Pathological role of the calcium-sensing receptor in sepsis-induced hypotensive shock: Therapeutic possibilities and unanswered questions.

Sepsis is a life-threatening disease involving multiorgan dysfunction, prompted by an unregulated host response to infection. Shock is a complication of sepsis in which the circulatory and cellular metabolism anomalies are significant enough to raise the risk of death. Calcium dyshomeostasis occurs during sepsis condition due to imbalance between calcium uptake and excessive release induced by inflammatory cytokines. This calcium imbalance can cause activation of calcium-sensing receptors (CaSRs) located on the surface of T cells and thereby promote release of reactive oxygen species (ROS). The elevated ROS and inflammatory cytokines during sepsis condition have been reported to directly damage the endothelial cells, disrupt the barrier functions that might result in leakage of fluids, and inflammatory cells in tissues Moreover, several evidence have revealed that the calcium mediated activation of CaSR could produce systemic vasodilatory response by stimulating the nitric oxide production and opening of calcium-activated potassium channels, while infusion of its antagonist elevated the blood pressure. These evidence indicate that activation of CaSR during sepsis conditions results in release of ROS and inflammatory cytokines, which could produce an endothelial barrier damage, cardiomyocyte apoptosis. These pathological events could produce loss of fluid in tissues and cardiac dysfunction. Further the direct vasodilatory effects of CaSR activation might add to the shock-like condition. Thus, we hereby propose that inhibition of CaSR could suppress the release of ROS, inflammatory mediators, and thereby prevent the endothelial damage, cardiac dysfunction, and maintain systemic vascular tone.

Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression.

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1ß (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

Cyclic Nucleotides Signaling and Phosphodiesterase Inhibition: Defying Alzheimer's Disease.

Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer's disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.

CREB: A Multifaceted Target for Alzheimer's Disease.

Alzheimer's disease (AD) is a persistent neuropathological stipulation manifested in the form of neuronal/synapse demise, the formation of senile plaques, hyperphosphorylated tau tangles, neuroinflammation, and apoptotic cell death. The absence of a therapeutic breakthrough for AD has continued the quest to find a suitable intervention. Apart from various candidates, the cyclic AMPprotein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway is the most sought-after drug target AD as the bulk of quality literature documents that there is downregulation of cAMP signaling and CREB mediated transcriptional cascade in AD. cAMP signaling is evolutionarily conserved and can be found in all species. cAMP response element-binding protein (CREB) is a ubiquitous and integrally articulated transcription aspect that regulates neuronal growth, neuronal differentiation/ proliferation, synaptic plasticity, neurogenesis, maturation of neurons, spatial memory, longterm memory formation as well as ensures neuronal survival. CREB is a central part of the molecular machinery that has a role in transforming short-term memory to long-term. Besides AD, impairment of CREB signaling has been well documented in addiction, Parkinsonism, schizophrenia, Huntington's disease, hypoxia, preconditioning effects, ischemia, alcoholism, anxiety, and depression. The current work highlights the role and influence of CREB mediated transcriptional signaling on major pathological markers of AD (amyloid ß, neuronal loss, inflammation, apoptosis, etc.). The present work justifies the continuous efforts being made to explore the multidimensional role of CREB and related downstream signaling pathways in cognitive deficits and neurodegenerative complications in general and AD particularly. Moreover, it is reaffirmed that cyclic nucleotide signaling may have vast potential to treat neurodegenerative complications like AD.

Pharmacological modulation of farnesyltransferase subtype I attenuates mecamylamine-precipitated nicotine withdrawal syndrome in mice.

This study was designed to investigate the effect of FTI-276 trifluoroacetate, a selective inhibitor of subtype I, on the development of the mecamylamine-induced nicotine withdrawal syndrome. Mice were administered nicotine (2.5 mg/kg, subcutaneously) four times daily for 7 days. To precipitate nicotine withdrawal, mice were administered one injection of mecamylamine (3 mg/kg, intraperitoneally) 1 h after the last nicotine injection on the test day (day 8). Behavioral observations were made for a period of 30 min immediately after mecamylamine treatment. FTI-276 trifluoroacetate treatment markedly and dose-dependently attenuated the precipitated nicotine withdrawal syndrome, measured by a composite withdrawal severity score, jumping frequency, hyperalgesia in the tail flick test, and anxiety-like behavior in the elevated plus maze test. The results suggest that FTI-276 trifluoroacetate can inhibit the development of a precipitated nicotine withdrawal syndrome, and thus that farnesyltransferase subtype I may be a viable pharmacological target to tackle the problem of nicotine addiction.

Pharmacological preconditioning of the brain: a possible interplay between opioid and calcitonin gene related peptide transduction systems.

The present study has been undertaken to investigate the possible link between calcitonin gene related peptide (CGRP) and opioid receptor transduction systems in the neuroprotective mechanism of pharmacological preconditioning. Occlusion of the bilateral carotid artery for 17 min, followed by reperfusion for 24 h, was employed to produce ischemia and reperfusion (I/R) induced cerebral injury in mice. Cerebral infarct size was measured by using triphenyltetrazolium chloride staining. Memory was assessed using the Morris water maze (MWM) test. Degree of motor incoordination was evaluated using the inclined beam walk test, rota-rod test, and lateral push test. Morphine (8 mg/kg, ip), an opioid agonist, and capsaicin (0.1 mg/kg, iv), a CGRP releasing agent, were administered 24 h before surgery to separate groups of animals to induce pharmacological preconditioning. Bilateral carotid artery occlusion, followed by reperfusion, produced a significant increase in the cerebral infarct size and impaired memory as well as motor coordination. Morphine and capsaicin treatment produced both a significant decrease in the cerebral infarct size and a reversal of I/R-induced impairment of memory and motor-coordination. Morphine-induced (8 mg/kg, ip) neuroprotective effects were completely decreased by sumatriptan (8 mg/kg, ip, a CGRPrelease inhibitor) administered 1 h before and 6 h and 12 h after morphine administration. Capsaicin-induced neuroprotection was decreased by naloxone (5 mg/kg, ip, an opioid antagonist) administered 1 h before and 6 h and 12 h after capsaicin administration. These findings indicate that the transduction systems mediating morphine- and capsaicin-induced pharmacological preconditioning in brain are possibly interlinked with one another.