Current Pharmaceutical Design - Volume 17, Issue 35, 2011

Metabolic therapy can be considered as an important new challenge in the cure of different forms of human diseases. Promising and innovative therapeutic strategies are in fact arising from a plethora of experimental and clinical studies. In this Special Issue of Current Pharmaceutical Design, several of these different strategies have been reviewed by leading scientists involved in different areas of investigation either in the field of basic sciences and translational research or in the field of clinical studies on therapeutic intervention. They provide novel insights as concerns metabolic therapy for cardiovascular, neurodegenerative, autoimmune and infectious diseases as well as illustrate new concrete cellular targets of interest for the development of metabolically targeted drugs of possible use in the clinical practice. In particular, Adams and co-authors [1], from the University of Leipzig (Germany), have discussed the role of cachexia that is often associated with severe loss of skeletal muscle mass and a reduced energy metabolism. The maintenance of muscle mass can be generally regarded as a simple balance between protein synthesis and protein degradation. The authors sustain that, in cachexia, all molecular alterations regulating muscle mass and energy production in the skeletal muscle finally leads to a reduction in exercise capacity and provide some suggestion as concerns novel potential targets for the management of this complex metabolic syndrome associated with chronic diseases such as cancer, chronic obstructive pulmonary disease, chronic heart failure, and chronic kidney disease. Nagoshi and co-authors [2], from the Jikei University of Tokyo (Japan), in order to optimize cardiac metabolism in heart failure, suggest a therapeutic approach based on the modification substrate utilization. The derangement of the cardiac energy substrate metabolism plays in fact a key role in the pathogenesis of heart failure. Thus, manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. The authors argue that acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. Three works of this issue are dedicated to neurodegenerative diseases. The work of Manole and co-workers [3], from the University of Pittsburgh (USA), deals with a novel and intriguing matter of modern medicine: gender differences in cell metabolism. The paper considers different molecular aspects that can be responsible for the observed differences between males and females also analyzing the importance of host factors (sex, age, hormones) and environmental factors (nutrient deprivation, ischemic stress, trauma etc.). In this work, neuronal cell metabolic pathways have been taken into consideration but, conceivably, the gender issue should be expanded to other cell types in a near future. This might lead to an increase of our knowledge on this matter and give raise to innovative gender-“tailored” therapeutic strategies. Viña and co-authors [4], from the University of Valencia (Spain), have discussed the role of oxidative stress in Alzheimer's disease. In fact, it was suggested that several pathogenetic mechanisms involved in the onset and progression of Alzheimer's disease could be related to cell metabolic impairment and to the generation of pro-oxidant species. The authors debate about the need of a putative treatment of Alzheimer's disease with antioxidants. In the same field, but from a different point of view, Smaili and co-workers [5], from the University of Sao Paulo (Brazil), have reviewed the different aspects related to cell loss occurring in neurodegenerative diseases. In particular, these authors described the role of mitochondria in glutamate signaling and brain diseases and provided key information on how these organelles can influence cell fate during glutamate stimulation and calcium signaling. These authors also suggested that autophagy, a key cellular answer to metabolic stress, may function as a protective mechanism that is activated during mitochondrial dysfunction and may protect neuronal cells from injury and degeneration. Hence, autophagy could be considered as a novel target for metabolic therapeutic interventions.....

Cachexia is often associated with severe loss of skeletal muscle mass and a reduced energy metabolism. The maintenance of muscle mass can be generally regarded as a simple balance between protein synthesis and protein degradation. Several evidences are available in the current literature favoring a model in which myofilaments are released from the sarcomere by the action of calciumactivated calpains followed by the degradation of the myofilaments by the ubiquitin proteasome system. The initiation of the protein breakdown machinery is regulated by several factors like inflammatory cytokines, angiotensin II, insulin / insulin like growth factor 1 and reactive oxygen species. These factors also have the capability to influence PGC-1alpha activity, thereby regulating mitochondrial energy production. All these molecular alterations regulating muscle mass and energy production in the skeletal muscle finally leads to a reduction in exercise capacity in cachexia.

The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure.

Both classic and emerging literature point to sex-based disparity in neuronal metabolism. While detectable under baseline conditions, this phenomenon appears to be exaggerated or sometimes unmasked in neurons by cellular stress. A complex sex-dependent response to nutrient deprivation, excitotoxicity, oxidative/nitrositive stress, oxygen-glucose deprivation, and chemical toxicity has been observed in neurons in vitro, as well as after various insults including ischemic or traumatic brain injury in vivo. Importantly, sex-based disparity in response to diverse therapeutics has been seen in neurons in culture, contemporary animal models of brain injury, and in human disease. These have clear implications for pharmacological design of therapeutics targeting central nervous system diseases involving both males and females, and preclinical testing of promising agents.

Alzheimer's disease (AD) is closely related to the occurrence of oxidative stress. It was claimed that all pathophysiological mechanisms involved in the onset and progression of AD are related to oxidative stress. Thus, it is important to evaluate if there is oxidative stress as well as the mechanism by which this happens in AD patients as well as in animal models of AD. Extracellular plaques of amyloid b peptides (Aβ), a hallmark of the disease, have been postulated to be more protective than damaging in terms of oxidative stress because they may be chemical sinks in which heavy metals are placed. More than a decade ago we reasoned that damage due to Ab might be caused not by extracellular, but rather intracellular Ab peptide interacting with normal cell metabolism. Ab binds to mitochondrial membranes, interacts with heme and thus interferes with the normal electron flow through the respiratory chain. This results in a faulty mitochondrial energy metabolism and in an increased production of reactive oxygen species (ROS). The low mitochondrial energy metabolism may important to explain the hypo metabolism observed in AD patients in vivo (measured by positron emission tomography) and in isolated neurons incubated in the presence of Ab peptide. The increased ROS production results in oxidative stress. The occurrence of such stress provides the basis for a putative treatment of AD with antioxidants. Major efforts have been made to determine whether antioxidant supplementation could be a means of preventing, or even treating AD, but this idea is far from being well- established. We found that even though there is oxidative stress in AD, the administration of antioxidant vitamins, particularly vitamin E, is not effective in preventing the progression of the disease in all patients. We termed this the vitamin E paradox in AD. The paradox is the fact that for some patients, vitamin E could even be detrimental whereas for others vitamin E treatment partially prevents the loss memory associated with the progression of the disease. It is clear, however, that increasing the intake of fruits and vegetables rich in antioxidant vitamins, prevents or retards the onset of AD. Thus, the issue of whether antioxidant treatment is of use in AD is not settled and more research is warranted to clarify this point.

Glutamate is an important neurotransmitter in neurons and glial cells and it is one of the keys to the neuron-glial interaction in the brain. Glutamate transmission is strongly dependent on calcium homeostasis and on mitochondrial function. In the present work we presented several aspects related to the role of mitochondria in glutamate signaling and in brain diseases. We focused on glutamateinduced calcium signaling and its relation to the organelle dysfunction with cell death processes. In addition, we have discussed how alterations in this pathway may lead or aggravate a variety of neurodegenerative diseases. We compiled information on how mitochondria can influence cell fate during glutamate stimulation and calcium signaling. These organelles play a pivotal role in neuron and glial exchange, in synaptic plasticity and several pathological conditions related to Aging, Alzheimer's, Parkinson's and Huntington's diseases. We have also presented autophagy as a mechanism activated during mitochondrial dysfunction which may function as a protective mechanism during injury. Furthermore, some new perspectives and approaches to treat these neurodegenerative diseases are offered and evaluated.

Fibrosis may represent the final step induced by autoimmune mechanism(s). This may be due to the excess in fibroblast recruitment, activation and differentiation in myofibroblasts. These events may be triggered by cytokines, chemokines and growth factors released by lymphocytes or macrophages. Autophagy is an essential conserved homeostatic process that has long been appreciated for cell adaptation to nutrient deprivation. Autophagy is also recognized as an important component of both innate and acquired immunity to pathogens. Recently, dysregulation of autophagy in haematopoietic cells has been suggested to amplify the autoimmune responses. On the other hand, it is possible that defective autophagy in non-haematopoietic cells contributes to the progression to fibrosis. In fibroblasts some alterations in the metabolic pathways and pharmacological data suggest that a defective autophagy could contribute to excess in the production of extracellular matrix by altering the turnover of protein such as collagen. Our goal in this review is to describe the current knowledge on the role of autophagy in the development of fibrotic autoimmune diseases. Further studies could confirm whether agents modulating autophagy may be used in the treatment of these autoimmune diseases.

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that forms a multisubunit complex with numerous protein partners and it regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. A central role for mTOR in regulating T cell homeostasis is emerging. In various autoimmune diseases abnormal functioning, differentiation and/or activation of T cells have been documented and recent studies have detailed anomalous activation of various signaling axes including the mTOR pathway in these cells. In this review we summarize recent studies on the involvement of mTOR in T cell differentiation and metabolism, supporting a key role for this molecule in providing a direct link between these two processes. We also describe how the mTOR pathway affects multiple molecular processes in autoimmune diseases and discuss the potential of targeting this pathway in these disorders.

Reactive oxygen and nitrogen species play complex roles in the physiological regulation of cell metabolism and in many disease processes as well, including viral infections. Viral replication occurs within living cells and is totally dependent on its host's biosynthetic machinery. Many intracellular signaling pathways exploited by viruses for their own replication are regulated by the oxidoreductive (redox) state of the host cell. Consequently, factors that alter the balance between reactive oxygen/nitrogen species and antioxidant molecules/enzymes-including metabolic conditions like malnutrition, obesity, and diabetes-can influence cells' susceptibility to viral infection, the efficiency of viral replication, and as a result the progression and severity of virus-induced diseases. This review examines the ways in which the host-cell redox state affect viral replication and the actual potential of antioxidants to combat viral infections.

Nitric oxide participates in a wide array of physiological processes, ranging from neurotransmission to precursor of cytotoxic effector molecules of the immune system. Although nitric oxide is a mildly reactive intermediary, it can act as a precursor of strong oxidants under pathological conditions associated with oxidative stress including cardiovascular, inflammatory and neurodegenerative disorders. Peroxynitrite, the reaction product of nitric oxide with superoxide radicals, emerges as one of the principal players of nitric oxidederived toxicity due to its facile formation and ability to react with several critical cellular targets including, thiols, proteins, lipids and DNA. The extent of “nitroxidative stress” is determined by several factors, including the concentration and exposure time to this reactive species or its derived radicals and by the ability of the cell to face the oxidative challenge by means of its antioxidant defenses. The inflicted biomolecular damage can result on minimal and reversible changes to cell and tissue physiology, to alteration in bioenergetics, disruption of DNA integrity, mitochondrial dysfunction and even cell death. Although dissecting the free radical chemistry pathways responsible of cell/tissue disturbance of oxidative signaling and promotion of oxidative damage arising from nitric oxide-derived oxidants in a biological context is a vast endeavor, is an ineludible task in order to generate a rational therapeutic approach to modulate nitroxidative stress. Several redox-based pharmacological strategies with a collection of compounds with varying mechanisms of action have been tested at the cellular, preclinical and even clinical levels, and some novel and promising developments are underway. This review deals with key kinetic and biochemical aspects of nitric oxide-derived oxidant formation and reactions in biological systems, emphasizing the current evidence at the biochemical, cell/tissue and animal/human levels that support a pathophysiological role for peroxynitrite and related species in human pathology. In addition, a selection of available pharmacological tools will be discussed as an effort to rationalize antioxidant and/or redox-based therapeutic interventions in disease models.

Fatty liver disease is one of most prevalent metabolic liver diseases, which includes alcoholic (ASH) and nonalcoholic steatohepatitis (NASH). Its initial stage is characterized by fat accumulation in the liver, that can progress to steatohepatitis, a stage of the disease in which steatosis is accompanied by inflammation, hepatocellular death, oxidative stress and fibrosis. Recent evidence in experimental models as well as in patients with steatohepatitis have uncovered a role for cholesterol and sphingolipids, particularly ceramide, in the transition from steatosis to steatohepatitis, insulin resistance and hence disease progression. Cholesterol accumulation and its trafficking to mitochondria sensitizes fatty liver to subsequent hits including inflammatory cytokines, such as TNF/Fas, in a pathway involving ceramide generation by acidic sphingomyelinase (ASMase). Thus, targeting both cholesterol and/or ASMase may represent a novel therapeutic approach of relevance in ASH and NASH, two of the most common forms of liver diseases worldwide.