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Micronutrients for Improved Management of Huntington’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Using a transgenic HD mouse model, caspase-1 and caspase-3 were found to be transcriptionally upregulated and activated. The degree of activation of caspases correlated with the progression of this disease in HD mice.72 Similar observations were made in autopsied brain samples of HD patients. Activation of caspase-2 cleaves HD protein selectively at amino acid 552, and fragmented HD proteins become aggregated. The aggregated form of HD protein causes selective neuronal cell death in the striatum and cortex of autopsied brain samples of human HD as well as in HD mouse model expressing full length HD gene (YAC72 mice).73 Inhibitors of caspase delayed the onset of symptoms in the transgenic HD mouse model. Treatment of animals with quinolinic acid- and 3-NP increased oxidative stress and induced HD-like changes in the brain.74,75 HD protein also activates microglia causing the release of pro-inflammatory cytokines and reactive oxygen species (ROS).
Basics of Radiation and Radiotherapy
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Prakash Srinivasan Timiri Shanmugam, Pramila Bakthavachalam
Following exposure to ionizing radiation, cells can undergo apoptosis, mitotic catastrophe, and/or terminal cell arrest. The extent to which one mode of cell death predominates over another is unclear but may be influenced by cell type, radiation dose, and the cell's microenvironment (e.g., relative oxygenation). Depending on the severity of damage, the tumor suppressor protein P53 can trigger cell cycle arrest or initiate apoptosis via transcriptional activation of pro-apoptotic proteins, including those of the Bcl-2 family. P53-induced protein with a death domain, another P53 pro-apoptotic target, also plays a critical role in DNA damage-induced apoptosis, leading to caspase-2 activation and subsequent mitochondrial cytochrome c release.
Oncolytic Viruses and Histone Deacetylase Inhibitors
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Vaishali M. Patil, Satya P. Gupta
Some exceptional results were observed when HDIs were used in combination with engineered oncolytic adenoviruses (Ad5-TRAIL adenoviral vector), such as enhanced transgene expression, increased Ad5-TRAIL infection, induced CAR expression, and enhanced cancer cell sensitivity to TRAIL-induced apoptosis (Vanoosten et al 2005, 2006). Some mechanistic studies focused on HDAC inhibition, which caused decreased PCKC2 activity, activation of caspase-2, and partial cleavage of caspase-8 to sensitize the tumor cells to TRAIL (Vanoosten et al. 2007).
Induction of caspase-2 gene expression in carboxyl-functionalized carbon nanotube-treated human T-cell leukemia (Jurkat) cell line
Published in Drug and Chemical Toxicology, 2021
Shirin Lotfipanah, Majid Zeinali, Parichehreh Yaghmaei
Caspase-2 exhibits features of both initiator and effector caspases, but its role in apoptosis is controversial and its function as an initiator/effector caspase is still unknown (Fava et al. 2012, Imre et al. 2017). In contrast to conventional initiator caspases-8/9, caspase-2 does not exert enzymatic activation function on effector caspases-3/6/7. It is shown that during pore-forming toxin (PFT)-mediated apoptosis in different cell type, caspase-2 may function as an initiator caspase (Imre et al. 2017). Fava et al. (2012) believe that caspase-2 does not have a direct role in death, neither as an initiator nor as an effector caspase. A damage-sensing function which will be resulted in limited proteolysis for signaling has been suggested for caspase-2 (Fava et al. 2012). Endoplasmic reticulum (ER) stress or some damages to DNA may be resulted in activation of caspase-2 and regulation of cell death.
Regulation of microRNAs by IRE1α in apoptosis: implications for the pathomechanism of neurodegenerative diseases
Published in International Journal of Neuroscience, 2020
Zhonghao Su, Lanyue Sheng, Ping Yu, Na Ren, Yajuan Li, Zhenxia Qin
UPR miRNAs can act as adaptive or apoptotic, depending on their expression profile changes, specific targets, and diseases model that is involved. It has been reported several pro-apoptotic miRNAs as effector contribute to induction of IRE1α-related apoptosis in non-NDs models such as miR-17 [35,36], miR-34a [36], miR-96 [36], miR-7 [37], miR-216b [38] and miR-125b [36]. Under prolonged stress, accumulating evidence supports the decay of particular miRNAs through RIDD process plays a role in the regulation of apoptosis. It was shown that the induction of a pro-apoptotic protein Caspase-2 [36], thioredoxin-interacting protein (TXNIP) [35], transmembrane E3 ligase RNF183 [37] and c-Jun [38] through IRE1α-dependent specific miRNAs degradation mediated apoptosis in vitro studies. Caspase-2 as an orphan is the most evolutionarily conserved of Caspases identified to date. Although its role in the apoptotic cascade is still elusive, Caspase-2 functions as a tumor suppressor [39]. The endogenous level of RNF183 is most abundant in the testes and kidneys in mouse tissues and may play a role in regulating apoptosis there. RNF183 is implicated in the regulation of colorectal cancer [40]. TXNIP a regulator of ER stress and a tumor suppressor gene play a pro-apoptotic role [41]. c-Jun is a component of the AP-1 transcription factor and JNK has previously been demonstrated to activated and contribute to Ire1α-dependent UPR signaling pathway to induce apoptosis.
Emerging therapeutic targets for NASH: key innovations at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
Another potential target downstream of IRE1α is Caspase 2. The activation of regulated IRE1α-dependent decay (RIDD) in UPR upon ER stress leads to increased protein translation of Caspase 2 by the decay of regulating miRNAs [43]. Both genetic deletion of Caspase 2 and pharmacological inhibition of Caspase 2 activity can alleviate histological features of NASH, including inflammation and fibrosis, and expression of ER stress markers [38]. Though Caspase 2 has initially been implicated in ER-stress mediated apoptosis [43], the deletion of Caspase 2 does not have any impact on ER-stress mediated apoptosis in vitro [44]. Unlike other caspases, Caspase 2 localizes in the ER lumen and the Golgi and does not seem to be directly implicated in lipotoxic cell death [44,45]. Instead, Caspase 2 recently has been identified to promote NASH by cleavage of site 1 protease (S1P) and subsequent activation of sterol regulatory element-binding protein 1/2 (SREBP1/2) signaling which positively regulates DNL and hepatocellular free cholesterol accumulation [38]. Most intriguingly, the deletion and pharmacologic inhibition of Caspase 2 leads to increased energy expenditure and prevents high-fat diet-induced body weight gain, involving increased expression of uncoupling protein 1 (UCP1) and adipose tissue browning in mice [38]. This goes along with reduced adipocyte size, alleviated adipose tissue inflammation and reduced circulating triglycerides and cholesterol [38]. Thus, Caspase 2 inhibition seems a promising dual therapeutic approach, targeting both liver disease and metabolic risk factors in patients with NASH.