WISP1 Research Articles

WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma

In recent years, much research has focused on the role of angiogenesis in osteosarcoma, which occurs predominantly in adolescents and young adults. The vascular endothelial growth factor-A (VEGF-A) pathway is the key regulator of angiogenesis and in osteosarcoma. VEGF-A expression has been recognized as a prognostic marker in angiogenesis. Aberrant WNT1-inducible signaling pathway protein-1 (WISP-1) expression is associated with various cancers. However, the function of WISP-1 in osteosarcoma angiogenesis is poorly understood. We demonstrate a positive correlation between WISP-1 and VEGF-A expression in human osteosarcoma. Moreover, we show that WISP-1 promotes VEGF-A expression in human osteosarcoma cells, subsequently inducing human endothelial progenitor cell (EPC) migration and tube formation. The focal adhesion kinase (FAK), Jun amino-terminal kinase (JNK), and hypoxia-inducible factor (HIF)-1α signaling pathways were activated after WISP-1 stimulation, while FAK, JNK, and HIF-1α inhibitors or small interfering RNA (siRNA) abolished WISP-1-induced VEGF-A expression and angiogenesis. In vitro and in vivo studies revealed down-regulation of microRNA-381 (miR-381) in WISP-1-induced VEGF-A expression and angiogenesis. Our findings reveal that WISP-1 enhances VEGF-A expression and angiogenesis through the FAK/JNK/HIF-1α signaling pathways, as well as via down-regulation of miR-381 expression. WISP-1 may be a promising target in osteosarcoma angiogenesis.

Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease.

Noncommunicable diseases (NCDs) contribute to a significant amount of disability and death in the world. Of these disorders, vascular disease is ranked high, falls within the five leading causes of death, and impacts multiple other disease entities such as those of the cardiac system, nervous system, and metabolic disease. Targeting the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) pathway and the modulation of micro ribonucleic acids (miRNAs) may hold great promise for the development of novel strategies for the treatment of vascular disease since each of these pathways are highly relevant to cardiac and nervous system disorders as well as to metabolic dysfunction. SIRT1 is vital in determining the course of stem cell development and the survival, metabolism, and life span of differentiated cells that are overseen by both autophagy and apoptosis. SIRT1 interfaces with a number of pathways that involve forkhead transcription factors, mechanistic of rapamycin (mTOR), AMP activated protein kinase (AMPK) and Wnt1 inducible signaling pathway protein 1 (WISP1) such that the level of activity of SIRT1 can become a critical determinant for biological and clinical outcomes. The essential fine control of SIRT1 is directly tied to the world of non-coding RNAs that ultimately oversee SIRT1 activity to either extend or end cellular survival. Future studies that can further elucidate the crosstalk between SIRT1 and non-coding RNAs should serve well our ability to harness the power of SIRT1 and non-coding RNAs for the treatment of vascular disorders.

Gene expression profiling of the 8q22-24 position in human breast cancer: TSPYL5, MTDH, ATAD2 and CCNE2 genes are implicated in oncogenesis, while WISP1 and EXT1 genes may predict a risk of metastasis.

Gene expression profiling has been suggested to predict breast cancer outcome. The prognostic value of the 8q22-24 position in breast cancer remains to be elucidated. The present study evaluated expression patterns of the genes located at this position in metastatic and non-metastatic breast cancer. A total of 85 patients with recurrent/metastatic (n=15) and non-metastatic (n=70) early-stage, estrogen receptor-positive and lymph node-negative breast tumors were included. In addition, 15 normal breast tissue samples were used as controls. Demographic and clinical features were recorded. Subsequently, mRNA copy numbers of exostosin glycosyltransferase 1 (EXT1), WNT1 inducible signaling pathway protein 1 (WISP1), ATPase family, AAA domain containing 2 (ATAD2), TSP-like 5 (TSPYL5), metadherin (MTDH) and cyclin E2 (CCNE2) genes were measured by reverse transcription-quantitative polymerase chain reaction assay. The expression of EXT1 and WISP1 exhibited a significant decline in the metastatic breast cancer group compared to the control (P=0.015 and P=0.012, respectively). The expression of TSPYL5, MTDH and ATAD2 was significantly decreased in the metastatic (P=0.002, P=0.018 and P=0.016, respectively) and non-metastatic (P=0.038, P=0.045 and P=0.000, respectively) breast cancer groups compared with the control. The expression of CCNE2 in the metastatic and non-metastatic breast cancer groups was significantly increased compared with the control (P=0.002 and P=0.001, respectively). WISP1 expression demonstrated a correlation with patient age and tumor size, and TSPYL5 expression was correlated with lymphovascular invasion. None of the genes investigated exhibited any correlation with stage and grade of disease. The TSPYL5, MTDH, ATAD2 and CCNE2 genes may be implicated in the pathogenesis of human breast cancer, while the WISP1 and EXT1 genes may have the potential to serve as promising indicators of the risk of metastasis. However, further studies are required to validate these results.

Erythropoietin and mTOR: A "One-Two Punch" for Aging-Related Disorders Accompanied by Enhanced Life Expectancy.

Life expectancy continues to increase throughout the world, but is accompanied by a rise in the incidence of non-communicable diseases. As a result, the benefits of an increased lifespan can be limited by aging-related disorders that necessitate new directives for the development of effective and safe treatment modalities. With this objective, the mechanistic target of rapamycin (mTOR), a 289-kDa serine/threonine protein, and its related pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), proline rich Akt substrate 40 kDa (PRAS40), AMP activated protein kinase (AMPK), Wnt signaling, and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), have generated significant excitement for furthering novel therapies applicable to multiple systems of the body. Yet, the biological and clinical outcome of these pathways can be complex especially with oversight of cell death mechanisms that involve apoptosis and autophagy. Growth factors, and in particular erythropoietin (EPO), are one avenue under consideration to implement control over cell death pathways since EPO can offer potential treatment for multiple disease entities and is intimately dependent upon mTOR signaling. In experimental and clinical studies, EPO appears to have significant efficacy in treating several disorders including those involving the developing brain. However, in mature populations that are affected by aging-related disorders, the direction for the use of EPO to treat clinical disease is less clear that may be dependent upon a number of factors including the understanding of mTOR signaling. Continued focus upon the regulatory elements that control EPO and mTOR signaling could generate critical insights for targeting a broad range of clinical maladies.

Expression of IGFBP6, IGFBP7, NOV, CYR61, WISP1 and WISP2 genes in U87 glioma cells in glutamine deprivation condition.

We have studied gene expression of insulin-like growth factor binding proteins in U87 glioma cells upon glutamine deprivation depending on the inhibition of IRE1 (inositol requiring enzyme-1), a central mediator of endoplasmic reticulum stress. We have shown that exposure of control glioma cells upon glutamine deprivation leads to down-regulation of NOV/IGFBP9, WISP1 and WISP2 gene expressions and up-regulation of CYR61/IGFBP10 gene expression at the mRNA level. At the same time, the expression of IGFBP6 and IGFBP7 genes in control glioma cells was resistant to glutamine deprivation. It was also shown that the inhibition of IRE1 modifies the effect of glutamine deprivation on the expression of all studied genes. Thus, the inhibition of IRE1 signaling enzyme enhances the effect of glutamine deprivation on the expression of CYR61 and WISP1 genes and suppresses effect of the deprivation on WISP2 gene expression in glioma cells. Moreover, the inhibition of IRE1 introduces sensitivity of the expression of IGFBP6 and IGFBP7 genes to glutamine deprivation and removes this sensitivity to NOV gene. We have also demonstrated that the expression of all studied genes in glioma cells growing with glutamine is regulated by IRE1 signaling enzyme, because the inhibition of IRE1 significantly down-regulates IGFBP6 and NOV genes and up-regulates IGFBP7, CYR61, WISP1, and WISP2 genes as compared to control glioma cells. The present study demonstrates that glutamine deprivation condition affects most studied IGFBP and WISP gene expressions in relation to IRE1 signaling enzyme function and possibly contributes to slower glioma cell proliferation upon inhibition of IRE1.

WISP1 overexpression promotes proliferation and migration of human vascular smooth muscle cells via AKT signaling pathway

Proliferation and migration of vascular smooth muscle cells (VSMCs) play crucial roles in the development of vascular restenosis. Our previous study showed that CCN4, namely Wnt1 inducible signaling pathway protein 1 (WISP1), significantly promotes proliferation and migration of rat VSMCs, but its mechanism remains unclear. This study aims to investigate whether and how WISP1 stimulates proliferation and migration of human VSMCs. Western blot analysis showed that FBS treatment increased WISP1 protein levels in human VSMCs in a dose-dependent manner. Overexpression of WISP1 using adenovirus encoding WISP1 (AD-WISP1) significantly increased proliferation rate of human VSMCs by 2.98-fold compared with empty virus (EV)-transfected cells, shown by EdU incorporation assay. Additionally, Scratch-induced wound healing assay revealed that adenovirus-mediated overexpression of WISP1 significantly increased cell migration compared with EV-transfected cells from 6h (4.56±1.14% vs. 11.23±2.25%, P<0.05) to 48h (25.25±5.51% vs. 97.54±13.12%, P<0.01) after injury. Transwell Migration Assay confirmed that WISP1 overexpression significantly promoted human VSMC migration by 2.25-fold compared with EV. Furthermore, WISP1 overexpression stimulated Akt signaling activation in human VSMCs. Blockage of Akt signaling by Akt inhibitor AZD5363 or PI3K inhibitor LY294002, led to an inhibitory effect of WISP1-induced proliferation and migration in human VSMCs. Moreover, we found that WISP1 overexpression stimulated GSK3α/β phosphorylation, and increased expression of cyclin D1 and MMP9 in human VSMCs, and this effect was abolished by AZD5363. Collectively, we demonstrated that Akt signaling pathway mediates WISP1-induced migration and proliferation of human VSMCs, suggesting that WISP1 may act as a novel potential therapeutic target for vascular restenosis.

Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling.

Plumbagin, a naphthoquinone constituent of Plumbago zeylanica L. (Plumbaginaceae) is widely used in traditional Chinese medicine as an antifungal, antibacterial and anti-inflammatory agent. Plumbagin is known to exhibit proapoptotic, antiangiogenic and antimetastatic effects in cancer cells. The transcriptional co-factor four and a half LIM domains 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of gene expression, signal transduction and cell proliferation and differentiation, and also acts as a tumor suppressor or oncoprotein depending on the tissue microenvironment. The present study investigated the effect of plumbagin on FHL2 expression, Wnt/β-catenin signalling and its anti-proliferative activity in various human osteosarcoma cell lines, including SaOS2, MG63, HOS and U2OS. The cells were exposed to plumbagin and the expression of FHL2 was evaluated using western blot analysis. Furthermore, the anti-proliferative effect of plumbagin was evaluated using a 3-(4,5 dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, since FHL2 is involved in Wnt/β-catenin signaling, the effect of plumbagin on β-catenin and its primary target genes, including v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) and WNT1 inducible signaling pathway protein-1 (WISP-1), was evaluated using western blot analysis. It was observed that plumbagin suppressed the expression of FHL2 and exhibited significant anti-proliferative activity in osteosarcoma cells. It also attenuated Wnt/β-catenin signalling by downregulating β-catenin and its target genes, including c-Myc and WISP-1. In conclusion, plumbagin demonstrated anti-proliferative activity in osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling.

WISP1 is a novel adipokine linked to metabolic parameters in gestational diabetes mellitus

Objective: To investigate Wnt1-inducible signaling pathway protein-1 (WISP1) levels and their correlation with metabolic parameters in pregnant women with gestational diabetes mellitus (GDM) and non-GDM healthy pregnant women.Materials and Methods: In this prospective cross-sectional study, the study group was composed of 62 women with GDM and 73 healthy pregnant women matched for age, body mass index (BMI) and gestational age. Blood samples were collected at 25–29th gestational week. Serum WISP1, betatrophin, glucose, fasting insulin, glycosylated hemoglobin A1c, total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, C reactive protein, alanine aminotransferase and creatinine levels were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) values was calculated. The level of significance was accepted as p < 0.05.Results: Circulating WISP1 in the GDM group was significantly higher than the control group (p <0.001). Further, WISP1 was positively correlated with BMI, HOMA-IR values and fasting glucose, fasting insulin, triglyceride, betatrophin levels. BMI, HOMA-IR and betatrophin independently and positively predicted WISP1 levels.Conclusion: These results demonstrate a relationship between WISP1 and the metabolic parameters of GDM. And, WISP1 might be involved in the pathophysiology of GDM. As a part of this pathophysiological mechanism, the activation of WISP1 and betatrophin might take place through several ways; WISP1 and betatrophin might either use same signaling pathways and potentiate each other or they might also constitute the sequential steps of a common pathway.

Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration.

Increased vascular smooth muscle cell (VSMC) migration leads to intimal thickening which acts as a soil for atherosclersosis, as well as causing coronary artery restenosis after stenting and vein graft failure. Investigating factors involved in VSMC migration may enable us to reduce intimal thickening and improve patient outcomes. In this study, we determined whether Wnt proteins regulate VSMC migration and thereby intimal thickening. Wnt2 mRNA and protein expression were specifically increased in migrating mouse aortic VSMCs. Moreover, VSMC migration was induced by recombinant Wnt2 in vitro. Addition of recombinant Wnt2 protein increased Wnt1-inducible signaling pathway protein-1 (WISP-1) mRNA by ≈1.7-fold, via β-catenin/T-cell factor signaling, whereas silencing RNA knockdown of Wnt-2 reduced WISP-1 mRNA by ≈65%. Treatment with rWISP-1 significantly increased VSMC migration by ≈1.5-fold, whereas WISP-1 silencing RNA knockdown reduced migration by ≈40%. Wnt2 and WISP-1 effects were integrin-dependent and not additive, indicating that Wnt2 promoted VSMC migration via WISP-1. Additionally, Wnt2 and WISP-1 were significantly increased and colocated in human coronary arteries with intimal thickening. Reduced Wnt2 and WISP-1 levels in mouse carotid arteries from Wnt2(+/-) and WISP-1(-/-) mice, respectively, significantly suppressed intimal thickening in response to carotid artery ligation. In contrast, elevation of plasma WISP-1 via an adenovirus encoding WISP-1 significantly increased intimal thickening by ≈1.5-fold compared with mice receiving control virus. Upregulation of Wnt2 expression enhanced WISP-1 and promoted VSMC migration and thereby intimal thickening. As novel regulators of VSMC migration and intimal thickening, Wnt2 or WISP-1 may provide a potential therapy for restenosis and vein graft failure.

WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by a poor prognosis and a low survival rate. Vascular endothelial growth factor-C (VEGF-C) has been implicated in lymphangiogenesis and is correlated with cancer metastasis. WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4 is an extracellular matrix-related protein that belongs to the CCN family and stimulates many biological functions. Our previous studies showed that WISP-1 plays an important role in OSCC migration and angiogenesis. However, the effect of WISP-1 on VEGF-C regulation and lymphangiogenesis in OSCC is poorly understood. Here, we showed a correlation between WISP-1 and VEGF-C in tissue specimens from patients with OSCC. To examine the lymphangiogenic effect of WISP-1, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. The results showed that conditioned media from WISP-1-treated OSCC cells promoted tube formation and cell migration in LECs. We also found that WISP-1-induced VEGF-C is mediated via the integrin αvβ3/integrin-linked kinase (ILK)/Akt signaling pathway. In addition, the expression of microRNA-300 (miR-300) was inhibited by WISP-1 via the integrin αvβ3/ILK/Akt cascade. Collectively, these results reveal the detailed mechanism by which WISP-1 promotes lymphangiogenesis via upregulation of VEGF-C expression in OSCC. Therefore, WISP-1 could serve as therapeutic target to prevent metastasis and lymphangiogenesis in OSCC.

Picking a bone with WISP1 (CCN4): new strategies against degenerative joint disease

As the world's population continues to age, it is estimated that degenerative joint disease disorders such as osteoarthritis will impact at least 130 million individuals throughout the globe by the year 2050. Advanced age, obesity, genetics, gender, bone density, trauma, and a poor level of physical activity can lead to the onset and progression of osteoarthritis. However, factors that lead to degenerative joint disease and involve gender, genetics, epigenetic mechanisms, and advanced age are not within the control of an individual. Furthermore, current therapies including pain management, improved nutrition, and regular programs for exercise do not lead to the resolution of osteoarthritis. As a result, new avenues for targeting the treatment of osteoarthritis are desperately needed. Wnt1 inducible signaling pathway protein 1 (WISP1), a matricellular protein and a downstream target of the wingless pathway Wnt1, is one such target to consider that governs cellular protection, stem cell proliferation, and tissue regeneration in a number of disorders including bone degeneration. However, increased WISP1 expression also has been associated with the progression of osteoarthritis. WISP1 has an intricate relationship with a number of proliferative and protective pathways that include phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin -6 (IL-6), transforming growth factor-β, matrix metalloproteinase, small non-coding ribonucleic acids (RNAs), sirtuin silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and the mechanistic target of rapamycin (mTOR). Taken together, this complex association WISP1 holds with these signaling pathways necessitates a fine biological regulation of WISP1 activity that can offset the progression of degenerative joint disease, but not limit the cellular protective capabilities of the WISP1 pathway.

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR.

Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

Forkhead transcription factors: new considerations for alzheimer's disease and dementia.

Life expectancy of individuals in both developed and undeveloped nations continues to rise at an unprecedented rate. Coupled to this increase in longevity for individuals is the rise in the incidence of chronic neurodegenerative disorders that includes Alzheimer’s disease (AD). Currently, almost ten percent of the population over the age of 65 suffers from AD, a disorder that is presently without definitive therapy to prevent the onset or progression of cognitive loss. Yet, it is estimated that AD will continue to significantly increase throughout the world to impact millions of individuals and foster the escalation of healthcare costs. One potential target for the development of novel strategies against AD and other cognitive disorders involves the mammalian forkhead transcription factors of the O class (FoxOs). FoxOs are present in “cognitive centers” of the brain to include the hippocampus, the amygdala, and the nucleus accumbens and may be required for memory formation and consolidation. FoxOs play a critical role in determining survival of multiple cell types in the nervous system, drive pathways of apoptosis and autophagy, and control stem cell proliferation and differentiation. FoxOs also interface with multiple cellular pathways that include growth factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1 (WISP1), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that ultimately may control FoxOs and determine the fate and function of cells in the nervous system that control memory and cognition. Future work that can further elucidate the complex relationship FoxOs hold over cell fate and cognitive function could yield exciting prospects for the treatment of a number of neurodegenerative disorders including AD.

EFFECT OF HYPOXIA ON THE EXPRESSION OF GENES THAT ENCODE SOME IGFBP AND CCN PROTEINS IN U87 GLIOMA CELLS DEPENDS ON IRE1 SIGNALING.

We have studied hypoxic regulation of the expression of different insulin-like growth factor binding protein genes in U87 glioma cells in relation to inhibition of IRE1 (inositol requiring enzyme-1), a central mediator of endoplasmic reticulum stress, which controls cell proliferation and tumor growth. We have demonstrated that hypoxia leads to up-regulation of the expression of IGFBP6, IGFBP7, IGFBP10/CYR61, WISP1, and WISP2 genes and down-regulation--of IGFBP9/NOV gene at the mRNA level in control glioma cells, being more signifcant changes for IGFBP10/CYR61 and WISP2 genes. At the same time, inhibition of IRE1 modifies the effect of hypoxia on the expression of all studied genes: eliminates sensitivity to hypoxia the expression of IGFBP7 and IGFBP9/NOV genes, suppresses effect of hypoxia on IGFBP6, IGFBP10/CYR61, and WISP2 genes, and slightly enhances hypoxic regulation of WISP1 gene expression in glioma cells. We have also demonstrated that the expression of all studied genes in glioma cells is regulated by IRE1 signaling enzyme upon normoxic condition, because inhibition of IRE1 significantly up-regulates IGFBP7, IGFBP10/CYR61, WISP1, and WISP2 genes and down-regulates IGFBP6 and IGFBP9/NOV genes as compared to control glioma cells. The present study demonstrates that hypoxia, which contributes to tumor growth, affects all studied IGFBP and WISP gene expressions and that inhibition of IRE1 preferentially abolishes or suppresses the hypoxic regulation of these gene expressions and thus possibly contributes to slower glioma growth. Moreover, inhibition of IRE1, which correlates with suppression of cell proliferation and glioma growth, is down-regulated expression of pro-proliferative IGFBP genes, attesting to the fact that endoplasmic reticulum stress is a necessary component of malignant tumor growth.

Effect of siRNA on Wisp-1 gene expression, proliferation, migration and adhesion of mouse hepatocellular carcinoma cells.

To study the inhibition effect of siRNA on the expression of Wisp-1 gene in Hca-F of mouse hepatocellular carcinoma cells strain and also its effect on the proliferation, migration and adhesion of hepatocellular carcinoma cells. Three expression vectors of siRNA were constructed. Lipo2000 was employed to transfect Hca-F cells and Western blot was used to detect the inhibition effect of siRNA on the expression of Wisp-1 gene. Afterward, CCK8 was adopted to detect the effect of Wisp-1 siRNA on the proliferation of Hca-F cells; Annexin V-FITC/PI double staining flow cytometry was used to detect the effect of Wisp-1 siRNA on the apoptosis of Hca-F cells; Transwell was used to detect the effect of Wisp-1 siRNA on the migration of Hca-F cells. The invitro cell adhesion kit was used to detect of Wisp-1 siRNA on the change in the components of extracellular matrix to which Hca-F cells adhered. Western blot was used to detect the activation of protein kinase B (AKT)/glycogen synthase kinase-3β pathway and the expression of downstream target protein p53 and matrix metalloproteinases-2. The siRNA showed interference effect on the expression of Wisp-1 gene. Compared with the control group, after being transfected to cells, Wisp-1 siRNA could significantly inhibit the proliferation, migration and adhesion of Hca-F cells and also promote the cell apoptosis, which was related to the down-regulated phosphorylation of AKT and glycogen synthase kinase-3β and the expression of p53 and matrix metalloproteinases-2 (P<0.05). The inhibition of Wisp-1 expression can reduce the proliferation, migration and adhesion of mouse hepatocellular carcinoma cells, which is related to the AKT/glycogen synthase kinase-3β pathway. Wisp-1 gene may be the potential target to cure the hepatocellular carcinoma.

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus.

Mammalian forkhead transcription factors of the O class (FoxO) are exciting targets under consideration for the development of new clinical entities to treat metabolic disorders and diabetes mellitus (DM). DM, a disorder that currently affects greater than 350 million individuals globally, can become a devastating disease that leads to cellular injury through oxidative stress pathways and affects multiple systems of the body. FoxO proteins can regulate insulin signaling, gluconeogenesis, insulin resistance, immune cell migration, and cell senescence. FoxO proteins also control cell fate through oxidative stress and pathways of autophagy and apoptosis that either lead to tissue regeneration or cell demise. Furthermore, FoxO signaling can be dependent upon signal transduction pathways that include silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), Wnt, and Wnt1 inducible signaling pathway protein 1 (WISP1). Cellular metabolic pathways driven by FoxO proteins are complex, can lead to variable clinical outcomes, and require in-depth analysis of the epigenetic and post-translation protein modifications that drive FoxO protein activation and degradation.

Aldehyde dehydrogenase-2 protects against myocardial infarction-related cardiac fibrosis through modulation of the Wnt/β-catenin signaling pathway.

BackgroundAldehyde dehydrogenase-2 (ALDH2) has a protective effect on ischemic heart disease. Here, we examined the protective effects of ALDH2 on cardiac fibrosis through modulation of the Wnt/β-catenin signaling pathway in a rat model of myocardial infarction (MI).MethodsWistar rats were divided into the sham (control), MI (model), and ALDH2 activator (Alda-1) groups. After 10 days of treatment, the left ventricular (LV) remodeling parameters of each animal were evaluated by echocardiography. Myocardial fibrosis was evaluated by Masson’s trichrome staining and Sirius Red staining. Expression levels of collagen types I and III and α-smooth muscle actin (α-SMA) were examined. Finally, the expression and activity of ALDH2 and the levels of several Wnt-related proteins and genes, such as phosphoglycogen synthase kinase (GSK)-3β, GSK-3β, β-catenin, Wnt-1, WNT1-inducible signaling-pathway protein 1, and tumor necrosis factor (TNF)-α, were also analyzed.ResultsAfter MI, the heart weight/body weight ratio, LV dimension at end diastole, and LV dimension at end systole were decreased, while the LV ejection fraction and LV fractional shortening were increased in the Alda-1 group. Myocardial fibrosis was also reduced in the Alda-1 group, accompanied by decreased expression collagen types I and III and α-SMA. β-Catenin, phosphorylated GSK-3β, and Wnt-1 levels were significantly increased in the model group. Interestingly, this alteration was partly reversed by Alda-1 treatment. Immunohistochemical staining showed that numerous WNT1-inducible signaling-pathway protein 1 (WISP-1)- and TNF-α-positive cells were found in the model group. However, few WISP-1- and TNF-α-positive cells were detected in the Alda-1 group.ConclusionThe reduction of cardiac fibrosis and the down-regulation of β-catenin, phosphorylated GSK-3β, Wnt-1, and WISP-1 may be mediated by increased ALDH2 activity, leading to reduction of MI-related cardiac fibrosis.

Stem cell guidance through the mechanistic target of rapamycin.

Stem cells offer great promise for the treatment of multiple disorders throughout the body. Critical to this premise is the ability to govern stem cell pluripotency, proliferation, and differentiation. The mechanistic target of rapamycin (mTOR), 289-kDa serine/threonine protein kinase, that is a vital component of mTOR Complex 1 and mTOR Complex 2 represents a critical pathway for the oversight of stem cell maintenance. mTOR can control the programmed cell death pathways of autophagy and apoptosis that can yield variable outcomes in stem cell survival and be reliant upon proliferative pathways that include Wnt signaling, Wnt1 inducible signaling pathway protein 1 (WISP1), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and trophic factors. mTOR also is a necessary component for the early development and establishment of stem cells as well as having a significant impact in the regulation of the maturation of specific cell phenotypes. Yet, as a proliferative agent, mTOR can not only foster cancer stem cell development and tumorigenesis, but also mediate cell senescence under certain conditions to limit invasive cancer growth. mTOR offers an exciting target for the oversight of stem cell therapies but requires careful consideration of the diverse clinical outcomes that can be fueled by mTOR signaling pathways.

Functional Effects of WNT1-Inducible Signaling Pathway Protein-1 on Bronchial Smooth Muscle Cell Migration and Proliferation in OVA-Induced Airway Remodeling.

Upregulation of WISP1 has been demonstrated in lung remodeling. Moreover, it has been recently found that some signaling components of WNT pathway can activate GSK3β signaling to mediate remodeling of airway smooth muscle (ASM) in asthma. Therefore, we hypothesized that WISP1, a signaling molecule downstream of the WNT signaling pathway, is involved in PI3K/GSK3β signaling to mediate ASM remodeling in asthma. Our results showed that WISP1 depletion partly suppressed OVA-induced ASM hypertrophy in vivo. In vitro, WISP1 could induce hBSMC hypertrophy and proliferation, accompanied by upregulation of levels of PI3K, p-Akt, p-GSK3β, and its own expression. TGF-β treatment could increase expression of PI3K, p-Akt, p-GSK3β, and WISP1. SH-5 treatment could partly suppress TGF-β-induced hypertrophy and proliferation of hBSMC, and depress expression of p-GSK3β and WISP1. In conclusion, WISP1 may be a potential inducer of ASM proliferation and hypertrophy in asthma. The pro-remodeling effect of WISP1 is likely due to be involved in PI3K-GSK3β-dependent noncanonical TGF-β signaling.

Programming apoptosis and autophagy with novel approaches for diabetes mellitus.

According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe.