Unraveling the potential of endothelial progenitor cells as a treatment following ischemic stroke

Angiogénesis; Células progenitoras endoteliales; IctusAngiogènesi; Cèl·lules progenitores endotelials; IctusAngiogenesis; Endothelial progenitor cells; StrokeIschemic stroke is becoming one of the most common causes of death and disability in developed countries. Since current therapeutic options are quite limited, focused on acute reperfusion therapies that are hampered by a very narrow therapeutic time window, it is essential to discover novel treatments that not only stop the progression of the ischemic cascade during the acute phase, but also improve the recovery of stroke patients during the sub-acute or chronic phase. In this regard, several studies have shown that endothelial progenitor cells (EPCs) can repair damaged vessels as well as generate new ones following cerebrovascular damage. EPCs are circulating cells with characteristics of both endothelial cells and adult stem cells presenting the ability to differentiate into mature endothelial cells and self-renew, respectively. Moreover, EPCs have the advantage of being already present in healthy conditions as circulating cells that participate in the maintenance of the endothelium in a direct and paracrine way. In this scenario, EPCs appear as a promising target to tackle stroke by self-promoting re-endothelization, angiogenesis and vasculogenesis. Based on clinical data showing a better neurological and functional outcome in ischemic stroke patients with higher levels of circulating EPCs, novel and promising therapeutic approaches would be pharmacological treatment promoting EPCs-generation as well as EPCs-based therapies. Here, we will review the latest advances in preclinical as well as clinical research on EPCs application following stroke, not only as a single treatment but also in combination with new therapeutic approaches.This study was partially supported by grants from the Xunta de Galicia (PH, JC, and TS: IN607A2018/3, TS: IN607D 2020/09, AC: IN606A-2021/015), the Science Ministry of Spain (TS: RTI2018-102165-B-I00 and RTC2019-007373-1), and the Instituto de Salud Carlos III (AR: PI19/00186 and RD21/0006/0007). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (LF and TS: EAPA_791/2018_ NEUROATLANTIC Project), INTER-REG V A España Portugal (POCTEP) (LF and TS: 0624_2IQBIONEURO_6_E), the European Regional Development Fund (ERDF), the PT2020 program (LF: FEDER, project LABEL: POCI-01-0247-FEDER-049268), and the Fundação para a Ciência e Tecnologia (LF: project ENDEAVOUR: EXPL/BTM-ORG/1348/2021). Moreover, DR-S (CD21/00166), MA-N (IFI18/00008), and TS (CPII17/00027) are recipients of Sara Borrell, iPFIS, and Miguel Servet contracts, respectively, from the Instituto de Salud Carlos III. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease.This study was partially supported by grants from the Xunta de Galicia (Consellería de Economía e Industria: IN607A2018/3 & IN607D 2020/09), and Science Ministry of Spain (RTI2018-102165-B-I00 & RTC2019-007373-1). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (EAPA_791/2018_ NEUROATLANTIC project), INTERREG V A España Portugal (POCTEP) (0624_2IQBIONEURO_6_E) and the European Regional Development Fund (ERDF). Work in AGM lab is supported by grant IT-1106-16 from “Departamento de Educación, Universidades e Investigación” (Gobierno Vasco, Gasteiz-Virtoria, Spain). Moreover, M. Aramburu-Núñez (IFI18/00008) is recipient of iPFIS contract, and Sobrino (CPII17/00027) is recipient of a research contract from the Miguel Servet Program from the Instituto de Salud Carlos III. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Association of periodontitis with cognitive decline and its progression: Contribution of blood‐based biomarkers of Alzheimer's disease to this relationship

Aim To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood-based markers of Alzheimer's disease. Materials and Methods Data from a 2-year follow-up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full-mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini-Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aβ)1-40, Aβ1-42, phosphorylated and total Tau (p-Tau and t-Tau) were determined at baseline, 12 and 24 months. Results Periodontitis was associated with poor cognitive performance (MMSE: β = −1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0–3.1). Subjects with periodontitis showed greater baseline levels of p-Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p < .001) and Aβ1-40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p = .036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p = .005). Conclusions Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p-Tau and Aβ1-40 may play a role in this associationThis study was partially supported by grants from the Xunta de Galicia (TS & JC: IN607A2018/3, TS: IN607D 2020/09 and IN607A2022/07), Institute of Health Carlos III (TS: PI22/00938 and CB22/05/00067) and Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (TS: EAPA_791/2018_NEUROATLANTIC project), INTER-REG V A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E) and the European Regional Development Fund. Moreover, several members of the research team are supported by the Institute of Health Carlos III: MAN holds an iPFIS contract (IFI18/00008), DR-S and YL are recipients of a Sara Borrell fellowship (CD21/00166 and CD22/00051, respectively) and TS held a Miguel Servet contract (CPII17/00027). Finally, AC is supported by a predoc contract of Xunta de Galicia (IN606A-2021/015). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscriptS

Endothelial Progenitor Cells and Vascular Alterations in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease representing the most common type of dementia worldwide. The early diagnosis of AD is very difficult to achieve due to its complexity and the practically unknown etiology. Therefore, this is one of the greatest challenges in the field in order to develop an accurate therapy. Within the different etiological hypotheses proposed for AD, we will focus on the two-hit vascular hypothesis and vascular alterations occurring in the disease. According to this hypothesis, the accumulation of β-amyloid protein in the brain starts as a consequence of damage in the cerebral vasculature. Given that there are several vascular and angiogenic alterations in AD, and that endothelial progenitor cells (EPCs) play a key role in endothelial repair processes, the study of EPCs in AD may be relevant to the disease etiology and perhaps a biomarker and/or therapeutic target. This review focuses on the involvement of endothelial dysfunction in the onset and progression of AD with special emphasis on EPCs as a biomarker and potential therapeutic target

Neuroprotection Afforded by an Enriched Mediterranean-like Diet Is Modified by Exercise in a Rat Male Model of Cerebral Ischemia

Ischemic stroke is an important cause of mortality and disability worldwide. Given that current treatments do not allow a remarkably better outcome in patients after stroke, it is mandatory to seek new approaches to preventing stroke and/or complementing the current treatments or ameliorating the ischemic insult. Multiple preclinical and clinical studies highlighted the potential beneficial roles of exercise and a Mediterranean diet following a stroke. Here, we investigated the effects of a pre-stroke Mediterranean-like diet supplemented with hydroxytyrosol and with/without physical exercise on male rats undergoing transient middle cerebral artery occlusion (tMCAO). We also assessed a potential synergistic effect with physical exercise. Our findings indicated that the diet reduced infarct and edema volumes, modulated acute immune response by altering cytokine and chemokine levels, decreased oxidative stress, and improved acute functional recovery post-ischemic injury. Interestingly, while physical exercise alone improved certain outcomes compared to control animals, it did not enhance, and in some aspects even impaired, the positive effects of the Mediterranean-like diet in the short term. Overall, these data provide the first preclinical evidence that a preemptive enriched Mediterranean diet modulates cytokines/chemokines levels downwards which eventually has an important role during the acute phase following ischemic damage, likely mediating neuroprotection

Stress Granules and Acute Ischemic Stroke: Beyond mRNA Translation

Ischemic stroke is a leading cause of death and disability worldwide. Following an ischemic insult, cells undergo endoplasmic reticulum (ER) stress, which increases the ER&rsquo;s protein-folding and degradative capacities and blocks the global synthesis of proteins by phosphorylating the eukaryotic translation initiation factor 2-alpha (eIF2&alpha;). Phosphorylation of eIF2&alpha; is directly related to the dynamics of stress granules (SGs), which are membraneless organelles composed of RNA-binding proteins and mRNA. SGs play a critical role in mRNA metabolism and translational control. Other translation factors are also linked to cellular pathways, including SG dynamics following a stroke. Because the formation of SGs is closely connected to mRNA translation, it is interesting to study the relationship between SG dynamics and cellular outcome in cases of ischemic damage. Therefore, in this review, we focus on the role of SG dynamics during cerebral ischemia

Stress Granules and Acute Ischemic Stroke: Beyond mRNA Translation

Ischemic stroke is a leading cause of death and disability worldwide. Following an ischemic insult, cells undergo endoplasmic reticulum (ER) stress, which increases the ER’s protein-folding and degradative capacities and blocks the global synthesis of proteins by phosphorylating the eukaryotic translation initiation factor 2-alpha (eIF2α). Phosphorylation of eIF2α is directly related to the dynamics of stress granules (SGs), which are membraneless organelles composed of RNA-binding proteins and mRNA. SGs play a critical role in mRNA metabolism and translational control. Other translation factors are also linked to cellular pathways, including SG dynamics following a stroke. Because the formation of SGs is closely connected to mRNA translation, it is interesting to study the relationship between SG dynamics and cellular outcome in cases of ischemic damage. Therefore, in this review, we focus on the role of SG dynamics during cerebral ischemia

Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

In 1959, E. G. Gray described two different types of synapses in the brain for the first time: symmetric and asymmetric. Later on, symmetric synapses were associated with inhibitory terminals, and asymmetric synapses to excitatory signaling. The balance between these two systems is critical to maintain a correct brain function. Likewise, the modulation of both types of synapses is also important to maintain a healthy equilibrium. Cerebral circuitry responds differently depending on the type of damage and the timeline of the injury. For example, promoting symmetric signaling following ischemic damage is beneficial only during the acute phase; afterwards, it further increases the initial damage. Synapses can be also altered by players not directly related to them; the chronic and long-term neurodegeneration mediated by tau proteins primarily targets asymmetric synapses by decreasing neuronal plasticity and functionality. Dopamine represents the main modulating system within the central nervous system. Indeed, the death of midbrain dopaminergic neurons impairs locomotion, underlying the devastating Parkinson’s disease. Herein, we will review studies on symmetric and asymmetric synapses plasticity after three different stressors: symmetric signaling under acute damage—ischemic stroke; asymmetric signaling under chronic and long-term neurodegeneration—Alzheimer’s disease; symmetric and asymmetric synapses without modulation—Parkinson’s disease

Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

In 1959, E. G. Gray described two different types of synapses in the brain for the first time: symmetric and asymmetric. Later on, symmetric synapses were associated with inhibitory terminals, and asymmetric synapses to excitatory signaling. The balance between these two systems is critical to maintain a correct brain function. Likewise, the modulation of both types of synapses is also important to maintain a healthy equilibrium. Cerebral circuitry responds differently depending on the type of damage and the timeline of the injury. For example, promoting symmetric signaling following ischemic damage is beneficial only during the acute phase; afterwards, it further increases the initial damage. Synapses can be also altered by players not directly related to them; the chronic and long-term neurodegeneration mediated by tau proteins primarily targets asymmetric synapses by decreasing neuronal plasticity and functionality. Dopamine represents the main modulating system within the central nervous system. Indeed, the death of midbrain dopaminergic neurons impairs locomotion, underlying the devastating Parkinson&rsquo;s disease. Herein, we will review studies on symmetric and asymmetric synapses plasticity after three different stressors: symmetric signaling under acute damage&mdash;ischemic stroke; asymmetric signaling under chronic and long-term neurodegeneration&mdash;Alzheimer&rsquo;s disease; symmetric and asymmetric synapses without modulation&mdash;Parkinson&rsquo;s disease