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Volpe C.M.O.,Nucleo de Pos Graduacao e Pesquisa NPGP | Nogueira-Machado J.A.,Nucleo de Pos Graduacao e Pesquisa NPGP
Recent Patents on Endocrine, Metabolic and Immune Drug Discovery

Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s disease is an axonopathy with adultonset, progressive and irreversible degeneration of upper and lower motor neurons. Around 90% of ALS is considered as sporadic ALS (sALS) without apparent genetic cause while in the familial type of ALS (fALS) at least one affected blood relative needs to be identified. Both sALS and fALS show similar progression and pathological profile. Biochemical and immunological roles have been reported for both types of ALS. It has been suggested that mutation in SOD1 gene would be responsible for the oxidative stress and neurotoxicity. Besides, oxidative stress, protein aggregation, altered cholinergic synapse, neuro-inflammation and production of pro-inflammatory cytokines have also been reported. Thus, the focus of the present review was on biochemical and immunological biomarkers and pathogenic mechanism. Regulatory T cells, pro-inflammatory cytokines and activation of pro-inflammatory signaling pathway are discussed. The activation of NRL inflammasomes in ALS and the involvement of IL-18, IL-1β and capases-1 are also suggested. The presence and importance of HMGB-1 (DAMP) and activation of Tolllike receptors and/or RAGE also are envisaged. The patents US20140212508, WO2014145776, WO2014145118, US20140255371, US20140194427, US20140243400, WO2014128254, WO2014076702, WO2014071449, WO2014043696, WO2014001742, and WO2013082299 are summarized. This review intends to evaluate the biochemical and immunological responses and the involvement of inflammasomes in the pathogenesis of ALS. In the present review, we suggest hypothetical model for ALS pathogenesis and we discuss some patents that suggest new treatment and/or therapeutic targets. Due to a large number of patents covering therapy and control of neurodegenerative diseases, our focus was restricted only to discuss the latest registered patents in 2014. © 2015 Bentham Science Publishers. Source

Nogueira-Machadoa J.A.,Nucleo de Pos Graduacao e Pesquisa NPGP | de Oliveira Volpea C.M.,Nucleo de Pos Graduacao e Pesquisa NPGP
Recent Patents on Endocrine, Metabolic and Immune Drug Discovery

In the present study, we evaluated recent patents that describe products or methods able to down-regulate the pro-inflammatory action of HMGB-1, also called as amphoterin. High Mobility Group Box-1 (HMGB-1) has been implicated in the pathogenesis of inflammatory diseases. HMGB-1 has been proposed to be a crucial mediator in the pathogenesis of many diseases including sepsis, arthritis, cancer, autoimmunity diseases and diabetes. It has been suggested that HMGB-1 itself can signal through RAGEs (receptor for advanced glycation end products) and through the Toll-Like Receptors TLR2 and TLR4. Activation of these receptors results ultimately in the activation of Nuclear Factor-kappaB (NFkappaB), inducing the up-regulation of leukocyte adhesion molecules, production of pro-inflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. There are several patents proposed for controlling the production, secretion and neutralization of HMGB-1 and consequently the inflammatory process. We have divided the patents in six groups based on mechanism of action. The group 1 is associated with inhibition of HMGB-1 using anti-HMGB-1 antibodies; group 2: inhibition of HMGB-1 releases from the nucleus into the extracellular space; group 3: HMGB-A box as a competitive antagonist of HMGB-1; group 4: blockage of RAGE-HMGB-1 signaling using RAGE antagonists; group 5: blockage of TLR-HMGB-1 signaling using anti-TLR2 antibodies and group 6: other molecules that modulate HMGB-1 activity using e.g. human soluble thrombomodulin. The mechanism of HMGB-1 action, its role and efficiency of each group of patents proposed for controlling inflammation are discussed. © 2012 Bentham Science Publishers. Source

Volpe C.M.O.,Nucleo de Pos Graduacao e Pesquisa NPGP | Abreu L.F.M.,Nucleo de Pos Graduacao e Pesquisa NPGP | Gomes P.S.,Nucleo de Pos Graduacao e Pesquisa NPGP | Gonzaga R.M.,Nucleo de Pos Graduacao e Pesquisa NPGP | And 2 more authors.
Oxidative Medicine and Cellular Longevity

We examined nitric oxide (NO), IL-6, and TNF- α secretion from cultured palmitate-stimulated PBMNCs or in the plasma from type 2 diabetes mellitus (T2MD) patients or nondiabetic (ND) controls. Free fatty acids (FFA) have been suggested to induce chronic low-grade inflammation, activate the innate immune system, and cause deleterious effects on vascular cells and other tissues through inflammatory processes. The levels of NO, IL-6, TNF- α, and MDA were higher in supernatant of palmitate stimulated blood cells (PBMNC) or from plasma from patients. The results obtained in the present study demonstrated that hyperglycemia in diabetes exacerbates in vitro inflammatory responses in PBMNCs stimulated with high levels of SFA (palmitate). These results suggest that hyperglycemia primes PBMNCs for NO, IL-6, and TNF-alpha secretion under in vitro FFA stimulation are associated with the secretion of inflammatory biomarkers in diabetes. A combined therapy targeting signaling pathways activated by hyperglycemia in conjunction with simultaneous control of hyperglycemia and hypertriglyceridemia would be suggested for controlling the progress of diabetic complications. © 2014 Caroline Maria Oliveira Volpe et al. Source

Veloso C.A.,Nucleo de Pos Graduacao e Pesquisa NPGP | Volpe C.M.O.,Nucleo de Pos Graduacao e Pesquisa NPGP | Carrara C.L.,Fundacao Biominas | Chaves M.M.,Federal University of Minas Gerais | Nogueira-Machado J.A.,Nucleo de Pos Graduacao e Pesquisa NPGP
Recent Patents on Endocrine, Metabolic and Immune Drug Discovery

Advanced glycation end products (AGEs) are important biochemical compounds found in diabetes mellitus and are likely to be associated with an inflammatory process. Within the vessel wall, AGEs may interact with specific receptors to modulate a large number of cellular properties by activating several signaling pathways. One of these receptors is called "receptor for AGE" (RAGE). The AGE-RAGE interactions enhance transcription genes encoding for cytokines, growth factors, adhesive molecules and increased classical acute phase proteins. Potential preventive and therapeutic approaches toward diabetes and its complications include inhibition of AGE formation, breakage of preformed AGE-proteins crosslink, blockade of AGE-RAGE interactions with RAGE competitors, antibody antagonists and RAGE specific metabolic inhibition. Blockade of AGE-RAGE complex formation suppresses the levels of pro-inflammatory cytokines and growth factors and it may be considered as a target for overcoming diabetic complications. This concise review about AGE-RAGE interaction and diabetes complications discusses pathophysiological mechanisms at a glance. Patents on inhibition of AGE formation, RAGE expression and AGE-RAGE interaction are shown and discussed here. © 2010 Bentham Science Publishers Ltd. Source

Anjos P.M.F.,Nucleo de Pos Graduacao e Pesquisa NPGP | Fagundes-Netto F.S.,Nucleo de Pos Graduacao e Pesquisa NPGP | Volpe C.M.O.,Nucleo de Pos Graduacao e Pesquisa NPGP | Nogueira-Machado J.A.,Nucleo de Pos Graduacao e Pesquisa NPGP
Recent Patents on Endocrine, Metabolic and Immune Drug Discovery

Neutrophils Extracellular Trap (NET) is composed of nuclear chromatin with hyper segmentation of nuclear lobes, citrullination of histone-associated DNA and mixing with cytoplasmic proteins including the enzyme myeloperoxidase. It is believed that neutrophils trap can kill microorganisms and constitutes a new form of innate defense. However, in some conditions, NET formation may be detrimental to the organism due to its association with autoantibody formation. Thus, NETs can be beneficial or detrimental depending of the DNA clearance recent registered patents describing the processes, products, methods and therapeutic indications of the neutrophil extracellular trap (NET) phenomenon have been reported. The patents US8710039; EP2465536; EP2651440; US20130302345; US20140099648; US20130183662; WO2012166611; and RU2463349C2, related to NETosis, suggest an association between NET formation and autoimmunity. However, its function is still not fully understood. Some parasites have learned to escape from NET using nucleases. NET persistence could be due to a possible enzymatic inhibition as suggested in Grabar´s theory for explaining the induction of physiologic or pathologic autoantibodies. In the present mini-review NET persistence due to impairment in the homeostasis clearance of DNA is discussed. © 2014 Bentham Science Publishers. Source

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