Targeting Galectin 3 illuminates its contributions to the pathology of uterine serous carcinoma.

BACKGROUND: Uterine serous cancer (USC) comprises around 10% of all uterine cancers. However, USC accounts for approximately 40% of uterine cancer deaths, which is attributed to tumor aggressiveness and limited effective treatment. Galectin 3 (Gal3) has been implicated in promoting aggressive features in some malignancies. However, Gal3's role in promoting USC pathology is lacking. METHODS: We explored the relationship between LGALS3 levels and prognosis in USC patients using TCGA database, and examined the association between Gal3 levels in primary USC tumors and clinical-pathological features. CRISPR/Cas9-mediated Gal3-knockout (KO) and GB1107, inhibitor of Gal3, were employed to evaluate Gal3's impact on cell function. RESULTS: TCGA analysis revealed a worse prognosis for USC patients with high LGALS3. Patients with no-to-low Gal3 expression in primary tumors exhibited reduced clinical-pathological tumor progression. Gal3-KO and GB1107 reduced cell proliferation, stemness, adhesion, migration, and or invasion properties of USC lines. Furthermore, Gal3-positive conditioned media (CM) stimulated vascular tubal formation and branching and transition of fibroblast to cancer-associated fibroblast compared to Gal3-negative CM. Xenograft models emphasized the significance of Gal3 loss with fewer and smaller tumors compared to controls. Moreover, GB1107 impeded the growth of USC patient-derived organoids. CONCLUSION: These findings suggest inhibiting Gal3 may benefit USC patients.

In situ architecture of Opa1-dependent mitochondrial cristae remodeling.

Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.

The State-of-the-Art and Perspectives of Laser Ablation for Tumor Treatment.

Tumors significantly impact individuals' physical well-being and quality of life. With the ongoing advancements in optical technology, information technology, robotic technology, etc., laser technology is being increasingly utilized in the field of tumor treatment, and laser ablation (LA) of tumors remains a prominent area of research interest. This paper presents an overview of the recent progress in tumor LA therapy, with a focus on the mechanisms and biological effects of LA, commonly used ablation lasers, image-guided LA, and robotic-assisted LA. Further insights and future prospects are discussed in relation to these aspects, and the paper proposed potential future directions for the development of tumor LA techniques.

Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification.

Background: The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX® nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd3+ cations with higher Z Bi3+. These next-generation nanoparticles are based on the AGuIX® platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy. Methods: In this clinically scalable methodology, AGuIX® is used as an initial chelation platform to exchange Gd3+ for Bi3+. AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi3+. Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results: We demonstrated that increasing Bi3+ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi3+ by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidence of toxicity. Conclusions: We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi. These results provide crucial evidence towards patient translation.

Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX.

Although external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histologic analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single-cell RNA sequencing data revealed that neural cell vulnerability stems from heightened expression of proapoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, proapoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by proapoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. On the basis of these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM, or BID via direct or upstream mechanisms is expected to ameliorate NI in pediatric patients with CNS tumor. SIGNIFICANCE: Age- and differentiation-dependent apoptotic priming plays a pivotal role in driving radiotherapy-induced neurocognitive impairment and can be targeted for neuroprotection in pediatric patients.

Targeting TBK1 to overcome resistance to cancer immunotherapy.

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

In situ architecture of Opa1-dependent mitochondrial cristae remodeling.

Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.

Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy-induced toxicities.

Although major organ toxicities frequently arise in patients treated with cytotoxic or targeted cancer therapies, the mechanisms that drive them are poorly understood. Here, we report that vascular endothelial cells (ECs) are more highly primed for apoptosis than parenchymal cells across many adult tissues. Consequently, ECs readily undergo apoptosis in response to many commonly used anticancer agents including cytotoxic and targeted drugs and are more sensitive to ionizing radiation and BH3 mimetics than parenchymal cells in vivo. Further, using differentiated isogenic human induced pluripotent stem cell models of ECs and vascular smooth muscle cells (VSMCs), we find that these vascular cells exhibit distinct drug toxicity patterns, which are linked to divergent therapy-induced vascular toxicities in patients. Collectively, our results demonstrate that vascular cells are highly sensitive to apoptosis-inducing stress across life span and may represent a "weakest link" vulnerability in multiple tissues for development of toxicities.

Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics.

Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, currently the standard of care for this disease and the related plasma cell disorder multiple myeloma, due to upregulation of pro-apoptotic Noxa and its inhibitory binding to MCL-1. BCL-2 inhibitors sensitize clonal plasma cells to multiple front-line therapies including bortezomib, dexamethasone and lenalidomide. Strikingly, in mice bearing AL amyloidosis cell line xenografts, single agent treatment with the BCL-2 inhibitor ABT-199 (venetoclax) produces deeper remissions than bortezomib and triples median survival. Mass spectrometry-based proteomic analysis reveals rewiring of signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapies. These findings provide a roadmap for the use of BH3 mimetics to exploit endogenous and induced apoptotic vulnerabilities in AL amyloidosis.

Small molecule SJ572946 activates BAK to initiate apoptosis.

Poration of the outer mitochondrial membrane by the effector BCL-2 proteins BAK and BAX initiates apoptosis. BH3-only initiators BID and BIM trigger conformational changes in BAK and BAX transforming them from globular dormant proteins to oligomers of the apoptotic pores. Small molecules that can directly activate effectors are being sought for applications in cancer treatment. Here, we describe the small molecule SJ572946, discovered in a fragment-based screen that binds to the activation groove of BAK and selectively triggers BAK activation over that of BAX in liposome and mitochondrial permeabilization assays. SJ572946 independently kills BAK-expressing BCL2allKO HCT116 cells revealing on target cellular activity. In combination with apoptotic inducers and BH3 mimetics, SJ572946 kills experimental cancer cell lines. SJ572946 also cooperates with the endogenous BAK activator BID in activating a misfolded BAK mutant substantially impaired in activation. SJ572946 is a proof-of-concept tool for probing BAK-mediated apoptosis in preclinical cancer research.

Global Evolution of Skeletal Muscle Tissue Engineering: A Scientometric Research.

Skeletal muscle tissue engineering (SMTE) is of great significance in the study of skeletal muscle physiology and pathology, which could be used in skeletal muscle graft. The scientometric analysis of SMTE can help researchers to quickly understand the evolutive history, status, novelties, and trend of this field. In this study, we performed a scientometric study that can be used to construct and visualize networks of SMTE using VOSviewer. A total of 1384 documents published between 1994 and 2020 were retrieved and analyzed. Our results showed that number of publications in SMTE has increased slowly from 1994 to 2014 and has increased rapidly from 2015 to 2020. The geographical distribution of publications in terms of total publications about SMTE is concentrated in Europe and the United States. The most productive institution was University of Michigan, while Harvard University and the University of Pittsburgh were ranked the second and third places. SMTE influenced a wide spectrum of disciplines, including Biology and Medicine and Physical Sciences. In addition, the research hotspot of SMTE was expanding from seed cells to the combination with advanced strategies (electrostatic spinning, bioprinting, and materials) for emulating the highly bionic engineered skeletal muscle tissues. This study provided a unique perspective for understanding the history and trends of SMTE, which could help to promote the rapid development of the field. Impact statement Skeletal muscle tissue engineering (SMTE), which acts as an important branch of tissue engineering, hold a great promise in the study of skeletal muscle physiology and pathology. The field of SMTE has developed rapidly in recent decades while still lacking studies based on scientometric methods. This article provided the first scientometric study of SMTE from development trends and evolution of the field. The results indicated that the field of SMTE was experiencing rapid growth and had a significant impact on multiple fields, particularly in Biology and Medicine and Physical Sciences.

Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 severity.

Novel coronavirus disease 2019 (COVID-19) severity is highly variable, with pediatric patients typically experiencing less severe infection than adults and especially the elderly. The basis for this difference is unclear. We find that mRNA and protein expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, increases with advancing age in distal lung epithelial cells. However, in humans, ACE2 expression exhibits high levels of intra- and interindividual heterogeneity. Further, cells infected with SARS-CoV-2 experience endoplasmic reticulum stress, triggering an unfolded protein response and caspase-mediated apoptosis, a natural host defense system that halts virion production. Apoptosis of infected cells can be selectively induced by treatment with apoptosis-modulating BH3 mimetic drugs. Notably, epithelial cells within young lungs and airways are more primed to undergo apoptosis than those in adults, which may naturally hinder virion production and support milder COVID-19 severity.

Peri-tumoral brain edema associated with glioblastoma correlates with tumor recurrence.

Glioblastoma is the most common malignant tumor of the brain. Despite advances in treatment, the prognosis for the condition has remained poor. Glioblastoma is often associated with peritumoral brain edema (PTBE), which can result in increased intracranial pressure and devastating neurological sequelae if left untreated. Surgery is the main treatment for glioblastoma, however current international surgical guidelines do not specify whether glioblastoma-induced PTBE tissue should be resected. In this study, we analyzed treatment outcomes of PTBE using surgical resection. We performed a retrospective analysis of 255 cases of glioblastoma between 2014 and 2016, and found that a significant proportion of patients had a degree of PTBE. We found that surgical resection led to reduction in midline shift that had resulted from edema, however, postoperative complications and KPS scores were not significantly different in the two conditions. We also observed a delay in glioblastoma recurrence in patients undergoing PTBE tissue resection vs patients without resection of PTBE tissue. Interestingly, there was an abnormal expression of tumor associated genes in PTBE, which has not been previously been found. Taken together, this study indicates that glioblastoma-induced PTBE should be investigated further particularly as the tumor microenvironment is a known therapeutic target and therefore interactions between the microenvironment and PTBE should be explored. This study also highlights the importance of resection of PTBE tissue to not only reduce the mechanical obstruction associated with edema but also to delay recurrence of glioblastoma.

Association between Angiotensin-Converting Enzyme- Insertion/Deletion Polymorphism and Diabetes Mellitus-2 in Saudi Population.

OBJECTIVES: The association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the development of type 2 diabetes mellitus (T2DM) has been debated vigorously but still remains controversial. Therefore, the current study was designed to determine the possible association between ACE I/D polymorphism and T2DM and hypertension (HTN) in a population of Saudi Arabian participants. METHODS: A total of 143 individuals were recruited for the study, consisting of 74 controls and 69 patients with T2DM. Genotyping was performed via polymerase chain reaction. RESULTS: The genotype frequencies for DD, ID and II in controls were 52.7%, 39.2% and 8.1%, whereas in T2D patients it was 52.2%, 40.6% and 7.2% respectively. The DD frequency was highest out of the three genotypes in both the controls and the T2DM patients. CONCLUSION: There was no significant difference found in the genotype and allele frequencies between cases and controls, suggesting that insertion/deletion polymorphism in the ACE gene may not be associated with an increased susceptibility to type 2 diabetes in our study population.

Corrigendum: The Pathophysiology of Degenerative Cervical Myelopathy and the Physiology of Recovery Following Decompression.

[This corrects the article DOI: 10.3389/fnins.2020.00138.].

Adaptive Immunity Regulation and Cerebral Ischemia.

Stroke is a disease that occurs due to a sudden interruption of the blood supply to the brain. It is a leading cause of death and disability worldwide. It is well-known that the immune system drives brain injury following an episode of ischemic stroke. The innate system and the adaptive system play distinct but synergistic roles following ischemia. The innate system can be activated by damage-associated molecular patterns (DAMPs), which are released from cells in the ischemic region. Damaged cells also release various other mediators that serve to increase inflammation and compromise the integrity of the blood-brain barrier (BBB). Within 24 h of an ischemic insult, the adaptive immune system is activated. This involves T cell and B cell-mediated inflammatory and humoral effects. These cells also stimulate the release of various interleukins and cytokines, which can modulate the inflammatory response. The adaptive immune system has been shown to contribute to a state of immunodepression following an ischemic episode, and this can increase the risk of infections. However, this phenomenon is equally important in preventing autoimmunity of the body to brain antigens that are released into the peripheral system as a result of BBB compromise. In this review, we highlight the key components of the adaptive immune system that are activated following cerebral ischemia.

The Pathophysiology of Degenerative Cervical Myelopathy and the Physiology of Recovery Following Decompression.

Background: Degenerative cervical myelopathy (DCM), also known as cervical spondylotic myelopathy is the leading cause of spinal cord compression in adults. The mainstay of treatment is surgical decompression, which leads to partial recovery of symptoms, however, long term prognosis of the condition remains poor. Despite advances in treatment methods, the underlying pathobiology is not well-known. A better understanding of the disease is therefore required for the development of treatments to improve outcomes following surgery. Objective: To systematically evaluate the pathophysiology of DCM and the mechanism underlying recovery following decompression. Methods: A total of 13,808 published articles were identified in our systematic search of electronic databases (PUBMED, WEB OF SCIENCE). A total of 51 studies investigating the secondary injury mechanisms of DCM or physiology of recovery in animal models of disease underwent comprehensive review. Results: Forty-seven studies addressed the pathophysiology of DCM. Majority of the studies demonstrated evidence of neuronal loss following spinal cord compression. A number of studies provided further details of structural changes in neurons such as myelin damage and axon degeneration. The mechanisms of injury to cells included direct apoptosis and increased inflammation. Only four papers investigated the pathobiological changes that occur in spinal cords following decompression. One study demonstrated evidence of axonal plasticity following decompressive surgery. Another study demonstrated ischaemic-reperfusion injury following decompression, however this phenomenon was worse when decompression was delayed. Conclusions: In preclinical studies, the pathophysiology of DCM has been poorly studied and a number of questions remain unanswered. The physiological changes seen in the decompressed spinal cord has not been widely investigated and it is paramount that researchers investigate the decompressed spinal cord further to enable the development of therapeutic tools, to enhance recovery following surgery.

Dumbbell shaped craniorbital cavernous hemangioma.

BACKGROUND: Cavernous hemangioma of the orbit is a benign tumor mostly located behind the eye globe, but it rarely spread into the brain, which is called cerebral cavernous malformation as well, the lesion in the brain is irregular and enlarged blood. Here we report one particular case of craniorbital cavernous hemangioma. CASE PRESENTATION: A 53-year-old woman presented with exophthalmos of the right eye and reduced vision. Computerized tomographical (CT) scan showed osteolytic honeycomb radial changes of the outer plate of the skull. A magnetic resonance imaging (MRI) scan was performed to obtain further details. T1-weighted (T1W) imaging showed slightly low signal mixed with small patchy high signal. T2-weighted (T2W) imaging showed uneven high signal. There was obvious enhancement in the middle and no enhancement in the peripheral bars. A surgically manage was performed using a left frontotemporal approach, the tumor excised fully, and the histopathology results revealed a cavernous hemangioma. The patient recovered well in the follow-up. Post-operative CT scan identified the lesion was successfully resected, MRI scan also showed full resection and enhanced signal from the presence of fat. CONCLUSIONS: Craniorbital cavernous hemangioma is uncommon, however within the cranium, they can lead to numerous complications particularly if affecting the visual apparatus. it could be diagnosed by imaging, which CT scan shows osteolytic honeycomb radial changes of the outer plate of the skull, T1W imaging shows slightly low signal mixed with small patchy high signal, T2W imaging shows uneven high signal, it is obvious enhancement in the middle and no enhancement in the peripheral bars. The surgically manage is the ideally treatment when there are some symptoms.

TCF4 promotes colorectal cancer drug resistance and stemness via regulating ZEB1/ZEB2 expression.

The present study aims to investigate the roles of TCF4 and its underlying mechanism in colorectal cancer (CRC). Doxorubicin-resistant DLD-1 (DLD1 DR), TCF4 overexpression, and TCF4 knockdown cell lines were constructed. A flow cytometer was used to analyze frequencies of CD133+ cell in the DLD1 and DLD1 DR cells. Quantitative real-time PCR (qPCR) was used to determine the expressions of cancer stem cell (CSC) makers. Stemness of CRC cells were determined using tumorsphere formation assay. The correlation between TCF4 and ZEB1/ZEB2 were determined using public data from The Cancer Genome Atlas (TCGA) datasets. ZEB1/ZEB2 overexpression cell lines were constructed and cell viabilities were then determined using MTT and colony formation assays. TCF4 overexpression promoted proliferation of CRC cell lines and relative expressions of TCF4 were significantly increased in the DLD1 DR cells. TCF4 overexpression promoted CRC cell doxorubicin resistance, whereas TCF4 knockdown significantly decreased doxorubicin resistance. Additionally, TCF4 overexpression also significantly increased frequencies of CSC cells, expressions of CSC markers, and CRC ability to form tumorsphere. Furthermore, TCF4 promoted ZEB1 and ZEB2 expression, leading to CRC proliferation and doxorubicin resistance. TCF4 promoted CRC doxorubicin resistance and stemness by regulating expressions of ZEB1 and ZEB2.

PTEN Inhibition Protects Against Experimental Intracerebral Hemorrhage-Induced Brain Injury Through PTEN/E2F1/ß-Catenin Pathway.

Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. We have previously demonstrated that dipotassium bisperoxo (picolinato) oxovanadate (V), (bpV[pic]) inhibits phosphatase and tensin homolog (PTEN) and activates extracellular signal-regulated kinase (ERK)1/2. In this study, we examined the effect of bpV[pic] in the rat ICH model in vivo and the hemin-induced injury model in rat cortical cultures. The rat model of ICH was created by injecting autologous blood into the striatum, and bpV[pic] was intraperitoneally injected. The effects of bpV[pic] were evaluated by neurological tests, Fluoro-Jade C (FJC) staining, and Nissl staining. We demonstrate that bpV[pic] attenuates ICH-induced brain injury in vivo and hemin-induced neuron injury in vitro. The expression of E2F1 was increased, but ß-catenin expression was decreased after ICH, and the altered expressions of E2F1 and ß-catenin after ICH were blocked by bpV[pic] treatment. Our results further show that bpV[pic] increases ß-catenin expression through downregulating E2F1 in cortical neurons and prevents hemin-induced neuronal damage through E2F1 downregulation and subsequent upregulation of ß-catenin. By testing the effect of PTEN-siRNA, PTEN cDNA, or combined use of ERK1/2 inhibitor and bpV[pic] in cultured cortical neurons after hemin-induced injury, we provide evidence suggesting that PTEN inhibition by bpV[pic] confers neuroprotection through E2F1 and ß-catenin pathway, but the neuroprotective role of ERK1/2 activation by bpV[pic] cannot be excluded.