A transcriptional regulatory nuclear factor kappa B (NF-κB) protein is a modulator of cellular biological activity via binding to a promoter region in the nucleus and transcribing various protein genes. The recent research implicated the intensive role of nuclear factor kappa B (NF-κB) in diseases like autoimmune disorder, inflammatory, cardiovascular and neurodegenerative diseases. Therefore, targeting the nuclear factor kappa B (NF-κB) protein offers a new opportunity as a therapeutic approach. Activation of IκB kinase/NF-κB signaling pathway leads to the development of various pathological conditions in human beings, such as neurodegenerative, inflammatory disorders, autoimmune diseases, and cancer. Therefore, the transcriptional activity of IκB kinase/NF- κB is strongly regulated at various cascade pathways. The nuclear factor NF-kB pathway plays a major role in the expression of pro-inflammatory genes, including cytokines, chemokines, and adhesion molecules. In response to the diverse stimuli, the cytosolic sequestered NF-κB in an inactivated form by binding with an inhibitor molecule protein (IkB) gets phosphorylated and translocated into the nucleus further transcribing various genes necessary for modifying various cellular functions. The various researches confirmed the role of different family member proteins of NF-κB implicated in expressing various genes products and mediating various cellular cascades. MicroRNAs, as regulators of NF- κB microRNAs play important roles in the regulation of the inflammatory process. Therefore, the inhibitor of NF-κB and its family members plays a novel therapeutic target in preventing various diseases. Regulation of NF- κB signaling pathway may be a safe and effective treatment strategy for various disorders.

Neurodegenerative diseases (NDDs) are the primary cause of disabilities in the elderly people. Growing evidence indicates that oxidative stress, mitochondrial dysfunction, neuroinflammation and apoptosis are associated with aging and the basis of most neurodegenerative disorders. Quercetin is a flavonoid with significant pharmacological effects and promising therapeutic potential. It is widely distributed among plants and typically found in daily diets mainly in fruits and vegetables. It shows a number of biological properties connected to its antioxidant activity. Neuroprotection by quercetin has been reported in many in vitro as well as in in vivo studies. However, the exact mechanism of action is still mystery and similarly there are a number of hypothesis exploring the mechanism of neuroprotection. Quercetin enhances neuronal longevity and neurogenesis by modulating and inhibiting wide number of pathways. This review assesses the food sources of quercetin, its pharmacokinetic profile, structure activity relationship and its pathophysiological role in various NDDs and it also provides a synopsis of the literature exploring the relationship between quercetin and various downstream signalling pathways modulated by quercetin for neuroprotection for eg. nuclear factor erythroid 2-related factor 2 (Nrf2), Paraoxonase-2 (PON2), c-Jun N-terminal kinase (JNK), Tumour Necrosis Factor alpha (TNF-α), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α), Sirtuins, Mitogen-activated protein kinases (MAPKs) signalling cascades, CREB (Cyclic AMP response element binding protein) and Phosphoinositide 3- kinase(PI3K/Akt). Therefore, the aim of the present review was to elaborate on the cellular and molecular mechanisms of the quercetin involved in the protection against NDDs.

: The gene based therapeutics and drug targets have shown incredible and appreciable advances in alleviating human sufferings and complexities. Epigenetics simply means above genetics or which controls the organism beyond genetics. At present it is very clear that all characteristics of an individual are not determined by DNA alone, rather the environment, stress, life style and nutrition play a vital part in determining the response of an organism. Thus, nature (genetic makeup) and nurture (exposure) play equally important roles in the responses observed, both at the cellular and organism levels. Epigenetics influence plethora of complications at cellular and molecular levels that includes cancer, metabolic and cardiovascular complications including neurological (psychosis) and neurodegenerative disorders (Alzheimer’s disease, Parkinson disease etc.). The epigenetic mechanisms include DNA methylation, histone modification and non coding RNA which have substantial impact on progression and pathways linked to Alzheimer’s disease. The epigenetic mechanism gets deregulated in Alzheimer’s disease and is characterized by DNA hyper methylation, deacetylation of histones and general repressed chromatin state which alter gene expression at the transcription level by upregulation, downregulation or silencing of genes. Thus, the processes or modulators of these epigenetic processes have shown vast potential as a therapeutic target in Alzheimer’s disease.

A salient pathological features in Alzheimer's disease includes redox impairment and neuroinflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) and Nuclear factor kappa B (NF-ҡB) are the two key transcription factors that regulate cellular responses to redox impairment and neuroinflammation respectively. An effective way to confer neuroprotection in central nervous system (CNS) is the activation of a transcription factor i.e Nuclear factor erythroid 2-related factor 2 (Nrf2). An enhancer element known as Antioxidant Response Element (ARE) mediates the expression of phase II detoxification enzymes. Nrf2 is a nuclear transcription factor that binds to ARE thereby transcribing expression of several antioxidant genes. Kelch ECH associating protein-1 (Keap1), a culin 3-based E3 ligase, polyubiquitinates Nrf2 and targets it for its degradation. Disruption in the interaction between Keap1/Nrf2 can increase the brain's endogenous antioxidant capacity and thereby responsible for cell defence against oxidative stress and neuroinflammation in Alzheimer's disease (AD). The current review discusses about Keap1-Nrf2-ARE structure and function with special emphasis on the various pathways involved in positive and negative modulation of Nrf2, namely Phosphoinositide 3- kinase (PI3K), Glycogen synthase kinase-3β (GSK-3β), Nuclear factor kappa-b (NF-ҡb), Janus kinase/signal transducer and activator of transcription (JAK-STAT),Tumour Necrosis Factor- α (TNF-α), p38Mitogen-activated protein kinases (p38MAPK), Cyclic AMP response element binding protein (CREB) and intrinsic & extrinsic apoptotic pathway. Furthermore, this review highlights the miscellaneous Nrf2 activators as promising therapeutic agents for slowingdown the progression of AD.