: Rapamycin is a new antifungal antibiotic produced by Streptomyces hygroscopicus NRRL 5491. It was isolated from the mycelium by solvent extraction, purified by silica gel column chromatography and crystallized as a colorless solid which melts at 183 approximately to 185 degrees C and has the empirical formula C56H89NO14. From its characteristic ultraviolet absorption spectrum rapamycin can be classified as a triene. It is highly active against various Candida species, especially Candida albicans. Its activity is compared with that of amphotericin B, candicidin and nystatin.

Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization.:II. FERMENTATION, ISOLATION AND CHARACTERIZATION

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell's response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.

NRF2, a Transcription Factor for Stress Response and Beyond.

Aging is a general degenerative process related to deterioration of cell functions in the entire organism. Mitochondria, which play a key role in energy homeostasis and metabolism of reactive oxygen species (ROS), require the lifetime control and constant renewal. This explains recently peaked interest in the processes of mitochondrial biogenesis and mitophagy. The principal event of mitochondrial metabolism is regulation of mitochondrial DNA (mtDNA) transcription and translation, which is a complex coordinated process that involves at least two systems of transcription factors. It is commonly believed that its major regulatory protein is PGC-1α, that acts as a key factor connecting several regulator cascades involved in the control of mitochondrial metabolism. In recent years, the number of publications on the essential role of Nrf2/ARE signaling in the regulation of mitochondrial biogenesis has grown exponentially. Nrf2 is induced by various xenobiotics and antioxidants that oxidize some Nrf2 negative regulators. Thus, ROS, in particular H2O2, were found to be strong Nrf2 activators. At present, there are two major concepts of mitochondrial biogenesis. Some authors suggest direct involvement of Nrf2 in the regulation of this process. Others believe that Nrf2 regulates expression of the antioxidant genes, while the major and only regulator of mitochondrial biogenesis is PGC-1α. Several studies have demonstrated the existence of the regulatory loop involving both PGC-1α and Nrf2. In this review, we summarized recent data on the Nrf2 role in mitochondrial biogenesis and mutual regulation of Nrf2 and PGC-1α as promising targets for drug application and other therapies aimed to increase active longevity.

/pdf/regulation-of-mitochondrial-biogenesis-as-a-way-for-active-193ksrfysr.pdf

Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

/pdf/pgc-1a-inflammation-and-oxidative-stress-an-integrative-view-3iw1n40pib.pdf

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism.

Poultry in commercial settings are exposed to a range of stressors. A growing body of information clearly indicates that excess ROS/RNS production and oxidative stress are major detrimental consequences of the most common commercial stressors in poultry production. During evolution, antioxidant defence systems were developed in poultry to survive in an oxygenated atmosphere. They include a complex network of internally synthesised (e.g., antioxidant enzymes, (glutathione) GSH, (coenzyme Q) CoQ) and externally supplied (vitamin E, carotenoids, etc.) antioxidants. In fact, all antioxidants in the body work cooperatively as a team to maintain optimal redox balance in the cell/body. This balance is a key element in providing the necessary conditions for cell signalling, a vital process for regulation of the expression of various genes, stress adaptation and homeostasis maintenance in the body. Since ROS/RNS are considered to be important signalling molecules, their concentration is strictly regulated by the antioxidant defence network in conjunction with various transcription factors and vitagenes. In fact, activation of vitagenes via such transcription factors as Nrf2 leads to an additional synthesis of an array of protective molecules which can deal with increased ROS/RNS production. Therefore, it is a challenging task to develop a system of optimal antioxidant supplementation to help growing/productive birds maintain effective antioxidant defences and redox balance in the body. On the one hand, antioxidants, such as vitamin E, or minerals (e.g., Se, Mn, Cu and Zn) are a compulsory part of the commercial pre-mixes for poultry, and, in most cases, are adequate to meet the physiological requirements in these elements. On the other hand, due to the aforementioned commercially relevant stressors, there is a need for additional support for the antioxidant system in poultry. This new direction in improving antioxidant defences for poultry in stress conditions is related to an opportunity to activate a range of vitagenes (via Nrf2-related mechanisms: superoxide dismutase, SOD; heme oxygenase-1, HO-1; GSH and thioredoxin, or other mechanisms: Heat shock protein (HSP)/heat shock factor (HSP), sirtuins, etc.) to maximise internal AO protection and redox balance maintenance. Therefore, the development of vitagene-regulating nutritional supplements is on the agenda of many commercial companies worldwide.

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

Crosstalk between the mTOR and Nrf2/ARE signaling pathways as a target in the improvement of long-term potentiation.

Instead of the progress in the understanding of etiology of Parkinson's disease (PD), effective methods to prevent the progression of the disease have not been developed and only symptomatic treatment is currently possible. One of possible pathways to slow the progression of the disease is protection of dopaminergic neurons by maintaining mitochondrial quality control in neuron cells. Recent studies showed that the most promising target for pharmacological effects on mitochondria is the Nrf2/ARE signaling cascade. It participates in the maintenance of mitochondrial homeostasis, which is provided by an optimal ratio in the processes of mitochondrial biogenesis and mitophagy, as well as the optimal ratio of ROS production and ROS scavenging. Nrf2 activators are capable of modulating these processes, maintaining mitochondrial homeostasis in neurons. In addition, Nrf2 can synergistically interact with other transcription factors, for example, PGC-1a in the regulation of mitochondrial biogenesis and YY1 with the increase of antioxidant defense. All this makes Nrf2 an optimal target for drugs that could support the mitochondrial quality control, which, in combination with antioxidant protection, can significantly slow down the pathogenesis of PD. Some of these compounds have undergone laboratory studies and are at the stage of clinical trials now.

Nrf2/ARE Pathway as a Therapeutic Target for the Treatment of Parkinson Diseases.

Simplified qPCR method for detecting excessive mtDNA damage induced by exogenous factors.

Turnover of the mitochondrial pool due to coordinated processes of mitochondrial biogenesis and mitophagy is an important process in maintaining mitochondrial stability. An important role in this process is played by the Nrf2/ARE signaling pathway, which is involved in the regulation of the expression of genes responsible for oxidative stress protection, regulation of mitochondrial biogenesis, and mitophagy. The p62 protein is a multifunctional cytoplasmic protein that functions as a selective mitophagy receptor for the degradation of ubiquitinated substrates. There is evidence that p62 can positively regulate Nrf2 by binding to its negative regulator, Keap1. However, there is also strong evidence that Nrf2 up-regulates p62 expression. Thereby, a regulatory loop is formed between two important signaling pathways, which may be an important target for drugs aimed at treating neurodegeneration. Constitutive activation of p62 in parallel with Nrf2 would most likely result in the activation of mTORC1-mediated signaling pathways that are associated with the development of malignant neoplasms. The purpose of this review is to describe the p62-Nrf2-p62 regulatory loop and to evaluate its role in the regulation of mitophagy under various physiological conditions.

https://www.mdpi.com/2076-3425/10/11/847/pdf

Artem P. Gureev

Papers

Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways

Crosstalk between the mTOR and Nrf2/ARE signaling pathways as a target in the improvement of long-term potentiation.

Nrf2/ARE Pathway as a Therapeutic Target for the Treatment of Parkinson Diseases.

Simplified qPCR method for detecting excessive mtDNA damage induced by exogenous factors.

p62-Nrf2-p62 Mitophagy Regulatory Loop as a Target for Preventive Therapy of Neurodegenerative Diseases