抗氧化蛋白Prxs基因是新近发现的一类编码过氧化物酶的基因，广泛存在于原核生物和真核生物中，参与多种细胞活动的信号转导。文章综述了Prxs的结构及分型、定位和功能，并讨论了Prxs与运动的关系。

抗氧化蛋白（Peroxiredoxins）与运动

In the heart, membrane voltage (Vm) and intracellular Ca (Cai) are bidirectionally coupled, so that ionic membrane currents regulate Cai cycling and Cai affects ionic currents regulating action potential duration (APD). Although Cai reliably and consistently tracks Vm at normal heart rates, it is possible that at very rapid rates, sarcoplasmic reticulum Cai cycling may exhibit intrinsic dynamics. Non-voltage-gated Cai release might cause local alternations in APD and refractoriness that influence wavebreak during ventricular fibrillation (VF). In this study, we tested this hypothesis by examining the extent to which Cai is associated with Vm during VF. Cai transients were mapped optically in isolated arterially perfused swine right ventricles using the fluorescent dye rhod 2 AM while intracellular membrane potential was simultaneously recorded either locally with a microelectrode (5 preparations) or globally with the voltage-sensitive dye RH-237 (5 preparations). Mutual information (MI) is a quantitative statistical measure of the extent to which knowledge of one variable (Vm) predicts the value of a second variable (Cai). MI was high during pacing and ventricular tachycardia (VT; 1.13 +/- 0.21 and 1.69 +/- 0.18, respectively) but fell dramatically during VF (0.28 +/- 0.06, P < 0.001). Cai at sites 4-6 mm apart also showed decreased MI during VF (0.63 +/- 0.13) compared with pacing (1.59 +/- 0.34, P < 0.001) or VT (2.05 +/- 0.67, P < 0.001). Spatially, Cai waves usually bore no relationship to membrane depolarization waves during nonreentrant fractionated waves typical of VF, whereas they tracked each other closely during pacing and VT. The dominant frequencies of Vm and Cai signals analyzed by fast Fourier transform were similar during VT but differed significantly during VF. Cai is closely associated with Vm closely during pacing and VT but not during VF. These findings suggest that during VF, non-voltage-gated Cai release events occur and may influence wavebreak by altering Vm and APD locally.

https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/113016/1/T200404865.pdf

Intracellular Ca dynamics in ventricular fibrillation

Mitochondria are multifunctional cellular organelles that are major producers of reactive oxygen species (ROS) in eukaryotes; to maintain the redox balance, they are supplemented with different ROS scavengers, including mitochondrial peroxiredoxins (Prdxs). Mitochondrial Prdxs have physiological and pathological significance and are associated with the initiation and progression of various cancer types. In this review, we have focused on signaling involving ROS and mitochondrial Prdxs that is associated with cancer development and progression. An upregulated expression of Prdx3 and Prdx5 has been reported in different cancer types, such as breast, ovarian, endometrial, and lung cancers, as well as in Hodgkin’s lymphoma and hepatocellular carcinoma. The expression of Prdx3 and Prdx5 in different types of malignancies involves their association with different factors, such as transcription factors, micro RNAs, tumor suppressors, response elements, and oncogenic genes. The microenvironment of mitochondrial Prdxs plays an important role in cancer development, as cancerous cells are equipped with a high level of antioxidants to overcome excessive ROS production. However, an increased production of Prdx3 and Prdx5 is associated with the development of chemoresistance in certain types of cancers and it leads to further complications in cancer treatment. Understanding the interplay between mitochondrial Prdxs and ROS in carcinogenesis can be useful in the development of anticancer drugs with better proficiency and decreased resistance. However, more targeted studies are required for exploring the tumor microenvironment in association with mitochondrial Prdxs to improve the existing cancer therapies and drug development.

https://www.mdpi.com/1422-0067/20/18/4407/pdf

Interplay Between Mitochondrial Peroxiredoxins and ROS in Cancer Development and Progression

Cell death pathways such as apoptosis can be activated in response to oxidative stress, enabling the disposal of damaged cells. In contrast, controlled intracellular redox events are proposed to be a significant event during apoptosis signaling, regardless of the initiating stimulus. In this scenario oxidants act as second messengers, mediating the post-translational modification of specific regulatory proteins. The exact mechanism of this signaling is unclear, but increased understanding offers the potential to promote or inhibit apoptosis through modulating the redox environment of cells. Peroxiredoxins are thiol peroxidases that remove hydroperoxides, and are also emerging as important players in cellular redox signaling. This review discusses the potential role of peroxiredoxins in the regulation of apoptosis, and also their ability to act as biomarkers of redox changes during the initiation and progression of cell death.

Peroxiredoxins and the Regulation of Cell Death

Tauopathies are neurodegenerative diseases characterized by tau protein pathology in the nervous system. EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), also known as PERK (protein kinase R-like endoplasmic reticulum kinase), was identified by genome-wide association study as a genetic risk factor in several tauopathies. PERK is a key regulator of the Unfolded Protein Response (UPR), an intracellular signal transduction mechanism that protects cells from endoplasmic reticulum (ER) stress. PERK variants had previously been identified in Wolcott-Rallison Syndrome, a rare autosomal recessive metabolic disorder, and these variants completely abrogated the function of PERK's kinase domain or prevented PERK expression. In contrast, the PERK tauopathy risk variants were distinct from the Wolcott-Rallison variants and introduced missense alterations throughout the PERK protein. The function of PERK tauopathy variants and their effects on neurodegeneration are unknown. Here, we discovered that tauopathy-associated PERK alleles showed reduced signaling activity and increased PERK protein turnover compared to protective PERK alleles. We found that iPSC-derived neurons carrying PERK risk alleles were highly vulnerable to ER stress-induced injury with increased tau pathology. We found that chemical inhibition of PERK in human iPSC-derived neurons also increased neuronal cell death in response to ER stress. Our results indicate that tauopathy-associated PERK alleles are functional hypomorphs during the UPR. We propose that reduced PERK function leads to neurodegeneration by increasing neuronal vulnerability to ER stress-associated damage. In this view, therapies to enhance PERK signaling would benefit at-risk carriers of hypomorphic alleles.

/pdf/tauopathy-associated-perk-alleles-are-functional-hypomorphs-53l2oewf5d.pdf

Tauopathy-associated PERK alleles are functional hypomorphs that increase neuronal vulnerability to ER stress.

β-N-methylamino-L-alanine (BMAA) is a neurotoxin that is closely associated with the incidence of amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. In cultured neuronal cells, BMAA notably induces the upregulation of endoplasmic reticulum (ER) chaperons and activates the unfolded protein response (UPR) receptor pathways of protein kinase RNA‑like endoplasmic reticulum kinase, inositol‑requiring kinase 1 and transcription factor 6. The ER stress‑specific protein CCAAT/‑enhancer‑binding protein homologous protein (CHOP) affords pro‑apoptotic responses that cause mitochondrial damage and caspase activation. BMAA also induces the activation of mitogen‑activated protein kinase member c‑JUN N‑terminal kinase, p38 and extracellular signal‑regulated kinase, which have been suggested to be involved in the signaling pathway of UPR‑mediated apoptosis. Inhibition of ER stress using ER stress antagonist, salubrinal, attenuated the expression of CHOP and alleviated neuronal death. Overexpression of heat shock protein 70 suppressed the activation of UPR receptors and UPR‑evoked apoptotic signaling. The present findings demonstrated that ER stress induced by BMAA is the important mediator of neuronal injury and apoptotic death, and suggests development in novel therapeutic strategies for treatment.

/pdf/neurotoxin-b-n-methylamino-l-alanine-induces-endoplasmic-2pofu3b403.pdf

Neurotoxin β‑N‑methylamino‑L‑alanine induces endoplasmic reticulum stress‑mediated neuronal apoptosis.

Endometrial cancer is a common type of malignant tumor of the human female genital tract, which typically occurs after menopause. Asian nations, including Korea, Japan and China, have a 4-5 times lower incidence than Western industrialized nations. However, in recent years, there has been a marked increase in the incidence of the disease. Peroxiredoxin (Prx) is an antioxidant enzyme that consists of six isoforms in mammals. These enzymes share a common reactive Cys residue in the N-terminal region, and are capable of breaking down H(2)O(2) as a peroxidase and involving thioredoxin or glutathione as the electron donor. In the present study, we evaluated the expression of Prx isoforms in normal endometrium, endometrial hyperplasia and endometrial cancer. A total of 240 patients, diagnosed with endometrial cancer by immunohistochemistry, were enrolled in this study. Results showed that Prx I, III, IV and V were negative or weakly expressed in normal endometrium, whereas levels of Prx II and VI were strongly expressed. Notably, the expression levels of Prx III and V were upregulated in endometrial cancer, compared with normal endometrium and endometrial hyperplasia. However, no differences in the staining intensities according to the grade of lesion were observed in the other Prx isoforms. The Kaplan-Meier survival analysis demonstrated that Prx V expression in endometrial cancer is significantly associated with survival rate. Therefore, we suggest that Prx V is a clinically significant prognostic marker for the development of endometrial cancer.

/pdf/expression-and-prognostic-significance-of-human-2brh5t4a6t.pdf

Expression and prognostic significance of human peroxiredoxin isoforms in endometrial cancer

Action potential, which is the foundation of physiology and electrophysiology, is most vital in physiological research. This work starts by detecting cardiac electrophysiology (tachyarrhythmias), combined with all spontaneous discharge phenomena in vivo such as wound currents and spontaneous neuropathic pain, elaborates from generation, induction, initiation, to all of the features of spontaneous high-frequency action potential—SSL action potential mechanism, i.e., connecting-end hyperpolarization initiates spontaneous depolarization and action potential in somatic membrane. This work resolves the conundrums of in vivo spontaneous discharge in tachyarrhythmias, wounds, denervation supersensitivity, neurogenic pain (hyperalgesia and allodynia), epileptic discharge and diabetic pain in pathophysiological and clinical researches that have puzzled people for a hundred years.

/pdf/spontaneous-high-frequency-action-potential-2m98ytnnez.pdf

Spontaneous high-frequency action potential.

Following the publication of the above article and a Corrigendum published in July 2018, the authors have noted an additional error, associated with the presentation of Fig. 1C. Fig 1C showed that β‑N‑methylamino‑L‑alanine induces neuronal apoptotic cell death; however, an error was made in the compilation of this figure and an incorrect band image was selected for α‑actinin, the loading control panel for Fig. 1C. A corrected version of Fig. 1 is shown opposite, incorporating the correct α‑actinin protein bands in Fig. 1C. This change affects neither the interpretation of the data nor conclusions of this work. We regret that this further error went unnoticed at the time, and thank the Editor for allowing us the opportunity to publish this additional Corrigendum. [the original article was published in the Molecular Medicine Reports 14: 4873‑4880, 2016; DOI: 10.3892/mmr.2016.5802].

/pdf/corrigendum-neurotoxin-b-n-methylamino-l-alanine-induces-1niwnk89pk.pdf

Haiying Shen

Papers

Neurotoxin β‑N‑methylamino‑L‑alanine induces endoplasmic reticulum stress‑mediated neuronal apoptosis.

Expression and prognostic significance of human peroxiredoxin isoforms in endometrial cancer

Spontaneous high-frequency action potential.

[Corrigendum] Neurotoxin β‑N‑methylamino‑L‑alanine induces endoplasmic reticulum stress‑mediated neuronal apoptosis