dissemination and metastasis with consideration of gelsolin status.

Gelsolin role in microapocrine secretion.

A role of gelsolin in opening the way along the microvilli for secretory vesicles during microapocrine secretion is proposed here. Data obtained with different techniques showed that many digestive enzymes are released by microapocrine secretion in insects. Proteins that might be involved in the machinery of microapocrine secretion were selected from our transcriptomes and literature searches. The proteins were annexin, Complex actin-related proteins 2 and 3 (ARP 2/3) cofilin, fimbrin, gelsolin 1, gelsolin 2, moesin, myosin 1, myosin 6, protein disulphide isomerase 1 (PDI 1), PDI 2 and profilin. The cDNAs coding for annexin, fimbrin, gelsolin 1, myosin 1, PDI 1 and PDI 2 were cloned and their sequences deposited in GenBank. Only gelsolin 1 and myosin 1 are expressed exclusively in the midgut (semiquantitative reverse transcriptase PCR). As myosin 1 may have a structural role in microvilli, gelsolin 1 is the best guess to be involved in the secretory machinery. A truncated recombinant gelsolin 1 was used to generate antibodies with which it was shown labelling inside and around midgut cell microvilli shown in an electron microscope, reinforcing a microvillar role for gelsolin 1. Suppression of gelsolin 1 synthesis by RNA interference prevents secretory vesicles from advancing inside the microvilli, in agreement with its putative role in severing the actin filaments to free the way for the vesicles.

Abstract 80: PI3Kα Regulates Biomechanical Stress-induced Cytoskeletal Remodeling: A Critical Role of Gelsolin

Background: Biomechanical stress and cytoskeletal remodeling are key determinants in pressure overload-induced heart failure. Class Ia phosphoinositide 3-kinases (PI3Ks) mediate a variety of cellular activities, in response to agonist binding to cell-surface receptors, by generating the phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) phosphoinositide lipid. Gelsolin is a Ca 2+ - and phosphoinositide-regulated actin filament severing and capping protein that is upregulated in failing human hearts and animal models of heart failure. Hypothesis: We hypothesize that PI3Kα regulates cytoskeletal remodeling through PIP 3 -mediated regulation of gelsolin. In addition, loss of gelsolin could attenuate the adverse cytoskeletal remodeling and result in increased resistance to the development of heart failure in response to pressure-overload. Methods and Results: Loss of p110α kinase activity, in two different transgenic models (PI3Kα dominant-negative (PI3KαDN) and cardiomyocyte-specific PI3Kα-null), resulted in dilated cardiomyopathy and markedly worsened cardiac dysfunction in response to transverse aortic constriction-induced pressure overload. Increased levels of mechanosensor proteins along with decreased F/G-actin ratio exhibited an uncoupling between cardiac mechanotransduction and cytoskeletal remodeling in p110α-null mice. Gelsolin activity was markedly increased in the p110α-null hearts in response to pressure-overload, whereas loss of gelsolin in PI3KαDN/gelsolin-null double mutant mice prevented the adverse cytoskeletal remodeling and preserved the cardiac function. In a murine model of chronic heart failure, loss of gelsolin prevented the pressure overload-induced cardiac dysfunction, fibrosis, and impaired cardiomyocyte contractility resulting in increased survival. Loss of gelsolin also mitigated the biomechanical stress-induced adverse cytoskeletal remodeling, via the attenuation of actin severing activity. Conclusions: We have identified a novel role of gelsolin as a mediator of adverse cytoskeletal remodeling leading to heart failure, where PI3Kα is a key regulator of gelsolin activity.

Role of gelsolin in cell proliferation and invasion of human hepatocellular carcinoma cells

ObjectiveGelsolin (GSN), one of the most important actin structure regulating proteins, has been implicated in the oncogenesis of some cancers. In this study, we investigated the expression of GSN in hepatocellular carcinoma (HCC) and revealed its potential mechanisms. The mRNA and protein levels of GSN were overexpressed in HCC cells and HCC tissues compared to adjacent noncancerous tissues. GSN expression was correlated with venous invasion (P=0.0199) and Edmonson grading (P=0.0344) expression in HCC. Overexpression of GSN in Huh7 and SMMC-7721 cells significantly promoted cell proliferation and the number of Matrigel™-invading cells compared with control cells, with increased expression of matrix metalloproteinase MCL-1, MMP-2 and MMP-9, a key regulator of growth and invasion. In contrast, knockdown of GSN expression with small interfering RNA (siRNA) in MHCC-97L and MHCC-97H cell lines resulted in decreased cell viability and cell invasion. Our findings indicated that GSN expression promoted tumor-associated phenotypes by facilitating proliferative and invasive capacities of HCC cells, which might serve as a potential therapeutic target for HCC treatment.

Expression of Cytoplasmic Gelsolin in Rat Brain After Experimental Subarachnoid Hemorrhage.

Convincing evidence indicates that apoptosis contributes to the unfavorable prognosis of subarachnoid hemorrhage (SAH), a significant cause of morbidity and case fatality throughout the world. Gelsolin (GSN) is a Ca(2+)-dependent actin filament severing, capping, and nucleating protein, as well as multifunctional regulator of cell structure and metabolism, including apoptosis. In the present study, we intended to investigate the expression pattern and cell distribution of GSN in rat brain after experimental SAH. GSN expression was examined in sham group and at 3, 6, 12 h, day 1 (1 day), 2, 3, 5, and 7 days after SAH by Western blot analysis as well as real-time polymerase chain reaction. Immunohistochemistry and immunofluorescence were performed to detect the localization of GSN. The level of GSN protein expression was significantly decreased in SAH group and reached a bottoming point on 1 day after SAH. GSN mRNA level was significantly decreased in SAH groups in comparison with the sham group, and reached a minimum value at 12 h after SAH. Immunohistochemistry showed that GSN was constitutively and obviously expressed in the cortex of the normal rat brain and significantly decreased in the rat cortex after SAH. In addition, immunofluorescence results revealed that GSN expression could be found in both neurons and microglias, as well as in glialfibrillary acidic protein-positive astrocytes. The decreased expression of GSN could mainly be found in neurons and astrocytes as well, and GSN-positive microglias showed different cell morphological characteristics. Interestingly, the protein and gene levels of GSN seemed to be constant in the rat hippocampus of sham and SAH groups. These findings suggested a potential role of GSN in the pathophysiology of the brain at the early stage of SAH.

Correlation between platelet gelsolin levels and different types of coronary heart disease

Gelsolin is an important cytoskeletal protein of platelets and studies have shown a close relationship between gelsolin and cardiovascular disease. However, the role of gelsolin in the development of coronary heart disease (CHD) is unclear. In this study, we record the distribution of gelsolin in human platelets and plasma and its association with different types of CHD. This study included 114 cases, with 33 stable angina pectoris (SAP) cases, 81 acute coronary syndrome (ACS) cases—composed of 39 unstable angina pectoris (UAP) and 42 acute myocardial infarction (AMI) cases, and 31 healthy control participants. Gelsolin concentration in platelet rich plasma (PRP) and platelet poor plasma (PPP), actin filament (F-actin) and Gc-globulin of PPP were determined by enzyme-linked immunoadsorbent assay (ELISA). The fluorescence intensity of CD62p and cytoplasmic calcium ([Ca2+]i) in human platelets measured by flow cytometry. We also used turbidimetry to detect the platelet aggregation rate (PAR). We analyzed the correlation between platelet gelsolin concentration and CD62p or plasma F-actin levels among each different patient group. Compared with the control group, the gelsolin level in PRP of UAP and AMI groups increased significantly (P<0.01), while the gelsolin level in PPP of all the three patient groups decreased markedly (P<0.01), and the CD62p, PAR, [Ca2+]i of platelets, F-actin and Gc-globulin of the UAP and AMI groups increased significantly (P<0.01). Compared with the SAP group, the gelsolin level in PRP, the PAR, [Ca2+]i of platelets and CD62p of other two groups increased significantly (P<0.01), F-actin of the AMI group increased markedly (P<0.01). Platelet cytoskeleton protein dynamics vary among the different types of CHD. Platelet gelsolin levels are markedly increased and accompanied by increased platelet activity, F-actin and [Ca2+]i of ACS patients, while gelsolin levels in PPP are markedly lower. Abnormally increased platelet gelsolin levels show high positive correlation with the level of platelet activity. Therefore, platelet gelsolin might be a novel molecular marker and/or a new potential therapeutic target of anti-platelet therapy of ACS.

Electron-microscopical localization of gelsolin in various crustacean muscles

Gelsolin was localized by immunoelectron microscopy in fast and slow cross-striated muscles of the lobster Homarus americanus. When ultrathin sections of the muscles were labelled with anti-gelsolin and a gold-conjugated second antibody, 90% of all gold particles in the myoplasm were detected on myofibrils, preferentially in the I-band and AI-region of the sarcomeres. Both the region of the H-zone (lacking thin filaments) and the Z-disc contained no or little gold label. Under physiological conditions, a close association of gelsolin with the thin filaments was observed for both muscle types. The preferential localization of particles in the I- and AI-region indicated that gelsolin was distributed randomly over the whole length of the thin filaments. Preincubation of muscle strips with Ringer solution containing 0.5 mM EGTA resulted in a significantly different distribution pattern; gold particles were now localized preferentially in the cell periphery close to the sarcolemma, with significantly decreased abundance in the centre of the cell. Compared with the muscle under physiological conditions, the number of gold particles over sarcomeric structures was significantly reduced. Thus, binding of gelsolin to the thin filaments is apparently reversible in vivo and depends on the presence of calcium ions. We assume a functional role for gelsolin in the actin turnover processes in invertebrate muscle systems.

Gelsolin as therapeutic target in Alzheimer's disease

Importance of the field: Fibrillar amyloid beta-protein (Aβ) is a major component of amyloid plaques in the brains of individuals with Alzheimer's disease (AD). However, a comprehensive explanation of the mechanisms leading to brain amyloidosis is still pending. Previous studies have identified the anti-amyloidogenic role of gelsolin in AD. Gelsolin can reduce amyloid burden by acting as an inhibitor of Aβ fibrillization, and as an antioxidant and anti-apoptotic protein.Areas covered in this review: Recent evidence indicates reduced brain gelsolin levels in AD. Therefore, a better understanding of the roles of gelsolin in AD pathology, particularly those related with cognition, is required.What the reader will gain: Most of the information reviewed here relates to experimental studies. However, gelsolin may progress from the present evidence to preclinical and clinical applications. In addition, a greater insight into the environmental factors contributing to abnormally reduced gelsolin function in AD brains may become crucial for the development of much needed disease-modifying strategies.Take home message: Because, the efficacy of available medicines is still poor, there is an urgent need for novel AD treatments. In this sense, gelsolin could play an important role.

Gelsolin, an Actin Regulatory Protein, is Required for Differentiation of Mouse 3T3-L1 Cells into Adipocytes

To elucidate molecular mechanisms of adipocyte differentiation, we previously isolated TC10-like/ TC10betaLong (TCL/TC10betaL), which was transiently expressed in the early phase of adipogenesis of 3T3-L1 cells and seemed to be a positive regulator of adipogenesis. By using TCL/TC10betaL-overexpressing NIH-3T3 cells, we also isolated gelsolin as a gene whose expression was up-regulated by TCL/TC10betaL. However, the roles of gelsolin in adipocyte differentiation are unclear. In this paper we characterized the function of gelsolin in adipogenesis in 3T3-L1 cells. The level of gelsolin changed during adipocyte differentiation. Knockdown of the expression of gelsolin using RNAi inhibited adipocyte differentiation, and impaired the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein (C/EBP) alpha. Interestingly, the knockdown also impaired mitotic clonal expansion (MCE), and increased cell size, though it reduced levels of C/EBPbeta and C/EBPdelta, markers for the early stage of adipogenesis, only slightly. Gelsolin plays a crucial role in the differentiation of 3T3-L1 cells into adipocytes.

Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis

Background:Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actin-binding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease...