G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity

Pramanick, Arnab; Chakraborti, Sreemoyee; Mahata, Tarun; Basak, Madhuri; Das, Kiran; Verma, Sumit Kumar; Sengar, Abhishek Singh; Singh, Praveen Kumar; Kumar, Pranesh; Bhattacharya, Bolay; Biswas, Sayan; Pal, Parag Baran; Sarkar, Subhasish; Agrawal, Vinita; Saha, Sudipta; Nath, Debjani; Chatterjee, Suvro; Stewart, Adele; Maity, Biswanath

doi:10.1016/j.redox.2021.101965

Cited by 8 publications

(16 citation statements)

References 47 publications

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“…At 8–10 weeks of age animals were exposed to chemotherapeutic drug treatment regimens as outlined above. For the double KD experiments, Invivofectamine 3.0 (Thermo Fisher Scientific, Waltham, MA, USA) was used to deliver scramble (WT) or RGS7‐targeted (RGS7 KD) shRNA to the liver by tail vein injection as we previously described 19 . Mice received three injections with a 3‐day interval between injections beginning at 8 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

et al. 2023

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Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin‐induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin‐treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin‐related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro‐oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

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Section: Methodsmentioning

confidence: 99%

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

et al. 2023

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“…Reagents were utilized as per the manufacturers’ protocols. Immunohistochemical staining of both mouse and human tissue sections was performed as per a standard protocol [ 32 ]. For RGS11, 4-Hydroxynonenal (4HNE), and CaMKII staining, 7–10 sections were stained from each animal with 5 pictures randomly selected from each slide.…”

Section: Methodsmentioning

confidence: 99%

“…Rather than mediating signal transduction via G protein coupled receptors, Gβ 5 forms a requisite co-stabilizing complex with members of the R7 subfamily of Regulators of G protein Signaling (RGS) proteins [ 28 ], 3 of which are expressed in heart (RGS6, RGS7, and RGS11) [ 29 , 30 ]. Like Gβ 5 , RGS6 is up-regulated following doxorubicin exposure [ 27 , 31 ], and the RGS6-Gβ 5 complex has been shown to ATM serine/threonine kinase (ATM)-dependent apoptotic signaling [ 27 , 31 , 32 ]. However, the function of RGS11 in heart remains unknown.…”

Section: Introductionmentioning

confidence: 99%

RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis

Das¹,

Basak²,

Mahata³

et al. 2022

Redox Biology

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“…Furthermore, the inhibition of NLRP3 inflammasome, autophagy, and CTSB, and Tau treatment did not reduce lipid accumulation induced by As 2 O 3 , indicating that Tau dampened As 2 O 3 -induced liver inflammation and pyroptosis by inhibiting the autophagic-CTSB-NLRP3 inflammasome pathway rather than reducing lipid accumulation [ 63 ]. Autophagic death often contributes to many liver disorders [ 64 , 65 ]. Similarly, in the above study, As 2 O 3 -induced autophagy leads to hepatocyte pyroptosis, which is involved in the development of NASH.…”

Section: The Role Of Autophagy and Pyroptosis In Liver Disordersmentioning

confidence: 99%

The Role of Autophagy and Pyroptosis in Liver Disorders

Zhao

Liu

Yang

et al. 2022

IJMS

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Pyroptosis is a programmed cell death caused by inflammasomes, which can detect cell cytosolic contamination or disturbance. In pyroptosis, caspase-1 or caspase-11/4/5 is activated, cleaving gasdermin D to separate its N-terminal pore-forming domain (PFD). The oligomerization of PFD forms macropores in the membrane, resulting in swelling and membrane rupture. According to the different mechanisms, pyroptosis can be divided into three types: canonical pathway-mediated pyroptosis, non-canonical pathway-mediated pyroptosis, and caspase-3-induced pyroptosis. Pyroptosis has been reported to play an important role in many tissues and organs, including the liver. Autophagy is a highly conserved process of the eukaryotic cell cycle. It plays an important role in cell survival and maintenance by degrading organelles, proteins and macromolecules in the cytoplasm. Therefore, the dysfunction of this process is involved in a variety of pathological processes. In recent years, autophagy and pyroptosis and their interactions have been proven to play an important role in various physiological and pathological processes, and have gradually attracted more and more attention to become a research hotspot. Therefore, this review summarized the role of autophagy and pyroptosis in liver disorders, and analyzed the related mechanism to provide a basis for future research.

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G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity

Cited by 8 publications

References 47 publications

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis

The Role of Autophagy and Pyroptosis in Liver Disorders

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