Abstract:Ferroptosis is a type of regulated cell death dependent on iron and reactive oxygen species. Ferroptosis is distinct from other cell death modalities, including apoptosis, autophagy and necrosis. Dysregulated ferroptosis has been implicated in a number of diseases, including neuropathy, ischemia reperfusion injury, acute kidney failure and cancer. The digestive system consists of several organs. The morbidity and mortality rates of digestive system cancer are high. The current review summarizes the role of fer… Show more
“…Of particular note is the information that specific RCD ferroptosis induction through sorafenib interference with cysteine transport for GSH synthesis emerged as a side effect in recent studies involving this antineoplastic multiple kinase inhibitor's mode of action in hepatocellular carcinoma (HCC). HCC cells can escape ferroptotic death and become resistant to sorafenib by inducing specific isoform MT-1G and possible other members of the MT family through the action of NRF2/ARE binding resulting in consequent ROS scavenging, which for now seems to be without changes in free iron abundance (28,44,45).…”
Section: Regulation Of Mt Expressionmentioning
confidence: 99%
“…The concept that GSH abundance is probably the main chaperon of iron in LIP, and a direct association between GSH and iron metabolism most visible in the process of RCD ferroptosis opens a wider perspective from both the physiological and toxicological points of view (28,45,57).…”
Section: Further Considerationsmentioning
confidence: 99%
“…Recent data pointed out sex differences even in constitutive autophagy (59) that includes ferritinophagy, as a special autophagy form of ferritin degradation, through nuclear receptor coactivator 4 (NCOA4, known as androgen receptor-specific coactivator ARA70) that directly or through protein interaction may be dependent on steroid hormones (60). Also, ferritinophagy may as well as autophagy, if not regulated and coordinated with protective mechanisms that involve GPX4 activity through use of GSH, lead to iron-mediated ROS induction that oxidizes lipids and causes ferroptosis as a form of non-apoptotic RCD (28,45).…”
Metallothioneins are peculiar cysteine rich, heat resistant, small cellular plasma proteins expressed through almost all life forms. The currently established biological functions of metallothioneins are the homeostasis of essential metals and protection against toxic transitional metals (TM) alongside defence from oxidative stress by direct scavenging of reactive oxygen and nitrogen species (ROS and RNS). In mammals, among the four main evolutionary conserved forms, only the ubiquitously expressed metallothionein 1 and 2 (here abbreviated as MT) are inducible by TM, oxidative stress, glucocorticoids and starvation among various other stimuli. However, more than sixty years after being discovered, metallothioneins still bear unresolved issues about their possible physiological function and regulation. The biological function of MTs has still not been associated with the in vitro-demonstrated capacity of MT interaction with cellular molecules glutathione (GSH) or adenosine triphosphate (ATP), or with the possibility of direct iron-MT binding in the reducing intracellular environment of some organelles, e.g. lysosomes. Iron as the most abundant cellular TM is also one of the main physiological sources of ROS. Moreover, iron exhibits strain, sex and age differences that reflected ROS generation and MT induction in (patho)physiology and toxicology studies. A recent study showed that iron sex differences follows expression of both ferritin and MT leading to wide implications from essential TM interconnectivity to aging. This review places emphasis on biochemically proven but physiologically ignored interactions of MT with iron to stimulate advanced research for establishing a wide frame of the biological roles of MTs important for health and longevity.
“…Of particular note is the information that specific RCD ferroptosis induction through sorafenib interference with cysteine transport for GSH synthesis emerged as a side effect in recent studies involving this antineoplastic multiple kinase inhibitor's mode of action in hepatocellular carcinoma (HCC). HCC cells can escape ferroptotic death and become resistant to sorafenib by inducing specific isoform MT-1G and possible other members of the MT family through the action of NRF2/ARE binding resulting in consequent ROS scavenging, which for now seems to be without changes in free iron abundance (28,44,45).…”
Section: Regulation Of Mt Expressionmentioning
confidence: 99%
“…The concept that GSH abundance is probably the main chaperon of iron in LIP, and a direct association between GSH and iron metabolism most visible in the process of RCD ferroptosis opens a wider perspective from both the physiological and toxicological points of view (28,45,57).…”
Section: Further Considerationsmentioning
confidence: 99%
“…Recent data pointed out sex differences even in constitutive autophagy (59) that includes ferritinophagy, as a special autophagy form of ferritin degradation, through nuclear receptor coactivator 4 (NCOA4, known as androgen receptor-specific coactivator ARA70) that directly or through protein interaction may be dependent on steroid hormones (60). Also, ferritinophagy may as well as autophagy, if not regulated and coordinated with protective mechanisms that involve GPX4 activity through use of GSH, lead to iron-mediated ROS induction that oxidizes lipids and causes ferroptosis as a form of non-apoptotic RCD (28,45).…”
Metallothioneins are peculiar cysteine rich, heat resistant, small cellular plasma proteins expressed through almost all life forms. The currently established biological functions of metallothioneins are the homeostasis of essential metals and protection against toxic transitional metals (TM) alongside defence from oxidative stress by direct scavenging of reactive oxygen and nitrogen species (ROS and RNS). In mammals, among the four main evolutionary conserved forms, only the ubiquitously expressed metallothionein 1 and 2 (here abbreviated as MT) are inducible by TM, oxidative stress, glucocorticoids and starvation among various other stimuli. However, more than sixty years after being discovered, metallothioneins still bear unresolved issues about their possible physiological function and regulation. The biological function of MTs has still not been associated with the in vitro-demonstrated capacity of MT interaction with cellular molecules glutathione (GSH) or adenosine triphosphate (ATP), or with the possibility of direct iron-MT binding in the reducing intracellular environment of some organelles, e.g. lysosomes. Iron as the most abundant cellular TM is also one of the main physiological sources of ROS. Moreover, iron exhibits strain, sex and age differences that reflected ROS generation and MT induction in (patho)physiology and toxicology studies. A recent study showed that iron sex differences follows expression of both ferritin and MT leading to wide implications from essential TM interconnectivity to aging. This review places emphasis on biochemically proven but physiologically ignored interactions of MT with iron to stimulate advanced research for establishing a wide frame of the biological roles of MTs important for health and longevity.
“…Collectively, we suppose that therapeutic strategy specific to hepatic disease on divergent cell type would be prioritized due to complicated function of ferroptosis itself. In current review, we focus on the relevance of ferroptosis and pathophysiological aspects of ferroptotic manipulation in a variety of non-cancer liver diseases, whereas the role of ferroptosis in HCC has been well documented by others and ours 21 , 22 . Fig.…”
Ferroptosis is an iron- and lipotoxicity-dependent form of regulated cell death (RCD). It is morphologically and biochemically distinct from characteristics of other cell death. This modality has been intensively investigated in recent years due to its involvement in a wide array of pathologies, including cancer, neurodegenerative diseases, and acute kidney injury. Dysregulation of ferroptosis has also been linked to various liver diseases and its modification may provide a hopeful and attractive therapeutic concept. Indeed, targeting ferroptosis may prevent the pathophysiological progression of several liver diseases, such as hemochromatosis, nonalcoholic steatohepatitis, and ethanol-induced liver injury. On the contrary, enhancing ferroptosis may promote sorafenib-induced ferroptosis and pave the way for combination therapy in hepatocellular carcinoma. Glutathione peroxidase 4 (GPx4) and system xcâ have been identified as key players to mediate ferroptosis pathway. More recently diverse signaling pathways have also been observed. The connection between ferroptosis and other forms of RCD is intricate and compelling, where discoveries in this field advance our understanding of cell survival and fate. In this review, we summarize the central molecular machinery of ferroptosis, describe the role of ferroptosis in non-cancer hepatic disease conditions and discuss the potential to manipulate ferroptosis as a therapeutic strategy.
“…Piperlongumine (PL), also known as piplartine ( Fig. 1), has been well documented for its biological activities against various human diseases, including digestive system cancer [17], colorectal cancer [18], breast cancer [19], rheumatoid arthritis [20], and platelet aggregation [21]. PL has been isolated from Piper plants, especially the roots of Piper longum [22], and has been developed for formulation in nanofiber mats that are used in PL-eluting gastrointestinal stents to treat cholangiocarcinoma [23].…”
In this study, the antimelanogenic activity of piperlongumine in murine B16F10 melanoma cells and zebrafish was investigated, and its mode of antimelanogenic action was elucidated using quantitative reverse transcription-polymerase chain reaction. A melanocyte-stimulating hormone (α-MSH, 200 nM) was used to induce melanin production in B16F10 melanoma cells, and kojic acid (200 ΌM) was used as a positive control. Piperlongumine had no inhibitory effects on cell growth at the treated concentrations (3 and 6 ΌM), and it significantly reduced total melanin production. Piperlongumine decreased the expression of Mitf, Tyr, Trp-1, and Trp-2 and tyrosinase activity was also dramatically reduced by the piper amide addition under α-MSH treatment. With these findings, zebrafish embryos were used to confirm antimelanogenic activity of piperlongumine, and it showed the potent antimelanogenic activity at the concentration of 1 ΌM. Altogether, piperlongumine has potent antimelanogenic activity, and these results support it as a candidate for natural depigmentation agent in a cosmetic and pharmaceutical industries.
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