Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders affecting humans and animals. Human TSEs are often categorized with other protein misfolding neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, fronto-temporal dementia and amyotrophic lateral sclerosis. The mechanism of disease propagation is well understood and involves the conformational conversion of a normal cell-surface protein (PrPc) into a protease-resistant, Beta-sheet-rich form (PrPSc) that is infectious in the absence of nucleic acid. However, some forms of spongiform encephalopathies are commonly associated with inherited mutations at the PrPc coding gene (PrnP), particularly[..]

CDKN2A (Cyclin Dependent Kinase Inhibitor-2A), which is also referred to as p16(INK4A) encodes ARFs (Alternative Reading Frames), or transcript variants. In mice the p16(INK4A) encodes a transcript variant known as p19(ARF), whereas in humans it encodes p14(ARF).p19(ARF) is a key component of a major human tumor suppressor pathway that is responsible for arresting cell-cycle progression and inducing cell death in response to DNA damage and oncogenic stress. It plays an important role as an inhibitor of the MDM2-mediated degradation of p53. p19(ARF) activity is linked to its oligomerization and is sensitive to the redox status of the cell. Oxidative stress affects p19(ARF) oligomerization. Tumor promotion is associated with an altered redox status, and it is known that[..]

PI3Ks (Phosphoinositide-3 Kinases) are heterodimeric lipid kinases that are composed of a regulatory and catalytic subunit that are encoded by different genes. The phosphorylated lipid phosphatidylinositol 3-phosphate (PtdIns3P) is an important signaling molecule and has been found to localize to endosomes, multivesicular bodies, phagosomes, midbodies, peroxisomes and omegasomes. The generated PtdIns3P attracts PtdIns3P-binding factors, which either contain a PX (Phox homology) domain or a FYVE (Fab1p, YOTB, Vac1p and EEA1) domain. The subsequent signaling cascades are involved in endocytic transport and endocytic signaling, cytokinesis as well as autophagy. (Ref.1). Two distinct VPS34P (Vacuolar Protein-Sorting-34-PI3K (Phosphatidylinositde-3 Kinase)) complexes occur[..]

Bacterial meningitis is an inflammation of the meninges, in particular the arachnoid and the pia mater, associated with the invasion of bacteria into the subarachnoid space.The pathogens take advantage of the specific features of the immune system in the CNS, replicate and induce inflammation. A hallmark of bacterial meningitis is the recruitment of highly activated leukocytes into the CSF.The predominant causative pathogens in adults are Streptococcuspneumoniae, Neisseriameningitidis, and Listeria monocytogenes which are responsible for about 80% of all cases, while GBS(group B Streptococcus), S. pneumoniae, Escherichiacoli,N.meningitidis, and Haemophilusinfluenza type B cause about 90% of cases of BM in children globally.The mortality rate of neonatal meningitis was[..]

Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone.This is a chronic debilitating autoimmune disease of unknown etiology affecting diarthrodial joints. Although the disease is characterized by synovitis of the joints, tendon sheaths, and bursae, manifestations that do not involve the synovium are also frequent (Ref.1 & 2). These articular and systemic manifestations are mediated by hyperplasia of the synovial lining cells and extensive infiltration of macrophages, lymphocytes, fibroblasts, and leukocytes[..]

The innate immune response to bacteria is essential for survival but the systemic release of inflammatory mediators results in the life-threatening Septic-shock reaction. Macrophages are essential effector cells of innate immunity that play a pivotal role in the recognition and elimination of invasive microorganisms. Mediators released by activated macrophages orchestrate innate and adaptive immune host responses. The cytokine MIF (Macrophage Migration Inhibitory Factor) is an integral mediator of the innate immune system. Monocytes and macrophages constitutively express large amounts of MIF, which is rapidly released after exposure to bacterial toxins and cytokines. MIF exerts potent proinflammatory activities and is an important cytokine of septic shock. MIF[..]

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines, enzymes involved in the inflammatory process and of several cell surface molecules required for immune function. Glucocorticoids mediate these effects through an intracellular receptor, the GR (Glucocorticoid Receptor), a member of the steroid/thyroid hormone receptor super family. The Glucocorticoid hormones affect the metabolism of carbohydrates, proteins, and lipids in a manner nearly opposite to that of insulin and influence a wide variety of other vital functions, including nucleic acid synthesis, maintenance of blood pressure, inflammatory reactions and the capacity to cope with stress. Data presently indicates that[..]

The (Phosphatidylinositde-3-Kinase) family of enzymes regulate diverse biological functions in every cell type by generating lipid second messengers that ultimately results in the mediation of cellular activities such as proliferation, differentiation, chemotaxis, survival, trafficking and Glucose homeostasis. On the basis of structural similarities, the members are sub-divided into three classes; Class I, II and III. The Class I and II PI3Ks are found only in metazoa, whereas, Class III PI3Ks are also found in unicellular eukaryotes. The Class I PI3Ks are sub-divided into two groups-the Class IA and Class IB PI3Ks. Class IA PI3Ks are heterodimeric enzymes consisting of regulatory subunits (p85-Alpha, p85-Beta or p55-Gamma) and a catalytic subunit (p110-Alpha, or[..]

The PI3K (Phosphatidylinositde-3 Kinase) family of enzymes is recruited upon growth factor receptor activation and produces 3' phosphoinositide lipids. The lipid products of PI3K act as second messengers by binding to and activating diverse cellular target proteins. Therefore, PI3Ks play a central role in many cellular functions. In mammals, the PI3Ks have a p110 catalytic subunit associated with a p85, p55 or p50 regulatory subunit (Ref.1). In Drosophila, the dPI3K (Phosphatidylinositde-3 Kinase) regulatory subunit dp60 (p60 Regulatory Subunit of PI3K) lacks the SH3 and BH (Bcr homology) domains like that of the mammals showing that these additional domains have been added during evolution to confer additional functions or modes of regulation to the PI3K[..]

One of the key functions of catabolic metabolism is to maintain high levels of ATP (Adenosine Triphosphate) and cells rapidly respond to any stress that threatens to lower ATP levels by arresting non-essential ATP-utilizing functions and stimulating available ATP-generating pathways. A central player in this system is the AMPK (AMP (Adenosine 5'-Monophosphate)-Activated Protein Kinase). AMPK is a master metabolic regulator responsible for modulating cellular responses to an energy challenge. The evolutionarily conserved Serine/Threonine Kinase, AMPK acts as a “Fuel Gauge” or “Cellular Energy Sensor” and inhibits key enzymes of ATP-consuming pathways and induces pathways that generate ATP. When AMPK is activated by stimuli like muscle contraction, inflammation,[..]

PI3Ks (Phosphoinositide 3-Kinases) are an important type of lipid kinase that form a large evolutionarily conserved family of enzymes that specifically phosphorylate inositol phospholipids at the D-3 position of the inositol ring. The C. elegans (Caenorhabditis elegans) PI3K is required for functional membrane trafficking machinery (Ref.1). C. elegans PI3K adaptor subunit aap-1 (Phosphoinositide 3-Kinase age-1 Adapter Subunit-58.5 KD) shares moderate sequence similarity with the p50/p55 adaptor subunits of their vertebrate and Drosophila counterparts. C. elegans PI3K also contains age-1 (Ageing Alteration-age-1), a homolog of vertebrate p110 catalytic subunits of PI3K (Ref.2).   An insulin receptor-like signaling pathway regulates C. elegans metabolism,[..]

Cardiac hypertrophy describes an abnormal condition where the heart becomes enlarged. Several factors, such as increased mechanical loading and neuro-hormonal chemicals can induce hypertrophy. ET1 (Endothelin-1) is a 21-amino acid vasoconstrictor peptide, which is able to induce cardiac hypertrophy. In mammals this peptide family also includes ET2 and ET3. ET1 is the principal isoform in the human cardiovascular system and remains the most ubiquitous, potent, and unusually long-lasting constrictor of human vessels discovered. Biosynthesis of ET1 is primarily regulated by autocrine mechanisms, physico-chemical factors, including mechanical forces, changes in oxygen tension, changes in pH, Angiotensin-II, Vasopressin, Norepinephrine, growth factors, cytokines,[..]