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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.
Serum and glucocorticoid-regulated kinases (SGK) are serine/threonine kinases that belong to AGC. The SGK-1, which responds to stress, controls a range of ion channels, cell growth, transcription ...factors, membrane transporters, cellular enzymes, cell survival, proliferation and death. Its expression is highly controlled by various factors such as hyperosmotic or isotonic oxidative stress, cell shrinkage, radiation, high blood sugar, neuronal injury, DNA damage, mechanical stress, thermal shock, excitement, dehydration and ischemia. The structural and functional deterioration that arises after a period of ischemia when blood flow is restored is referred to as ischemia/ reperfusion injury (I/R). The current review discusses the structure, expression, function and degradation of SGK-1 with special emphasis on the various ischemic injuries in different organs such as renal, myocardial, cerebral, intestinal and lungs. Furthermore, this review highlights the various therapeutic agents that activate the SGK-1 pathway and slow down the progression of I/R injuries.
Mitochondrial dysfunction is one of the fundamental causes of ischemia reperfusion (I/R) damage. I/R refers to the paradoxical progression of cellular dysfunction and death that occurs when blood ...flow is restored to previously ischemic tissues. I/R causes a significant rise in mitochondrial permeability resulting in the opening of mitochondrial permeability transition pores (MPTP). The MPTP are broad, nonspecific channels present in the inner mitochondrial membrane (IMM), and are known to mediate the deadly permeability alterations that trigger mitochondrial driven cell death. Protection from reperfusion injury occurs when long-term ischemia is accompanied by short-term ischemic episodes or inhibition of MPTP from opening via mitochondrial ATP dependent potassium (mitoKATP) channels. These channels located in the IMM, play an essential role in ischemia preconditioning (PC) and protect against cell death by blocking MPTP opening. This review primarily focuses on the interaction between the MPTP and mitoKATP along with their role in the I/R injury. This article also describes the molecular composition of the MPTP and mitoKATP in order to promote future knowledge and treatment of diverse I/R injuries in various organs.
The main goal of the treatment of patients is its effectiveness and safety. However, all currently prescribed drugs being used also have certain adverse effects, which might be seen as an unavoidable ...but necessary cost of pharmacotherapy. The kidney is the primary organ for xenobiotics elimination, making it particularly susceptible to the harmful effects of drugs and their metabolites during their excretion from the body. Moreover, certain medications have a preferential nephrotoxicity potential, which means that using them increases the risk of kidney injury. Drug nephrotoxicity is, therefore, both a significant problem and a complication of pharmacotherapy. It should be noted that, there is presently no accepted definition of drug-induced nephrotoxicity and no established diagnostic criteria. The current review briefly describes the pathogenic mechanism of drug-induced nephrotoxicity, the various basic drugs with nephrotoxicity potential and the renal biomarkers for the treatment of the drug-related kidney damage.
Cerebral ischemia is a leading cause of death in the globe, with a large societal cost. Deprivation of blood flow, together with consequent glucose and oxygen shortage, activates a variety of ...pathways that result in permanent brain damage. As a result, ischemia raises energy demand, which is linked to significant alterations in brain energy metabolism. Even at the low glucose levels reported in plasma during ischemia, glucose transport activity may adjust to assure the supply of glucose to maintain normal cellular function. Glucose transporters in the brain are divided into two groups: sodium-independent glucose transporters (GLUTs) and sodium-dependent glucose cotransporters (SGLTs).This review assess the GLUT structure, expression, regulation, pathobiology of GLUT in cerebral ischemia and regulators of GLUT and it also provides the synopsis of the literature exploring the relationship between GLUT and the various downstream signalling pathways for e.g., AMP-activated protein kinase (AMPK), CREB (cAMP response element-binding protein), Hypoxia-inducible factor 1 (HIF)-1, Phosphatidylinositol 3-kinase (PI3-K), Mitogen-activated protein kinase (MAPK) and adenylate-uridylate-rich elements (AREs). Therefore, the aim of the present review was to elaborate the therapeutic implications of GLUT in the cerebral ischemia.
A stroke is a complicated neurological illness that occurs when there is a disruption in the blood flow to the brain. This disruption results in the damage of neurons, which then leads to functional ...abnormalities. The Wnt signalling pathway, which is already well-known for its important function in development and tissue homeostasis, has recently been recognised as a critical factor in the pathophysiology of stroke. Recent studies have shown the Wnt pathway’s roles in stroke-related events. The complex-interactions between the Wnt pathway and stroke emphasising the pathway’s contributions to neuro-protection and synaptic plasticity. The Wnt pathway’s influence on neuro-genesis and synaptic plasticity underscores its potential for driving stroke recovery and rehabilitation strategies. The current review discusses about the Wnt signalling pathway in brain pathophysiology and stroke with special emphasis on the various pathways involved in the positive and negative modulation of Wnt pathway namely Phosphoinositide 3-kinase (PI3-K), Glycogen synthase kinase-3β (GSK-3β), Mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
The growth factor brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin-related kinase receptor type B (TrkB) play an active role in numerous areas of the adult brain, where they ...regulate the neuronal activity, function, and survival. Upregulation and downregulation of BDNF expression are critical for the physiology of neuronal circuits and functioning in the brain. Loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric disorders. This article reviews the BDNF gene structure, transport, secretion, expression and functions in the brain. This article also implicates BDNF in several brain-related disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, major depressive disorder, schizophrenia, epilepsy and bipolar disorder.
Coronaviruses, SARS-CoV-2 particles are spherical and have proteins called spikes that stick out on the surface. COVID-19 most commonly affects the respiratory system, but various clinical ...manifestations on coronavirus have revealed their potential neurotropism. The neuroinvasive affinity of Coronavirus infections has been reported nearly for all the β Coronavirus infections, including MERS-CoV, SARS-CoV, HCoV-OC43 and HEV. Coronavirus invasion occurs through hypoxia injury, immune injury, ACE2, and direct infection. The pathophysiology of SARS-CoV-2 and other human Coronaviruses reveals the possible mechanisms of neurodegeneration.
A systematic literature review carried out from various search engines like Scopus, PubMed, Medline, and Elsevier for investigating the therapeutic perspective of association between Covid-19 and Guillain-Barré syndrome.
SARS-CoV-2 uses angiotensin-converting enzyme 2 as its entry receptor and enters the central nervous system through a Blood-brain barrier constituted of inflammatory mediators, direct infection of the endothelial cells, or endothelial injury. Guillain-Barré syndrome is an autoimmune disease that injures and attacks the nerves in the peripheral nervous system. Studies suggest that the virus can infect peripheral neurons to cause direct damage through various mechanisms, including direct damage by cytokine-related injury, ACE2 receptors, and the sequelae of hypoxia.
we have discussed the possible mechanisms between neuroinvasion of SARs-cov2 and Guillain-barre syndrome.
•SARS-CoV-2 uses angiotensin-converting enzyme 2 as its entry receptor.•Guillain-Barre syndrome is an autoimmune disease.•Guillain-Barré Syndrome cases correlated to COVID-19.
The term Autism spectrum disorder (ASD) refers to a neuro-developmental disorder that include repetitive behaviours, extremely constrained interests and deficits in social communication. In the last ...ten years, the numerous epidemiological papers discussing connection between autism and environmental chemical exposures has significantly increased. These findings are crucial because they focus on modifiable risk factors that may open up new possibilities for the primary prevention of the autism-related disability, which is now recognised to be more strongly related to environmental factors than was previously thought. A variety of environmental factors have been known as significant factors relevant to aetiology of ASD, such as lead and mercury (heavy metals), PCB(organic contaminant) and phthalates and BPA. The most accurate animal model of autism among all other models is valproic acid-induced autism, which can reproduce almost all of the molecular and cellular changes seen in humans with ASD. This review provide insight into various diagnostic available for autism, pathophysiology of autism and animal model of autism to develop a pharmacological therapeutic intervention for the treatment of disease.
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