Psychosis susceptibility zinc finger protein 804A (ZNF804A) gene polymorphism in schizophrenia patients treated with olanzapine in North Indian population.

PURPOSE: The Zinc finger protein 804A (ZNF804A) is a potential schizophrenia candidate gene that has emerged from genome-wide association studies. The aim of the study is to investigate whether this gene variant influences the response of positive or negative symptoms to antipsychotic drug olanzapine in North Indian schizophrenia patients. MATERIALS AND METHODS: Our study involved 184 unrelated schizophrenia cases (114 males and 70 females; mean age: 52.8 ± 11.6 years) and 300 normal controls (168 males and 132 females; mean age: 54.9 ± 6.9 years). At the start of treatment and after four weeks, we assessed the response of positive and negative symptoms by positive and negative syndrome scale (PANSS). Olanzapine drug level was estimated using HPLC Method and Genotyping was performed using PCR-Snap Shot technique. RESULTS: Significant differences were observed in the genotype distribution (χ2 = 6.10, d.f. = 2, p = 0.04) and allele frequencies (χ2 = 5.14, d.f. = 1, p = 0.02; odds ratio = 0.57, 95% confidence interval =1.09-3.48) between schizophrenia patients and controls group. The improvement of positive and negative schizophrenia symptoms after 4 weeks of treatment with olanzapine was assessed. Patients homozygous for the ZNF804A risk allele for AA show poorer improvement of positive symptoms compared to patients with a protective allele. CONCLUSIONS: Our findings indicate that ZNF804A gene polymorphism plays a significant role in the treatment of schizophrenia, suggesting that ZNF804A may be an effective marker for schizophrenia treatment.

Downregulated KLF2 in polycythemia vera and essential thrombocythemia induces prothrombotic gene expression.

Thromboses are major causes of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET) diseases associated with JAK2V617F mutation. However, the molecular mechanism(s) of increased thrombosis in PV and ET remain unknown. Kruppel-like factor 2 (KLF2) is a transcription factor that regulates expression of genes associated with inflammation and thrombosis; the absence of KLF2 in neutrophils causes thrombosis by inducing tissue factor. We studied the role of KLF2 in regulating prothrombotic gene expression in PV and ET. Neutrophils and platelets KLF2 expression in PV and ET was lower than the controls. Furthermore, in patients with thromboses, KLF2 transcripts were lower in platelets than those without thromboses. JAK2V617F allelic burden was inversely correlated with KLF2 transcript levels, suggesting JAK-STAT pathway may downregulate KLF2 expression. Whole transcriptome analyses of neutrophils and platelets showed that a lower KLF2 expression was associated with an upregulation of KLF2-regulated thrombotic genes. In addition, low KLF2 expression in platelets positively correlated with thrombotic events. In patients with PV and ET, KLF2 expression was induced by pegylated interferon alfa (PegINF-α) but not by hydroxyurea treatments. These data suggest that KLF2 may be a regulator of PV and ET thrombosis and a novel therapeutic target to prevent thrombosis.

SHIP-1 affects herpetic simplex keratitis prognosis by mediating CD4+ T lymphocytes migration through PI3K signaling and transcription factor KLF2 in the cornea.

Herpetic simplex keratitis (HSK) mainly represents an immune cell-mediated, and more specifically, CD4+ T cell-orchestrated inflammatory response to virus invasion. The virus in infected corneas could be easily inhibited or hidden in the trigeminal ganglion using antiviral drugs, but the immune-related inflammation will last for a long time and lead to significant complications. In the present study, we found that the subconjunctival injection of SHIP-1 activator AQX1125 in mouse HSK model alleviated the corneal inflammatory and angiogenic responses, as well as promoted quicker recovery of the cornea, with significantly fewer infiltration of CD4+ T lymphocytes. Furthermore, using primary CD4+ T lymphocytes, we observed that by modulating PI3K signaling and the expression of transcription factors KLF2 and CCR7, SHIP-1 could significantly influence the migration of lymphocytes toward CCL19 and 21, which are the "exit cues" for cells to emigrate from inflammatory sites. Thus, we propose that the pharmacological SHIP-1 activation represents a new potential therapeutic approach to control HSK lesions, and its function on the CCR7-CCL19/21 biological axis may be a novel underlying mechanism for its anti-inflammatory action.

Fraxinellone ameliorates intracerebral hemorrhage-induced secondary brain injury by regulating Krüppel-like transcription factor 2 expression in rats.

Damage to the blood-brain barrier (BBB) is an important factor leading to intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Krüppel-like transcription factor 2 (KLF2) plays an important role in the maintenance of the BBB. This study aims to detect the changes of KLF2 after ICH and evaluate the potential effects of fraxinellone on ICH-induced SBI and its correlation with KLF2. An ICH model was established by injecting autologous blood into the right basal ganglia of Sprague-Dawley (SD) rats. First, after ICH induction, the protein levels of KLF2 were reduced. Then, we found that the decrease of KLF2 protein levels induced by ICH could be effectively reversed with the treatment of fraxinellone in vascular endothelial cells. Furthermore, fraxinellone treatment effectively alleviated brain edema, decreased the levels of TNF-α and IL-1ß, and improved neuronal cell degeneration induced by ICH. Meanwhile, fraxinellone ameliorated neurobehavioral disorders, motor and sensory impairments, and neurobehavioral disorders and memory loss caused by ICH. Collectively, these findings reveal that KLF2 may be a potential target for fraxinellone to exert neuroprotective effects after ICH, and fraxinellone could be a potential therapeutic agent for SBI after ICH.

Downregulated PEG3 ameliorates cardiac fibrosis and myocardial injury in mice with ischemia/reperfusion through the NF-κB signaling pathway.

Expression of paternally-expressed gene 3 (PEG3) has been identified in new cardiac adult stem cell population, which is involved in post-myocardial infarction remodeling. The cardiac fibroblasts function in the repair and remodeling events after myocardial ischemia, while the role of PEG3 in these events has not been investigated yet. In this study, artificial knockdown of PEG3 through p-LV-GFP-sh-PEG3 injection was performed in a ischemia/reperfusion (I/R) mouse model to explore the role of PEG3 in cardiac fibrosis, myocardial injury and cardiomyocyte apoptosis. Besides, the involvement of nuclear factor kappa B (NF-κB) pathway was illuminated by transduction of inhibitor pyrrolidine dithiocarbamate (PDTC). Both shRNA-mediated silencing of PEG3 and inhibition of the NF-κB signaling pathway were shown to significantly reduce myocardial injury, infarction size, alleviated myocardium remodeling and cardiac fibrosis, along with repressed cardiomyocyte apoptosis. Additionally, we also found that the NF-κB signaling pathway activation was blocked by PEG3 silencing, which could further enhance the protective effects of PEG3 inhibition against I/R induced injury. This study highlights the importance of PEG3 silencing in preventing cardiac fibrosis and myocardial injury after I/R by inactivating the NF-κB signaling pathway.

Vascular protective effects of KLF2 on Aß-induced toxicity: Implications for Alzheimer's disease.

Alzheimer's disease (AD) is characterized by excessive amounts of senile plaques and neurofibrillary tangles in the brain, and cerebrovascular pathologies in AD are attracting increasingly more attention. Krüppel-like factor (KLF) 2, a transcription regulator expressed in the mouse embryonic vasculature and involved in the regulation of vascular gene expression, serves as a protective factor in endothelial cells. However, whether KLF2 is involved in neurodegenerative disease, and especially in AD, remains unknown. In the present study, the effects of KLF2 in Aß-induced neurotoxicity were investigated. Firstly, we found that KLF2 expression decreased at both the RNA and protein levels in AD cases. The following results show that KLF2 was found to be decreased in both a time- and dose-dependent manner in response to Aß1-42 treatment in primary mouse brain microvascular endothelial cells. Overexpression of KLF2 attenuated Aß-induced oxidative stress, improved mitochondrial function, and reduced the rate of apoptosis. Furthermore, inhibition of KLF2 promoted Aß1-42-induced oxidative stress, exacerbated mitochondrial dysfunction, and increased the rate of apoptosis. Our data imply that the promotion of KLF2 expression in cerebral endothelial cells has the potential to be developed as a novel therapeutic strategy for the treatment of cerebral vascular dysfunction in AD.

Sciatic nerve regeneration in KLF7-transfected acellular nerve allografts.

OBJECTIVE: Krüppel-like Factor 7 (KLF7) is a transcription factor that promotes axon regeneration in the central nervous system. Here, we assessed whether KLF7 stimulates regeneration after peripheral nerve injury. METHODS: C57BL/6 mice received an acellular nerve allograft (ANA) injected with either adeno-associated virus 2 (AAV2) vector or AAV2-KLF7 for sciatic nerve gap repair. After 4 weeks, KLF7 was detected by RT-PCR, western blot and immunohistochemistry in regenerated nerves. Axonal regeneration and functional recovery were examined by immunohistochemistry, Fluorogold (FG) and cholera toxin B (CTB) retrograde neural tracing, sciatic function index (SFI), angle of ankle, Hargreaves test and electrophysiological analysis. RESULTS: With AAV2-KLF7 injection, KLF7 expression increased in regenerated nerves, and amplitude, score of SFI, angle of ankle and FG-labelled spinal cord neurons were increased. We observed elevated CTB-labelled neurons in dorsal root ganglia (DRG), neurofilaments, P0 (peripheral myelin) and S100 and decreased latency period and withdrawal latencies in the Hargreaves test. The SFI was significantly correlated with amplitude and regenerated axon number. Tyrosine kinase A (TrkA) and B (TrkB) receptors were also increased in the DRG. CONCLUSIONS: Our findings suggest that KLF7 promoted peripheral nerve axonal regeneration, further supporting a role for KLF7 as a growth-promoting transcription factor in the injured nervous system.

Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway / La simvastatina inhibe el microambiente proangiogénico de las células estelares del hígado a través de la vía del factor similar a Kruppel 2

BACKGROUND AND AIMS: Statins are reported to have a beneficial effect on portal hypertension (PTH); however, the exact mechanism remains unknown. Hepatic stellate cells (HSCs) can be activated by transforming growth factor beta (TGFβ) and play an important role in angiogenesis leading to PTH. Statins potently stimulate the transcription factor, Kruppel-like factor 2 (KLF2), which can negatively regulate angiogenesis. Our present study aimed to investigate the anti-angiogenic potential of statins in HSCs through the KLF2 pathway. METHOD: TGFβ-induced human HSCs were exposed to simvastatin. Cell viability and proliferation were determined by MTT and BrdU-proliferation assays, respectively. Cell migration was investigated using a transwell and wound-healing assays. Gene quantification was measured by real-time polymerase chain reaction. Protein expression was detected by western blot analysis and immunohistochemistry. Inflammatory factors were measured using enzyme-linked immunosorbent assays. RESULT: Simvastatin was found to reduced cell migration and proliferation and inhibit expression of alpha smooth muscle actin in TGFβ-induced HSCs. Furthermore, simvastatin promoted already increased mRNA and protein levels of KLF2 in TGFβ-induced HSCs. In accordance with KLF2 overexpression, simvastatin increased production of endothelial nitric oxide synthesis (eNOS) and downregulated expression of some proangiogenic proteins, such as vascular endothelial growth factor, hypoxia inducible factor-1a and nuclear factor-kappa B in TGFβ-induced HSCs. At the same time, secretion of interferon-gamma increased in TGFβ induced HSCs, which was decreased by simultaneous addition of simvastatin. CONCLUSION: Simvastatin suppressed the proangiogenic environment of HSCs activated by TGFβ, and KLF2 pathway is involved in the course

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TIMP-1 regulates cell proliferation by interacting with the ninth zinc finger domain of PLZF.

The tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that specifically inhibit matrix metalloproteinases (MMPs) and regulate extracellular matrix (ECM) turnover and tissue remodeling. This is directed by forming tightly bound inhibitory complexes with MMPs. Recent years have revealed important differences of various biological activities between TIMP families but molecular mechanisms are not clear. To define the molecular mechanisms of TIMP-1-dependent biological processes, we used TIMP-1 as bait in a yeast two-hybrid screen, along with a human ovary cDNA library. Further characterization revealed the ninth zinc finger domain as an interacting domain of the promyelocytic leukemia zinc finger protein (PLZF). Interaction of PLZF with TIMP-1 in mammalian cells was also confirmed by co-immunoprecipitation and with in vitro binding assays. We investigated whether TIMP-1-mediated anti-apoptotic activity could promote the growth of ovarian cancer in an experimental model system. TIMP-1 treatment was found to be more effective at increasing ovarian cancer growth when compared with PLZF in parallel experiments. Subsequently, the efficacy of a combined treatment with TIMP-1 and PLZF was investigated. In the presence of both of these proteins, TIMP-1 significantly reduced apoptosis induced by PLZF in cervical carcinoma cells. These combined results indicate that TIMP-1 functions as an anti-activator of the transcriptional repressive activity of PLZF.