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.
Insulin has a well-established role in cognition, neuronal detoxification and synaptic plasticity. Insulin transduction affect neurotransmitter functions, influence bioenergetics and regulate ...neuronal survival through regulating glucose energy metabolism and downward pathways.
A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out with the help of the keywords like “Alzheimer's disease; Hypometabolism; Oxidative stress; energy failure in AD, Insulin; Insulin resistance; Bioenergetics” till June 2020. The review was conducted using the above keywords to collect the latest articles and to understand the nature of the extensive work carried out on insulin resistance and bioenergetic manifestations in Alzheimer's disease.
The article sheds light on insulin resistance mediated hypometabolic state on pathological progression of AD. The disrupted insulin signaling has pathological outcome in form of disturbed glucose homeostasis, altered bioenergetic state which increases build-up of senile plaques (Aβ), neurofibrillary tangles (τ), decline in transportation of glucose and activation of inflammatory pathways. The mechanistic link of insulin resistant state with therapeutically explorable potential transduction pathways is the focus of the reviewed work.
The present work opines that the mechanism by which the insulin resistance mediates dysregulation of bioenergetics and progresses to neurodegenerative state holds the tangible potential to succeed in the development of novel dementia therapies. Further, hypometabolic complications and altered insulin signaling may be explored as a mechanistic relation between bioenergetic deficits and AD.
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•Alzheimer’s therapy has opened the way for pursuit of novel mechanisms and targets.•Modulation of Insulin signaling has strengthened the association of type 2 diabetes and Alzheimer’s disease•Disrupted insulin signaling navigates to a state of bioenergetic failure and hypometabolism in brain.•Insulin signaling divulge in cross talk with an assortment of enormously important mechanisms of Alzheimer’s disease
Objectives
Rheumatoid arthritis is a chronic autoimmune disease manifested clinically by polyarthralgia associated with joint dysfunction triggering the antibodies targeting against the ...self‐neoepitopes determined by autoimmune responses associated with chronic arthritic attacks. The activation of macrophages and other defence cells in response to self‐epitopes as biomarkers in RA provides a better understanding of pathogenesis of disease and has led to the development of novel therapeutic approaches acting as potent inhibitors of these cells.
Key findings
The current review retrieved the various medicinal plants possessing an active phytoconstituents with anti‐inflammatory and antioxidant properties, which tends to be effective alternative approach over the synthetic drugs concerned with high toxic effects. The current available literature provided an evident data concluding that the active constituents like fatty acids, flavonoids, terpenes and sesquiterpene lactones attenuate the RA symptoms by targeting the inflammatory biomarkers involved in the pathogenesis of RA.
Summary
Despite the various synthetic treatment approaches targeting immune cells, cytokines improved the quality of life but still the drug management is challenging due to toxic and chronic teratogenic effects with anti‐arthritic drugs. The current review has elaborated the selected traditionally used herbal medicinal plants with phytoconstituents possessing anti‐inflammatory activity by suppressing the inflammatory biomarkers with lesser side effects and providing the future exploration of natural drug therapy for rheumatoid arthritis.
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•In ageing and neurodegeneration, activity of Nrf2 is compromised, specially in AD.•The Keap-1-Nrf2-ARE pathway in AD.•Nrf2 regulation is achieved by various pathways both in ...cytoplasm and nucleus•The various pathways involved in positive Nrf2 modulation are PI3K, MAPKs and CREB.•The GSK-3β,NF-Kb, JAK-STAT,TNF-α are potential therapeutic targets in AD.
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.
Vitamin D deficiency has been linked to several major chronic diseases, such as cardiovascular and neurodegenerative diseases, diabetes, and cancer, linked to oxidative stress, inflammation, and ...aging. Vitamin D deficiency appears to be particularly harmful to the cardiovascular system, as it can cause endothelial dysfunctioning and vascular abnormalities through the modulation of various downstream mechanisms. As a result, new research indicates that therapeutic approaches targeting vitamin D inadequacies or its significant downstream effects, such as impaired autophagy, abnormal pro-inflammatory and pro-oxidant reactions, may delay the onset and severity of major cerebrovascular disorders such as stroke and neurologic malformations. Vitamin D modulates the various molecular pathways, i.e., Nitric Oxide, PI3K-Akt Pathway, cAMP pathway, NF-kB Pathway, Sirtuin 1, Nrf2, FOXO, in cerebrovascular disorder. The current review shows evidence for vitamin D's mitigating or slowing the progression of these cerebrovascular disorders, which are significant causes of disability and death worldwide.
Traumatic brain injury (TBI) causes brain damage, which involves primary and secondary injury mechanisms. Primary injury causes local brain damage, while secondary damage begins with inflammatory ...activity followed by disruption of the blood–brain barrier (BBB), peripheral blood cells infiltration, brain edema, and the discharge of numerous immune mediators including chemotactic factors and interleukins. TBI alters molecular signaling, cell structures, and functions. Besides tissue damage such as axonal damage, contusions, and hemorrhage, TBI in general interrupts brain physiology including cognition, decision-making, memory, attention, and speech capability. Regardless of the deep understanding of the pathophysiology of TBI, the underlying mechanisms still need to be assessed with a desired therapeutic agent to control the consequences of TBI. The current review gives a brief outline of the pathophysiological mechanism of TBI and various biochemical pathways involved in brain injury, pharmacological treatment approaches, and novel targets for therapy.
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.
Abstract
Objective
Ischaemia/reperfusion (I/R) injury is defined as the damage to the tissue which is caused when blood supply returns to tissue after ischaemia. To protect the ischaemic tissue from ...irreversible injury, various protective agents have been studied but the benefits have not been clinically applicable due to monotargeting, low potency, late delivery or poor tolerability.
Key Findings
Strategies involving preconditioning or postconditioning can address the issues related to the failure of protective therapies. In principle, postconditioning (PoCo) is clinically more applicable in the conditions in which there is unannounced ischaemic event. Moreover, PoCo is an attractive beneficial strategy as it can be induced rapidly at the onset of reperfusion via series of brief I/R cycles following a major ischaemic event or it can be induced in a delayed manner. Various pharmacological postconditioning (pPoCo) mechanisms have been investigated systematically. Using different animal models, most of the studies on pPoCo have been carried out preclinically.
Summary
However, there is a need for the optimization of the clinical protocols to quicken pPoCo clinical translation for future studies. This review summarizes the involvement of various receptors and signalling pathways in the protective mechanisms of pPoCo.
Parkinson's disease (PD) is a neurodegenerative disorder that alters either motor or non-motor activities. Dopamine-based medications can help alleviate symptoms at an early stage, but the disease ...worsens due to fewer neuroprotective drugs. PD's pathogenic mechanism involves α-synuclein accumulations, lipid peroxidation damage, iron deposition, and enhanced oxidative stress. An iron-dependent method of programmed cell death known as ferroptosis, which results from the dangerous accumulation of lipid peroxides, is similar to PD. The interesting fact is that α-synuclein has been functionally connected to iron or lipid metabolism, suggesting that dysregulated α-syn may interact with other PD clinical traits associated with ferroptosis. Treatments aimed at restoring dopamine levels in the brain are already available; however, they only alleviate symptoms and do not stop the progression of neurodegeneration. Ferroptosis-related mechanisms that could be targeted for treatment will be discussed in this review. Researchers have found that anti-ferroptosis molecules such as iron chelators and anti-oxidants protect the brains of PD animal models and humans. The ferroptosis pathway in PD and the treatment prospects of addressing the molecular pathways engaged in ferroptosis are both examined in this review.
The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It is widely known for its ...role in degrading abnormal protein substrates and maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) and the proteasome. Therefore, aberrant expression in these enzymes results in an altered biological process, including transduction signaling for cell death and survival, resulting in cancer. In this review, an overview of profuse enzymes involved as a pro-oncogenic or progressive growth factor in tumors with their downstream signaling pathways has been discussed. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on modulation of ubiquitin-proteasome pathways in oncogenic signaling. Various in vitro, in vivo studies demonstrating the involvement of ubiquitin-proteasome systems in varied types of cancers and the downstream signaling pathways involved are also discussed in the current review. Several inhibitors of E1, E2, E3, deubiquitinase enzymes and proteasome have been applied for treating cancer. Some of these drugs have exhibited successful outcomes in in vivo studies on different cancer types, so clinical trials are going on for these inhibitors. This review mainly focuses on certain ubiquitin-proteasome enzymes involved in developing cancers and certain enzymes that can be targeted to treat cancer.
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