Tumor-derived lactate and myeloid-derived suppressor cells: Linking metabolism to cancer immunology

Many malignant cells produce increased amounts of lactate, which promotes the development of myeloid-derived suppressor cells (MDSCs). MDSCs, lactate, and a low pH in the tumor microenvironment inhibit the function of natural killer (NK) cells and T lymphocytes, hence allowing for disease progression. Ketogenic diets can deplete tumor-bearing animals from MDSCs and regulatory T cells, thereby improving their immunological profile

Current evidence-based therapy does not restore plasma apelin level in phenotypically diverse chronic heart failure patients

Background: Apelin, endogenous peptide acting through its receptor (APJ), is the most potent inotropic agent known to man. Plasma apelin and cardiac APJ mRNA levels rise in early stages of chronic heart failure (CHF) but fall later in decompensated CHF. The effect of current evidence-based management of CHF on plasma apelin level is not known. We estimated change in plasma apelin level in CHF patients of diverse phenotypes treated with standard pharmacotherapy and compared it with the corresponding change in left ventricular ejection fraction (LVEF), plasma brain natriuretic peptide (BNP) level and quality of life (QoL).Methods: With ethical approval and written informed consent, venous blood samples were collected from 39 CHF [dilated cardiomyopathy (DCM) (n=21), restrictive cardiomyopathy (RCM) (n=9) and chronic constrictive pericarditis (CCP) (n=9)] patients and 10 age-matched healthy controls, at baseline and after 12 weeks. Plasma apelin and BNP were estimated by competitive ELISA (RayBiotech Inc.) and an auto-analyzer (Triage, Allere Inc.), respectively. QoL was assessed using Kansas City Cardiomyopathy Questionnaire (KCCQ). Nonparametric tests were applied and p-value <0.05 was considered significant.Results: Low LVEF, KCCQ score and high BNP levels were observed in all CHF patients compared to controls. Plasma apelin level was depressed in RCM and CCP patients compared to controls but not in DCM patients. These parameters did not change in any group after 3 months of standard pharmacotherapy.Conclusions: Current evidence-based management of CHF does not restore the depressed apelin-APJ axis. New drugs are required for specifically modulating this promising therapeutic target in CHF

Capability’ development through ICT enabled business opportunity development model of e-Choupal

The purpose of this study is to check how ICT led business opportunity devel- opment model of ITC e-Choupal affected “Capability” development of the people in rural India. The survey of three different regions of India, included 319 e-Choupal beneficiaries and 10 ITC officials and elected representatives of villages. Statistical analysis revealed that Capability Enhancement of farmers depended on the extent to which farmers trusted and participated in ICT activities that varied based on their education level but specifically e-Choupal could generate only limited business opportunities for rural masses. However, the business opportunities definitely affected the capability enhancement parameters. The ICT enabled business models can be well used by corporates and governments of devel- oping economies in Asia and Africa for capability development of rural masses as these models provide new business opportunities for them. The field survey based framework showed how ICT based business opportunity development model of e-Choupal can affect the income, time and saving of farmers in developing economy

Isolation and Purification of C-phycocyanin From Nostoc Muscorum (Cyanophyceae and Cyanobacteria) Exhibits Antimalarial Activity in Vitro

The phycobilin pigments are intensively fluorescent and water soluble. They are categorized into three types, such as pigments containing high, intermediate and low energies are phycoerythrins (phycoerythrocyanins), phycocyanins and allophycocyanins, respectively. Besides light harvesting, the phycobiliproteins have shown industrial and biomedical importance. Among them, C-phycocyanin (C-PC) has been considered to be the most preferred one. The present study was undertaken to evaluate the antimalarial activity of C-PC isolated from a nitrogen-fixing cyanobacterium and Nostoc muscorum. C-PC was extracted and purified by acetone extraction and ammonium sulfate precipitation and dialysis followed by amicon filtration. It was isolated as a~124 kDa water soluble protein molecule. It showed antimalarial activity in vitro against chloroquine sensitive and resistant Plasmodium falciparum strains. Inhibitory concentrations at 50%, 90% and 95% were determined as 10.27±2.79, 53.53±6.26 and 73.78±6.92 µg/ml against the chloroquine-sensitive strains; 10.37±1.43, 56.99±11.07 and 72.79±8.59 µg/ml against chloroquine resistant of Plasmodium falciparum strains. C-PC was found to have antimalarial activity even at a concentration of 3.0µg/ml. The possible mechanism might be relied on the destruction of polymerization of haemozoin by binding of C-PC with ferriprotoporphyrin-IX at the water surface of the plasma membrane

Isolation and Purification of C-phycocyanin From Nostoc Muscorum (Cyanophyceae and Cyanobacteria) Exhibits Antimalarial Activity in Vitro

The phycobilin pigments are intensively fluorescent and water soluble. They are categorized into three types, such as pigments containing high, intermediate and low energies are phycoerythrins (phycoerythrocyanins), phycocyanins and allophycocyanins, respectively. Besides light harvesting, the phycobiliproteins have shown industrial and biomedical importance. Among them, C-phycocyanin (C-PC) has been considered to be the most preferred one. The present study was undertaken to evaluate the antimalarial activity of C-PC isolated from a nitrogen-fixing cyanobacterium and Nostoc muscorum. C-PC was extracted and purified by acetone extraction and ammonium sulfate precipitation and dialysis followed by amicon filtration. It was isolated as a~124 kDa water soluble protein molecule. It showed antimalarial activity in vitro against chloroquine sensitive and resistant Plasmodium falciparum strains. Inhibitory concentrations at 50%, 90% and 95% were determined as 10.27±2.79, 53.53±6.26 and 73.78±6.92 µg/ml against the chloroquine-sensitive strains; 10.37±1.43, 56.99±11.07 and 72.79±8.59 µg/ml against chloroquine resistant of Plasmodium falciparum strains. C-PC was found to have antimalarial activity even at a concentration of 3.0µg/ml. The possible mechanism might be relied on the destruction of polymerization of haemozoin by binding of C-PC with ferriprotoporphyrin-IX at the water surface of the plasma membrane

Zika virus E protein modulates functions of human brain microvascular endothelial cells and astrocytes: implications on blood-brain barrier properties

Neurotropic viruses can cross the otherwise dynamically regulated blood-brain barrier (BBB) and affect the brain cells. Zika virus (ZIKV) is an enveloped neurotropic Flavivirus known to cause severe neurological complications, such as encephalitis and fetal microcephaly. In the present study, we employed human brain microvascular endothelial cells (hBMECs) and astrocytes derived from human progenitors to establish a physiologically relevant BBB model. We used this model to investigate the effects of ZIKV envelope (E) protein on properties of cells comprising the BBB. E protein is the principal viral protein involved in interaction with host cell surface receptors, facilitating the viral entry. Our findings show that the presence of ZIKV E protein leads to activation of both hBMECs and astrocytes. In hBMECs, we observed a decrease in the expression of crucial endothelial junction proteins such as ZO-1, Occludin and VE-Cadherin, which are vital in establishment and maintenance of the BBB. Consequently, the ZIKV E protein induced changes in BBB integrity and permeability. We also found upregulation of genes involved in leukocyte recruitment along with increased proinflammatory chemokines and cytokines upon exposure to E protein. Additionally, the E protein also led to astrogliosis, evident from the elevated expression of GFAP and Vimentin. Both cell types comprising the BBB exhibited inflammatory response upon exposure to E protein which may influence viral access into the central nervous system (CNS) and subsequent infection of other CNS cells. Overall, our study provides valuable insights into the transient changes that occur at the site of BBB upon ZIKV infection

Japanese encephalitis virus induces human neural stem/progenitor cell death by elevating GRP78, PHB and hnRNPC through ER stress

Japanese encephalitis virus (JEV), which is a causative agent of sporadic encephalitis, harbours itself inside the neural stem/progenitor cells. It is a well-known fact that JEV infects neural stem/progenitor cells and decreases their proliferation capacity. With mass spectrometry-based quantitative proteomic study, it is possible to reveal the impact of virus on the stem cells at protein level. Our aim was to perceive the stem cell proteomic response upon viral challenge. We performed a two-dimensional gel electrophoresis-based proteomic study of the human neural stem cells (hNS1 cell line) post JEV infection and found that 13 proteins were differentially expressed. The altered proteome profile of hNS1 cell line revealed sustained endoplasmic reticulum stress, which deteriorated normal cellular activities leading to cell apoptosis. The proteomic changes found in hNS1 cell line were validated in vivo in the subventricular zone of JE infected BALB/c mice. Congruent alterations were also witnessed in multipotent neural precursor cells isolated from human foetus and in autopsy samples of human brain clinically diagnosed as cases of JE patients. Endoplasmic reticulum resident chaperone GRP78, mitochondrial protein Prohibitin and heterogeneous nuclear ribonucleoprotein hnRNPC (C1/C2) have been shown to interact with viral RNA. Hence it is proposed that these are the principle candidates governing endoplasmic reticulum stress-induced apoptosis in JEV infection

Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of Substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Activation of the mixed lineage kinase and c-Jun N-terminal kinase (JNK) has been reported in models of PD. Our focus was to discern whether distinct pathways were activated in cell-specific manner within the SNpc. We now demonstrate the selective phosphorylation of p38 MAP kinase within the dopaminergic neurons, whereas JNK activation occurs predominantly in the microglia. p38 activation results in downstream phosphorylation of p53 and increased p53 mediated transcription of Bax and Puma in the ventral midbrain. Treatment with p38 inhibitor, SB239063 protected primary dopaminergic neurons derived from human progenitor cells from MPP+ mediated cell death and prevented the downstream phosphorylation of p53 and its translocation to the nucleus in vivo, in the ventral midbrain. The increased staining of phosphorylated p38 in the surviving neurons of SNpc in human brain sections from patients with PD and in MPTP treated mice but not in the ventral tegmental area provides further evidence suggesting a role for p38 in the degeneration of dopaminergic neurons of SNpc. We thus demonstrate the cell specific activation of MAP kinase pathways within the SNpc after MPTP treatment emphasizing the role of multiple signaling cascades in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression

Knockdown of Malic Enzyme 2 Suppresses Lung Tumor Growth, Induces Differentiation and Impacts PI3K/AKT Signaling

Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to yield CO2 and pyruvate, with concomitant reduction of dinucleotide cofactor NAD+ or NADP+. We find that ME2 is highly expressed in many solid tumors. In the A549 non-small cell lung cancer (NSCLC) cell line, ME2 depletion inhibits cell proliferation and induces cell death and differentiation, accompanied by increased reactive oxygen species (ROS) and NADP+/NADPH ratio, a drop in ATP, and increased sensitivity to cisplatin. ME2 knockdown impacts phosphoinositide-dependent protein kinase 1 (PDK1) and phosphatase and tensin homolog (PTEN) expression, leading to AKT inhibition. Depletion of ME2 leads to malate accumulation and pyruvate decrease, and exogenous cell permeable dimethyl-malate (DMM) mimics the ME2 knockdown phenotype. Both ME2 knockdown and DMM treatment reduce A549 cell growth in vivo. Collectively, our data suggest that ME2 is a potential target for cancer therapy