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Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance., Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe; 1165

While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.

The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress. To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded/aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurode-generative diseases such as Alzheimer's (AD), Parkinson's (PD) or even Huntington's (HD) diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.

Projeto de Graduação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Licenciado em Fisioterapia Objectivo: Verificar a eficácia do treino excêntrico no tratamento da tendinopatia rotuliana em atletas. Metodologia: Foi efetuada uma pesquisa computorizada nas bases de dados Web of Knowledge, Pubmed e PEDro, utilizando as palavras-chave: “patellar tendinopathy”, “eccentric exercise” e “athletes”, usando os operadores de lógica AND/OR. Resultados: Nesta revisão foram incluídos 8 artigos envolvendo 163 indivíduos, 128 eram do sexo masculino e 35 do sexo feminino, com classificação média metodológica de 6 na escala PEDro. As modalidades encontradas nos estudos foram o voleibol, basquetebol, futebol, remo, squash, ténis, corredores, andebol, futebol americano, hoquéi no gelo, ski, ginástica, hóquei em campo, capoeira, desportos de luta, skateboard, triatlo e salto em altura. Conclusão: Na maioria dos estudos, o treino excêntrico melhorou os sintomas da patologia verificando-se melhoria na dor e na função do joelho, em atletas com tendinopatia rotuliana. Objective: To analyze the efficacy of eccentric training in the treatment of patellar tendinopathy in athletes. Methodology: A computerized search was performed in the databases Web of Knowledge, Pubmed and PEDro, using the keywords: "patellar tendinopathy", "eccentric exercise" and "athletes", using AND/OR. Results: In this review 8 randomized controlled trials were included involving 163 individuals, 128 were male and 35 female, with an average methodological classification of 6 on the PEDro scale. The modalities found in the studies were volleyball, basketball, soccer, rowing, squash, tennis, runners, handball, american football, ice hockey, skiing, gymnastics, field hockey, capoeira, fighting sports, skateboarding, triathlon and vertical jump. Conclusion: In most of the analyzed studies, eccentric training seems to improve the symptoms of the pathology by improvement pain and knee function in athletes with patellar tendinopathy. N/A

Submitted by Isabel Gomes (itg@lisboa.ucp.pt) on 2017-05-29T08:47:21Z No. of bitstreams: 1 Master Thesis 2017 - José Castro.pdf: 864126 bytes, checksum: 695ec56369130255c6d4af1b665f4049 (MD5) Approved for entry into archive by Isabel Gomes (itg@lisboa.ucp.pt) on 2017-05-29T08:49:00Z (GMT) No. of bitstreams: 1 Master Thesis 2017 - José Castro.pdf: 864126 bytes, checksum: 695ec56369130255c6d4af1b665f4049 (MD5) Made available in DSpace on 2017-05-29T08:49:00Z (GMT). No. of bitstreams: 1 Master Thesis 2017 - José Castro.pdf: 864126 bytes, checksum: 695ec56369130255c6d4af1b665f4049 (MD5) Previous issue date: 2017-04-03

White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/ release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho) physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e. g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance.

Submitted by Mariana Lopes (mariana@ipb.pt) on 2016-06-13T17:07:00Z No. of bitstreams: 1 96-650-1-PB.pdf: 131096 bytes, checksum: be309d59055aeec742fb44d8862063e8 (MD5) Made available in DSpace on 2016-06-13T17:07:00Z (GMT). No. of bitstreams: 1 96-650-1-PB.pdf: 131096 bytes, checksum: be309d59055aeec742fb44d8862063e8 (MD5) Previous issue date: 2013

Submitted by Biblioteca Escola Superior de Saúde (biblioteca@ess.ipp.pt) on 2022-01-31T10:15:24Z No. of bitstreams: 1 Dissertação_ACSP_Sónia Carvalho_V.Final.pdf: 7817461 bytes, checksum: 8e12c5d1a8d210eca4e4934eef34ac5b (MD5) Made available in DSpace on 2022-01-31T10:15:24Z (GMT). No. of bitstreams: 1 Dissertação_ACSP_Sónia Carvalho_V.Final.pdf: 7817461 bytes, checksum: 8e12c5d1a8d210eca4e4934eef34ac5b (MD5) Previous issue date: 2021-09-28

Since its first description in 1906 by Dr. Alois Alzheimer, Alzheimer's disease (AD) has been the most common type of dementia. Initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated AD with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of AD by using transcriptomic data from congenital diseases known to increase AD risk, namely Down Syndrome, Niemann Pick Disease Type C (NPC), and Mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of AD pathology, many of which have never been associated with AD. We then investigated common molecular alterations in brain samples from an NPC disease mouse model by juxtaposing them with brain samples of both human and mouse models of AD. Detailed phenotypic and molecular analyses revealed that the NPC mut mouse model can serve as a potential short-lived in vivo model for AD research and for understanding molecular factors affecting brain aging. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on AD research while highlighting shortcomings and lack of correlation in diverse in vitro models. Considering the lack of an AD mouse model that recapitulates the physiological hallmarks of brain aging, the characterization of a short-lived NPC mouse model will further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of AD from a perspective of accelerated brain aging.