NLRP3: a new therapeutic target in alcoholic liver disease.

The liver is in charge of a wide range of critical physiological processes and it plays an important role in activating the innate immune system which elicits the inflammatory events. Chronic ethanol exposure disrupts hepatic inflammatory mechanism and leads to the release of proinflammatory mediators such as chemokines, cytokines and activation of inflammasomes. The mechanism of liver fibrosis/cirrhosis involve activation of NLRP3 inflammasome, leading to the destruction of hepatocytes and subsequent metabolic dysregulation in humans. In addition, increasing evidence suggests that alcohol intake significantly modifies liver epigenetics, promoting the development of alcoholic liver disease (ALD). Epigenetic changes including histone modification, microRNA-induced genetic modulation, and DNA methylation are crucial in alcohol-evoked cell signaling that affects gene expression in the hepatic system. Though we are at the beginning stage without having the entire print of epigenetic signature, it is time to focus more on NLRP3 inflammasome and epigenetic modifications. Here we review the novel aspect of ALD pathology linking to inflammation and highlighting the role of epigenetic modification associated with NLRP3 inflammasome and how it could be a therapeutic target in ALD.

An Insight into the Molecular Mechanism of Mitochondrial Toxicant-induced Neuronal Apoptosis in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders affecting approximately 1% of the world's population at the age of 50 and above. Majority of PD cases are sporadic and show symptoms after the age of 60 and above. At that time, most of the dopaminergic neurons in the region of substantia nigra pars compacta have been degenerated. Although in past decades, discoveries of genetic mutations linked to PD have significantly impacted our current understanding of the pathogenesis of this devastating disorder, it is likely that the environment also plays a critical role in the etiology of sporadic PD. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural and industrial chemicals, may contribute to the pathogenesis of several neurodegenerative disorders, including PD. Furthermore, there is a strong correlation between mitochondrial dysfunction and several forms of neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and PD. Interestingly, substantia nigra of patients with PD has been shown to have a mild deficiency in mitochondrial respiratory electron transport chain NADH dehydrogenase (Complex I) activity. This review discusses the role of mitochondrial toxicants in the selective degeneration of dopaminergic neurons targeting the electron transport system that leads to Parkinsonism.

Inflammasome Signaling in the Aging Brain and Age-Related Neurodegenerative Diseases.

Inflammasomes are intracellular protein complexes, members of the innate immune system, and their activation and regulation play an essential role in maintaining homeostatic conditions against exogenous and endogenous stimuli. Inflammasomes occur as cytosolic proteins and assemble into a complex during the recognition of pathogen-associated or danger-associated molecular patterns by pattern-recognition receptors in host cells. The formation of the inflammasome complex elicits signaling molecules of proinflammatory cytokines such as interleukin-1ß and interleukin 18 via activation of caspase-1 in the canonical inflammasome pathway whereas caspase-11 in the case of a mouse and caspase-4 and caspase-5 in the case of humans in the non-canonical inflammasome pathway, resulting in pyroptotic or inflammatory cell death which ultimately leads to neuroinflammation and neurodegenerative diseases. Inflammasome activation, particularly in microglial cells and macrophages, has been linked to aging as well as age-related neurodegenerative diseases. The accumulation of abnormal/ misfolded proteins acts as a ligand for inflammasome activation in neurodegenerative diseases. Although recent studies have revealed the inflammasomes' functionality in both in vitro and in vivo models, many inflammasome signaling cascade activations during biological aging, neuroinflammation, and neurodegeneration are still ambiguous. In this review, we comprehensively unveil the cellular and molecular mechanisms of inflammasome activation during neuronal aging and age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, prion disease, and amyotrophic lateral sclerosis.