Targeting altered calcium homeostasis and uncoupling protein-2 promotes sensitivity in drug-resistant breast cancer cells.

Metastatic breast cancer has the highest mortality rate among women owing to its poor clinical outcomes. Metastatic tumors pose challenges for treatment through conventional surgery or radiotherapy because of their diverse organ localization and resistance to various cytotoxic agents. Chemoresistance is a significant obstacle to effective breast cancer treatment owing to cancer's heterogeneous nature. Abnormalities in intracellular calcium signaling, coupled with altered mitochondrial metabolism, play a significant role in facilitating drug resistance and contribute to therapy resistance. Uncoupling protein-2 (UCP2) is considered as a marker of chemoresistance and is believed to play a major role in promoting metabolic shifts and tumor metastasis. In this context, it is imperative to understand the roles of altered calcium signaling and metabolic switching in the development of chemotherapeutic resistance. This study investigates the roles of UCP2 and intracellular calcium signaling (Ca2+ ) in promoting chemoresistance against cisplatin. Additionally, we explored the effectiveness of combining genipin (GP, a compound that reverses UCP2-mediated chemoresistance) and thapsigargin (TG, a calcium signaling modulator) in treating highly metastatic breast cancers. Our findings indicate that both aberrant Ca2+ signaling and metabolic shifts in cancer cells contribute to developing drug-resistant phenotypes, and the combination treatment of GP and TG significantly enhances drug sensitivity in these cells. Collectively, our study underscores the potential of these drug combinations as an effective approach to overcome drug resistance in chemoresistant cancers.

CD36 and GPR120 mediated orogustatory perception of dietary lipids and its physiological implication in the pygmy mouse Mus booduga.

Fat taste perception has long been concerned in the regulation of dietary fat intake. Substantial experimental evidence defends fat as a sixth taste modality, but its allied peripheral mechanisms are not yet well established. The present study aimed to analyse the diet-induced changes in fat taste perception and its associated physiological variations in Mus booduga. Four groups of animals were used for the present study and were fed any one of the following diet; normal diet (10% fat), low-fat diet (4% fat), high-fat diet (36% fat), or high-fat diet (HFD) (36% fat) + rapeseed oil (HFRDO) (14%) for 9 weeks. The animals were then subjected to metabolic tolerance, fat preference, and conditioned taste aversion studies. Diet-induced alterations in the expression of genes associated with lipogenesis, inflammation, and fat taste (CD36 and GPR120) were analysed. Capacitative calcium signalling induced by both linoleic acid and grifolic acid in taste bud cells (TBCs) was also analysed. In result, both the HFD and HFDRO groups revealed deterioration in glucose homoeostasis and displayed decreased preference scores for fatty acids, which are associated with lower CD36 expression and increased GPR120 expression in TBCs. Furthermore, change in [Ca2+ ]i induced by LA was also compromised in CD36 positive TBCs along with elevated systemic inflammatory and lipidemic responses in both these obese groups. Overall, for the first time, our results support that chronic HFD feeding alters the CD36 and GPR120 mediated fat taste perception in M. booduga.

A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders.

The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.

Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia.

The comprehensive genetic alterations underlying the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5, and targeted pharmacologic inhibition of STAT5 with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia.

Regulation of airway and alveolar epithelial cell apoptosis by p53-Induced plasminogen activator inhibitor-1 during cigarette smoke exposure injury.

Increased expression of tumor suppressor protein p53 and of plasminogen activator inhibitor (PAI)-1 is associated with cigarette smoke (CS) exposure-induced lung epithelial injury. p53 induces PAI-1 through mRNA stabilization in lung epithelial cells. However, it is unclear how this process affects lung epithelial damage. Here, we show that CS induces p53 and PAI-1 expression and apoptosis in cultured Beas2B and primary alveolar type (AT)II cells. CS exposure augmented binding of p53 protein with PAI-1 mRNA. Inhibition of p53 from binding to PAI-1 mRNA through expression of p53-binding 70 nt PAI-1 mRNA 3'UTR sequences suppressed CS-induced PAI-1 expression. Treatment of Beas2B cells with caveolin-1 scaffolding domain peptide (CSP) suppressed p53 expression and p53-PAI-1 mRNA interaction. These changes were associated with parallel inhibition of CS-induced PAI-1 expression and apoptosis in Beas2B cells. Wild-type mice exposed to passive CS likewise show augmented p53 and PAI-1 with parallel induction of ATII cell apoptosis, whereas mice deficient for p53 or PAI-1 expression resisted apoptosis of ATII cells. CSP suppressed CS-induced ATII cell apoptosis in wild-type mice and abrogated p53-PAI-1 mRNA interaction with parallel inhibition of p53 and PAI-1 expression. The protection against ATII cell apoptosis by CSP involves inhibition of passive CS-induced proapoptotic Bax and Bak expression and restoration of the prosurvival proteins Bcl-X(L). These observations demonstrate that inhibition of p53 binding to PAI-1 mRNA 3'UTR attenuates CS-induced ATII cell apoptosis. This presents a novel link between p53-mediated PAI-1 expression and CS-induced ATII cell apoptosis.

Genetic variation in sweet taste receptors and a mechanistic perspective on sweet and fat taste sensation in the context of obesity.

Taste sensation enables humans to make nutritionally important decisions such as food preference and consumption. It functions as deterministic factors for unpropitious eating behavior, leading to overweight and obesity. The hedonistic feeling on consumption of fat and sugar-rich meals, in particular, has a negative influence on health. In addition, impairment in the taste receptors alters the downstream signaling of taste transduction pathway. Hence, genetic polymorphism in typical taste receptors is a predictor of taste sensitivity variance across individuals. The present review summarizes the effect of a single nucleotide polymorphism (SNP) in sweet taste receptors (T1R2/T1R3) on taste perception among individuals of various body mass index (BMI). Furthermore, in the context of obesity, we discussed the possibility of crosstalk between fat and sweet receptors as well as taste dysfunction in diseased individuals. In overall, a greater understanding of the physiological relationship between taste receptors, altered taste sensitivity, and genetic polymorphisms should lead to more effective obesity prevention approaches.

Development of optimized novel liposome loaded with 6-gingerol and assessment of its therapeutic activity against NSCLC In vitro and In vivo experimental models.

6-Gingerol (Gn) is an active compound derived from ginger which possesses various biological activities. The therapeutic applications of Gn are limited due to its hydrophobic nature. To ease its administration, one of the nano-emulsion methods, liposome was selected to encapsulate Gn. Response Surface Methodology (RSM) was used to optimize liposome ratio. 97.2% entrapment efficiency was achieved at the ratio of 1:20:2 (Drug: Lipid: Cholesterol). The optimized liposome attained size below 200 d nm, spherical shape, negative surface charge and showed sustain release upon physical characterization methods such as FESEM, DLS, Zeta potential, Drug release. The signature FTIR peaks of both free Gn and free liposome (FL) were also observed in Lipo-Gn peak. Lipo-Gn showed significant cytotoxic effect on A549 cells (IC50 160.5 ± 0.74 µM/ml) as well as inhibits the cell migration. DAPI staining showed higher apoptotic nuclear morphological change in the cells treated with Lipo-Gn, and also Lipo-Gn increased the apoptotic percentage in A549 as 39.89 and 70.32 for 12 and 24 h respectively which were significantly more than free Gn. Moreover, the formulation of Lipo-Gn showed significant cell cycle arrest at the G2/M phase compared with free Gn (28.9% and 34.9% in Free Gn vs. 42.7% and 50.1% in Lipo -Gn for 12 and 24 h respectively). Lipo-Gn have been assessed in NSCLC induced BALB/c mice and showed significantly improved pharmacological properties compared to those of free Gn. Thus, Lipo-Gn may be considered for its widening applications against lung cancer.

Induction of tissue factor by urokinase in lung epithelial cells and in the lungs.

RATIONALE: Urokinase-type plasminogen activator (uPA) regulates extracellular proteolysis in lung injury and repair. Although alveolar expression of uPA increases, procoagulant activity predominates. OBJECTIVES: This study was designed to investigate whether uPA alters the expression of tissue factor (TF), the major initiator of the coagulation cascade, in lung epithelial cells (ECs). METHODS: Bronchial, primary airway ECs and C57B6 wild-type, uPA-deficient (uPA(-/-)) mice were exposed to phosphate-buffered saline, uPA, or LPS. Immunohistochemistry, protein, cellular, and molecular techniques were used to assess TF expression and activity. MEASUREMENTS AND MAIN RESULTS: uPA enhanced TF mRNA and protein expression, and TF-dependent coagulation in lung ECs. uPA-induced expression of TF involves both increased synthesis and enhanced stabilization of TF mRNA. uPA catalytic activity had little effect on induction of TF. By contrast, deletion of the uPA receptor binding growth factor domain from uPA markedly attenuated the induction of TF, suggesting that uPA receptor binding is sufficient for TF induction. Lung tissues of uPA-deficient mice expressed less TF protein and mRNA compared with wild-type mice. In addition, intratracheal instillation of mouse uPA increased TF mRNA and protein expression and accelerated coagulation in lung tissues. uPA(-/-) mice exposed to LPS failed to induce TF. CONCLUSIONS: uPA increased TF expression and TF-dependent coagulation in the lungs of mice. We hypothesize that uPA-mediated induction of TF occurs in lung ECs to promote increased fibrin deposition in the airways during acute lung injury.

Anti-Obesity Effect of T. Chebula Fruit Extract on High Fat Diet Induced Obese Mice: A Possible Alternative Therapy.

Occurrence of obesity and its associated metabolic disorders continues to escalate. The present study evaluates the anti-obesity effects of ethanolic fruit extract of Terminalia chebula (EETC) on high fat diet induced obese mice. The bioactive compounds present in the EETC is evaluated by Fourier-transform infrared (FT-IR), Gas chromatography-mass spectrometry (GC-MS), and Liquid chromatography-mass spectrometry (LC-MS) analysis. The effects of EETC on energy intake, glucose tolerance, and various biochemical parameters were analyzed using laboratory mice. Relative gene expression of Fatty acid synthase (FAS), Peroxisome proliferator-activated receptors α (PPARα), Carnitine palmitoyltransferase-1 (CPT-1), Tumor necrosis factor alpha (TNF-α) as well as Interleukin 6 (IL-6) were analyzed in liver and adipose tissues. The findings reveal the hypolipidemic and anti-obesity potential of EETC on high fat fed obese mice. EETC exerts its anti-obesity effects by suppressing lipogenesis through reduction in lipogenic enzyme (FAS) expression, increased fatty acid oxidation via PPARα and CPT-1 and by triggering the anti-inflammatory responses. To our knowledge, this is the first report of the effect of EETC on PPARα and CPT-1 in in vivo.

Post-transcriptional regulation of plasminogen activator inhibitor type-1 expression in human pleural mesothelial cells.

The plasminogen activator inhibitor type-1 (PAI-1) effectively blocks the activities of free and receptor-bound urokinase-type plasminogen activator. Incubation of cultured human pleural mesothelial (Met5A) cells with TGF-beta increased PAI-1 protein. TGF-beta, phorbol myristate acetate, and the translation inhibitor cycloheximide induced PAI-1 mRNA and slowed its degradation, suggesting that PAI-1 mRNA could be regulated by interaction of a PAI-1 binding protein (PAI-1 mRNABp) with PAI-1 mRNA. We found that an approximately 60 kD cytoplasmic PAI-1 mRNABp is detectable in cytoplasmic extracts of MeT5A human pleural mesothelial and malignant mesothelioma cells. The PAI-1 mRNABp specifically binds to a 33-nt sequence in the 3' untranslated region of PAI-1 mRNA. Insertion of this 33-nt sequence destabilizes otherwise stable beta-globin mRNA, indicating that the binding sequence accelerates decay of endogenous PAI-1 mRNA. Competitive inhibition by overexpression of the 33-nt binding sequence in MeT5A cells reduced PAI-1 mRNA decay and increased PAI-1 protein and mRNA expression, indicating that the PAI-1 mRNABp destabilizes PAI-1 mRNA by its interaction with the endogenous 33-nt binding sequence. Incubation of Met5A cells with TGF-beta attenuated the interaction of the PAI-1 mRNABp with the 33-nt sequence. By conventional and affinity purification, we isolated the PAI-1 mRNABp and confirmed its identity as 6-phospho-d-gluconate-NADP oxidoreductase, which specifically interacts with the full-length and the 33-nt sequence of the PAI-1 mRNA 3' untranslated region. This newly recognized pathway could influence expression of PAI-1 by mesothelial or mesothelioma cells at the level of mRNA stability in the context of pleural inflammation or malignancy.

Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase.

The interaction of urokinase-type plasminogen activator (uPA) with its receptor, uPAR, plays a central role in several pathophysiological processes, including cancer. uPA induces its own cell surface receptor expression through stabilization of uPAR mRNA. The mechanism involves binding of a 51 nt uPAR mRNA coding sequence with phosphoglycerate kinase (PGK) to down regulate cell surface uPAR expression. Tyrosine phosphorylation of PGK mediated by uPA treatment enhances uPAR mRNA stabilization. In contrast, inhibition of tyrosine phosphorylation augments PGK binding to uPAR mRNA and attenuates uPA-induced uPAR expression. Mapping the specific peptide region of PGK indicated that its first quarter (amino acids 1-100) interacts with uPAR mRNA. To determine if uPAR expression by uPA is regulated through activation of tyrosine residues of PGK, we mutated the specific tyrosine residue and tested mutant PGK for its ability to interfere with uPAR expression. Inhibition of tyrosine phosphorylation by mutating Y76 residue abolished uPAR expression induced by uPA treatment. These findings collectively demonstrate that Y76 residue present in the first quarter of the PGK molecule is involved in lung epithelial cell surface uPAR expression. This region can effectively mimic the function of a whole PGK molecule in inhibiting tumor cell growth.

Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA.

We found that p53-deficient (p53(-/-)) lung carcinoma (H1299) cells express robust levels of cell surface uPAR and uPAR mRNA. Expression of p53 protein in p53(-/-) cells suppressed basal and urokinase (uPA)-induced cell surface uPAR protein and increased uPAR mRNA degradation. Inhibition of p53 by RNA silencing in Beas2B human airway epithelial cells conversely increased basal as well as uPA-mediated uPAR expression and stabilized uPAR mRNA. Purified p53 protein specifically binds to the uPAR mRNA 3' untranslated region (3'UTR), and endogenous uPAR mRNA associates with p53. The p53 binding region involves a 37-nucleotide uPAR 3'UTR sequence, and insertion of the p53 binding sequence into beta-globin mRNA destabilized beta-globin mRNA. Inhibition of p53 expression in these cells reverses decay of chimeric beta-globin-uPAR mRNA. These observations demonstrate a novel regulatory role for p53 as a uPAR mRNA binding protein that down-regulates uPAR expression, destabilizes uPAR mRNA, and thereby contributes to the viability of human airway epithelial or lung carcinoma cells.

Post-transcriptional regulation of urokinase-type plasminogen activator receptor expression in lipopolysaccharide-induced acute lung injury.

RATIONALE: Urokinase-type plasminogen activator (uPA) receptor (uPAR) is required for the recruitment of neutrophils in response to infection. uPA induces its own expression in lung epithelial cells, which involves its interaction with cell surface uPAR. Regulation of uPAR expression is therefore crucial for uPA-mediated signaling in infectious acute lung injury (ALI). OBJECTIVES: To determine the role of uPA in uPAR expression during ALI caused by sepsis. METHODS: We used Western blot, Northern blot, Northwestern assay, and immunohistochemistry. Phosphate-buffered saline- and lipopolysaccharide (LPS)-treated wild-type and uPA(-/-) mice were used. MEASUREMENTS AND MAIN RESULTS: Biological activities of uPA, including proteolysis, cell adhesion, migration, proliferation, and differentiation, are dependent on its association with uPAR. Bacterial endotoxin (LPS) is a major cause of pulmonary dysfunction and infection-associated mortality. The present study shows that LPS induces uPAR expression both in vitro and in vivo, and that the mechanism involves post-transcriptional stabilization of uPAR mRNA by reciprocal interaction of phosphoglycerate kinase (PGK) and heterogeneous nuclear ribonucleoprotein C (hnRNPC) with uPAR mRNA coding region and 3' untranslated region determinants, respectively. The process involves tyrosine phosphorylation of PGK and hnRNPC. uPA(-/-) mice failed to induce uPAR expression after LPS treatment. In these mice, LPS treatment failed to alter the binding of PGK and hnRNPC protein with uPAR mRNA due to lack of tyrosine phosphorylation. CONCLUSIONS: Our study shows that induction of LPS-mediated uPAR expression is mediated through tyrosine phosphorylation of PGK and hnRNPC. This involves expression of uPA as an obligate intermediary.

RNA sequencing analyses reveal differentially expressed genes and pathways as Notch2 targets in B-cell lymphoma.

Splenic marginal zone lymphoma (SMZL) is a low grade, indolent B-cell neoplasm that comprises approximately 10% of all lymphoma. Notch2, a pivotal gene for marginal zone differentiation is found to be mutated in SMZL. Deregulated Notch2 signaling has been involved in tumorigenesis and also in B-cell malignancies. However the role of Notch2 and the downstream pathways that it influences for development of B-cell lymphoma remains unclear. In recent years, RNA sequencing (RNA-Seq) has become a functional and convincing technology for profiling gene expression and to discover new genes and transcripts that are involved in disease development in a single experiment. In the present study, using transcriptome sequencing approach, we have identified key genes and pathways that are probably the underlying cause in the development of B-cell lymphoma. We have identified a total of 15,083 differentially expressed genes (DEGs) and 1067 differentially expressed transcripts (DETs) between control and Notch2 knockdown B cells. Gene Ontology (GO) term enrichment and pathway analysis were applied for the identification of key genes and pathways involved in development of B-cell lymphoma. In addition, intermediate genes of top canonical pathways such as PI3K/AKT and NF-kB were found to be downregulated with Notch2 knockdown, indicating that these pathways could be the putative downstream effectors through which Notch2 mediates its oncogenic effects. Taken collectively, the identified crop of genes and pathways may be considered as targets for the treatment of B-cell lymphoma.

Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover.

Lung carcinoma (H1299) cells deficient in p53 (p53(-/-)) express large amounts of urokinase-type plasminogen activator (uPA) protein and uPA mRNA, and exhibit slower degradation of uPA mRNA than that of p53-expressing nonmalignant Beas2B human airway epithelial cells. Expression of p53 protein in H1299 cells, upon transfection with p53 cDNA, suppressed basal as well as uPA-induced expression of uPA protein in both conditioned media and cell lysates, and decreased the level of steady-state uPA mRNA primarily due to increased uPA mRNA turnover. Inhibition of p53 expression by RNA silencing (SiRNA) in Beas2B cells enhanced basal and uPA-mediated uPA protein and mRNA expression with stabilization of uPA mRNA. Purified p53 binds to the uPA mRNA 3' untranslated region (UTR) in a sequence-specific manner and endogenous uPA mRNA associates with p53 protein isolated from Beas2B cytosolic extracts. p53 binds to a 35-nucleotide uPA 3'UTR sequence and insertion of this sequence into beta-globin mRNA accelerates degradation of otherwise stable beta-globin mRNA. These observations confirm a new role for p53 as a uPA mRNA binding protein that down-regulates uPA mRNA stability and decreases cellular uPA expression.

Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C.

Interaction of urokinase-type plasminogen activator (uPA) with its receptor, uPAR, is a key regulatory step in uPA-mediated cell proliferation and migration. Our previous studies demonstrated that posttranscriptional stabilization of uPAR mRNA by uPA contributes to the induction of cell surface uPAR expression, and heterogeneous nuclear ribonuclear protein C1 (hnRNPC) binds to a 110 nt sequence of uPAR mRNA 3'-UTR, thereby preventing its degradation. These observations indicate that hnRNPC could be involved in the induction of uPAR expression by uPA. In the present study, we investigated this possibility and confirmed that uPA increased the binding of hnRNPC to the 3'-UTR of uPAR mRNA. Furthermore, uPA induced tyrosine phosphorylation of hnRNPC and uPAR expression through mRNA stabilization. Inhibition of hnRNPC tyrosine phosphorylation abolished its interaction with uPAR mRNA and suppressed mRNA stabilization and cell surface uPAR expression. Deletion experiments revealed that hnRNPC binds to uPAR mRNA through its RNA binding domain (RBD). Site-directed mutagenesis studies further indicated that phosphorylation of tyrosine residue 57 (Y57) present in RBD of hnRNPC by uPA is essential for uPAR 3'-UTR mRNA binding and uPAR expression. Increased hnRNPC interaction with the uPAR mRNA 3'-UTR through phosphorylation of Y57 represents a novel mechanism by which uPA regulates posttranscriptional uPAR mRNA turnover and cell surface uPAR expression.

Protective effect of Zizyphus spinachristi on MPP+-induced oxidative stress.

Oxidative stress and mitochondrial dysfunction mediated neuro apoptosis is reported to play a major role in the pathology of Parkinson's disease. Zizyphus spina-christi fruits (ZSCF) are used as traditional medicines that are well-known for their high antioxidant properties. In the present study, we investigated the protective effects of ZSCF extract against 1-methyl-4-phenylpyridinium (MPP+) induced neurotoxicity in SH-SY5Y cell lines. The effect of ZCSF on MPP+ induced cell viability (MTT - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay), membrane damage - (lactate dehydrogenase (LDH),  oxidative stress  (levels of ROS, nitric oxide and GSH and activities of SOD and catalase),  mitochondrial membrane potential and apoptosis (activity of caspase 3 and protein expressions of cyto c, Bax and Bcl-2) were measured. Our results showed that ZSCF could be able to reduce the neurotoxicity of MPP+ and offer neuroprotection in vitro. This protective effect of ZCF might be mediated by its potent antioxidant properties. However, further research is necessary to isolate active compounds and performing preclinical and clinical studies to confirm the neuro-protective effects of ZSCF in PD.

Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington's Disease.

Huntington's disease (HD) is characterised by movement disorders, cognitive impairments, and psychiatric problems. The abnormal generation of reactive oxygen species and the resulting oxidative stress-induced mitochondrial damage in neurons upon CAG mutations in the HTT gene have been hypothesized as the contributing factors of neurodegeneration in HD. The potential use of antioxidants against free radical toxicity has been an emerging field in the management of ageing and many neurodegenerative disorders. Neural stem cells derived adult neurogenesis represents the regenerative capacity of the adult brain. The process of adult neurogenesis has been implicated in the cognitive functions of the brain and is highly modulated positively by different factors including antioxidants. The supportive role of antioxidants to reduce the severity of HD via promoting the functional neurogenesis and neuroprotection in the pathological adult brain has great promise. This review comprehends the recent studies describing the therapeutic roles of antioxidants in HD and other neurologic disorders and highlights the scope of using antioxidants to promote adult neurogenesis in HD. It also advocates a new line of research to delineate the mechanisms by which antioxidants promote adult neurogenesis in HD.

Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.

Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS.