Insomnia Impairs Both the Pro-BDNF and the BDNF Levels Similarly to Older Adults with Cognitive Decline: An Exploratory Study.

Sleep disorders, including insomnia, are common during aging, and these conditions have been associated with cognitive decline in older adults. Moreover, during the aging process, neurotransmitters, neurohormones, and neurotrophins decrease significantly, leading to the impairment of cognitive functions. In this sense, BDNF, the most abundant neurotrophic factor in the human brain, has been suggested as a potential target for the prevention and improvement of cognitive decline during aging; however, the current evidence demonstrates that the exogenous administration of BDNF does not improve cognitive function. Hence, in the present study, we quantified pro-BDNF (inactive) and BDNF (active) concentrations in serum samples derived from older individuals with insomnia and/or cognitive decline. We used linear regression to analyze whether clinical or sociodemographic variables impacted the levels of BNDF concentration. We observed that insomnia, rather than cognitive decline, is significantly associated with BDNF concentration, and these effects are independent of other variables. To our knowledge, this is the first study that points to the impact of insomnia on improving the levels of BDNF during aging and suggests that opportune treatment of insomnia may be more beneficial to prevent cognitive decline during aging.

IL10 trains macrophage profibrotic function after lung injury.

Cx3cr1+ monocyte-derived macrophages (moMacs) are recruited to tissues after injury and are known to have profibrotic effects, but the cell-cell interactions and specific pathways that regulate this polarization and function are incompletely understood. Here we investigate the role of moMac-derived Pdgfa in bleomycin-induced lung fibrosis in mice. Deletion of Pdgfa with Cx3cr1-CreERT2 decreased bleomycin-induced lung fibrosis. Among a panel of in vitro macrophage polarizing stimuli, robust induction of Pdgfa was noted with IL10 in both mouse and human moMacs. Likewise, analysis of single-cell data revealed high expression of the receptor IL10RA in moMacs from human fibrotic lungs. Studies with IL10-GFP mice revealed that IL10-expressing cells were increased after injury in mice and colocalized with moMacs. Notably, deletion of IL10ra with Csf1r-Cre: IL10ra fl/fl mice decreased both Pdgfa expression in moMacs and lung fibrosis. Taken together, these findings reveal a novel, IL10-dependent mechanism of macrophage polarization leading to fibroblast activation after injury.

Encapsulation of hydrophobic components in dendrimersomes and decoration of their surface with proteins and nucleic acids.

Reconstructing the functions of living cells using nonnatural components is one of the great challenges of natural sciences. Compartmentalization, encapsulation, and surface decoration of globular assemblies, known as vesicles, represent key early steps in the reconstitution of synthetic cells. Here we report that vesicles self-assembled from amphiphilic Janus dendrimers, called dendrimersomes, encapsulate high concentrations of hydrophobic components and do so more efficiently than commercially available stealth liposomes assembled from phospholipid components. Multilayer onion-like dendrimersomes demonstrate a particularly high capacity for loading low-molecular weight compounds and even folded proteins. Coassembly of amphiphilic Janus dendrimers with metal-chelating ligands conjugated to amphiphilic Janus dendrimers generates dendrimersomes that selectively display folded proteins on their periphery in an oriented manner. A modular strategy for tethering nucleic acids to the surface of dendrimersomes is also demonstrated. These findings augment the functional capabilities of dendrimersomes to serve as versatile biological membrane mimics.

Structural and Pharmacological Network Analysis of miRNAs Involved in Acute Ischemic Stroke: A Systematic Review.

Acute ischemic stroke (AIS) is among the main causes of mortality worldwide. A rapid and opportune diagnosis is crucial to improve a patient's outcomes; despite the current advanced image technologies for diagnosis, their implementation is challenging. MicroRNAs have been recognized as useful as biomarkers since they are specific and stable for characterization of AIS. However, there is still a lack of consensus over the primary miRNAs implicated in AIS. Here, we performed a systematic review of the literature covering from 2015-2021 regarding miRNAs expression during AIS and built structural networks to analyze and identify the most common miRNAs expressed during AIS and shared pathways, genes, and compounds that seem to influence their expression. We identified two sets of miRNAs: on one side, a set that was independent of geographical location and tissue (miR-124, miR-107, miR-221, miR-223, miR-140, miR-151a, miR-181a, miR-320b, and miR-484); and on the other side, a set that was connected (hubs) in biological networks (miR-27b-3p, miR-26b-5p, miR-124-3p, miR-570-3p, miR-19a-3p, miR-101-3p and miR-25-3p), which altered FOXO3, FOXO4, and EP300 genes. Interestingly, such genes are involved in cell death, FOXO-mediated transcription, and brain-derived neurotrophic factor signaling pathways. Finally, our pharmacological network analysis depicted a set of toxicants and drugs related to AIS for the first time.

Soluble Intercellular Adhesion Molecule-1 (sICAM-1) as a Biomarker of Vascular Cognitive Impairment in Older Adults.

BACKGROUND: Endothelial dysfunction and subsequent inflammation contribute to the development of vascular cognitive impairment (VCI). Soluble intercellular adhesion molecule-1 (sICAM-1) is upregulated in endothelial dysfunction and promotes an inflammatory response; however, the relationship between sICAM-1 and VCI remains equivocal. OBJECTIVE: To determine whether sICAM-1 contributes to the prediction of VCI. METHODS: Community-dwelling older adults (n = 172) from the "Cohort of Obesity, Sarcopenia and Frailty of Older Mexican Adults" (COSFOMA) study were identified as VCI or controls using standard neuropsychological evaluations and neuroimaging. sICAM-1 was quantified using ELISA, and multivariate logistic regression determined the association between sICAM-1 and VCI. RESULTS: A total of 31 VCI cases were identified. sICAM-1 was higher in VCI (VCI: 450.7 [241.6] ng/mL vs. controls: 296.9 [140.9] ng/mL). sICAM-1 concentrations above the 90th percentile (464.1 ng/mL) were associated with VCI group membership in all models (OR: 6.9, 95% CI: 1.1-42.2). The final saturated model explained 64% of the variance in VCI group membership. CONCLUSION: High concentrations of sICAM-1 are independently associated with VCI group membership. Efforts to further characterize the relationship between indices of endothelial dysfunction and pathological changes to the aging brain should be further pursued.

OXIDATIVE STRESS, TELOMERE LENGTH, AND FRAILTY IN AN OLD AGE POPULATION.

Background: A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. In this field, oxidative stress and telomere length have been suggested as biomarkers of aging. Objective: The objective of the study was to study the association of oxidative stress, telomere length, and frailty in an old age population. Methods: We conducted a cross-sectional study based on 2015 data from 202 members of a cohort of older adults (n = 202; F/M gender ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species were measured by dichlorofluorescein diacetate and lipid peroxidation by malondialdehyde. Telomere length was determined using quantitative polymerase chain reaction with SYBR Green Master Mix. Results: Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress and telomere length or frailty. Conclusions: Telomere length could eventually be used as a marker to differentiate between healthy and unhealthy aging as expressed by frailty phenotype; oxidative stress seemed merely a biological process of aging.

Multiphase water-in-oil emulsion droplets for cell-free transcription-translation.

The construction of genetically encoded cellular mimics in compartments containing organized synthetic cytosols is desirable for the development of artificial cells. Phase separated aqueous domains were placed within water-in-oil emulsion droplets in a manner compatible with transcription and translation machinery. Aqueous two-phase and three-phase systems (ATPS and A3PS) were assembled with dextran, poly(ethylene glycol), and Ficoll. Aqueous two-phase systems were capable of supporting the cell-free expression of protein within water droplets, whereas the aqueous three-phase-based system did not give rise to detectable protein synthesis. The expressed protein preferentially partitioned to the dextran-enriched phase. The system could serve as a foundation for building cellular mimics with liquid organelles.

Treatment of a Severe Form of Euglycemic Ketoacidosis in a Patient Treated with SGLT-2 Inhibitors with the Aid of Somatostatin.

Currently, the use of SGLT2 inhibitors is becoming more widespread, both for their role in controlling diabetes, and for their pleiotropic effects on glomerular hyperfiltration and heart failure. Along with their positive effects, these drugs can lead to various complications, the most severe being euglycemic ketoacidosis. The clinical case we have reported precisely describes this potentially serious complication which occurred in a 47-year-old patient who had been on SGLT2 inhibitor therapy for 5 years. In the resolution of this case we used, in addition to standard therapy, the continuous infusion of somatostatin, resulting in a rapid resolution of ketoacidosis and an improvement in the clinical condition.

Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury.

Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (MacΔCx43) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages. Furthermore, MacΔCx43 mice had decreased lung fibrosis after bleomycin-induced injury. Interrogating single cell data for human and mouse, we found that P2rx4 was the most highly expressed ATP receptor and calcium channel in lung fibroblasts and that its expression was increased in the setting of fibrosis. Fibroblast-specific deletion of P2rx4 in mice decreased lung fibrosis and collagen expression in lung fibroblasts in the bleomycin model. Taken together, these studies reveal a Cx43-dependent profibrotic effect of lung macrophages and support development of fibroblast P2rx4 as a therapeutic target for lung fibrosis.

Tibolone Improves Memory and Decreases the Content of Amyloid-ß Peptides and Tau Protein in the Hippocampus of a Murine Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) affects women more than men and consequently has been associated with menopause. Tibolone (TIB) has been used as a hormone replacement therapy to alleviate climacteric symptoms. Neuroprotective effects of TIB have also been reported in some animal models. OBJECTIVE: This study aimed to assess the effect of TIB on memory and Aß peptides and tau protein content in the hippocampus and cerebellum of transgenic 3xTgAD ovariectomized mice. METHODS: Three-month-old female mice were ovariectomized. Ten days after surgery, animals were divided into four groups: wild-type (WT)+vehicle; WT+TIB (1 mg/kg); 3xTgAD+vehicle; and 3xTgAD+TIB (1 mg/kg). TIB was administered for three months, and memory was evaluated using the object-in-context recognition task. Subsequently, animals were decapitated, and the hippocampus and cerebellum were dissected. Using commercial ELISA kits, these brain structures were homogenized in a PBS buffer for quantifying Aß40 and Aß42 and phosphorylated and total tau.ResultsA long-term memory deficit was observed in the 3xTgAD+vehicle group. In contrast, TIB treatment improved long-term memory in the 3xTgAD+TIB group than those treated with vehicle (p < 0.05). Furthermore, TIB treatment decreased Aß and tau content in the hippocampus of 3xTgAD mice compared to vehicle-treated groups (p < 0.05). No significant changes were observed in the cerebellum. CONCLUSION: Chronic treatment with TIB showed neuroprotective effects and delayed AD neuropathology in the 3xTgAD mice. Our results support hormone replacement therapy with TIB in menopausal women for neuroprotection.

Direct Visualization of Vesicle Disassembly and Reassembly Using Photocleavable Dendrimers Elucidates Cargo Release Mechanisms.

Release of cargo molecules from cell-like nanocarriers can be achieved by chemical perturbations, including changes to pH and redox state and via optical modulation of membrane properties. However, little is known about the kinetics or products of vesicle breakdown due to limitations in real-time imaging at nanometer length scales. Using a library of 12 single-single type photocleavable amphiphilic Janus dendrimers, we developed a self-assembling light-responsive dendrimersome vesicle platform. A photocleavable ortho-nitrobenzyl inserted between the hydrophobic and hydrophilic dendrons of amphiphilic Janus dendrimers allowed for photocleavage and disassembly of their supramolecular assemblies. Distinct methods used to self-assemble amphiphilic Janus dendrimers produced either nanometer size small unilamellar vesicles or micron size giant multilamellar and onion-like dendrimersomes. In situ observation of giant photosensitive dendrimersomes via confocal microscopy elucidated rapid morphological transitions that accompany vesicle breakdown upon 405 nm laser illumination. Giant dendrimersomes displayed light-induced cleavage, disassembling and reassembling into much smaller vesicles at millisecond time scales. Additionally, photocleavable vesicles demonstrated rapid release of molecular and macromolecular cargos. These results guided our design of multilamellar particles to photorelease surface-attached proteins, photoinduce cargo recruitment, and photoconvert vesicle morphology. Real-time characterization of the breakdown and reassembly of lamellar structures provides insights on partial cargo retention and informs the design of versatile, optically regulated carriers for applications in nanoscience and synthetic biology.

Investigations of the effects of the antimalarial drug dihydroartemisinin (DHA) using the Frog Embryo Teratogenesis Assay-Xenopus (FETAX).

Artemisinin derivatives are effective and safe drugs for treating malaria, but they are not recommended during the first trimester of pregnancy because of resorptions and abnormalities observed in animal reproduction studies. Previous studies in rats showed that artemisinin embryotoxicity derives from the depletion of primitive red blood cells (RBCs) over a narrow critical time window (gestation Days 9-14). In order to further investigate the susceptibility of primitive RBCs to artemisinins and to establish whether this susceptibility is species-specific or inherent to the compound, we studied dihydroartemisinin (DHA), both a drug in its own right and the main metabolite of current artemisinin derivatives in use, in the Frog Embryo Teratogenesis Assay-Xenopus (FETAX). This model readily allows investigation and monitoring of primitive and definitive RBCs. Effects on frog larvae exposed to DHA for 48 h during early embryonic development, starting from 24 h post fertilization, were similar to those on rat embryos in terms of reduction in the number of primitive RBCs (clonally produced within the ventral blood island). In contrast, RBCs of older larvae (stage 47, produced at the definitive sites of hematopoiesis) were affected minimally and subsequently recovered. Compared to rat embryos, the frog larvae had no areas of necrosis but they shared similar heart defects. The mitochondrion appeared to be the main subcellular target, similar to observations in Plasmodium. These results implicate artemisinin-induced embryotoxicity through perturbation of metabolically active RBCs; whereas this mode of action does not appear to be species-specific, the stages of susceptibility varied between different species. The window of susceptibility and duration of exposure must be considered to evaluate the clinical relevance of these findings.

Different responses to rivastigmine in subcortical vascular dementia and multi-infarct dementia.

Vascular dementia (VaD) is associated with a large amount of heterogeneity, as it groups together a broad category of patients in whom various manifestations of cognitive decline are attributed to cerebrovascular or cardiovascular disease. Thus, a study was designed to determine the effects of rivastigmine on cognitive function, global daily living performance, and behavioral disorders in VaD patients versus an active control (nimodipine), stratifying patients according to the type of VaD, subcortical vascular dementia (sVAD), and multi-infarct dementia (MID). The trial was a prospective study. This study shows that long-term treatment with rivastigmine, at dosages approved for therapeutic use in Alzheimer's disease, produces significant improvement in all behavioral symptoms in 2 forms of VaD, MID and sVaD, except delusions. It also suggests that rivastigmine may enable a reduction in concomitant neuroleptics and benzodiazepines in VaD, especially in MID. The results are discussed with an overview of the literature.

Risk factors for vascular dementia: hypotension as a key point.

Physiologically, the cerebral autoregulation system allows maintenance of constant cerebral blood flow over a wide range of blood pressure. In old people, there is a progressive reshape of cerebral autoregulation from a sigmoid curve to a straight line. This implies that any abrupt change in blood pressure will result in a rapid and significant change in cerebral blood flow. Hypertension has often been observed to be a risk factor for vascular dementia (VaD) and sometimes for Alzheimer disease although not always. Indeed, high blood pressure may accelerate cerebral white matter lesions, but white matter lesions have been found to be facilitated by excessive fall in blood pressure, including orthostatic dysregulation and postprandial hypotension. Many recent studies observed among other data, that there was a correlation between systolic pressure reduction and cognitive decline in women, which was not accounted for by other factors. Baseline blood pressure level was not significantly related to cognitive decline with initial good cognition. Some researchers speculate that blood pressure reduction might be an early change of the dementing process. The most confounding factor is that low pressure by itself might be a predictor of death; nevertheless, the effect of low blood pressure on cognition is underestimated because of a survival bias. Another explanation is that clinically unrecognized vascular lesions in the brain or atherosclerosis are responsible for both cognitive decline and blood pressure reduction. We discuss the entire process, and try to define a possible mechanism that is able to explain the dynamic by which hypotension might be related to dementia.

Telomere shortening and frailty in Mexican older adults.

AIM: Telomere shortening has been associated with several age-related diseases, in addition to being considered a hallmark of aging. Frailty is a clinical syndrome characterized by an accentuated physiological and functional decline that might be a predictor of an adverse condition in older age. The present study evaluated the relationship between frailty and telomere shortening in older adults from Mexico City, Mexico. METHODS: This was a cross-sectional study. Data were collected from 323 frail older adults, including physical and environmental factors, such as body mass index, comorbidities, physical activity and tobacco consumption. Telomere length was measured by real-time polymerase chain reaction. The frailty syndrome was diagnosed using the Fried criteria. RESULTS: An association between frailty and telomere shortening was found in both sexes. Telomere length decreased from 6.05 kb (5.54-6.48 kb) to 4.20 kb (3.80-4.54 kb; P < 0.001). It was also observed that tobacco consumption could be a significant modifying factor in the association between these two variables. Previous reports are contradictory, suggesting that there is no relationship between telomere length and frailty; however, it is possible that there are genetic and/or environmental variables to be elucidated, that might influence this association, particularly in the studied population. CONCLUSIONS: Telomere length is inversely related to frailty in Mexican frail older adults, and tobacco consumption is the main environmental modifying factor. Geriatr Gerontol Int 2018; 18: 1286-1292.

Oxidative stress in the elderly with diabetes mellitus or hypertension / Estrés oxidativo en adultos mayores con diabetes mellitus o hipertensión arterial

Background: Mexico City has the highest aging rate in the country, as well as a high prevalence of diabetes mellitus (DM) and hypertension (HT). It is known that each one of these conditions increase oxidative stress (OS) independently. Methods: With this study we described changes in OS of 18 patients without DM or HT (controls), 12 with DM, 23 with HT, and 18 with DM and HT, all of them members of the COSFAMM (Cohorte de Obesidad, Sarcopenia y Fragilidad en Adultos Mayores de México). OS was measured by the quantification of reactive oxygen species (ROS), by the oxidation of diclorofluorosceine, and by determination of lipid peroxidation by product malondialdehyde (MDA). Results: HT patients showed increased ROS levels, as did men with HT compared with the respective DM and HT groups. Also, women of control group showed higher levels of ROS compared with men. Conclusions: Generally, HT turned out to be the most influential factor for the increase of oxidative stress in the elderly while DM has no effect whatsoever.

Introducción: la Ciudad de México tiene el mayor índice de envejecimiento del país, así como una alta prevalencia de diabetes mellitus (DM) e hipertensión arterial (HTA). Se sabe que cada una de estas condiciones incrementa el estrés oxidativo (EO) de forma independiente. Métodos: en este estudio describimos los cambios en el EO de 18 pacientes sin DM ni HTA (controles), 12 con DM, 23 con HTA y 18 con DM y HTA, todos miembros de la Cohorte de Obesidad, Sarcopenia y Fragilidad en Adultos Mayores de México (COSFAMM). El EO fue medido por la cuantificación de especies reactivas de oxígeno (ERO) por la oxidación de la diclorofluorosceína (DCFH) y por determinación de peroxidación de lípidos por producto malondialdehído (MDA). Resultados: los pacientes con HTA mostraron niveles de ERO elevados, así como los hombres con HTA, comparados con los grupos correspondientes de DM y HTA. Asimismo, las mujeres del grupo control mostraron mayor cantidad de ERO que los hombres. Conclusiones: en general, la HTA en el adulto mayor resultó ser el factor que mayor contribución tiene en el incremento del estrés oxidativo, mientras que la DM no tiene efecto alguno.

Behavioral alterations and vascular dementia.

BACKGROUND: Vascular dementia is one of the most frequent forms of dementia, where behavioral and cognitive symptoms coexist. Negative signs, such as apathy, abulia, opposition, and agnosia, are badly tolerated and dramatically experienced by caregivers, even worse than the other signs of cognitive decline. REVIEW SUMMARY: We have studied 120 subjects affected by subcortical vascular dementia (group A) and 120 subjects suffering from multiinfarct dementia (group B) for 24 months. The main outcomes of the study were the global performance, the global behavioral symptoms, the caregiver stress, the depression status, and the insight in their clinical situation. CONCLUSIONS: Group A manifested a reduction of depression, agitation and suicidal ideation during follow-up, with a constant tendency to refer somatic pain, to exhibit anxiety, and an evident increase in apathy, cognitive abulia, social withdrawal, and loss of insight. On the contrary, group B showed a constant tendency to manifest depression, somatic pain, anxiety, agitation, cognitive abulia, social withdrawal, and suicide ideations; they manifested a decrease of apathy and an increase in delusions, hallucinations, craving for food, and loss of insight and awareness. Their behavioral alterations were stronger than those exhibited by group A, and that was reflected by an increment of caregivers' burden score. Even from a behavioral perspective, multiinfarct dementia is not the same as subcortical vascular dementia. This opinion must be taken into account to find more suitable and tailored therapy to specific pathologies and not to a single, generic entity.

In vivo and in vitro investigations of the effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos.

Artemisinin derivatives are clinically effective and safe antimalarials, but are not recommended during the first trimester of pregnancy because of the resorptions and abnormalities seen in animal reproduction studies. Understanding how, when and what toxicity occurs is crucial to any assessment of clinical relevance. Previously, DHA has been shown in the rat whole embryo culture (WEC) to primarily affect primitive red blood cells (RBCs) causing subsequent tissue damage and dysmorphogenesis. To verify the primary target of DHA in vivo and to detect consequences induced by early damage on embryo development, pregnant female rats were orally treated on gestation days (GD) 9.5 and 10.5 with 7.5 or 15 mg/kg/day DHA and caesarean sectioned on GD11.5, 12.5, 13.5, 15 and 20. A parallel in vitro WEC study evaluated the role of oxidative damage and examined blood islands and primitive RBCs. In accordance with the WEC results, primitive RBCs from yolk sac hematopoiesis were the target of DHA in vivo. The resulting anemia led to cell damage, which depending on its degree, was either diffuse or focal. Embryonic response to acute anemia varied from complete recovery to malformation and death, depending on the extent of cell death. Malformations occurred only in litters with embryonic deaths. DHA induced low glutathione levels in RBCs, indicating that oxidative stress may be involved in artemisinin toxicity; effects were extremely rapid, with altered RBCs seen as early as GD10. In establishing the relevance of these findings to humans, one should consider differences in the development of rodents and humans. While yolk sac hematopoiesis occurs similarly in the two species, early placentation and extent of exposure differ. In particular, early hematopoiesis takes only 7 days in rats (during which RBCs expand in a clonal fashion) compared with 6 weeks in humans; thus the susceptible period in relation to the duration of exposure to an artemisinin-based treatment may be substantially different.

Peripheral neuropathy in hepatitis C virus-related mixed cryoglobulinaemia: existing treatments and a positive symptomatic response to oxcarbazepine.

Peripheral neuropathy is the most common symptom in patients with hepatitis C virus (HCV) associated mixed cryoglobulinaemia, in whom it may be the first clinical manifestation. Very frequently, the medical therapy proposed to treat HCV and cryoglobulinaemia causes an exacerbation of the disabling neuropathy. Therefore, other neuropathy treatments have been proposed, such as alternative immunosuppressive agents (steroids or cyclosporine) and plasma exchange, which, according to case reports, have yielded inconsistent results and presumably exert only temporary effects as they do not promote clearance of HCV. We present five cases of cryoglobulinaemia-related neuropathy resistant to steroids and gabapentin. Oxcarbazepine was introduced and produced moderate and persistent relief of symptoms without side effects.