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Liver fibrosis is an intrinsic repair process of chronic injury with excessive deposition of extracellular matrix. As an early stage of various liver diseases, liver fibrosis is a reversible pathological process. Therefore, if not being controlled in time, liver fibrosis will evolve into cirrhosis, liver failure, and liver cancer. It has been demonstrated that hepatic stellate cells (HSCs) play a crucial role in the formation of liver fibrosis. In particular, the activation of HSCs is a key step for liver fibrosis. Recent researches have suggested that autophagy and inflammasome have biological effect on HSC activation. Herein, we review current studies about the impact of autophagy and NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome on liver fibrosis and the underlying mechanisms. [ABSTRACT FROM AUTHOR]

The harm of air pollution to public health has become a research hotspot, especially atmospheric fine-particulate matter (PM2.5). In recent years, epidemiological investigations have confirmed that PM2.5 is closely related to chronic kidney disease and membranous nephropathy Basic research has demonstrated that PM2.5 has an impact on the normal function of the kidneys through accumulation in the kidney, endothelial dysfunction, abnormal renin-angiotensin system, and immune complex deposition. Moreover, the mechanism of PM2.5 damage to the kidney involves inflammation, oxidative stress, apoptosis, DNA damage, and autophagy. In this review, we summarized the latest developments in the effects of PM2.5 on kidney disease in human and animal studies, so as to provide new ideas for the prevention and treatment of kidney disease. [ABSTRACT FROM AUTHOR]

Abstract The activation of hepatic stellate cells (HSCs) is a key event in the development of hepatic fibrosis caused by arsenic. However, it is unclear how arsenic induces the activation of HSCs. In the present study, we found that arsenic trioxide (As 2 O 3) induced liver tissue damage, stimulated autophagy and HSCs activation, and increased collagen accumulation in the liver of mice. Supplemented with taurine (Tau) attenuated the changes mentioned above caused by As 2 O 3. In human hepatic stellate cell line LX-2 cells, we found that As 2 O 3 -induced activation of HSCs was autophagy-dependent, and we found that peroxisome proliferator activated receptors alpha (PPARα) played an important role in arsenic-induced HSCs activation. In addition, inhibiting autophagy and PPARα alleviated the activation of HSCs and lipid droplet loss induced by As 2 O 3. Moreover, we found that Tau alleviated As 2 O 3 -induced elevation of autophagy and PPARα expression, and activation of the HSCs. Our results indicated that autophagy was regulated by PPARα and was involved in lipid droplet loss during the activation of HSCs. Tau alleviated As 2 O 3 -induced HSCs activation by inhibiting the PPARα/autophagy pathway. These findings give an innovative insight into the association of PPARα, autophagy, the activation of HSCs and hepatic fibrosis induced by As 2 O 3. Highlights • As 2 O 3 -induced the activation of hepatic stellate cells was autophagy-dependent. • PPARα played an important role in arsenic-induced HSCs activation. • Taurine decreased the level of autophagy, and inhibited the activity of hepatic stellate cells. [ABSTRACT FROM AUTHOR]

Patulin (PAT), a kind of mycotoxin, is produced by many common fungi in fruit and vegetable-based products. It has been shown to cause hepatotoxicity. However, the possible mechanisms are not completely elucidated. The present study aimed to characterize the role of autophagic-inflammasomal pathway on pyroptosis induced by PAT. In mouse livers, PAT induced pyroptosis, and increased inflammation through the activation of NLRP3 inflammasome. In liver cells, we noticed that PAT induced pyroptotic cell death, which was confirmed by the activation of GSDMD, caspase-1, the release of LDH, and the result of PI/Hoechst assay. In addition, PAT-induced pyroptosis was dependent upon the activation of NLRP3 inflammasome and the release of cathepsin B. Cells had less expression of caspase-1 and IL-1β protein levels after treated by NLRP3 inhibitor MCC950 or cathepsin B inhibitor CA-074Me. The expression of GSDMD and IL-1β protein levels were also decrease after treated by caspase-1 inhibitor Ac-YVAD-cmk. Moreover, autophagy inhibitor 3-methyladenine (3-MA) attenuated PAT-induced increase in cytoplasmic cathepsin B expression, and subsequent LDH release, the activation of NLRP3 inflamosomes, pyroptotic cell death, and inflammation. These findings suggested that PAT-induced pyroptosis maybe through autophagy-cathepsin B-inflammasomal pathway in the liver. These results provide new mechanistic insights into PAT-induced hepatotoxicity. • PAT could induce pyroptosis in mice liver and liver cells. • Autophagy may play an important role in PAT-induced pyroptosis. • PAT-induced pyroptosis maybe through autophagy-cathepsin B-inflammasomal pathway. [ABSTRACT FROM AUTHOR]

Glioma is the most common type of malignant tumor of the nervous system, and aggressiveness and recurrence are major obstacles for treatment. This study is designed to explore the effects of amentoflavone (AF) on glioma, and to investigate the underlying mechanism of the anti-cancer activities of AF. Cell morphology was recorded under microscopy. Cell viability and cell death ratio were determined by CCK-8 assay and lactate dehydrogenase (LDH) release assay, respectively. Cell cycle progression was assessed by flow cytometry. The levels of iron, MDA (malondialdehyde), lipid ROS, and GSH (reduced glutathione) were assessed by ELISA kit. The cycle-related proteins, ferroptosis-related protein, autophagy-related protein, and the phosphorylation of AMPK, mTOR and p70S6K were analyzed by western blotting. The autophagic flux was observed by transfecting cells with mRFP-GFP-LC3 plasmids. The xenograft murine models were established to analyze the effects of amentoflavone in vivo. The immunohistochemistry assay was performed to analyze the expression of LC3B, Beclin1, ATG5, ATG7, and ferritin heavy chain (FTH). Our results showed that AF treatment led to reduction in cell viability and cell death. In addition, AF was found to block cell cycle progression in a dose-dependent manner in vitro. Following treatment with AF, the intracellular levels of iron, MDA, and lipid OS were increased, and the levels of GSH and the mitochondrial membrane potential were reduced. In addition, our results showed that AF promoted the autophagic by regulating autophagy-relevant proteins. Our results also showed that the autophagy-induction by AF was associated with regulation of AMPK/mTOR signaling. Mechanistically, the inhibition effects of AF on glioma cell were reversed by DFO, ferreostatin-1 as well as upregulation of FTH. Meanwhile, the FTH levels were increased by compound C and knockdown of ATG7. Moreover, both autophagy inhibitor Baf A1 and knockdown of ATG7 were able to compromising AF-induce ferroptosis and cell death. In vivo , the tumor growth was suppressed by AF in a dose-dependent manner. The level of MDA in the tumor tissue was increased while the level of GSH in tumor tissue was decreased by AF in a dose-dependent manner. Furthermore, the expression of LC3B, Beclin1, ATG5, ATG7 were increased, and the expression of FTH were decreased by AF in a dose-dependent manner in vivo. Conclusion These results demonstrate that AF triggered ferroptosis in autophagy-dependent manner. Our results suggest that AF has the potential to be considered as a novel treatment agent in glioma. [ABSTRACT FROM AUTHOR]

Long-term exposure to arsenic can cause liver injury and fibrosis. The activation of hepatic stellate cells (HSCs) plays an essential role in the process of liver fibrosis. We found that NaAsO 2 caused liver damage and fibrosis in vivo , accompanied by excessive collagen deposition and HSCs activation. In addition, NaAsO 2 upregulated autophagy flux, elevated the level of cytoplasmic cathepsin B (CTSB), and activated the NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome in a subtle way. Consistent with these findings in vivo , we demonstrated that NaAsO 2 -induced activation of HSCs depended on CTSB-mediated NLRP3 inflammasome activation in HSC-t6 cells and rats primary HSCs. Moreover, inhibition of autophagy decreased the cytoplasmic CTSB and alleviated the activation of the NLRP3 inflammasome, thereby attenuating the NaAsO 2 -induced HSCs activation. In summary, these results indicated that NaAsO 2 induced HSCs activation via autophagic-CTSB-NLRP3 inflammasome pathway. These findings may provide a novel insight into the potential mechanism of NaAsO 2 -induced liver fibrosis. Image 1 • Chronic arsenic exposure leads to inflammation and fibrosis in livers. • NLRP3 inflammasome plays a crucial role in the activation of HSCs induced by arsenic. • Autophagy and lysosomal rupture are involved in the arsenic-activated of NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

• Ferroptosis existed in animal models of NaAsO 2 -induced pancreatic dysfunction. • NaAsO 2 -induced ferroptotic cell death is relied on the MtROS-dependent autophagy. • NaAsO 2 -induced ferroptosis involves MtROS, autophagy, ferritin. Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO 2 -induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin. [ABSTRACT FROM AUTHOR]

• ZEA triggered pyroptosis in INS-1 cells. • ZEA-induced pyroptosis was NLRP3 inflammasome-dependent. • ZEA-induced activation of NLRP3 inflammasome was regulated by autophagy. • ZEA-triggered NF-κB p65 activation was involved in NLRP3 inflammasome activation. Zearalenone (ZEA), one of the mycotoxins widely found in food and feed, can stimulate an inflammatory reaction. In the present study, we demonstrated that ZEA induced the activation of NLRP3 inflammasome even pyroptotic cell death in rat Insulinoma Cell Line (INS-1). Meanwhile, according to the results of western blot and TEM, the level of autophagy was elevated by ZEA, which protected against the activation of NLRP3 inflammasome and inflammatory response caused by ZEA. Furthermore, we indicated that ZEA-induced NF-κB p65 activation contributed to the activation of the NLRP3 inflammasome, inflammatory response, and pyroptosis in INS-1 cells, which were indicated by western blot and immunofluorescence, and the activation of NF-κB p65 induced by ZEA was autophagy-dependent. This study demonstrates that ZEA induces NLRP3-dependent pyroptosis via activation of NF-κB modulated by autophagy in INS-1 cells. [ABSTRACT FROM AUTHOR]

• DOX induced autophagy-depending apoptosis in HUVECs. • DOX-induced apoptosis was via lysosomal-mitochondrial axis to some extent. • PQQ protected HUVECs from autophagy-dependent apoptosis induced by DOX. The cardiotoxicity of doxorubicin (DOX) limits its clinical use in the treatment of a variety of solid tumors and malignant hematologic disease. However, the mechanism by which it causes cardiotoxicity is not fully understood. Apoptosis has been regarded as one of mechanisms underlying the cardiotoxic effects of DOX. In our study, we found that treatment of human umbilical vein endothelial cells (HUVECs) with DOX induced autophagy and apoptosis in a dose- and time-dependent manner. Treatment with DOX induced autophagy at earlier time (3 h), then lysosomal membrane permeabilization (LMP) altered after treatment for 12 h which followed by the release of cathepsin D (CTSD). Lysosome-associated membrane proteins-1 and -2 (LAMP1 and LAMP2) were decreased in DOX-treated cells. Additionally, DOX induced the collapse of mitochondrial transmembrane potential, reduction of translocase of the outer mitochondrial membrane-20 (TOM-20), and release of cytochrome c. Furthermore, autophagy inhibitor 3-MA relieved DOX-induced apoptosis as assessed by the expression of cleaved caspase-3, cleaved caspase-9 and TUNEL assay. CTSD inhibitor, pepstatin A, upregulated TOM-20 and suppressed the mitochondria release of cytochrome c as well as apoptosis under DOX stress. Pyrroloquinoline quinine (PQQ), a new B vitamin, ameliorated aforementioned phenomenon. In conclusion, our results suggested that DOX-induced apoptosis was autophagy-dependent via lysosomal-mitochondrial axis. PQQ had an ability to protect cell from autophagy-dependent apoptosis induced by DOX via lysosomal-mitochondrial axis to some extent. This study provided new mechanistic insight toward understanding the pathogenesis of DOX-induced cardiotoxicity and the protection effect of PQQ. [ABSTRACT FROM AUTHOR]