Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 7, Issue 2, 2013

The 18 kDa translocator protein (TSPO) is able to modulate several mitochondria-related cell death processes due to close association with proteins and other molecules involved to the mitochondrial permeability transition pore. In this way, herein we review cell death mechanisms targeting mitochondria, including programmed cell death type I, II and III. Several proteins involved in these cell death processes and with a possible interplay with the TSPO are also discussed including the voltage dependent anion channel, the adenine nucleotide transporter, cardiolipin, and the Bcl-2 family proteins. Noteworthy, TSPO has been also implicated in various other functions including mitochondrial respiration, immune and phagocytic host-defense response, microglial activation, inflammation, cell growth and differentiation, cancer, cell proliferation, ischemia, and mental and neuropathological disorders. We focused in recent studies of the TSPO particularly on cancer and neurodegeneration, thus presenting the TSPO as a core element in the role of mitochondria in diseases and related processes. Clinical benefit may be attainable by increasing pharmacological knowledge related to the TSPO. Recent patents typically relate to diagnosis and treatment of TSPO-related pathological conditions including cancer, and inflammatory conditions, as well as disorders associated with central nervous system, such as neurodegeneration, convulsions, anxiety, mental disorders, and dementia.

Complete knowledge about the evolution of the carcinogenic process has to include cancer stem cells (CSCs), which are essential to understand tumor occurrence, recurrence, and also its reduction rate after radio- and/or chemotherapeutic treatments. Understanding CSCs physiology and metabolism may be crucial for the development of novel effective therapies. Therefore, being mitochondria an undeniable target for cancer therapy and a central hub in metabolism and cell and death decisions, it is essential to take this organelle into account and explore its actions and involvements in the context of CSCs physiology. In this review, we focus on recent patents and discoveries about mitochondrial bioenergetics and physiology of CSCs. A full understanding of the role of mitochondrial activity in CSCs and the creation of new strategies, methods and discoveries to support actual treatments with novel ones are of pivotal importance in order to ultimately eradicate cancer.

In addition to their participation in metabolic processes and control of programmed cell death, the role of mitochondria as a fundamental hub for innate anti-viral immunity is now emerging. The participation of the mitochondrial antiviral signaling protein (MAVS) as a central regulator of a complex signaling cascade, which results in the induction of antiviral and inflammatory responses has been described. A patent based on this role of MAVS is highlighted in this review.

The possibility that mitochondria are involved in cellular dysfunction is particularly high in situations associated with increases in free radical activity, like hypoxia or ischemia; therefore its potential role in the muscle post-mortem metabolism is reviewed. In the dying muscle, different routes of cell death catabolism (apoptosis, autophagy) may occur having great influence on the process of conversion of muscle into meat. Mitochondria are the first and also one of the main organelles affected by post-mortem changes; therefore they are decisive in the subsequent cellular responses influencing the pathway to cell demise and thus, the final meat quality. Depending on the cell death programme followed by muscle cells after exsanguination, diverse proteases would be activated to a different extent, which is also reviewed in order to understand how they affect meat tenderization. This review also summarizes recent patents relating cell death processes and meat tenderness. Further research is encouraged as there is still a need of knowledge on cell death post-mortem processes to increase our understanding of the conversion of muscle into meat.

Galectin-9 is a tandem-repeat type galectin with two carbohydrate-recognition domains, and it was first identified as an eosinophil chemoattractant and activation factor. Subsequent studies revealed that galectin-9, similar to other galectins, modulates a variety of biological functions including cell aggregation and adhesion, as well as apoptosis of tumor cells. Galectin-9 has recently been shown to have an anti-proliferative effect on cancer cells. Recent studies have uncovered additional mechanisms by which T cell immunoglobulin mucin-3 (Tim-3), a receptor for galectin-9, negatively regulates T cell responses by promoting CD8+ T cell exhaustion and inducing expansion of myeloid-derived suppressor cells. These mechanisms are involved in tumor growth and escape from immunity. In many solid cancers, the loss of galectin-9 expression is closely associated with metastatic progression, and treatment with recombinant galectin-9 prevents metastatic spread in various preclinical cancer models. Here, we review the biology and physiological role of galectin-9, and discuss the therapeutic potential of galectin-9 in cancer as well as relevant patents.

The canonical Wnt cascade has emerged as a critical regulator of cancer cells. Activation of the Wnt signaling pathway has also been associated with stem cell, thus raising the possibility of its role in embryogenesis and in the proliferation of malignant cancer cells. Wnt pathway has been reported to be involved in normal physiological processes in adult animals and integrally associated with cancer cell growth and maintenance, thus has been harnessed to devise strategies for anticancer therapy. The presence or absence of some members in this pathway, such as β-catenin, Axin or APC, has been found to involve in different types of tumors in human beings. Dysregulation of the canonical Wnt/β-catenin signaling pathway, mostly by inactivating mutations of the APC tumor suppressor, or oncogenic mutations of β-catenin, has been implicated in colorectal tumorigenesis. Further, elevated levels of β-catenin protein, a hallmark of activated canonical Wnt pathway, have been significantly observed in common forms of human malignancies, indicating that activation of the Wnt pathway may play an important role in tumor development and hence could be a crucial consideration for drug development. The paper discusses the potential therapeutic and diagnostic strategies directing on Wnt pathways on the basis of recent patents and their analysis.

One major issue regarding the clinical use of many peptides is their short half-life span in the body, due to the rapid clearance from the circulation. Thus, at the clinical level, there is a need for a regime of frequent injections of the peptides into the patients to overcome this low stability factor. The major strategies for overcoming this problem by pharmaceutical companies are based on chemical techniques and using specific peptidase inhibitors or cocktails. For this purpose, the cassette gene contains the sequence of the carboxyl-terminal peptide (CTP) of human chorionic gonadotropin β subunit which was ligated to the coding sequence of follitropin (FSH), erythropoietin (EPO), growth hormone (GH) and thus to increase the longevity and bioactivity of these proteins in vivo. Interestingly, FSH-CTP and GH-CTP were found to be not immunogenic in humans. FSH-CTP was approved by The European Commission. In addition, GH-CTP is not toxic and it passed successfully clinical trials Phase II in adults. Thus, using this technology seems to be promising in designing long acting peptides. Development of long acting peptides will diminish the cost of these drugs and perhaps reduce the number of injections in the clinical protocols. The article also summarizes some relevant patents.

The aim of this manuscript is to provide a brief review of the link between diabetes mellitus with cognitive impairment, the possible pathophysiology linking the two, and some possible therapeutic interventions for the treatment of this condition. The prevalence of diabetes increases with age, so also dementia increases in later life. As the population ages, type 2 diabetes and AD are increasing. Both diseases are chronic and are the leading causes of morbidity and mortality. Recent studies showed that older people with type 2 diabetes have a higher risk of cognitive decline. The precise mechanism linking the two remains to be found out. Several hypothetical mechanisms have been postulated. Type 2 diabetes is a risk factor for AD and vascular dementia. The association between diabetes and AD is particularly strong among carriers of the APOE ε4. Several studies have linked dementia to diabetes. Impaired fasting glucose and impaired glucose tolerance and insulin resistance have also been associated with poor cognitive performance and at risk of developing cognitive impairment. Studies have suggested that metabolic syndrome may be linked to vascular dementia, while contrasting findings showed the role of metabolic syndrome to AD. In this review, how diabetes and cognitive impairment and Alzheimer's disease are mutually linked, possible mechanism linking the two and some possible therapeutic interventions with some patents that seem to be good therapeutic targets in future are discussed.