Ginkgolide C attenuates cerebral ischemia/reperfusion-induced inflammatory impairments by suppressing CD40/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. (Ginkgoaceae), a traditional Chinese medicine, has been applied for thousands of years for the treatment of cardio-cerebral vascular diseases in China. It is written in Compendium of Materia Medica that Ginkgo has the property of "dispersing poison", which is now referred to as anti-inflammatory and antioxidant. Ginkgolides are important active ingredients in Ginkgo biloba leaves and ginkgolide injection has been frequently applied in clinical practice for the treatment of ischemic stroke. However, few studies have explored the effect and mechanism of ginkgolide C (GC) with anti-inflammatory activity in cerebral ischemia/reperfusion injury (CI/RI). AIM OF THE STUDY: The present study aimed to demonstrate whether GC was capable of attenuating CI/RI. Furthermore, the anti-inflammatory effect of GC in CI/RI was explored around the CD40/NF-κB pathway. MATERIALS AND METHODS: In vivo, middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in rats. The neuroprotective effect of GC was assessed by neurological scores, cerebral infarct rate, microvessel ultrastructure, blood-brain barrier (BBB) integrity, brain edema, neutrophil infiltration, and levels of TNF-α, IL-1ß, IL-6, ICAM-1, VCAM-1, and iNOS. In vitro, rat brain microvessel endothelial cells (rBMECs) were preincubated in GC before hypoxia/reoxygenation (H/R) culture. The cell viability, levels of CD40, ICAM-1, MMP-9, TNF-α, IL-1ß, and IL-6, and activation of NF-κB pathway were examined. In addition, the anti-inflammatory effect of GC was also investigated by silencing CD40 gene in rBMECs. RESULTS: GC attenuated CI/RI as demonstrated by decreasing neurological scores, reducing cerebral infarct rate, improving microvessel ultrastructural features, ameliorating BBB disruption, attenuating brain edema, inhibiting MPO activity, and downregulating levels of TNF-α, IL-1ß, IL-6, ICAM-1, VCAM-1, and iNOS. Coherently, in rBMECs exposed to H/R GC enhanced cell viability and downregulated levels of ICAM-1, MMP-9, TNF-α, IL-1ß, and IL-6. Furthermore, GC suppressed CD40 overexpression and hindered translocation of NF-κB p65 from the cytosol to the nucleus, phosphorylation of IκB-α, and activation of IKK-ß in H/R rBMECs. However, GC failed to protect rBMECs from H/R-induced inflammatory impairments and suppress activation of NF-κB pathway when CD40 gene was silenced. CONCLUSIONS: GC attenuates cerebral ischemia/reperfusion-induced inflammatory impairments by suppressing CD40/NF-κB pathway, which may provide an available therapeutic drug for CI/RI.

Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer.

Lysine-specific demethylase 5A (KDM5A), an enzyme that removes activating H3K4 di- and trimethylation marks, plays critical roles in controlling transcription and chromatin architecture, yet its biological functions largely remain uncharacterized, particularly in the context of human cancer. In the present study, we found that the KDM5A gene was significantly amplified and over-expressed in various human tumors, including breast cancer. Reducing the expression of KDM5A by shRNA knockdown inhibited proliferation of KDM5A-amplified breast cancer cells. More importantly, we demonstrated that KDM5A over-expression was associated with breast cancer drug resistance. Furthermore, knockdown of KDM5A gene expression altered H3K4 methylation and induced upregulation of CDK inhibitors as well as genes mediating apoptotic cell death. Taken together, our study strongly links KDM5A histone demethylase activity to breast cancer proliferation and drug resistance, and suggests KDM5A is a potential target for breast cancer therapy.

EPO relies upon novel signaling of Wnt1 that requires Akt1, FoxO3a, GSK-3ß, and ß-catenin to foster vascular integrity during experimental diabetes.

Multiple complications can ensue in the cardiovascular, renal, and nervous systems during diabetes mellitus (DM). Given that endothelial cells (ECs) are susceptible targets to elevated serum D-glucose, identification of novel cellular mechanisms that can protect ECs may foster the development of unique strategies for the prevention and treatment of DM complications. Erythropoietin (EPO) represents one of these novel strategies but the dependence of EPO upon Wnt1 and its downstream signaling in a clinically relevant model of DM with elevated D-glucose has not been elucidated. Here we show that EPO can not only maintain the integrity of EC membranes, but also prevent apoptotic nuclear DNA degradation and the externalization of membrane phosphatidylserine (PS) residues during elevated D-glucose over a 48-hour period. EPO modulates the expression of Wnt1 and utilizes Wnt1 to confer EC protection during elevated D-glucose exposure, since application of a Wnt1 neutralizing antibody, treatment with the Wnt1 antagonist DKK-1, or gene silencing of Wnt1 with Wnt1 siRNA transfection abrogates the protective capability of EPO. EPO through a novel Wnt1 dependent mechanism controls the post-translational phosphorylation of the "pro-apoptotic" forkhead member FoxO3a and blocks the trafficking of FoxO3a to the cell nucleus to prevent apoptotic demise. EPO also employs the activation of protein kinase B (Akt1) to foster phosphorylation of GSK-3ß that appears required for EPO vascular protection. Through this inhibition of GSK-3ß, EPO maintains ß-catenin activity, allows the translocation of ß-catenin from the EC cytoplasm to the nucleus through a Wnt1 pathway, and requires ß-catenin for protection against elevated D-glucose since gene silencing of ß-catenin eliminates the ability of EPO as well as Wnt1 to increase EC survival. Subsequently, we show that EPO requires modulation of both Wnt1 and FoxO3a to oversee mitochondrial membrane depolarization, cytochrome c release, and caspase activation during elevated D-glucose. Our studies identify critical elements of the protective cascade for EPO that rely upon modulation of Wnt1, Akt1, FoxO3a, GSK-3ß, ß-catenin, and mitochondrial apoptotic pathways for the development of new strategies against DM vascular complications.

Wnt1 neuroprotection translates into improved neurological function during oxidant stress and cerebral ischemia through AKT1 and mitochondrial apoptotic pathways.

Although essential for the development of the nervous system, Wnt1 also has been associated with neurodegenerative disease and cognitive loss during periods of oxidative stress. Here we show that endogenous expression of Wnt1 is suppressed during oxidative stress in both in vitro and in vivo experimental models. Loss of endogenous Wnt1 signaling directly correlates with neuronal demise and increased functional deficit, illustrating that endogenous neuronal Wnt1 offers a vital level of intrinsic cellular protection against oxidative stress. Furthermore, transient overexpression of Wnt1 or application of exogenous Wnt1 recombinant protein is necessary to preserve neurological function and rescue neurons from apoptotic membrane phosphatidylserine externalization and genomic DNA degradation, since blockade of Wnt1 signaling with a Wnt1 antibody or dickkopf related protein 1 abrogates neuronal protection by Wnt1. Wnt1 ultimately relies upon the activation of Akt1, the modulation of mitochondrial membrane permeability, and the release of cytochrome c to control the apoptotic cascade, since inhibition of Wnt1 signaling, the phosphatidylinositol 3-kinase pathway, or Akt1 activity abrogates the ability of Wnt1 to block these apoptotic components. Our work identifies Wnt1 and its downstream signaling as cellular targets with high clinical potential for novel treatment strategies for multiple disorders precipitated by oxidative stress.

Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress.

Elucidating the underlying mechanisms that govern microglial activation and survival is essential for the development of new treatment strategies for neurodegenerative disorders, since microglia serve not only as guardian sentries of the nervous system, but also play a significant role in determining neuronal and vascular cell fate. Here we show that endogenous and exogenous Wnt1 in inflammatory microglial cells is necessary for the prevention of apoptotic early membrane phosphatidylserine exposure and later DNA degradation, since blockade of Wnt1 signaling abrogates cell survival during oxidative stress. Wnt1 prevents apoptotic demise through the post-translational phosphorylation and maintenance of FoxO3a in the cytoplasm to inhibit an apoptotic cascade that relies upon the loss of mitochondrial membrane permeability, cytochrome c release, Bad phosphorylation, and activation of caspase 3 and caspase 1 as demonstrated by complimentary gene knockdown studies of FoxO3a. Furthermore, subcellular trafficking and gene knockdown studies of NF-kappaB p65 illustrate that microglial cell survival determined by Wnt1 during oxidative stress requires NF-kappaB p65. Our work highlights Wnt1 and the control of novel downstream transcriptional pathways as critical components for the oversight of nervous system microglial cells.

Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation.

Complications of diabetes mellitus (DM) weigh heavily upon the endothelium that ultimately affect multiple organ systems. These concerns call for innovative treatment strategies that employ molecular pathways responsible for cell survival and longevity. Here we show in a clinically relevant model of DM with elevated D-glucose that endothelial cell (EC) SIRT1 is vital for the prevention of early membrane apoptotic phosphatidylserine externalization and subsequent DNA degradation supported by studies with modulation of SIRT1 activity and gene knockdown of SIRT1. Furthermore, during elevated D-glucose exposure, we show that SIRT1 is sequestered in the cytoplasm of ECs, but specific activation of SIRT1 shuttles the protein to the nucleus to allow for cytoprotection. The ability of SIRT1 to avert apoptosis employs the activation of protein kinase B (Akt1), the post-translational phosphorylation of the forkhead member FoxO3a, the blocked trafficking of FoxO3a to the nucleus, and the inhibition of FoxO3a to initiate a "pro-apoptotic" program as shown by complimentary gene knockdown studies of FoxO3a. Vascular apoptotic oversight by SIRT1 extends to the direct modulation of mitochondrial membrane permeability, cytochrome c release, Bad activation, and caspase 1 and 3 activation, since inhibition of SIRT1 activity and gene knockdown of SIRT1 significantly accentuate cascade progression while SIRT1 activation abrogates these apoptotic elements. Our work identifies vascular SIRT1 and its control over early apoptotic membrane signaling, Akt1 activation, post-translational modification and trafficking of FoxO3a, mitochondrial permeability, Bad activation, and rapid caspase induction as new avenues for the treatment of vascular complications during DM.

FOXO3a governs early and late apoptotic endothelial programs during elevated glucose through mitochondrial and caspase signaling.

Mechanisms that preserve endothelial cell (EC) integrity remain elusive, but are critical for new strategies directed against endocrine disorders such as diabetes mellitus (DM). Here we demonstrate in primary cerebral ECs with a clinically relevant model of elevated d-glucose that Akt1 and the post-translational modification and subcellular trafficking of the forkhead transcription factor FoxO3a are critical for early apoptotic membrane signaling and subsequent degradation of nuclear DNA. FoxO3a also directly governs apoptotic mitochondrial signal transduction pathways, since gene knockdown of FoxO3a prevents mitochondrial membrane depolarization as well as the release of cytochrome c. Control of this apoptotic cascade extends to the rapid and progressive activation of caspases. The presence of FoxO3a is necessary for cleaved (active) caspase 1 and 3 expression, since loss of FoxO3a abrogates the induction of caspase activity. Our work identifies Akt1, FoxO3a and closely aligned pathways as key therapeutic targets during impaired glucose tolerance and DM.

Diabetes mellitus: channeling care through cellular discovery.

Diabetes mellitus (DM) impacts a significant portion of the world's population and care for this disorder places an economic burden on the gross domestic product for any particular country. Furthermore, both Type 1 and Type 2 DM are becoming increasingly prevalent and there is increased incidence of impaired glucose tolerance in the young. The complications of DM are protean and can involve multiple systems throughout the body that are susceptible to the detrimental effects of oxidative stress and apoptotic cell injury. For these reasons, innovative strategies are necessary for the implementation of new treatments for DM that are generated through the further understanding of cellular pathways that govern the pathological consequences of DM. In particular, both the precursor for the coenzyme beta-nicotinamide adenine dinucleotide (NAD(+)), nicotinamide, and the growth factor erythropoietin offer novel platforms for drug discovery that involve cellular metabolic homeostasis and inflammatory cell control. Interestingly, these agents and their tightly associated pathways that consist of cell cycle regulation, protein kinase B, forkhead transcription factors, and Wnt signaling also function in a broader sense as biomarkers for disease onset and progression.

Oxidative stress: Biomarkers and novel therapeutic pathways.

Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO) and members of the mammalian forkhead transcription factors of the O class (FoxOs) may offer the greatest promise for new treatment regimens since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. However, biological outcome with EPO and FoxOs may sometimes be both unexpected and undesirable that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as complicated role EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.

Erythropoietin, forkhead proteins, and oxidative injury: biomarkers and biology.

Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO), and members of the mammalian forkhead transcription factors of the O class (FoxOs), may offer the greatest promise for new treatment regimens, since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. Yet, EPO and FoxOs may sometimes have unexpected and undesirable effects that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as the complex role that EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.

FoxO3a governs early microglial proliferation and employs mitochondrial depolarization with caspase 3, 8, and 9 cleavage during oxidant induced apoptosis.

Microglia of the central nervous system have a dual role in the ability to influence the survival of neighboring cells. During inflammatory cell activation, microglia can lead to the disposal of toxic cellular products and permit tissue regeneration, but microglia also may lead to cellular destruction with phagocytic removal. For these reasons, it is essential to elucidate not only the underlying pathways that control microglial activation and proliferation, but also the factors that determine microglial survival. In this regard, we investigated in the EOC 2 microglial cell line with an oxygen-glucose deprivation (OGD) injury model of oxidative stress the role of the "O" class forkhead transcription factor FoxO3a that in some scenarios is closely linked to immune system function. We demonstrate that FoxO3a is a necessary element in the control of early and late apoptotic injury programs that involve membrane phosphatidylserine externalization and nuclear DNA degradation, since transient knockdown of FoxO3a in microglia preserves cellular survival 24 hours following OGD exposure. However, prior to the onset of apoptotic injury, FoxO3a facilitates the activation and proliferation of microglia as early as 3 hours following OGD exposure that occurs in conjunction with the trafficking of the unphosphorylated and active post-translational form of FoxO3a from the cytoplasm to the cell nucleus. FoxO3a also can modulate apoptotic mitochondrial signal transduction pathways in microglia, since transient knockdown of FoxO3a prevents mitochondrial membrane depolarization as well as the release of cytochrome c during OGD. Control of this apoptotic cascade also extends to progressive caspase activation as early as 1 hour following OGD exposure. The presence of FoxO3a is necessary for the expression of cleaved (active) caspase 3, 8, and 9, since loss of FoxO3a abrogates the induction of caspase activity. Interestingly, elimination of FoxO3a reduced caspase 9 activity to a lesser extent than that noted with caspase 3 and 8 activities, suggesting that FoxO3a in relation to caspase 9 may be more reliant upon other signal transduction pathways potentially independent from caspase 3 and 8.

The vitamin nicotinamide: translating nutrition into clinical care.

Nicotinamide, the amide form of vitamin B(3) (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acide/nicotinamide adenylyltransferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs.

The forkhead transcription factor FOXO3a controls microglial inflammatory activation and eventual apoptotic injury through caspase 3.

Memory loss and cognitive failure are increasingly being identified as potential risks with the recognized increase in life expectancy of the general population. As a result, the development of novel therapeutic strategies for disorders such as Alzheimer's disease have garnered increased attention. The etiologies that can lead to Alzheimer's disease are extremely varied, but a number of therapeutic options are directed against amyloid-beta peptide and inflammatory cell regulation to prevent or halt progressive cognitive loss. In particular, inflammatory microglial cells may have disparate functions that in some scenarios lead to disability through the removal of functional neurovascular cells and in other circumstances foster tissue repair. Given the significance microglial cells hold for neurodegenerative disorders, we therefore examined the function that amyloid (Abeta(1-42)) has upon the microglial cell line EOC 2 and identified a novel role for the forkhead transcription factor FoxO3a and caspase 3. Here we show that Abeta(1-42) leads to progressive injury and apoptotic cell loss in microglial cells that involves both early phosphatidylserine (PS) externalization and late genomic DNA fragmentation over a 24 hour course. Prior to these injury programs, Abeta(1-42) results in the activation and proliferation of microglia as demonstrated by increased proliferating cell nuclear antigen (PCNA) expression and bromodeoxyuridine (BrdU) uptake. Both apoptotic injury as well as the prior activation and proliferation of microglial cells relies upon the presence of FoxO3a, since specific gene silencing of FoxO3a promotes microglial cell protection and prevents the early activation and proliferation of these cells. Furthermore, Abeta(1-42) exposure maintained FoxO3a in an unphosphorylated "active" state and facilitated the cellular trafficking of FoxO3a from the cytoplasm to the cell nucleus to potentially lead to "pro-apoptotic" programs by this transcription factor. One apoptotic program in particular appears to involve the activation of caspase 3, since loss of FoxO3a through gene silencing prevents the induction of caspase 3 activity by Abeta(1-42).

FoxO proteins: cunning concepts and considerations for the cardiovascular system.

Dysfunction in the cardiovascular system can lead to the progression of a number of disease entities that can involve cancer, diabetes, cardiac ischaemia, neurodegeneration and immune system dysfunction. In order for new therapeutic avenues to overcome some of the limitations of present clinical treatments for these disorders, future investigations must focus upon novel cellular processes that control cellular development, proliferation, metabolism and inflammation. In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) have increasingly become recognized as important and exciting targets for disorders of the cardiovascular system. In the present review, we describe the role of these transcription factors in the cardiovascular system during processes that involve angiogenesis, cardiovascular development, hypertension, cellular metabolism, oxidative stress, stem cell proliferation, immune system regulation and cancer. Current knowledge of FoxO protein function combined with future studies should continue to lay the foundation for the successful translation of these transcription factors into novel and robust clinical therapies.

A "FOXO" in sight: targeting Foxo proteins from conception to cancer.

The successful treatment for multiple disease entities can rest heavily upon the ability to elucidate the intricate relationships that govern cellular proliferation, metabolism, survival, and inflammation. Here we discuss the therapeutic potential of the mammalian forkhead transcription factors predominantly in the O class, FoxO1, FoxO3, FoxO4, and FoxO6, which play a significant role during normal cellular function as well as during progressive disease. These transcription factors are integrated with several signal transduction pathways, such as Wnt proteins, that can regulate a broad array of cellular process that include stem cell proliferation, aging, and malignancy. FoxO transcription factors are attractive considerations for strategies directed against human cancer in light of their pro-apoptotic effects and ability to lead to cell cycle arrest. Yet, FoxO proteins can be associated with infertility, cellular degeneration, and unchecked cellular proliferation. As our knowledge continues to develop for this novel family of proteins, potential clinical applications for the FoxO family should heighten our ability to limit disease progression without clinical compromise.

A fork in the path: Developing therapeutic inroads with FoxO proteins.

Advances in clinical care for disorders involving any system of the body necessitates novel therapeutic strategies that can focus upon the modulation of cellular proliferation, metabolism, inflammation and longevity. In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) that include FoxO1, FoxO3, FoxO4 and FoxO6 are increasingly being recognized as exciting prospects for multiple disorders. These transcription factors govern development, proliferation, survival and longevity during multiple cellular environments that can involve oxidative stress. Furthermore, these transcription factors are closely integrated with several novel signal transduction pathways, such as erythropoietin and Wnt proteins, that may influence the ability of FoxOs to act as a "double-edge sword" to sometimes promote cell survival, but at other times lead to cell injury. Here we discuss the fascinating but complex role of FoxOs during cellular injury and oxidative stress, progenitor cell development, fertility, angiogenesis, cardiovascular function, cellular metabolism and diabetes, cell longevity, immune surveillance and cancer.

The "O" class: crafting clinical care with FoxO transcription factors.

Forkhead Transcription Factors: Vital Elements in Biology and Medicine provides a unique platform for the presentation of novel work and new insights into the vital role that forkhead transcription factors play in both cellular physiology as well as clinical medicine. Internationally recognized investigators provide their insights and perspectives for a number of forkhead genes and proteins that may have the greatest impact for the development of new strategies for a broad array of disorders that can involve aging, cancer, cardiac function, neurovascular integrity, fertility, stem cell differentiation, cellular metabolism, and immune system regulation. Yet, the work clearly sets a precedent for the necessity to understand the cellular and molecular function of forkhead proteins since this family of transcription factors can limit as well as foster disease progression depending upon the cellular environment. With this in mind, our concluding chapter for Forkhead Transcription Factors: Vital Elements in Biology andMedicine offers to highlight both the diversity and complexity of the forkhead transcription family by focusing upon the mammalian forkhead transcription factors of the O class (FoxOs) that include FoxO1, FoxO3, FoxO4, and FoxO6. FoxO proteins are increasingly considered to represent unique cellular targets that can control numerous processes such as angiogenesis, cardiovascular development, vascular tone, oxidative stress, stem cell proliferation, fertility, and immune surveillance. Furthermore, FoxO transcription factors are exciting considerations for disorders such as cancer in light of their pro-apoptotic and inhibitory cell cycle effects as well as diabetes mellitus given the close association FoxOs hold with cellular metabolism. In addition, these transcription factors are closely integrated with several novel signal transduction pathways, such as erythropoietin and Wnt proteins, that may influence the ability of FoxOs to lead to cell survival or cell injury. Further understanding of both the function and intricate nature of the forkhead transcription factor family, and in particular the FoxO proteins, should allow selective regulation of cellular development or cellular demise for the generation of successful future clinical strategies and patient well-being.

Clever cancer strategies with FoxO transcription factors.

Given that cancer and related disorders affect a wide spectrum of the world's population, and in most cases are progressive in nature, it is essential that future care must overcome the present limitations of existing therapies in the absence of toxic side effects. Mammalian forkhead transcription factors of the O class (FoxOs) may fill this niche since these proteins are increasingly considered to represent unique cellular targets directed against human cancer in light of their pro-apoptotic effects and ability to lead to cell cycle arrest. Yet, FoxOs also can significantly affect normal cell survival and longevity, requiring new treatments for neoplastic growth to modulate novel pathways that integrate cell proliferation, metabolism, inflammation and survival. In this respect, members of the FoxO family are extremely compelling to consider since these transcription factors have emerged as versatile proteins that can control angiogenesis, stem cell proliferation, cell adhesion and autoimmune disease. Further elucidation of FoxO protein function during neoplastic growth should continue to lay the foundation for the successful translation of these transcription factors into novel and robust clinical therapies for cancer.

Rogue proliferation versus restorative protection: where do we draw the line for Wnt and forkhead signaling?

BACKGROUND: Disease entities such as diabetes, neurodegeneration and cardiovascular disorders affect a significant portion of the world's population. OBJECTIVE: Given that cellular survival and longevity in multiple disorders are tied to oxidative stress, apoptotic cell injury and immune system deregulation, the development of robust therapeutic strategies rests heavily upon the ability to balance each of these parameters. METHODS: Here we discuss two exciting signaling pathways, namely Wnt and mammalian forkhead transcription factors predominantly of the O class superfamily, which can share integrated cytoprotective pathways during oxidative stress but may also adversely influence cellular survival and promote cancer cell proliferation. CONCLUSION: Future investigations must elucidate the cellular determinants that govern the ability of Wnt and forkhead proteins to promote cellular longevity and possible disease remission but also allow for detrimental biological consequences and clinical compromise.

[Different types of tissue transplantation in repairing tissue defects and function reconstruction].

OBJECTIVE: To explore the clinical effect of different types of free tissue transplantation on repairing tissue defects and reconstructing functions. METHODS: From November 2001 to September 2004, 14 types of free tissue transplantation and 78 free tissue flaps were applied to repairing tissue defects and reconstructing functions in extremities and maxillofacial region in 69 cases. Of the 69 cases, there were 53 males and 16 females (their ages ranged from 18 to 56, 31 on average). Five cases were repaired because of skin defects in foot, 22 cases were repaired because of skin defects in leg, 36 cases were repaired as the result of skin defects in hand or forearm and finger reconstruction, 3 cases were restored by virtue of ulna or radius defects, and 3 cases were repaired in maxillofacial region. There were 55 cases of open wound, in which 16 cases were infectious wound, 6 cases were osteomyelitis or pyogenic arthritis. There were 14 cases of non-infectious wound. The area of these tissue flaps ranged from 2.0 cm x 1.5 cm to 43.0 cm x 12.0 cm. The length of bone transplantation ranged from 10 cm to 15 cm. RESULTS: Arterial crisis occurred in 2 cases, venous crisis occurred in 2 cases. Seventy-six flaps survived completely and 2 flaps survived partially which were later healed. Fifty-two cases were healed at stage I, 13 cases were healed at stage I (healing time ranged from 20 to 30 days), purulent infection occurred to 4 cases(healing time ranged from 3 to 11 months). Bone healing time ranged from 6 to 8 weeks in finger reconstruction. Bone healing time ranged from 4 to 6 months in fibula transplantation. The function reconstruction and appearance were satisfying. The functions of all regions, where free tissues were supplied, were not disturbed. CONCLUSION: Tissue transplantation and composite tissue transplantation are effective in repairing tissue defects and reconstructing functions.