Papers by Emanuel Candeias
Redox biology, Jul 1, 2023
Cellular and Molecular Life Sciences
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013
According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particula... more According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socioeconomic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.
International Journal of Molecular Sciences
Mitochondria play a key role in regulating host metabolism, immunity and cellular homeostasis. Re... more Mitochondria play a key role in regulating host metabolism, immunity and cellular homeostasis. Remarkably, these organelles are proposed to have evolved from an endosymbiotic association between an alphaproteobacterium and a primitive eukaryotic host cell or an archaeon. This crucial event determined that human cell mitochondria share some features with bacteria, namely cardiolipin, N-formyl peptides, mtDNA and transcription factor A, that can act as mitochondrial-derived damage-associated molecular patterns (DAMPs). The impact of extracellular bacteria on the host act largely through the modulation of mitochondrial activities, and often mitochondria are themselves immunogenic organelles that can trigger protective mechanisms through DAMPs mobilization. In this work, we demonstrate that mesencephalic neurons exposed to an environmental alphaproteobacterium activate innate immunity through toll-like receptor 4 and Nod-like receptor 3. Moreover, we show that mesencephalic neurons incr...
International Journal of Molecular Sciences
Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tra... more Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tract, especially in the epididymis. Although it is known that T2DM alters epididymal physiology, disturbing mitochondrial function and favoring oxidative stress, the mechanisms remain unknown. Sirtuin 1 (SIRT1), peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α), and sirtuin 3 (SIRT3) are key regulators of mitochondrial function and inducers of antioxidant defenses. In this study, we hypothesized that the epididymal SIRT1/PGC-1α/SIRT3 axis mediates T2DM-induced epididymis dysfunction by controlling the oxidative profile. Using 7 Goto-Kakizaki (GK) rats (a non-obese model that spontaneously develops T2DM early in life), and 7 age-matched Wistar control rats, we evaluated the protein levels of SIRT1, PGC-1α, and SIRT3, as well as the expression of mitochondrial respiratory complexes. The activities of epididymal glutathione peroxidase (GPx), glutathione reductase (GR), sup...
Springer Series in Translational Stroke Research, 2017
Type 2 diabetes (T2D) is a highly disabling, major socioeconomic burden, whose long-term complica... more Type 2 diabetes (T2D) is a highly disabling, major socioeconomic burden, whose long-term complications (particularly those affecting the central nervous system (CNS), as Alzheimer disease (AD)) can be further exacerbated by the frequent development of comorbid hypertension. Although the precise mechanisms involved herein remain elusive, it is conceivable that chronic T2D-related brain insulin resistance (IRES) and hyperglycemia may crosstalk with an overactivated brain renin-angiotensin-II-aldosterone system (RAAS) further potentiating the hypertension-related injury and culminating in cognitive dysfunction and AD. Indeed, several studies showed the contribution of abnormal RAAS activation upon hypertension per se to the pathophysiology of CNS disorders, such as stroke and AD. However, most of this available knowledge relies on the indirect effects of pharmacological inhibition of RAAS by drugs belonging either to the angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors (ACEi) groups. For instance, antihypertensive drugs have also shown anti-neuroinflammatory properties, widely known to play a pivotal role in brain and cognitive dysfunction.
Gut, 2021
ObjectiveIdiopathic Parkinson’s disease (PD) is characterised by alpha-synuclein (aSyn) aggregati... more ObjectiveIdiopathic Parkinson’s disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin β-N-methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities.DesignTo test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific ef...
Mitochondrial Diseases, 2018
Mitochondria are exceptionally primed to play a key role in neuronal cell survival since they are... more Mitochondria are exceptionally primed to play a key role in neuronal cell survival since they are involved in energy production and function as the metabolic center of cells. Several findings provide evidence for the role of mitochondria in neurodegeneration associated with Alzheimer's and Parkinson's diseases (AD and PD). Recent data highlight the role of mitochondrial proteins and mitochondrial reactive oxygen species in the intracellular signaling that regulates innate immunity and inflammation. In this chapter, we will discuss the relevance of the interplay between mitochondria and innate immunity, focusing on mitochondrial damage-associated molecular patterns (DAMPs) and how they can activate innate immunity and elicit AD and PD neurodegenerative process.
Journal of Neuroinflammation, 2020
Background After decades of research recognizing it as a complex multifactorial disorder, sporadi... more Background After decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer’s disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-l-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms. Methods Freshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and ...
International Journal of Molecular Sciences, 2020
Alzheimer’s disease (AD) is the most common form of dementia worldwide, being characterized by th... more Alzheimer’s disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Aβ) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Aβ and p-tau, motor and cognitive function, glucose metabolism, inflammatio...
Molecules, 2019
Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer’s disease (AD),... more Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer’s disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifactorial nature and complexity of AD, a multi-target-directed ligand approach was herein employed, by designing a set of six selected hybrids (14–19) that combine in the same entity two pharmacophores: tacrine (TAC) and 2-phenylbenzothiazole (PhBTA). The compounds contain a methoxy substituent at the PhBTA moiety and have a variable length linker between that and the TAC moiety. The docking studies showed that all the compounds assure a dual-binding mode of acetylcholinesterase (AChE) inhibition, establishing π-stacking and H-bond interactions with aminoacid residues at both active binding sites of the enzyme (CAS and PAS). The bioassays revealed that the designed compounds display excellent AChE inhibitory activity in the sub-microm...
Metallomics, 2018
Two in one drug: repurposing 2 existing drugs into polypharmacological compounds for targeting an... more Two in one drug: repurposing 2 existing drugs into polypharmacological compounds for targeting and regulating multiple pathological factors, including acetylcholine esterase (AChE), metal ions (Mn+) as well as metal associated amyloid-β (Aβ) aggregates and redox active species (ROS), found in Alzheimer's disease (AD).
Journal of enzyme inhibition and medicinal chemistry, 2018
A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have... more A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer's disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC=4.0-30.0 μΜ) and moderate ability for inhibition of Aβ self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ induced toxicity. Structure-activity relationship allowed the identifi...
Molecular Neurobiology, 2016
Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. C... more Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e.g., Alzheimer disease (AD)), the impairment of insulin signaling may be a key link. However, these may also involve changes in sex hormones' function and metabolism, ultimately contributing to the different susceptibilities between females and males to some pathologies. For example, female sex has been pointed as a risk factor for AD, particularly after menopause. However, less is known on the underlying molecular mechanisms or even if these changes start during middle-age (perimenopause). From the above, we hypothesized that sex differentially affects hormone-mediated intracellular signaling pathways in T2D brain, ultimately modulating the risk for neurodegenerative conditions. We aimed to evaluate sexassociated alterations in estrogen/insulin-like growth factor-1 (IGF-1)/insulin-related signaling, oxidative stress markers, and AD-like hallmarks in middle-aged control and T2D rat brain cortices. We used brain cortices homogenates obtained from middle-aged (8-month-old) control Wistar and nonobese, spontaneously T2D Goto-Kakizaki (GK) male and female rats. Peripheral characterization of the animal models was done by standard biochemical analyses of blood, plasma, or serum. Steroid sex hormones, oxidative stress markers, and AD-like hallmarks were given by specific ELISA kits and colorimetric techniques, whereas the levels of intracellular signaling proteins were determined by Western blotting. Albeit the high levels of plasma estradiol and progesterone observed in middle-aged control females suggested that they were still under their reproductive phase, some gonadal dysfunction might be already occurring in T2D ones, hence, anticipating their menopause. Moreover, the higher blood and lower brain cholesterol levels in female rats suggested that its E. Candeias and A. I. Duarte contributed equally to this work.
Molecular neurobiology, Jan 2, 2017
Type 2 diabetes (T2D) is a modern socioeconomic burden, mostly due to its long-term complications... more Type 2 diabetes (T2D) is a modern socioeconomic burden, mostly due to its long-term complications affecting nearly all tissues. One of them is the brain, whose dysfunctional intracellular quality control mechanisms (namely autophagy) may upregulate apoptosis, leading to cognitive dysfunction and Alzheimer disease (AD). Since impaired brain insulin signaling may constitute the crosslink between T2D and AD, its restoration may be potentially therapeutic herein. Accordingly, the insulinotropic anti-T2D drugs from glucagon-like peptide-1 (GLP-1) mimetics, namely, exendin-4 (Ex-4), could be a promising therapy. In line with this, we hypothesized that peripherally administered Ex-4 rescues brain intracellular signaling pathways, promoting autophagy and ultimately protecting against chronic T2D-induced apoptosis. Thus, we aimed to explore the effects of chronic, continuous, subcutaneous (s.c.) exposure to Ex-4 in brain cortical GLP-1/insulin/insulin-like growth factor-1 (IGF-1) signaling, ...
World journal of diabetes, Jan 25, 2015
Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatmen... more Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importa...
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Papers by Emanuel Candeias