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Significance: Iron is an essential element for every life on earth as a primary media for electron flow. Sulfur compounds as sulfhydryls counteract catalytic activity of iron whereas sulfur overdose is also toxic. In aerobic organisms, oxygen is the major media for electron transfer with higher intracellular mobility, which cooperates with the iron system. Based on the importance of iron, there is no active pathway to excrete iron outside the body in higher species. Whereas bacterial infection causes a scramble for iron in situ, cancer can be the outcome of the side effects of long use of iron and oxygen. Recent Advances: Ferroptosis is a recently coined cell death, defined as catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation. Researchers recently recognized that ferroptosis is involved in a variety of physiological and pathological contexts, including embryonic erythropoiesis, aging, neurodegeneration and cancer cell death. Alternatively, carcinogenesis is a process to obtain iron addiction with ferroptosis-resistance, based on rodent animal studies. Critical Issues: Here we propose that ferroptosis is three-dimensionally regulated by iron, sulfur and oxygen, which correspond to oxidants, antioxidants and membrane fluidity with susceptibility to lipid peroxidation, respectively. Future Directions: Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron. Antioxid. Redox Signal. 39, 807–815. [ABSTRACT FROM AUTHOR]

Cancer is the primary cause of human mortality in Japan since 1981. Although numerous novel therapies have been developed and applied in clinics, the number of deaths from cancer is still increasing worldwide. It is time to consider the strategy of cancer prevention more seriously. Here we propose a hypothesis that cancer can be side effects of long time-use of iron and oxygen and that carcinogenesis is an evolution-like cellular events to obtain "iron addiction with ferroptosis-resistance" where genes and environment interact each other. Among the recognized genetic risk factors for carcinogenesis, we here focus on BRCA1 tumor suppressor gene and how environmental factors, including daily life exposure and diets, may impact toward carcinogenesis under BRCA1 haploinsufficiency. Although mice models of BRCA1 mutants have not been successful for decades in generating phenotype mimicking the human counterparts, a rat model of BRCA1 mutant was recently established that reasonably mimics the human phenotype. Two distinct categories of oxidative stress, one by radiation and one by iron-catalyzed Fenton reaction, promoted carcinogenesis in Brca1 rat mutants. Furthermore, mitochondrial damage followed by alteration of iron metabolism finally resulted in ferroptosis-resistance of target cells in carcinogenesis. These suggest a possibility that cancer prevention by active pharmacological intervention may be possible for BRCA1 mutants to increase the quality of their life rather than preventive mastectomy and/or oophorectomy. [ABSTRACT FROM AUTHOR]

Objectives: This network meta-analysis compares different lasers, placebo, and no treatment in terms of their effects on dentine hypersensitivity (DH) immediately after treatment and over the long term (1 month). Methods: A systematic electronic literature search of four databases and a manual search were performed to identify randomized controlled trials (RCTs) examining different laser treatments for the treatment of DH. Pairwise and network meta-analyses were performed to analyze the desensitization effect immediately after treatment and over the long term. The risk of bias was assessed based on the Cochrane guidelines and funnel plots. The quality of the evidence, statistical heterogeneity, inconsistencies, and ranking probability were also evaluated. Results: A total of 11 RCTs were included in the network meta-analysis; 11 and 9 of these studies analyzed immediate and long-term effects, respectively. All four types of laser had a better desensitizing effect than controls immediately after treatment and over the long term, but there were no significant differences among the four different lasers. There was a significant placebo effect immediately after treatment. The laser with the highest probability of being the most effective treatment for DH was Er,Cr:YSGG immediately after treatment and over the long term (73% and 47%, respectively). Conclusions: All four types of laser had significantly better effects than no treatment on DH immediately after treatment and in the long term, but there were no significant differences among the four lasers. In addition, there was a significant placebo effect, supporting the importance of including a placebo group in future studies. Furthermore, Er,Cr:YSGG may be the most effective laser for the treatment of DH immediately and over the long term. Clinical relevance: This study used network meta-analyses to compare different lasers, placebo, and no treatment over different time periods, which is to provide guidance for selecting an appropriate laser treatment in patients with DH. [ABSTRACT FROM AUTHOR]

Current progress in biology and medical science is based on the observation at the level of nanometers via electron microscopy and computation. Of note, the size of most cells in higher species exists in a limited range from 5 to 50 μm. Recently, it was demonstrated that endogenous extracellular nanoparticles play a role in communication among various cellular types in a variety of contexts. Among them, exosomes in serum have been established as biomarkers for human diseases by analyzing the cargo molecules. No life on the earth can survive without iron. However, excess iron can be a risk for carcinogenesis in rodents and humans. Nano-sized molecules may cause unexpected bioeffects, including carcinogenesis, which is a process to establish cellular iron addiction with ferroptosis-resistance. Asbestos and carbon nanotubes are the typical examples, leading to carcinogenesis by the alteration of iron metabolism. Recently, we found that CD63, one of the representative markers of exosomes, is under the regulation of iron-responsive element/iron-regulatory protein system. This is a safe strategy to share excess iron in the form of holo-ferritin between iron-sufficient and -deficient cells. On the other hand, damaged cells may secrete holo-ferritin-loaded exosomes as in the case of macrophages in ferroptosis after asbestos exposure. These holo-ferritin-loaded exosomes can cause mutagenic DNA damage in the recipient mesothelial cells. Thus, there is an iron link between exogenous and endogenous nanoparticles, which requires further investigation for better understanding and the future applications. [Display omitted] • Exogenous and endogenous fine particles cooperate in cells. • Nano-sized fibrous materials can be carcinogenic by causing iron excess. • Iron replete cells secrete extracellular vesicles (EVs) containing holoferritin. • Ferroptotic macrophages engulfing asbestos secrete EVs containing holoferritin. [ABSTRACT FROM AUTHOR]

This commentary concerns a highly cited paper by Robert L Heath and Lester Packer in Archives of Biochemistry and Biophysics published in 1968. Chloroplasts are organelles in algae and plants that use light energy for carbon fixation and oxygen production. These authors discovered that isolated chloroplasts exposed to visible light undergo a cyclic peroxidation of tri-unsaturated fatty acids, contributing to the double-edged sword concept of electron transfer reactions. [ABSTRACT FROM AUTHOR]

Plasma is the fourth physical state of matter, characterized by an ionized gaseous mixture, after solid, liquid, and gas phases, and contains a wide array of components such as ions, electrons, radicals, and ultraviolet ray. Whereas the sun and thunder are typical natural plasma, recent progress in the electronics enabled the generation of body-temperature plasma, designated as low-temperature plasma (LTP) or non-thermal plasma since the 1990s. LTP has attracted the attention of researchers for possible biological and medical applications. All the living species on earth utilize water as essential media for solvents and molecular transport. Thus, biological application of LTP naturally intervenes water whether LTP is exposed directly or indirectly, where plasma-activated lactate (PAL) is a standard, containing H2O2, NO2− and other identified molecules. Electron spin resonance and immunohistochemical studies demonstrated that LTP exposure is a handy method to load local oxidative stress. Cancer cells are characterized by persistent self-replication and high cytosolic catalytic Fe(II). Therefore, both direct exposure of LTP and PAL can provide higher damage to cancer cells in comparison to non-tumorous cells, which has been demonstrated in a variety of cancer types. The cell death mode is either apoptosis or ferroptosis, depending on the cancer-type. Thus, LTP and PAL are expected to work as an additional cancer therapy to the established guideline protocols, especially for use in somatic cavities or surgical margins. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a major cause of human mortality worldwide. No life on earth can live without iron. Persistent oxidative stress resulting from continuous use of iron and oxygen may be a fundamental cause of carcinogenesis. Many animal models demonstrated that excess iron may lead to carcinogenesis. This is supported by a variety of human epidemiological data on cancer risk and prognosis. Cancer is basically a disease of the genome with persistently activated oncogenes and inactivated tumor suppressor genes through which iron addiction with ferroptosis-resistance is established. We predict that fine use of nanomaterials and non-thermal plasma may be able to reverse this situation. Evolution from the first life on earth to humans took ~3.8 billion years. During the time there have been countless struggles among the species. Mycobacterium tuberculosis was the last major uncontrollable species against the human public health worldwide. After the victory with antibiotics, cancer has become the leading cause of death since 1981 in Japan. Considering that life inevitably depends on ceaseless electron transfers through iron and oxygen, we believe that carcinogenesis is intrinsically unavoidable side effects of using iron and oxygen. Many animal models unequivocally revealed that excess iron is a risk for carcinogenesis. This is supported by a variety of human epidemiological data on cancer risk and prognosis. Cancer is basically a disease of the genome with persistently activated oncogenes and inactivated tumor suppressor genes through which iron addiction with ferroptosis-resistance is maintained. Engineering has made a great advance in the past 50 years. In particular, nanotechnology is distinct in that the size of the engineered molecules is similar to that of our biomolecules. While some nano-molecules are found carcinogenic, there are principles to avoid such carcinogenicity with a smart possibility to use nano-molecules to specifically kill cancer cells. Non-thermal plasma is another modality to fight against cancer. [ABSTRACT FROM AUTHOR]

Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here, we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC–MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Although direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis. [ABSTRACT FROM AUTHOR]