Janeiro-Arenas, M.H. (Manuel Humberto)
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- Trimethylamine N-oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model(Elsevier, 2022) Pineda-Lucena, A. (Antonio); Puerta, E. (Elena); Ludwig, I.A. (Iziar Amaia); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto); Lanz, M. (María)It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.
- Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target(2018) Martinez, J.A. (José Alfredo); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto)Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.
- Implication of Trimethylamine N-Oxide (TMAO) in disease: Potential biomarker or new therapeutic target(MDPI AG, 2018) Martinez, J.A. (José Alfredo); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto)Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.
- Deciphering the connection between aging, insulin resistance and cognitive decline in Alzheimer's disease: role of TMAO as linking mechanism(Universidad de Navarra, 2021-12-21) Janeiro-Arenas, M.H. (Manuel Humberto); Ramirez, M.J. (María Javier); Solas, M. (Maite)Insulin resistance and neurodegenerative diseases such as Alzheimer s disease are considered part of the main threats to health in old age. In light of the high numbers of overweight/obese and diabetic individuals, there is a clear need to better understand the pathophysiological mechanisms underpinning insulin resistance/obesity and the accompanying impact on cognitive function. The aim of the present study was to investigate the missing link between aging, insulin resistance and cognitive decline as aging and insulin resistance are both risk factors for Alzheimer s disease. TMA is a gut metabolite which proceeds from the bacterial synthesis of substrates such as L-carnitine and choline. TMA is then rapidly further oxidized by hepatic flavin monooxygenases FMO3 and FMO1 to form TMAO. At first, TMAO was thought to be a waste product of choline metabolism without action in our organism, but nowadays, there is emerging evidence linking TMAO to atherosclerosis, systemic inflammation, type 2 diabetes mellitus and even neuropathologies. Plasma TMAO levels show wide inter- and intra-individual variations. These levels are influenced by several factors but the main factor influencing TMAO levels is aging. Some studies performed in human and rats have revealed that plasma TMAO levels are closely related to aging showing increasing levels with age. In this context, we have investigated if TMAO could be the link between metabolic diseases and cognitive deficiencies. In vitro studies showed that TMAO was able to raise the differentiation of mature adipocytes from preadipocytes, increase expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) from macrophages and neurons and reduce expression of tight junction proteins in blood brain barrier cells. Moreover, TMAO was able to activate microglia and raise the expression of the pro-inflammatory marker CD16/CD32, increasing aberrantly myelin phagocytosis. SAMP8 a senescence accelerated mouse model was used to study the effect of aging (the main risk factor for AD) in peripheral inflammation and neuroinflammation. Studies were performed at three different ages: 2-months-old SAMP8 (young mice), 6-months-old SAMP8 (adult mice) and 10-month-old SAMP8 (old mice). Aging altered peripheral insulin sensitivity and glucose homeostasis in SAMP8 mice but not brain insulin signaling. Moreover, aging induced cognitive deficiencies and promoted peripheral and central inflammation. Finally, aging also induced gut dysbiosis, showing reduced diversity and changes in gut microbiota composition with enterotypes that could be associated to higher TMAO levels. This fact was further contrasted using LC-SM/SM what showed greater TMAO levels in serum of SAMP8 mice. Brain TMAO levels also increased with age in mice and humans. Treatment with 3,3-dimethyl-1-butanol (DMB), which is a choline TMA lyase enzyme inhibitor that decreases TMAO serum levels, restored peripheral inflammation reducing fat adipose tissue and reversing insulin and glucose alterations. Moreover, DMB also restored neuroinflammation decreasing expression of pro-inflammatory cytokines in hippocampus, reducing gliosis and restoring GFAP levels back to normal. Finally, SAMP8 performance in behavioral test was improved after DMB treatment ameliorating and restoring cognitive dysfunction.