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1.
Biochem Biophys Res Commun ; 612: 1-7, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35500436

RESUMO

Cranial radiation therapy (CRT) is an effective treatment for brain tumors; however, it also causes brain injuries. The pediatric brain is considered especially vulnerable compared to the adult brain; thus, brain injuries caused by CRT may severely affect their quality of life. In this study, we determined the neuroprotective effects of nasal oxytocin administration following cranial radiation in mice. We investigated the cognitive behavior of mice (novel object recognition test and novel object location test), phosphorylated histone H2AX (γ-H2AX) and K+-Cl- transporter (KCC2) by immunohistochemical analysis of the hippocampal sections, and neuronal cells by immunocytochemistry after radiation and oxytocin administration. We found that the number of γ-H2AX foci was increased, and the surface signal intensity of KCC2 immunofluorescence was decreased in cells that were irradiated with X-rays (1.5 Gy, for three consecutive days) compared with cells that were not. Furthermore, using MQAE, we found that the intracellular chloride ion concentration was downregulated in oxytocin-treated cells by increasing surface KCC2 expression. These results indicate that nasal oxytocin administration after cranial irradiation attenuates cognitive dysfunction in mice and exerts multifaceted neuroprotective effects on DNA damage and maintains chloride ion concentration in neuronal cells.

2.
Curr Drug Res Rev ; 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35431009

RESUMO

BACKGROUND: Methamphetamine (METH) is classified as a Schedule II stimulant drug under the United Nations Convention on Psychotropic Substances of 1971. METH and other amphetamine analogues (AMPHs) are powerful addictive drugs. Treatments are needed to treat the symptoms of METH addiction, chronic METH use, and acute METH overdose. No effective treatment for METH abuse has been established because alterations of brain functions under excessive intake of abused drug intake are largely irreversible due in part to brain damage that occurs in the course of chronic METH use. OBJECTIVE: Modulation of brain histamine neurotransmission is involved in several neuropsychiatric disorders, including substance use disorders. This review discusses the possible mechanisms underlying the therapeutic effects of histamine H3 receptor antagonists on symptoms of methamphetamine abuse. CONCLUSION: Treatment of mice with centrally acting histamine H3 receptor antagonists increases hypothalamic histamine contents and reduces high-dose METH effects, while potentiating low-dose effects, via histamine H1 receptors that bind released histamine. On the basis of experimental evidence, it is hypothesized that histamine H3 receptors may be an effective target for the treatment METH use disorder or other adverse effects of chronic METH use.

3.
Hum Cell ; 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35415781

RESUMO

Despite the recent advances in cancer therapy, cancer chemoresistance looms large along with radioresistance, a major challenge in dire need of thorough and minute investigation. Not long ago, cancer cells were reported to have proven refractory to the ferroptotic cell death, a newly discovered form of regulated cell death (RCD), conspicuous enough to draw attention from scholars in terms of targeting ferroptosis as a prospective therapeutic strategy. However, our knowledge concerning the underlying molecular mechanisms through which cancer cells gain immunity against ferroptosis is still in its infancy. Of late, the implication of non-coding RNAs (ncRNAs), including circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) in ferroptosis has been disclosed. Nevertheless, precisely explaining the molecular mechanisms behind the contribution of ncRNAs to cancer radio/chemotherapy resistance remains a challenge, requiring further clarification. In this review, we have presented the latest available information on the ways and means of regulating ferroptosis by ncRNAs. Moreover, we have provided important insights about targeting ncRNAs implicated in ferroptosis with the hope of opening up new horizons for overcoming cancer treatment modalities. Though a long path awaits until we make this ambitious dream come true, recent progress in gene therapy, including gene-editing technology will aid us to be optimistic that ncRNAs-based ferroptosis targeting would soon be on stream as a novel therapeutic strategy for treating cancer.

4.
Sci Rep ; 12(1): 1056, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35058559

RESUMO

Cancer stem-like cells (CSCs) within solid tumors exhibit radioresistance, leading to recurrence and distant metastasis after radiotherapy. To experimentally study the characteristics of CSCs, radioresistant cell lines were successfully established using fractionated X-ray irradiation. The fundamental characteristics of CSCs in vitro have been previously reported; however, the relationship between CSC and acquired radioresistance remains uncertain. To efficiently study this relationship, we performed both in vitro experiments and theoretical analysis using a cell-killing model. Four types of human oral squamous carcinoma cell lines, non-radioresistant cell lines (SAS and HSC2), and radioresistant cell lines (SAS-R and HSC2-R), were used to measure the surviving fraction after single-dose irradiation, split-dose irradiation, and multi-fractionated irradiation. The SAS-R and HSC2-R cell lines were more positive for one of the CSC marker aldehyde dehydrogenase activity than the corresponding non-radioresistant cell lines. The theoretical model analysis showed that changes in both the experimental-based ALDH (+) fractions and DNA repair efficiency of ALDH (-) fractions (i.e., sub-lethal damage repair) are required to reproduce the measured cell survival data of non-radioresistant and radioresistant cell lines. These results suggest that the enhanced cell recovery in SAS-R and HSC2-R is important when predicting tumor control probability in radiotherapy to require a long dose-delivery time; in other words, intensity-modulated radiation therapy is ideal. This work provides a precise understanding of the mechanism of radioresistance, which is induced after irradiation of cancer cells.


Assuntos
Reparo do DNA , Células-Tronco Neoplásicas/efeitos da radiação , Tolerância a Radiação , Aldeído Desidrogenase/metabolismo , Linhagem Celular Tumoral/efeitos da radiação , Sobrevivência Celular , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Raios X
5.
Peptides ; 150: 170734, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34974081

RESUMO

Inflammation, especially neuroinflammation, which is caused by stress, leads to central nervous system (CNS) dysfunction. Because lipopolysaccharides (LPSs) cause neuroinflammation, we investigated the effect of LPSs to CNS. In PC-12 cells, LPSs derived from oral bacteria reduced the expression of KCC2, a Cl- transporter. LPS derived from P. gingivalis (P. g) administered to rat primary cultured cells also reduced the KCC2 expression. However, LPSs derived from E. coli did not reduce the KCC2 expression. LPS treatment activated TLR4, IL-1ß, and REST gene expressions, which led to KCC2 inactivation in PC-12 cells. The mechanism of KCC2 has been shown to play an important role in brain maturation, function (such as the GABA switch), and behavioral problems, we investigated the GABA function. We found that the GABA function was changed from inhibitory to excitatory by the LPS derived from P. g treatment. We demonstrated that the GSK3ß also involved in the KCC2 reduction by LPS treatment. We show that oxytocin rescued the reduction in KCC2 expression caused by LPSs by inhibiting GSK3ß signaling but vasopressin could not. Considered together, our results indicate that the LPSs from oral bacteria but not the LPS from E. coli increase the risk for brain disorders and oxytocin might be a candidate to overcome the abnormal behavior caused by brain disorders such as psychiatric disorders.


Assuntos
Encefalopatias , Simportadores , Animais , Células Cultivadas , Escherichia coli/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Lipopolissacarídeos/toxicidade , Ocitocina/metabolismo , Ocitocina/farmacologia , Células PC12 , Ratos , Simportadores/genética , Simportadores/metabolismo , Ácido gama-Aminobutírico
6.
Artigo em Inglês | MEDLINE | ID: mdl-34856903

RESUMO

Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.

7.
Life Sci ; 286: 120051, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34666039

RESUMO

AIMS: To overcome radioresistant cancer cells, clinically relevant radioresistant (CRR) cells were established. To maintain their radioresistance, CRR cells were exposed 2 Gy/day of X-rays daily (maintenance irradiation: MI). To understand whether the radioresistance induced by X-rays was reversible or irreversible, the difference between CRR cells and those without MI for a year (CRR-NoIR cells) was investigated by the mitochondrial function as an index. MAIN METHODS: Radiation sensitivity was determined by modified high density survival assay. Mitochondrial membrane potential (Δψm) was determined by 5,5',6,6'-tetrachloro-1,1', tetraethylbenzimidazolocarbo-cyanine iodide (JC-1) staining. Rapid Glucose-Galactose assay was performed to determine the shift in their energy metabolism from aerobic glycolysis to oxidative phosphorylation in CRR cells. Involvement of prohibitin-1 (PHB1) in Δψm was evaluated by knockdown of PHB1 gene followed by real-time PCR. KEY FINDINGS: CRR cells that exhibited resistant to 2 Gy/day X-ray lost their radioresistance after more than one year of culture without MI for a year. In addition, CRR cells lost their radioresistance when the mitochondria were activated by galactose. Furthermore, Δψm were increased and PHB1 expression was down-regulated, in the process of losing their radioresistance. SIGNIFICANCE: Our finding reveled that tune regulation of mitochondrial function is implicated in radioresistance phenotype of cancer cells. Moreover, as our findings indicate, though further studies are required to clarify the precise mechanisms underlying cancer cell radioresistance, radioresistant cells induced by irradiation and cancer stem cells that are originally radioresistant should be considered separately, the radioresistance of CRR cells is reversible.


Assuntos
Potencial da Membrana Mitocondrial/fisiologia , Membranas Mitocondriais/metabolismo , Tolerância a Radiação/fisiologia , Biomarcadores Farmacológicos , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Membranas Mitocondriais/fisiologia , Neoplasias/metabolismo , Células-Tronco Neoplásicas , Tolerância a Radiação/efeitos da radiação , Raios X/efeitos adversos
8.
Genes (Basel) ; 12(9)2021 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-34573330

RESUMO

Mitochondria are very important intracellular organelles because they have various functions. They produce ATP, are involved in cell signaling and cell death, and are a major source of reactive oxygen species (ROS). Mitochondria have their own DNA (mtDNA) and mutation of mtDNA or change the mtDNA copy numbers leads to disease, cancer chemo/radioresistance and aging including longevity. In this review, we discuss the mtDNA mutation, mitochondrial disease, longevity, and importance of mitochondrial dysfunction in cancer first. In the later part, we particularly focus on the role in cancer resistance and the mitochondrial condition such as mtDNA copy number, mitochondrial membrane potential, ROS levels, and ATP production. We suggest a therapeutic strategy employing mitochondrial transplantation (mtTP) for treatment-resistant cancer.


Assuntos
DNA Mitocondrial/fisiologia , Longevidade/fisiologia , Mitocôndrias/fisiologia , Mutação , Neoplasias/terapia , Trifosfato de Adenosina/metabolismo , Transplante de Células/métodos , DNA Mitocondrial/genética , Humanos , Mitocôndrias/transplante , Doenças Mitocondriais/genética , Neoplasias/metabolismo , Neoplasias/patologia , Tolerância a Radiação/genética
9.
Life Sci ; 285: 119958, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34534562

RESUMO

Ferroptosis is a new type of non-apoptotic regulated cell death (RCD) driven by unrestricted lethal lipid peroxidation, which is totally distinct from other forms of RCD in genetic and biochemical characteristics. It is generally believed that iron dependency, malfunction of the redox system, and excessive lipid peroxidation are the main hallmarks of ferroptosis. Accumulating pieces of evidence over the past few years have shown that ferroptosis is tightly related to various types of diseases, especially cancers. Ferroptosis has recently attracted great attention in the field of cancer research. A plethora of evidence shows that employing ferroptosis as a powerful weapon can remarkably enhance the efficacy of tumor cell annihilation. Better knowledge of the ferroptosis mechanisms and their interplay with cancer biology would enable us to use this fashionable tool in the best way. Herein, we will briefly present the relevant mechanisms of ferroptosis, the multifaceted relation between ferroptosis and cancer, encompassing tumor immunity, overcoming chemoresistance, and epithelial to mesenchymal transition. In the end, we will also briefly discuss the potential approaches to ferroptosis-based cancer therapy, such as using drugs and small molecules, nanoparticles, mitochondrial targeting, and photodynamic therapy.


Assuntos
Ferroptose/fisiologia , Neoplasias , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Ferroptose/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia
10.
Pharmacol Biochem Behav ; 209: 173257, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418452

RESUMO

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.


Assuntos
Histamina/metabolismo , Locomoção/efeitos dos fármacos , Metanfetamina/farmacologia , Pirimetamina/análogos & derivados , Transmissão Sináptica/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Inibidores Enzimáticos/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Histamina N-Metiltransferase/antagonistas & inibidores , Hipotálamo/metabolismo , Masculino , Metanfetamina/efeitos adversos , Camundongos , Camundongos Endogâmicos ICR , Núcleo Accumbens/metabolismo , Pirimetamina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos
11.
Front Neurosci ; 15: 703440, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408624

RESUMO

Management of time and circadian disruption is an extremely important factor in basic research on pain and analgesia. Although pain is known to vary throughout the day, the mechanism underlying this circadian variation remains largely unknown. In this study, we hypothesized that the process of pain transmission to the central nervous system (after receiving nociceptive stimuli from outside the body) would show day-night differences. Ten-week-old male mice were kept under a strict 12/12-h light/dark cycle for at least 10 days. Formalin was then injected into the second branch region of the trigeminal nerve and the duration of pain-related behaviors (PRBs) was assessed. Immunohistochemical staining was then performed, and the c-Fos-immunopositive cells in the trigeminal spinal tract subnucleus caudalis (Sp5C) were counted. The results showed that the duration of PRBs was longer and the number of c-Fos immunopositive cells in the Sp5C was higher at nighttime than during the day. In addition, the trigeminal ganglia (TG) were extracted from the mice and examined by quantitative real-time PCR to evaluate the daytime and nighttime expression of nociceptive receptors. The results showed that the mRNA expression of transient receptor potential ankyrin 1 in the TG was significantly higher at night than during the day. These results suggest that pain in the trigeminal nerve region is more intense at nighttime, when rodents are active, than during the daytime, partly due to differences in nociceptor expression.

12.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361070

RESUMO

In cancer therapy, radioresistance or chemoresistance cells are major problems. We established clinically relevant radioresistant (CRR) cells that can survive over 30 days after 2 Gy/day X-ray exposures. These cells also show resistance to anticancer agents and hydrogen peroxide (H2O2). We have previously demonstrated that all the CRR cells examined had up-regulated miR-7-5p and after miR-7-5p knockdown, they lost radioresistance. However, the mechanism of losing radioresistance remains to be elucidated. Therefore, we investigated the role of miR-7-5p in radioresistance by knockdown of miR-7-5p using CRR cells. As a result, knockdown of miR-7-5p increased reactive oxygen species (ROS), mitochondrial membrane potential, and intracellular Fe2+ amount. Furthermore, miR-7-5p knockdown results in the down-regulation of the iron storage gene expression such as ferritin, up-regulation of the ferroptosis marker ALOX12 gene expression, and increases of Liperfluo amount. H2O2 treatment after ALOX12 overexpression led to the enhancement of intracellular H2O2 amount and lipid peroxidation. By contrast, miR-7-5p knockdown seemed not to be involved in COX-2 and glycolysis signaling but affected the morphology of CRR cells. These results indicate that miR-7-5p control radioresistance via ROS generation that leads to ferroptosis.


Assuntos
Ferroptose , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Bucais/patologia , Tolerância a Radiação , Espécies Reativas de Oxigênio/metabolismo , Araquidonato 12-Lipoxigenase/metabolismo , Células HeLa , Humanos , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial , Neoplasias Bucais/genética , Neoplasias Bucais/radioterapia , Transdução de Sinais , Células Tumorais Cultivadas
13.
Brain Res ; 1768: 147580, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260963

RESUMO

Kamishoyosan (KSS), a Japanese traditional herbal formula, is used to treat symptoms related to the autonomic nervous system in men and women; it is especially known for improving the symptoms of irritability (e.g., bad temper and persistent anger). Although clinical and ethological studies of KSS have been conducted, its efficacy in reducing irritability remains to be validated. In the present study, male and female ddY-strain mice were isolation-reared for 8 weeks (from the third postnatal week) to induce pathologically aggressive biting behavior (ABB), which was used as an indicator of irritability. The ABB of mice toward metal rods was measured using the Aggressive Response Meter. An intraperitoneal administration of KSS (100 mg/kg) effectively reduced ABB in male and female mice at 2 h after the administration; however, this effect was canceled by prior administration of WAY-100635 [a 5-hydroxytryptoamine (5-HT)-1A receptor antagonist; 0.5 mg/kg] and bicuculline (a type-A gamma-aminobutyric acid receptor antagonist; 1.0 mg/kg). Additionally, tamoxifen, ICI-182780, and G-15 (all estrogen receptor antagonists) inhibited the action of KSS in a dose-dependent manner. Furthermore, gene expression of tryptophan hydroxylase (Tph) 1 and Tph2 were increased and 5-HT immunofluorescence was slightly increased in the dorsal raphe nucleus (DRN) of isolation-reared mice administered with KSS. Collectively, these results indicate that KSS effectively reduces ABB in isolation-reared male and female mice through stimulation of 5-HT production in the DRN. Our findings also suggest that gene expression of estrogen receptor (Esr) 2 increased in the DRN might be associated with the reduction of ABB.


Assuntos
Agressão/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Humor Irritável/efeitos dos fármacos , Animais , Núcleo Dorsal da Rafe/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Expressão Gênica/genética , Japão , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos , RNA Mensageiro/metabolismo , Serotonina/metabolismo , Isolamento Social , Transcriptoma/efeitos dos fármacos , Triptofano Hidroxilase/metabolismo
14.
Technol Cancer Res Treat ; 19: 1533033820980077, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33334271

RESUMO

BACKGROUND: Radiation therapy is a highly cost-effective treatment for cancer, but the existence of radio-resistant cells remains the most critical obstacle in radiotherapy. We have been established clinically relevant radioresistant (CRR) cell lines by exposure to a stepwise increase of fractionated X-rays. We are trying to overcome the radio-resistance by analyzing the properties of these cells. In this study, we tried to evaluate the effects of hydrogen peroxide (H2O2) on the CRR cells because this can evaluate the efficacy of Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) that treats H2O2 before irradiation. We also established H2O2-resistant cells to compare the radiation and H2O2 resistant phenotype. MATERIALS AND METHODS: We used human cancer cell lines derived from hepatoblastoma (HepG2), oral squamous cell carcinoma (SAS), and cervical cancer (HeLa). We established HepG2, SAS, and HeLa CRR cells and HepG2, SAS, and HeLa H2O2-resistant cells. To evaluate their sensitivity to radiation or H2O2, high-density survival assay, or WST assay was performed. CellROXTM was used to detect intracellular Reactive Oxygen Species (ROS). RESULTS: CRR cells were resistant to H2O2-induced cell death but H2O2-resistant cells were not resistant to irradiation. This phenotype of CRR cells was irreversible. The intracellular ROS was increased in parental cells after H2O2 treatment for 3 h, but in CRR cells, no significant increase was observed. CONCLUSION: Fractionated X-ray exposure induces H2O2 resistance in CRR cells. Therefore, it is necessary to carry out cancer therapy such as KORTUC with the presence of these resistant cells in mind, and as the next stage, it would be necessary to investigate the appearance rate of these cells immediately and take countermeasures.


Assuntos
Peróxido de Hidrogênio/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Humanos , Espécies Reativas de Oxigênio/metabolismo , Raios X
15.
Free Radic Biol Med ; 161: 60-70, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33017631

RESUMO

Most anti-cancer agents and radiotherapy exert their therapeutic effects via the production of free radicals. Ferroptosis is a recently described cell death process that is accompanied by iron-dependent lipid peroxidation. Hydrogen peroxide (H2O2) has been reported to induce cell death. However, it remains controversial whether H2O2-induced cell death is ferroptosis. In the present study, we aimed to elucidate the involvement of mitochondria in H2O2-induced ferroptosis and examined the molecules that regulate ferroptosis. We found that one mechanism underlying H2O2-induced cell death is ferroptosis, which occurs soon after H2O2 treatment (within 3 h after H2O2 treatment). We also investigated the involvement of mitochondria in H2O2-induced ferroptosis using mitochondrial DNA-depleted ρ0 cells because ρ0 cells produce more lipid peroxidation, hydroxyl radicals (•OH), and are more sensitive to H2O2 treatment. We found that ρ0 cells contain high Fe2+ levels that lead to •OH production by H2O2. Further, we observed that aquaporin (AQP) 3, 5, and 8 bind nicotinamide-adenine dinucleotide phosphate oxidase 2 and regulate the permeability of extracellular H2O2, thereby contributing to ferroptosis. Additionally, the role of mitochondria in ferroptosis was investigated using mitochondrial transfer in ρ0 cells. When mitochondria were transferred into ρ0 cells, the cells exhibited no sensitivity to H2O2-induced cytotoxicity because of decreased Fe2+ levels. Moreover, mitochondrial transfer upregulated the mitochondrial quality control protein prohibitin 2 (PHB2), which contributes to reduced AQP expression. Our findings also revealed the involvement of AQP and PHB2 in ferroptosis. Our results indicate that H2O2 treatment enhances AQP expression, Fe2+ level, and lipid peroxidation, and decrease mitochondrial function by downregulating PHB2, and thus, is a promising modality for effective cancer treatment.


Assuntos
Aquaporinas , Ferroptose , Mitocôndrias , Aquaporinas/metabolismo , Células HeLa , Humanos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos , Mitocôndrias/metabolismo , Permeabilidade
16.
Brain Res Bull ; 165: 70-80, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33010349

RESUMO

Acute ischemia stroke (AIS) is one of the leading causes of mortality and disability worldwide, and its neurological impacts are devastating and permanent. There is no efficient and real treatment for acute ischemia stroke so far. Therefore, development of efficient therapeutic strategies is under focus of investigations by basic and clinical scientists. Brain is one of the organs with high energy consumption and metabolism. Hence, its functionality is highly dependent on mitochondrial activity and integrity. Therefore, mitochondria play a vital homeostatic role in neurons physiology and mitochondrial dysfunction implications have been reported in a variety of nervous system diseases including acute ischemia stroke. In an attempt to investigate and introduce a novel potential therapeutic strategy for AIS, we isolated healthy mitochondria from human umbilical cord derived mesenchymal stem cells (hUC-MSCs) followed by their intracerebroventricular transplantation in a rat model of ischemia, i.e. middle cerebral artery occlusion (MCAO). Here we report that the mitochondrial transplantation ameliorated the reperfusion/ischemia-induced damages as reflected by declined blood creatine phosphokinase level, abolished apoptosis, decreased astroglyosis and microglia activation, reduced infarct size, and improved motor function. Although further preclinical and clinical studies are required, our findings strongly suggest that transplantation of MSCs-derived mitochondria is a suitable, potential and efficient therapeutic option for acute ischemia stroke.


Assuntos
Apoptose/fisiologia , AVC Isquêmico/metabolismo , Transplante de Células-Tronco Mesenquimais , Destreza Motora/fisiologia , Traumatismo por Reperfusão/terapia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Mitocôndrias/metabolismo , Neurônios/metabolismo , Ratos , Traumatismo por Reperfusão/metabolismo
17.
Mol Biol Rep ; 47(6): 4401-4411, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32394308

RESUMO

Mitochondrial dysfunction is known to contribute to cancer initiation, progression, and chemo-and radio-resistance. However, the precise role of mitochondria in cancer is controversial. Hence, here we tried to further clarify the role of mitochondria in cancer by transferring healthy mitochondria to cancer cells, and also to cells with depleted mitochondrial DNA (ρ0). Healthy mitochondria were isolated from WI-38 cells and were transferred to HeLa, SAS, HeLa ρ0, and SAS ρ0 cells. Then, cell proliferation was verified. In addition, the cells were treated by different concentrations of cisplatin and assessed for apoptosis induction and quantifying the mRNA expression of apoptosis-related genes. Results revealed that incubation of the HeLa, SAS and HeLa ρ0 cells with 5 µg/ml of the isolated mitochondria for 24 h significantly (p < 0.001) increased cell proliferation compared to non-treated controls. Interestingly, the mitochondria transfer rescued the ρ0 cells and made them capable of growing under conventional culture medium. However, the number of apoptotic cells was significantly higher in the HeLa ρ0 cells that received the mitochondria (HeLa-Fibro-Mit) compared to the HeLa ρ0. Furthermore, the expression level of BCL-2 anti-apoptotic gene was down-regulated in both HeLa-Fibro-Mit and SAS-Fibro-Mit cell lines while the expression levels of the BAX, caspase8, caspase9, and AIF pro-apoptotic genes were upregulated. Our findings indicated that although the response of cancer cells to the mitochondria transfer is cancer-type dependent, but the introduction of normal exogenous mitochondria to some cancer cells might be considered as a potential novel therapeutic strategy.


Assuntos
Fibroblastos/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Cisplatino/farmacologia , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
19.
Life Sci ; 244: 117339, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972210

RESUMO

AIM: Despite recent advances in therapeutic strategies, cancer is still a leading cause of mortality worldwide. Mitochondrial dysfunction is implicated in cancer initiation and metastasis, and even in chemo- and radio-resistance. However, the precise role of mitochondria in cancer is crosstalk and controversial. This study is trying to find out the effect of transferring normal mitochondria into the highly aggressive and proliferative MDA-MB-231 cancer cells, and to evaluate the effect of the transfer with/without a combination therapy with cisplatin. MATERIALS AND METHODS: Normal mitochondria were isolated from human umbilical cord derived-mesenchymal stem cells. The mitochondria were transferred into the MDA-MB-231 cells, and also into cells with mitochondrial dysfunction induced by rhodamine red 6 (R6G). Cell proliferation and sensitivity of the cells to cisplatin were measured by cell counting after the mitochondria transfer. Also, apoptosis was evaluated by DAPI staining and in situ cell death detection (TdT-mediated dUTP nickend labeling; TUNEL) methods. Migration capability of the cells was studied by transwell assay. KEY FINDINGS: Transfer of normal mitochondria into MDA-MB-231 cells increased cell proliferation. However, the transfer of mitochondria enhanced cisplatin-induced apoptosis in MDA-MB-231 cells in which mitochondria were already disrupted. Introduction of normal cell-derived mitochondria into the MDA-MB-231 cells increased their invasive, but decreased the migration potency of the cells in the group with mitochondrial dysfunction (MDA + RG6 + Cisplatin). CONCLUSION: The introduction of healthy mitochondria to highly aggressive and proliferative cells would be considered as a new therapeutic modality for some types of cancer.


Assuntos
Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Células-Tronco Mesenquimais/patologia , Mitocôndrias/patologia , Cordão Umbilical/patologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Células Tumorais Cultivadas , Cordão Umbilical/efeitos dos fármacos
20.
Biochem Biophys Res Commun ; 518(4): 712-718, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31472959

RESUMO

MicroRNA (miRNA) is a non-coding RNA involved in regulating both cancer gene promotion and suppression. We investigated the role of miRNA in inducing radiation resistance in cancer cell lines using clinically relevant radioresistant (CRR) cells. Analysis using miRNA arrays and qPCR revealed that miR-7-5p is highly expressed in all examined CRR cells. Additionally, CRR cells lose their radioresistance when daily irradiation is interrupted for over 6 months. MiR-7-5p expression is reduced in these cells, and treating CRR cells with a miR-7-5p inhibitor leads to a loss of resistance to irradiation. Conversely, overexpression of miR-7-5p in CRR cells using a miR-7-5p mimic shows further resistance to radiation. Overexpression of miR-7-5p in parent cells also results in resistance to radiation. These results indicate that miR-7-5p may control radioresistance in various cancer cells at the clinically relevant dose of irradiation. Furthermore, miR-7-5p downregulates mitoferrin and reduces Fe2+, which influences ferroptosis. Our findings have great potential not only for examining radiation resistance prior to treatment but also for providing new therapeutic agents for treatment-resistant cancers.


Assuntos
Espaço Intracelular/metabolismo , Ferro/metabolismo , MicroRNAs/genética , Tolerância a Radiação/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Células HeLa , Células Hep G2 , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Interferência de RNA , Tolerância a Radiação/genética
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