Current Pharmaceutical Design - Volume 22, Issue 18, 2016

Proper function of the endoplasmic reticulum (ER) and mitochondria is essential for cellular homeostasis and the regulation of metabolic pathways. Perturbation of their function has been linked to pathophysiological states, including metabolic and liver diseases. Fatty liver diseases are a major health problem whose prevalence is dramatically increasing, may be induced by several factors (mainly chronic alcohol consumption, drugs or metabolic alterations), and share common features as lipid deposition, inflammation, oxidative stress and progression to more severe clinical stages, such as fibrosis, cirrhosis or even hepatocellular carcinoma. Besides their independent contributions to metabolic and hepatic pathologies, mitochondria and ER directly interact regulating each other’s function, and ER-mitochondria interface is involved in several molecular pathways, as induction of autophagy and triggering of inflammatory cascades. Disturbances in these interactions have already been implicated in different human diseases, and increasing interest is arising in their role on liver illnesses. This review summarizes the current understanding regarding mitochondrial and ER implication in fatty liver diseases, focusing on lipid accumulation and inflammation, and the relevance of both the individual functions of these organelles and of ER-mitochondria interactions in such processes. In addition, it describes the clinical implications and the available therapeutic options targeting directly these organelles or associated molecular mechanisms.

Heat preconditioning is a rapid cellular adaptive mechanism shared by many cells/ organs / organisms that results in synthesis and accumulation of heat shock proteins (HSPs), which are responsible for increased tolerance and survival of animals during and after heat stress (HS). HSPs function as molecular chaperones by restoring cellular homeostasis and promoting cell survival, and their major functions include protection of cells from injury by preventing protein damage and aggregation. Abundant evidence points to the ability of one kind of stress caused by external factors that induce primary adaptations in the organism to provide protection against additional stress of the same or another type, a phenomenon known as cross-tolerance. Diabetes mellitus (DM) is one of the diseases which have been associated with increased tissue sensitivity and vulnerability due to incorrect protein folding. Thus, HSPs may play an important role in minimizing the protein damage that can occur under the stressful conditions created by the disease. By increasing HSP production, heat preconditioning may be a promising therapy for patients with lifestylerelated diseases such as hypercholesterolemia, hypertension, DM and obesity. Also, pancreatic β-cells exposed to acute HS activate defence mechanisms which include HSP synthesis and are less sensitive to the effects of cytotoxic agents such as NO, oxygen radicals and -cytotoxic diabetogenic agents, such as streptozotocin (STZ). Mitochondrial dysfunction and mitochondria-specific cell stress are associated and can even be a primary abnormality caused by DMinduced hyperglycaemia and oxidative stress. There are an increasing number of genetic and/or pharmacological modulations of HSPs that have revealed the connection between HSPs, mitochondria and diabetes. HSPs may affect mitochondrial function in multiple ways, but the influence on skeletal muscle and adipose tissue, as well as on the pancreas, has attracted most interest as a key element in the development of novel pharmacological approaches to treating DM and associated metabolic conditions.

It is generally accepted that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are related to insulin resistance and type 2 diabetes. Mitochondria use substrates from lipid and glucose metabolism in order to generate ATP, and when mitochondrial O2 consumption is decreased due to an altered metabolism there is an increase in reactive oxygen species (ROS) that can impair different types of molecules and cells, especially in β- cells during type 2 diabetes. Furthermore, the maintenance of ER function in insulin-secreting β-cells is crucial, and when ER homeostasis is disrupted, the ER develops an unfolded protein response (UPR) in order to maintain the homeostasis of this organelle. However, when homeostasis fails in mitochondria and ER, these organelles can initiate death signalling pathways. New research has suggested that hyperlipidemia and hyperliglucaemia, known as key factors of type 2 diabetes (T2D), disrupt mitochondrial activity and ER homeostasis, thus triggering a disruption of energy metabolism, unresolvable UPR activation and β-cell death. This review explains the mechanisms of mitochondrial function and ER stress related to the pathological effects of type 2 diabetes in different tissues.

Type 2 diabetes can increase the risk of skeletal muscle dysfunction and, consequently, that of cardiovascular diseases, including coronary artery disease and stroke. It is also related to a reduced capacity for exercise, but the underlying mechanism is only partially understood. There are several factors that contribute to the development of skeletal muscle dysfunction, of which oxidative stress and mitochondrial dysfunction are among the most important. This review discusses the role of oxidative stress in the development and progression of skeletal and cardiac dysfunction associated with diabetes. It also provides an overview of the potential actions of antioxidants in general and mitochondria-targeted antioxidants in particular in the treatment of muscle dysfunction in type 2 diabetes.

The intent of this article is to summarize current body of knowledge on the potential implication of the xanthine oxidase pathway (XO) on skeletal muscle damage. The possible involvement of the XO pathway in muscle damage is exemplified by the role of XO inhibitors (e.g., allopurinol) in attenuating muscle damage. Reliance on this pathway (as well as on the purine nucleotide cycle) could be exacerbated in conditions of low muscle glycogen availability. Thus, we also summarize current hypotheses on the etiology of both baseline and exertional muscle damage in McArdle disease, a condition caused by inherited deficiency of myophosphorylase. Because myophosphorylase catalyzes the first step of muscle glycogen breakdown, patients are unable to obtain energy from their muscle glycogen stores. Finally, we provide preliminary data from our laboratory on the potential implication of the XO pathway in the muscle damage that is commonly experienced by these patients.

Sarcopenia could be currently defined as a geriatric syndrome initially characterized by a decrease in muscle mass that will get worse causing deterioration in strength and physical performance. A negative protein turnover, impaired mitochondrial dynamics and functions, a decreased muscle regeneration capacity, as well as an exacerbation of apoptosis are usually considered to be cellular mechanisms involved in muscle atrophy leading to sarcopenia. In this review, we first present that muscle overproduction of reactive oxygen and nitrogen species (RONS) and oxidative stress observed during aging are associated with sarcopenia, and then discuss how RONS are involved in redox-sensitive signaling pathways leading to sarcopenia. The identification of cost-effectiveness interventions to maintain muscle mass and physical functions in the elderly is one of the most important public health challenges. Here, we also discuss about the efficiency of different kind of antioxidant strategies against sarcopenia. Since exercise is the best strategy to prevent and reverse sarcopenia, we also highlight that exercise acts as an antioxidant.

The preservation of mitochondrial function and integrity is critical for cell viability. Under stress conditions, unfolded, misfolded or damaged proteins accumulate in a certain compartment of the organelle, interfering with oxidative phosphorylation and normal mitochondrial functions. In stress conditions, several mechanisms, including mitochondrial unfolded protease response (UPRmt), fusion and fission, and mitophagy are engaged to restore normal proteostasis of the organelle. Mitochondrial proteases are a family of more than 20 enzymes that not only are involved in the UPRmt, but actively participate at multiple levels in the stress-response system. Alterations in their expression levels, or mutations that determine loss or gain of function of these proteases deeply impair mitochondrial functionality and can be associated with the onset of inherited diseases, with the development of neurodegenerative disorders and with the process of carcinogenesis. In this review, we focus our attention on six of them, namely CLPP, HTRA2 and LONP1, by analysing the current knowledge about their functions, their involvement in the pathogenesis of human diseases, and the compounds currently available for inhibiting their functions.

Background: Molecular pathogenesis of hepatocellular carcinoma is complex and implies a multistep process involving different genetic and epigenetic alterations, as well as altered molecular pathways. Among these features, oxidative stress and mitochondria dysfunction represent an important trigger to hepatocarcinogenesis regardless of underlying liver disease etiology. An important part of the actual cancer research is focused on the molecular mechanisms and the signaling pathways involved in the process of so called “mitochondrial malignancy”. Method: Aim of this review is to summarize the main molecular mechanisms and the pathological consequences of oxidative stress and mitochondrial dysfunction in liver cancer. Furthermore, an up-to-date insight in therapeutic implications of the aforementioned processes is consistently developed. A literature search was conducted using PubMed until October 2015, based on English language journals. Results: Mitochondrial dysfunction may dramatically alter cell growth and proliferation by means of several “retrograde” mitochondria-nucleus signaling pathways, all of which have been shown to play a significant role in hepatocarcinogenesis. Nuclear oncogenes and tumor suppressors alike regulate mitochondrial turnover and function in a thick cross-talk whose role is fundamental in human oncology. Conclusion: The current knowledge on the role of mitochondrial signaling and oxidative stress in hepatocarcinogenesis seems to support the use of antioxidant agents in hepatocarcinoma patients, for instance in the adjuvant setting after radical treatments where their favorable cost-effective and safety profile may enable long-terms therapies aimed at preventing tumor recurrence. Data from randomized-controlled trials are warranted in order to confirm these promising results.

Background: The double stranded RNA (dsRNA)-activated protein kinase PKR is a well-established protein kinase that is activated by dsRNA during viral infection, and it inhibits global protein synthesis by phosphorylating the alpha subunit of eukaryotic initiation factor 2α (eIF2agr;). Recent studies have greatly broadened the recognized physiological activities of PKR by demonstrating its fundamental role in inflammatory signaling, particularly in chronic, low-grade inflammation induced by metabolic disorders, known as metaflammation. Metaflammation is initiated by the activation of the NOD-like receptor (NLR), leucine-rich repeat, pyrin domaincontaining 3 (NLRP3) gene by mitochondrial reactive oxygen species (ROS). A protein complex defined as the metaflammasome is assembled in the course of metaflammation. This complex integrates nutritional signaling with cellular stress, inflammatory components, and insulin action and is essential in maintaining metabolic homeostasis. PKR is a key constituent of the metaflammasome and interacts directly with several inflammatory kinases, such as inhibitor κB (IκB) kinase (IKK) and c-Jun N-terminal kinase (JNK), insulin receptor substrate 1 (IRS1), and component of the translational machinery such as eIF2α. Conclusion: This review highlights recent findings in PKR-mediated metaflammation and its association with the onset of metabolic syndrome in both human and animal models, with a focus on the molecular and biochemical pathways that underlie the progression of obesity, insulin resistance, and type-2 diabetes.

Cardiovascular disease (CVD) remains a major cause of death and disability worldwide, thus preventing and inhibiting CVD remains a health priority. Several lines of pharmacological interventions have not met with great success, thus inhibition of novel cellular stress pathways could be a novel therapeutic avenue to treat CVD. This review will focus on homocysteine and endoplasmic reticulum stress linked to mitochondria function, and possible therapeutic avenues for treatment.

Backgrouund: Polycystic ovary syndrome is a multifaceted disorder with a pathogenetic pathway that is not fully understood yet. Apart from hormonal derangements, insulin signaling defects and adipose tissue dysfunction, oxidative stress, defined as an imbalance derived from excessive formation of oxidants in the presence of limited antioxidants defenses, has been actively implicated in the etiology of the syndrome. Methods: This review focuses on understanding the putative role of oxidative stress in the pathophysiology of PCOS and analyzing its interconnection with the rest etiologic parameters and its contribution to the reproductive and metabolic manifestations of the syndrome. Results: Although underlying mechanisms have not been fully elucidated yet, it becomes evident that oxidative stress holds a respectable share in the pathogenesis of PCOS. In fact, PCOS can be considered as a purely oxidative state, where the body antioxidants cannot outweigh the excessive production of free radicals. Conclusion: Oxidative stress, in conjunction with the rest etiologic mechanisms of PCOS and the cardinal contribution of environmental factors, leads to an adverse redox status that stigmatizes the natural process of the syndrome.

In a review [1] published in this journal in 2014 we updated the role of statin treatment in patients with type 2 diabetes mellitus (T2DM). This is an important topic because the prevalence of T2DM is increasing and this disease is associated with a high risk of cardiovascular disease (CVD) as well as microvascular complications [1]. The relationship between T2DM and statins is further complicated since these drugs can cause new onset diabetes (NOD) although there is an overall benefit in terms of preventing vascular events [1, 2]. The cost implications of T2DM in terms of quality of life as well as providing healthcare are obvious. This is a brief update of our earlier review [1] based on recently published data.

Nowadays, millions of people worldwide are affected by problems of bones and articulations. These conditions represent about a half of the chronic diseases developed in individuals over 50 years, leading to problems of prolonged pain and physical inability, which usually require surgery, where bone grafts or implants are used. Nonetheless, despite the success of these therapeutic solutions, some drawbacks have been pointed out, related with the risk of developing infections after implant application within the body. Moreover, grafts are associated to pain, infection, tissue death at the donor site and immunological rejection. To overcome these limitations, tissue engineering has an important role that constitutes a promising area for repair and rebuild bone lesions, through the development of three-dimensional (3D) porous matrices, commonly known as scaffolds. Associated with these structures are mesenchymal stem cells and growth factors, which lead to the formation of new bone by stimulating the natural regeneration ability of the patient's tissue. In this review, we address the most important methodologies and concepts regarding tissue engineering for the replacement of bone tissue. The concept of scaffold, and examples of different types of scaffolds and their respective production methods are presented. In vitro and in vivo techniques to evaluate the suitability of scaffolds for human use are discussed. In addition, some of the most recent studies regarding the application of scaffolds for bone tissue engineering are described.