Frontiers in cell and developmental biology, Mar 21, 2024
Editorial on the Research Topic Emerging roles of circular RNAs in the tumor: functions and poten... more Editorial on the Research Topic Emerging roles of circular RNAs in the tumor: functions and potential applications-volume II Circular RNA (circRNA), a class of non-coding RNAs without the 3′cap and 5′poly(A) and linked by covalent bonds, has attracted substantial attention in the field of biological research. The surge in interest has led to a collective understanding of circRNA's pivotal roles in physiological development and various diseases (
Editorial on the Research Topic Emerging Roles of Circular RNAs in the Tumor: Functions and Poten... more Editorial on the Research Topic Emerging Roles of Circular RNAs in the Tumor: Functions and Potential Applications Circular RNA (circRNA), which was firstly described in mammals in 1991, has undergone an explosion in studies on its biology resulting in the common understanding of the molecule's role as important players in physiology and pathology/disease developments (Kristensen et al., 2018; Chen and Lu, 2021). CircRNAs are single-stranded RNAs produced by back splicing of exons and/or intron sequences of primary RNA transcripts. Compared to traditional linear RNAs formed by forward splicing, a 3′-5′ covalently closed ring within the circRNAs keeps them stable even without posttranscriptional modification such as the addition of 5′-cap and 3′-poly (A) tails. CircRNAs are classified as four groups based on biogenesis and locations. Exonic circRNAs (EcircRNAs) are produced by back splicing from exon sequence and are predominantly localized in the cytoplasm. Exon-intro circRNAs (EIciRNAs) are circulized with intronic sequences retained between the back-splicing-exons and are localized in the nucleus. Intronic circRNAs (ciRNAs) from intronic lariat RNA precursors are localized in the nucleus as well, while mitochondria-encoded circRNAs (mecciRNAs) are distributed in the mitochondria and the cytoplasm (Chen et al., 2021). CircRNAs have diverse functions including 1) inhibiting miRNA activities by sponging miRNAs, 2) initiating RNA polymerase II (Pol II) to regulate transcription, 3) acting as a protein scaffold and a protein sponge, and 4) encoding proteins by serving as translation templates (Chen et al., 2021). CircRNAs have been accepted as the specific regulators in gene expression rather than erroneous noise during gene transcription. Deregulation of circRNAs may influence proliferative signaling, epithelial-to-mesenchymal transition (EMT), angiogenesis, apoptosis and drug resistance, therefore may have a causative role in cancer development (Kristensen et al., 2018). So far, aberrant expressions of circRNAs have been identified in diverse cancer types and tissues, including basal cell carcinoma (BCC), bladder cancer, breast cancer, ovarian cancer, oral squamous cell carcinomas, esophageal squamous cell carcinoma (ESCC), gastric cancer, colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), lung cancer, cutaneous squamous cell carcinoma, osteosarcoma, glioma, and hematological malignancies (Kristensen et al., 2018). The participation of circRNAs in cancer stemness (Su et al., 2019; Lagunas-Rangel, 2020) and tumor-associated immunology (Tang et al., 2020; Duan et al., 2021) further provided insight into their widespread roles in cancer. Therefore, circRNAs can be used as molecular markers and potential therapeutic targets for the early diagnosis and treatment of tumors. Activating and/or blocking the expression of circRNAs will effectively regulate the growth process of tumors and will provide a new therapeutic strategy.
Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma... more Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling. However, which Notch component(s) is crucial for its activity regulated by TRPM7, and its relationship with other GSC markers, such as CD133 and ALDH1, remain unclear. In the current project, we elucidate the mechanisms of TRMP7’s regulation of Notch signaling pathway that contribute to the development and progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using multiple glioma cell lines (GC) with different molecular subtypes and GSCs derived from the GC lines. 1) We first analyzed TRPM7 expression using the Oncomine database (https://www.o...
We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma ... more We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma stem cells (GSC) growth and proliferation through Notch, STAT3-ALDH1, and CD133 signaling pathways. In this study, we determined the major contributor(s) to TRPM7 mediated glioma stemness by further deciphering each individual Notch signaling. We first determined whether TRPM7 is an oncotarget in glioblastoma multiforme (GBM) using the Oncomine database. Next, we determined whether TRPM7 silencing by siRNA TRPM7 (siTRPM7) induces cell growth arrest or apoptosis to reduce glioma cell proliferation using cell cycle analysis and annexin V staining assay. We then examined the correlations between the expression of TRPM7 and Notch signaling activity as well as the expression of GSC markers CD133 and ALDH1 in GBM by downregulating TRPM7 through siTRPM7 or upregulating TRPM7 through overexpression of human TRPM7 (M7-wt). To distinguish the different function of channel and kinase domain of TRPM...
The interaction between the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface ... more The interaction between the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of parasitized red blood cells (pRBC) and the endothelial cells (EC) receptors during P. falciparum infection results in the sequestration of pRBC from blood circulation. The amount of sequestration is determined by specific interactions among PfEMP1 and several host adhesion receptors, including intercellular adhesion molecule 1 (ICAM-1), CD36, and endothelial protein C receptor (EPCR). PfEMP1 is composed of multiple domains such as the cysteine-rich inter domain region (CIDR) and Duffy binding –like (DBL) domains. CIDRα1 competitively binds to EPCR with activated protein C (APC) and impair cytoprotective and anticoagulant effects by APC, which plays an important role in severe malaria (SM) pathogenesis such as cerebral malaria (CM) and severe malaria anemia (SMA). The strategy to inhibit EPCR binding to pRBC while to concomitantly strengthen its binding to APC may be crucial in restori...
International Journal of Brain Disorders and Treatment, 2018
vous system, heart, breast and other organs. Independent studies described a ligand for the oncog... more vous system, heart, breast and other organs. Independent studies described a ligand for the oncogene ErbB2 (neu, Her2) and factors that stimulated proliferation of Schwann cells, as well as synthesis of receptors for acetylcholine by muscle. These ligands and factors are essentially products of the same gene, referred to by Marchionni M. as neuregulin (NRG-1) [1]. Besides NRG-1 gene, there are other genes that encode related proteins, such as NRG-2 (Don-1, NTAK), NRG-3 and NRG-4. There are few studies that describe NRG-2,-3 and-4 and a complete analysis of their function remains a challenge. However, NRG-2 was recently reported as a component of stress granules (SG), microscopically visible aggregates of translationally stalled messenger ribonucleoprotein complexes that are formed in response to direct stress conditions [2]. Furthermore, it was shown that NRG-2, secreted from astrocytes, bound to ErbB3 on neurons and promoted neuronal survival [3]. NRG-3 was shown to be associated with schizophrenia (SZ) in a Chinese population [4], with bipolar disorder (BD) [5] and with the risk and age of onset of Alzheimer disease (AD) [6]. In addition, NRG-3 has a key function in promoting early mammary morphogenesis and is involved in breast cancer (BC) [7]. NRG-4 expression was decreased in human inflammatory bowel disease samples and mouse models of colitis, suggesting that activation of ErbB4 is altered [8]. An interesting study [9] showed that NRG-4 overexpression prevents high fat diet-induced weight gain and fatty liver and reduces obesity-induced chronic inflammation.
High-glucose (HG) levels and hyperglycemia associated with diabetes are known to cause neuronal d... more High-glucose (HG) levels and hyperglycemia associated with diabetes are known to cause neuronal damage. The detailed molecular mechanisms, however, remain to be elucidated. Here, we investigated the role of transient receptor potential melastatin 7 (TRPM7) channels in HG-mediated endoplasmic reticulum stress (ERS) and injury of NS20Y neuronal cells. The cells were incubated in the absence or presence of HG for 48 h. We found that mRNA and protein levels of TRPM7 and of ERS-associated proteins such as C/EBP homologous protein (CHOP), 78 KDa glucose-regulated protein (GRP78), and inducible nitric oxide synthase (iNOS) increased in HG-treated cells, along with significantly increased TRPM7-associated currents in these cells. Similar results were obtained in cerebral cortical tissue from an insulin-deficiency model of diabetic mice. Moreover, HG treatment of cells activated ERS-associated proapoptotic caspase activity and induced cellular injury. Interestingly, a NOS inhibitor, L-NAME, ...
Cultured neuronal cell lines can express properties of mature neurons if properly differentiated.... more Cultured neuronal cell lines can express properties of mature neurons if properly differentiated. Although the precise mechanisms underlying neuronal differentiation are not fully understood, the expression and activation of ion channels, particularly those of Ca 2+-permeable channels, have been suggested to play a role. In this study, we explored the presence and characterized the properties of acid-sensing ion channels (ASICs) in NS20Y cells, a neuronal cell line previously used for the study of neuronal differentiation. In addition, the potential role of ASICs in cell differentiation was explored. Reverse Transcription Polymerase Chain Reaction and Western blot revealed the presence of ASIC1 subunits in these cells. Fast drops of extracellular pH activated transient inward currents which were blocked, in a dose dependent manner, by amiloride, a non-selective ASIC blocker, and by Psalmotoxin-1 (PcTX1), a specific inhibitor for homomeric ASIC1a and heteromeric ASIC1a/2b channels. Incubation of cells with PcTX1 significantly reduced the differentiation of NS20Y cells induced by cpt-cAMP, as evidenced by decreased neurite length, dendritic complexity, decreased expression of functional voltage gated Na + channels. Consistent with ASIC1a inhibition, ASIC1a knockdown with small interference RNA significantly attenuates cpt-cAMP-induced increase of neurite outgrowth. In summary, we described the presence of functional ASICs in NS20Y cells and demonstrate that ASIC1a plays a role in the differentiation of these cells.
Pathology and Laboratory Medicine International, 2010
To examine whether aberrant DNA methylation in the promoter region might occur earlier in tumorig... more To examine whether aberrant DNA methylation in the promoter region might occur earlier in tumorigenesis, particularly in premalignant lesions, we examined biopsies from 111 participants in a chemoprevention trial aimed at reversal of oral leukoplakia, using methylation-specific polymerase chain reaction for the promoter regions of the tumor suppressor gene CDKN2A (p16), the putative metastasis suppressor gene for death-associated protein kinase (DAP-K), the DNA repair gene O 6-methyguanine-DNA-methyltransferase (MGMT), and the detoxification gene glutathione S-transferase p1(GSTP1). p16 promoter hypermethylation was detected in 21 of 82 (25.6%), DAP-K hypermethylation in 28 of 87 (32.2%), and MGMT hypermethylation in 32 of 106 (30.2%) oral leukoplakia lesions analyzed. No aberrant methylation was found at the GSTP1 gene in 110 lesions examined. Among 68 biopsies analyzed for all three genes (p16, DAP-K, MGMT), 17 biopsies were detected with an abnormal methylation pattern at only one gene, 15 at two genes, and 8 at all three genes. Among clinical characteristics and their correlation with methylation, only alcohol consumption was correlated with DAP-K methylation (P = 0.027), while MGMT methylation was more frequent in females (P = 0.003) and nonsmokers (P = 0.0005). A significant correlation was found between p16 and DAP-K hypermethylation; p16 promoter was methylated in 14 (56%) of 25 lesions with DAP-K methylation, and only 5 (11.1%) of 45 DAP-K methylation-negative lesions (P = 0.0001). DAP-K aberrant methylation was also significantly correlated with MGMT methylation (16 of 31 in MGMT methylation-positive lesions versus 12 of 52 MGMT methylation-negative lesions, P = 0.0016). Our results suggest that epigenetic mechanisms of inactivation, such as aberrant methylation of p16, DAP-K, and MGMT genes, occur early in head and neck tumorigenesis, and might play a role in the progression of these lesions.
32D cells are a murine hemopoietic cell line that undergoes apoptosis upon withdrawal of interleu... more 32D cells are a murine hemopoietic cell line that undergoes apoptosis upon withdrawal of interleukin-3 (IL-3) from the medium. 32D cells have low levels of the type 1 insulin-like growth factor (IGF-I) receptor and do not express insulin receptor substrate-1 (IRS-1) or IRS-2. Ectopic expression of IRS-1 delays apoptosis but cannot rescue 32D cells from IL-3 dependence. In 32D/IRS-1 cells, IRS-1 is detectable, as expected, in the cytosol/ membrane compartment. The SV40 large T antigen is a nuclear protein that, by itself, also fails to protect 32D cells from apoptosis. Co-expression of IRS-1 with the SV40 T antigen in 32D cells results in nuclear translocation of IRS-1 and survival after IL-3 withdrawal. Expression of a human IGF-I receptor in 32D/IRS-1 cells also results in nuclear translocation of IRS-1 and IL-3 independence. The phosphotyrosine-binding domain, but not the pleckstrin domain, is necessary for IRS-1 nuclear translocation. Nuclear translocation of IRS-1 was confirmed in mouse embryo fibroblasts. These results suggest possible new roles for nuclear IRS-1 in IGF-Imediated growth and anti-apoptotic signaling.
Introduction We previously reported that TRPM7 regulates glioma cells’ stemness through STAT3. In... more Introduction We previously reported that TRPM7 regulates glioma cells’ stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1 gene serves as an oncogene to promote glioma proliferation and invasion. Methods In the present study, we determined the effects of FOSL1 on glioma stem cell (GSC) markers CD133 and ALDH1 by flow cytometry, and the maintenance of stem cell activity by extreme limiting dilution assays (ELDA). To further gain insight into the mechanism by which TRPM7 activates transcription of the FOSL1 gene to contribute to glioma stemness, we constructed a FOSL1 promoter and its GAS mutants followed by luciferase reporter assays and ChIP-qPCR in a glioma cell line and glioma patient-derived xenoline. We further examined GSC markers ALDH1 and TRPM7 as well as FOSL1 by immunohistochemistry staining (IHC) in brain tissue microarray (TMA) of glioma patients. Results We revealed that FOSL1 knockdown reduces the expression of GSC...
The American Journal of Tropical Medicine and Hygiene, 2021
ABSTRACT. In malaria endemic countries, anemia in pregnant women occurs as a result of erythrocyt... more ABSTRACT. In malaria endemic countries, anemia in pregnant women occurs as a result of erythrocyte destruction by Plasmodium infections and other causes including malnutrition. Iron supplementation is recommended as treatment of iron-deficiency anemia. Erythrocyte destruction results in increased release of cytotoxic free heme that is scavenged by haptoglobin (Hp), hemopexin (Hx) and heme oxygenase-1 (HO-1). Paradoxically, iron supplementation in pregnant women has been reported to enhance parasitemia and increase levels of free heme. The relationship between free heme, heme scavengers, and birth outcomes has not been investigated, especially in women who are on iron supplementation. We hypothesized that parasite-infected pregnant women on routine iron supplementation have elevated heme and altered expression of heme scavengers. A cross-sectional study was conducted to determine the association between plasma levels of free heme, HO-1, Hp, Hx, and malaria status in pregnant women wh...
Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite... more Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite intensive therapy including surgery, radiation, and chemotherapy, invariable tumor recurrence occurs, which suggests that glioblastoma stem cells (GSCs) render these tumors persistent. Recently, the induction of GSC differentiation has emerged as an alternative method to treat GBM, and most of the current studies aim to convert GSCs to neurons by a combination of transcriptional factors. As the tumor microenvironment is typically acidic due to increased glycolysis and consequently leads to an increased production of lactic acid in tumor cells, in the present study, the role of acid-sensing ion channel 1a (ASIC1a), an acid sensor, was explored as a tumor suppressor in gliomagenesis and stemness. The bioinformatics data from The Cancer Genome Atlas revealed that ASIC1 expression levels in GBM tumor tissues were lower than those in normal brain, and glioma patients with high ASIC1 expression had longer survival than those with low ASIC1 expression. Our immunohistochemistry data from tissue microarray revealed that ASIC1a expression was negatively associated with glioma grading. Functional studies revealed that the downregulation of ASIC1a promoted glioma cell proliferation and invasion, while upregulation of ASIC1a inhibited their proliferation and invasion. Furthermore, ASIC1a suppressed growth and proliferation of glioma cells through G1/S arrest and apoptosis induction. Mechanistically, ASIC1a negatively modulated glioma stemness via inhibition of the Notch signaling pathway and GSC markers CD133 and aldehyde dehydrogenase 1. ASIC1a is a tumor suppressor in gliomagenesis and stemness and may serve as a promising prognostic biomarker and target for GBM patients.
Background: Cerebral malaria (CM) is characterized by the sequestration of Plasmodium-infected er... more Background: Cerebral malaria (CM) is characterized by the sequestration of Plasmodium-infected erythrocytes (pRBCs) to host brain microvasculature beds via P. falciparum erythrocyte membrane protein 1 (PfEMP1). Under normal conditions, activated protein C (APC) bound to endothelial protein C receptor (EPCR) has cytoprotective properties via the activation of protease-activated receptor 1 (PAR1). During malaria infection, pRBCs transports PfEMP1 to the membranes to bind EPCR in the same region as APC. As a result, APC is less capable of inducing cytoprotective effects via PAR1. Two studies involving adult malaria patients revealed that EPCR rs867186-GG allele is associated with protection against severe malaria, while three other studies involving child malaria patients could not show association between EPCR rs867186-GG genotype and severe malaria or increased mortality among children with CM. Methods: We examined the association between the EPCR rs867186-GG genotype and the protection against cerebral malaria. Peripheral blood samples were collected from 47 malaria patients and 34 healthy individuals from a study conducted from 2004 to 2007 at the NSCB Medical College Hospital in India. CM and malaria-associated complications were defined based on WHO criteria. Genomic DNA was isolated from the peripheral blood mononuclear cells. Primer sequences were designed to contain rs867186 of the PROCR gene (NM 006404) and were used to amplify a 660 bp product as described before. PCR products were purified, and DNA sequences were determined by Sanger Sequencing (Genewiz, NJ). Nonparametric tests were used to compare the groups. To analyze differences in allele frequencies, we used chi-squared or Fisher's exact tests for categorical variables if the expected values were less than 5. P-value <0.05 was considered statistically significant. Results: Our results showed significantly higher rates of AG and GG genotypes in CM patients compared to mild malaria (P = 0.0034). Conclusion: Our results indicate that rs867186-GG or rs867186-AG genotypes are not associated with protection against HCM.
Human cerebral malaria (HCM), a severe encephalopathy associated with Plasmodium falciparum infec... more Human cerebral malaria (HCM), a severe encephalopathy associated with Plasmodium falciparum infection, has a 20–30% mortality rate and predominantly affects African children. The mechanisms mediating HCM-associated brain injury are difficult to study in human subjects, highlighting the urgent need for non-invasive ex vivo human models. HCM elevates the systemic levels of free heme, which damages the blood-brain barrier and neurons in distinct regions of the brain. We determined the effects of heme on induced pluripotent stem cells (iPSCs) and a three-dimensional cortical organoid system and assessed apoptosis and differentiation. We evaluated biomarkers associated with heme-induced brain injury, including a pro-inflammatory chemokine, CXCL-10, and its receptor, CXCR3, brain-derived neurotrophic factor (BDNF) and a receptor tyrosine-protein kinase, ERBB4, in the organoids. We then tested the neuroprotective effect of neuregulin-1 (NRG-1) against heme treatment in organoids. Neural st...
Frontiers in cell and developmental biology, Mar 21, 2024
Editorial on the Research Topic Emerging roles of circular RNAs in the tumor: functions and poten... more Editorial on the Research Topic Emerging roles of circular RNAs in the tumor: functions and potential applications-volume II Circular RNA (circRNA), a class of non-coding RNAs without the 3′cap and 5′poly(A) and linked by covalent bonds, has attracted substantial attention in the field of biological research. The surge in interest has led to a collective understanding of circRNA's pivotal roles in physiological development and various diseases (
Editorial on the Research Topic Emerging Roles of Circular RNAs in the Tumor: Functions and Poten... more Editorial on the Research Topic Emerging Roles of Circular RNAs in the Tumor: Functions and Potential Applications Circular RNA (circRNA), which was firstly described in mammals in 1991, has undergone an explosion in studies on its biology resulting in the common understanding of the molecule's role as important players in physiology and pathology/disease developments (Kristensen et al., 2018; Chen and Lu, 2021). CircRNAs are single-stranded RNAs produced by back splicing of exons and/or intron sequences of primary RNA transcripts. Compared to traditional linear RNAs formed by forward splicing, a 3′-5′ covalently closed ring within the circRNAs keeps them stable even without posttranscriptional modification such as the addition of 5′-cap and 3′-poly (A) tails. CircRNAs are classified as four groups based on biogenesis and locations. Exonic circRNAs (EcircRNAs) are produced by back splicing from exon sequence and are predominantly localized in the cytoplasm. Exon-intro circRNAs (EIciRNAs) are circulized with intronic sequences retained between the back-splicing-exons and are localized in the nucleus. Intronic circRNAs (ciRNAs) from intronic lariat RNA precursors are localized in the nucleus as well, while mitochondria-encoded circRNAs (mecciRNAs) are distributed in the mitochondria and the cytoplasm (Chen et al., 2021). CircRNAs have diverse functions including 1) inhibiting miRNA activities by sponging miRNAs, 2) initiating RNA polymerase II (Pol II) to regulate transcription, 3) acting as a protein scaffold and a protein sponge, and 4) encoding proteins by serving as translation templates (Chen et al., 2021). CircRNAs have been accepted as the specific regulators in gene expression rather than erroneous noise during gene transcription. Deregulation of circRNAs may influence proliferative signaling, epithelial-to-mesenchymal transition (EMT), angiogenesis, apoptosis and drug resistance, therefore may have a causative role in cancer development (Kristensen et al., 2018). So far, aberrant expressions of circRNAs have been identified in diverse cancer types and tissues, including basal cell carcinoma (BCC), bladder cancer, breast cancer, ovarian cancer, oral squamous cell carcinomas, esophageal squamous cell carcinoma (ESCC), gastric cancer, colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), lung cancer, cutaneous squamous cell carcinoma, osteosarcoma, glioma, and hematological malignancies (Kristensen et al., 2018). The participation of circRNAs in cancer stemness (Su et al., 2019; Lagunas-Rangel, 2020) and tumor-associated immunology (Tang et al., 2020; Duan et al., 2021) further provided insight into their widespread roles in cancer. Therefore, circRNAs can be used as molecular markers and potential therapeutic targets for the early diagnosis and treatment of tumors. Activating and/or blocking the expression of circRNAs will effectively regulate the growth process of tumors and will provide a new therapeutic strategy.
Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma... more Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling. However, which Notch component(s) is crucial for its activity regulated by TRPM7, and its relationship with other GSC markers, such as CD133 and ALDH1, remain unclear. In the current project, we elucidate the mechanisms of TRMP7’s regulation of Notch signaling pathway that contribute to the development and progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using multiple glioma cell lines (GC) with different molecular subtypes and GSCs derived from the GC lines. 1) We first analyzed TRPM7 expression using the Oncomine database (https://www.o...
We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma ... more We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma stem cells (GSC) growth and proliferation through Notch, STAT3-ALDH1, and CD133 signaling pathways. In this study, we determined the major contributor(s) to TRPM7 mediated glioma stemness by further deciphering each individual Notch signaling. We first determined whether TRPM7 is an oncotarget in glioblastoma multiforme (GBM) using the Oncomine database. Next, we determined whether TRPM7 silencing by siRNA TRPM7 (siTRPM7) induces cell growth arrest or apoptosis to reduce glioma cell proliferation using cell cycle analysis and annexin V staining assay. We then examined the correlations between the expression of TRPM7 and Notch signaling activity as well as the expression of GSC markers CD133 and ALDH1 in GBM by downregulating TRPM7 through siTRPM7 or upregulating TRPM7 through overexpression of human TRPM7 (M7-wt). To distinguish the different function of channel and kinase domain of TRPM...
The interaction between the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface ... more The interaction between the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of parasitized red blood cells (pRBC) and the endothelial cells (EC) receptors during P. falciparum infection results in the sequestration of pRBC from blood circulation. The amount of sequestration is determined by specific interactions among PfEMP1 and several host adhesion receptors, including intercellular adhesion molecule 1 (ICAM-1), CD36, and endothelial protein C receptor (EPCR). PfEMP1 is composed of multiple domains such as the cysteine-rich inter domain region (CIDR) and Duffy binding –like (DBL) domains. CIDRα1 competitively binds to EPCR with activated protein C (APC) and impair cytoprotective and anticoagulant effects by APC, which plays an important role in severe malaria (SM) pathogenesis such as cerebral malaria (CM) and severe malaria anemia (SMA). The strategy to inhibit EPCR binding to pRBC while to concomitantly strengthen its binding to APC may be crucial in restori...
International Journal of Brain Disorders and Treatment, 2018
vous system, heart, breast and other organs. Independent studies described a ligand for the oncog... more vous system, heart, breast and other organs. Independent studies described a ligand for the oncogene ErbB2 (neu, Her2) and factors that stimulated proliferation of Schwann cells, as well as synthesis of receptors for acetylcholine by muscle. These ligands and factors are essentially products of the same gene, referred to by Marchionni M. as neuregulin (NRG-1) [1]. Besides NRG-1 gene, there are other genes that encode related proteins, such as NRG-2 (Don-1, NTAK), NRG-3 and NRG-4. There are few studies that describe NRG-2,-3 and-4 and a complete analysis of their function remains a challenge. However, NRG-2 was recently reported as a component of stress granules (SG), microscopically visible aggregates of translationally stalled messenger ribonucleoprotein complexes that are formed in response to direct stress conditions [2]. Furthermore, it was shown that NRG-2, secreted from astrocytes, bound to ErbB3 on neurons and promoted neuronal survival [3]. NRG-3 was shown to be associated with schizophrenia (SZ) in a Chinese population [4], with bipolar disorder (BD) [5] and with the risk and age of onset of Alzheimer disease (AD) [6]. In addition, NRG-3 has a key function in promoting early mammary morphogenesis and is involved in breast cancer (BC) [7]. NRG-4 expression was decreased in human inflammatory bowel disease samples and mouse models of colitis, suggesting that activation of ErbB4 is altered [8]. An interesting study [9] showed that NRG-4 overexpression prevents high fat diet-induced weight gain and fatty liver and reduces obesity-induced chronic inflammation.
High-glucose (HG) levels and hyperglycemia associated with diabetes are known to cause neuronal d... more High-glucose (HG) levels and hyperglycemia associated with diabetes are known to cause neuronal damage. The detailed molecular mechanisms, however, remain to be elucidated. Here, we investigated the role of transient receptor potential melastatin 7 (TRPM7) channels in HG-mediated endoplasmic reticulum stress (ERS) and injury of NS20Y neuronal cells. The cells were incubated in the absence or presence of HG for 48 h. We found that mRNA and protein levels of TRPM7 and of ERS-associated proteins such as C/EBP homologous protein (CHOP), 78 KDa glucose-regulated protein (GRP78), and inducible nitric oxide synthase (iNOS) increased in HG-treated cells, along with significantly increased TRPM7-associated currents in these cells. Similar results were obtained in cerebral cortical tissue from an insulin-deficiency model of diabetic mice. Moreover, HG treatment of cells activated ERS-associated proapoptotic caspase activity and induced cellular injury. Interestingly, a NOS inhibitor, L-NAME, ...
Cultured neuronal cell lines can express properties of mature neurons if properly differentiated.... more Cultured neuronal cell lines can express properties of mature neurons if properly differentiated. Although the precise mechanisms underlying neuronal differentiation are not fully understood, the expression and activation of ion channels, particularly those of Ca 2+-permeable channels, have been suggested to play a role. In this study, we explored the presence and characterized the properties of acid-sensing ion channels (ASICs) in NS20Y cells, a neuronal cell line previously used for the study of neuronal differentiation. In addition, the potential role of ASICs in cell differentiation was explored. Reverse Transcription Polymerase Chain Reaction and Western blot revealed the presence of ASIC1 subunits in these cells. Fast drops of extracellular pH activated transient inward currents which were blocked, in a dose dependent manner, by amiloride, a non-selective ASIC blocker, and by Psalmotoxin-1 (PcTX1), a specific inhibitor for homomeric ASIC1a and heteromeric ASIC1a/2b channels. Incubation of cells with PcTX1 significantly reduced the differentiation of NS20Y cells induced by cpt-cAMP, as evidenced by decreased neurite length, dendritic complexity, decreased expression of functional voltage gated Na + channels. Consistent with ASIC1a inhibition, ASIC1a knockdown with small interference RNA significantly attenuates cpt-cAMP-induced increase of neurite outgrowth. In summary, we described the presence of functional ASICs in NS20Y cells and demonstrate that ASIC1a plays a role in the differentiation of these cells.
Pathology and Laboratory Medicine International, 2010
To examine whether aberrant DNA methylation in the promoter region might occur earlier in tumorig... more To examine whether aberrant DNA methylation in the promoter region might occur earlier in tumorigenesis, particularly in premalignant lesions, we examined biopsies from 111 participants in a chemoprevention trial aimed at reversal of oral leukoplakia, using methylation-specific polymerase chain reaction for the promoter regions of the tumor suppressor gene CDKN2A (p16), the putative metastasis suppressor gene for death-associated protein kinase (DAP-K), the DNA repair gene O 6-methyguanine-DNA-methyltransferase (MGMT), and the detoxification gene glutathione S-transferase p1(GSTP1). p16 promoter hypermethylation was detected in 21 of 82 (25.6%), DAP-K hypermethylation in 28 of 87 (32.2%), and MGMT hypermethylation in 32 of 106 (30.2%) oral leukoplakia lesions analyzed. No aberrant methylation was found at the GSTP1 gene in 110 lesions examined. Among 68 biopsies analyzed for all three genes (p16, DAP-K, MGMT), 17 biopsies were detected with an abnormal methylation pattern at only one gene, 15 at two genes, and 8 at all three genes. Among clinical characteristics and their correlation with methylation, only alcohol consumption was correlated with DAP-K methylation (P = 0.027), while MGMT methylation was more frequent in females (P = 0.003) and nonsmokers (P = 0.0005). A significant correlation was found between p16 and DAP-K hypermethylation; p16 promoter was methylated in 14 (56%) of 25 lesions with DAP-K methylation, and only 5 (11.1%) of 45 DAP-K methylation-negative lesions (P = 0.0001). DAP-K aberrant methylation was also significantly correlated with MGMT methylation (16 of 31 in MGMT methylation-positive lesions versus 12 of 52 MGMT methylation-negative lesions, P = 0.0016). Our results suggest that epigenetic mechanisms of inactivation, such as aberrant methylation of p16, DAP-K, and MGMT genes, occur early in head and neck tumorigenesis, and might play a role in the progression of these lesions.
32D cells are a murine hemopoietic cell line that undergoes apoptosis upon withdrawal of interleu... more 32D cells are a murine hemopoietic cell line that undergoes apoptosis upon withdrawal of interleukin-3 (IL-3) from the medium. 32D cells have low levels of the type 1 insulin-like growth factor (IGF-I) receptor and do not express insulin receptor substrate-1 (IRS-1) or IRS-2. Ectopic expression of IRS-1 delays apoptosis but cannot rescue 32D cells from IL-3 dependence. In 32D/IRS-1 cells, IRS-1 is detectable, as expected, in the cytosol/ membrane compartment. The SV40 large T antigen is a nuclear protein that, by itself, also fails to protect 32D cells from apoptosis. Co-expression of IRS-1 with the SV40 T antigen in 32D cells results in nuclear translocation of IRS-1 and survival after IL-3 withdrawal. Expression of a human IGF-I receptor in 32D/IRS-1 cells also results in nuclear translocation of IRS-1 and IL-3 independence. The phosphotyrosine-binding domain, but not the pleckstrin domain, is necessary for IRS-1 nuclear translocation. Nuclear translocation of IRS-1 was confirmed in mouse embryo fibroblasts. These results suggest possible new roles for nuclear IRS-1 in IGF-Imediated growth and anti-apoptotic signaling.
Introduction We previously reported that TRPM7 regulates glioma cells’ stemness through STAT3. In... more Introduction We previously reported that TRPM7 regulates glioma cells’ stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1 gene serves as an oncogene to promote glioma proliferation and invasion. Methods In the present study, we determined the effects of FOSL1 on glioma stem cell (GSC) markers CD133 and ALDH1 by flow cytometry, and the maintenance of stem cell activity by extreme limiting dilution assays (ELDA). To further gain insight into the mechanism by which TRPM7 activates transcription of the FOSL1 gene to contribute to glioma stemness, we constructed a FOSL1 promoter and its GAS mutants followed by luciferase reporter assays and ChIP-qPCR in a glioma cell line and glioma patient-derived xenoline. We further examined GSC markers ALDH1 and TRPM7 as well as FOSL1 by immunohistochemistry staining (IHC) in brain tissue microarray (TMA) of glioma patients. Results We revealed that FOSL1 knockdown reduces the expression of GSC...
The American Journal of Tropical Medicine and Hygiene, 2021
ABSTRACT. In malaria endemic countries, anemia in pregnant women occurs as a result of erythrocyt... more ABSTRACT. In malaria endemic countries, anemia in pregnant women occurs as a result of erythrocyte destruction by Plasmodium infections and other causes including malnutrition. Iron supplementation is recommended as treatment of iron-deficiency anemia. Erythrocyte destruction results in increased release of cytotoxic free heme that is scavenged by haptoglobin (Hp), hemopexin (Hx) and heme oxygenase-1 (HO-1). Paradoxically, iron supplementation in pregnant women has been reported to enhance parasitemia and increase levels of free heme. The relationship between free heme, heme scavengers, and birth outcomes has not been investigated, especially in women who are on iron supplementation. We hypothesized that parasite-infected pregnant women on routine iron supplementation have elevated heme and altered expression of heme scavengers. A cross-sectional study was conducted to determine the association between plasma levels of free heme, HO-1, Hp, Hx, and malaria status in pregnant women wh...
Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite... more Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite intensive therapy including surgery, radiation, and chemotherapy, invariable tumor recurrence occurs, which suggests that glioblastoma stem cells (GSCs) render these tumors persistent. Recently, the induction of GSC differentiation has emerged as an alternative method to treat GBM, and most of the current studies aim to convert GSCs to neurons by a combination of transcriptional factors. As the tumor microenvironment is typically acidic due to increased glycolysis and consequently leads to an increased production of lactic acid in tumor cells, in the present study, the role of acid-sensing ion channel 1a (ASIC1a), an acid sensor, was explored as a tumor suppressor in gliomagenesis and stemness. The bioinformatics data from The Cancer Genome Atlas revealed that ASIC1 expression levels in GBM tumor tissues were lower than those in normal brain, and glioma patients with high ASIC1 expression had longer survival than those with low ASIC1 expression. Our immunohistochemistry data from tissue microarray revealed that ASIC1a expression was negatively associated with glioma grading. Functional studies revealed that the downregulation of ASIC1a promoted glioma cell proliferation and invasion, while upregulation of ASIC1a inhibited their proliferation and invasion. Furthermore, ASIC1a suppressed growth and proliferation of glioma cells through G1/S arrest and apoptosis induction. Mechanistically, ASIC1a negatively modulated glioma stemness via inhibition of the Notch signaling pathway and GSC markers CD133 and aldehyde dehydrogenase 1. ASIC1a is a tumor suppressor in gliomagenesis and stemness and may serve as a promising prognostic biomarker and target for GBM patients.
Background: Cerebral malaria (CM) is characterized by the sequestration of Plasmodium-infected er... more Background: Cerebral malaria (CM) is characterized by the sequestration of Plasmodium-infected erythrocytes (pRBCs) to host brain microvasculature beds via P. falciparum erythrocyte membrane protein 1 (PfEMP1). Under normal conditions, activated protein C (APC) bound to endothelial protein C receptor (EPCR) has cytoprotective properties via the activation of protease-activated receptor 1 (PAR1). During malaria infection, pRBCs transports PfEMP1 to the membranes to bind EPCR in the same region as APC. As a result, APC is less capable of inducing cytoprotective effects via PAR1. Two studies involving adult malaria patients revealed that EPCR rs867186-GG allele is associated with protection against severe malaria, while three other studies involving child malaria patients could not show association between EPCR rs867186-GG genotype and severe malaria or increased mortality among children with CM. Methods: We examined the association between the EPCR rs867186-GG genotype and the protection against cerebral malaria. Peripheral blood samples were collected from 47 malaria patients and 34 healthy individuals from a study conducted from 2004 to 2007 at the NSCB Medical College Hospital in India. CM and malaria-associated complications were defined based on WHO criteria. Genomic DNA was isolated from the peripheral blood mononuclear cells. Primer sequences were designed to contain rs867186 of the PROCR gene (NM 006404) and were used to amplify a 660 bp product as described before. PCR products were purified, and DNA sequences were determined by Sanger Sequencing (Genewiz, NJ). Nonparametric tests were used to compare the groups. To analyze differences in allele frequencies, we used chi-squared or Fisher's exact tests for categorical variables if the expected values were less than 5. P-value <0.05 was considered statistically significant. Results: Our results showed significantly higher rates of AG and GG genotypes in CM patients compared to mild malaria (P = 0.0034). Conclusion: Our results indicate that rs867186-GG or rs867186-AG genotypes are not associated with protection against HCM.
Human cerebral malaria (HCM), a severe encephalopathy associated with Plasmodium falciparum infec... more Human cerebral malaria (HCM), a severe encephalopathy associated with Plasmodium falciparum infection, has a 20–30% mortality rate and predominantly affects African children. The mechanisms mediating HCM-associated brain injury are difficult to study in human subjects, highlighting the urgent need for non-invasive ex vivo human models. HCM elevates the systemic levels of free heme, which damages the blood-brain barrier and neurons in distinct regions of the brain. We determined the effects of heme on induced pluripotent stem cells (iPSCs) and a three-dimensional cortical organoid system and assessed apoptosis and differentiation. We evaluated biomarkers associated with heme-induced brain injury, including a pro-inflammatory chemokine, CXCL-10, and its receptor, CXCR3, brain-derived neurotrophic factor (BDNF) and a receptor tyrosine-protein kinase, ERBB4, in the organoids. We then tested the neuroprotective effect of neuregulin-1 (NRG-1) against heme treatment in organoids. Neural st...
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Papers by Mingli Liu