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International Journal of Molecular... Feb 2022Ferroptosis has been previously implicated in the pathological progression of cardiomyopathy. Herceptin (trastuzumab), which targets HER2, is commonly applied for the...
Ferroptosis has been previously implicated in the pathological progression of cardiomyopathy. Herceptin (trastuzumab), which targets HER2, is commonly applied for the treatment of HER2 breast cancer. However, its clinical use is limited by its cardiotoxicity. Therefore, the present study aimed to investigate if targeting ferroptosis could protect against Herceptin‑induced heart failure in an model of H9c2 cells after treatment of Herceptin, Herceptin + ferroptosis inhibitor ferrostatin‑1 (Fer‑1) or Herceptin + Deferoxamine. H9c2 cell viability was measured by MTT assay. Reactive oxygen species (ROS) levels were detected by measuring the fluorescence of DCFH‑DA‑A and MitoSOX™ Red. Glutathione (GSH)/oxidized glutathione (GSSG) ratio was measured using the GSH/GSSG Ratio Detection Assay kit. Mitochondrial membrane potential and ATP content were evaluated by JC‑1 staining and bioluminescent assay kits, respectively. Protein expressions of glutathione peroxidase 4, recombinant solute carrier family 7 member 11, mitochondrial optic atrophy1‑1/2, mitofusin, Acyl‑CoA synthetase long chain family member 4, cytochrome , voltage‑dependent anion‑selective channel, dynamin‑related protein, mitochondrial fission 1 protein and mitochondrial ferritin were evaluated by western blotting. It was found that Herceptin reduced H9c2 cell viability whilst increasing intracellular and mitochondrial ROS levels in a dose‑ and time‑dependent manner. Furthermore, Herceptin decreased glutathione peroxidase (GPX) protein expression and the GSH/ GSSG ratio in H9c2 cells in a dose‑ and time‑dependent manner. The Fer‑1 abolished this Herceptin‑induced reduction in cell viability, GSH/GSSG ratio, mitochondrial membrane potential and ATP content. Fer‑1 also reversed the suppressive effects of Herceptin on the protein expression levels of GPX4, recombinant solute carrier family 7 member 11, mitochondrial optic atrophy1‑1/2 and mitofusin in H9c2 cells. Subsequently, Fer‑1 was found to reverse the Herceptin‑induced increase in mitochondrial ROS and iron levels in H9c2 cells, as well as the increased protein expression levels of Acyl‑CoA synthetase long chain family member 4, cytochrome , voltage‑dependent anion‑selective channel, dynamin‑related protein, mitochondrial fission 1 protein and mitochondrial ferritin in H9c2 cells. However, compared with deferoxamine, an iron chelator, the effects of Fer‑1 were less effective. Collectively, these findings provided insights into the pathogenic mechanism that underlie Herceptin‑induced cardiomyopathy, which potentially provides a novel therapeutic target for the prevention of cardiotoxicity in HER2 breast cancer treatment.
Topics: Animals; Cell Line; Cyclohexylamines; Cytoprotection; Ferroptosis; Mitochondria; Oxidative Stress; Phenylenediamines; Rats; Trastuzumab
PubMed: 34935058
DOI: 10.3892/ijmm.2021.5072 -
Autophagy 2015Hexokinases (HKs) catalyze the first step of glucose metabolism, phosphorylating glucose to glucose 6-phosphate (G6P). HK2/hexokinase-II is a predominant isoform in... (Review)
Review
Hexokinases (HKs) catalyze the first step of glucose metabolism, phosphorylating glucose to glucose 6-phosphate (G6P). HK2/hexokinase-II is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues and is also upregulated in many types of tumors associated with enhanced aerobic glycolysis (the Warburg effect). Accumulating evidence indicates that HK2 plays an important role not only in glycolysis but also in cell survival. Although there is increasing recognition that cellular metabolism and cell survival are closely related, the molecular link between metabolism and autophagic pathways has not been fully elucidated. We recently discovered that HK2 facilitates autophagy in response to glucose deprivation (HK substrate deprivation) to protect cardiomyocytes, and suggest that HK2 functions as a molecular switch from glycolysis to autophagy to ensure cellular energy homeostasis under starvation conditions.
Topics: Animals; Autophagy; Cytoprotection; Glucose; Glycolysis; Hexokinase; Humans; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; TOR Serine-Threonine Kinases
PubMed: 26075878
DOI: 10.1080/15548627.2015.1042195 -
Nature Reviews. Neurology Apr 2022For over 40 years, attempts to develop treatments that protect neurons and other brain cells against the cellular and biochemical consequences of cerebral ischaemia in... (Review)
Review
For over 40 years, attempts to develop treatments that protect neurons and other brain cells against the cellular and biochemical consequences of cerebral ischaemia in acute ischaemic stroke (AIS) have been unsuccessful. However, the advent of intravenous thrombolysis and endovascular thrombectomy has taken us into a new era of treatment for AIS in which highly effective reperfusion therapy is widely available. In this context, cytoprotective treatments should be revisited as adjunctive treatment to reperfusion therapy. Renewed efforts should focus on developing new drugs that target multiple aspects of the ischaemic cascade, and previously developed drugs should be reconsidered if they produced robust cytoprotective effects in preclinical models and their safety profiles were reasonable in previous clinical trials. Several development pathways for cytoprotection as an adjunct to reperfusion can be envisioned. In this Review, we outline the targets for cytoprotective therapy and discuss considerations for future drug development, highlighting the recent ESCAPE-NA1 trial of nerinetide, which produced the most promising results to date. We review new types of clinical trial to evaluate whether cytoprotective drugs can slow infarct growth prior to reperfusion and/or ameliorate the consequences of reperfusion, such as haemorrhagic transformation. We also highlight how advanced brain imaging can help to identify patients with salvageable ischaemic tissue who are likely to benefit from cytoprotective therapy.
Topics: Brain; Brain Ischemia; Cytoprotection; Endovascular Procedures; Humans; Ischemic Stroke; Reperfusion; Stroke; Thrombectomy; Treatment Outcome
PubMed: 35079135
DOI: 10.1038/s41582-021-00605-6 -
Toxins Feb 2022The lifestyle associated with good nutritional quality of food is well known for its widely recognized health benefits, especially when rich in bioactive compounds [...].
The lifestyle associated with good nutritional quality of food is well known for its widely recognized health benefits, especially when rich in bioactive compounds [...].
Topics: Animals; Cytoprotection; Food Contamination; Humans; Toxins, Biological
PubMed: 35202141
DOI: 10.3390/toxins14020114 -
Cells Nov 2022Aging is a process associated with life [...].
Aging is a process associated with life [...].
Topics: Rejuvenation; Cytoprotection; Dietary Supplements
PubMed: 36497045
DOI: 10.3390/cells11233786 -
Journal of Applied Physiology... Mar 2016Studying "phenotypic plasticity" involves comparison of traits expressed in response to environmental fluctuations and aims to understand tolerance and survival in new... (Review)
Review
Studying "phenotypic plasticity" involves comparison of traits expressed in response to environmental fluctuations and aims to understand tolerance and survival in new settings. Reversible phenotypic changes that enable individuals to match their phenotype to environmental demands throughout life can be artificially induced, i.e., acclimation or occur naturally, i.e., acclimatization. The onset and achievement of acclimatory homeostasis are determined by molecular programs that induce the acclimated transcriptome. In heat acclimation, much evidence suggests that epigenetic mechanisms are powerful players in these processes. Epigenetic mechanisms affect the accessibility of the DNA to transcription factors, thereby regulating gene expression and controlling the phenotype. The heat-acclimated phenotype confers cytoprotection against novel stressors via cross-tolerance mechanisms, by attenuation of the initial damage and/or by accelerating spontaneous recovery through the release of help signals. This indispensable acclimatory feature has a memory and can be rapidly reestablished after the loss of acclimation and the return to the physiological preacclimated phenotype. The transcriptional landscape of the deacclimated phenotype includes constitutive transcriptional activation of epigenetic bookmarks. Heat shock protein (HSP) 70/HSP90/heat shock factor 1 memory protocol demonstrated constitutive histone H4 acetylation on hsp70 and hsp90 promotors. Novel players in the heat acclimation setup are poly(ADP-ribose)ribose polymerase 1 affecting chromatin condensation, DNA linker histones from the histone H1 cluster, and transcription factors associated with the P38 pathway. We suggest that these orchestrated responses maintain euchromatin and proteostasis during deacclimation and predispose to rapid reacclimation and cytoprotection. These mechanisms represent within-life epigenetic adaptations and cytoprotective memory.
Topics: Acclimatization; Animals; Cytoprotection; Epigenesis, Genetic; Heat-Shock Proteins; Hot Temperature; Humans; Transcription Factors; Transcriptional Activation; Transcriptome
PubMed: 26472869
DOI: 10.1152/japplphysiol.00552.2015 -
Chemico-biological Interactions Dec 2018Phloretin (Phl) is a dihydrochalcone flavonoid with significant cytoprotective properties; e.g., free radical trapping, electrophile scavenging. Based on this, it has...
Phloretin (Phl) is a dihydrochalcone flavonoid with significant cytoprotective properties; e.g., free radical trapping, electrophile scavenging. Based on this, it has been suggested that Phl might be useful in the treatment of pathogenic processes and prevention of drug toxicities. Therefore, we determined the ability of Phl to provide route- and dose-dependent hepatoprotection in a mouse model of acetaminophen (APAP) overdose. Intraperitoneal (i.p.) administration of Phl produced a bimodal effect; i.e., the highest dose (2.40 mmol/kg) did not prevent APAP-induced lethality, whereas lower doses (0.2-0.4 mmol/kg) afforded modest hepatoprotection. When given alone, the highest i.p. Phl dose was lethal within 24 h, whereas the lower doses were not toxic. Oral Phl (0.40-2.40 mmol/kg) did not prevent APAP-induced hepatotoxicity. The highest oral dose given alone (2.4 mmol/kg) produced 64% lethality, whereas lower doses were not lethal. This toxicity profile was reflected in a study using APAP-exposed isolated mouse hepatocytes, which showed that the Phl pharmacophores, 1,3,5-trihydroxyacetophenone (PG) and 2',4',6'-trihydroxyacetophenone (THA) where protective. Corroborative cell free studies showed that polyphenol protectants prevented glutathione loss mediated by the APAP metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Thus, in spite of possessing cytoprotective attributes, Phl was generally toxic in our APAP models. These and earlier findings suggest that Phl is not a candidate for drug design. In contrast, we have found that the enol-forming pharmacophores, THA and PG, are potential platforms for pharmacotherapeutic development.
Topics: Animals; Benzoquinones; Cytoprotection; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Glutathione; Hepatocytes; Imines; Injections, Intraperitoneal; Kinetics; Male; Mice; Mice, Inbred C57BL; Phloretin; Protective Agents; Structure-Activity Relationship
PubMed: 30287234
DOI: 10.1016/j.cbi.2018.09.020 -
International Journal of Molecular... Apr 2017Hydroxytyrosol (HT) ((3,4-Dihydroxyphenyl)ethanol) is a polyphenol mainly present in extra virgin olive oil (EVOO) but also in red wine. It has a potent antioxidant... (Review)
Review
Hydroxytyrosol (HT) ((3,4-Dihydroxyphenyl)ethanol) is a polyphenol mainly present in extra virgin olive oil (EVOO) but also in red wine. It has a potent antioxidant effect related to hydrogen donation, and the ability to improve radical stability. The phenolic content of olive oil varies between 100 and 600 mg/kg, due to multiple factors (place of cultivation, climate, variety of the olive and level of ripening at the time of harvest), with HT and its derivatives providing half of that content. When consumed, EVOO's phenolic compounds are hydrolyzed in the stomach and intestine, increasing levels of free HT which is then absorbed in the small intestine, forming phase II metabolites. It has been demonstrated that HT consumption is safe even at high doses, and that is not genotoxic or mutagenic in vitro. The beneficial effects of HT have been studied in humans, as well as cellular and animal models, mostly in relation to consumption of EVOO. Many properties, besides its antioxidant capacity, have been attributed to this polyphenol. The aim of this review was to assess the main properties of HT for human health with emphasis on those related to the possible prevention and/or treatment of non-communicable diseases.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Autophagy; Cytoprotection; Humans; Mitochondria; Olive Oil; Oxidative Stress; Phenylethyl Alcohol
PubMed: 28452954
DOI: 10.3390/ijms18050930 -
Molecules (Basel, Switzerland) Jul 2020A large number of diverse mechanisms that lead to cytoprotection have been described to date. Perhaps, not surprisingly, the role of mitochondria in these phenomena is... (Review)
Review
A large number of diverse mechanisms that lead to cytoprotection have been described to date. Perhaps, not surprisingly, the role of mitochondria in these phenomena is notable. In addition to being metabolic centers, due to their role in cell catabolism, ATP synthesis, and biosynthesis these organelles are triggers and/or end-effectors of a large number of signaling pathways. Their role in the regulation of the intrinsic apoptotic pathway, calcium homeostasis, and reactive oxygen species signaling is well documented. In this review, we aim to characterize the prospects of influencing cytoprotective mitochondrial signaling routes by natural substances of plant origin, namely, flavonoids (e.g., flavanones, flavones, flavonols, flavan-3-ols, anthocyanidins, and isoflavones). Flavonoids are a family of widely distributed plant secondary metabolites known for their beneficial effects on human health and are widely applied in traditional medicine. Their pharmacological characteristics include antioxidative, anticarcinogenic, anti-inflammatory, antibacterial, and antidiabetic properties. Here, we focus on presenting mitochondria-mediated cytoprotection against various insults. Thus, the role of flavonoids as antioxidants and modulators of antioxidant cellular response, apoptosis, mitochondrial biogenesis, autophagy, and fission and fusion is reported. Finally, an emerging field of flavonoid-mediated changes in the activity of mitochondrial ion channels and their role in cytoprotection is outlined.
Topics: Animals; Antioxidants; Cytoprotection; Flavonoids; Humans; Mitochondria; Signal Transduction
PubMed: 32635481
DOI: 10.3390/molecules25133060 -
Translational Stroke Research Aug 2017Acute ischemic stroke is inadequately treated in the USA and worldwide due to a lengthy history of neuroprotective drug failures in clinical trials. The majority of... (Review)
Review
Acute ischemic stroke is inadequately treated in the USA and worldwide due to a lengthy history of neuroprotective drug failures in clinical trials. The majority of victims must endure life-long disabilities that not only affect their livelihood, but also have an enormous societal economic impact. The rapid development of a neuroprotective or cytoprotective compound would allow future stroke victims to receive a treatment to reduce disabilities and further promote recovery of function. This opinion article reviews in detail the enormous costs associated with developing a small molecule to treat stroke, as well as providing a timely overview of the cell-death time-course and relationship to the ischemic cascade. Distinct temporal patterns of cell-death of neurovascular unit components provide opportunities to intervene and optimize new cytoprotective strategies. However, adequate research funding is mandatory to allow stroke researchers to develop and test their novel therapeutic approach to treat stroke victims.
Topics: Animals; Cost-Benefit Analysis; Cytoprotection; Humans; Neuroprotective Agents; Stroke; Thrombolytic Therapy; Translational Research, Biomedical
PubMed: 28039575
DOI: 10.1007/s12975-016-0518-y